69
f CHAPTER -III '
f
CHAPTER -III
'
153
INTRAMOLECULAR WITTIG REACTION:
SYNTHESIS OF COUMARINS AND 2-
QUINOLONES
This chapter is divided into two sections, the first section deals with
synthesis of coumarin and the second section deals with synthesis of
2-quinolones.
Section I
3.1a Introduction
Coumarins 1 occupy a special place in the field of heterocyclic
chemistry because many products which contain this subunit exhibit
useful and diverse biological activities along with their presence in
nature 3,2 . The derivative of coumarin usually occurs as secondary
metabolites present in seeds, roots and leaves of many plant species.
Their function is far from clear, though suggestions include waste
products, plant growth regulators, fungistats and bacteriostats 3 .
The biolOgical activities 4 exhibited by coumarin derivative includes
molluscacidal activity5 , anthelmintic, hypnotic and insecticidal
activity6 . Chemotherapeutically valuable compounds in this group are
a series of coumarins of which Acenocoumarol 2 is one, which are
valuable as anticoagulants'.
0 4
154
2
3
Calanolide A 3 shows promising inhibitory activity towards the
immuno deficiency virus-1(HIV-I) reverse transcriptase 8 . 4-hydroxy
coumarin derivative warfarin is a well know anticoagulant 9,
4-hydroxy-3-nitro coumarins are known to possess antiallergic
activitym. Retinal analogues 4 and 5 are known to be synthesized
from 6-methyl and 7-methyl coumarins respectivelyll.
5
7-methoxy coumarin (Herniarin) is a well known naturally occuring
coumarin effective against microbes 12 and also used as hypotensive
155
and tranquillizing agent 13 . Polycyclic coumarins Benzo [a] pyrene 6
have anticarcinogenic properties and potent inhibitor of tumor
induction 14 .
6
Coumarins also have other diverse uses such as it is used as
additives to food and cosmetics 18 . Benzocoumarins because of their
intense blue fluorescence and good light fastness constitute an
important group of optical brightners 16 , for synthetic fibres. They are
also used as dispersed fluorescent and laser dyes'''. These
compounds can also be used for the synthesis of other products,
such as furocoumarins, chromenes, coumarones and 2-
acylresorcinols 18 . 3-Aryl coumarins are well known as they play a
vital role in electrophotographic and electroluminiscent devices19.
156
3.2a Synthesis of Coumarins
Retrosynthetic analyses of coumarin suggests that
there should be three approaches A, B & C for their synthesis.
Based on these three approaches the methods reported for
their synthesis could be classified as shown below.
Approach A : Starting from phenols
The most common and widely used method for the
synthesis of coumarin is the Pechmann condensation 20 . In this,
phenol is treated with malic acid or (6-keto ester in the presence of
some acid catalysts like sulphuric, hydrochloric, phosphoric 21 ,
hydrogen fluoride 22 and trifluoroacetic acid 23 and with lewis acids
such as zinc chloride, iron (III) chloride, tin (III) chloride, titanium
chloride and aluminium chloride 21 . Since conventional catalysts have
157
to be used in excess and are subject to increasing environmental
pollution and are non-recoverable, recently, there is a trend to use
inexpensive, easily handled and non-polluting heterogeneous
catalyst. For example cation exchange resin 24, Nafion-H25 ,
montinorillonite clay26, zeolite-HBEA and other solid acids 27 have
been employed for this purpose. More recently, microwave irradiation
was applied to accelerate this reaction 28 .
The Pechmann synthesis works best with more
nucleophilic aromatics such as resorcinols, electrophilic attack on the
benzene ring ortho to phenolic oxygen by the protonated ketone
carbonyl is probably the first step, though aryl acetoacetates
prepared from phenol and a diketene, also undergo ring closure to
give coumarins29 . The production of hetero-ring unsubstituted
coumarins can be achieved by condensing with formylacetic acid,
generated in situ by the decarbonylation of malic acid (Scheme I).
0 COOEt
R
HO
+ HOOC-CH2 CH-COOH 1 OH
43%
Scheme 1
Similar approach wherein malic or fumaric acid is used instead of a
(3-keto ester is also reported 3° (Scheme II).
Er
Me
1-0
I I I
(dpa)3 Pd2 .CHC13(cat)
Na0Ac,FICOOH,RT
C 02 C 2 11 5 • R R
158
HOOC COOH
Me
Scheme II
Here probably decarboxylation leads to formation of double
bond after the formation of dihydrocoumarin.
An interesting route involving acid catalysed dearylation is
suggested31 for the synthesis of coumarins via dihydrocoumarins
(SchemeIII).
OMe
Scheme M
Recently B.M.Trost and F.D.Toste have reported 32 a new
palladium-catalysed mild method for the synthesis of coumarins
(SchemelV).
Scheme IV
0 C)
II C0011
I 0 0 4
159
Das Gupta and co-workers 33 have devised a method in which
1- and 2-naphthols were reacted with methylmethaacrylate in the
presence of A1C13 to get 3,4-dihydro-3-methylbenzocoumarin, which
on dehydrogenation afforded 3-methylbenzocoumarins (SchemeV).
OH
Methyl
met h aacryll AlC13
0 0))
0 0
Scheme V
Swaminathan and coworkers 34 have developed a method from
2-naphthols, which involved formation of 13-aryloxymethylacrylic acid.
This acid on heating with triethyl amine gives 3-
methylbenzocoumarin. The steps involved are presented in (Scheme
VI). COOH
OH CH2 B r 0 .....----",,,,----- NaFL'I)MF N(C2 Hs )3.
+ Br-CH2 - H-COOH 0 0 \,.,--''''''■/-
Scheme VI
0
0 //iLr'CH=CH
Oj
HOOC
160
Heteroatom directed lithiation 35 have also been used for the
synthesis of benzocoumarins (SchemeVII).
OMe
OCH2OCH,
nBuLi
OMe
OMe
0 0 COOEt
OMe
Scheme VII
Naphthylfurylacrylates can also be converted to
benzocoumarins using A1C13. The cyclisation step with simultaneous
loss of furan provides benzocoumarin 36 (SchemeVIII).
O
0
AICI3
0 0 Chlorobenzene
•
Scheme VIII
Rapoport and co-worker37 have used triethyl orthoacrylate and
2-naphthol for the synthesis of 5,6-benzocoumarin (Scheme IX).
+ =— Ct0Ent
161
KOH
Nie0H
1 0%Pd C 0 0
Scheme IX
Stanovik et a1 38 have reported a method for the synthesis of
3-substituted benzocoumarins in which 1- and 2-naphthols were
treated with methyl-2-benzoylamino-3-dimethylaminopropeonate
(Scheme X).
0 I I
NH--C— Ph
0 OH I
NH _C_ ph
H 7/ NCOOE t
AcOH
Scheme X
Nucleophilic addition of organolithium in 1,4 fashion to
a-phenylthio-a,(3-unsaturated oxazolines leading to 3,4-disubstituted
coumarins is shown in SchemeXI39.
V
R S Ph —
/\
rnCPBA SPh • 0 CCL,
\ reflux I E
R
R
0 (C6 I-15)3 p + I-13C 02 0-0O2 C 113 +
OH CH2 CI, reflux
/
R'
R
0
Scheme XI.
A recent report 40 utilising aromatic electrophilic substitution of
phenols with the reactive intermediate obtained by mixing
triphenylphosphine and dimethyl acetylenedicarboxylate is depicted
in Scheme XII.
CO:Me
Scheme XII
162
Approach B: Starting from o-hydroxy benzaldehyde
The simplest of methods employed for the synthesis from o-
hydroxybenzaldehydes is the Perkin condensation in which aromatic
Zx
Ij
163
aldehyde is heated with an anhydride and sodium salt of an acid ."
(Scheme XIII).
r f13 0 AcONa1
0 OC OMe
Scheme XIII
Knoevanagel condensation 42 using malonic acid 43 or diethyl
malonate44 has also been employed for the synthesis of coumarin
which involves additional steps of hydrolysis and decarboxylation
(Scheme XIV).
,on piperidine
0 CHICO2Et)2 pipendthe acetate
Et() I-I/heat
H
0 hydrolysis
02
COOEt
0
Scheme XIV
Mali and coworker have reported 45 use of intermolecular Wittig
reaction for the synthesis of 3,4-substituted coumarins (Scheme XV).
,OH iR
Ph, COOEt
R
Scheme XV
164
An approach using Wittig-Horner reaction is shown in Scheme XVI 46 .
