NZ235075A - Substituted carboxylic esters - Google Patents
Substituted carboxylic estersInfo
- Publication number
- NZ235075A NZ235075A NZ23507588A NZ23507588A NZ235075A NZ 235075 A NZ235075 A NZ 235075A NZ 23507588 A NZ23507588 A NZ 23507588A NZ 23507588 A NZ23507588 A NZ 23507588A NZ 235075 A NZ235075 A NZ 235075A
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Description
New Zealand Paient Spedficaiion for Paient Number £35075
Priority Date(s): ^'.. f?l \ 2^t.
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Complete Specification Filed:
Class: CZjOT)
<=£?. % ol) SRlOtfj
271^2] .C-cfl d .Sv3. \9$V* *'
Publication Date:
P.O. Journal. No: .....©.44t
235075
Class Cont: C-sSl k-J.'S 1 J.Q&)
life(5^0Qo7/ob)
Class Cont: L£&.) .<rrwT]Q.?rO/[
ixns&?3.h%
. fe?0 h-.t. & .^.,.
Und®r the provisions of Reyu- -
NEW ZEALAND PATENT OFFICE
2 8 AUG 1990
RECEiver-
(ation 23 (1) the .QOttofjA#*.
NEW ZEALAND
No.: Date
Specification has been ants-dated to 19 .&£
PXTENTS ACT, 1953
Initials
Class Cont: cc>7P2SS/sb.>.
9??reg3. l?z>-,<zZ]£?3ni\%
Divided out of No. 225945 Filed 26 August 1988
Class Cont: C,Q*7l Q^Q
COMPLETE SPECIFIC ATI 01 i gj^xp2a2/ai+y.Cp7. f3.
"INTERf'IEDIATES USEFUL IN THE PREPARATION OF FUNGICIDES" '
xi/We, IMPERIAL CHEMICAL INDUSTRIES PLC a British Company of Imperial Chemical House, Mill bank, London, SW1P 3JF, England hereby declare the invention for whichXtOtXwe p~ay that a patent may be granted to i5S0&is, and the method by which it is to be performed, to be particularly dsscribsc in —r. d by the following 5ts.terr.ent: -
- 1 - (followed by page la)
mstiI?"'#WS*WW.»
235075
- ]Or iwteri^diates useful in the preparation of fungicides p
This invention relates to intermediates useful in the preparation of derivatives of propenoic acid useful as fungicides.
EP—A—0178826 describes fungicidal derivatives of propenoic acid and lists the compound (E)-methyl 2-[2-(3-phenoxyphenoxy)phenyl]-3-methoxypropenoate.
The reader's attention is directed to New Zealand Patent Specification No. 225945 which describes and claims a compound having the formula (I):
(I)
ch3o2c
CH.OCH-
o
and stereoisomers thereof, wherein K is oxygen or sulphur? Z is optionally substituted aryl or optionally substituted heteroaryl? X is O, S(0)n, NR4, CR1R2, chr9, CO, CR1(OR2), C=CR1R2, CHR1CHR2, CR1=CR2/ CHR1CR2=CH, C=C, OCHR1, CHR1©,
0CHR10, StOjjjCHR1, S (0 )nCHR^0, CHR1S(0)n> CHR10S02<1
NR4CHR1, CHR1NR4, C02, 02C, S020, 0S02, CO.CO, COCHR1, COCHR^O, CHR1CO, CHOH.CHR1, CHR1.CHOH,
CR1 CR2,
cr
CR^
CONR4,OCONR4, NR4C0, CSNR4, OCS.NR4, SCO.NR4, -NR4CO2,
nr^sff^fc,, cs nr4cs, nr4cso, nr4cos, nr4conr4, s(0)nnr4
S2C, CO.S, SCO, N=N, N=CRX/ CRW, CHR1CHR2CH (OH) ,
CHR1OCO, CHR1SCO, CHR1NR4CO, CHR1NR4conk4, CHR1CHR2C0,
o
235075
O.NaCR1, CHR10.N=CR2, CO.OCR1R2, CHR1CHR2CHR3/ OCHR1CHR2,
(CH2)mO, CHR1OCHR2/ CHR1CHR20, 0CHR1CHR20, S(O)nCHR1CHR2,
CHR1S(0)nCHR2, CHR1CHR2S(0)n, CR1=NNR4, NR4N=CR^,
CHR1CONR2, CHR1OCO.NR2, CH=CHCH20, C0CHR1CHR20, or
(R^ )2P+CHR2Q~; A, B and E, which may be the same or different are H, hydroxy, halo, C1-4 alkyl, C1-4 alkoxy,
cl-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkylcarbonyl, C1-4
1 0 ^
alkoxycarbonyl/ phenoxy, nitro or cyano; R1, R and RJ,
which may be the same or different, are H, alkyl or
phenyl? R4 is H, C^_4 alkyl or COR1? R5 is optionally substituted phenyl; R® is substituted phenyl; Q~ is a halide anion; n is 0, 1 or 2 and m is 3, 4 or 5? except that when Z is unsubstituted phenyl and X and K are oxygen, A, B and E are not all hydrogen.
Of particular interest are those compounds in which X
is 0, especially when Z is optionally substituted heteroaryl, S, S02, NH, NCH3, NC0CH3, CH(CgH5), CH(OH),
ch=ch, och2, ch2o, ch(ch3)o, s(o)ch2, s(o)2ch2, so2o,
C0.CH20 or C02CH2 and, more particularly, 0, CH20, 0CH2, 20 S020 or CH(OH).
The compounds of the invention of NZ 225945 contain at least one carbon-carbon double bond, and are sometimes obtained in the form of mixtures of geometric isomers. However, these mixtures can be separated into individual isomers, and 25 this invention embraces such isomers, and mixtures thereof in all proportions including those which consist substantially of the (Z^)-isomer and those which consist substantially of the (E)-isomer.
The individual isomers which result from the 30 unsymmetrically substituted double bond of the propenoate group are identified by the commonly used terms "E" and "Z". These terms are defined according to the Cahn-Ingold-Prelog system which is fully described in the literature (see, for example, J March, "Advanced Organic 35 Chemistry", 3rd edition, Wiley-Interscience, page 109 et seq) .
/
235075
Usually one isomer is more active fungicidally than the other, the more active isomer usually being the one wherein the groups -CO2CH3 and -OCH3 are on opposite sides of the olefinic bond of the propenoate group (the (E)-isomer). These (E)-isomers form a preferred embodiment of the invention.
The substituent Z in compound (I) is optionally substituted aryl or optionally substituted heteroaryl.
Where valency allows, each of the optionally substituted groups aryl or heteroaryl can carry up to 5 substitutents. The term "aryl" includes phenyl in particular, and naphthyl. The term "heteroaryl" includes 5- and 6-membered heterocyclic groups containing one or more of each of the heteroatoms O, S and N (preferably S or N),
fused benzenoid and heteroaromatic ring systems, and, in each case, the corresponding N-oxides. Examples of heteroaryl groups which Z may be are pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-, 1,2,4-, and 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, 1,2,3- and 1,2,4-triazolyl, thienyl, furyl, pyrrolyl, thiazolyl,
oxadiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothienyl, benzoxazolyl and benzthiazolyl and, where appropriate, the corresponding N-oxide^. Substituents which may be present in the optionally substituted aryl and heteroaryl moieties include one or more of the following; halo, hydroxy, mercapto, C^_4 alkyl (especially methyl and ethyl), C2_4 alkenyl (especially allyl), C2_4 alkynyl (especially propargyl), Ci_4 alkoxy (especially methoxy), C2_4 alkenyloxy (especially allyloxy), C2_4 alkynyloxy (especially propargyloxy), halo(C1-4)alkyl (especially trifluoromethyl), halo(C-^_4)alkoxy (especially trifluoromethoxy), C1-4 alkylthio (especially methylthio), hydroxy(C1-4)alkyl, C1_4-alkoxy(C1_4)alkyl, C3_6 cycloalkyl, C3_6 cycloalkyl(C1_4)alkyl, optionally substituted aryl (especially optionally substituted phenyl), optionally substituted heteroaryl (especially
235 07
optionally substituted pyridinyl or pyrimidinyl),
optionally substituted aryloxy (especially optionally substituted phenoxy), optionally substituted heteroaryloxy (especially optionally substituted pyridinyloxy or pyrimidinyloxy), optionally substituted aryl(Cj^)alkyl (especially optionally substituted benzyl, optionally substituted phenethyl and optionally substituted phenyl n-propyl) in which the alkyl moiety is optionally substituted with hydroxy, optionally substituted heteroaryl(C^_4)alkyl (especially optionally substituted pyridinyl- or pyrimidinyl(C1_4)alkyl), optionally substituted aryl(C2_4)alkenyl (especially optionally substituted phenylethenyl), optionally substituted heteroaryl(C2_4)alkenyl (especially optionally substituted pyridinylethenyl or pyrimidinylethenyl), optionally substituted aryl(C1_4)alkoxy (especially optionally substituted benzyloxy), optionally substituted heteroaryl(C1_4)alkoxy (especially optionally substituted pyridinyl- or pyrimidinyl(C^_4)alkoxy), optionally substituted aryloxy(C^_4)alkyl (especially phenoxymethyl), optionally substituted heteroaryloxy(C1-4)alkyl (especially optionally substituted pyridinyloxy- or pyrimidinyloxy(C^_4)alkyl), acyloxy, including alkanoyloxy (especially acetyloxy) and benzoyloxy, cyano, thiocyanato, nitro, -Nr'r", -NHCOr', -NHCONr'r",
-conr'r", -coor', -oso2r', -so2r', -cor', -cr'=nr" or
I II I
-N=CR R in which R and R" are independently hydrogen, CL_4 alkyl, Cx_4 alkoxy, C1-4 alkylthio, C3_g cycloalkyl, £3-6 cycloalkyl(C1_4)alkyl, phenyl or benzyl, the phenyl and benzyl groups being optionally substituted with halogen, C^_4 alkyl or C^_4 alkoxy.
Substituents which may be present in the aryl or heteroaryl rings of any of the foregoing substituents and in the phenyl ring of R^ include one or more of the following; halo, hydroxy, mercapto, C^_4 alkyl, C2_4 alkenyl, C2_4 alkynyl, C1-4 alkoxy, C2_4 alkenyloxy, C2_4
235 07
alkynyloxy, halo(C1—4)alkyl, halo(C^_4)alkoxy, C1_4-alkylthio, hydroxy(C^_4)alkyl, ci-4 alkoxy(C^_4)alkyl, C3_g cycloalkyl, C3_g cycloalkyMC^^Jalkyl, alkanoyloxy, benzyloxy, cyano, thiocyanato, nitro, -NR'R", -NHCOR', -NHCONR1 R" , -CONR'R", -COOR', -0S02R', -S02R', -COR',
-CR'=NR" or -N=CR'R" in which R' and R" have the meanings given above.
When any of the substituents A, B and E are C^_4-alkyl or C1-4 alkoxy, the alkyl moiety can be in the form of straight or branched chains, that is, the moiety may be methyl, ethyl, n- or iso-propyl, or n-, sec-, iso- or t-butyl. Other references herein to C^_4 alkyl and C^_4 alkoxy carry the same meaning; C2_4 Alkenyl groups can be in the form of straight or branched chains and, where appropriate, may have either the (E)- or (5S)-configuration. Examples of such groups are vinyl, allyl, -C(CH3):CH2, and (E)- and (Z_)-crotyl.
The substituents A and B are preferably in the 4- and 5-positions of the phenyl ring, and the substituent E is preferably a small group or a single atom such as hydrogen or halogen. Usually, E and one or both of A and B will be hydrogen.
In one aspect, the invention of NZ 225945 includes a canpouirl having the formula (la) :
n an P.
wherein X is O, S(0)n in which n is 0, 1 or 2, NH, NCH3,
nch2ch3, ncoch3, nch(ch3)2, ch2, ch(ch3), c(ch3)2, co, c=ch2, c=c(ch3)2, ch2ch2, ch(ch3)ch2, ch2ch(ch3), (E)-ch=ch, (z)-ch=ch, (e)-c(ch3)=c(ch3), c=c, och2, och(ch3),
da)
©
235075
(CH2)pO in which p is an integer of 1 to 5, CH(CH3)0,
sch2, sch(ch3), s(o)ch2, s(o)ch(ch3), s(o)2ch2, s(0)2ch(ch3), ch2s, ch(ch3)s, ch2s(o), ch(ch3)s(o), ch2s(0)2, ch(ch3)s(0)2, nhch2, n(ch3)ch2, n(coch3)ch2f
nhch(ch3), n(ch3)ch(ch3), n(coch3)ch(ch3), ch2nh, ch2n(ch3), ch2n(coch3)/ ch(ch3)nh, ch(ch3)n(ch3), ch(ch3)n(coch3), co2, o2c, so2o, oso2, co.co, coch2, coch(ch3), ch2co, ch(ch3)co, ch(oh)ch2, ch(oh)ch(ch3),
CH2CH(0H), CH(CH3)CH(OH), CONH, CON(CH3), CON(CH2CH2CH3),
con(cho), con(coch3), nhco, n(ch3)co, n(ch2ch3)co, n(cho)co, n(coch3)co, csn(ch3), csnh, nhcs, n(ch3)cs, so2nh, so2n(ch3), nhso2, n(ch3)so2, n(ch2ch3)so2, cs2,
S2c, COS, SCO, (E)-N=N, (E)-N=CH, (E)-N=C(CH3), (E)-CH2=N,
(e)-c(ch3)=n, ch2ch2ch2, ch(ch3)ch2ch2, ch2ch(ch3)ch2, 15 ch2ch2ch(ch3), och2ch2, ch2och2, sch2ch2, s(o)ch2ch2, s(o)2ch2ch2, ch2sch2, ch2s(o)ch2, ch2s(o)2ch2, ch2ch2s, ch2ch2s(o), ch2ch2s(o)2, (e)-ch=nnh, (e)-c(ch3)=nnh, (e)-ch=nn(ch3), (e)-nhn=ch, (e)-nhn=c(ch3), (e)-n(ch3)n=ch, ch2conh, ch(ch3)con(ch3), (e)-ch=chch2o,
C0CH2CH20, ^ch2
trans CH CH, trans CH CH,
CH(C6H5), C0CH20, CH(OH), C02CH2, (C6H5)2P+CH2Br~, CHjOCO,
ch2nhco, ch2sco, och2o, och2ch2o, s(o)ch2o, coch(ch3)o, (e)-ch2on=ch, (z)-ch2on=ch, ch2ch2ch(oh), (e)-ch2ch=ch,
C(CH3)(OH), CH20S02, CH2NHCO.NH, OCO.NH, NHCO.NH or
CH2OCO.NH; A is H, hydroxy, halo, C1-4 alkyl, C1-4 alkoxy,
trifluoromethyl, nitro, cyano, acetyl or phenoxy; B and E
are H or halo; D is H, hydroxy, halo, C1-4 alkyl, C1-4
alkoxy, nitro, cyano, halo(C^_4)alkyl (especially
trifluoromethyl), halo(C1_4)alkoxy (especially trifluoro-
methoxy), phenyl, phenoxy, NHCOR®, NHS02R®, NR^R®, C02R^
wherein R® is C^_4 alkyl (especially methyl) or phenyl 7 ft
R' and R° are independently H or C1-4 alkyl, or CH3O2C.CsCH.OCH3; and G is H, halo, C1-4 alkyl, C1-4 3 5 alkoxy or nitro; or D and G, when they are adjacent, joi to form a benzene or pyridine ring; provided that^when A,
.it v
235075
7
B, D, E and G are all H, X is not 0. More particularly, it includes a compound having the formula (la) wherein X is 0, S(0)n in which n is 0, 1 or 2, CH2, CH2CH2, 0CH2,
(CH2)pO in which p is an integer of 1 to 5, 0CH20,
och2ch2o, ch(oh), co, co2, 02c, cos, sco, co2ch2, so2o,
(e)—ch=ch, (z)-ch=ch, (e)-ch=chch20, ch(ch3)0, sch2, sch20, s(0)ch2, s(0)ch20, s(0)2ch2, conh, nh, nch3, ch2nh, n(ch3)ch2, nhco, ch2oco.nh, ncoch3, nhso2, (e)-n=n, (Z)-n=n, (e)-n=ch, (e)-n(ch3)n=ch, (e)-ch2on=n, (z)-ch2on=ch,
ch(c6h5), coch2o, coch(ch3)o, ch2oco, ch2nhco, ch2sco or
(CgHg) 2P+CH2Br~; A is H, hydroxy, halo, C-^_4 alkyl, C^_4 alkoxy, acetyl or phenoxy; B and E are both H; D is H,
hydroxy, halo, C^_4 alkyl, C^_4 alkoxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, amino or CH302C.C=CH.0CH3; and G is H, halo, C1-4 methyl, nitro; or D and G, when they are adjacent, join to form a benzene or pyridine ring; provided that when A, B, D, E and G are all H, X is not 0.
In another aspect, the invention of NZ 225945 includes a compound having the formula (lb) :
wherein D and G are independently halo, C^_4 alkyl, C^_4 alkoxy, trifluoromethyl, nitro, cyano, phenyl, phenoxy, nhcor6, nhs02r6 and nr7r8, in which r6 to r8 have the meanings given above; and A is halo, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, nitro, cyano, acetyl or phenoxy.
Particularly favoured compounds of the formula (lb) are those in which D is hydrogen, G is 2- or 3-chloro, 3-
ch.och3
ch3o2c
' -y- \ -
23 5
07
8
bromo, 2- or 4-methoxy, 3- or 4-nitro, 2- or 3-cyano or 3-or 4-phenoxy and A is hydrogen or D and G are both hydrogen and A is 4- or 6-bromo or 4- or 6-acetyl.
In yet another aspect, the invention of NZ 225945 includes compound having the formula (Ic) :
wherein Z is pyridinyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl, quinolinyl, benzoxazolyl, benzthiazolyl, thienyl, quinoxalinyl, thiazolyl, isoquinolinyl, quinazolinyl, purinyl, oxazolyl, thiadiazolyl,
oxadiazolyl, furyl, pyrrolyl or thienopyrimidinyl, each optionally substituted with halo, alkyl, C1-4 alkoxy,
cl-4 alkylthio, halo(C1_4)alkyl (especially trifluoromethyl), cyano, nitro, COOR7, phenyl, phenoxy, C1-4 alkanoyl and CONR7R® in which R7 and R® are independently H or C^_4 alkyl; and N-oxides thereof; be is 0, S, NH, N(CH3), SOzO, CH2, CH2CH2, OCH2, CH20, CH(OH), CONH or CO; A and B are independently H, halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, halo(C1_4)alkyl (especially trifluoromethyl) or halo(C^_4)alkoxy (especially trifluoromethoxy); and E is H or halo.
More particularly, it includes a compound having the formula (Ic) wherein X is 0, S, OCH2, S020, CH2, CH20,
CONH or CON(CH3); Z is pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyridazin-3-yl, 1,3,5-triazin-2-yl, thien-2-yl, pyrrol-2-yl, quinolin-2-yl, quinoxalin-2-yl, 1,2,4-triazol-l-yl, thiazol-4-yl, benzthiazol-2-yl, or benzoxazol-2-yl, each optionally
ch3o2c
(Ic)
ch.och3
235075
substituted with halogen, trifluoromethyl, C^_4 alkyl, C^_4 alkoxy, cyano or nitro, and N-oxides thereof and A, B and E are all H.
In still yet another aspect, the invention of NZ 225945 includes a compound having the formula (Id):
ch3o2c
CH.OCH-
(Id)
wherein X, A, B, D, E and G have the meanings given for the compound (la) and also wherein X is O and A, B, D and E are all H.
Compounds having the formula (Id) of particular interest are those wherein X is 0, CH20 or S020 and A, B, D, E and G are all H or D is 2- or 4-nitro.
In still yet another aspect, the invention of NZ 225945 includes a compound having the formula (Ie):
(Ie)
CH302C
CH.OCH-
wherein Z, X, A, B and E have the meanings given for the 15 compound (Ic). Compounds having the formula (Ie) of particular interest are those wherein Z is pyrimidin-2-yl or pyrimidin-5-yl, X is 0 and A, B and E are all H.
The invention of NZ 225945 is illustrated by the compounds listed in Tables I, II, III and IV which follow. Throughout 20 Tables I, II, III and IV the methyl 3-methoxypropenoate group has the (E)-configuration.
table i
235 075
S |
i
Q
c= c
^och3
/
ch3o2c
Conpound
Melting
No.
X
D
G
A
B
E
Olefinic"1"
Point (°C)
1
S
h h
h h
h
7.42
Gum
2
SO
h h
h h
h
Obscured
Gum
3
so2
h h
h h
h
Obscured
Wax
4
nh h
h h
h h
7.44
Wax
nch3
h h
h h
h
7.44
Gum
6
nch2ch3
h h
h h
h
]
7
ncoch3
h h
h h
h
7.39
50-54
8
nch(ch3)2
h h
h h
h
9
ch2
h h
h h
h
7.47
Gum
ch(ch3)
H
H
h
H
H
11
c(gh3)2
H
H
H
H
H
12
CO
H
H
H
H
H
7.47
Gum
13
C:CH2
H
H
H
H
H
14
C:C(CH3)2
H
H
h
H
H
^2^2
H
H
H
H
H
7.49
Gum
16
CH(CH3)CH2
H
H
H
h
H
17
CH2CH(CH3)
H
H
H
H
H
18
(E)—CH:CH
H
H
h
H
H
7.49
Gum
:
- 11 -table i (cont/d)
235 0
r
Conpound
No.
X
D
G
A
B
E
Olefinic*"
Melting Point (°C)
19
(E^-C(CH3) :C(CH3)
H
H
H
H
H
C:C
H
H
H
H
H
21
och2
H
H
H
H
H
7.46
Gum
22
och(ch3)
H
H
H
H
H
23
ch2o
H
H
H
H
H
7.44
84
24
ch(ch3)o
H
H
H
H
H
7.39
99-102
sch2
H
H
H
H
H
7.47
Gum
26
sch(ch3)
H
H
H
H
H
27
s(o)ch2
H
H
H
H
H
7.48
82-86
28
s(o)ch(ch3)
H
H
H
H
H
29
s(o)2ch2
H
H
H
H
H
7.48
140-144
s(o)2ch(ch3)
H
H
H
H
H
31
ch2s
H
H
H
H
H
32
ch(ch3)s
H
H
H
H
H
33
ch2s(o)
H
H
H
»
H
34
ch(ch3)s(o)
H
H
H
H
H
ch2s(o)2
H
H
H
H
H
36
CH(CH3)S(0)2
H
H
H
H
H
t
37
nhch2
H
H
H
H
H
38
n(ch3)ch2
H
H
H
H
H
7.44
Gum
39
n(coch3)ch2
H
H
H
H
H
40
nhch(ch3)
H ,
H
H
H
H
41
n(ch3)ch(ch3)
H
H
H
H ! H
42
n(ooch3)ch(ch3)
H
H
H
H
H
43
c&2nh
H
H
H
H
H
44
ch2n(ch3)
H
H
H
H
H
45
o^tcochg)
H
H
H
H
H
46
ch(ch3)nh
H
H
H
H
H
47
ch(ch3)n(ch3)
H
H
H
H
h
1
f,
^ £
F
€
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
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7.47 7.40
1
i !
7.46
i
7.40
0
H'
a>
1 °+
94-95 oil
Gum
Gum Gum
Melting Point (°C)
D
to I
ro
CM
cn o cn
V.1 :
2350
TABLE I (CONT/P)
Ccnpound No.
X
D
G
A
B
E
01efinic+
Melting Point (°C)
74
NHCS
H
h
H
h
H
75
n(ch3)cs
H
h h
h
H
76
SO2NH
h h
h h
H
77
S02N(CH3)
H
H
h
H
H
78
nhso2
H
H
H
.H
H
7.43
Oil
79
n(ch3)so2
H
H
H
H
H
80
n(ch2gh3)so2
H
H
H
H
H
81
cs2
H
H
H
H
H
82
S2c
H
H
H
H
H
83
cos
H
H
H
H
h
7.38
87-91
84
SCO
H
H
H
H
H
7.50
Gum
85
(E)-N:N
H
H
H
H
H
86
(E)-N:CH
H
H
h h
H
7.49 or
Gum
7.50
87
(E)-N:C(CH3)
H
H
H
H
H
88
(E)-CH:N
H
H
H
H
H
i
89
(e)-c(ch3):n
H
H
H
H
H
90
CH2CH2CH2
H
H
H
H
H
91
ch(ch3)ch2ch2
H
H
h
H
H
92
ch2ch(ch3)ch2
H
h
H
h h
93
CH2CH2CH(CH3)
H
h
H
H
H
94
och2ch2
H
H
H
H
H
95
CH2OCH2
H
H
H
H
H
96
CH2GH2O
H
H
H
H
h
7.48
Oil
97
SCH2CH2
H
H
H
H
h
| 98
s(o)ch2ch2
H
H
H
H
H
j 99
|
s(o)2ch2ch2
H
H
H
H
H
235 075
table i (cont/d)
Conpound No.
X
D
G
A
B
E
Olefinic"1"
Melting Point CO
100
ch2sch2
h h
h h
h
101
ch2s(o)ch2
h h
h h
h
102
ch2s(0)2ch2
h h
h h
h
103
ch2ch2s h
h h
h h
104
ch2ch2s(o)
h h
h h
h
105
ch2ch2s(0)2
h h
h h
h
106
(E)-CH:NNH
h h
h
H
h
107
(E)-C(CH3):NNH
h h
H
H
H
108
(E) -CH: NN (CH3)
h h
h
H
H
109
(E)- NHN:CH
h
H
h
H
H
110
(E)-NHN:C(CH3)
h h
h h
h
111
(E)-N(CH3)N:CH
h h
h
H
H
7.50
121.5-
123.5
112
ch2conh h
h h
h
H
!
113
CH(CH3)CQN(CH3)
h
H
h
H
1
H
114
CH(CH3)CCW(CH3)
H
H
H
h
H
115
(E)-CHsCHCH20
H
H
h h
H
7.47
Gum .
116
c0ch2ch20
H
H
h
H
H
117
yCHo
/ 2\
H
trans CH., CH
H
H
h
H
I
118 \
irans CH CH
h
H
H
H
H
119
O
2-C1
H
H
H
H
7.48
51-54
120
o
3-C1
h h
h
H
7.48
Gum
121
O
4-C1
H
H
h
H
122
O
2-F
H
H
H
H
7.50
Gum
rir-voy <
TABLE I (CONT/D)
235 0
1 Compound No.
X
D
G
A
B
E
01efinic+
Melting
Point
(°C)
123
0
3-F
H
H "
H
H
7.51
Gum
124
0
4-F
H
H
H
H
7.35
Gum
125
0 .
2-CH3 .
H
H
H
H
7.51
Gum
126
0
3-ch3 .
H
H -
H
H
7.49
Gum
127
0
4^H3
H
H
H
H
7.49
Gum
128
0
2-ch3o
H
H
H
H
7.46
Gum
129
0
3-ch3o
H
H
H
H
7.48
Gum
130
0
4-ch3o
H
H
H
H
7.48
Gum
131
0
2-N02
H
H
H
H
7.47
Gum
132
0
3-N02
H
H
H
H
7.49
Gum
133
0
4-N02
H
H
H
H
7.44
67-71
134
0
2-CN
H
H
H
H
7.51
108-110
135
0
3-CN
H
H
H
H
7.51
Gum
136
0
4-CN
H
H
H
H.
137
0
2-Br
H
H
H
H
138
0
3-Br
H
H
H
H
7.48
Gum
139
0
4-Br
H
H
H
H
140
0
2-cf3
H
H
H
H
141
0
3-cf3
H
H
H
H
7.49
Oil
142
0
4-cf3
H
H
H
H
143
0
2-C6H50
H
H
H
H
7.46
Gum
144
0
3-C6HsO
H
H
H
H
7.48
Gum
145
0
4-C6HsO
H
H
H
H
7.50
Gum
146
0
2-CH3CH2O
H
H
H
H
147
0
3-CH3CH2O
H
H
H
H
148
0
4-CH3CH2O
--
H
H
H
H
i
- ■ "/w'-
235 0
TABLE I (CONT/P)
Compound No.
X
D
G
1
A
B
E
Olefinic*"
Melting
Point
(°C)
149
O
2-C6H5
H
H'
H
H
150
O
3-C6hs
H
H
H
H
7.50
Gum
151
0
4^6H5.
H
H
H
H
152
. 0
2-C1
3-C1
H-
H
H
153
o
2-C1
4-C1
H
H
H
154
0
2-C1
-C1
H
H
H
155
0
2-C1
6-C1
H
H
H
156
0
3-C1
4-C1
H
H
H
157
0
3-C1
-C1
H
H
H
7.53
Gum
158
0
2-C1
3-CH3O
H
H
H
159
0
2-C1
4-CH3O
H
H
H
160
o
2-C1
-CH3O
H
H
H
161
o
2-C1
6-CH3O
H
H
H
162
0
3-C1
4-CH3O
H
H
H,
J
163
o
3-C1
-CH3O
H
H
H
164
0
2-CH30
3-C1
H
H
H
165
0
2-CH3O
4-C1
H
H
H
166
o
2-CH3O
-C1
H
H
H
167
0
3-CH3O
4-C1
H
H
H
168
0
-t
H
H
H
169
o
-f
H
H
H
170
0
H
H
2-F
H
H
171
0
H
H
4-F
H
H
7.51
Gum
172
o
H
H
-F
H
H
173
0
H
H
6-F
H
H
174
0
>
s
I
H
1
H
4-C1
H
1
H
©
2350
TABLE I (CONT/D)
Compound No.