/°H 0
O (0E0311CH2—00017t NaH
THF. \v/ 0
Scheme XVI
A method, involving the reaction of N,N-diethylacetamide-P0C13
complex with 2-hydroxybenzaldehyde is depicted in Scheme XVII 47 .
0
'CHO
0 POC13+
N(Et)2 - R
o
R
Scheme XVII
Harvey and co-workers 48 have developed a method in which
a-lithioacetamide was reacted with 2-(methoxymethyl) hydroxy-
benzaldehyde. The resulting intermediate on acid hydrolysis yielded
coumarins (Scheme XVIII).
0 . I . LiCH2CONMe2
CHO
20 CH3
0
OH 0 AcOH ZN
CD
Scheme XVIII
165
An approach using cumulated ylide for the synthesis of
coumarins is depicted in Scheme XIX 49 .
0 - Ph3P=C=C=0
CHO
Scheme XIX
Synthesis of 3-chlorocoumarins from o-hydroxybenzaldehydes
and chloroacetyl chloride using triethyl amine is shown in Scheme
)0(50
,OH -----
0 + CICH2COC1 TEA
CHC13:7' '-'-'--------'- '-- CHO
0 I
Scheme XX
Barton and co-workers have reported Enamine condensation of
o-hydroxybenzaldehyde for the synthesis of coumarins (Scheme
XXI) 51 .
Scheme XXI
0
(n 1) Nal-I, DM17
2) (Nle) 3 Si-CH=C=0
166
An approach using intermolecular Reformatsky reaction is
depicted in Scheme XXI1 52 .
o ^
•CHO
CH,
1) Br-C1I-COOEt /Zn 0
2) aq. H 2 SO4
Scheme XXII
A method utilising diethylphosphonoketenes is shown in
Scheme )0(111 53
U
O
(Et)DP, ,c=c=o
NaH 0
R2 12'
Scheme XXIII
Taylor & Cassel have reported use of trimethylsilylketene54
(Scheme XXIV).
Scheme XXIV
167
Approach C : Starting from benzaldehyde.
An elegant approach by Pandey et al is reported 55 by this route.
The photochemical cyclisation of cinnamic acids leads to coumarins
(Scheme XXV).
ho. DCN
RO COOH RO'
Scheme XXV
Perkin reaction on o-fluorobenzaldehydes leading
3-arylcoumarins is depicted in Scheme XXVI 56 .
0
Ar—CH2— COOH Ac20, TEA
0
-\\ CHO
Ar
Scheme XXVI
A few other approaches which do not follow the pathway A B,
or C for the synthesis of benzocoumarins is depicted in Schemes
XXVII & XXIX.
Thus, Brandy and Agho have used cycloaddition reaction of
chloroketenes with 13-(methoxymethylene)-a-tetralone to obtain
benzocoumarins (Scheme XXVII)57.
O ci
168
CI 0 I II
R—CH — C—C1 NEt3
O R
OMe
O I I
0
Zn/AcOkil I DDQ, C6H6_ H2o
Scheme XXVII
Bestmann and Lang 58 have used two moles of stable Wittig
reagent to obtain benzocoumarin from 1,2-naphthoquinone as shown
in Scheme XXVIII.
0
0 ± Ph, P----CI [-COOEt
O ('OOEt
CH—CH-- PPII, - P Ph,
0
C:00 Et
0 I 1 CH -COO Et
Ph, P= CH -COOEt
OH COC)Et
I (
COC)FA
O
C(X)Et
Scheme XXVIII
0
CH,
COOE t
HCN
169
Chakraborty has built a polycyclic coumarin molecule from
monosubstituted benzene using an interesting sequence of reactions
(Scheme XXIX) 59 .
• o
EtOOC , R ----,„,---
,--- Et 00C 1,---- CN ----
' ■ ,----, \
0 I
() /
CI 1 3 dehydroeenatnin
.s.
ITCX)C R
HOOC H
----, 00H )
__J CH,
0 ° I
Scheme XXIX
170
3.3a Present work towards synthesis of Coumarins
Careful examination of the reported methods, described above
revealed that although intermolecular Wittig reaction 45 has been
reported for the synthesis of coumarin, surprisingly intramolecular
version using haloacetyl derivatives of o-hydroxybenzaldehydes is not
reported. Though intramolecular version using phosphocumulenes 49
and phosphate ketenes53 was reported. We were also intrigued by the
method reported 5° for the synthesis of 3-chloro coumarins using o-
hydroxybenzaldehydes, chloroacetylchloride and triethyl amine. Here,
it was postulated that 3-chloro coumarins are obtained via
chloroacetyl derivative of o-hydroxybenzaldehyde but no chloroacetyl
derivative was isolated except incase of methyl salicylate where the
corresponding coumarin was not formed. So we thought that if we
use a slightly weaker base pyridine instead of triethyl amine we may
be able to isolate the chloroacetyl derivative and then further react
with triphenyl phosphine to form salt which can then undergo
intramolecular Wittig reaction to give coumarins. The obvious
advantage that was thought here was better yield reported for such
intramolecular Wittig reaction for other heterocycles 6° and also we
could have got 3-substituted coumarins which would not be possible
to obtain using Bestmann's phosphocumulenes method. Thus, the
strategy visualised for the synthesis of coumarins is shown in
Scheme XXX.
171
R I R' 12 2 Rl R2 a ) R2 - OH
1 ci,,,,. i
CM 0 CI
1113 .) i. r n CICOCHCI ; --) I 0 PPh2.
11
L — pyridine
R — . R3 ----, ,..... ,------, ,P ..----" .
R3 ' I R4
R
7 a-f 8 a-f 9 a-f
R- !Z i
base I k 1 ,L -0
R 3 R3
R '
10 a-f •
R2
' 1
R4
11 a-f
Scheme XXX
Compound
(7- 1 1)
R R 1 R2 R3 R4
c0 c..)
-0
H
H
H
H
OMe
OMe csl
X X
X
X
X
X
H
OCH3
H
CH3
H
H
C.)
X X
X
X
X
X
th
X X
U X
X X
Our first attempt was to make the procedure one pot and check
whether the product formed is coumarin or 3-chlorocoumarin. Thus,
salicylaldehyde (leq.) and pyridine (leq.) in chloroform was stirred at
0°C and then to it chloroacetyl chloride (leq.) was added slowly.
When tic indicated absence of starting, triphenyl phosphine was
added. Stirring at room temperature indicated some starting
172
remained. So, the reaction mixture was refluxed for 2 hours when the
starting spot on tic disappeared. Triethyl amine (2eq.) were added and
the reaction mixture was stirred for 1 hour when a new fluorescent
(under uv) spot had appeared. Intensity of this spot did not change
on stirring for prolonged time or by refluxing the reaction mixture.
Hence, the reaction mixture was concentrated and column
chromatographed using pet.ether as eluent. Initial fractions gave
unreacted triphenyl phosphine followed by salicylaldehyde. After that,
fluorescent spot was separated followed by triphenylphosphine oxide.
The fraction which showed fluorescent spot were combined and
concentrated to give a solid. The solid was recrystallised in
dichloromethane : pet.ether. It melted at 68°C. Elemental analysis
suggested C9H602 as the molecular formula. In its IR (nujol) spectrum
[Fig.3A1] it exhibited a band .at 1725cm -1 indicating the presence of
carbonyl group of coumarin. In PMR (CDC13) [Fig.3A2] spectrum it
showed a doublet at 6.435 [J=9.46 Hz), which integrated for one
proton. This could be due to the C-3 olefinic hydrogen of coumarin.
In the aromatic region, a multiplet 7.26-7.55 for four protons was
seen, which could be due to the four aromatic hydrogens of
coumarin. A doublet ( J=9.46 Hz) was seen at 7.715 for one proton,
which could be assigned to the C-4 hydrogen of the coumarin.
Thus, on the basis of the mode of formation , analytical data and
spectral properties structure of parent coumarin (11a) was assigned
to it. This structure was also supported by the similarity of its m.p.
68°C with that of the reported 49 m.p.69°C for coumarin. The IR
spectrum of this compound matched well with commercial coumarin
[Fig: 3A1]. The yield of the product was found to be 30%.