X
D
G
A
B
E
Olefinic"1"
Melting
Point
(°C)
175
o
H
H
-CI •
H
H
7.41
Gum
176
0
H
H
4-CH3
H
H
177
0
H
H
-ch3
H
H
7.47
Gum
178
0
H
H
4-ch3o
H
H
179
0
H
H
-ch3o
H
H
7.42
Gum
180*
o
H
H
4-Br
H
H
7.47
Gum
181
o
H
H
-Br
H
H
182
0
H
H
4-CF3
H
H
183
0
H
H
-CF3
H
H
184
0
H
H
4-N02
H
H
185
o
H
H
-N02
H
H
186
0
H
H
4-CN
H
H
187
o
H
H
-CN
H
H
188
0
H
H
4-F
-F
H
189
0
H
H
4-C1
-C1
1
H
190
o
H
H
4-F
-C1
H
191
o
H
H
4-C1
-F
H
192
0
H
H
4-ch3o
-C1
H
193
0
H
H
4-ch3o
-F
H
194
0
H •
H
H
H
-F
195
o
H
H
H
H
6-C1
196
(E)-N:N
H
H
4-ch3o
H
H
197
(E)-N:N
H
h
4-CH3CH20
h
H
198
ch2°
2-Cl
H
H
H
H
199
ch2o
3-C1
h
H
h
H
200
ch2°
4-C1
H i
: .
H
H
>
h
IMh T r ' '' MHMMHl' Iln"nwan»www..«.
23 5 0 75
© -is-
table i (aw/d)
Conpound No.
X
D
G
A
B
E
Olefinic4"
Melting
Point
(°c)
201
ch2o
2-f h
h h
H
202
ch2o
3-f h
h h
h
203
ch2o
4-f h
h h
h
204
ch2o
2-ch3
h h -
h
H
.7.25
108-110
205
ch2o
3-CH3
h h
H
H
7.24
Gum
206
ch2o
4-CH3
h h
h
H
7.40
88-90
207
ch2o
2-CH30
H
h h
h
208
ch2o
3-CH30
H
h
H
h
7.39
Gum
209
ch2o
4-CH30
H
H
H
H
210
ch2o
2-n02
H
H
H
H
211
ch2o
3-n02
H
H
H
H
212
ch2o
4-n02
H
H
H
H
7.42
109
213
ch2o
2-cn
H
H
H
H
214
ch2o
3-cn
H
H
H
H
7.41
89-92.5
215
ch2o
4-cn
H
H
H
H
216
ch2o
2-Br
H
H
H
H
7.41
78-80
217
ch2o
3-Br
H
H
H
H
7.45
Gum
218
ch2o
4-Br
H
H
H
H
7.4
86-88.5
219
ch2o
2-CF3
H
H
H
H
220
ch2o
3-^3
H
H
H
H
obscured
Gum
221
ch2°
4-CF3
H
H
h
H
222
ch2o
2-c6h5°
H
h
H
H
223
ch2o
3-c6hso
H
H
H
H
224
ch2o
4-C6HsO
H
H
H
H
225
ch2o
2-ch3ch20
H
H
H
H
.-Wf
235 0 7J
TABLE I (CONT/D)
Compound No.
X
D
G
A
B
E
Olefinic1"
Melting
Point
(°c)
226
CH2°
3-CH3CH20
H
H
H
H
227
ch2°
4HZH2CH20
H
H
H
H
228
ch2o
2-C6H5
H
H
h h
229
ch2o
3-C6H5
H
H
H
H
230
ch2°
4-c6h5
H
H
H
H
obscured
Gum
231
CH 2°
2-C1
3-C1
H
H
H
232
ch2o
2-C1
4-C1
H
H
H
233
ch2o
2-C1
-C1
H
H
H
234
ch2o
2-C1
6-C1
H
H
H
235
ch2°
3-C1
4-C1
H
H
H
236
ch2o
3-CI
-C1
H
H
H
237
ch2o
2-C1
3-CH3O
H
H
H
238
ch2o
2-C1
4-CH3O
h
H
H
239
ch2o
2-C1
-CH3O
H
H
H
240
ch2o
2-C1
6-CH3O
h
H
i
H
241
ch2o
3-C1
4-CH3O
h
H
H
242
ch2o
3-C1
-CH3O
H
H
H
243
ch2o
2-CH3O
3-C1
h
H
h
244
ch2o
2-CH3O
4-C1
H
H
H
245
ch2°
2-CH3O
-C1
H
h
H
246
ch20
3-CH3O
4-C1
h
H
H
247
ch2o
-*
H
H
H
7.42
100-102.5
248
ch2o
+
"#■
h
H
H
7.42
102-106
249
ch2o h
h
2-F
H
H
250
ch2o h
h
4-F
h h
TABLE I (CONT/P)
235 07
Conpound No.
X
D
G
A
B
E
01efinic+
Melting
Point
(°C)
251
ch2o h
h
-f h
h
252
ch2o h
h
6-f h
h
253
ch2o h
h
4-c1
h h
254
ch2°
h h
-c1
h h
255
ch2o h
h
4-CH3
h h
256
ch2o h
h
-CH3
h h
257
ch2o h
h
4-CH3O
h h
258
ch2°
h h
-CH3O
h h
259
ch2o h
h
4-Br h
h
260
ch2°
h h
-Br h
h
261
ch2o h
h
4-CF3
h h
262
ch2°
h h
-cf3
h h
263
ch2o h
h
4-NOz h
h
264
ch2o h
h
-N02
h h
t
265
ch2o h
h
4-CN
h h
266
ch2o h
h
-CN
h h
267
ch2o h
h
4-f
-f h
268
ch2°
h h
4-c1
-c1
h
269
ch2o h
h
4-f
-c1
h
270
ch20
h h
4-c1
-f h
271
ch2°
h h
4-CH3O
-c1
h
272
ch2o h
h
4-CH3O
-f h
273
ch2o h
h h
h
-f
274
ch20
h h
h h
6-c1
275
o
1
i
1
J
4-nh.COCH3
h h
h h
!
pouj
No.
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
235 0
TABLE I (CONT/D)
X
D
G
i
A
B
E
Olefinic"*"
Melting Point (°C)
0
4-NH.S02C6H5
H
H •
H
H
0
4-NH.C0C6H5
H
H
H
H
0
4-NH.S02CH3
H
H
H
H
0
4-N(CH3)2
H
H -
H
H
so2o
4-NH.ccxh3
H
H
H
H
so2o
3-N02
4-C1
H
H
H
(E)-tf:N
4-C1
H
4-HO
H
H
7.38
143-144
so2o
2-C1
H
H
H
H
7.37
Gum so2o
3-C1
H
H
H
H
7.45
Gum so2o
4-C1
H
H
H
H
7.45
53-59
so2o
2—F
H
H
H
H
S020
3—F
H
H
H
H
so2o
4-F
H
H
H
H
7.45
Gum so2o
2-ch3
H
H
H
H
1
so2o
3-ch3
H
H
H
H
7.34
Gum so2o .
4-ch3
H
H
H
H
7.38
70-76
S020
2-ch3o
H
H
H
H
so2o
3-ch3o
H
H
H
H
so2o
4-ch3o
H
H
H
H
7.39
96-97
S020
2-N02
H
H
H
H
7.40
Gum so2o
3-N02
H
H
H
H
7.41
90-93.5
so2o
4^02
H
H
H
H
S020
2-CN
H
H
H
H
S020
3-CN
H
H
H
H
so2o
4-CN
H
H
H
H
so2o
2-Br
H
H
H
H
in in ro cm
CM CN
H
Melting
Point
CC)
j
Olefinic"1"
7.53
i i i w
CQ
H H H H H H H H H H H H H H
H ! H H ! H H H
! H 1
H !
H H H H H
<
H H H H H H H H H H H
Hi
H H H H H H H H H H H H H H H
i o
' o o o o o o r) ro C") m n m
? ? 9 ? 9 ? v tCKKIClCtdaBKICWajIBinn^invD^inOTj'mm^inPi
Q
O O o
O O o J? j E1
u , „<•> r"> r™ & & if % °n % if if if %
X
WroWWWWtowcomwacotOCOCQKlWWWCQroCQCO CO CO CO
Compound No.
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
o o o •
©
235075 '
TABLE I (OONT/D)
Compound No.
X
D
G
A
1
B
E
Olefinic"1"
Melting
Point
(°C)
329
SO^
2-CH30
4-Cl
H
H
H
330
SO2O
2-CH30
-C1
H
H
H
331
SO2O
3-CH30
4-Cl
H
H
H
332
SOjO
4-
4-
H
H
H
7.34
Gum
333
S020
4
4
H
H
H
7.35
98-100
334
S020
H
H
2-F
H
H
335
S020
H
H
4-F
H
H
336
S02P
H
H
-F
H
H
337
sop
H
H
6-F
H
H
338
sop
H
H
4-Cl
H
H
339
so^
H
H
-CI
H
H
340
SO2O
H
H
4-CH3
H
H
341
so^
H
H
-CH3
H
H
342
SO2O
H
H
4-CH3
H 1
H
343
so^
H
H
-CH3
H
H
344
SO2O
H
H
4-Br
H
H
345
sop
H
H
-Br
H
H
346
SOzO
H
H
4-cf3
H
H
347
sop
H
H
-cf3
H
H
348
S020
H
H
4-N02
H
H
349
S020
H
H
-N02
H
H
350
S020
H
H
4-CN
H
H
351
S020
H
H
-CN
H
H
352
so2o
H
H
4-F
-F
H
353
S020
H
H
4-Cl
-CI
H
354
so2o
H
H
4-F
-CI
H
" — JiL .
23 5 0
table i (coot/d)
Ccnpound No.
X
D
G
A
B
E
1
Olefinic*"
Melting
Point
(°C)
355
so2o h
h
4-Cl
-F
h
356
so2o h
h
4-ch3o
-c:
h
357
so2o h
h
3-ch3o
-F
h
358
so2o h
H
h -
h
-F
359
so2o h
h h
h
6-C1
360
ch(c6h5)
H
h
H
H
H
7.44
Gum
361
0
3-Cl
H
4-Cl
H
H
362
o
3-CH30
4-Cl
-F
H
H
363
CH20
4-F
H
-CH30
H
H
364
so2o
3-ch3
H
4-F
H
H
365©
o
H
H
4-ch3co
H
H
7.43
90-92
366©
0
H
H
6-ch3co
H
h
7.48
82-85
367*
o
H
H
6-Br
H
h
7.45
Gum
368
0
h
H
-C6H5°
H
.H
1
7.46
Gum
369
SO20
3-NH2
H
H
H
H
7.43
88-92
370
cochgo
H
H
H
H
h
7.47
49-52
371
och2
4-ch3o
H
H
H
h
7.49
66—69
372
och2
3-ch3o
H
H
H
h
7.47
Gum
373
och2
3-CN
H
H
h h
7.48
71-75
374
och2
4-CN
H
H
H
h
7.48
Gum
375
och2
4-N02
h
H
H
h
7.48
108-110
376
och2
2-Cl
H
H
H
h
7.46
83-87
377
och2
2-ch3o
H
H
H
h
7.48
Gum
378
och2
2-CN
H
H
H
h
7.47
95-10
379
(E)-N:N
4-Cl
H
4-ch3o
H
H
obscured
61
380
CH(CH)
H
1
H
H
H
H
7.45
Gum
■HWS1W5W* ■-'• M-WJ*.
23 5 07
table i (cont/d)
Conpound No.
X
D
G
A
B
£
Olefinic4"
Melting
Point
(°C)
381
och2
2-N02
h h •
h h
7.48
Gum
382
och2
3-N02
h h
h h
7.48
Gum
383
och2
3-Br h
h h
h
7.47
Oil
384
och2
3-Cl h
h _
h h
7.40
Oil
385
och2
3-c6h5°
h h
h h
7.47
Oil
386
och2
4-Cl h
h h
h
7.47
72-76
387
s(o)ch2
4-Cl h
h h
h
7.42
105-11
388 S(0)2aH2
4-Cl h
h h
h
7.47 126-130.5
389
och2
2-Br h
h h
h
7.46
87.5-9
390
0
2-NOz
4s02
h h
h
7.46
54-57
391
0
2-Me
3-Me h
h h
7.50
Gum
392
0
2-Me
4-Me h
h h
7.51
Gum
393
0
2-Me
-Me h
h h
7.50
Gum
394
0
2-Me
6-Me h
h h
7.50
Gum
395
0
3-Me
4-Me h
h i
h
7.50
Gum
396
0
3-Me
-Me h
h h
7.51
Wax
397
och2
4-Br h
h h
h
7.47
Oil
398
CO^GE^
h h
h h
h
7.47
Gum
399
sch2
2-Cl h
h h
h
7.47
74-78
400
sch2
4-^2
h h
h h
7.48
Gum
401
s(o)ch2
2-Cl h
h h
h
7.60
Gum
402
s(o)2ch2
2-Cl
H
H
h
H
7.59
Gum
403 (E/
'z)-ch=ch^
4-N02
H
H
h
H
7.49
Gum
404 ph2+PCH2Br
H
H
H
h
H
7.40
176-177
405
CH20 4-tert-C4Hg
H
H
h
H
7.31
Gum
406
„
cr2ooo
H
H
H
H
H
7.46
Gum
23 5 07
tftrtie i (oont/d)
1
Conpound No.
X
D
G
A
B
E
01efinic+
Melting
Point
(°C)
407
CH^IHCO
H
H
H
H
H
7.41
Gum
408
chjscd
H
h
H
H
H
7.45
Gum
409
o2c
3-N02
H
Ji
H
H
7.50
Gum
410
och2o
4-Cl
H
H
H
H
7.47
Oil
411
S(O)CH^0
H
H
H
H
H
7.47
Oil
412
C0CH(CH3)0
H
H
H
H
H
7.45
Oil
413
(E)-CH^0N:CH
H
H
H
H
H
7.49
Gum
414
(Z)-CH^DN:CH
H
H
H
H
H
7.46
Gum
415
(CH2)3O .
H
H
H
H
H
7.48
Oil
416
(CK^J^O
H
H
H
H
H
7.47
Oil
417
(CH2)gO
H
H
H
H
H
7.48
Oil
418
(E)-N:N
4-OH
H
h h
H
7.50
Oil
419
(E)-N:N
4-ch3o
H
H
H
H
7.49
Gum
420
CO.NH
2-Br
H
H
H
H
7.49
Foam
421
CO.NH
3-Br
H
H
H
H
7.47
Etoam
422
CO.NH
3-ch3o
H
H
H
H
7.48
Fbam
423
ochgch^o
H
H
h h
H
7.45
Gum
424
SO2O
4-
H
H
H
7.29
Gum
425
SCH^
H
H
H
H
H
7.47
Oil
426
CI^O 2-
(ch3o2c-
h
H
H
H
7.40 or
Gum
c=ch.och3)
7.52
;
427
SO2O 1
4-CF30
H
H
H
h obscured
Gum
428
S020 2
-ch3o2c
H
H
H
H
7.41
Gum
429
zh2ch2ch(oh)
h
H
H
H
H
430
(e)-ch2ch=ch
H
1
H
H
H
H
r
' '.•*', ,x, .--
l, ttj'-C, • '' "■/' ' |m|a.
.mmmmvi1"" -mrr-1 ',
235 075
TABLE I (OQNT/D)
F
Ccnpound No.
1
\
X
D
G
A
B
E
Olefinic*
Melting
Point
(°C)
431
c(ch3) (oh)
h h
h h
h
432
ch(oh)
2-Cl h
.h h
h
433
ch(oh)
4-Cl h
h h
h
434
ch(oh)
2-ch3o h
H
H
H
435
CH(OH)
3-cf3
H
H
h
H
436
CH(OH)
3-CN
H
H
H
H
437
CH(OH)
4-N02
H
H
H
H
438
CH2OSO2
H
H
H
H
H
439
CH2NHCO.NH
H
H
H
H
H
440
CB^NH
H
h
H
H
H
441
OCO.NH
H
H
H
H
H
442
NHOO.NH
H
H
H
H
H
443
ch2oco.nh
H
H
H
H
H
7.47
Gum
444
sognh
4-Br
H
H
H
H
445
CH^H
j
3-ch3
H
H
H
H
235 07
TABLE I - FOOTNOTES:
+ Chemical shift of singlet from olefinic proton on beta-methoxypropenoate group (p.p.m from tetramethylsilane)
Solvent: cdci3 unless otherwise stated.
Substituents D and G join to form a fused ring. Thus 5 compound numbers 168, 169, 247, 248, 332 and 333 are:
OCH-
COMPOUND NO
168
CH20 247
S020 332
"••"jwwu la****""*'"*
x compound no
0
O^O SO20
169 248 333
And Conpound No. 424 is :
- /C \ /0CH3
CH3O2C C
H
*, © Indicate, in each case, that structural assignment nay be reversed. Thus the characterising data attributed to Ccnpound No. 180 nay, in fact, be that for Gonpound No. 367 and vice versa. The same applies to Qstpound Nos. 365 and 366.
\
4s (E):(Z) ratio = 85:15 (see Exanple 20).
Ph is phenyl.
235 075
table ii
A B
z—X
ch3°2'
/°ch3
,c c
H
Carpound No.
z
X
A
b
" E
i
Olefinic*
Melting Point (°C)
1
Pyridin-2-yl
0
h h
h
7.48
Gum
2
Pyridin-2-yl s
h h
h
3
Fyridin-2-yl
N(CH3)
h h
h
4
Pyridin-2-yl so2o h
h h
Pyridin-2-yl
GH2C!H2
h h
h
6
Pyridin-2-yl och2
h h
h
7.48
Gum
7
Pyridin-2-yl ch2o
H
H
H
8
Pyridin-3-yl
0
H
H
H
; 7.48
Gum
9
Pyridin-3-yl s
H
H
H
Pyridin-3-yl
N(CH3)
H
H
H
11
Pyridin-3-yl
S020
H
H
H
12
Eyridin-3-yl
CH2CH2
H
H
H
13
Pyridin-3-yl och2
H
H
H
14
Pyridin-3-yl ch2o
H
H
H
Pyridin-4-yl
0
H
H
H
7.48
Gun
16
Pyridin-4-yl s
H
H
H
17
Pyridin-4-yl
N(CH3)
H
H
H
•
18
Pyridin-4-yl so2o
H
H
H
19
J
Pyridin-4-yl
CH2CH2
H
H
H
e 235 075
table ii (cont/d)
Ccnpound No.
Z
X
A
B
E
j 01efinic+
Melting Point (°C)
Pyridin-4-yl och2
H
H
H
21
Pyridin-4-yl
CHjO
H
H
H
22
Pyriirtidin-2-yl
0
H
H
H
7.38
Gum
23
Pyrrmidin-2-yl
S
H
H
H
7.49
Gum
24
Pyrimidln-4-yl
N(CH3)
H
- H
H
Pyrimidin-4-yl
S020
H
H
H
26
Pyrimidin-5 -y 1
ch2ch2
H
H
H
27
Pyrimidin-5-yl
<3*2°
h h
h
28
1,2,4-Triazin-3-yl och2
h h
h
29
1,3,5-Triazin-2-yl
0
h h
h
Pyrazin-2-yl
0
H
H
H
7.49
Gum
31
Pyrazin-2-yl s
H
h
H
32
Pyrazin-2-yl
N(CH3)
H
H
H
33
Pyrazin-2-yl so2o
H
H
H
34
Eyrazin-2-yl ch2o
H
H
H
Pyridazin-3-yl
0
H
H
H
7.49
Gum
36
Pyridazin-3-y1
s
H
H
H
37
Pyridazin-3-yl
S020
H
H
H
38
Qu±nolin-2-yl
0
H
H
H
7.43
109-110
39
Quinolin-2-yl ch2°
H
H
H
40
Quinolin-3-yl
0
H
H
H
41
Quinolin-3-yl so2o
H
H
H
42
Benzoxazol-2-yl
0
H
H
H
43
Benzoxazol-2-yl s
H
H
H
44
Benzoxazol-2-yl
N(CH3)
H
H
H
45
Benzoxazol-2-yl so2o
H
H
H
l
23 5 07 5
© -32 -
table ii (cont/d)
Conrpounc
Melting
No.
Z
X
A
B
E
Olefinic*
Point (°C)
46
Benzthiazol-2-yl ch2CH2
H
H
H
47
Benzthiazol-2-yl och2
H
H "
H
7.49
Gum
48
Benzthiazol-2-yl ch2o
H
H
H
49
rhien-2-yl ch2°
H
H
H
50
rhien-2-yl
H
H-
H
51
rhien-3-yl
0
H
H
H
1
52
rhien-2-yl so2o
H
H
H
7.40
Gum
53
-CF3-Pyridin-2-yl
0
H
H
H
7.49
Oil
54
-CF3-Pyridin-2-y 1
s
H
H
H
55
-CF3-Pyridin-2-yl
CH20
H
H
H
56
3-F-Pyridin-2-yl
0
H
H
H
57
3-Cl-Pyridin-2-yl
0
H
H
H
58
4-Br-Pyridin-2-yl
0
H
H
H
59
-CH3-Pyridin-2-yl
0
H
H
H
60
6-CH30-Pyridin-2-yl
0
H
H
H
i
61
2-F-Pyridin-3-yl o
H
H
H
62
3-CF3-Pyridin-4-yl
0
H
H
H
63
4,6-di-F-Pyridin-2-y3
0
H
H
H
64
1
1
3-^K>2~5"cp3"
?yridin-2-yl
0
H
H
H
65
i
>
-(CH302C)-Pyridin-2-yl
0
H
H
H
66
3-CH3-Pyridin-2-yl
0
H
H
H
67
4-CH3-Pyridin-2-yl
0
H
H
H
68
6-CH3-Pyridin-2-yl
0
H
H
H
69
- (CN) -Pyridin-2-yl o
H
H
H
7.49
Gum
o
235075
TftBLE II (CONT/D)
Ccnpound No.
Z
X
1
A
B
E
Olefinic*
Melting Point (°C)
70
3-Cl-5-(C6H50)-l/
o
H
H
H
3,5-triazin-2-yl
71
Pyridin-2-yl
0
2-F
H
H
72
Pyridin-2-yl
0
4-Cl
H
H
73
Pyridin-4-yl
0
-CH3
H
H
74
Pyridin-4-yl
0
4-ch3o
H
H
75
-CF2-Pyridin-2-yl
0
-CN
H
H
76
-CF3-Pyridin-2-yl
0
4-F
-ch3o
H
77
Pyrimidin-2-yl
0
H
H
-C1
78
Pyrimidin-2-yl
0
H
H
6-F
79
Benzoxazol-2-yl
0
4-cf3o
H
-F
80
Benzoxazol-2-yl
0
-N02
H
H
81
1,2,4-Triazol-l-yl ch2
H
H
H
7.48
Gum
82
1,2,3-Triazol-l-yl ch2
H
H
H
83
Benzthiazol-2-yl
0
H
H
H .
1
7.38
Gum
84 3-Chloroquinoxalin-2-yl o
H
H
H
7.50
117-119
85
Pyrimidin-2-yl och2
H
H
H
7.49
Oil
86
3,5-di-Cl-l,3,5-
0
H
H
H
7.52
Gum
triazin-2-yl
87
Pyrimidin-5-yl
0
H
H
H
7.47
Oil
88
3-Cl, 5-(CH30)-1,3,5-
0
H
H
H
7.50
Gum
triazin-2-yl
89
6-Cl-Eyrimi<ain-4-yl
0
H
H
H
7.49
Oil
90
-Br-Pyriitiidin-2-yl
0
H
H
H
7.48
Gum
91
-Cl-Pyrimidin-2-yl
0
h h
h
7.48
Oil-
92
Pyrimidin-4-y 1
0
h h
h
7.48
Oil
93
2,6-Di-CH30-
0
h h
h
7.48
Oil
Pyrimidin-4-yl
mrpV"-' -
' i ,,'nwii III III I I "" " II WlWlWiWH'f'l ^rrrT.... . —|f| \ , v _
2 3507
table ii (cont/d)
Ccnpound No.
Z
X
A
B
E
Olefinic*
1
Melting Point (°C)
94
2-Cl-6-CH3-Pyrimidin-
0
H
H
H
7.50
113-118
4-yl
95
2,6-Di-Cl-Pyrimidin-
0
H
H
H
7.50
113-115
4-yl
96
2,5,6-Tri-Cl-
0
H
H
H
7.49
Gum
Pyrimidin-4-yl
97
2-Cl-Pyrimidin-4-yl
0
H
H
H
*
Oil
98
2-CH3-Thiazol-4-yl ch2o
H
H
H
7.48
Oil
99
Benzoxazol-2-yl och2
H
H
H
7.50
Gum
100
Pyrazin-2-yl och2
H
H
H
7.49
Gum
101
6-Cl-Pyrazin-2-yl och2
H
H
H
7.49
Gum
102
Quinolin-2-yl och2
H
H
H
7.49
Gum
103
6-Cl-Pyridazin-3-yl och2
H
H
H
7.49
Gum
104
Pyridin-4-y1, N-oxide och2
H
H
H
7.49
Foam
105
-CF3-Pyridin-2-yl och2
H
H
' H ,
t
7.48
Gum
106
3-Cyanqpyridin-2-yl
0
H
H
H
7.48
Gum
107
-N02H?yridin-2-yl
0
H
H
H
7.49
Gum
108
Pyrimidin-2-yl ch2o
H
H
H
109
Pyrimidin-2-yl so2°
H
H
h
110
Pyrimidin-2-yl
NH
H
H
H
111
Pyrimidin-2-yl n(ch3)
H
H
H
112
Pyrimidin-2-yl ch2
H
H
H
113
Pyrimidin-2-yl
CH(OH)
H
H
H
114
Pyrimidin-2 -y 1
ch2ch2
h
H
H
115
Pyrimidin-4-yl
0
H
H
H
116
Pyrixnidin-4-yl
CHjO | H
H
H
117
Pyrimidin-4-yl och2
H
H
H
i
1
118
Pyriinidin-4-yl
NH
H
H
H
I
J
235 075
«
TABLE II (CONT/D)
Ccnpound
Melting
No.
Z
X
A
B
E
Olefinic*
Point (°C)
119
Pyrimidin-4-yl s
h h
h
120
Pyrimidin-4-yl ch2
h h
h
121
Pyrimidin-4-yl ch(oh)
h h
h
122
Pyrimidin-4-yl ch2ch2
h h
h
123
Pyrimidln-5-yl so2o h
"h h
124
Pyrimidin-5-yl och2
h h
h
125
Pyrimidln-5-yl nh h
h h
126
Pyriraidin-5-yl n(ch3)
h h
H
127
Pyrimidln-5-yl s
H
H
H
128
Pyrimidin-5-yl ch2
H
H
h
129
Pyrimidin-5-yl
CH(OH)
H
H
h
130
6-Chloropyridazin-3-yi o
H
H
H
7.50
Gum
131
6-Chlorqpyridazin-3-yl
CH2o
H
H
H
t
132
6-Chlorcpyridazin-3-yl nh
H
H
H
133
6-Chlorcpyridazin-3-yl n(ch3)
h h
H
134
6-Chlorcpyridazin-3-yl ch(oh)
H
H
H
135
Pyridazin-4-yl o
H
H
H
136
Pyridazin-4-yl och2
H
H
H
137
Pyridazin-4-yl
NH
H
H
H
. 138
Pyridazin-4-yl so2o
H
H
H
139
1,3,5-Triazin-2-yl
NH
H
H
H
140
1,3,5-Triazin-2-yl n(ch3)
h
H
H
141
1,2,4-Triazin-3-yl o
h h
H
©
235075
TABLE II (OONT/D)
Ccnpound
Melting no.
Z
X
A
B
E
Olefinic*
Point (°C)
142
1,2,4-Triazin-3-yl nh h
h h
143
1,2,4-Triazin-3-yl n(ch3)
h h
h
144
1,2,4-Triazin-5-yl
0
h h
h
145
1,2,4-Tr iazin-5-y 1
nh h
h h
146
1,2,4-Triazin-6-y 1
0
h
•H
h
147
1,2,4-Triazin-6-yl n(ch3)
h h
h
148
Pyrimidin-2-yl, N-oxide
0
h h
h
149
Pyrimidin-4-y1, 1-N-oxide
0
h h
h
150
Pyrimidin-4-yl, 3-N-oxide
0
h h
h
151
Pyridin-2-yl, N-oxide
0
h h
h
152
Pyridin-3-yl, N-oxide o
h h
h
153
Pyrazin-2-yl, 1-N-oxide 0
h h
H ,
154
Pyrazin-2-y1, 4-N-oxide O
h h
h
155
Pyridazin-3-yl, 1-N-oxide
0
h h
h
156
Pyridazin-3-yl, 2-N-oxide o
h h
H
157
Isoquinolin-l-yl o
H
H
H
158
Isoquinolin-l-yl
NH
h
H
H
159
Isoquinolin-l-yl ch2o
H
H
H
160
Isoquinolin-l-yl och2
H
H
H
161
Isoquinolin-l-yl
CH(OH)
H
H
h
162
Isoquinolin-l-yl
S
H
H
H
163
Isoquinolin-l-yl so2o
H
h
H
164
Quinolin-4-yl o
H
h
H
©
235 075
TABLE II (CCNT/D)
COnpound No.
z x
a b
e
01efinic+
Melting Point (°C)
165
Quinoli n-4-yl
NH
h
H
H
166
Quinolin-4-yl cbjo
H
H
H
167
Quinolin-4-yl och2
H
H
H
168
Quinolin-4-yl
CH(OH)
H
H
H
.169
Quinoli n-4-yl s
H
H
H
170
Quinolin-4-yl so2o
H
H
H
171
Quinazolin-4-yl
0
H
H
H
172
Quinazolin-4-yl
NH
H
H
H
173
QuinazDlin-4-yl ch2o
H
H
H
174
Quinazolin-4-yl och2
H
H
H
175
Quinazolin-4-yl
CH(OH)
H
H
H
176
Quinazolin-4-yl
S
H
H
H
177
Quinazoli n-4-yl so2o h
h
H
178
7 -Chloroquinolin-4-yl
0
H
H
H
179
7 -Chloroquinoli n-4-yl s
H
H
H
180
7-Chloroquinolin-4-yl
NH
H
H
H
181
Purin-6-yl
O
H
H
H
1
182
2-Chlorqour in-6-yl s
h
H
H
183
2-Chlor cpurin-6 -yl
NH
H
H
H
184
-NC^-Thien-2-yl och2
H
H
H
185
-N02-Ihien-2-yl
0
H
H
H
186
Thiazol-2-yl
CH20
H
H
H
187
ThiazDl-2-yl
0
H
H
H
188
Thiazol-2-yl
NH
H
H
H
189
Thiazol-4-yl ch2o
H
H
H
190
lhiazol-4-yl
0
H
H
H
191
Ihiaaol-4-yl
NH
H
H
H
192
Ihiazol-5-yl
(2^0
H
h
H
193
Thiazol-5-yl
0
H
H
H
194
"Ihiazol-5-yl
NH
H
H
H
G
M M N U M H H H I—.
Ji. to tsj M o
M (O M M M M
Q O O O o Q
id CO vl » UI 5
N) O to
KJ O NJ
to O
N>
O
o vQ vO
at
^ ,fk
J}
WWw tn ui T ^
|4I|I
P. ft | §. & ft ? ? ft ?
? ? y ? r u I<I K m K:
4 ^ M ^ >-
_±f £
^ i|i 4^ Ji Ji y 6 6 6 •}> & h A £ tf J? & 7 i
_ J*. U1 UI
ft fS ft h ft <S
" 0? § 0?
vO
(—1 VO
M VO
-J
0\
UI
&
9
8
U>
U)
0)
8
0
8
V
T*
M
UI
■L
N>
4
£
i
O O O O
33 33 P3 33 W
33 33 33 3! 33
33 33 33 33 33 33
33 35 ® 31 W W
X
a a
33 . ffi 33 a a a a a
a a a a a a as a a a a a a a a a a a a
a a
a a a a a
•p>
vo ui i
<S\
8
Qi a
w
S
n>
hi o!
¥
6 S
ft k D
*—s iQ 0
n
Hi to
CO
fO CnJ
ai
CO -•J
<_n
?
c
23
075
TABLE II (OONT/D)
©
©
Gonpound
]
Melting
No.
Z
X
A
B
E
Olefinic*
Point (°C)
215
-F-Pyr imidin-2-yl o
H
H
H
216
-CH3-Pyrimidin-2-yl
0
H
H
H
217
-CH30-Pyr imidin-2-yl
0
H
H
H
218
-CH3CH20-Pyriinidin-2-yl
0
H
H
H
219
-NC^-Pyrimidin-2-yl
0
H
H
H
220
-Cyano-Pyr imidin-2-yl
0
H
~H
H
221
-CF3-Pyrimidin-2-yl
0
H
H
H
222
-CgH5-Pyrimidin-2-yl
0
H
H
H-
223
-CgHgO-Pyr iinidin-2-yl
0
H
H
H
224
4,5 -Di-Cl-Pyr imidi n-2-yl
0
H
H
H
225
4,6-Di-Cl-Pyrimidin-2-yl
0
H
H
H
226
4-Cl-6-CH3-Pyrimidixi-2-yl
0
H
H
H
227
4^1-5-CH30-Eyrimidiri-
2-yl
0
H
H
H i
228
2-F-Pyrimidin-4-yl
0
H
H
H
229
2-Br-Pyrimidir>-4-yl
0
H
H
H
230
2-CH3-Pyrimidin-4-yl
0
H
H
H
231
2-CH30-Pyrimidin-4-yl
0
H
H
H
232
2-CH3CE^O-Eyriinidin-4-yl
0
H
H
H
233
2-N0^-PyrinriLdin-4--yl
0
H
H
H
234
2-CH3S-Pyriniidin-4-yl
0
H
H
H
235
2-Cyano-Pyrimidin-4-yl
0
H
H
H
236
2-CF3~Pyrimidi n-4-yl
0
H
H
H
237
2-CgH50-Pyriniidin-4-yl
0
H
H
H
235075
TABLE II (OCNT/D)
Ccnpound
Melting
No.
Z
X
A
B
E
Olefinic*
Point (°C)
238
2-CgH5-Pyrimidin-4-yl
0
H
H
H
239
6-F-Pyrimidin-4-yl
0
H
H
H
240
6-Br-Pyrimidin-4-yl
0
H
H
H
241
6-CH3-Pyrimidin-4-yl
0
H
H
H
242
6-CH30-Pyr imidi n-4-yl
0
H
H
H
243
6-CH3CH20-Pyrimidin-4-yl
0
H
H
H
244
6-N02-Pyrimidin-4-yl
0
H
H
H
245
6-Cyano-Pyrimidin-4-yl
0
H
H
H
246
6-CF3-Pyrimidiiv-4-yl
0
H
H
H
247
6-CgH50-Pyrimidin-4-yl
0
H
H
H
248
6-CgH5~Pyrimidin-4-yl
0
H
H
H
249
-F-Pyr imidi n-4-yl
0
H
H
H
250
-Cl-Pyrimidin-4-yl
0
H
H
H
251
-Br-Pyr imidi rv-4-yl
0
H
H
H
252
-CH3-Pyrimidin-4-yl
0
H
H
H
253
-CE^O-Pyr imidin-4-yl
0
H
H
H
254
-CH3CH20-Pyrimidin-4-yl
0
H
H
H
255
-N0^-Pyrimidin-4-yl
0
H
H
H
256
-Cyano-Pyr imidin-4-yl
0
H
H
H
257
-CF3~E>yrimidin-4-yl
0
H
H
H
258
-CgHjO-Pyr imidin-4-yl
0
H
H
H
259
-CgHg-Pyr iirddin-4-yl
0
H
H
H
260
2-Cl-Pyrimidir>-5-yl
0
H
H
H
261
2-CH3~Pyr imidin-5-yl
0
H
H
H
262
2-F-Pyr imidi n-5-yl
0
H
H
H
263
2-CH30-Pyrimidin-5-yl
0
H
H
H
264
2-Cyano-Pyr imidi n-5 -yl
0
H
H
H
235075
TABLE II (OCNT/D)
Compound
:
Melting
No.
Z _
X
A
B
E
Olefinic"1"
Point (°C)
265
4-CH3~Pyr imidin-5 -yl
0
H
H
H
266
4-<H30-Pyr imidin- 5-yl
0
H
H
H
267
4-CF3~Pyr imidi n-5-yl
0
H
H
H
268
2,4-di-CH3-Pyr imidin-5-yl
0 .
H
H
H
269
2-ch3s-4-ch3o-Pyr imidi n-5-yl
0
H
H
H
270
Pyrrol-2-yl
CONH
H
H
H
7.48
Foam
271
6-Cl-3-N02-Pyridin-
2-yl and 6-Cl-5-NO^-Pyridir>-2-yl, 1:1 mixture
0
H
H
H
7.50
Gum
272
3,6-Di-CH3-Pyrazin-2-
yi
0
H
H
H
7.49
Gum
273
6-Cl-Pyrazin-2-yl
0
H
H
H
7.50
Gum
274
6-CH30-Pyridazin-3-yl
0
H
H
H
7.50
Gum
275
6-Cl-4-CH3-E>yridazin-3-yl
0
H
H
H
276
6-Cl-5-CH3-Pyridazin-3-yl
0
H
H
H
277
4-CF3-Pyridin-2-yl
0
H
H
H
278
6-Cyancpyridin-2-yl
O
H
H
H
279
4-Cyanq?yridin~2-yl
0
H
H
H
280
4-Acetylpyridin-2-yl
0
H
H
H
281
6-C6H5-Pyridazin-3-Yl
0
H
H
H
282
3 - (CH302C) -Pyridin-2-yl
0
H
H
H
283
- (CH3O2C) -Pyridin-3-
yi
0
H
H
"(<
V «> 1
284
4-CF2Cl-Pyridinr-2-yl
0
H
H
1
\ St1^l99J
°l i f/ 1
// 1
W t il
23 5 075
TABLE II (OONT/D)
Conpound
Melting
No.
z
X
A
B
E
01efinic+
Point (°C)
285
3,5-Di-CF3-Pyridin-2-
yi
0
H
H
H
286
6-CF3~Pyridin-2-yl
0
H
•H
H
287
-CF3-Pyridin-3-yl
0
H
H
H
288
2-Cl-Pyridin-3-yl
0
H
H
H
289
2-CH30-Pyridin-3-yl
0
H
_H
H
290
2-Cl-Pyridin-4-yl
0
H
H
H
291
2-CH30-Pyridin-4-yl
0
H
H
H
292
2-Cl-Pyridin-5-yl
0
H
H
H
293
2-CH30-Pyr idi n-5 -yl
0
H
H
H
294
3-CH3S-Pyridin-2-yl
0
H
H
H
295
4-CF3<>-Pyridin-2-yl
0
H
H
H
296
4-C0N(CH3) 2~Pyridin-2-yl
0
H
H
H
297
3-C1-1,2,4-Oxa-diazol-5-yl
0
H
H
H
298
3-C1-1,2,4-Oxa-diazDl-5-yl
S
H
H
H
299
-ch3s-1,2,4-0xa-diaaol-3-yl
0
H
H
H
300
Eyridin-2-yl
CH(OH)
H
H
H
301
Pyridin-3-yl
CH(OH)
H
H
H
302
Pyridin-4-yl
CH(OH)
H
H
H
303
Pyridin-2-yl
CO
H
H
H
304
Pyridin-3-yl
CO
H
H
H
305
Pyridin-4-yl
CO
H
H
H
306 j
Thien-2-yl
CH(OH)
H
H
H
307 j
Furan-2-yl
CH(OH)
H
H
H
| 308 |N-CH3~Pyrrol-2-yl !
i ,
CH(OH)
H
H
H
'—"■""•-•••■■www"**-...
" ^ \
\
235075
TABLE II (OONT/D)
GDrnpound No.
z
X
A
1
B
E
Olefinic"1"
Melting Point (°C)
309
N-ch3 -Pyrrol-2-yl cd h
h h
310
6-Br-Pyr idin-2-yl och2
h h
h
7.49
Oil
311
4-Cl-Pyrimidin-2-yl dch2
h h
h
7.49
Oil
and 2-Cl-Pyrimidin-
-4-yl (3:1 mixture,
not necessarily
respective ly)
312
2,6-Di-F-Pyrinddin-4-yl
0
h h
h
313
2-ch3s-6-ch3-
0
h h
h
7.48
Gum
Pyrimidin-4-yl
314
2-CH3S-Pyrimidin-4-yl
0
H
H
H
315
N-CH3-Pyrrol-2-yl
03N-
H
H
H
7.47
Gum i j
(ch3)
j
316
-CF3-Pyridin-2-yl
NH
H
H
H
1
1
317
2-Cl-Pyrimidinr-4-yl
NH
H
H
H
,
318
4-Cl-Pyrimidin-2-yl
NH
H
H
H
j \
319
-N02-6-(GH3)2N-
0
H
H
H '
7.48
Gum
Pyridin-2-yl
!
320
6-Cl-4-ch3~Pyridazin-
0
H
H
H
7.50
Gum j
■
3-yl and 6-Cl-5-CH3-Pyrida zin-3-yl
I
j
S
(3:2 mixture, not necessarily respectively)
1 1 i 1
f t {
FOOTNOTES :
+ Chemical shift of singlet fran olefinic proton on beta-roethoxyprcpenoate group (p.p.m fran tetramethylsilane).
Solvent: CDCI3 unless otherwise stated.
* See Table V for carbon-13 n.m.r. data.
23507
TABLE III
D
ch3°2C
/ ^ / C X
A
OCH-
Table III comprises 446 compounds of the general structure above. The first 445 of these have all the values of X, D, G, A, B and E listed in Table I. That is, Compound Nos. 1 to 445 of Table III are the same as those of Table I except that the value of K is oxygen in Table I and sulphur in Table III. Compound No. 446 has the above structure wherein X is oxygen and A, B, D, E and G are all hydrogen. A description of the preparation of Compound No. 446 is given in Example 11.
r' -- -,^r_
TABLE III
235075
Ccnpound No.
X
D
G
A
B
E
Olefinic*
Melting Point (°C)
23
i ch20
h h
h h
H
7.49
Gum
!
1 51
i so2o h
h h
h h
7.46
Gum
131
0
2-N02
h h
h
. h
7.48
Gum
1
212
ch20
4-N02
h h
h h
7.49
Gum
446
l !
0
h h
h h
h
7.48
48-51.5
i i
TABLE IV
I
ch3o2c c I
H
Table IV ccnprises 3'20 ccrnpounds of the general structure above with all the values of Z, X, A, B and E listed in Table II. That is, carpounds Nos. 1 to 320 of Table IV are the same as those of Table II except that the value of K is oxygen in Table II and sulphur din Table IV.
23 5 0 7 5
Conpound No.
Z
X
A
B
E
Olefinic1"
Melting
Point
(°C)
22 I 87 I
t i
3yrimidin-2-yl Pyrimidin-5-yl
0 0
H H
H H
H H
7.49 7.48 '
Gum
Gum j
1
1
TABLE V : SELECTED PROTON NMR DATA
Table V shews selected proton n.m.r data for certain ccrnpounds described in Tables I, II, III and IV. Chemical shifts are measured in p.p.m from tetramethylsilane, and deuterochloroform was used as solvent throughout. The 5 column headed 'frequency' refers to the operating 1 frequency of the n.m.r spectrometer. The following abbreviations are used :
br = broad s = singlet 10 d = doublet t = triplet q = quartet m = multiplet u* #iiy=uw— -- "• j--.vj'«
235 07
TABLE NO.
COMPOUND NO.
FREQUENCY (MHz)
I
2
60
3.36 (3H, s), 3.46 (3H, s), 6.6-7.6 (14H, m) ppm.
I
7
60
1.98 (3H, s), 3.48 (3H, s), 3.59 (3H, s), 6.6-7.3 (13H, m), 7.39 (IH, s) ppm.
I
270
2.88 (4H, sj, 3.60 (3H, s), 3.77 (3H, s), 6.76-3.93 (4H, m), 7.07-7.33 (9H, m), 7.49 (IH, s) ppm.
I
270
3.59 (3H, s), 3.74 (3H, s), 4.05 (2H, s), 6.80-7.32 (13H, m) , 7.47 (IH, s) ppm.
I
27
270
3.60 (3H, s), 3.77 (3H, s), 3.98 (2H, q), 6.60-6.90 (4H, m), 7.10-7.30 (4H, m), 7.39-7.50 (5H, m), 7.48 (IH, s) ppm.
I
29
400
3.59 (3H, s), 3.77 (3H, s), 4.26 (2H, s), 6.70-6.90 (4H, m), 7.10-7.30 <5H, m), 7.45-7.52 (IH, m), 7.48 (IH, s), 7.60-7.70 (3H, m) ppm.
I
1
38 j i
t
270
2.99 (3H, s), 3.56 (3H, s), 3.69 (3H, s), 4.46 (2H, s),
235075
TABLE NO.
COMPOUND NO.
FREQUENCY (MHz)
6.65-6.73 (3H, t), 6.79 (IH, d), 6.85-6.95 (3H, t), 7.10 (IH, t), 7.16-7.29 (5H, m), 7.44 (IH, s) ppm.
I
62
270
3.61 (3H, s), 3.78 (3H, s), 6.7-7.6 (11H, m), 7.46 (IH, s), 7.8 (3H, m) ppm.
I
67
270
3.59 (3H, s), 3.79 (3H, s), 7.02-7.40 (10H, m), 7.40 (IH, s), 7.70 (2H, d), 8.32 (IH, s) ppm.
I
84
270
3.60 (3H, s), 3.75 (3H, s), 6.97 (IH, d), 7.14-7.53 (11H, mj, 7.50 (IH, s), 7.59 (IH, d), 7.70 (IH, d) ppm.
I
86
400
3.60 (3H, s), 3.74 (3H, s), 6.99 (IH, d), 7.09 (IH, d), 7.12-7.41 (9H, m), 7.49 (IH, s), 7.50 (IH, s), 7.59 (IH, d), 8.38 (IH, s) ppm.
I
:
96
400
3.07 (2H, t), 3.60 (3H, s), 3.75 (3H, s), 4.10 (2H, t), 6.5-7.4 (13H, m), 7.48 (IH, s) ppm.
'{» inwiiwi'i'miiwywrrr rrnr,-,! ,
235 075
TABLE NO.
COMPOUND NO.
FREQUENCY (MHz)
I
115
270
3.60 (3H, s), 3.75 (3H, s), 4.63 (2H, d), 6.3-7.4 (15H, m), 7.47 (IH, s) ppm.
I
119
270
3.60 (3H, s), 3.76 (3H, s), 6.58-6.72 (3H, m) , 6.96-7.32 (8H, m), 7.41-7.50 (1H, m), 7.48 (IH, s) ppm.
I
120
270
3.60 (3H, s), 3.76 (3H, s), 6.62-7.36 (12H, m), 7.48 (IH, s) ppm.
I
122
90
3.61 (3H, s), 3.77 (3H, s), 6.5-6.8 (3H, m), 6.9-7.4 (9H, m), 7.50 (IH, s) ppm.
1
I
123
90
3.64 (3H, s), 3.79 (3H, s), 6.6-6.9 (2H, m), 6.9-7.5 (10H, m), 7.51 (IH, s) ppm.
I
125
90
2.23 (3H, s), 3.61 (3H, s), 3.77 (3H, s), 6.5-6.8 (3H, 6.8 (3H, m), 6.8-7.5 (9H,m) 7.51 (IH, s) ppm.
I
1
I
126
I !
400
2.33 (3H, s), 3.61 (3H, s), 3.76 (3H, s), 6.62-7.3 ! (12H, m), 7.49 (IH, s) ppm.j
235 075^
fl5b
TABLE
COMPOUND
FREQUENCY
*lsr
NO.
NO.
(MHz)
O
I
127
90
2.32 (3H, s), 3.60 (3H, s), 3.75 (3H, s), 6.62-7.40 (12H, m), 7.49 (IH, s) ppm.
I
128
270
3.58 (3H, s), 3.74 (3H, s), . 3.82 (3H, s), 6.56-6.65 (3H, m), 6.84-7.00 (4H, m), 7.06-7.28 (5H, m), 7.46 (IH, s) ppm.
I
130
60
3.6 (3H, s), 3.75 (3H, s), 3.8 (3H, s), 6.57-7.3 (12H, m), 7.48 (IH, s) ppm.
I
131
270
3.61 (3H, s), 3.76 (3H, s),
©
6.62-6.79 (3H, m), 6.97-7.34 (7H, m), 7.47 (IH, s), 7.48-7.56 (1H, m), 7.94 (IH, d) ppm.
0
I
135
90
3.62 (3H, s), 3.78 (3H, s), 6.6-6.9 (3H, m), 6.9-7.6 (9H, m), 7.51 (IH, s) ppm.
I
138
270
3.60 (3H, s), 3.76 (3H, s), 6. 62-r6. 76 (3H, m), 6.90-7.02 (2H, m), 7.12-7.38 (7H, m), 7.48 (1H, s) ppm.
:
gliiiaiiw.'-"-'""";1"
. — : -■ '' —~w«g«.. ..
235 0
i
| TABLE NO.
COMPOUND NO.
i
FREQUENCY (MHz)
I
141
250
3.59 (3H, s), 3.70 (3H, s) , 6.6-6.8 (3H, m), 6.9-7.1 (1H, m), 7.1-7.5 (8H, m), 7.49 (lH,s) ppm.
I
143
90
3.56 (3H, s), 3.68 (3H, s), 6.54-7.36 (17H, m), 7.46 (IH, s) ppm.
I
144
400
3.60 (3H, s), 3.75 (3H, s), 6.65-6.76 (5H, m), 6.97 (1H, d), 7.02 (2H, d), 7.10-7.38 (9H, m) , 7.48 (IH, s).
I
145
90
3.62 (3H, s), 3.77 (3H, s), 6.64-7.49 (17H, m), 7.50 (IH, s) ppm.
I
150
90
3.59 (3H, s), 3.74 (3H, s), 6.6-6.9 (3H, m), 6.9-7.7 (14H, m), 7.50 (IH, s) ppm.
I
157
90
3.64 (3H, s), 3.79 (3H, s), 6.6-7.5 (1IH, m), 7.53 (IH, s) ppm.
j I
:
!
*
171
90
3.61 (3H, s), 3.76 (3H, s), 6.6-6.8 (2H, m), 6.8-7.5 (10H, m), 7.51 (IH, s) ppm.
.. f
'S;r'7. * - , /
235075
TABLE NO.
COMPOUND NO.
FREQUENCY (MHz)
■ T
I
175
90
3.57 (3H, s), 3.73 (3H, s), 6.50 (IH, t), 6.58 (2H, d), 6.9-7.4 (9H, m), 7.41 (IH, s) ppm.
I
177
90
2.25 (3H, s), 3.60 (3H, s), 3.76 (3H, s), 6.4-6.6 (3H, m), 6.9-7.4 (9H, m), 7.47 (1H, s) ppm.
I
179
90
3.57 . (3H, s), 3.68 (3H, s), 3.72 (3H, s), 6.20 (3H, m), 6.8-7.4 (9H/ m), 7.42 (1H, j s) ppm.
I
180
250
3.61 (3H, s), 3.76 (3H, s), 6.4-6.6 (2H, m), 6.9-7.0 (3H, mh 7.07 (IH, t), 7.16 (1H, t), 7.2-7.4 (4H, m), 7.46 (IH, d), 7.47 (1H, s) ppm.
I
205
60
2.11 (3H, s), 3.35 (3H, s), 3.40 (3H, s), 4.71 (2H, s), 6.2-7.2 (12H, m), 7.24 (IH, s) ppm.
I
206
90
2.32 (3H, s), 3.55 (3H, s), 3.7 (3H, s), 4.9 (2H, s), 6.45-7.28 (12H, m), 7.40 (IH, s) ppm.
, -|1-v * ~ —i-ArjMJITHJBMliH.'U.
jjs,^ ,'"-'u '
\
\ V.
^'^m*?~~ •■-;* _,. ,..,*«&$$ \
r
235075
TABLE NO.
COMPOUND NO.
FREQUENCY (MHz)
1
:
I
208
90
3.54 (3H, s), 3.7 (3H, s), 3.77 (3H, s), 6.44-7.3 (12H, m), 7.39 (1H, s) ppm.
I
214
90
3.56 (3H, s), 3.73 (3H, s), 5.0 (2H, s), 6.5-7.65 (12H, m), 7.41 (1H, s) ppm.
I
216
90
3.56 (3H, s), 3.69 (3H, s), 5.04 (2H, s), 6.49-7.57 (12H, m), 7.41 (1H, s) ppm.
I
217
60
3.55 (3H, s), 3.65 (3H, s), 4.90 (2H, s), 7.45 (IH, s), 6.4-7.5 (12H, m) ppm.
I
218
90
3.54 (3H, s), 3.7 (3H, s) , 4.9 (2ff, s), 6.42-7.48 (12H, m), 7.4 (IH, s) ppm.
I
220
60
3.40 (3H, s), 3.49 (3H, s), 4.85 (2H, s), 6.2-7.5 (13H, m) ppm.
I
230
60
3.44 (3H, s), 3.52 (3H, s), 4.87 (2H, s), 6.3-7.6 (18H, m) ppm.
I
^ \
....
235 075
o
TABLE NO
COMPOUND NO
FREQUENCY (MHz)
©
I
247
90
3.5 (3H, s), 3.61 (3H, s), 5.07 (2H, s), 6.41-7.79 (15H, m), 7.42 (IH, s) ppm.
I
248
90
3.56 (3H, s), 3.7 (3H, s), 5.4 (2H, s), 6.5-8.4 (15H, m), 7.42 (1H, s) ppm.
I
283
60
3.45 (3H, s), 3.59 (3H, s), 6.5-8.0 (13H, m) ppm.
I
284
60
3.45 (3H, s), 3.57 (3H, s), 6.3-7.8 (13H, m) ppm.
o
I
285
250
3.57 (3H, s), 3.72 (3H, s), 6.55-7.78 (12H, m), 7.45 (IH, s) ppm.
©
I
288
60
3.39 (3H, s), 3.52 (3H, s), 6.4-7.4 (10H, m), 7.45 (IH, s), 7.7-8.0 (2H, m) ppm.
I
290
60
2.25 (3H, s), 3.43 (3H, s), 3.55 (3H, s), 6.4-7.7 (13H, m) ppm.
■1
I
291
90
1
i
!
i i
2.43 (3H, s), 3.54 (3H, s), 3.71 (3H, s), 6.5-7.68 (12H, m), 7.38 (IH, s) ppm."
' ''^"''''-^i'*^
BWM>*iWlWWWWmBBlwsaiwwt»»i»
235 07
TABLE NO
COMPOUND NO
FREQUENCY (MHZ )
I
295
60
3.52 (3H, s), 3.67 (3H, s), 6.6-8.0 (13H, m) ppm.
I
296
90
3.54 (3H, s), 3.72 (3H, s), 6.48-8.69 (12H, m), 7.41 (IH, s) ppm.
1
I
318
60
3.59 (3H, s), 3.72 (3H, s), 6.7-8.0 (12H, m) ppm.
I
332
90
3.48 (3H, s), 3.63 (3H, s), 6.48-8.3 (15H, m), 7.34 (IH, s) ppm.
I
333
90
3.44 (3H, s), 3.61 (3H, .s), 6.41-8.71 (15H, Hi), 7.35 (IH, s)'ppm.
I
360
250
3.55 (3H, s), 3.71 (3H, s), 6.15 (IH, s), 6.48-7.39 (14H, m), 7.44 (IH, s) ppm.
I
j
J
367
250
i
3.56 (3H, s), 3.70 (3H, s), 6.5-6.7 (2H, m), 6.95 (3H, t), 7.12 (2H, q), 7.2-7.4 (4H, m), 7.45 (IH, s), 7.48 (IH, d) ppm.
235 075
TABLE NO
COMPOUND NO
f
FREQUENCY (MHz)
1
I
368
90
3.57 (3H, s), 3.73 (3H, s), 6.33 (3H, s), 6.9-7.5 (14H, . m), 7.46 (IH, s) ppm.
I
369
60
3.5 (3H, s), 3.6 (3H,s ), 4.1 (2H, br s), 6.6-7.3 (12H, m), 7.43 (IH, s) ppm.
I
370
90
3.6 (3H, s), 3.76 (3H, s), 5.24 (2H, s), 6.51-8.04 j (13H, m), 7.47 (IH, s) ppm. |
I
371
400
3.60 (3H, s), 3.75 (3H, s), 3.76 (3H, s), 4.95 (2H, s), 6.80-6.94 (6H/ m), 7.03 (IH, s), 7.08-7.16 (2H, q), 7. 24-7. 3*0 (3H, m) , 7.49 (IH, s) ppm. |
I
373
270
3.60 (3H, s), 3.76 (3H, s), 5.02 (2H, s), 6.88-6.96 (2H, d), 6.98-7.40 (10H, m), 7.48 (IH, s) ppm.
I
374
270
i
I
3.61 (3H, s), 3.76 (3H, s), 5.05 (2H, s), 6.76-7.60 (m), 7.48 (s) ppm. j i J
235 0
TABLE NO.
COMPOUND NO.
FREQUENCY
376
270
377
400
378
400
381
270
382
400
3.59 (3H, s), 3.73 (3H, s), 5.08 (2H, s), 6.84-6.96 (4H, m), 7.04-7.40 (8H, m), 7.46 (1H, s) ppm.
3.59 (3H, s), 3.75 (3H, s), 3.87 (3H, s), 5.10 (2H, s), 6.8-6.95 (6H, m), 7.05-7.15 (3H, m), 7.22-7.30 (3H, m), 7.48 (IH, s) ppm.
3.60 (3H, s), 3.75 (3H, s), 5.14 (2H, s), 6.90-7.04 (5H, m), 7.13-7.19 (2H, m), 7.24-7.32 (3H, m), 7.47 (IH, s), 7.48-7.60 (2H, m) ppm.
i
3.59 (3H, s), 3.75 (3H, s), 5.17 (2H, s), 6.75 (IH, d) , 6.88-7.35 (11H, m), 7.48 (IH, s), 7.50 (IH, m), 7.85 (IH, d) ppm.
3.60 (3H, s), 3.77 (3H, s), 5.10 (2H, s) 6.94 (2H, d), 7.50 (IH, s), 7.10-7.18 (2H, m), 7.40-7.33 (4H, m), 7.42 (1H, t), 7.48 (IH, s), 7.78 (1H, s), 7.84 (IH, d) ppm.
'"'t limn'«fti»r'"T r'1 rritf • - - ✓w«p"iv.
235 075
TABLE
COMPOUND
FREQUENCE
1
NO
NO
(MHz)
I
383
270
3.60 (3H, s), 3.72 (3H, s),
4.97 (2H,s), 6.84-7.36
(12H, m), 7.47 (IH, s) ppm.
I
384
400
3.53 (3H, s), 3.68 (3H, s),
4.91 (2H, s), 6.73-7.26
(12H, m), 7.40 (IH, s), ppm
I •
385
270
3.58 (3H, s), 3,73 (3H, s),
4.95 (2H, m), 6.58 (2H, m),
6.66 (IH, d), 6.86-7.35
(14H, m) ppm.
I
386
270
3.59 (3H, s), 3.73 (3H, s),
4.97 (2H, s), 6.80-6.92
(4H, m), 7.0-7.32 (8H, m),
7.47 (IH, s) ppm
1
I
387
270
3.60 (3H, s), 3.77 (3H, d),
3.96 (2H, s), 6.60 (IH, s),
6.70-6.90 (3H, m), 7.18
(2H, q), 7.24-7.36 (3H, m),
7.27 (IH, s), 7.40-7.48
(3H, m) ppm.
I
388
400
3.60 (3H, s), 3.78 (3H, s),
4.25 (2H, d), 6.68 (1H, s),
6.75 (IH, d), 6.82 (IH, d),
6.90 (IH, d), 7.13 (4H, m),
7.27 (IH, s), 7.42-7.48
(3H, m), 7.57 (2H, d) ppm i
i' :
wumwwtff'"^'"" -' t-"-' •"*•» -4 -,
235 075
o o
TABLE NO
COMPOUND NO
FREQUENCY
■
I
389
270
3.58 (3H, s), 3.72 (3H, s),
.08 (2H, s), 6.80-6.96 (4H
m), 7.08-7.32 (7H, m), 7.46
(IH, s), 7.54 (IH, d) ppm.
I
391
250
2.22 (6H, s), 3.65 (3H, s),
_
3.75 (3H, s)/ 6.60-7.30
(11H, m), 7.50 (IH, s), ppm
I
392
90
2.17 (3H, s), 2.34 (3H, s),
3.55 (3H, s) 3.70 (3H s),
6.50-7.24 (11H, m), 7.51
(IH, s) ppm.
I
393
90
2.14 (3H, s), 2.27 (3H, s),
3.59 (3h, s), 3.76 (3H, s),
6.53-7.28 (11H, m), 7.50
(1H, s)'ppm.