37..38 7.r
25 4000
3000
8eeta
000 cort
Fig. 3
CD
OO
- • I
4
0
CD
z CD
0
CD 2
z 0 CD
0 0
.J
z 0
Di cr
10 P 3 2 5 4 8 7 6
Fig. 3 A2
175
Attempts to isolate chloroacetyl derivative in the first step failed
as invariably we recovered salicylaldehyde but no 3-chlorocoumarin
was isolated. We tried different solvents like, ether, benzene, toluene,
DMF, DMSO, and pyridine itself. Instead of pyridine, NaH in ether,
THF, DMF, & DMSO was also tried. Neat heating of sodium salt of
salicylaldehyde with chloroacetyl chloride also did not give us the
product. Heating salicylaldehyde with chloroacetic acid in high
boiling solvent like diphenyl ether also failed. We were also unable to
isolate the intermediate salt and the phosphorane. Attempts to
increase the yield by changing the reaction conditions (temp &
solvent) were also unsuccessful. The regeneration of salicylaldehyde
was observed during salt formation.
To check the feasibility of the generality of this reaction we
decided next to synthesize herniarin (11b) a naturally occuring
coumarin. 2-Hydroxy-4-methoxybenzaldehyde (7b) required for this
purpose was prepared from resorcinol using a known method.
Resorcinol was first converted to its dimethylether 61 which on
Vilsmeier-Haack reaction 62 followed by demethylation63 provided 7b
in 70% yield. It was then treated with chloroacetyl chloride in
presence of pyridine followed by treatment with triphenyl phosphine
and triethyl amine as was done in case of salicylaldehyde. After
column chromatography separation the solid product obtained
melted at 117°C which matched with literature 45 m.p.117-118°C of
that of herniarin. IR spectrum matched with corresponding IR
spectrum of 7-methoxy coumarin (1 1 b) prepared by intermolecular
Wittig reaction. The yield of the product was found to be 27%.
Similarly 2-hydroxy naphthaldehyde (7c) and 2-hydroxy-4-
methyl benzaldehyde (7d) prepared by known reaction were subjected
to similar Intramolecular Wittig reaction. Column chromatographic
separation yielded corresponding coumarin 11c & 1 ld in l.7 and 16
% yield. The structure of these compounds were confirmed by
matching of the IR spectrum with authentic coumarins and similarity
of their literature 49,64 melting points.
176
After successfully synthesizing 3,4-unsubstituted coumarins
we thought of synthesizing 4-methoxy coumarin from methyl
salicylate as, intermolecular Wittig reaction do not give this product.
Thus, methyl salicylate was converted to its chloroacetyl derivative
(8e). The structure was confirmed based on similarity of the m.p.
reported 5° and the carbonyl peak at 1780 & 1715cm -1 in its IR
spectrum. The chloroacetyl derivative of methyl salicylate was then
refluxed in benzene in the presence of triphenyl phosphine.
Formation of salt could be seen as indicated by the presence of a
solid. Attempted filtration resulted in conversion of the solid into a
liquid indicating hygroscopic nature of the salt. So it was decided to
add triethyl amine to the reaction mixture and cheCk whether
phosphorane formation results. However, tic did not indicate usual
phosphorane spot. Assuming that phosphorane formation may not be
taking place at room temperature the reaction mixture was refluxed
for prolonged time but, no new spot on tic was seen. Change of
solvent from benzene to toluene to xylene also showed no formation
of 4-methoxy coumarin. The whole sequence of reaction thus,
indicated that expected phosphonium salt and further formation to
phosphorane may not be taking place in the reaction, however what
may be formed is triphenyl phosphine hydrochloride. The only
compound isolated from the reaction mixture was methyl salicylate.
The fate of acetyl group is not clear whether it is converting to acid
(acetic acid). We were also not able to isolate acetyl salicylate in case
if triphenyl phosphine reacted to give triphenyl phosphine
hydrochloride. While working on this we also came across a report 65
where such deacylation has occurred. The authors of the article,
when contacted could not give any explanation for how such
deacylation occurred.
Simultaneously 2-hydroxy naphthoic acid was converted to
its methyl ester 7f and converted further to the corresponding
chloroacetyl derivative 8f. The structure of which was suggested by
the following spectral data.
177
IR (KBr): v.. 1780, 1720 cm -1
PMR (CDC13) : [Fig.3B]
(8 )
3.93 s 3H COOCH3
4.46 s 2H COCH2CI
7.5-7.6 m 3H Ar-H
7.83 d (J=8.05 Hz) 1H Ar-H
7.95 d (J= 7.68 Hz) 1H Ar-H
8.64 s 1H Ar-H
This chloroacetyl derivative also failed to give the phosphonium
salt and consequently the corresponding coumarin.
111
0)(11
COOMe
1- i:••"_77:- "-=---- -- u------ur— ' ----•
..:-.-7-2----.71.1=-.......=--..1-- -. - - 1... -. --:.±.-.::::.-.,..--.. , _ : ,.E-I ---•,--.
. .. .. nr--:-:
___:. - r ! .: :-.• ....:••••---: -.-- ..,-- - ',..--- : -, '--- 7 - 4, :;, . -: -.:.• . • ....
_ • : -- .:-- l' : - , --•: - 7.-1111 LT— '-. :.:i. 1 i----1 ,•!--••i• ! ,
-,- -. - . .• - I :, / - 4, - , - • . • \,.) (1 . •
- - :-. .L:-.:• .j .' "i- Lull --L'-'-,..,.-- .--; - "T'l•- • ' . --
17 „ 1 , r .. -.i 1 t . c II i 1 t I j 1 11 11 1 i ..../ t-i. -r-r-1 -1-- I r r r.1 1 i -r r
-r—r r I rrrrr —r
2 1 PP
—1- I 1"— 1-1- 1 I 1-1 I-1 I: TT 1-7 I-1 z r— r—r —7-7-1- 1- 1 I I I FT I
12 11 jO 9 8 7 3 14 13
T—T—r
• . . •
.....____ . .
• - • -- • ,., _ .
"'":, .. •
:95 7 .-96: :7 . 8-5 - 7. 80 7.75 - 7.70 7.65 7.60 ppm-
HE
CIO
NAt S
OPH
ISTI
CA
TE
- • . .T.Y•
Fig. 3 8
..• .7 • " • .
•
7-t.•••• .
— •_7.„
, . •
•
• . .•••••••••••••••-,
• ••
•.• • •
•. • ••
• • • •
•
. ..
-. • . • ■ --••.- • . • 7. 7
H N ,0
179
Section II
3.1b Introduction
Carbostyrils 12, are important class of heterocyclic compound,
containing both nitrogen as well as oxygen functionalities. Various
substituted derivatives of carbostyril are known to exhibit diverse
biological activities.
12
Pyranoquinolin-2-one 13 & 14, have potent antithrombotic and
antiallergic properties 68 .
O j H N 0
0
H 0 ,--- ---,,,,,____---,,.___ _____,N 0 ..>" 0
13
14
SeVeral carbostyril derivatives containing heterocyclic side
chains exhibit varying biological activities. 3 & 4- substituted
piperazinyl-2-quinolone derivatives are effective against congestive
heart failure69.
180
4-hydroxy quinolones act as glycine antagonists found to be
active in the DBA/ 2 mouse anticonvulsant assay", & also act as
antimalarials71 . N-substituted quinolone derivative also show potent
biological activity especially if the substituent is an heterocyclic
moiety72,73 . Some act as allergic inhibitors 74, antimicrobial active
agents75 , & antitumour agent 76 . 6,7-methylenedioxy carbostyril is a
cancerocidal agent 77 .
4-Trifluoromethyl-2-quinolone derivatives exhibit high
fluorescence 78 . 4-hydroxy-2-quinolones are useful intermediates for
many industrial products like dyestuff, 9a,b,c, & herbicides 8oa,b,c .
•
C H \ /-0
B _ —0
1: c
1 xH,N
R X = halogen
= hydrogen
NI42 • COOH > )
_
R= OR, =H = alkyl, aryl
R
0
X
181
3.2b Synthesis of 2-Quinoiones
Retrosynthetic analyses of 2-quinolones suggests, three
approaches towards its synthesis.
Based on these the approaches can be classified as shown below.
Approach A : Starting from Aniline
The most common reaction employed using aniline with j3-keto
esters giving Conrad Limpach Synthesis 81 . This involves condensation
of arylamines with 13-keto anilides under controlled conditions, which
on cyclisation gives quinol-2-ones (Scheme XXXI).
H
NH-, , . . , .,_ , _... - N , , , ,, /20 ----/- COR
U + Ci H—R 0
i' ' i R1
>✓
CO------'--'R COOEt / i
R 1 R
Scheme XXXI
Several carbostyrils having substituents at 4 position & 3,4
position have been reported by this method.