I
394
250
2.08 (6H, s), 3.52 (3H, s),
3.75 (3H, s), 6.40-7.20
(11H, m), 7.50 (IH, s) ppm.
I
395
90
2.24 (6H, s), 3.61 (3H, s),
3.77 (3H /s)/ 6.63-7.30
[ j
(11H, m) 7.50 (IH, s) ppm
I
i i
j 396
90
2.28 (6H, s), 3.60 (3H, s),
: .
3.77 (3H, s), 6.63-7.24
1
1
(11H, m), 7.51 (IH s), ppm.
' •' WSWlWHWUMt.'
23 5 075
TABLE NO
COMPOUND NO
FREQUENCY
I
397
270
3.58 (3H, s), 3.73 (3H, s),
4.96 (2H, s), 6.80 (2H, d),
6.86-6.92 (2H, m),7.0-7.16
(3H, m), 7.20-7.38 (5H, m),
7.47 (IH, s) ppm.
I
399
270
3.60 (3H, s), 3.76 (3H, s),
4.08 (2H, s), 6.80-7.58
(12H, m), 7.47 (IH, s), ppm
I
400
400
3.59 (3H, s), 3.75 (3H, s),
4.18 (2H, s), 6.85 (2H, d),
7.00 (IH, s), 7.05 (IH, d),
7.10-7.35 (5H, m), 7.48
(1H, s), 8.10 (2H, d) ppm.
I
401
400
3.72 (3H, s), 3.88 (3H, s),
4.22 (2H, q), 6.83 (IH, s),
6.88-7.0 (3H, m), 7.21-7.42
(4H, m), 7.50 (3H, d), 7.60
(IH, s), 7.66 (IH, m) ppm.
I
402
400
3.70 (3H, s), 3.87 (3H, s),
4.70 (2H, s) 6.80 (1H, d),
6.95-7.05 (3H, m), 7.22-
7.48 (5H, m), 7.59 (IH, s),
7.65 (2H, s), 7.92 (1H, d)
ppm
f ■' '«m.in-n*-i'ir-i-~- —-ty - - ...... _
235075
TABLE NO
COMPOUND NO
FREQUENCY
r
405
60
1.21 (9H, s), 3.42 (3H, s),
3.46 (3H, s), 4.80 (2H, s),
6.3-7.3 (12H, m), 7.31 (IH,
'
s) ppm.
i
406
270
3.57 (3H, s), 3.71 (3H, s),
.32 (2H, s), 6.92 (IH, d),
7.16 (2H, t), 7.24-7.43 (8H,
m), 7.46 (1H, s), 7.66 (IH,
d), 7.76 (IH, d) ppm.
i
407
270
3.51 (3H, s), 3.73 (3H, s),
4.59 (2H, d), 6.70 (IH, t),
6.96 (IH, d), 7.08 (IH,
dd), 7.19 (IH, d), 7.22-
7.37 (9H, m), 7.41 (IH, s),
7.48 (IH, d) ppm. j j ;
i
408
270
1 I
t
3.59 (3H, s), 3.71 (3H, s), j
4.29 (2H, s), 6.94 (IH, d),
7.13-7.38 (10H, m), 7.45
(IH, s), 7.51 (IH, t), 7.63 \
(IH, d) ppm. !
1 I
i
409
270
3.61 (3H, s), 3.78 (3H, s), j
6.99 (IH, d), 7.15-7.36 j
(4H, m), 7.44 (IH, t), 7.50 j
(IH, s), 7.53-7.65 (2H, m), |
7.78 (IH, t), 7.89 (IH, d), ;
8.10-8.19 (2H, m) ppm. j
^ > WMMlMJil lfW^gBiggSSg|»^&W /_*_ ^ 'l'-,"/,^v(j^^'!-frWH '
y
, 235075
o
TABLE NO
COMPOUND NO
FREQUENCY
o
I
410
400
3.60 (3H, s), 3.75 (3H, s), 5.63 (2H, s), 6.6-7.3 (12H, m), 7.47 (IH, s) ppm.
I
411
400
3.60 (3H, s), 3.75 (3H, s), 4.8 (IH, d), 4.94 (IH, d), . 6.6-7.7 (13H, m), 7.47 (1H, s) ppm.
I
412
270
1.67 (3H, d)/ 3.55 (3H, s), 3.70 (3H, s), 5.45 (IH, q), 6.5-8.1 (13H, m), 7.45 (IH, s) ppm.
I
413
270
3.59 (3H, s), 3.73 (3H, s), 5.17 (2H, s), 6.90-6.99 (2H, m), 7.12-7.43 (1H, m), 7.49 (IH, s), 8.08 (1H, s) ppm.
©
I
414
270
3.55 (3H, s), 3.70 (3H, s), 5.21 (2H, s), 6.91-7.0 (2H, m), 7.10-7.19 (1H, m), 7.21-7.38 (9H, m), 7.46 (1H, s), 7.53-7.60 (2H, m) ppm.
I
415
'
270
2.05 (2H, m), 2.78 (2H, t), 3.60 (3H, s), 3.75 (3H, s), 3.90 (2H, t), 6.5-7.3 (13H, m), 7.48 (IH, s) ppm.
TABLE NO
COMPOUND NO
FREQUENCY
I
416
270
1.78 (4H, m), 2.65 (2H, m), 3.60 (3H, s), 3.75 (3H, s), 3.9 (2H, m), 6.5-7.3 (13H, m), 7.47 (IH, s) ppm.
I
417
270
1.44-1.85 (6H, m), 2.62 . (2H, t), 3.60 (3H, s), 3.75 (3H, s), 3.87 (2H, t), 6.48-7.31 (13H, m), 7.48 (IH, s) ppm.
I
418
270
3.61 (3H, s), 3.76 (3H, s), 5.68 (1H, s), 6.8-7.6 (10H, m), 7.50 (IH, s), 7.8 (2H, m) ppm.
I
419
270
3.60 (3H, s), 3.74 (3H, s), 3.89 (3H/s ), 6.9-7.6 (10H, m), 7.49 (IH, s), 7.9 (2H, m) ppm.
I
420
270
3.62 (3H, s), 3.78 (3H, s), 6.72-7.67 (13H, m), 7.49 (IH, s) ppm.
I
422
4.s
270
3.62 (3H,s ), 3.80 (3H, s), 3.87 (3H, s), 6.72-7.48 (12H, m), 7.48 (IH, s), 7.78 (IH, s) ppm.
\
c
235 07 5
O
TABLE NO
COMPOUND NO
FREQUENCY
I
423
270
3.60 (3H, s), 3.70 (3H, s),
4.23 (4H, m), 6.53-7.3
(13H, m), 7.45 (IH, s)
ppm.
I
424
60
3.40 (3H, s), 3.50 (3H, s),
6.40-8.4 (15H, m), 8.95
(IH, s) ppm.
I
425
270
3.60 (3H, s), 3.75 (3H, s),
.40 (2H, s), 6.55-7.5
(13H, m), 7.47 (IH, s) ppm.
I
426
90
3.53 (3H, s), 3.61 (3H, s),
3.63 (3H, s), 3.66 (3H, s),
4.90 (2H, s), 6.40-7.6 .
(14H, m) ppm.
t
I
427
90
\
3.43 (3H, s), 3.61 (3H, s),
6.4-7.4 (10H, m), 7.32 (1H,
s), 7.77 (2H, d) ppm.
I
428
90
3.55 (3H, s), 3.65 (3H, s),
3.85 (3H, s), 6.7-8.0 (13H,
m) ppm.
I
443
270
3.59 (3H, s), 3.74 (3H, s),
.17 (2H, s), 6.6-7.4 (14H,
m), 7.47 (IH, s) ppm.
§11$®^"^
235 075
TABLE NO
COMPOUND NO
FREQUENCY
II
23
270
3.63 (3H, s), 3.74 (3H, s) ,
6.97-7.05 (3H, m), 7.10
(IH, d), 7.22-7.33 (4H, m),
.
7.48 (1H, d), 7.49 (1H, s),
8.54 (2H, d) ppm.
II '
270
3.60 (3H, s), 3.74 (3H, s),
6.73-7.35 (8H, m), 7.49
(1H, s), 8.10 (IH, m), 8.25
(IH, m), 8.38 (IH, m) ppm.
II
47
270
3.60 (3H, s), 3.75 (3H, s) ,
.52 (2H, s), 6.96 (2H, d),
7.07-7.40 (8H, m), 7.49
(IH, s), 7.61-7.71 (2H, q)
ppm.
II
52
60
3.51 (3H, s), 3.64 (3H, s),
7.40 (IH, s), 6.5-7.8 (11H,
m) ppm.
II
53
270
3.60 (3H, s), 3.75 (3H, s),
6.74-7.35 (9H, m), 7.49
(IH, s), 7.88 (IH, m), 8.43
(IH, m) ppm.
II
69
270
3.60 (3H, s), 3.75 (3H, s),
6.73-7.36 (9H, m), 7.49
(IH, s), 7.89 (IH, m), 8.45
1
1
(IH, m).
i i
, , *' ;'
,
.Wc^krti: W{*»'
235075
TABLE NO
COMPOUND NO
FREQUENCY
II
81
270
3.63 (3H, s), 3.78 (3H, s),
.32 (2H, s), 6.84-6.92
(4H, m), 7.10-7.30 (4H, m),
7.48 (IH, s)/ 7.98 (IH, s),
8.08 (IH, s) ppm.
II
83
90
3.54 (3H, s), 3.65 (3H, s),
6.76-7.68 (12H, m), 7.38
(IH, s) ppm.
II
86
90
3.62 (3H, s), 3.79 (3H, s),
6.8-7.5 (8H, m), 7.52 (IH,
s) ppm.
II
87
270
3.61 (3H, s), 3.76 (3H, s),
6.66-6.74 (2H, m), 6.79
(IH, dd), 7.00 (IH, d),
7.16 (1H, m), 7.24-7.34
(3H, m), 7.47 (IH, s), 8.47
(2H, s), 8.96 (IH, s) ppm.
II
88
90
3.62 (3H, s), 3.76 (3H, s),
4.30 (3H, s), 6.80-7.42
(8H, m) , 7.50 (1H, s) ppm.
II
90
270
3.61 (3H, s), 3.76 (3H, s),
6.77 <1H, t) , 6.86 (2H, m) ,
7.04 (1H, d), 7.15 (IH, m),
7.29 (3H, m), 7.48 (1H, s) ,
8.55 (2H, s) ppm.
\
\
m■ , ' . - !
235 0
.
TABLE NO
COMPOUND NO
FREQUENCY
II
91
270
3.61 (3H, s), 3.75 (3H, s),
6.77 (IH, t), 6.83-6.89
(2H, m), 7.04 (IH, d), 7.15
(1H, t), 7.25-7.35 (3H, m),
7.48 (1H, s), 8.47 (2H, s)
ppm.
II
93
270
3.60 (3H, s), 3.75 (3H, s),
3.90 (3H, s), 3.94 (3H, s).
.67 (1H, s), 6.76 (IH, t),
6.84 (2H, m), 7.00 (1H, d),
7.15 (1H, m), 7.25-7.32
(2H, m) , 7.48 (IH, s) ppm.
II
96
270
3.61 (3H, s), 3.75 (3H, s),
6.75 (1H, t), 6.83 (IH,
dd), 6.95 (1H, dd), 7.07
(1H, d) ] 7.18 (IH,' m),
7.29-7.37 (3H, m), 7.49
(IH, s) ppm.
II
97
Proton-decoupled Carbon -
13 n.m.r. at 67.7 MHz :
delta 51.25, 61.59, 106.54,
107.41, 110.85, 114.96,
115.45, 119.58, 123.72,
125.06, 128.90, 130.05,
132.41, 152.29, 153.57,
158.81, 160.03, 160.13,
160.22, 167.49, 169.95 ppm.
235075
TABLE NO
COMPOUND NO
FREQUENCY
II
98
270
2.72 (3H, s), 3.60 (3H, s),
3.77 (3H, s), 5.08 (2H, s),
6.5-7.4 (9H, m), 7.48 (1H,
s) ppm.
II
99
270
3.60 (3H, s), 3.74 (3H, s),
.50 (2H, s), 6.92-7.0 (2H,
m), 7.09-7.36 (9H, m), 7.47
(IH, s), 7.50 (IH, d) ppm.
II
100
270
3.60 (3H, s)/ 3.75 (3H, s),
.33 (2H, s), 6.90-6.96
(2H, m), 7.06-7.18 (3H, m) ,
7.24-7.34 (3H, m), 7.49
(IH, s), 8.07 (1H, d), 8.14
(1H, d), 8.28 (IH, s) ppm.
II
101
270
3.60 (3H, s), 3.75 (3H, s),
.31 (2H, s), 6.90-6.99
(2H, m), 7.06 (1H, s),
7.10-7.18 (2H, m), 7.25-
7.34 (3H, m), 7.49 (IH, s),
8.17 (2H, s) ppm.
II
102
270
3.60 (3H, s), 3.75 (3H, s),
.50 {2H, s), 6.89-6.99
(3H, m), 7.1-7.42 (7H, m),
7.49 (IH, s), 7.62 (IH, t),
7.71 (1H, d), 7.83 (IH, d),
8.0 (IH, d) ppm.
235 075
©
0
TABLE NO
COMPOUND NO
FREQUENCY
II
103
270
3.60 (3H, s), 3.77 (3H, s),
.49 (2H, s), 6.90-6.98
(2H, m), 7.0 (IH, d), 7.08-
7.20 (3H, m), 7.24-7.33
(3H, m), 7.39 (1H, d), 7.49
(IH, s) ppm.
II
104
270
3.44 (3H, s), 3.70 (3H, s),
.09 (2H, s), 6.82 (2H, d),
6.90 (IH, s), 7.0-7.14 (4H,
m), 7.16-7.36 (3H, m) , 7.49
-
(IH, s), 8.05 (2H, d) ppm.
II
105
270
3.60 (3H, s), 3.75 (3H, s),
.38 (2H, s), 6.82-6.98
(3H, m), 7.05-7.20 (3H, m),
7.20-7.35 (3H, m), 7.48
1
(1H, s), 7.78 (IH, d), 8.43
(IH, s) ppm.
II
106
270
3.60 (3H, s), 3.76 (3ft, s),
6.74-7.38 (9H, m), 7.48
(IH, s), 7.98 (IH, m), 8.30
(IH, m) ppm.
II
107
270
3.60 (3H, s), 3.76 (3H, s),
6.75-7.37 (9H, m), 7.49
(IH, s), 8.45 (IH, m), 9.03
1
i
(IH, m) ppm.
235075
o
CD
TABLE NO
COMPOUND NO
FREQUENCY
II
270
270
3.61 (3H, s), 3.78 (3H, s), 6.28 (1H, m), 6.70 (2H, m), 6.9-7.5 (9H, m), 7.48 (1H, s), 9.55 (IH, br, s) ppm.
II
271
270
3.60 (3H, s), 3.74 (3H, s), 6.74-7.39 (9H, m), 7.50 (IH, s), 8.32 (IH, m) ppm.
II
272
270
2.32 (3H, s), 2.54 (3H, s), 3.60 (3H, s), 3.76 (3H, s), 6.72-7.35 (8H, m), 7.49 (IH, s), 8.00 (IH, s) ppm.
o
II
273
270
3.60 (3H, s), 3.72 (3H, s), 6.72-7.36 (8H, m), 7.50 (IH, s),. 8.26 (2H, m) ppm.
jifr
II
274
270
3.60 (3H, s), 3.75 (3H, s),
4.04 (3H, s), 6.74-7.36
*
(10H, m), 7.50 (IH, s) ppm.
Q
II
310
270
3.60 (3H, s), 3.75 (3H, s), 5.30 (2H, s), 6.72 (IH, d), 6.87-7.35 (9H, m), 7.43 (IH, t), 7.49 (IH, s) ppm.
II
311
270
Data in common for both regioisomers : 3.60 (3H, s), 3.77 (3H, s), 5.38 (2H,
~ =Uri~1
235075
TABLE NO
COMPOUND NO
FREQUENCY
II
315
II
II
II
II
313
270
270
270
270
270
s), 6.90-7.18 (5H, m), 7.23-7.33 (3H, m) , 7.49 (IH, s) ppm. Data for major isomer : 6.70 (IH, d), 8.32 (IH, d) ppm. Data for minor isomer : 6.98 (1H, d), 8.38 (1H, d) ppm.
3.39 {3H, s), 3.60 (3H, s),
3.73 (3H, s), 3.84 (3H, s),
.63 (1H, m) , 5.85 (1H, m),
6.59 (1H, m), 6.7-7.3 (8H, m), 7.47 (1H, m) ppm.
3.60 (3H, s), 3.75 (3H, s), 6.62-7.36 (10H, m), 7.48
(IH, s), 8.38 (2H/ m) ppm.
!
3.60 (3H, s), 3.74 (3H, s), 6.66-7.37 (10H, m), 7.48 (IH, s), 8.45 (2H, m) ppm.
3.60 (3H, s), 3.74 (3H, s), 6.70-7.50 (10H, m), 7.49 (IH, s), 8.92 (1H, m) ppm.
2.38 (3H, s), 2.41 (3H, s), 3.59 (3H, s), 3.75 (3H, s), 6.29 (IH, s), 6.75 (IH, t), 6.84 (2H, t of d), 6.98 (IH, d), 7.15 (IH, t),
'vvwiiikr>
235075
TABLE NO ,
COMPOUND NO
FREQUENCY
II
319
II
320
III
23
III
51
III
131
270
270
270
270
270
7.25-7.34 (3H, m) , 7.48 (IH, s) ppm.
2.90 (6H, s) , 3.60 ( . r, s) ,
3.77 (3H, s), 6.18 (IH, d),
6.75-7.37 (8H, m), 7.48
(IH, s) , 8.22 (1H, d) ppm.
Data in common for both regioisomers: 3.61 (3H, s), 3.74 (3H, s), 7.50 (IH, s) ppm. Data for major isomer: 2.35 (3H/ s) ppm. Data for minor isomer: 2.38 (3H, s) ppm.
3.65 (3H, s), 3.75 (3H, s), 4.97 (2H, s), 6.75-6.87 (3H m), 7.14 (1H, t), 7.21-7.40 (9H, m), 7.49 (IH, s) ppm.
3.61 (3H, s), 3.73 (3H, s),
6.75-6.82 (2H, m), 7.02-7.17 (2H, m), 7.22-7.38
(3H, m), 7.46 (IH, s),
7.47-7.59 (4H, m), 7.62-
7.72 (IH, m), 7.80 (1H, d) ppm.
3.63 (3H, s), 3.74 (3H, s),
6.80 (IH, d), 6.86 (IH, s),
Vv.,
^',v-
<
235 0
TABLE MO
COMPOUND NO
FREQUENCY
6.99 (2H, d), 7.15-7.37
'(6H, m), 7.48 (IH, s), 7.46
(1H, d), 7.93 (IH, d) ppm.
III
212
270
3.65 (3H, s), 3.77 (3H, s),
.08 (2H, s), 6.74-6.80
_
(2H, m), 6.85-6.89 (IH, d),
7.16 (IH, t), 7.20-7.38
(4H, m), 7.49 (IH, s), 7.54
(2H, d), 8.21 (2H, d) ppm.
IV
87
270
3.64 (3H, s), 3.75 (3H, s),
6.80 (IH, d), 6.86 (IH, s),
7.03 (IH, d), 7.21-7.38
(4H, m), 7.47 (IH, d), 7.48
(IH, s), 8.44 (2H, s), 8.95
(IH, s) ppm.
\
I ,-iSfci.1
235 075
The compounds of formula (I) can be made by a variety of methods, and some of these are illustrated in Schemes I to VIII. Throughout these Schemes, the terms Z, X, A, B, E, K, R1, R2, R3, R4 and R5 are as defined above, R® is hydrogen or a metal (such as sodium or potassium), R is an alkyl group, and L is a leaving group such as a halide (chloride, bromide or iodide), a CHgS04-anion, or a sulphonyloxy-anion. Each of the transformations described in Schemes I to VIII is performed at a suitable temperature and either in a suitable solvent or in the absence of a solvent.
Scheme I illustrates ways in which the methyl beta-methoxypropenoate group can be constructed in the final stages of the preparation of the compounds of the invention from precursors with a preformed framework of 3 aromatic rings. Alternatively, the methyl beta-methoxy-propenoate group may be constructed at an earlier stage of the preparation, in which case the final step or steps comprise elaboration of other parts of the compounds of the invention to form the framework of 3 aromatic rings. Examples of procedures of this kind are shown in Schemes III to VIII.
In whichever order the steps are carried out to prepare the compounds of the invention, the diphenyl ether or thioether linkage which is common to all the compounds of the invention can be prepared by one of the coupling reactions shown in Scheme II. For a review of the Ullmann ether synthesis see A.A. Moroz and M.S. Shrartsberg, Russian Chem.Reviews, 1974, 43, 679. See also D. Hands, H. Marley, S.J. Skittrall, S.H.B. Wright and T. R. Verhoeven, J.Heterocyclic Chem., 1986, 23, 1333. These couplings are often performed in the presence of a catalyst which consists of a transition metal or a salt or compound of a transition metal, such as copper or a copper salt or compound, or a mixture thereof. In Scheme II, the
235075
term W represents either the group Z-X-, wherein Z and X are as defined above, or a group which can be converted by standard procedures described in the chemical literature into the group Z-X-; for example V/ can be -OH, -SH, or -5 NHR4. The term Y represents either the alpha-linked methyl beta-methoxypropenoate group of the compounds of the invention or a group which can be converted into such a group by standard methods described in the chemical literature and/or described in Scheme I and the following 10 paragraphs. For example Y can be -CH2COOH, -CH2COOMe or -CHO. In the context of Scheme II, the term L is preferably a halogen. Thus compounds of formula (XI)
react with compounds of formula (XII) under the conditions of the Ullmann reaction already described to give the 15 intermediates of formula (VIII). As an example of one of the coupling reactions shown in Scheme II, substituted 3-phenoxyphenols, as their salts, undergo coupling with 2-bromo- or 2-chlorophenylacetic acid salts to give, after acidification, substituted 2-(3-phenoxyphenoxy)phenyl-20 acetic acids (compare, for example, GB 2078-743, Ihara Chem.Ind., 27.06.80). Alternatively, intermediates of formula (VIII) can be made by reacting compounds of formula (IX) with compounds of formula (X) under the conditions of the Ullmann reaction already described. 25 In one particular aspect, the invention of NZ 225945 includes a process for the preparation of the compound of formula (I)
which comprises reacting a compound of general formula (Xlla) :
y'
ch3o2c ch.och-
wherein Y is halogen with a phenol or thiophenol of general formula (XIa) :
235 075
- 76 -A B
(XIa)
kh in the presence of a base, or with a salt of the phenol or thiophenol (xia), preferably in the presence of a catalyst which comprises a suitable transition metal, a transition metal salt or compound or a mixture thereof.
The compounds of formula (I) can be prepared from the phenylacetates of formula (III) or the ketoesters of formula (VI) by-the steps shown in Scheme I.
Thus compounds of formula (I) can be prepared by treatment of phenylacetates of formula (III) with a base (such as sodium hydride or sodium methoxide) and methyl formate. If a species of formula CHgL, wherein L is as defined above, is then added to the reaction mixture, compounds of formula (I) may be obtained. If a protic acid is added to the reaction mixture, compounds of formula (II) wherein R® is hydrogen are obtained. Alternatively, the species of formula (II) wherein R® is a metal (such as sodium) may themselves be isolated from the i
reaction mixture.
Compounds of formula (ii) wherein R^ is a metal can be converted into compounds of formula (I) by treatment with a species of formula CH^L, wherein L is as defined above. Compounds of formula (II) wherein R® is hydrogen can be converted into compounds of formula (I) by successive treatments with a base (such as potassium carbonate) and a species of general formula CHgL.
Alternatively, compounds of formula (I) can be prepared from acetals of formula (IV) by elimination of methanol under either acidic or basic conditions.
Examples of reagents or reagent mixtures which can be used for this transformation are lithium di-isopropylamide; potassium hydrogen sulphate (see, for example, T Yamada, H Hagiwara and H Uda, J.Chem.Soc. , Chemical Communications,
'7;' ♦ .
235 07 5
1980, 838, and references therein); and triethylamine, often in the presence of a Lewis acid such as titanium tetrachloride (see, for example, K Nsunda and L Heresi, J.Chem.Soc., Chemical Communications, 1985, 1000).
Acetals of formula (IV) can be prepared by treatment of methyl silyl ketene acetals of formula (V), wherein R is an alkyl group, with trimethyl orthoformate in the presence of a Lewis acid such as titanium tetrachloride (see, for example, K Saigo, M Osaki and T Mukaiyama, Chemistry Letters, 1976, 769).
Methyl silyl ketene acetals of formula (V) can be prepared from phenylacetates of formula (III) by treatment with a base and a trialkylsilyl halide of formula RgSiCl or RgSiBr, such as trimethylsilyl chloride, or a base (such as triethylamine) and a trialkylsilyl triflate of formula R3Si-0S02CF3 (see, for example, C Ainsworth,
F Chen and Y Kuo, J.Organometallic Chemistry, 1972, 46, 59) .
It is not always necessary to isolate the intermediates (IV) and (V); under appropriate conditions, compounds of formula (I) may be prepared from phenylacetates of formula (III) in "one pot" by the successive addition of suitable reagents listed above.
Alternatively, compounds of formula (I) can be prepared by treatment of ketoesters of formula (VI) with a methoxymethylenating reagent, for example,
methoxymethylenetriphenylphosphorane (see, for example, W Steglich, G Schramm, T Anke and F Oberwinkler, EP 0044448, 4.7.1980).
Ketoesters of formula (VI) may be prepared by methods described in the literature. Particularly useful methods include (i) the reaction of appropriate phenylmagnesium halides or phenyl-lithium species with dimethyl oxalate using the method described by L M Weinstock, R B Currie and A V Lovell, Synth. Commun. , 1981, 1_1, 943 and references therein; (ii) oxidation of phenylacetates of
235 0.75
formula (III) using selenium dioxide, generally in the absence of a solvent, and generally at a temperature above 100°C? and (iii) oxidation of mandelic acid esters using, for example, manganese oxide in a suitable solvent.
Phenylacetates of formula (III) and the corresponding phenylacetic acids of formula (VII) may also be prepared by numerous other methods described in the chemical O literature. For example, several useful methods are described by D C Atkinson, K E Godfrey, B Meek, J F 10 Saville and M R Stillings, J.Med.Chem., 1983, 26^, 1353 and D C Atkinson, K E Godfrey, P L Meyers, N C Phillips, M R Stillings and A P Welbourn, J-.Med.Chem. , 1983, 26^ 1361. Furthermore, many of the methods described for the preparation of 2-arylpropionic esters and acids by J-P 15 Rieu, A Boucherle, H Cousse and G Mouzin, Tetrahedron,
1986, 42^ 4095, are also applicable to the preparation of phenylacetates of formula (III) and phenylacetic acids of formula (VII) using appropriate precursors wherein the ortho substituted-phenoxy substituent and the substituent 20 E are already present.
3
(tyr.
- '--i.ii^"i
235075
Scheme I
E
(I)
(IV)
^CH^
CH302C ^ CH(0CH3)2
ZX
A B
Jdu
CH: C (OCH3) (OSiRg)
(V)
w
J
(II)
A B
ZX
K
/
(III) /
CH2CO2CH2
(VII)
CH2C02H
\
\ \
If vL5\?*-"V7 .
Scheme II
B
M
(IX)
f
235075
h:
(x)
Base
W S ~ ^KH / Y
L
(XI)
(xii)
_
235 075
Schemes III, IV, V, VI and VII illustrate examples of intermediates containing the methyl beta-methoxypropenoate group and show how they may be converted into certain specific types of compound of the formula (I).
Thus,, in scheme III, in the presence of a base, and sometimes in the presence of a transition metal or transition metal salt catalyst, such as a copper or copper salt catalyst, compounds of formula (XIII) react with aromatic or heteroaromatic compounds of formula ZL,
wherein Z and L are as defined above, or with iodonium salts of formula Z2I+T~, wherein Z is as defined as above and T~ is a counter ion, such as a halide ion, or with aryl or heteroarylbismuth species, to give compounds of formula (XIV). In addition, in the presence of a base, compounds of formula (XIII) react with aryl- or heteroarylsulphonyl halides of formula ZSO2Q/ wherein Z is as defined above and Q is a halogen, to give compounds of formula (XV). Furthermore, and also in the presence of a base, compounds of formula (XIII) react with arylalkyl or heteroarylalkyl species of formula ZCHR1L, wherein Z, R1 and L are as defined above, to give compounds of formula (XVI).
In scheme IV, the thiols of formula (XVII), generally in the presence of a base, react with aromatic or heteroaromatic compounds of formula ZL, or with iodonium salts of formula Z2l+T~, or with aryl- or heteroarylbismuth species, to give compounds of formula (XVIII) in ways which are analogous to the reactions of the corresponding phenols of formula (XIII) shown in Scheme III. Similarly, and again in the presence of a base, the thiols of formula (XVII) react with arylalkyl or heteroarylalkyl species- of formula ZCHR^L to give compounds of formula (XIX). The sulphides of formula (XVIII) and (XIX) can be oxidised to the corresponding sulphoxides and sulphones by standard methods described in the chemical literature.
In Scheme V, compounds of formula (XX) react with hydroxy-derivatives of aromatic or heteroaromatic compounds of formula ZOH, wherein Z is as defined above, often in the presence of a base, to form compounds of 5 formula (XXI). Furthermore, compounds of formula (XX) react with trialkylphosphites of formula P(OR)3 or with species of formula M+P~(O)(OR)2• wherein R is as defined above in each case and M is a metal such as sodium or lithium, to give phosphonates of formula (XXII). 10 Phosphonates of formula (XXII), in the presence of a base, react with aldehydes or ketones of formula ZR^C:0, wherein Z and R1 are as defined above,- to give olefins of formula (XXIV). In addition, aldehydes or ketones of formula (XXIII), on treatment with phosphonate anions of formula 15 ZR^C-P(0) (OR)2M"1", wherein Z, R, R^ and M are as defined above, or with the corresponding phosphoranes, also give olefins of formula (XXIV). The olefins of formula (XXIV) can be reduced to the compounds of formula (XXV) by, for example, hydrogenation over an appropriate catalyst. 20 In Scheme VI, compounds of formula (XXVI), in the presence of a base, react with acid halides of formula ZCOQ, wherein Z and Q are as defined above, or, in the presence of an appropriate dehydrating agent, react with acids of formula ZCO2H, wherein Z is as defined above, to 25 give compounds of formula (XXVII).
Intermediates of formula (XXVI) can also be converted into other types of compound of the invention of formula (I) by methods described in the chemical literature. For example, compounds of formula (XXVI) wherein R4 is 30 hydrogen can be converted, via diazotisation, into the corresponding sulphonyl chlorides (compare Organic Syntheses, 1981, 60, 121) and then, by treatment with alcohols or phenols in the presence of a base, into sulphonic esters.
235 075
Compounds of the invention of formula (I) wherein at least one of A and B is hydrogen may be converted into compounds of the invention of formula (I) wherein at least one of A and B are certain substituents (such as a halogen or a nitro or acyl group) by electrophilic substitution processes of the kind described in the chemical literature.
The intermediates of formulae (XIII), (XVII), (XX), (XXIII) and (XXVI) can be prepared by processes described in the chemical literature and by processes of the kinds described in Schemes I and II. For example, compounds of formula (XX) where L is bromine can be made from compounds of formula (XX) where L is H, by reaction with N-bromosuccinimide or N,N-dibromo-dimethylhydantoin, in the presence or absence of irradiation by light.
The intermediates of formulae (IX), (X), (XI), (XII), ZL, Z2I+T~, ZCH^L, ZSO2Q, ZOH, ZR^O, ZR1C~P(0) (OR)2M+, ZCOQ and ZC02H can be made by methods described in the chemical literature.
©
Scheme III
O
A B
zso2— O
CH3O2C
CH.OCH-
(XV)
235 0
Scheme IV
ch3o2c
CH.OCH,
Z —S
(XVII)
(xviii)
z — chrj-s
A B
ch3°2c ch* och^
(xix)
- v«vr.
235 07
Scheme V
O
(XX)
(xxi)
(ro)2pchr2
ch3°2c
ch.och,
%
(XXIV)
z chr^-chr2
gh3°2c (xxv)
CH.OCH3
235075
Scheme VI
*£>
% — C— N.
R
ch3°2C
A B
r<^
(XXVI)
K'
CH.OCH-
(XXVII)
CH302C CH.OCH,
o
In Scheme VII compounds of formula (XXVIII) can be oxidised, for example using pyridinium dichromate in a suitable solvent (such as methylene chloride) or oxalyl chloride in dimethyl sulphoxide in the presence of a base 5 (the Swern oxidation), to give aldehydes (where R2 is H) or ketones (where R2 is alkyl) of formula (XXIII). The aldehydes or ketones of formula (XXIII) can react with oxyamines of formula ZONH2 or ZCHR^ON^, or with hydrazines of formula ZNR^N^, wherein Z and R* are as 10 defined above, to give compounds of the invention of formula (I) where X is the group ON=C,R2, CHR^ON=CR2, or NR*N=CR2 respectively. Also, compounds of formula (XXIII) can react with Grignard reagents of formula ZMgHal or zcHR^MgHal, where Hal is chlorine, bromine or iodine and 15 z and R1 are as defined above, to give compounds of the invention of formula (I) where X is CR2(OH) or CHRi.CHOH respectively. Also, compounds of formula
(XXIII) can react with an amine of formula ZNHR10 wherein Z is as defined above and R10 is hydrogen or Cj^-4 alkyl, in 20 the presence of a reducing agent (such as sodium v*..>
*-»...». - -
235075
cyanoborohydride or hydrogen gas in the presence of a suitable metal catalyst) to give a compound of the invention of formula (I) where X is nr10chr2.
When the reducing agent is left out and when R* is H, then the immediately preceding procedure will give compounds of the invention of formula (I) where X is N=CR2 or, when an amine of the formula ZCH^O.NH is used, CHR^-O.N^CR2.
Compounds of formula (XXVIII) where R2 is H, can also be oxidised to carboxylic acids of formula (XXIX), using for example Jones' reagent (chromium trioxide in sulphuric acid). The carboxylic acids (XXIX) can be converted directly into compounds of the invention of formula (I) ~ where, for example, X is C^C, CHR^OCO, SCO, CHR^SCO,
NR4CO or CHRlNR^CO, using one of the standard coupling reagents well known in the literature, such as dicyclohexylcarbodiimide or carbonyldiimidazole, in a suitable solvent.
Alternatively, the carboxylic acids of formula (XXIX) can be converted into the acid chlorides of formula (XXX) by treatment with, for example, thionyl chloride or oxalyl chloride. The acid chlorides of formula (XXX) can then react, for example, with compounds of formula ZOH,
ZCHR1OH, ZSH, ZCHR1SH, ZNR4H or ZCHR^R^ in a suitable -solvent, in the presence of a base, to give compounds of the invention of formula (I) where X is O2C, CHR^OCO, SCO, CHR1SCO, NR4CO, or CHR1NR4CO respectively.
Compounds of formula (XXVIII) can also react directly with compounds of formula ZL, optionally in the presence of a base, where Z is a reactive aromatic group (for example nitrophenyl) or heteroaromatic group (for example 2-pyridyl or 2-pyrimidinyl) to give compounds of the invention of formula (XXI). It may be necessary first generate the oxygen anion of compounds of formula (XXVIII) with a strong base such as sodium hydride.
Additionally, compounds of formula (XXVIII) can be converted into compounds of formula (XX) by treatment, for
235 075
example, with a halogenation agent such as thionyl chloride or phosphorus tribromide, where L is chlorine or bromine, or by treatment with a sulphonyl halide (such as p-toluenesulphonyl chloride) in the presence of an acid acceptor, where L is a sulphonyloxy group. Compounds of formula (XX) can then be used as shown in Scheme V. Additionally, where L is halogen, they can be converted by reaction with a phosphine of formula ZfR^^P, wherein is as defined above, into compounds of the invention of formula (I), where X is the group (R5)2P+CHR2Q~. These compounds can then react successively with a base and a carbonyl compound of formula ZCOR^, wherein Z and are as defined above, to give olefins of formula (XXIV).
Scheme VIII illustrates examples of intermediates of formula (VIII), shown in Scheme II, where W is any group that can be converted to ZX-, and Y is any group that can be converted to the methyl beta-methoxypropenoate group.
Compounds of formula (XXXI) can react with compounds of formula (XXXII) to give compounds of formula (XXXIII), using the general Ullmann coupling conditions described in detail for the reaction of compounds of formula (XI) and
(XII) in Scheme II. The acids of formula (XXXIII) can be i
converted into methyl esters of formula (XXXIV) by reaction with methanol in the presence of acid (for example hydrochloric acid). Compounds of formula (XXXIV) can then be converted into methyl beta-methoxypropenoates of formula (XXVIII) by the methods described in detail in Scheme I.
Alternatively, the intermediates of formula (XXXIV) can be converted into intermediates of formulae (XXXVIII), (XXXV), (XXXVI), (XXXVII) and (III) using the methods described in Scheme VII for the conversion of the propenoates of formula (XXVIII) into compounds of formula (XXIII), (XX), (XXIX), (XXX) and (I). Compounds of formula (III) can be converted into compounds of formula (I) as shown in Scheme I.
-—jsmm- v.
Schane VII
23 5 075
o
235
Schane VIII
hochr kh l
(xxxi)
(xxxii)
(xxxiii)
A B
(xxviii) ch3o2c
2c02ch3
CE^CC^CHg
(XXXVIII)
I
(xxxvi) ,ch2c02CH3
(iii) ch2co2ch3
c1co' k
(xxxvii)
«•*»!»?,*.• *¥!>«•»
235C75
^Bra]
* *voi
In a further aspect the invention of NZ 225945 provides processes as hereindescribed for preparing the compounds of formula
(I).
The present invention is directed to intermediate compounds of formulae (II), (IV) and (VI). The intermediate compounds of formulae (XIII),! (XVIII), (XX), (XXII),(XXIII), (XXVI), (XXVIII), (XXIX) and (XXX) are the' subject of NZ 235074.
The compounds are active fungicides and may be used to control one or more of the following pathogens :
Pyricularia oryzae on rice.
Puccinia recondita, Puccinia striiformis and other rusts on wheat, Puccinia hordei, Puccinia striiformis and other rusts on barley, and rusts on other hosts, e.g. coffee,
pears, apples, peanuts, vegetables and ornamental plants.
Erysiphe graminis (powdery mildew) on barley and wheat and other powdery mildews on various hosts such as Sphaerotheca macularis on hops, Sphaerotheca fuliginea on cucurbits (e.g. cucumber), Podosphaera leucotricha on apple and Uncinula necator on vines.
Helminthosporium spp., Rhynchosporium spp., Septoria spp., Pseudocercosporella herepotrichoides and Gaeumannomyces graminis on cereals. Cercospora arachidicola and Cercosporidium personata on peanuts and other Cercospora species on other hosts, for example, sugar beet, bananas,
soya beans and rice.
Botrytis cinerea (grey mould) on tomatoes, strawberries, vegetables, vines and other hosts.
ternaria species on vegetables (e.g. cucumber),
ape, apples, tomatoes and other hosts.
Venturia inaequalis (scab) on apples.
Plasmopara viticola on vines.
Other downy mildews such as Bremia lactucae on Peronospora spp. on soya beans, tobacco, onions and StXfi hosts and Pseudoperonospora humuli on hops and Pseudoperonospora cubensis on cucurbits.
23507
Phytophthora infestans on potatoes and tomatoes and other Phytophthora spp. on vegetables, strawberries, avocado, pepper, ornamentals, tobacco, cocoa and other hosts. Thanatephorus cucumeris on rice and other Rhizoctonia 5 species on various host such as wheat and barley, vegetables, cotton and turf.
Some of the compounds show a broad range of activities against fungi in vitro. They may also have activity against various post-harvest diseases of fruit 10 (e.g. Penicillium digitatum and italicum and Trichoderma viride on oranges, Gloeosporium musarum on bananas and Botrytis cinerea on grapes). -
Further, some of the compounds may be active as seed dressings against Fusarium spp., Septoria spp., Tilletia 15 spp., (bunt, a seed borne disease of wheat), Ustilago spp., Helminthosporium spp. on cereals, Rhizoctonia solani on cotton and Pyricularia oryzae on rice.
The compounds may have systemic movement in plants. Moreover, the compounds may be volatile enough to 20 be active in the vapour phase against fungi on the plant.
Many of the compounds of formula (I), including those in which X is O, are safer on certain crops (e.g. vines)
i than known structurally related compounds.
The invention therefore provides a method of 25 combating fungi, which comprises applying to a plant, to seed of a plant, or to the locus of the plant or seed, an effective amount of a compound as hereinbefore defined, or a composition containing the same.
The compounds may also be useful as industrial (as 30 opposed to agricultural) fungicides, e.g. in the prevention of fungal attack on wood, hides, leather and especially paint films.
The compounds may be used directly for fungicidal purposes but are more conveniently formulated into 3 5 compositions using a carrier or diluent. The invention thus provides a fungicidal composition comprising a
235 075
compound of general formula (I) as hereinbefore defined, and a fungicidally acceptable carrier or diluent.
Used as fungicides, the compounds can be applied in a number of ways. For example they can be applied, formulated or unformulated, directly to the foliage of a plant, to seeds or to other medium in which plants are growing or are to be planted, or they can be sprayed on, dusted on or applied as a cream or paste formulation, or they can be applied as a vapour or as slow release granules. Application can be to any part of the plant including the foliage, stems, branches or roots, or to soil surrounding the roots, or to the seed before ic is planted; or to the soil generally, to paddy water or to hydroponic culture systems. The invention compounds may also be injected into plants or sprayed onto vegetation using electrodynamic spraying techniques or other low volume methods.
The term "plant" as used herein includes seedlings, bushes and trees. Furthermore, the fungicidal method of the invention includes preventative, protectant, prophylactic and eradicant treatment.
The compounds are preferably used for agricultural ..
t and horticultural purposes in the form of a composition, the type of composition used in any instance will depend upon the particular purpose envisaged.
The compositions may be in the form of dustable powders or granules comprising the active ingredient (invention compound) and a solid diluent or carrier, for example fillers such as kaolin, bentonite, kiesselguhr, dolomite, calcium carbonate, talc, powdered magnesia, Fuller's earth, gypsum, diatomaceous earth and China clay. Such granules can be performed granules suitable for application to the soil without further treatment. These
23 5 0 75
granules can be made either by impregnating pellets of filler with the active ingredient or by pelleting a mixture of the active ingredent and powdered filler. Compositions for dressing seed may include an agent (for example a mineral oil) for assisting the adhesion of the composition to the seed; alternatively the active ingredient can be formulated for seed dressing purposes using an organic solvent (for example N-methylpyrrolidone, propylene glycol or dimethylformamide). The compositions may also be in the form of wettable powders of water dispersible granules comprising wetting or dispersing agents to facilitate the dispersion in liquids. The powders and granules may also contain fillers and suspending agents.
Emulsifiable concentrates or emulsions may be prepared by dissolving the active ingredient in an organic solvent optionally controlling a wetting or emulsifying agent and then adding the mixture to water which may also contain a wetting or emulsifying agent. Suitable organic solvents are aromatic solvents such as alkylbenzenes and alkylnaphthalenes, ketones such as isophorone,
cyclohexanone, and methylcyclohexanone, chlorinated hydrocarbons such as chlorobenzene and trichlorethane, and alcohols such as benzyl alcohol, furfuryl alcohol, butanol and glycol ethers.
Suspension concentrates of largely insoluble solids may be prepared by ball or bead milling with a dispersing agent and including a suspending agent to stop the solid settling.
Compositions to be used as sprays may be in the form of aerosols wherein the formulation is held in a container under pressure in the presence of a propellant, e.g. fluorotrichloromethane or dichlorodifluoromethane.
■■»
235 075
The invention compounds can be mixed in the dry state with a pyrotechnic mixture to form a composition suitable for generating in enclosed spaces a smoke containing the compounds.
Alternatively, the compounds may be used in microencapsulated form. They may also be formulated in biodegradable polymeric formulations to obtain a slow, controlled release of the active substance.
By including suitable additives, for example additives for improving the distribution, adhesive power and resistance to rain on treated surfaces, the different compositions can be better adapted for various utilities.
The invention compounds can be used as mixtures with fertilisers (e.g. nitrogen-, potassium-, or phosphorus-containing fertilisers). Compositions comprising only granules of fertiliser incorporating, for example coated with, the compound are preferred. Such granules suitably contain up to 25% by weight of the compound. The invention therefore also provides a fertiliser composition comprising a fertiliser and the compound of general formula (I) or a salt or metal complex thereof.
Wettable powders, emulsifiable concentrates and suspension concentrates will normally contain surfactants e.g. wetting agent, dispersing agent, emulsifying agent or suspending agent. These agents can be cationic, anionic or non-ionic agents.
Suitable cationic agents are quaternary ammonium compounds, for example, cetyltrimethylammonium bromide. Suitable anionic agents are soaps, salts of aliphatic monoesters of sulphuric acid (for example sodium lauryl sulphate), and salts of sulphonated aromatic compounds (for example sodium dodecylbenzenesulphonate, sodium, calcium or ammonium lignosulphonate, butylnaphthalene sulphonate, and a mixture of sodium diisopropyl- and triisopropyl-naphthalene sulphonates).
235 07
Suitable non-ionic agents are the condensation products of ethylene oxide with fatty alcohols such as oleyl or cetyl alcohol, or with alkyl phenols such as octyl- or nonyl-phenol and octylcresol. Other non-ionic agents are the partial esters derived from long chain fatty acids and hexitol anhydrides, the condensation products of the said partial esters with ethylene oxide, and the lecithins. Suitable suspending agents are hydrophilic colloids (for example polyvinylpyrrolidone and sodium carboxymethylcellulose), and swelling clays such as bentonite or attapulgite.
Compositions for use as -aqueous dispersions or emulsions are generally supplied in the form of a concentrate containing a high proportion of the active ingredient, the concentrate being diluted with water before use. These concentrates should preferably be able to withstand storage for prolonged periods and after such storage be capable of dilution with water in order to form aqueous preperations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment. The concentrates may conveniently contain up to 95% suitably 10-85%, for example 25-60%, by weight of the active ingredient. After dilution to form aqueous preparations, suitable preparations may contain varying amounts of the active ingredient depending upon the intended purpose, but an aqueous preparation containing 0.00055 or 0.01% to 10% by weight of active ingredient may be used.
The compositions of this invention may contain other compounds having biological activity, e.g. compounds having similar or complementary fungicidal activity or which plant possess plant growth regulating, herbicidal or insecticidal activity.
235075
A fungicidal compound which may be present in the composition of the invention may be one which is capable of combating ear disease of cereals (e.g. wheat) such as Septoria, Gibberella and Helminthosporium spp., seed and soil-borne diseases and downy and powdery mildews on grapes and powdery mildew and scab on apple, etc. By including another fungicide, the composition can have a broader spectrum of activity than the compound of general formula (I) alone. Further the other fungicide can have a synergistic effect on the fungicidal activity of the compound of general formula (I). Examples of fungicidal compounds which may be included in the composition of the invention are carbendazim, benomyl, thiophanate-methyl, thiabendazole, fuberidazole, etridazole, dichlofluanid, cymoxanil, oxadixyl, ofurace, metalaxyl, furalaxyl, benalaxyl, fosetyl-aluminium, fenarimol, iprodione, prothiocarb, procymidone, vinclozolin, penconazole, myclobutanil, propamocarb, diniconazole, pyrazophos, ethirimol, ditalimfos, tridemorph, triforine, nuarimol, triazbutyl, guazatine, triacetate salt of 1,1'-iminodi(octamethylene)diguanidine, buthiobate,
propiconazole, prochloraz, flutriafol, hexaconazole, (2RS,
i
5RS)-5-(2,4-dichlorophenyl)tetrahydro-5-(1H-1,2,4-triazol-l-ylmethyl)-2-furyl-2,2,2-trifluoroethyl ether, cyproconazole, terbuconazole, pyrrolnitrin, l-[(2RS, 4RS; 2RS, 4RS)-4-bromo-2-(2,4-dichlorophenyl)tetrahydrofur-furyl]-lH-l, 2, 4-triazole, 5-ethyl-5,8-dihydro-8-oxo(l, 3)-dioxolo (4,5-g)quinoline-7-carboxylic acid, (RS)-l-aminopropylphosphonic acid, 3-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-l-yl)quinazolin-4(3H)-one, fluzilazole, triadimefon, triadimenol, diclobutrazol, fenpropimorph, pyrifenox, fenpropidin, chlorozolinate, imazalil,
fenfuram, carboxin, oxycarboxin, methfuroxam, dodemorph, BAS 454, blasticidin S, kasugamycin, edifenphos, Kitazin P, cycloheximide, phthalide, probenazole, isoprothiolane,
235075
tricyclazole, 4-chloro-N-(cyano(ethoxy)methyl)benzamide, pyroquilon, chlorbenzthiazone, neoasozin, polyoxin D, validamycin A, mepronil, flutolanil, pencycuron, diclomezine, phenazin oxide, nickel dimethyldithio-carbamate, techlofthalam, bitertanol, bupirimate, etaconazole, hydroxyisoxazole, streptomycin, cyprofuram, biloxazol, quinomethionate, dimethirimol, l-(2-cyano-2-methoxyiminoacetyl)-3-ethyl urea, fenapanil, tolclofos-methyl, pyroxyfur, polyram, maneb, mancozeb, captafol, chlorothalonil, anilazine, thiram, captan, folpet, zineb, propineb, sulphur, dinocap, dichlone, chloroneb, binapacryl, nitrothal-isopropyl, dodine, dithianon, fentin hydroxide, fentin acetate, tecnazene, quintozene,
dicloran, copper containing compounds such as copper oxychloride, copper sulphate and Bordeaux mixture, and organomercury compounds.
The compounds of general formula (I) can be mixed with soil, peat or other rooting media for the protection of plants against seed-borne, soil-borne or foliar fungal diseases.
Suitable insecticides which may be incorporated in the composition of the invention include pirimicarb, dimethoate, demeton-s-methyl, formothion, carbaryl, isoprocarb, XMC, BPMC, carbofuran, carbosulfan, diazinon, fenthion, fenitrothion, phenthoate, chlorpyrifos, isoxathion, propaphos, monocrotophas, buprofezin, ethroproxyfen and cycloprothrin.
Plant growth regulating compounds are compounds which control weeds or seedhead formation, or selectively control the growth of less desirable plants (eg.
grasses).
Examples of suitable plant growth regulating compounds for use with the invention compounds are the gibberellins (eg. GAg, GA^ or ga7), the auxins (eg. indoleacetic acid, indolebutyric acid, naphthoxyacetic
235 075
acid or naphthylacetic acid), the cytokinins (eg. fcinetin, diphenylurea, benzimidazole, benzyladenine or benzylaminopurine), phenoxyacetic acids (eg. 2,4-D or MCPA), substituted benzoic acid (eg. triiodobenzoic acid), morphactins (eg. chlorfluoroecol), maleic hydrazide, glyphosate, glyphosine, long chain fatty alcohols and acids, dikegulac, paclobutrazol, fluoridamid, mefluidide, substituted quaternary ammonium and phosphonium compounds (eg. chloromequat chlorphonium or mepiquatchloride), ethephon, carbetamide, methyl-3,6- dichloroanisate, daminozide, asulam, abscisic acid, isopyrimol, l-(4-chlorophenyl)-4,6-dimethyl-2-oxo-l,2-dihydropyridine-3-carboxylic acid, hydroxybenzonitriles (eg. bromoxynil), difenzoquat, benzoylprop-ethyl 3,6-dichloropicolinic acid, fenpentezol, inabenfide, triapenthenol and tecnazene.
The following Examples illustrate the invention. Throughout the Examples, the term 'ether' refers to diethyl ether, magnesium sulphate was used to dry solutions, and solutions were concentrated under reduced pressure. Reactions involving water-sensitive intermediates were performed under an atmosphere of nitrogen and solvents were dried befoi-e use, where appropriate. Unless otherwise stated, chromatography was performed on a column of silica gel as the stationary phase. Where shown, infrared and n.m.r. data are selective; no attempt is made to list every absorption in all cases. ^"H n.m.r. spectra were recorded using cdci3-solutions unless otherwise stated. The following abbreviations are used throughout :
DME = dimethoxyethane
THF = tetrahydrofuran s = singlet
DMF = N,N-dimethylformamide d = doublet n.m.r.= nuclear magnetic resonance t = triplet
IR = infrared m = multiplet
235
m.p. = melting point br = broad
GC = gas chromatography ppm = parts per
TLC = thin layer chromatography million
HPLC = high performance liquid chromatography
EXAMPLE 1
This Example illustrates the preparation of (E) methyl 2-[2-(3-benzyloxyphenoxy)phenyl]-3-methoxypropenoate (Compound No. 23 of Table I).
23 5 0
\
o
235 0
A mixture of 2-bromobenzaldehyde (lOOg; 0.54 mol), ethylene glycol (67.03g? 1.08 mol), £-toluenesulphonic acid (0.5g) and toluene was heated to and maintained at reflux temperature for 6 hours- During this period, 5 water/ethylene glycol (23 ml) was removed by azeotropic distillation. The mixture was cooled and ether (1 1) was added. The ether solution was washed with saturated sodium bicarbonate solution (200 ml) water (3 x 150 ml) and saturated brine (1 x 150 ml). After drying and 10 filtration, evaporation of the ether solution gave 2-(2-bromophenyl)-l,3-dioxolane (121.96g, 98.6% yield) as an oil.
^"H n.m.r. : (60 MHz) delta : 3.4 (4H, m), 6.0 (IH, s), 6.9-7.6 (4H, m), ppm.
This material was used without further purification for the following step.
Potassium hydroxide pellets (35.2g? 0.63 mol) were dissolved in water (50 ml) and 3-methoxyphenol (78g; 0.63 mol) was added together with toluene (250 ml) . The 20 mixture was heated to and maintained at reflux temperature until water ceased to distil over (a total of 65 ml of water was collected). The mixture was cooled to 80°C and 2-(2-bromophenyl)-l,3,-dioxolane (120 g; 0.524 mol), DMF (200 ml) and cuprous chloride (0.2g) were added. The 25 mixture was slowly heated to 150-155°C and toluene was distilled off. The mixture was maintained at 150-155"C for 6 hours then cooled to 25"C and water (500 ml) was added. The mixture was filtered and the residue was washed with ether (200 ml). The filtrate was extracted 30 with ether (3 x 150 ml). The combined ether extracts were washed with 2N sodium hydroxide solution (2 x 150 ml), water (4 x 150 ml) and saturated brine (1 x 200 ml).
After drying and filtration the ether solution
235 07
on evaporation gave 2-[2-(3-methoxyphenoxy)phenyl]-l,3-dioxolane (124.lg, 87.1% yield) as an oil.
1H n.m.r. (60 MHz) delta : 3.65 (3H, s), 3.95 (4H, d), 6.12
(IH, s), 6.6-7.6 (8H, m) ppm.
This material was used without further purification for the following step.
2-[2-(3-Methoxyphenoxy)phenyl]-l,3-dioxolane (32.7g; 0.12 mol) was stirred in a mixture of water (95 ml) and concentrated hydrochloric acid (5 ml) at ambient 10 temperature for 19 hours. The mixture was extracted with ether (2 x 60 ml) and the combined ether extracts were washed with saturated aqueous sodium bicarbonate solution (30 ml), water (3 x 30 ml) and saturated brine (30 ml). The resulting solution was dried, filtered and 15 concentrated to give almost pure 2-(3-methoxyphenoxy)-benzaldehyde (A) (26.17g, 95.4% yield) as an oil. This material was used without purification for the following step. However, an analytical sample was prepared by chromatography using a mixture of ether and hexane as 20 eluant to give an amber oil.
-*-H n.m.r. (90 MHz) delta : 3.79 (3H, s), 6.58-7.97 (8H, m),
.49 (IH, d) ppm.
IR maxima (film) : 1691, 1599 cm-1.
A mixture of 2-(3-methoxyphenoxy)benzaldehyde (25.0g, 25 0.109 mol), methyl methylthiomethylsulphoxide (13.64g,
0.11 mol) benzyltrimethylammonium hydroxide (8.0 ml of a 30% solution in methanol) and THF (150 ml), was stirred at reflux temperature for 45 minutes. The resulting solution was evaporated to dryness, and was then chromatographed 30 using a mixture of ether and hexane as eluant to give the sulphoxide (B) (27.67g, 75.3% yield) as an amber gum.
235 0 75
1H n.m.r. (60 MHz) delta : 2.2 (3H, s), 2.55 (3H, s), 3.65
(3H, s),6.35-8.15 (9H, m) ppm.
Acetyl chloride (20 ml) was added to absolute methanol (200 ml) dropwise over 15 minutes with water bath cooling to maintain the temperature at 20-25°C. A solution of the sulphoxide (B) (27.67g; 0.083 mol) in methanol (40 ml) was added in one portion and the resulting solution was stirred at ambient temperature for 18 hours. The methanol solution was evaporated to dryness under reduced pressure to leave a brown gum (22.78g) which was dissolved in ether (200 ml) . The ether solution was washed with saturated aqueous sodium bicarbonate solution and, after filtering off a small quantity of insoluble material, the ether solution was evaporated to dryness and the residue was chromatographed using a mixture of ether and hexane as eluant to give methyl 2-(3-methoxyphenoxy)-phenylacetate (C) (15.62g, 69.3% yield) as a viscous oil.
1H n.m.r. (60 MHz) delta : 3.5 (3H, s), 3.59 (2H, s), 3.63
(3H, s), 6.35-7.32 (8H, m) ppm.
t
Boron tribromide (12.89g, 0.051 mol) was dissolved in dichloromethane (50 ml) and cooled to 0-5°C. A solution of methyl 2-(3-methoxyphenoxy)phenylacetate (7. Og; 0.026 mol) in dichloromethane (80 ml) was added dropwise, with stirring over 1 hour. After stirring at 0-5°C for 20 minutes the mixture was added dropwise, with stirring to absolute methanol (100 ml) maintaining the temperature at 0-5°C. The resulting solution was poured into water (250 ml) containing sodium bicarbonate (12g), and the resulting mixture was extracted with ether (500 mis). The organic phase was washed with water (3 x 200 ml) and saturated brine (150 ml). After drying and filtration, evaporation of the ether solution gave methyl
^
&
235 075
©
o
0
2-(3-hydroxyphenoxy)phenylacetate (D) (6.12g, 92.3% yield) as a brown gum. This material was suitable for use in subsequent steps without further purification. However, chromatography using mixtures of ether and hexane as 5 eluant gave material of higher purity as a viscous golden oil which rapidly darkened on exposure to air.
In addition, methyl 2-(3-hydroxyphenoxy)phenylacetate (D) was prepared as follows:
A mixture of 2-chlorophenylacetic acid (30g» 0.18 mol), 10 potassium carbonate (48.6g, 0.34 mol), and 3-methoxyphenol (43.5g, 0.35 mol) was heated with stirring at 140°C in the presence of a catalytic amount of copper(I) chloride.
After 3 hours, GC and TLC analysis indicated the absence of the starting acid. The reaction mixture was allowed to 15 cool (with the addition of dry DMF (5 ml) at 70°C to prevent the mixture from becoming too viscous), poured into water and acidified with concentrated hydrochloric acid. The resulting mixture was extracted with ether and the combined ether extracts were washed with water until 20 neutral. The ether extracts were dried and evaporated to afford a mixture of 3-methoxyphenol (49%) and 2—(3— methoxyphenoxy)phenylacetic acid (41%) as a brown mobile oil which was used in the next stage Without further purification.
The brown oil was refluxed in methanol (70ml)
containing concentrated sulphuric acid (2 ml) for hours. The reaction mixture was allowed to cool to room temperature and was then poured into water. The resulting mixture was extracted (x 2) with ether and the combined 30 ether extracts were washed with dilute aqueous sodium hydroxide solution, and then with water until neutral and then dried. Evaporation gave crude methyl 2-(3-methoxyphenoxy)phenylacetate (34.9g) as an orange-brown oil (86% pure by GC). The crude product was combined with 35 another batch (8.2g) which had been prepared by the same method. Repeated short-path distillation (50—120°C at 4x10-2 mbar) then afforded methyl 2-(3-methoxyphenoxy)-
" "
. 8«S»»aia8gM5^^ «■ g*.-,.