Taichi Wang etal reported82 that substituted aniline on
treatment with 3-phenyl-2-propenoyl chloride gave an amide which
on Michael addition followed by dearylation with anhy.AIC13 in
chlorobenzene at 120°C gave 6,7,8-substituted-2-quinolones
(Scheme XXXII).
R
N112 Ph
;
•
c, iJ
11 -
182
Chlorobenzenel anhy AlC13
Ph
n
Scheme XXXII
183
3-substituted-2-quinolone synthesis has been reported 83 by
F. Effenberger and coworker using aniline and a,13-unsaturated acid
chloride (Scheme XXXIII).
NH2 OEt
z0 + HC=C—C—C1
1 0
H
0
OEt Chlorobenzene
anhy AlC13
N 0
'R'
Scheme XXXIII.
R7\
4-Hydroxy quinolone and 3-substituted-4-hydroxy quinolones
synthesis84 a, b ,c have been reported using malonic acid & substituted
malonic ester with PCi3, POC13/ ZnCi2, P205/CH3SO3H, under
thermal conditions, (Scheme XXXIV). NH2
+ CH2 (COOEt)2 PCI3
H
0
OH
H
CH2(COOH)2 100°C lhr POC13 & ZnC12
OH
NH 2
R 2 - ---
NH , _
i CH3SO3H
H .„---------..„1 „...-- -N ----,_ ( 1
,,./ -1, -1 -______ > / --- 1 R2 OH
RLCH(COOE1)2 P205, 1 70`)C
Scheme XXXIV
/1\T--,,/2
CH2Ph
Na HCO2Et 0
'13h
184
Another synthesis has been reported from aniline using ketene
dimer in presence of sulphuric acid 85 (Scheme XXXV).
Ketene Diener
CHz—C -0
CH2=C I 0
OCH3 H
0
O CH3
H2SO4
OCH3
Scheme XXXV
N-acetyl-N-methyl aniline on treatment with diethyl oxalate in
presence of base has been reported to yield 1,4-disubstituted-2-
quinolones86 (Scheme XXXVI).
0 Base
CH3 (C2HSOC)2
O COOEt
I
Scheme XXXVI
Similarly N-phenylacetyl-N-methyl aniline has been used for
the synthesis of N-methyl-3-phenyl quinol-2-one using ethyl formate
in presence of sodium 87 (Scheme XXXVII).
Scheme XXXVII
R' N 0
X • D 2
12. 1 RI 0
N i(PPh3)4 ' oT- I'd(071-6-1 2 1 0
0 R3
185
A report wherein cyclisation of o-halounsaturated anilide in
presence of metal complex like nickel tetratriphenyl phosphine &
palladium acetate has also appeared (Scheme XXXVIII) 88 .
3
R 3
Scheme XXXVIII
H. Boroweic & coworkers have synthesized 4-hydroxy-2-
quinolone via oc,a 1 - Diazoketene 39 (Scheme XXXIX).
Et
N ,0
)
CC/
El
1
o-
— CO
OH
Scheme XXXIX
Polycyclic quinolone functionality has been synthesized from
substituted aromatic isocyanate, cycloalkene amine in presence of
mineral acid 9° (Scheme XXXX).
186
R3 = c= o 0 Fp
R3 H
(h
R R 2N —
Scheme XXXX
R. Abdullah and coworker have reported synthesis of 3-cyano-
4-hydroxy-2-quinolone using aryl isocyanate with cyanoethyl
acetate 91 (Scheme XXXXI).
H N ,O
/„,,____N=C-=-0 ----- ,--- --------- 1, CN 1 Xvlene, re flux
CH-2—COOEt flux
20 hrs -...,,
, ,------_ ---%-, ,----_____--
f --„,,,„ 'CN OH
Scheme XXXXI
As shown in retrosynthetic analysis o-haloaniline also lead to
2-quinolones. A recent report has appeared wherein 3-substituted-2-
quinolones was obtained from o-iodoaniline using a,13- unsaturated
acids in the presence of palladium acetate 92 (Scheme XXXXII).
N1I 2 Ph
r 0 II2C=4— C0011 Pc1(0Ac) 2
2eq El3N 1(X)°C
I-1
C. )
Ph 20%
NH- / Ph
C0011 Scheme XXXXII
187
Approach B: Starting from o-amino carbonyl
compounds
This can be divided into three types, based on the type of
carbonyl group.
a) From o-aminobenzaldehydes
The commonly used method for the synthesis of 2-quinolones
from o-aminobenzaldehydes is Friedlander & Gobring Synthesis. In
this method such aromatic aldehydes are heated with
ethylacetoacetate 93 (Scheme XXXXIII)
H NH2 ---__
- ,---` 1) CH3COCH:COOEt .- 0 ,,, __.) 2) Heat ------ 2,,,,,,,,_-1-----.„ ..„..„..„.„--------,,,,,-- \
H3C0 'CHO H3C0---- COCH3
Scheme XXXXIII
R. Schmid has used Perkin Condensation for synthesizing 2-
quinolones94 (Scheme XXXXIV).
(s) Ac20, Na-acetate 1
Scheme XXXXIV
Intramolecular condensation of o-aminobenzaldehyde, leading
to 2-quinolones 7° is depicted in the Scheme XXXXV.
188
OMe H K, 0
- Me0F1, room temp 0
Cl
OMe NaOMe
H
0
R2 Hz
\ \ COOR
NO2
0 Pt02/C
R I
+ Other products
R2
RI
Scheme XXXXV
A reductive cyclisation using hydrogen over platinum oxide on
carbon has also been reported 95 (Scheme XXXXVI).
Scheme XXXXVI
Similar approach has been carried out in presence of u.v light
and a reducing agent 96 (Scheme XXXXVII).
NOZ
0
\COOH
U.V light
FeSO4; NH3
Scheme XXXXVII
H.
0
OH
189
b) From o-arninoketoues
The method most commonly used has been Camps Synthesis.
3,4-disubstituted-2-quinolones have been synthesized by this
method97 (Scheme XXXXVIII).
H
H .-N
NaOH 132SO4
C112R'
O
R
Scheme XXXXVIII
c) From o-aminobenzoic acids 8s esters
Rowley and coworkers 7° have reported an approach for the
synthesis of 3,4-disubstituted-2-quinolones from methyl
anthranillates. (Scheme XXXXIX).
.____.--,„.„,_____,NH 2
0 + 1 1) BOP-CI, CICH2CHI
CI,-------,,„„,-------,, HO------I s., .„----/---,//, '',--- -----.., me 2) KHMDS. THF, rt CO0Me (;/'
6
H 1)NH3, Me0H, 150°C ,/9 2) (CF3C0) 2 0, Et3N, THF, 0°C
3) K2CO3, Me0 H/H 2 0 , 70°C 0
4) phenylacetyl chloride CL
CH2C12, reflux NH2 5) NaH, DMF, 100°C
Ph
190
Scheme XXXXIX
Such aromatic esters have also been used for the synthesis of
0 4-methoxy quinolone49,95 utilising a novel phosphorane
phosphocumulene and diethylphosphonoketene 53 (Scheme L).
,-NH2
0
CO2Me
H ,0
Ph3P=C=C =0 0 OR 0
(Et0)2i',,
OMe
Scheme L
G. Cappola and coworkers have synthesized 4-hydroxy-2-
quinolone by reacting isotoic anhydride with sodio-diethylmalonate,
followed by hydrolysis and decarboxylation 99 (Scheme LI).
R
N a1) N CH (COOEt)2
2) 014, -CO 2
11"•1
rTh
0
011-
Scheme LI
191
2-Quinolone derivatives have been synthesized from o-amino
aromatic acids and acetic anhydridem (Scheme LII).
Cl
CI, R
0 Ac20
C0011
0H R= Me
Scheme LH
Phosphonium salts have also been used for the synthesis of
polycyclic compoundslo I (Scheme LIII).
H ‘a) PPh;• C 2 H 5 CI -T
`COOEt boil COO-
0
Scheme LIII
Approach C: This approach which has been reported for the
synthesis of coumarin is also reported for 2-quinolone synthesis 1 °2
(Scheme LIV).
Scheme LIV
Other method reported is the one reported for the synthesis of
3,4-diphenyl carbostyrils from 2,3-diphenyl indone and excess of
192
sodium azide in presence of a mineral acid at 70-80 0C in acetic
acidl° 3 (Scheme LV).
H2SO4 excess NaN3
70-80°C CH3COOH
H
Ph
Scheme LV
NH2 II H ,..,.,._ ---,4- -,,,, ,...,--
..---' -,.. ,,--1\1-----,.../ -C1 .....„--"\..„. ....--N---,/ ---- pp' 3 I ,-- - II
-- I. s 1 C1C061:C1
\--• (--.10 PP11.3 0 0 CI
R pyridine
..--- • ..,.,„,,,,,,,---\ R I I 12. 1 -,./. •, -,''R R' 0 0
i I )8
17 a-c
H 11
base CD 0
0
R'•
18 a-c 19 a-c
Scheme LVI
15 a-c 16 a-c
193
3.3b Present work towards synthesis of 2-quinolones
As described in the first section of this chapter a method using
intramolecular Wittig reaction was developed for the synthesis of
coumarins. It was then thought whether this methodology could be
extended for the synthesis of quinolones. Literature survey revealed
that neither intermolecular nor intramolecular Wittig reaction has
been reported except the phosphocumulene and phosphonoketene
method. This prompted us to visualise the synthesis of quinolones as
shown in Scheme LVI on line with the approach used for coumarins
(Scheme XXX).
Compound (15-19) R R 1
a
b
c
OMe
Ph
CH3
H
Cl
H
194
Thus, it was required to prepare the chloroacetyl derivative of o-
amino ketones/esters then, subject them to treatment with triphenyl
phosphine and base to generate a phosphorane which was then
subsequently needed to be condensed in an intramolecular fashion to
give 2-quinolones.
Ready availability of methyl anthranillate made us first to try
the sequence of reaction on it. Methyl anthranillate(15a) on treatment
with chloroacetyl chloride in presence of 10% sodium hydroxide
(Scotten Baumann method) gave a coloured solid which on
recrystallisation using ethanol afforded colourless needle shaped
crystals. The compound melted at 98°C, the structure 16a was
assigned to it. This was further supported by spectral data (given
below)
IR (nujol): vm. 3200, 1700, 1675 cm -1
PMR (CDC13): 300MHz [Fig.3C]
(6 )
3.98
4.21
s
s
3H
2H
COOCH3
COCH2C1
7.18 2dd(J=6.02 86 1.02 Hz) 1H C4-H
7.58 dd(J=6.02 86 1.02 Hz) 1H 05-H
7.09 dd(J = 7.0 86 1.65 Hz) 1H C6-H
8.07 dd(J = 7.0 86 1.65 Hz) 1H C3-H
11.89 bs 1H NH
(exchangeable with D20)
Once the chloroacetyl derivative 16a i.e 2-carboxymethyl
chloroacetanilide 85% yield was obtained, this was treated with leq.of
triphenyl phosphine in chloroform at room temperature for 24 hours.
TLC indicated no formation of salt, so the reaction was refluxed. After
12 hours tic indicated completion of reaction i.e disappearance of
starting and formation of salt. Chloroform was removed, on water bath
O
0
0 >- a rti 2 0
U
0
et
2 cc cc (s)
a
0 in
ce
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---- ------- ------- .. .........
. ..
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..... 1 .........
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I
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. •
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ppm
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:••,:-• :::::::,--•, -
■
1 1 ,
, —
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: .„ . , ... ._
... ... .., .. 7..- 7.7
— __ILL ,k_LJ.:,_.•_ -
--....7-.7 .7/ :ET .• ' ft-'•:__...-.
:f---'7 - 1 .. -.
' ,....LIC . :
---- I - r--- , , I I. , i
: 3... 2.. ■ : . 11
II__ .._..: .._ _PPM - -
Ult7I ill11.1I1717,•f•.1 • L • '-4- I. ' 1- . .
... . 1. ------. i
.. . 4._ .. - 11 --------13 . 10 9 8 • • --- o_:.--
Fig. 3 C
196
and the residue was concentrated under vacuum to give a solid which
on exposure to air resulted in formation of a gummy mass indicating
its hygroscopic nature. All attempts to isolate the free salt failed. So,
it was decided to convert it directly into the phosphorane. Thus, water
was added to the reaction mixture. The aqueous layer was washed
with ether and then basified with 2N NaOH solution when a solid
separated out. This was extracted in chloroform, the chloroform layer
on washing with water, brine and then drying over anhydrous Na2SO4
and evaporation furnished a solid. This solid was recrystallised using
chloroform+pet.ether as solvent for recrystallisation. The
recrystallised solid melted at 172 0C. The structure 18a was assigned
to the phosphorane on the basis of spectral data (given below). The
yield of the phosphorane was found to be 64%.
IR (nujol) : vmax 3400, 1700, 1625 cm - I
PMR (CDC13) :
( 8 )
3.92
6.7
7.3-7.8
7.92
8.6
10.43
s 3H
t 1H
m 17H
dd 1H
dd 1H
bs 1H
(exchangeable with D20)
COOCH3
-CH
Ar-H
Ar-C6-H
Ar-C3-H
NH
Once the required phosphorane was obtained, what was remaining
was the intramolecular Wittig reaction with the carbonyl of the ester
function. Initially refluxing of the compound in chloroform for 24
hours did not indicate any change in the reaction (tic). Since there
had been reports of intramolecular Wittig reaction carried on ester
function using solvents like toluene and even xylene, we attempted to
197
do the same but changing of solvents did not give any success. So, it
was decided to go for neat heating of the phosphorane at 180-200°C.
This attempt gave signs of change in the reaction mixture (tic) and
after 5 hours the reaction reached to completion with the
disappearance of starting phosphorane as indicated by tic. The tic
also showed two new spots, one of them was identified to be that of
triphenylphosphineoxide. The residue obtained was chromatographed
over silica gel. Using chloroform as eluent, the initial fractions gave
triphenylphosphine oxide, while later changing the eluent to 1:9
(MeOH:CHC13) gave fractions that formed solid which melted at
238°C. In IR (nujol) spectrum, it showed a band at
3400cm-1 indicating presence of an amide group. In the carbonyl
region it exhibited a band at 1678 cm - I characteristic for conjugated
amide carbonyl. In PMR (CDC13+DMSO) spectrum it showed a singlet
at 3.95 8 integrating for three hydrogens which could be assigned to
methyl hydrogens of OCH3. Further down it showed a singlet in the
olefinic region at 5.96 8, which could be assigned to hydrogen of
=CHCO group. In the aromatic region it showed a multiplet at 7.0-
8.08 for four protons which could be assigned to four aromatic
hydrogens. A singlet at 11.70 8, exchanged with D20 which indicated
the presence of -NH group of a secondary amide. The mode of
formation and the spectral properties exhibited by the solid,
suggested structure 19a for this compound. It was supported by the
similarity of its m.p. 238°C with the lit. 98m.p.240°C. The percentage
of the product was found to be 90%.
As the quinolone 19a was synthesized in good yield, it became
worthwhile to check whether the similar approach developed could be
a general one, so as to apply it to other substrates. Thus, it was
decided to synthesize 6-chloro-4-phenyl-2-quinolone and 4-methyl-2-
quinolone as corresponding 2-amino-5-chlorobenzophenone and
2-aminoacetophenone are commercially available.
2-Amino-5-chlorobenzophenone(15b) was chloroacetylated in a
similar manner as methyl anthranillate. The compound obtained
3.32 2H NHCH2C1
6.57-7.0 6H Ar-H
7.94 d (J= 8 Hz) 1H Ar-H
11.4 1H NH
(exchang eable with D20)
198
melted at
.200C. The mode of formation and spectral properties
(given elow) exhibited by the compound suggested that it should
have structure 16b.
IR (KBr):vmax 3400, 1690, 1640 cm-1
PMR (CDC13) :
( 6 )
The structure (16b) was further confirmed by similarity of it's
mp.120°C with the lit. 104 imp 119-120°C.
Compound 16b was treated with leq. triphenyl phosphine in
refluxing chloroform to obtain a salt (monitored by tic) which without
isolation was converted to phosphorane 18b by treatment with aq.
NaHCO3 soln. The phosphorane 18b melted at 230°C. On the basis
of mode of formation and spectral data (given below) exhibited by the
compound the sructure 18b was suggested for the compound.
IR (KBr) : v max 3400, 1650 cm-1
PMR (CDC13) : [ Fig.3D]
( 6 )
6.67
-cs 1H CH=PPh 3
6.9-7.1 5H Ar-H
7.2-7.6 19H . Ar-H
The yield of phosphorane was found to be 36%.
• - I -H " _ . :77 -.. _=_F ; . . .. . :'" ... - - .