235075
phenylacetate as an oil (37.lg, 95% pure, ca. 60% yield from 2-chlorophenylacetic acid). Further amounts of product were obtained in subsequent preparations.
Methyl 2-(3-methoxyphenoxy)phenylacetate (97g, 0.36 mol) was heated with concentrated hydrobromic acid (194 ml) in acetic acid (150 ml) at 110°C for 8 hours. After standing at room temperature overnight, more concentrated hydrobromic acid (100 ml) was added and the reaction mixture was reheated to 110°C. After a further 7 hours, all of the starting material had been consumed. The reaction mixture was allowed to cool to room temperature, poured into brine and then e-xtracted with dichloromethane (x 2).The dichloromethane was evaporated to give an oil which was heated at 70°C with methanol (400 ml) and concentrated sulphuric acid (2 ml) for 2 hours. The reaction mixture was allowed to cool to room temperature, poured into brine and extracted with dichloromethane (x 2).
The combined extracts were washed with water (until neutral) and then dried, filtered and evaporated to give a brown oil (92.8g). Short-path distillation (150"C, 1x10"^ mbar) of a portion (72.8g) afforded methyl 2-(3-hydroxyphenoxy)phenylacetate (D) (41.4g, 57% yield from methyl 2-(3-methoxyphenoxy)phenylacetate) as a golden syrup.
1H n.m.r. (60 MHz) delta : 3.57 (3H, s), 3.63 (2H, s), 5.82
.82 (IH, s), 6.4-7.35 (8H, m)
ppm.
IR maxima (film) : 3408, 1713 cm-1.
To a suspension of sodium hydride (0.558g, 0.023 moles in DMF (20ml) was added dropwise a solution of methyl 2-(3-hydroxyphenoxy)phenylacetate (D) (2.0g; 0.0077 mol) in DMF (10ml) and methylformate (lOg; 0.167 mol)
-* •
235 075
After stirring for 45 minutes, water (100 mis) was added and the mixture was extracted with ether (50 mis). The aqueous layer was acidified with hydrochloric acid to pH 3-4 and the mixture was extracted with ether (2 x 40 mis). The combined ether extracts were washed with water (3 x 30 mis) and saturated brine (1 x 30 ml), and then dried. The ether was evaporated off and the residue was dissolved in DMF (20 ml), and anhydrous potassium carbonate (0.64g; 0.0046 moles) and dimethyl sulphate (0.55g; 0.0044 moles) was added. The mixture was stirred at ambient temperature for 1 hour, then water (100 ml) was added, and the mixture was extracted with ether (2 x 40 ml). The combined ether extracts were washed with water (3 x 20 ml) and saturated brine (20 ml), dried, filtered, evaporate to dryness, then chromatographed using a mixture of ether and hexane as eluant to give (E)-methyl 2-C2-(3-hydroxyphenoxy)phenyl3-3-methoxypropenoate (E) as an amber gum which, on trituration with a mixture of hexane and dichloromethane, gave a white solid, [0.7g, 30% yield from methyl 2-(3-hydroxyphenoxy)phenylacetate (D)] m.p. 115-116°C.
In addition, (E)-methyl 2-[2-(3-hydroxyphenoxy)-phenyl]-3-methoxypropenoate (E) was prepared as follows :
A solution of methyl 2-(3-hydroxyphenoxy)phenylacetate (D) (12g, 0.0465 mol) and methyl formate (55.8g, 0.93 mol) in dry DMF (35 ml) was added dropwise over 45 minutes to a stirredsuspensionof sodium hydride (6.696g of a 50% dispersionin oil, 0.1395 mol, pre-washed with 40-60 petroleum ether) in dry DMF (65 ml). The reaction mixture was stirred at room temperature for 2h hours, poured into water (200 ml), acidified to pH3 with concentrated hydrochloric acid and then extracted with ether (2 x 200ml). The combined organic extracts were washed with brine (2 x 200 ml), dried, filtered and evaporated to give a yellow oil (12.5g, 0.0433 mol).
235 075
The oil (12.5g, 0.0433mol) was dissolved in dry DMF (100 ml) and potassium carbonate (5.98g, 0.043 3 mol) was added. After stirring for 10 minutes, a solution of dimethyl sulphate (5.19g, 0.042 mol) in DMF (10 ml) was added in one portion. The resulting mixture was stirred overnight at room temperature, poured into water (2 00 ml) and extracted with ether (2 x 200 ml). The combined ether extracts were washed with brine (3 x 200 ml), dried, filtered and evaporated to give a sticky gum. Crystallisation from dichloromethane-hexane gave (E)-methyl 2-[2-(3-hydroxyphenoxy)phenyl]-3-methoxypropenoate
(E) (9.54g, 73%), m.p. 117-118°C.
1H n.m.r. (90 MHz) delta : 3.58 (3H, s), 3.75 (3H, s), 5.38
(IH, s), 6.39-7.33 (8H, m), 7.4 (IH, s) ppm.
IR maxima (nujol) : 3295, 1672, 1630 cm-1.
A mixture of (E)-methyl 2-[2-(3-hydroxyphenoxy)-phenyl]-3-methoxypropenoate (l.Og; 0.0033 mol),
benzyl bromide (0.57g? 0.0033 mol) potassium carbonate (0.8g; 0.0053 mol) and dry DMF (15 ml) was stirred at ambient temperature for 3 hours. Water (50 ml) was added and the mixture was extracted with ether (2 x 30 ml). The combined organic extracts were washed with water (2 x 20 ml) and after drying and filtration the ether solution was evaporated to dryness then chromatographed using a mixture of ether and hexane as eluant to give the title compound
(F) as a colourless gum (l.llg, 85% yield).
1H n.m.r. (90 MHz) delta : 3.55 (3H, s), 3.7 (3H, s), 4.97
(2H, s), 6.5-7.32 (13H, m), 7.44 (IH, s) ppm.
IR maxima (film) : 1710, 1638 cm~l.
i rwnfaww. it •». ?-*.»—
235 07
- no -
EXAMPLE 2
This Example illustrates the preparation of (E)-methyl 3-methoxy-2-[2-(3-phenylsulphonyloxyphenoxy)-phenyl]propenoate (Compound No. 51 of Table I).
' A mixture of (E)-methyl 2-[2-(3-hydroxyphenoxy)-phenyl]-3-methoxypropenoate (0.5; 0.00166 moles, prepared as described in Example 1), benzenesulphonylchloride (0.36g; 0.002 mol) and pyridine (10 ml), was stirred at 60-70"C for 3 hours. The mixture was cooled to 25°C,
water (60 ml) was added and the mixture was extracted with ether (2 x 30 ml). The combi-ned ether extracts were washed with water (20 ml), dilute hydrochloric acid (20 mis), water (93 x 200 ml) and saturated brine (20 ml). The ether solution was dried, filtered, concentrated and chromatographed using a mixutre of chloroform and hexane as eluant to give the title compound (0.21g, 28.7% yield) as a colourless gum.
1H n.m.r. (90 MHz) delta : 3.56 (3H, sO, 3.75 (3H, s),
6.52-7.96 (13H, m), 7.40 (IH, s) ppm.
I
EXAMPLE 3
This Example illustrates the preparation of (E)-methyl 3-methoxy-2-(2-[3-(4-nitrophenoxy)phenoxy]phenyl)-propenoate (Compound No. 133 of Table I).
A mixture of E-methyl 2-[2-(3-hydroxyphenoxy)phenyl]-3-methoxypropenoate (1.2g; 0.004 mol, prepared as described in Example 1), 4-nitrofluorobenzene (0.68g; 0.008 mol), potassium carbonate (l.lg; 0.008 mol) and DMF (15 ml) was stirred at ambient temperature for 16 hours then poured into water (80 mis) and extracted with ether (2 x 30 ml). The combined organic extracts were washed with water (3 x 25 ml) and then saturated brine (25 ml).
SSJ075
- Ill -
They were then dried, filtered, concentrated and chromatographed using a mixture of chloroform and hexane as eluant to give the title compound as an amber-coloured gum (0.93g, 55.2% yield).
LH NMR (90 MHz) delta : 3.55 (3H, s), 3.72 (3H, s), 6.67-
8.41 (12H, m), 7.44 (IH, s) ppm.
EXAMPLE 4
This Example illustrates the preparation of (E)-methyl 2- (2-[3- (4-fluorophenoxy)phenoxy]phenyl)-3-methoxypropenoate (Compound No. 124 of Table I).
A mixture of (E)-methyl 2-[2-(3-(hydroxyphenoxy)-phenylH-3-methoxypropenoate (l.Og, 0.0033 mols, prepared as described in Example 1), bis (4-fluorophenyl)iodonium bromide (2.63g; 0.0069 mol), triethylamine (0.5 ml),
copper powder (0.5g) and absolute methanol (15 ml) was heated at reflux for 6 hours. Further bis (4-fluorophenyl ) iodonium bromide (lg; 0.0069 mol) was added and the mixture was stirred at reflux temperature for a further 3 hours. After cooling and filtration, water (80 ml) was added to the filtrate and the mixture was extracted with ether (2 x 30 ml). The combined ether extracts were washed with water (3 x 15 ml) and saturated brine (15 ml). After drying and filtration the ether solution was concentrated to give the title compound as an amber gum (0.16g, 12.3% yield).
^H n.m.r. (60 MHz) delta : 3.42 (3H, s), 3.51 (3H, s), 6.35-
7.30 (12H, m), 7.35 (IH, s) ppm.
IR maxima (film) : 1710, 1641 cm~l.
EXAMPLE 5
This Example illustrates the preparation of (E)-
23 5 0 7 5
methyl 2-[2-(3-benzoyloxyphenoxy)phenyl]-3-methoxyprop-enoate (Compound No. 49 of Table I).
A mixture of (E)-methyl 2-C2-(3-hydroxyphenoxy)-phenyl]-3-methoxypropenoate (0.5g, 0.00166 mol, prepared as described in Example 1, benzoyl chloride (0.26g;
0.00185 mol), potassium carbonate (0.23g; 0.00166 mol) and DMF (10 ml) was stirred at ambient temperature for 1%
hours. Further benzoyl chloride (0.26; 0.00166 mol) and potassium carbonate (0.23g; 0.00166 mol) were added and the mixture was stirred at ambient temperature for 16 hours. Water (80 ml) was added and the mixture was extracted with ether (2 x 40 jnl). The combined ether extracts were washed with water (3 x 20 ml) and saturated brine (20 ml), then dried, filtered, concentrated and chromatographed using a mixture of ether and hexane as eluant to give a white solid. Recrystallisation from aqueous methanol gave the pure title compound (0.32g, 47.7% yield) as a white solid, m.p. 94-95°C.
1H n.m.r. (90 MHz) delta : 3.62 (3H, s); 3.74 (3H, s), 6.76-
8.38 (13H, m), 7.46 (IH, s) ppm.
1 1
IR maxima (nujol) : 1741, 1698, 1627 cm" .
EXAMPLE 6
This Example illustrates the preparation of (E,E)-methyl 2-[2-(3-[4-chlorophenylazo]-4-hydroxyphenoxy)-phenyl]-3-methoxypropenoate (Compound No. 282 of Table I).
1M Hydrochloric acid (2.5 ml) was added to 3-chloroaniline hydrochloride (6.64 ml of 0.25M aqueous solution) and the mixture was cooled to below 10"C.
Sodium nitrite (3.32 ml of 0.5M aqueous solution) was added dropwise and the resulting mixture was stirred at below 10°C for 10 minutes. The resulting solution of 3-chlor.obenzenediazonium chloride was added dropwise with
235 0
stirring to a mixture of (E)-methyl 2-[2-(4-hydroxy-phenoxy)phenyl]-3-methoxypropenoate (0.5g, 0.00166 mol, prepared by a route analogous to that described in Example 1 for the preparation of the corresponding 3-hydroxy-compound) in sodium hydroxide (16.6 ml of 0.1M aqueous solution), and acetone (30 ml). Further aqueous sodium hydroxide solution was added simultaneously to maintain the pH between 8-10 and the temperature was maintained below 10°C. After stirring for 20 minutes the mixture was extracted with ether (2 x 40 ml). The combined ether extracts were washed with water (3 x 15 ml) and saturated brine (15 ml), then dried, filtered, concentrated, and chromatographed using a mixture of ether and hexane as eluant to give an orange solid. Recrystallisation from a mixture of hexane and dichloromethane gave the pure title compound (99.3mg, 13.6% yield), m.p. 143-144°C.
EXAMPLE 7
This Example illustrates the preparation of (E)-methyl 2-[2-(3-C3-methoxyphenoxy]phenoxy)phenyl]-3-methoxypropenoate (Compound No. 129 of.Table I).
To a stirred solution of sodium (0.61g) in methanol (10 ml) was added resorcinol (4.34g) in one portion.
After stirring the resulting mixture for \ hour at room temperature, the excess methanol was removed under reduced pressure. To the resulting orange oil was added pyridine (6.6 mis), 3-bromoanisole (14.74g) and cuprous chloride (192mg). The mixture was stirred at 125°C for 66 hours. The reaction mixture was allowed to cool and was then poured into dilute hydrochloric acid and extracted with ether. The ether extracts were re-extracted with dilute aqueous sodium hydroxide and these aqueous extracts were acidified with dilute hydrochloric acid and extracted with ether. These ether extracts were washed successively with water and brine, then dried and concentrated to give 3.72g
2350
of a red oil. Bulb-to-bulb distillation of this oil (170°C oven temp./0.05 mmHg) gave 3-(3-methoxyphenoxy)-phenol (1.71g) as a thick pale yellow oil.
^■H n.m.r. delta : 3.78 (3H, s), 4.93 (1H, s) ppm.
To a stirred solution of sodium (0.18g) in methanol (4 ml) was added 3-(3-methoxyphenoxy)phenol (1.70g) in one portion. After stirring the resulting mixture for \ hour at room temperature the excess methanol was removed under reduced pressure. To the resulting orange oil was added o-bromophenylacetic acid (0.85g) and cuprous chloride (40mg), and the reaction mixture was stirred at 130°C for 1 hour. Further o-bromophenylacetic acid (0.4g) and sodium ethoxide (0.13g) were added and the mixture was stirred at 130°C for a further 3 hours, allowed to cool, then acidified with dilute hydrochloric acid and extracted with ether. The ether extracts were washed successively with water and brine, then dried and concentrated to give 3.12g of a red oil containing 2-C3-(3-methoxyphenoxy)-phenoxy]phenylacetic acid. To this crude acid (3.12g) was added methanol (40 ml) and 3 drops of concentrated i
sulphuric acid. This reaction mixture was stirred at 90°C for 1 hour, then allowed to cool, poured into water and extracted with ether. The ether extracts were washed successively with dilute aqueous sodium hydroxide, water and brine, then dried and concentrated to give 1.33g of a yellow oil. Bulb-to-bulb distillation of this oil (160°C oven temp./0.07 mmHg) gave methyl 2-[3-(3-methoxyphenoxy)phenoxy]phenylacetate [1.03g, 36% yield from 3-(3-methoxyphenoxy)phenol].
1H N.m.r. delta : 3.62 (3H, s), 3.68 (2H, s), 3.78 (3H, s)
ppm.
A mixture of methyl 2-[3-(3-methoxyphenoxy)phenoxy3-phenylacetate (l.OOg) and methyl formate (3.34 ml) in DMF
235 075
(1 ml) was added dropwise over 10 minutes to a stirred suspension of sodium hydride (0.13g) in DMF (10 mis)
cooled in ice to below 10°C (effervescence). Following the addition, the reaction mixture was stirred at room temperature for 2 hours, poured into water, acidified with dilute hydrochloric acid, and then extracted with ether. The extracts were washed with water, dried and concentrated to give a yellow oil (1.09g). Potassium carbonate (0.76g) and dimethyl sulphate (0.33g) were added successively to a stirred solution of this yellow oil in DMF (20 ml) and the resulting mixture was stirred at room temperature for 2^ hours, poured into water and then extracted with ether. The extracts were washed with water, dried, concentrated and chromatographed using a 1:1 mixture of ether and petrol as eluant to give the title compound [0.61g, 55% yield from methyl 2-[3-(3-methoxyphenoxy)-phenoxy]phenylacetate3 as a colourless viscous oil.
XH n.m.r. delta : 3.60 (3H, s), 3.75 (3H, s), 3.78 (3H,s)
6.55-6.72 (5H, m), 6.97 (IH, d), 7.10-7.30 (6H, m), 7.48 (IH, s) ppm.
I
IR maxima (nujol) 1713, 1638 cm-1.
EXAMPLE 8
This Example illustrates the preparation of (E)-methy 1 3 -metho xy-2- [2 - (3 - [pheno xymethy 1 ]phenoxy) phenyl ] -propenoate (Compound No. 21 of Table I).
(E)-methyl 3 -methoxy-2-[2- (3-methylphenoxy)phenyl] -propenoate (0.50g, prepared from 3-methylphenol and 2-bromobenzaldehyde by the method described in Example 1) and N-bromosuccinimide (0.30g) were refluxed in carbon tetrachloride (25 mis) with a trace of azobisisobutyro-nitrile (AIBN), for 4.5 hours, with further traces of
•'"W: •> ■••• '-.v.
235075
AIBN being added at intervals of 1.5 hours. The reaction was monitored by GC. After standing at room temperature overnight a further trace of AIBN was added to the reaction mixture and refluxing was continued until GC analysis showed almost complete disappearance of the starting material (1 hour). The reaction mixture was filtered through celite, washed with water and evaporated to give a pale yellow gum (0.69g). GC and NMR analysis showed that this gum consisted of (E)-methyl 2-£2-(3-bromomethylphenoxy)phenyl]-3-methoxypropenoate (80%), the corresponding dibromomethyl compound (11%) and unreacted propenoate starting material_(8%).
n.m.r. data for the major component : delta 3.61 (3H,
s), 3.77 (3H, s), 4.42 (2H, s),
6.90-7.40 (8H, m), 7.48 (IH, s), ppm.
This material was carried through without further purification.
Part of the crude material (0.42g, 80% pure), was i
stirred with phenol (0.105g) and potassium carbonate (0.077g) in DMF (20 ml), and heated to 60°C for 1 hour.
After standing overnight at room temperature the mixture was heated to 60°C for a further 1 hour, cooled, poured into water, and extracted with ethyl acetate. The organic fraction was washed with water, dried and evaporated to yield a pale yellow oil (0.42g). Attempted purification by high performance liquid chromatography, eluting with a 3:1 mixture of petrol and ethyl acetate, gave the title compound (0.13g) as a colourless gum containing as an impurity 20% of (E)-methyl 2-[2-(3-dibromomethylphenoxy)-pheny1]-3-methoxypropenoate.
^"H n.m.r. data for the title compound : delta 3.58 (3H,
3.70 (3H, s), 4.98
»i i««iniii in wpWW 1 "•
235 0 7
(2H, s), 6.88-7.36s), (13H, m), 7.46 (1H, s) ppm.
EXAMPLE 9
This Example illustrates the preparation of (E)-methyl 2-[2-(2-acetyl-5-phenoxyphenoxy)phenyl]-3-methoxy-propenoate and (E)-methyl 2-[2-(4-acetyl-3-phenoxy-phenoxy)phenyl]-3-methoxypropenoate (Compound Nos. 366 and 365 respectively of Table I).
Methyl 2-(3-phenoxyphenoxy)phenylacetate was prepared from 3-phenoxyphenol and 2-bromobenzaldehyde by the steps described in Example 1 for the preparation of methyl 2-(3-methoxyphenoxy)phenylacetate. This was the converted into (E)-methyl 3-methoxy-2-[2-(3-phenoxyphenoxy)phenyl]-propenoate C1H n.m.r (250 MHz) 3.61 (3H, s), 3.78 (3H, s), 6.68-7.35 (13H, m), 7.48 (IH, s) ppm] using sodium hydride and methyl formate, and then potassium carbonate and dimethyl sulphate, using the procedure described in Example 1 for the preparation of (E)-methyl 2-C2-(3-hydroxyphenoxy)phenyl]-3-methoxypropenoate, except that just 2 equivalents of sodium hydride were used in this case.
Powdered aluminium chloride (0.512g, 3.84 mmol) was added to a stirred solution of (E)-methyl 3-methoxy-2-C2-(3-phenoxyphenoxy)phenyl]propenoate (0.722g, 1.92 mmol) in dry dichloromethane (20 ml) at 0-5"C. A solution of acetyl chloride (0.151g, 1.92 mmol) in dry dichloromethane (3 ml) was then added dropwise over 10 minutes and the resulting mixture was stirred overnight, being allowed to warm to ambient temperature. The reaction mixture was diluted with ether (125 ml) and washed with 2N hydrochloric acid (x 2), 10% aqueous sodium carbonate solution and finally with water. The residue obtained after removal of the solent was purified by flash
■
235 07!
chromatography using a mixture of ether and petrol as eluant to give an approximately 3:1 mixture of the two title compounds (individual identities not assigned) as a colourless gum (0.424g). Part of this gum (0.400g) was separated by high performance liquid chromatography on silica gel using a 70:25:5 mixture of hexane:dichloromethane:methyl t-butyl ether as eluant to give (i) Regioisomer A (0.179g), eluted first, major component of the mixture, as a white crystalline solid, m.p. 90-92°C.
XH n.m.r. (250 MHz) : delta 2,52 (3H, s), 3.56 (3H, s),
3.72 (3H, s), 6.48 (IH, d), 6.64 (IH, q), 6.9-7.4 (9H, m), 7.43 (IH, s), 7.84 (IH, d) ppm.
and (ii) Regioisomer B (0.061g, containing ca. 5% of regioisomer A), eluted second, minor component of the mixture, as a white crystalline solid, m.p. 82-85°C.
1H n.m.r (250 MHz) : delta 2.51 (3H, s), 3.60 (3H, s), 3.75
(3H, s), 6.45 (IH, d), 6.59 (IH, q), 20 6.9-7.4 (9H, m), 7.48 (IH, s), 7.82
(IH, d) ppm.
EXAMPLE 10
This Example illustrates the preparation of (E)-methyl 3-methoxy-2-C2-(3-pyrimidin-2-yloxyphenoxy)phenyl]-propenoate (Compound No. 22 of Table II).
A mixture of (E)-Methyl 2-[2-(3-hydroxyphenoxy)-phenyl]-3-methoxypropenoate (0.5g, prepared as described in Example 1), potassium carbonate (0.46g), 2-chloro-pyrimidine (0.23g) and cuprous chloride (O.Olg) in DMF (15 ml) was heated under reflux for 4 hours. After cooling, the mixture was poured into water and filtered. The
__ , ,,l|Mff»irit7iMt^Vt^>!^^w^gJ'^-ltlw^ll*\yriflHffffllfiWfiii|- iT-i'iT»nwii<iri.iii.irtii iin*niiit>urnnTrmTi"'iti" " • /"'W.?
235 07
filtrate was extracted with ether. The combined ether extracts were washed successively with water and brine, dried, concentrated and chromatographed using a mixture of ether and hexane as eluant to qive the title compound as a gum (0.26g, 41% yield).
IR (film) : 1707, 1633 cm-1.
lH n.m.r. (90 MHz) : delta 3.-54 (3H, s), 3.68 (3H, s),
6.74-7.34 (9H, m), 7.38 (IH, s), 8.28 (2H, d) ppm.
EXAMPLE 11
This Example describes the preparation of (E)-methyl
3-methoxy-2-C 2- (3-phenoxyphenylthio)phenyl]propenoate (Compound No. 446 of Table III) :
ch3o2c'
/°CH3
^ Cx h
2-Mercaptophenylacetic acid was prepared by a method described in the chemical literature (see D. Papa et al, 15 J.Org.Chem., 1949, 24, 723, R.H. Glauert and F.G. Mann, J.Chem.Soc., 1952, 2127 and references therein). 2-Mer-captophenylacetic acid (1.68g) was added to a stirred solution of sodium hydroxide (0.8g) in methanol (10 ml), (compare D.C. Atkinson et al, J.Med.Chem., 1983, 26, 20 1361). The resulting orange solution was stirred at room temperature for 90 minutes then concentrated under reduced pressure, removing the final residues of methanol by
o
G
235075
azeotroping with toluene, to leave a yellow solid.
Cuprous chloride (0.2g) and a solution of 3-phenoxybromo-benzene (2.49g, prepared from 3-phenoxyphenol and tri-phenylphosphine dibromide by the method described by J.P. Schaefer et al, Org.Synth., Coll. Vol.5, 142) in DMF (10 ml) were added successively to a stirred solution of this yellow solid in DMF (20 ml). The resulting mixture was heated at 95°C for 1% hours, at 125°C for 2 hours, and then at reflux for a further 2 hours. After cooling, the reaction mixture was poured into aqueous sodium hydroxide then washed with ether (x 3). The aqueous solution was acidified with concentrated hydrochloric acid and extracted with ether (x 3). These extracts were washed with water, dried and concentrated to give a purple oil (2.2g) consisting mainly of 2-(3-phenoxyphenylthio)-phenylacetic acid. A solution of this oil in methanol (20 ml) was added to acidic methanol [prepared by carefully treating methanol (30 ml) with acetyl chloride (3.5 ml)3 and the resulting mixture was stirred for 90 minutes at room temperature. The reaction mixture was concentrated and the residue was partitioned between ether and aqueous sodium bicarbonate. The organic layer was separated and washed successively with aqueous sodium hydroxide (x 2) and water (x 3) then dried and concentrated to give crude methyl 2-(3-phenoxyphenylthio)phenylacetate (2.06g) as a purple oil.
IR maximum (film) : 1740 cm"1, 94% pure by GC.
The crude methyl 2-(3-phenoxyphenylthio)phenylacetate was converted into the title compound in a yield of 53% by the 2 steps described in Example 7 for the conversion of methyl 2-[3-(3-methoxyphenoxy)phenoxy]phenylacetate into (E)-methy1 2-[2-(3-[3-methoxyphenoxy]phenoxy)pheny1]-3-methoxypropenoate, that is by formulation with methyl formate and sodium hydride, followed by O-methylation with
o
235075 -
dimethyl sulphate and potassium carbonate. The product was an orange gum, 98% pure by GC, which crystallised on standing.
m.p. 48-51.5°C.
IR maxima (film) : 1710 and 1632 cm"'-.
XH n.m.r. (270 MHz) : delta 3..62 (3H, s), 3.73 (3H, s),
6.78 (IH, dd), 6.88-7.00 (4H, m), 7.05-7.36 (7H, m) , 7.42 (IH, d), 7.48 (1H, s) ppm.
EXAMPLE 12
This example illustrates the preparation of (E)-methyl
2-[2-(3-pyrimidin-2-yloxyphenylthio)phenyl]-3-methoxypropenoate (compound No 2 2 of Table IV) .
A mixture of the sodium salt of 3-methoxythiophenol [prepared by treatment of 3-methoxythiophenol (2.8g) with 15 sodium hydroxide (0.8g) in methanol (20 ml) followed by evaporation to dryness], 2-bromophenylacetic acid (4.3g) and copper(I) chloride (0.4g) in dry DMF (25 ml) was heated overnight at reflux. The reaction mixture was cooled, poured into water and acidified with dilute 20 hydrochloric acid. The aqueous mixture was extracted with ether (x 3) and the combined ether extracts were extracted in turn with dilute sodium hydroxide solution (x 2). The combined aqueous hydroxide extracts were acidified with dilute hydrochloric acid and re-extracted with ether (x 2 5 3). These combined ether extracts were washed with water (x 3), dried and evaporated to give an orange oil (3.5g, 96.8% by GC) . The oil was treated with acidic methanol overnight at room temperature. Normal work-up afforded methyl 2-(3-methoxyphenylthio)phenylacetate (2.9g, 91% by 30 GC) as a yellow liquid which was used in the next stage without further purification.
I
23507
1H n.m.r. delta : 3.64 (3H, s), 3.74 (3H, s), 3.86 (2H, s)
ppm.
IR maxima (film): 1739 cm"1
Methyl 2-(3-methoxyphenylthio)phenylacetate (0.86g) and pyridinium hydrochloride (2.08g, excess) were heated together at 200®C under an atmosphere of nitrogen. After 3 hours, the reaction mixture was cooled and then partitioned between dilute hydrochloric acid and ethyl acetate. The acidic aqueous layer was extracted further (x 2) with ethyl acetate and the combined organic layers were extracted with dilute sodium hydroxide (x 3). The combined basic layers were acidified with concentrated hydrochloric acid and then extracted (x 3) with ethyl acetate. These organic extracts were combined and washed with water (x 3), dried and evaporated to give an off-white solid (0.64g). The off-white solid was treated with methanolic hydrogen chloride to afford after standard work-up conditions methyl 2-(3-hydroxyphenyl-thio)phenylacetate (0.44g) as a red oil (90.5% pure by GC) which was used in the next stage without further purification. i
IR max. : 3384, 1738 cm~l.
A solution of crude methyl 2-(3-hydroxyphenylthio) phenylacetate (0.44g) and methyl formate (1.92 ml) in dry DMF (2 ml) was added dropwise to a stirred suspension of sodium hydride (0.21g, 55% dispersion in oil, pre-washed with petroleum ether) in dry DMF (3 ml) at 0-5°C. After a total of 15 minutes, the temperature was allowed to rise to room temperature. After 2% hours, the reaction mixture was poured into water, acidified with concentrated hydrochloric acid, and then extracted with ether (x 3). The combined ether extracts were washed with water (x 3),
235 075
dried and evaporated to give a red gum (0.49g). The red gum was dissolved in DMF (5 ml) and cooled to 0°C. Potassium carbonate (0.132g) was added followed by the dropwise addition of a solution of dimethyl sulphate (O.lllg) in DMF. After stirring for 4^ hours, the reaction mixture was poured into water, and extracted with ether (x 3). The combined ether extracts were washed with water (x 3 ), dried and evaporated to give methyl 2-[2-(3-hydroxyphenylthio)phenyl]-3-methoxypropenoate (0.45g) as a red gum;
IR maxima 3240, 1709, 1665 cm-1; M+316
1H n.m.r. delta : 3.65 (3H, s); 3.76 (3H, s), 7.47 (IH, s)
ppm.