- ... . . • •
. . _ :.: .. ,_ _ .. -
.4 . .. .. . .... . _ .. _ - -------=-'3 '---, - n - --... .,.-- -.. -. - 7.: •... -7-: : - _ ; _ , .._ _ - - - : _ . :. : -,,,' , :', -,...- • .. .
- : -. 17-. I • — . . -......t.--:: - '-•'—':-:-... ::•• - :-: '-',-, • ' • ,..-., -,
— .- •• • - • • • ■ • • • • • - • • • • •
.... ..
- • • ... 7.17 . -7.
1
7 6 5
r 1---r
4 3 12 10 9 8 2
Fig. 3 D
•• .
• - • • .^ ■ •
I
ppm
A
200
The phosphorane 18b was heated in refluxing diphenyl ether
after 10 mins, it indicated absence of starting compound and
development of two new spots, one corresponding to triphenyl
phosphine oxide. After removal of diphenyl ether under vacuum the
residue remained was column chromatographed over silica gel. Initial
fractions gave a solid which melted at 260°C. In it's IR spectrum it
showed a peak at 3400cm -1 which could be due to the NH group.
Another peak appeared at 1660cm -1 which could be due to the
carbonyl of the amide group. In it's PMR (CDC13) spectrum it showed
a singlet at 6.75 which could be assigned to the olefinic proton of
C3-H. In the aromatic region it showed a multiplet integrating for
eight protons, which could be assigned for eight aromatic hydrogens.
A singlet at 12.29 5 which exchanged with D20 could be assigned for
NH proton of a secondary amide. The mode of formation and spectral
properties exhibited suggest 6-chloro-4-phenyl-2-quinolone (19b) as
the structure for this compound. This was supported by the similarity
of it's m.p.260°C with the lit. 105 m.p.262°C. The yield was found to be
65%. Similarly, 2-Aminoacetophenone (15c) was first
chloroacetylated. The structure of this compound was deduced by
following spectral data.
IR (KBr) : vin. 3400, 1680, 1660 cm -1
PMR (CDC13)
(6 )
1.65 s 3H COCH3
3.15 s 2H COCH2C1
6.18 t 1H Ar-H
6.63 t lH Ar-H
7.0 d (J=8 Hz) 1H Ar-H
7.82 d (J=8 Hz) 1H Ar-H
201
The mode of formation and spectral properties supported
structure 16c for the compound. It's melting point was determined to
be 80°C. The yield of the product was found to be 78%.
The compound 17c was then converted to phosphorane 18c in
the usual manner. The compound obtained melted at 140°C and it's
spectral properties are given below.
IR (KBr): v. 3400, 1650 cm - '
PMR (CDC13):
( 8)
2.51 s 3H COCH3
6.56 bs 1H COCH=PPh3
7.0-8.0 m 9H Ar-H
After the phosphorane 18c was obtained, it was heated in
refluxing diphenylether and chromatographic separation over silica
gel gave a solid. The solid obtained melted at 250°C. In it's IR
spectrum it showed a band at 3400 cm -, indicating presence of NH-
group and a band at 1650 cm -, indicating the presence of carbonyl
group. These observations suggested conjugated secondary amide
group. In it's PMR spectrum [Fig.3E] a singlet was seen at 2.538
integrating for three hydrogens, which could be attributed to methyl
group having allylic coupling. A broad singlet was seen at 6.68
integrating for one proton indicating presence of COCH= group. In the
aromatic region a four proton multiplet was observed at 7.2-7.68,
which could be assigned to four aromatic protons. Another singlet at
11.328 was also seen, which exchanged with D20 and could be
attributed to NH hydrogen. Thus, the mode of formation, spectral
data suggest 4-methyl-2-quinolone (19c), as the structure of this
compound. This was further supported by the similarity of its m.p.
222°C with the lit. 106 m.p.222-224°C. The yield of the compound was
found to be 41%.
CH3 Ui
. . : - • F. - - . _ • :.. .. . .
. ,
IST
ICA
TE
L. I N
ST
RU
ME
NT
AT
ION
CE
1 :1 111 111..1 . 1111,11
7.7 7.6 7.5 7. 4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 PAal
•
12
1 1 11 1 1T 1
9 8
v , ' 7
•/ ;111 F -
6 5 4 3 2 1 PPm
Fig. 3 E
203
As we had prepared stable phosphorane during the preparation
of authentic coumarin samples, we thought of trying intermolecular
Wittig reaction which is not reported, on o-aminoacetophenone as it
was expected to be more reactive of the other two substrates, used as
starting compounds earlier. Thus o-aminoacetophenone was refluxed
with the phosphorane in xylene for 36 hours but, no trace of product
formation was observed. Heating neat at 180-200°C or on refluxing in
diphenylether resulted in only air oxidation of the stable phosphorane
to triphenylphosphineoxide.
0
204
1.4 CONCLUSION
We were able to demonstrate that intramolecular Wittig
reaction could be of use for the synthesis of coumarins & 2-
quinolones. However, the reaction has a limitation as a good
methodology for the synthesis of coumarins, as the yields are low and
also we failed to get corresponding 4-methoxy coumarin, which forced
us not to try synthesis of 3 & 4 substituted coumarins. But, by this
method, one can synthesize 2- quinolones in good yields.
7a 1 la
0 (CH3)2SO4 NaOH
CH30,
)
0 C1130..
N—C—H ,
POC I3
Expt. 3.1 Preparation of 1H-Benzopyran-2-one (11a)
) — [ PPh3Triethylamine -CHO •
SOH
CICOCH2C1, Pyridine
Expt. 3.2 Preparation of 1,3-Dimethoxy benzene
CH 30
Expt. 3.3 Preparation of 2,4-Dimethoxy benzaldehvde
205
3.5 EXPERIMENTAL
Th 1 lb
OH CHC13, KOH
Preparation of 11I-1)ibenzopyran-2-one (11c) Expt. 3.7
CHO
OH - r C1COCH2C1, Pyridinc
PP11 3 ,Trieth ylam inc
Expt. 3.4 Preparation of 2-Hydroxy-4-methoxy benzaldehyde (7b)
C1-130
Expt. 3.5
__OCR; anhy AlC13
0-130
7b
01-1
CHO
(1 1 b)
• CHO
Preparation of 7-Methoxy-1H-benzopyran-2-one
1-1.3C0-„ OH H3CO
C1COCH2CL Pyridine P rPh3iethylamine - T
"-CHO
Expt. 3.6 Preparation of 2-Hydroxy naphthaldehyde (7c)
CHO
7c
7c 11c
206 -
207
OH H3CN
OH 0
I) Me0H, H" 2) CICOCH2CI
Pyridine
H3C OH
CHC13, NaOH..
7d l id
Pyridine CICOCH 2CI
0 COOMe
- ct L.)
—COOMe
7e 8e
Expt. 3.8 Preparation of 241ydroxy-4-methyl henzaldehvde (7d)
CHO
7d Expt. 3.9 Preparation of 7-Methyl -1 II-henzopyran-2-on e (I Id)
CICOCH2CI, Pyridine ( U P1113Triethylamine
Expt. 3.10 Preparation of (2' -Carbomethoxyphenyl) -2 -chloroacetate (8e)
Expt. 3.11 Preparation of (2 1 -Carbomethoxynaphthyl)-2-chloroacetate (80 0 I I CI
COOMe
8f
208
Expt. 3.12 Preparation of (2'-Carbomethoxy)-2-chloroacetanilide (16a)
-NI-1:
--"COOMe
CI
15a 16a
Expt. 3.13 Preparation of Carbomethoxvanilide methylidene - triphenyl phosphorane (18a)
1) PPh3
2) NaOH
H
I I Ph3 t 0 0
COOMe
16a 18a
Ex pt. 3.14 Preparation of 4-Methoxy-2-quinolone (19a)
I3 P113 ' ! 180-200°C
()Mc
18a 19a
4
18b
10 mins CI
CI
(D Retlux in P1120 C) N N
--'1)I311 3 0
209
Expt. 3.15 Preparation of (2'-Benzoy1-4'-ehloro)-2-chloroacetanilide (16b)
CICOCH2CI
0 O NaOH
Cl - COPh CI
CO Ph
15b
16b
Expt. 3.16 Preparation of 2 113enzoy14-chloroanilide methylidene-
triphenyl phosphorane (18b)
CI 1) PPh3
2) NaHCO3
CI
H
\I; 0
COPh
16b 18b
Expt. 3.17 Preparation of 6-Chloro-4-phenyl-2-quinolone (19b)
Ii N „
Ph
19b
Expt. 3.18 Preparation of 2'-Acetyl-2-chloroacetanilide (16c)
15c
Expt. 3.19 Preparation of 2:Aeetvlanilide methvlidene-
triphenvl phosphorane (18e)
16c
1:1„
0 COCH3
I) 13Ph 3
2) NaHCO3
H N
Ph3 • 0
-COCH3
16c
18c
Expt. 3.20 Preparation of 4-Methyl-2-fluinolone (19c)
r 0 ;
r-PPh 3
0 Reflux in Ph20
10 rains COCH3
C H3
18c 19c
0
--"- COCH3 L 0
3
C IC O CH2 C 1 NaOH
210
211
Expt.3.1 Preparation of 1H-Benzopyran-2-one (11a)
A mixture of salicylaldehyde (1g, 8mmol), dry pyridine (0.64g,
8mmol) in dry chloroform was stirred and cooled to about 0°C.
Chloroacetyl chloride (0.92g, 8mmol) was then added slowly. The
resulting heterogeneous mixture was stirred for 2 hours at about 0°C.
Triphenyl phosphine (2.14g, 8mmol) was added and the reaction
mixture was refluxed for 2 hours. The reaction was allowed to attain
room temperature. Triethyl amine (3.76g, 8mmol) was added and the
reaction mixture was stirred for 1 hour. The residue obtained after
evaporation of chloroform was chromatographed over silica gel using
ethylacetate:pet.ether (1:9) as an eluent. The initial fractions gave a
solid which on recrystallisation from dichloromethane+pet.ether
furnished coumarin (0.359g, 30%) as white crystals m.p.68°C (lit. 49
m.p.69°C).
Expt.3.2 Preparation of 1,3 -Dimethoxy benzene
To a stirred, well cooled (0°C) solution of resorcinol (5.5g,
50mmol) in 4N sodium hydroxide (37.5m1, 150mmol), dimethyl
sulphate (9.5m1, 100mmol) was added slowly over a period of 45
mins. After complete addition of dimethyl sulphate the reaction
mixture was heated on water bath for 2 hours. It was cooled &
extracted with ether. The ether layer was washed first with sodium
hydroxide solution & then with water. It was dried over anhydrous
sodium sulphate and evaporated to give an oily product, which was
distilled to give 1,3-dimethoxy benzene (5.7g, 82%) b.p.215°C (lit. 61
b.p.216-217°C).
Expt.3.3 Preparation of 2,4-Dimethoxy benzaldehyde
To a well cooled (0°C), mixture of 1,3-dimethoxybenzene (6.9g,
50mmol) & N,N-dimethyl formamide (4.3g, 60mmol), phosphorous
oxychloride (9.1g, 60mmol) was added slowly with stirring. The
reaction mixture was heated on water bath for 6 hours and poured
into ice cold water (75m1). The solid thus obtained was filtered,
washed with water & dried. It was recrystallised from ethanol to give
product (7.5g, 90%) as white needles m.p.71°C (lit. 62 m.p.71-72°C)
Expt.3.4 Preparation of 2-Hydroxy-4-methoxy
benzaldehyde (7b)
Anhydrous aluminium chloride (2g) was dissolved in methylene
chloride (40m1) with constant stirring. A solution of 2,4-dimethoxy
benzaldehyde (2g) in methylene chloride (10m1) was added to it with
stirring. The reaction mixture was stirred for 2 hours and poured in
ice cold water containing hydrochloric acid (50m1). The organic layer
,separated and the aqueous layer was extracted with methylene
chloride (2x25m1). The combined methylene chloride layer was
washed first with sodium bicarbonate solution and then with water. It
was dried over anhydrous sodium sulphate and evaporated to give a
gummy solid. This was purified by passing through a column of silica
gel using pet.ether as an eluent. The product (7b) was obtained as
white solid, (1.0g, 55%) m.p.41°C (lit. 63 m.p.41.2°C).
Expt.3.5 Preparation of 7-Methoxy-1H-benzopyran-2-
one (11b)
A mixture of 2-hydroxy-4-methoxy benzaldehyde (7b) (0.23g,
lmmol), dry pyridine (0.14m1, lmmol) in dry chloroform (5.0m1) was
stirred and cooled to about 0°C. Chloroacetyl chloride (0.12m1,
213
1 mmol) was then added slowly. The resulting heterogeneous mixture
was stirred for 2 hours at about 0°C. Triphenyl phosphine (0.165g,
1 mmol) was added and the reaction mixture was refluxed for
2 hours. The reaction was allowed to attain room temperature.
Triethyl amine (0.81g, 3mmol) was added and the reaction mixture
was stirred for 1 hour. The residue obtained after evaporation of
chloroform was chromatographed over silica gel using ethylacetate:
pet.ether (1:9) as an eluent. The initial fractions gave a solid which on
recrystallisation from dichloromethane+pet.ether furnished white
crystals of 1 lb (0.07g, 27%) m.p.118°C (lit. 45 m.p.117-118°C).
Expt.3.6 Preparation of 2 -Hydroxy naphthaldehyde (7c)
2-Naphthol (5g, 34mmol) and rectified spirit (15m1) was stirred
vigorously followed by rapid addition of a solution of sodium
hydroxide (10g) in water (21.0m1). The resulting mixture was heated
to 70-80°C on a water bath. Chloroform (2.72m1) was added dropwise
until reaction commences (indicated by the formation of a deep blue
colour), stopped heating & then continued addition of chloroform at
such a rate that the mixture refluxes gently for one and half an hour.
The sodium salt of the phenolic aldehyde separated near the end of
the addition. The stirring was continued for further one hour. The
excess of chloroform & ethanol was distilled off on water bath. To the
residue concentrated HC1 (8.8m1) was added dropwise with stirring,
until the reaction mixture was acidic to congo red paper. A dark oil
with a considerable amount of sodium chloride separated out. Then
sufficient amount of water was added to dissolve the salt, the oil was
extracted with ether (2x25m1), washed the ether solution with water,
dried over anhydrous sodium sulphate & concentrated on water bath.
The slightly coloured aldehyde was distilled at 177-180°C, which
solidified on cooling. The solid obtained on recrystallisation using
ethanol gave pure sample 7c (1.55g, 26%) m.p.47°C (lit.66m.p.47°C).
214
Expt.3.7 Preparation of 1H-Dibenzopyran-2-one (11c)
A mixture of 2-hydroxynaphthaldehyde (0.36g, 2mmol), dry
pyridine (0.16g, 0.16m1, 2mmol) in dry chloroform (5m1) was stirred in
ice cooled mixture at 0°C. Chloroacetyl chloride (0.23g, 0.16m1,
2mmol) was then added slowly. The resulting heterogeneous mixture
was stirred for 2 hours at about 0°C. Triphenyl phosphine (0.535g,
2mmol) was added and the reaction mixture was refluxed for 2 hours.
The reaction was allowed to attain room temperature. Triethyl amine
(0.94g, 2mmol) was added and the reaction mixture was stirred for
one hour. The residue obtained after evaporation of benzene was
chromatographed over silica gel using ethylacetate:pet.ether (1:9) as
an eluent. The initial fractions gave a solid which on recrystallisation
from dichloromethane+pet.ether furnished the product (11c) as white
crystals (0.07, 17%) m.p.116°C (lit. 49 m.p.116-117°C).
Expt.3.8 Preparation of 2-Hydroxy-4-methyl
benzaldehyde (7d)
3-Methylphenol (5.0g, 50mmol) and rectified spirit (10m1) was
well stirred. This was followed by rapid addition of sodium hydroxide
(6.9g) in water (10m1). The reaction mixture was heated at 60-70°C on
water bath and chloroform (4.0m1) added dropwise until the reaction
commences, stopped heating and then continued addition of
chloroform at such a rate that the mixture refluxes gently. After the
addition of chloroform was over, the mixture was further refluxed for
one hour. The excess of chloroform & ethanol was distilled off on
water bath. The residue was treated with stirring, dropwise
concentrated HC1 (12.9m1) until the reaction mixture was acidic, a
dark oil with some sodium chloride separated out. It was then steam
distilled to obtain 2-hydroxy-4-methylbenzaldehyde (2.83,45%)
m.p.59-60°C (lit.67m.p.59-59.6°C).