Crude (E)-methyl 2-[2-(3-hydroxyphenylthio)phenyl]-3-methoxypropenoate (0.4g) was treated with 2-chloro-pyrimidine (0.45g) and potassium carbonate (0.17g) in dry DMF (10 ml) at 80-90°C under nitrogen. After 4\ hours, GC analysis indicated complete formation of a single product.
The reaction mixture was cooled, poured into water and then extracted with ether (x 4). The'combined yellow ether extracts were washed with water (x 2), dried and evaporated to give an orange gum (0.39g). Chromatography (eluant ether) afforded the title compound as an orange viscous gum (0.3 4g);
IR maxima 1706, 1632cm-l;
1H n.m.r. delta : 3.64 (3H, s),3.75 (3H, s); 6.97-7.06 (3H,
m), 7.08-7.12 (IH, d), 7.25-7.35 (4H, m) , 7.46-7.48 7.48 (IH, d), 7.49 (IH, s); 8.53-8.56 (2H, d) ppm.
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EXAMPLE 13
This Example illustrates the preparation of (E)-methyl 2-[2-(3-phenylthiophenoxy)phenyl]-3-methoxy-propenoate (Compound No 1 of Table I).
3-Hydroxydiphenylsulphide (2.02g; O.Olmol), (E)-5 methyl 2-(2-bromophenyl)-3-methoxypropenoate (1.35g; 0.005 mol, prepared from methyl o-bromophenyl acetate, methyl formate and sodium hydride then potassium carbonate and dimethyl sulphate in the 2 steps described in Example 7 for a similar transformation), anhydrous potassium 10 carbonate (0.69g; 0.005 mol),- and a catalytic quantity of cuprous chloride, were mixed and heated to 17 58C with stirring. After 10 hours, the mixture was cooled to ambient temperature and dissolved in DMF (50 ml). The solution thus obtained was poured into water (100 ml) and 15 the resultant emulsion was extracted with ether (2 x 100
ml). The combined ether extracts were washed sequentially with water (2 x 100 ml), 2M sodium hydroxide solution (2 x 100 ml), and water (2 x 100 ml). The resulting ether solution was dried, filtered, and evaporated to dryness
under reduced pressure. Chromatography using hexane and i
chloroform as eluants gave the title compound (0.83g) as a viscous oil.
1H n.m.r. (60 MHz) delta : 3.52 (3H, s), 3.64 (3H, s), 6.5-
7.3 (13H, m), 7.42 (IH, s) ppm.
EXAMPLE 14
This Example illustrates the preparation of (E)-
Methyl 2-[2-(3-phenylthiophenoxy)phenyl]-3-methoxypropenoate-S,S-dioxide (compound No 3 of Table I).
3-Hydroxydiphenylsulphone (3-66g; 0.0156 mol), (E)-methyl 2-(2-bromophenyl)-3-methoxypropenoate (1.5g; 0.0055 30 mol, prepared as described in Example 13), and anhydrous potassium carbonate (l.lg; 0.0079 mol), were mixed with
23 5 0
catalytic quantities of cuprous chloride and copper bronze. The mixture was heated to 170"C under nitrogen for ten hours. After the melt had cooled to ambient temperature, the residue was dissolved in DMF (50 ml). The resultant solution was diluted with ether (100 ml), and the solution was filtered to remove inorganic salts. The solution was washed sequentially with water (100 ml), 2M sodium hydroxide solution (2 x 100 ml), water (100 ml), and saturated brine (100 ml).. The ether solution was dried, filtered, and evaporated to dryness under reduced pressure. Chromatography of the residue using hexane and chloroform as eluants gave the title compound (0.66g).
^■H n.m.r. (60 MHz) delta : 3.46 (3H, s), 3.57 (3H, s),
6.6-8.0 (14H, m) ppm.
EXAMPLE 15
This Example illustrates the preparation of (E)-methyl-2-[2-(3-anilinophenoxy)phenyl]-3-methoxypropenoate (Compound No. 4 of Table I).
3-Hydroxydiphenylamine (1.365g; 0.0074 mol), (E)-methyl 2-(2-bromophenyl)-3-methoxyprop'enoate (lg; 0.0037 mol, prepared as described in Example 13), and anhydrous potassium carbonate (0.517g; 0.0037 mol), were combined with catalytic quantities of cuprous chloride and copper bronze. The mixture was heated to 170°C for nine hours, and then cooled and dissolved in DMF (20 ml). This solution was then partitioned between ether and water. The ether layer was washed with water (2 x 100 ml), then with 1M sodium hydroxide solution (2 x 100 ml). The ether solution was then dried, filtered, and evaporated to dryness under reduced pressure. The residual gum was purified by chromatography using hexane and dichloromethane as eluants, to give the title compound (0.40g) .
235 07 5
XH n.m.r. (60 MHz) delta : 3.57 (3H, s), 3.67 (3H, s) ,
.75 (1H, brs), 6.3-7.4 (13H, m) , 7.44 (1H, s) ppm.
EXAMPLE 16
This Example illustrates the preparation of (E)-methyl 2-[2-(3-N-methylanilinophenoxy)phenyl]-3-methoxypropenoate (Compound No 5 of Table I).
Sodium hydride (300mg of an 80% dispersion in oil? 0.01 mol) was washed oil-free with hexane (2 x 50 ml). The hydride was then suspended in dry DMF (10 ml). To this suspension was added a solution of (E)-methyl 2-[2-(3-anilinophenoxy)phenyl]-3-methoxypropenoate (290 mg, prepared as described in Example 15) in dry DMF (10 ml), at such a rate as to maintain a steady effervescence.
When effervescence had ceased, the mixture was stirred for a further 15 minutes and then iodomethane (2 ml; large excess) was added over a period of 5 minutes. Stirring was continued for a further 30 minutes before the suspension was cautiously diluted with water (50 ml). The aqueous emulsion was extracted with ether (2 x 50 ml). These ether extracts were washed with water (2 x 50 ml), dried, filtered, and evaporated to dryness under reduced pressure to give the title compound as a viscous oil (211 mg).
XH NMR (60 MHz) delta : 3.20 (3H, s), 3.54 (3H, s), 3.65
(3H, s), 6.3-7.4 (13H, m), 7.44 (IH, s) ppm.
EXAMPLE 17
This Example illustrates the preparation of (E)-methyl 3-methoxy-2-(2-[3 -(alpha-hydroxybenzyl)phenoxy3-phenyl)propenoate (Compound No. 380 of Table I).
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3-Hydroxybenzyl alcohol (31.Og) was ground finely and stirred with potassium carbonate (34.6g), 2-bromophenyl-acetic acid (26.9g) and cuprous chloride (large spatula full) under nitrogen. The mixture was warmed to 140°C, 5 and stirred vigorously for 3\ hours. DMF (60 ml) was then added to the stirred melt and the solution was allowed to cool, poured into water and acidified with dilute hydrochloric acid. The aqueous layer was extracted with ether, and the ether extracts were washed with water, 10 dried and evaporated to give 2-(3-hydroxymethylphenoxy)-phenylacetic acid as a brown oil (42.03g) which was used without further purification."
The crude acid (41.Og) was refluxed in methanol (600 ml) containing concentrated sulphuric acid (2.5 ml), for 15 3.5 hours. After evaporation of the methanol, the residue was dissolved in ethyl acetate, washed with dilute aqueous sodium hydroxide and then water, dried and evaporated to yield a brown oil (26.31g). 1.31g was purified by HPLC (eluant 1:1, ethyl acetate:hexane) to give pure methyl 2-20 (3-hydroxymethylphenoxy)phenylacetate as a pale yellow oil.
\
n.m.r. (400 MHz) delta: 2.12(1H, s), 3.60 (3H, s), 3.69
(3H, s), 4.62 (2H, s), 6.95 (IH, s), 6.85-6.90 (2H, t), 25 7.04-7.14 (2H, m), 7.21-7.32
(3H, m) ppm.
IR maxima (film): 3450, 1742 cm-1.
A mixture of the crude methyl 2-(3-hydroxymethylphenoxy) phenyl acetate (25.0g) and methyl formate (56 ml) 30 in dry DMF (50 ml) was added dropwise to sodium hydride
(7.35g of a 60% dispersion in oil, washed with hexane) in dry DMF (100 ml) over 30 minutes at 5°C. After stirring at 5°C for another 30 minutes, the mixture was allowed to
235 07 5
warm to room temperature over several hours and then stood overnight. The reaction mixture was then poured into water and extracted with ether. The aqueous layer was then acidified with dilute hydrochloric acid and extracted with ether. The ether extracts were dried and evaporated to give crude methyl 3-hydroxy-2-(2-[3-hydroxymethylphenoxy]-phenylpropenoate as an orange oil (32.19g). The crude methyl ester (32.10g) was stirred in DMF (80 ml) at 5-10°C with potassium carbonate (25.4g) and a solution of dimethyl sulphate (11.6g) in DMF (20 ml) was added dropwise over 10 minutes. The mixture was allowed to warm to room temperature over a few hours and then stood overnight. The reaction mixture was poured into water, acidified with dilute hydrochloric acid and extracted with ether. The ether extracts were washed with water, dried and evaporated to give an orange brown oil (14.38g). Purification by HPLC yielded (E)-methyl 3-methoxy-2-(2-[3-hydroxymethylphenoxy]phenyl)propenoate as a slightly pinkish crystalline solid (7.8g).
1H n.m.r. (270 MHz) delta : 2.55 (IH, s), 3.58 (3H, s) ,
3.74 (3H, s), 4.55 (2H, s), 6.8-7.28 (8H, m), 7.44 (IH, s) ppm.
IR maxima (nujol): 3515, 1705, 1625 cm~l.
Part of this alcohol (0.314g) was stirred in dry methylene chloride (5 ml) and pyridinium dichromate (0.564g) was added, and the mixture was stirred for 4 hours at room temperature. The mixture was then filtered and the precipitate washed with ether. The combined methylene chloride and ether washings were evaporated to give (E)-methyl 3-methoxy-2-(2-[3-formylphenoxy]phenyl)-propenoate as a brown oil (0.309g).
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1H n.m.r. (270 MHz) delta : 3.59 (3h, s), 3.65 (3H, s),
6.98 (IH, d), 7.17-7.36 (4H,
m), 7.40-7.47 ( 3H, m), 7.47
(IH, s), 7.55 (IH, d) ppm.
IR maxima (film): 1710, 1640 cm"-'-.
(E)-Me thyl 3-methoxy-2-(2-[3-formylphenoxy]pheny1)-propenoate (0.50g) was stirred in dry THF (20 ml) at -20°C under nitrogen. Phenylmagnesium bromide (0.53 ml of a 3M solution in ether) as a dilute solution in dry THF (5 ml) was added slowly dropwise. After completion of the addition the reaction was stirred at -20"C for 3 0 minutes and then slowly warmed to room temperature over 1 hour, and then stood overnight. The mixture was then cooled to 5°C, water was added, and the resulting mixture was extracted with ethyl acetate. After washing with brine and drying, the ethyl acetate solution was evaporated to give a yellow oil. This was purified by HPLC (eluant 2:1, hexane:ether) to give the title compound as a colourless oil (0.340g).
XH n.m.r. (400MHz) delta : 2.30 (IH, d) , 3.57 (3H, s) ,
3.72(3H, s), 5.78 (IH, d), 6.82 (1H, d), 6.91 (IH, d), 7.02-7.08 (2H, m), 7.10-7.16 (IH, m), 7.20-7.38 (8H, m), 7.45 (IH, s) ppm.
IR maxima (film): 3460, 1715, 1635 cm-1.
EXAMPLE 18
This Example illustrates the preparation of (E)-methyl 3-methoxy-2-(2-C 3-(2-pyridyloxyme thyl)phenoxy]-phenyl)propenoate, (compound No. 6 of Table II).
Ml-"- • . ■ • , - T '■■J' - * .c. . . .
23507
Silver carbonate (0.2 8g) was added to (E)-methyl 3-methoxy-2-(2-C3-bromomethylphenoxy]phenyl)propenoate (0.75g, 70% pure, prepared by the method described in Example 8) and 2-pyridone (0.19g) in hexane. The mixture was refluxed and excluded from light by wrapping with foil, for 3 hours, and then stood overnight. The hexane was evaporated and the residue was taken up in methylene chloride and filtered through celite. The filtrate was washed with aqueous sodium bicarbonate and then water, dried and evaporated to yield an orange gum (0.72g).
This was purified by HPLC (eluant 1:1, ether .-hexane) to give the title compound as a_ colourless gum (0.188g).
1H n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.76 (3H, s),
.32 (2H, s), 6.78 (IH, d), 6.84-6.96 (3H, m), 7.04-7.16 (3H, m), 7.21-7.31 (3H, m), 7.48 (IH,s), 7.52-7.60 (IH, m), 8.15 (IH, d) ppm.
IR maxima (film) : 1715, 1670, 1645, 1600 cm"1.
EXAMPLE 19
This Example illustrates the preparation of (E)-methyl 3-methoxy-2-(2- [3-pyrimidin-2-yloxymethylphenoxy~|-phenyl)propenoate (Compound No 85 from Table II).
(E)-Methyl 3-methoxy-2-(2-[3-hydroxymethylphenoxy]-phenyl)propenoate (0.5g, prepared as described in Example 17) in dry DMF (a few ml) was added to sodium hydride (0.072g of 60% dispersion in oil, washed with hexane) stirred in dry DMF (10 ml), at room temperature. After completion of the addition, the mixture was stirred for 5 minutes, and then 2-chloropyrimidine (0.92g) was added, and then stood overnight. It was then poured into water, acidified and extracted with ether. The ether extracts
!.? ,, ..
ill IN ''
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were dried and evaporated to give a yellow oil (0.95g). This was purified by HPLC (eluant 1:1, ethyl acetate : hexane) to give the pure title compound (0.104g), as an oil.
XH n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.75 (3H, s),
.39 (2H, s), 6.86-6.96 (3H, m), 7.03-7.31 (6H, m), 7.49 (IH, s), 8.50 (2H, d) ppm.
IR maxima (film): 1713, 1640 cm-1.
EXAMPLE 20
This Example illustrates the preparation of (E,E)-
and (E, 55)-methyl 3-methoxy-2-(2-[3-(4-nitrostyryl)-phenoxy]phenyl)propenoate (Compound mixture No. 403 of Table I).
Dimethyl phosphite (1.39g) in dry DMF (5 ml) was 15 added dropwise to a stirred suspension of sodium hydride (0.61g of a 50% dispersion in oil, washed with hexane) in dry DMF (10 ml), at 20°C. After completion of the addition, and stirring for a further $0 minutes, (E)-methyl 3-methoxy-2- (2-[3-bromomethylphenoxy]phenyl) -20 propenoate (7.0g of 70% pure material, prepared as described in Example 8) was added dropwise. The reaction mixture stood for 6 0 hours, and was then heated to 55°C for 10 hours, and then poured into water and extracted with ethyl acetate. The extract was dried and evaporated 25 to give a viscous yellow gum, which was purified by flash chromatography (eluant 5% methanol in ethyl acetate) to give the phosphonate (E)-methyl 3-methoxy-2-[3-(dimethyl-phosphonomethyl)phenoxy]phenylpropenoate as a nearly colourless oil (1.50g).
1H n.m.r. (400 MHz) delta : 3.13 (2H, d), 3.62 (3H, s) ,
3.66 (3H, s), 3.68 (3H, s)
2 35
3.78 (3H, s), 6.92 (2H, d), 7.13 (1H, t), m), 7.48 (1H,
6.85 (IH, d),
7.00 (IH, d),
7.20-7.31 (4H, ) ppm.
IR maxima (film): 1715, 1645 cm"1.
This phosphonate (0.61g) in dry DME (5 ml) was added dropwise to sodium hydride (0.072g of a 50% dispersion in oil, washed with hexane) stirred in dry DME (10 ml) at 5°C under nitrogen. After completion of the addition, the 10 reaction mixture was warmed to room temperature and stirred for 15 minutes. 4-Nitrobenzaldehyde (0.227g) in dry DME (5 ml) was slowly added dropwise to the reaction mixture which was then stirred overnight at room temperature. Water was then added and the mixture was 15 extracted with ether. The ether layer was dried and evaporated to give a viscous yellow oil, which was purified by HPLC (eluent 3:1, hexane: ethyl acetate) to give the title compound as a 5:1 mixture of (20:(E)-stilbene isomers (yellow gum, 0.20g).
n.m.r. (270 MHz) delta : [data for (Z^)-isomer] 3.57
(3H, s), 3.74 (3H, s), 6.58 (IH, d), 6.72 (IH, d), 6.72-6.98 (3H, m), 7.05-7.36 (7H, m), 7.45(1H, s) 8.06 (2H, d) 2 5 ppm.
This mixture could be isomerised to an 85:15 (E)s(Z)-stilbene isomer mixture by heating uner reflux with a trace of iodine in toluene.
n.m.r. (400 MHz) delta (data for (E)-isomer) : 3.62 30 (3H, s), 3.78
(3H, s),
235 0
6.92-7.35 (lOH, m), 7.49 (1H, s) 7.61 (2H, d) 8.22 (2H, d) ppm.
EXAMPLE 21
This Example illustrates'the preparation of (E)-methyl 3-methoxy-2-(2-[3-benzoyloxymethylphenoxy]phenyl)-propenoate (Compound No. 398 of Table I).
(E)-Methyl 3-methoxy-2-(2-[3-bromomethylphenoxy]-phenyl)propenoate (0.5g of 75S pure material, prepared as described in Example 8), benzoic acid (0.13g) and potassium carbonate (0.076g) were stirred in dry DMF at room temperature overnight. Water was then added and the mixture was extracted with dilute aqueous bicarbonate, dried and evaporated to give a yellow viscous oil (0.49g) which was purified by HPLC (eluent 5:2, hexane:ethyl acetate) to give the title compound (0.120g).
n.m.r. (400 MHz) delta : 3.60 (3H, s), 3.75 (3H, s),
.31 (2H, s), 6.93 (IH, d),
6.96 (IH, d), 7.06 (IH, s), 7.12(IH, d), 7.16 (IH, d),
7.44 (2H, t), 7.25-7.32 (2H,
m), 7.47 (1H, s), 7.55 (IH,
d), 8.05 (2H, d) ppm.
EXAMPLE 22
This Example illustrates the preparation of (E)-methyl 3-methoxy-2-(2-[3-(triphenylphosphoniomethy1)-phenoxy]phenyl)propenoate bromide salt (Compound No. 404 of Table I).
nt^f^v^fa$»wtr,v?wl*^s*y'^p<rv-7,'i
-..-r,v« ,-i'Vf.-^.
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(E)-Methy1 3-me thoxy-2-(2-[3-bromome thy1phenoxy]-phenyl)propenoate (4.58g of 70% pure material, prepared as described in Example 8) and triphenylphosphine (2.33g)
> were stirred in dry THF (40 ml) at room temperature, for 4 5 hours, and then stood overnight. The solvent was evaporated to give a sticky residue which was triturated with ether/ethyl acetate to give the title compound as a yellow-white solid (4.38g), m.p. 176-177°C.
>
■"■H n.m.r. (270 MHz) delta : 3.'56 (3H, s), 3.74 (3H, s), 10 5.28 (2H, d), 6.48 (IH, s),
6.62 (IH, d), 6.77 (IH, d), 6,97 (IH, d), 7.04 (IH, t), 7.10-7.28 (3H, m), 7.40 (IH, s) 7.54-7.80 (15H, m) ppm.
EXAMPLE 23
This example illustrates the preparation of (E,E)-
methy1 3-methoxy-2-(2-[3-styryIphenoxy]pheny1)propenoate (Compound No. 18 of Table I).
(E)-Methyl 3-methoxy-2-(2-[3-(triphenylphosphonio-methyl)phenoxy]phenylJpropenoate bromide salt (l.Og, 20 prepared as described in Example 22) in dry DMF (5 ml) was added dropwise to sodium hydride [0.075g of a 50% dispersion in oil, washed with hexane] in dry DMF (5 ml) to give an orange solution. After completion of hydrogen evolution (2 hours), benzaldehyde (0.66g) in dry DMF (5 25 ml) was added and the reaction mixture was stirred at room temperature for 20 hours and then heated to 60°C for 2 hours. Water was then added and the mixture was extracted with ethyl acetate. The organic extract was dried and evaporated to give a yellow oil (1.3g) which was purified 30 by HPLC (eluent THF: hexane, Is4) to give a 1:1 mixture of the title compound and the corresponding (Z^)-styryl isomer (0.362g).
235 075
This (£):(E) mixture was isomerised to the (E)-isomer only by refluxing in toluene with a crystal of iodine for a few hours to give the (E)-isomer as a colourless gum.
n.m.r. (270 MHz) delta : 3.64 (3H, s), 3.77 (3H, s),
6.88(1H, d), 6.96-7.40 (10H, m), 7.49(IH, s), 7.48 (2H, m) ppm.
IR maxima (film) : 1710, 1640"cm-1.
EXAMPLE 24
This Example illustrates the preparation of (E)-methyl 3-methoxy-2-(2-[ 3-phenoxycarbonylphenoxy]pheny1)-propenoate (Compound No. 50 of Table I).
To (E)-methyl 3-methoxy-2-(2-[3-hydroxymethyl-phenoxy]phenyl)propenoate (2.43g, prepared as described in Example 17) stirred in acetone (100 ml) at 5-108C, was added chromic acid [made by dissolving chromium trioxide (6.5g) in 18.5 ml water containing 5.5 ml of concentrated sulphuric acid] until a reddish brown colour persisted, and GC indicated the disappearance of all the starting
I
alcohol. The mixture was then poured into water and extracted with ether. The ether extracts were washed with water, dried and evaporated to give (E)-methyl 3-methoxy-2-(2-[3-carboxyphenoxy]phenyl)propenoate as a pale yellow oil (2.495g).
n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.76 (3H, s),
6.95 (IH, d), 7.14-7.40 (5H, m), 7.50 (IH, s), 7.66 (IH, s), 7.78 (IH, d), 9.35 (IH, br s) ppm.
IR maxima (film): 3500-2500, 1725, 1640 cm-1.
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The carboxylic acid from the previous stage (0.33g) stirred in dry THF (10 ml) was treated with oxalyl chloride (0.11 ml) and one drop of dry DMF. The reaction mixture was stirred for 45 minutes, stood overnight and then evaporated to give crude (E)-methyl 3-methoxy-2-(2-C3-chlorocarbonylphenoxy]phenyl)propenoate as an orange-yellow oil.
IR maxima (film): 1760, 1715, 1640 cm-1.
To the acid chloride from the previous stage in dry THF (15 ml) was added a mixture of phenol (0.090g) and triethylamine (0.096g) in dry-THF (5 ml). The reaction mixture was stirred at room temperature for 1.5 hours and then poured into water and extracted with ether. The ether extracts were washed with dilute sodium hydroxide and then water, and were then dried and evaporated to give the title compound (136mg) as an orange oil.
^H n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.77 (3H, s),
6.94(1H, d), 7.14 (2H, t), 7.23-7.38(3H, m), 7.47 (IH, s), 7.61 (IH, t), 7.72 (IH, d)
I
ppm.
IR maxima (film) : 1755, 1710, 1640 cm-1.
EXAMPLE 25
This Example illustrates the preparation of (E)-methyl 2-[2-(3-[6-chloropyrimidin-4-yloxy3phenoxy)phenyl]-3-methoxypropenoate (Compound No. 89 of Table II).
Potassium carbonate (0.46g), cuprous chloride (0.027g) and 4,6-dichloropyrimidine (0.41g) were added successively to a stirred solution of (E)—methyl 2-[2-(3-hydroxyphenoxy)phenyl]-3-methoxypropenoate (l.Og, prepared as described in Example 1) in DMF (10 ml) and the
III—Tirr—■ >r ' '••A' Oil -*t •, . ^ ,
235 075
resulting mixture was stirred for 10 hours at room temperature. The mixture was diluted with water and . extracted with ether. The extracts were washed
! successively with aqueous sodium bicarbonate and water,
dried, concentrated and chromatographed using etherthexane (1:1) as eluant to give the title compound (0.39g, 28% yield) as a colourless oil.
)
■lH n.m.r. (270 MHz) delta : 3.60 .(3H, s), 3.76 (3H, s),
6.74 (IH, t), 6.81 (IH, dd), 10 . 6.90 (2H, m), 7.03 (IH, m),
7.17 (IH, t), 7.26-7.36 (3H, m), 7.49 (IH, s), 8.59 (IH, s) ppm.
EXAMPLE 26
This Example illustrates the preparation of (E)-15 methyl 3-methoxy-2~[2-(3-pyrimidin-4-yloxyphenoxy)phenyl]-propenoate (Compound No. 92 of Table II).
A solution of sodium hypophosphite (0.27g) in water . (5 ml) was added dropwise with stirring to a mixture of
(E) -methyl 2- [2- (3-C6-chloropyrimidin-4-yl'oxy]phenoxy)-20 phenyl]-3-methoxypropenoate (0.4g, prepared as described in Example 25), potassium carbonate (0.2g) and 5% palladium on carbon (0.08g) in THF (4 ml). The resulting mixture was stirred at room temperature for 2 hours, then filtered through 'Hyflo', rinsing with ethyl acetate and 25 water. The combined filtrate and washings were separated into aqueous and organic layers. The latter was dried, concentrated and chromatographed using a 1:1 mixture of ether and hexane as eluant to give the title compound (0.19g, 52% yield) as a colourless oil.
^H n.m.r. (270 MHz) delta : 3.61 (3H, s), 3.75 (3H, s),
6.75 (IH, t), 7.48 (IH, s),
ri v.w ^0" ■"f" •
""""witt
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8.56 (1H, d), 8.76 (1H, s)
ppm.
EXAMPLE 27
This Example illustrates the preparation of (E)-methy1 3-methoxy-2-[2-(3-C3-nitrophenoxy Jphenoxy)phenyl]-propenoate (Compound No. 132 of Table I).
A mixture of 3-(3-nitrophenoxyJphenol (1.7g), (E)-methyl 2-(2-bromophenyl)-3-methoxypropenoate (2.0g, prepared as described in Example 13), potassium carbonate (l.Og) and cuprous chloride (l.Og) was stirred at 170-180°C for 5 hours then allowed to cool. The mixture was diluted with water and extracted with ether. The extracts were washed successively with aqueous sodium hydroxide and brine, then dried and concentrated to give a brown oil (3.12g). Chromatography using varying proportions of ether (up to 20%) in hexane as eluant gave the title compound (1.06g, 34% yield) as a yellow oil.
^H n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.76 (3H, s),
6.66-6.83 (3H, m), 7.02 (1H, d), 7.18 (;1H, d), 7.22-7.38 (3H, m), 7.45-7.52 (1H, m), 7.49 (IH, s), 7.78 (1H, m), 7.92-7.97 (IH, m) ppm.
EXAMPLE 28
This Example illustrates the preparation of (E)-methyl 3-methoxy-2-(2-[3-(3-methoxyphenoxymethyl)phenoxy]-phenyl)propenoate (Compound No. 372 of Table I).
(E)-Methyl 3-methoxy-2-(2-[3-methylphenoxy]phenyl)-propenoate (0.50g, prepared as described in Example 8), 1,3-dibromo-5,5-dimethylhydantoin (0.32g) and azoisobutyronitrile (0.033g) were heated under reflux in
23 5 075
carbon tetrachloride (40 ml), while being irradiated with a 400 watt tungsten lamp. After 1 hour the mixture was cooled and poured into water. The organic layer was separated, washed with water, dried and evaporated to give a yellow viscous oil (0.825g), containing about 65% of (E)-methyl 3-methoxy-2-(2-[3-bromomethylphenoxy]phenyl)-propenoate, which was used without further purification (see Example 8 for n.m.r. data).
A solution of the crude bromide (0.41g) in dry DMF (4 ml) was added to a solution of sodium 3-methoxyphenoxide (generated from 3-methoxyphenol and sodium hydride) in dry DMF (6 ml), and the mixture was stirred for 4 hours and then allowed to stand overnight. The reaction mixture was poured into dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic fractions were dried and evaporated to give a brown oil. This was purified by HPLC (eluant 7:3, 40/60 petroleum ether:ethyl acetate) to give the title compound (0.20g) as a colourless gum.
IR maxima (film) : 1715, 1640 cm-1.
XH n.m.r. (400 MHz) delta : 3.60 (3H, s), 3.73 (3H, s),
3.77 (3H, §), 4.99 (2H, s),
I
6.50-6.55 (3H, m), 6.88-6.95 (2H, m), 7.05 (IH, s), 7.09-7.20 (3H, m), 7.24-7.31 (3H, m), 7.47 (IH, s) ppm.
EXAMPLE 29
This Example illustrates the preparation of (E)— methyl 3-methoxy-2-(2-[3-benzoylphenoxy]phenyl)propenoate, (Compound No. 12 of Table I).
Methyl 2-(3-hydroxymethylphenoxy)phenylacetate (10.Og, preparared as described in Example 17) and celite (lOg) were mixed in methylene chloride (100 ml), and t
235 0
pyridinium chlorochromate (15.85g) was added in one portion. After stirring at room temperature for 2.5 hours, the mixture was filtered and the filtrate was evaporated to give methyl 2-(3-formylphenoxy)phenylacetate as an orange oil (8.48g), which was pure enough to use without further purification.
IR maxima (film) : 1740, 1700 cm-1.
1H n.m.r. (270 MHz) delta : 3.'59 (3H, s), 3.69 (2H, s),
6.92 (IH, d), 7.14-7.20 (IH, t), 7.23-7.37 (3H, m), 7.43 (IH, m), 7.50 (IH, t), 7.60 (IH, dd), 9.95 (IH, s) ppm.
Phenylmagnesium bromide (2.84 ml of a 3M solution in ether) was added dropwise to a cooled and stirred solution of the aldehyde from the preceding stage (2.30g) in THF so that the temperature did not rise above -30°C. After completion of the addition (35 minutes), the reaction mixture was slowly warmed to room temperature, stirred ovenight and then cooled in an ice bath while water was carefully added. Dilute hydrochloric acid was then added, and the mixture was extracted with ethyl acetate. The extracts were dried and evaporated to give a yellow oil which was purified by flash chromatography (eluant 2:1, hexane:ethyl acetate) to give methyl 2-[(3-(alpha-hydroxy)benzyl)phenoxy]phenylacetate as a pale yellow oil (1.69g).
1H n.m.r. (270 MHz) delta : 3.57 (3H, s), 3.68 (2H, s),
.79 (IH, s), 6.79-6.90 (2H, m), 7.05-7.13 (3H, m), 7.18--7.40 (9H, m) ppm.
The hydroxy-ester from the preceding preparation
235 075
(0.91g) was stirred in methylene chloride (25 ml) at room temperature, with two spatula portions of celite. Pyridinium chlorochromate (0.65g) was then added, and the reaction mixture was stirred for 3 hours. The mixture was filtered and the filtrate was evaporated and purified by HPLC (eluant 3:1, hexane:ethyl acetate) to give methyl 2-(3-benzoylphenoxy)phenylacetate as a pale yellow gum (0.56g).
1H n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.70 (2H, s),
6.93 (IH, d), 7.10-7.63 (10H, m), 7.81 (2H, d) ppm.
IR maxima (film) : 1740, 1660 cm-1.
This material was converted into the title compound using sodium hydride and methyl formate and then potassium carbonate and dimethyl sulphate in the two steps described for a similar transformation in Example 7.
IR maxima (film) : 1710, 1660, 1635 cm"1.
1H n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.75 (3H, s),
6.98 (IH, d), 7.12-7.20 (2H, m), 7.26-7.52 (8H, m), 7.47 (IH, s), 7.55-7.63 (IH, m), 7.80 (2H, dd) ppm.
EXAMPLE 30
This Example illustrates the preparation of (E)-methyl 3-methoxy-2-(2-[3-benzylphenoxy]phenyl)propenoate, (Compound No. 9 of Table I).
Trifluoroacetic acid (3.28g) was added dropwise with stirring to methyl 2-[(3-(alpha-hydroxy)benzyl)phenoxy]-phenylacetate (1.68g, prepared as described in Example
235 0 7 5
29) at 5°C. After completion of the addition,
triethylsilane (2.24g) was slowly added dropwise. The resultant clear solution was then stirred overnight,
diluted with water and extracted with ether. The ether fraction was washed with aqueous sodium bicarbonate,
dried, concentrated and purified by HPLC (eluant 4:1, hexane:ether) to give methyl 2-(3-benzylphenoxy)pheny1-acetate (1.03g) as a colourless oil.
IR maximum (film) : 1742 cm-1.
This material was converted into the title compound using sodium hydride and methyl formate and then potassium carbonate and dimethyl sulphate in the two steps described for a similar transformation in Example 7.
IR maxima (film) : 1708, 1635 cm-1.
n.m.r. (270 MHz) delta : 3.56 (3H, s), 3.72 (3H,
3.93 (2H, s), 6.76-6.93 m), 7.08-7.31 (10H, m), (IH, s) ppm.
I
EXAMPLE 31
This Example illustrates the preparation of (E)-methyl 3-methoxy-2-[2-(3-[N-phenylsulphonamido3phenoxy)-phenyl]propenoate (Compound No. 78 of Table I).
A mixture of 2-bromophenylacetic acid (21.5g), 3-nitrophenol (29.2g), potassium carbonate (27.6g) and cuprous chloride (0.5g) was heated with stirring at 130°C for 6 hours. After cooling, the mixture was poured into water (500 ml), acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 200 ml). The extracts were dried, filtered and concentrated to give a dark oil. The oil was dissolved in methanol (400 ml)
s),
(4H,
7.47
235 0 75
containing concentrated sulphuric acid (4 ml) and the resulting solution was heated at reflux for 3 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (300 ml). This solution was 5 washed successively with sodium hydroxide (2 x 100 ml of 1M aqueous solution) and brine, then dried, filtered and concentrated to give a dark oil. Bulb-to-bulb distillation of this oil (220°C oven temperature, 0.2 mmHg) gave methyl 2-(3-nitrophenoxy)phenylacetate (16.74g, 10 58% yield from 2-bromophenylacetic acid) as a clear pale oil.
XH n.mr. (270 MHz) delta : 3.60 (3H, s), 3.70 (2H, s),
6.9-8.0 (8H, m) ppm.
IR maximum (film) : 1739 cm-1.
A mixture of methyl 2-(3-nitrophenoxy)phenylacetate
(15g), methanol (100 ml), glacial acetic acid (100 ml), and iron powder (15.Og) was gently heated with stirring to reflux. After 30 minutes the mixture was cooled and the excess iron powder was filtered off. This filtrate was 20 poured into water (700 ml) and extract'ed with ether (2 x 200 ml). The ether extracts were neutralized by stirring with aqueous sodium bicarbonate then dried, filtered and concentrated to give methyl 2-(3-
aminophenoxy)phenylacetate (13.Og, 97% yield) as a pale 25 yellow oil.
1H n.m.r. (270 MHz) delta : 3.63 (3H, s), 3.68 (2H, s),
3.9 (IH, br s), 6.2-7.3 (8H, m) ppm.
IR maxima (film) : 3400, 3373, 1733 cm-1.
A mixture of methyl 2-(3-aminophenoxy)phenylacetate
(11.54g) and methyl formate (27.7 ml) in DMF (25 ml) was
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n
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235 0 75
added dropwise to a stirred suspension of sodium hydride (3.25g) in DMF (50 ml) cooled in ice to below 10"C (effervescence). Following the addition, the reaction mixture was stirred at room temperature for 3 hours, 5 poured into water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. These extracts were washed with brine, dried and concentrated to give a viscous yellow oil. Potassium carbonate (12.4g) and dimethyl sulphate (4.25 ml) were added successively to 10 a stirred solution of this yellow oil in DMF (50 mis) and the resulting mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated to give (E)-methyl 2-£2-(3-formamidophenoxy)-15 phenyl]-3-methoxypropenoate (13.67, 93% yield) as a clear green gum.
1H n.mr. (270 MHz) delta : 3.60 (3H, s), 3.78 (3H, s),
7.47 (IH, s) ppm.
IR maxima (film) : 3309, 1702, 1606 cm-1.
Phosphoryl chloride (7.8 ml) was added dropwise to a stirred solution of (E)-methyl 2-[2-(3-formamidophenoxy)-phenyl]-3-methoxypropenoate (13.67g) in methanol (100 ml), the temperature during the addition being kept below 50°C with the aid of a cooling bath. After stirring for 20 25 minutes, the reaction mixture was poured into water (500 ml), neutralized with sodium bicarbonate and extracted with ether. The extracts were dried and concentrated to give a yellow oil which was chromatographed using ether as the eluant to give (E)-methyl 2-[2-(3-aminophenoxy)-30 phenyl]-3-methoxypropenoate (8.57g, 68% yield) as a yellow solid, m.p. 83-85°C.
n.m.r. (270 MHz) delta : 3.6 (2H, br s), 3.62 (3H, s),
3.77 (3H, s), 6.2-6.4 (3H, m),
""" " — --- - r -
235075
6.9-7.3 (5H, m), 7.48 (IH, s) ppm.
IR maxima (film) : 3450, 3370, 1703, 1632 cm"1.
A solution of (E)-methyl 2-[2-(3-aminophenoxy)-5 phenyl]-3-methoxypropenoate (0.4g) in glacial acetic acid (2 ml) was treated with 5.8M hydrochloric acid (1 ml), at -10°C. The stirred solution was then treated with sodium nitrite (O.lg in 2 ml of water) still at -10°C. After 30 minutes, the resulting solution (containing the diazonium 10 salt) was added to a stirred mixture of glacial acetic acid (0.5 ml) saturated with-sulphur dioxide, containing O.lg of cuprous chloride (effervescence). After 30 minutes, the reaction mixture was poured into water and extracted with ether. The ether extracts were neutralized 15 with a saturated aqueous solution of sodium bicarbonate, dried and concentrated to give (E)-methyl 2-[2-(3-chloro-sulphonylphenoxy )phenyl]-3-methoxypropenoate (0.14g) as a yellow oil.
IR maxima (film) : 1710, 1636 cm-1.
i
A solution of methyl 2-[2-(3-chlorosulphonylphenoxy)-
phenyl]-3-methoxypropenoate (0.14g) in pyridine (0.5ml) was treated dropwise with aniline (0.05 ml) at room temperature with stirring. After 3 hours the reaction mixture was poured into water. 2M Hydrochloric acid was 25 added to the resulting mixture until it was slightly acidic and it was extracted with ether. The ether extracts were washed with brine, dried, concentrated and chromatographed using ether as the eluant to give the title compound (0.145g) as a clear oil.
IR maxima (film) : 3240, 1693, 1635, 1600 cm-1.
n.m.r. (270 MHz) delta : 3.55 (3H, s), 3.69 (3H, s).
.
- '
235 075
6.53 (1H, br s), 6.8 (IH, m), 7.0-7.4 (12H, m), 7.43 (IH, s)
ppm.
EXAMPLE 32
This Example illustrates the preparation of (E)-methy1 2-[2-(3-[3-bromobenzoy1amino]phenoxy)pheny1]-3-methoxypropenoate (Compound No. 421 of Table I).
3-Bromobenzoyl chloride (0.37g) was added to a stirred solution of (E)-methyl 2-[2-(3-aminophenoxy)-phenyl]-3-methoxypropenoate (0.5g, prepared as described in Example 31) in dichloromethane (20 ml) containing triethylamine (0.17g). After 3 hours, the reaction mixture was poured into water and extracted with dichloromethane (2 x 50 ml). The extracts were dried, concentrated and chromatographed using ether as the eluant to give the title compound (0.61g) as a pale yellow foam.
IR maxima (nujol) : 1710, 1680, 1640, 1605 cm"1.
XH n.m.r. (270 MHz) delta : 3.62 (3H, s), 3.78 (3H, s),
6.73-8.0 (l^H, m), 7.47 (IH,
s) ppm.
EXAMPLE 33
This Example illustrates the preparation of (E)-methyl 2-[2-(3-pyridin-2-yloxyphenoxy)phenyl]-3-methoxypropenoate (Compound No. 1 of Table II).
Potassium carbonate (0.92g), cuprous chloride (catalytic), copper bronze (catalytic) and 2-fluoro-pyridine (1.94g) were added successively to a stirred solution of (E)-methyl 2-[2-(3-hydroxyphenoxy)phenyl]-3-methoxypropenoate (2.0g, prepared as described in Example 1) in DMF (15 ml). The resulting mixture was stirred for
*
235 075
3 hours at 130°C. After cooling, the mixture was diluted with water and extracted with ether (x 2). The combined extracts were washed successively with aqueous sodium w' hydroxide, water and brine, then dried and concentrated.
Chromatography using ether-hexane mixtures as eluant gave the title compound (1.68g, 67% yield) as an orange-yellow gummy oil.
O l-H n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.73 (3H, s),
6.72-7.32 (10H, m), 7.48 (IH, 10 s), 7.67 (1H, m), 8.19 (IH, m)
ppm.
EXAMPLE 34
This Example illustrates the preparation of (E)-methyl 2-[2- (3-[6-chloropyridazin-3-yloxy]phenoxy)phenyl]-3-methoxypropenoate (Compound No. 130 of Table II). 15 Potassium carbonate (0.93g), cuprous chloride
(catalytic) and 3,6-dichloropyridazine (l.Og) were added successively to a stirred solution of (E)-methyl 2-[2-(3-hydroxyphenoxy)phenyl]-3-methoxypropenoate (2.01g,
prepared as in Example 1) in DMF (30 ml). The resulting 20 mixture was stirred for 1% hours at 95®C. After cooling, the mixture was diluted with water and extracted with ether (x 2). The combined extracts were washed —. successively with aqueous sodium hydroxide, water and brine, then dried and concentrated. Chromatography using 25 ether-hexane mixtures gave the title compound (1.71g, 62% yield) as a yellow gum.
n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.73 (3H, s),
6.73-7.36 (9H, m), 7.46 (IH,
m), 7.50 (IH, s) ppm.
235075
The following are examples of compositions suitable for agricultural and horticultural purposes which can be formulated from the compounds of the invention. Such compositions from another aspect of the invention. Percentages are by weight. .
• • 4
EXAMPLE 35
An emulsifiable concentrate is made up by mixing and stirring the ingredients until all are dissolved.
Compound No. 212 of Table I 10%
Benzyl alcohol 30%
Calcium dodecylbenzenesulphonate 5% Nonylphenolethoxylate (13 moles ethylene oxide) 10%
AlXyl benzenes 45%
EXAMPLE 36
The active ingredient is dissolved in methylene dichloride and the resultant liquid sprayed on to the granules of attapulgite clay. The solvent is then allowed to evaporate to produce a granular composition.
Compound No. 212 of Table I 5%
Attapulgite granules 95%
EXAMPLE 37
A composition suitable for use as a seed dressing is prepared by grinding and mixing the three ingredients.
Compound No. 212 of Table I Mineral oil China clay
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23507J
EXAMPLE 38
A dustable powder is prepared by grinding and mixing the active ingredient with talc.
Compound No. 212 of Table I 5%
Talc 95%
EXAMPLE 39
A suspension concentrate is prepared by ball milling the ingredients to form an aqueous suspension of the ground mixture with water.
Compound No. 212 of Table I 40%
Sodium lignosulphonate 10%
Bentonite clay 1%
Water 49%
This formulation can be used as a spray by diluting into water or applied directly to seed.
EXAMPLE 40 i
A wettable powder formulation is made by mixing 15 together and grinding the ingredients until all are thoroughly mixed.
Compound No. 212 of Table I 25%
Sodium lauryl sulphate 2%
Sodium lignosulphonate 5%
Silica 25%
China clay 43%
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235 075
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EXAMPLE 41
The compounds were tested against a variety of foliar fungal diseases of plants. The technique employed was as follows.
The plants were grown in John Innes Potting Compost ^5 (No. 1 or 2) in 4cm diameter minipots. The test compounds were formulated either by bead milling with aqueous Dispersol T or as a solution in acetone or acetone/ethanol which was diluted to the required concentration immediately before use. For the foliage diseases, the 10 formulations (100 ppm active ingredient except where otherwise indicated) were sprayed onto the foliage and applied to the roots of the plants in the soil. The sprays were applied to maximum retention and the root drenches to a final concentration equivalent to approximately 40 ppm 15 a.i./dry soil. Tween 20, to give a final concentration of 0.05%, was added when the sprays were applied to cereals.
For most of the tests the compound was applied to the soil (roots) and to the foliage (by spraying) one or two } days before the plant was inoculated with the disease. An 20 exception was the test on Erysiphe graminis in which the plants were inoculated 24 hours before treatment. Foliar pathogens were applied by spray as spore suspensions onto the leaves of test plants. After inoculation, the plants ) were put into an appropriate environment to allow 25 infection to proceed and then incubated until the disease was ready for assessment. The period between inoculation and assessment varied from four to fourteen days according to the disease and environment.
The disease control was recorded by the following 30 grading :
4 = no disease
3 = trace -5% of disease on untreated plants
235 075
2 = 6-25% of disease on untreated plants 1 = 26-59% of disease on untreated plants ^ 0 = 60-100% of disease on untreated plants
The results are shown in Table VI.
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TABLE VI
O
O
0
COMPOUND
TABLE
PUCCINIA
ERYSIPHE
VENTURIA
PYRICULARIA
CERCOSPORA
PUSMOPARA
PHYTOPHTHORA
NO
NO.
RECONDITA
GRAMINIS
INAEQUALIS
ORYZAE
ARACHIDIOOLA
VITICOLA
INFESTANS
(WHEAT)
(BARLEY)
(APPLE)
(RICE)
(PEANUT)
(VINE)
(TOMATO)
1
I
4
4
4
4
4
4
3
2
I
4
2
4
4
4
4
0
3
I
3
0
4
2
4
4
0
4
I
4
4
4
3
4
4
3
I
4
4
4
3
4
4
2
6
II
4
4
4
4
4
4
4
7
I
3
4
4
3
4
4
0
12
I
4
3
4
4
4
4
4
18
I
4
3
4
4
-
4
0
21
I
4
4
0
0
4
4
4
22
II
4
4
4
3
4
4
4
22
IV
4
0
4
4
4
4
3
23
I
4
3
4
4
4
4
4
24
I
4
4
4
3
4 ,
4
2
I
4
3
4
3
4
4
3
27
I
4
0
4
4
4
3
29
I
4
3
4
0
4
4
3
38
I '
4
3
3
4
4
4
4
38
II
4
4
4
4
2
4
3
47
II
0
4
- 4
3
4
4
3
49
I
4
2
4
3
4
4
3
50
I
3
0
3
2
0
4
2
51
I
4
4
3
4
4
4
4
52
II
4
4
4
4
4a
-
0
53
II
4
3
4
4
4
4
4
62
I
4
3
4
4
4
3
4
67
I
3
4
4
3
3
4
3
81
II
4
4
0
3
I
4
3
UI
to ro
CM <JI
•VJ ui
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TABLE VI (CONT/D)
O O
o
COMPOUND
TABLE
PUCCINIA
ERYSIPHE
VENTURIA
PYRICULARIA
CERCOSPORA
PLASMOPARA
PHYTOPHTHORA
NO
NO.
RECONDITA
GRAMINIS
INAEQIJALIS
ORYZAE
ARACHIDICOLA
VITICOLA
INFESTANS
(WHEAT)
(BARLEY)
(APPLE)
(RICE)
(PEANUT)
(VINE)
(TOMATO)
R3
II
3
4
4
4
2
4
3
84
I
3
0
4
0
0
4
0
84
II
4
4
4
3
4
4
1
85
II
4
4
4
4
4
4
4
86
I
1
0
4
1
4
4
0
86
II
0
0
0
0
0
2
0
87
II
3
4
4
4
2
4
3
87
IV
3a
0a
4a
3a
4a
4a
Oa
89
II
4
4
4
3
4
4
3
90
II
4
4
4
4
4
4
3
93
II
4
3
4
3
2
4
0
94
II
4
3
4
4
4
4
4
95
II
1
0
4
0
1
4
0
96
I
4
4
4
2
4 ,
4
2
96
II
4
0
3
1
0
4
3
98
II
4
4
4
4
4
4
4
99
II
3
4
4
3
1
4
0
100
II
4
4
4
4
4
4
3
105
II
3
4
4
4
4
4
3
111
I
3
0
- 4
3
2
4
0
115
I
4
3
4
4
4
4
3
119
I
4
4
4
4
4
4
4
120
I
4
3
4
3
4
4
4
1 22
I
4
4
4
3
4
4
4
124
I
4
4
4
4
4
4a
4
125
I
4
4
4
3
4
4
4
126
I
4
3
4
3
4
4
3
127
I
4
3
4
4
4
4
2
UI u>
K>
CM CJl
CJl
NO
128
129
130
131
131
132
133
1.34
135
138
141
143
144
145
150
157
171
175
177
179
204
205
206
208
212
214
216
21.7
G ©
TABLE VI (CONT/P)
O O
TABLE
PUCCINIA
ERYSIPHE
VENTURIA
PYRICULARIA
CERCOSPORA
PUSMOPARA
PHYTOPHTHORA
NO.
RECONDITA
GRAMINIS
INAEQUALIS
ORYZAE
ARACHIDICOLA
VITICOU
INFESTANS
(WHEAT)
(BARLEY)
(APPLE)
(RICE)
(PEANUT)
(VINE)
(TOMATO)
I
4
4
4
3
4
4
4
I
4
2
4
4
4
4
4
I
4
3
4
-
4
4
4
I
4a
4a
4a
4a
-
4a
4a
III
0a
Oa
4c
4a
4a
Oc
Oc
I
4
4
4
4
4
4
3
I
4
2
4
4
4
4
2
I
4
4
4
4
4
4
4
I
4
4
4
4
4
4
3
I
4
4
4
3
4
4
4
I
4
4
4
3
4
4
0
I
4
4
4
3
4
3
3
I
4
4
4
3
4
4
0
I
4
3
4
3
4
4
1
I
3
3
4
4
3a'
'
0
I
3
3
4
3
4
0
0
4
4
4
4
3a
-
0
I
4
4
4
4
3
4
0
I
4
4
4
3
-
4
0
I
1
1
- 0
0
2
4
0
i
4
4
4
4
4a
-
0
I
4
4
4
4
3a
-
1
I
4
4
4
4
4
4
3
I
4
4
4
-
3
4
3
I
4
4
4
4
4
4
0
I
4
4
4
-
4
4
4
I
4
3
4
-
4
4
4
I
4
4
i
4
3
3a
-
0
I
© o o o
TABLE VI (CONT/D)
COMPOUND
TABLE
PUCCINIA
ERYSIPHE
VENTURIA
PYRICULARIA
CERCOSPORA
PLASMOPARA
PHYTOPHTHORA
NO
NO.
RECONDITA
GRAMINIS
INAEQUALIS
ORYZAE
ARACHIDICOLA
VITICOLA
INFESTANS
(WHEAT)
(BARLEY)
(APPLE)
(RICE)
(PEANUT)
(VINE)
(TOMATO)
218
I
4
3
3
4
4
4
220
I
4
3
4
2
4
4
0
230
I
4
2
4
4
4
4
0
247
I
4
4
4
0
3
4
3
248
I
4
3
4
-
4
4
2
282
I
4
2
4
0
4
4
2
283
I
4
3
4
4
3
4
0
284
I
4
4
4
4
3
4
0
285
I
4
4
4
4
3
4
2
288
r
4
3
4
4
4
4
0
290
i
4
1
4
3
4
4
0
291
i
4
0
0
3
-
4
1
294
i
3
4
4
4
4
4
1
295
i
4
0
4
1
4
4
0
296
i
4
0
4
4
f
4
0
332
0a
Oa
-
2a
-
4a
2a
333
i
4
I
2
3
-
4
0
360
i
4
4
4
4
4
4
1
365
i
4
3
4
3
-
• 4
3
366
i
Oa
4a
-3a
Oa
-
4a |
Oa
367
i
3a la
Oa la
4a
3a
3a
368
i
1
0
0
0
-
0
o !
369
i
4
0
3
2
-
4
0
370
i
4
2
4
4
4
4
371
i
4
4
4
3
4
4
3
372
i
4
4
4
3
4
4
2
373
i
3
4
4
3
4
4
3
374
i
3
4
4
4
3
4
3
375
i
4
4
4
3
1
4
2
i ui cn
C4
Ol
CJl
o o
TABLE VI (CONT/D)
COMPOUND
TABLE
PUCCINIA
ERYSIPHE
VENTURIA
PYRICULARIA
CERCOSPORA
PLASMOPARA
PHYTOPHTHORA
NO
NO.
RECONDITA
GRAMINIS
INAEQUALIS
ORYZAE
ARACHIDICOLA
VITIC0LA
INFESTANS
(WHEAT)
(BARLEY)
(APPLE)
(RICE)
(PEANUT)
(VINE)
(TOMATO)
376
I
4
3
0
4
1
4
3
377
I
4
4
0
4
3
4
3
378
I
3
4
0
4
4
4
4
380
I
3
4
0
4
4
4
3
381
I
3
4
0
4
4
4
4
382
I
4
4
4
3
4
4
2
383
I
4
3
4
4
4
4
0
384
I
4
4
4
4
4
0
0
385
I
4
1
4
4
4
4
0
386
I
4
4
4
3
4
4
2
387
I
4
1
0
4
4
4
3
388
I
3a
4a
4a
4a
4a
3a
0a
389
I
4
3
4
3
4
4
4
390
I
4
4
4
2
4
4
2
391
I
4
3
4
4
4 '
4
2
392
I
4
2
4
4
4
4
0
393
I
4
4
4
4
4
4
0
394
I
4
3
4
4
4
■ 4
0
395
I
3a la
4b
4a
4a
4b
3b
396
I
4
3
-4
3
4
4
3
397
I
4
4
4
4
4
4
0
398
I
3
0
3
2
2
4
2
399
I
4a
3a
4a
4a
4a
4a
2a
400
I
2
0
4
4
2
4
0
401
I
4a
3a
4a
4a
4a
Oa
402
I
4
2
2
3
4
4
3
403
I
4
4
4
3
3
3
0
404
I
4
3
3
0
4
3
0
I
M
UI CTl
I
l\» CM
CJl o
CJl
I
o o
TABLE VI (CONT/D) jj||
COMPOUND
TABLE
PUCCINIA
ERYSIPHE
VENTURIA
PYRICULARIA
CERCOSPORA
PUSMOPARA
PHYTOPHTHORA
NO
NO.
RECONDITA
GRAMINIS
INAEQUALIS
ORYZAE
ARACHIDICOLA
VITICOU
INFESTANS
(WHEAT)
(BARLEY)
(APPLE)
(RICE)
(PEANUT)
(VINE)
(TOMATO)
405
I
4
4
4
4
4a
0
406
I
3
0
4
0
0
4
0
407
I
4
4
4
0
4
0
408
I
3
0
4
1
4
4
0
409
I
4
0
3
0
4
4
0
410
I
4
2
4
3
4
4
1
410
III
4
2
3
3
-
4
1
411
I
4
3
4
4
4
4
3
411
III
4
2
3
0
0
3
0
412
I
4
3
4
4
4
4
2
413
I
4
2
4
4
4
4
0
414
I
4
1
4
3
4
4
0
423
I
4
4
4
4
4
4
3
424
4
3
4
4
4
f
3
4
UI -J
I
a - 25 ppm foliar spray b = 15 ppm foliar spray c = 10 ppra foliar spray - = test failed/missing
P34461MAIN MJH/dlc 15 Aug 88 DC025/DC026
l\»
Ol cn o cn
235 075
o pa /
ch3o2c
/\h.OR*
(ii)
e
(iv)
(vi)
xt-aewtu-v*
* >
235075
Claims (1)
1. Intermediate compounds of the formulae (II), (IV) and (VI) as hereinbefore set out on page 158, and stereoisomers thereof, wherein as appropriate for each formula: K is oxygen or sulphur; Z is optionally substituted aryl or optionally substituted heteroaryl; X is 0, S(0)n, NR4, CR^R2, CHr9, CO, CR^OR2), C=CR1R2, CHR1CHR2, cr1=cr2, chr1cr2=ch/ csc, ochr1, chr^-o, 0chr10, stojjchr1, s(0)nchr10, chr^-sco)^ chr10s02, nr^chr1, chr^-nr4, c02, 02c, s020, cs02, co. co, cochr1, cochr10, chr1co, choh.chr1, chr^-.choh, XCH2 \ /°\ CR1— CR2, CR1 .CR CONR4, OCONR4, NR4C0, CSNR4, OCS.NR4, SCO.NR4, NR4C02, NR4CS, NR4CS0, NR4COS, NR4CONR4, S(0)nNR4, NR4S(0)n, CS2, S2C, CO.S, SCO, N=N, N^CR1, CR1=N, CHR1CHR2CH(OH), CHR1OCO, CHR1SCO, CHR-'-NR^O, CHR1NR4CONR4, CHR1CHR2CO, O.N^R1, CHR^-O.N^R2, COOCRLR2, CHR^-CHR^HR3, OCHR^HR2, (CH2)mO, CHR1OCHR2, CHR1CHR20, OCHR^-CHR^, S (0) ^HR^-CHR2, CHR1S (0)nCHR2x CHR1CHR2S(0)n, CR1=NNR4, NR^^R1, CHR1CONR2, CHR1OCO.NR2, CH=CHCH20, C0CHR1CHR20, or . (R5)2P+CHR2Q~; A, B and E, which may be the same or different, are H, halo, hydroxy, CL_4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, Cx_4 haloalkoxy, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, phenoxy, nitro or cyano; R1, R2 and R3, which may^e. the same or "* i— , „ „ different, are H< C1-4 alkyl or phenyl^gg^isWSrHH^ '- V«V"»-»"«-.-r 235075 - 160 - alkyl or COR1; R5 is optionally substituted phenyl; R6 is a metal atom; R9 substituted phenyl; Q~ is a halide anion; n is 0, 1 or 2 and m is 3, 4 or 5; except that when Z is unsubstituted phenyl and X and K are oxygen, A, B and E are not all hydrogenr A compound of the formula (II) as defined in claim 1 or a stereoisomer thereof. A compound of the formula (IV) as defined in claim 1 or a stereoisomer thereof. A compound of the formula (VI) as defined in claim 1 or a stereoisomer thereof. A compound of the formula (II) as defined in claim 1 or a stereoisomer thereof substantially as herein described with reference to any example thereof. A compound of the formula (IV) as defined in claim 1 or a stereoisomer thereof substantially as herein described with reference to any example thereof. A compound of the formula (VI) as defined in claim 1 or a stereoisomer thereof substantially as herein described with reference to any example thereof. iMfEKSAL CM€h\CA,L Ui/QUS7/?l£S PlC. By _>Hlf/ThGir authorised Agent A. J. PARK & SON Per:
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB878721221A GB8721221D0 (en) | 1987-09-09 | 1987-09-09 | Chemical process |
GB878721706A GB8721706D0 (en) | 1987-09-15 | 1987-09-15 | Fungicides |
GB888801485A GB8801485D0 (en) | 1988-01-22 | 1988-01-22 | Fungicides |
GB888806317A GB8806317D0 (en) | 1988-03-17 | 1988-03-17 | Fungicides |
GB888814734A GB8814734D0 (en) | 1988-06-21 | 1988-06-21 | Fungicides |
NZ225945A NZ225945A (en) | 1987-09-09 | 1988-08-26 | Methyl-3-methoxy propenoate derivatives, preparation thereof and fungicidal compositions |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ235075A true NZ235075A (en) | 1991-05-28 |
Family
ID=27546984
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ23507588A NZ235075A (en) | 1987-09-09 | 1988-08-26 | Substituted carboxylic esters |
NZ235074A NZ235074A (en) | 1987-09-09 | 1988-08-26 | Methyl-3-methoxy-propenoate derivatives |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ235074A NZ235074A (en) | 1987-09-09 | 1988-08-26 | Methyl-3-methoxy-propenoate derivatives |
Country Status (1)
Country | Link |
---|---|
NZ (2) | NZ235075A (en) |
-
1988
- 1988-08-26 NZ NZ23507588A patent/NZ235075A/en unknown
- 1988-08-26 NZ NZ235074A patent/NZ235074A/en unknown
Also Published As
Publication number | Publication date |
---|---|
NZ235074A (en) | 1991-05-28 |
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