215
Expt.3.9 Preparation of 7-Methyl-1H-benzopyran-2-one
(11d)
A mixture of 2-hydroxy-4-methyl benzaldehyde (0.207g,
1.5mmol), dry pyridine (0.093m1, 1.5mmol) in dry chloroform was
stirred and cooled to about 0°C. Chloroacetyl chloride (0.92g, 8mmol)
was then added slowly. The resulting heterogeneous mixture was
stirred for 2 hours at about 0°C. Triphenyl phosphine (0.368g,
1.5mmol) was added and the reaction mixture was refluxed for 2
hours. The reaction was allowed to attain room temperature. Triethyl
amine (1.22g, 3mmol) was added and the reaction mixture was
stirred for one hour. The residue obtained after evaporation of
chloroform was chromatographed over silica gel using
ethylacetate:pet.ether (1:9) as an eluent. The initial fractions gave a
solid which on recrystallisation from dichloromethane+pet.ether gave
lld (0.040g, 16%) m.p.118°C (lit. 64 m.p.119°C).
Expt.3.10 Preparation of (2'-Carbomethoxypheny1)-2-
chloroacetate (8e)
Methyl Salicylate 7e, (4.0, 20mmol), chloroacetylchloride
(2.08m1, 20mmol) and pyridine (2.12m1, 20mmol] was stirred .
vigorously in dry benzene (10m1) for two hours. The reaction mixture
was concentrated, water added and the aqueous layer extracted in
ether (3x25m1). The ethereal solution was then washed with 2N HC1
(2x15m1) to remove pyridine and then with water (2x15m1). The ether
layer was then dried over anhy.sodium sulphate and concentrated to
give the product as white solid, (4.95, 82.37%) which was
recrystallised from ethanol m.p.65°C (lit. 50a m.p.65°C).
216
Expt.3.11 Preparation of (2'-Carbomethoxynaphthyl)-2-
chloroacetate (8f)
A mixture of 2-hydroxy naphthoic acid (2.0g, 10.6mmol),
methanol (0.34g, 10.6mmol) and a drop of sulphuric acid was
refluxed for two hours. The reaction mixture was concentrated and
taken in ether (15m1) and washed the ether layer with saturated
sodium bicarbonate solution (2x10m1). The ether layer was dried over
anhydrous sodium sulphate and concentrated on water bath. The
solid obtained on purification using ethanol gave methyl-2-hydroxy
naphthoate of 2- hydroxy naphthoic acid m.p. 78°C (lit. 50b m.p 78°C)
Methyl-2-hydroxynapthoate (2.0g, 9mmol), chloroacetyl
chloride (0.78m1, 9mmol) and dry pyridine (0.79m1, 9mmol) was
stirred vigorously in dry benzene (10m1) for two hours. The reaction
mixture was concentrated, water added and the aqueous layer
extracted in ether (3x25m1). The ethereal solution was then washed
with 2N HC1 (2x15m1) to remove pyridine and then with water
(2x15m1). The ether layer was then dried over anhydrous sodium
sulphate and concentrated to give the product as white solid, (4.95,
82.37%) which was recrystallised from ethanol (1.54g, 55.84%) m.p.
108°C.
Expt.3.12 Preparation of 2'-Carbomethoxy-2-
chloroacetanilide (16a)
Chloroacetyl chloride (1.02g, 9mmol) was added to a stirred
solution of methyl anthranillate (1.4g, 9.2mmol) and pyridine (0.7g,
9mmol) in dry chloroform (5m1). The reaction mixture was stirred
overnight at room temperature. The reaction mixture was
concentrated, water was added and then the aqueous layer was
extracted with ether (3x25m1). The ether layer washed with sat.
NaHCO3 (2x15m1) & dilute HC1 (2x15m1). Finally washed with water
0
217
(15m1) and the ethereal solution was dried over anhydrous sodium
sulphate. On concentration a solid was obtained, which on
recrystallisation from ethanol gave white crystals (1.89, 85.3%) m.p.
98°C.
Alternate method using sodium hydroxide
Chloroacetyl chloride (1.02g, 9mmol) was added to a swirled
solution of methyl anthranillate, (1.4g, 9.2mmol) and 10% sodium
hydroxide (12m1). Once the addition was complete the reaction
mixture was swirled for further 10 mins. Crude dark coloured solid
separated out, which was filtered under suction pump, and
recrystallised from ethanol to give white crystals of 16a (1.66g, 75%)
m.p.98°C.
Expt.3.13 Preparation of 2 1 -Carbomethoxyanilide
methylidene triphenyl phosphorane (18a)
Compound 16a and triphenyl phosphine (0.98g, 3mmol) was
stirred overnight in dry chloroform (5m1). The reaction mixture was
concentrated on water bath & water (10m1) was added to it. The
aqueous layer was washed with ether (2x15m1). Sodium hydroxide
(2N) (20m1) was added to the aqueous layer, formation of
phosphorane observed. The basic aqueous layer was extracted using
ether (2x15m1). The ether layer was dried over anhydrous sodium
sulphate. Then it was concentrated to give light yellow coloured solid
which on recrystallisation from ethanol gave cream coloured crystals
(1.008g,.63.93%) m.p.172°C.'
218
Expt.3.14 Preparation of 4-Methoxy-2-quinolone (19a)
Phosphorane 18a (0.152g, 0.3mmol) was heated at 180-200°C
in oil bath for 5 hours. Column Chromatography separation using
methanol:chloroform (1:9) mixture as eluent gave pure solid (0.057,
90%) m.p.238°C (lit. 49 ' 98 m.p.240°C).
Expt.3.15 Preparation of 2'-Benzoy1-4'-chloro-2-
chloroacetanilide (16b)
2-amino-5-chlorobenzophenone (3.0g, 0.0 lmol), chloroacetyl
chloride (1.68m1, 0.01mol) and sodium hydroxide in water (10%) was
stirred for 15 mins. This was continued till no smell of acid chloride
remained, a solid (crude) appeared. The solid was filtered, dried and
recrystallised from ethanol to give pure white compound 16b (3.47g,
87%) m.p.120 °C (lit. 104 m.p119-120°C)
Expt.3.16 Preparation of 2'-Benzoyl-4'-chloroanilide
methylidene triphenyl phosphorane (18b)
Compound 16b (0.53g, 1.7mmol) and triphenyl phosphine
(0.45g, 1.7mmol) in dry chloroform (10m1) was refluxed for 12 hours.
The reaction mixture concentrated under vacuum. Water was added,
the aqueous layer was washed with ether (3x15m1). Then sodium
bicarbonate (sat.) was added to the aqueous layer. This solution was
then extracted in chloroform (3x25m1). The chloroform layer was dried
over anhydrous sodium sulphate and concentrated to yield
phosphorane 18b (0.325g, 35.6%) m.p.230°C.
219
Expt.3.17 Preparation of 6-Chloro-4-pheny1-2-
quinolone (19b)
Phosphorane 18b (0.1,0.2mmol) in diphenyl ether (5.0m1) was
refluxed for 10 minutes. The solvent was distilled off on oil bath
under vacuum. Column chromatography using methanol:chloroform
(1:9) gave white coloured product, which was recrystallised from
chloroform:pet.ether (3:7) (0.025g, 65.25%) m.p.260°C
(lit 105 m.p.262°C).
Expt.3.18 Preparation of 2'-Acetyl-2-chloroacetanilide
(16c)
2-Amino acetophenone (2.0g, 0.01mol), chloroacetyl chloride
(1.67g, 0.01mol) and sodium hydroxide in water (10%) was stirred for
15 mins. This was continued till no smell of acid chloride remained, a
solid (crude) appeared. This solid was filtered, dried and recrystallised
using chloroform:pet.ether (3:7) mixture to give pure white compound
16c (1.88g, 60%) m.p.80°C.
Expt.3.19 Preparation of 2'-Acetylanilide methylidene
triphenyl phosphorane (18c)
Compound 16c (1.0g, 4.7mmol) and triphenyl phosphine
(1.24g, 4.7mmol) in dry chloroform (10m1) was refluxed for 12 hours.
The reaction mixture concentrated under vacuum. Water was added,
the aqueous layer was washed with ether (3x15m1). Then sodium
bicarbonate (sat.) was added to the aqueous layer. This solution was
then extracted in chloroform (3x25m1). The chloroform layer was dried
over anhydrous sodium sulphate and concentrated to yield
phosphorane 18c (1.62g, 78%) which was recrystallised from
chloroform:petether (3:7) m.p.140°C.
220
Expt.3.20 Preparation of 4-Methyl-2-quinolone
(19c)
Phosphorane 18c (0.1g, 0.2mmol) in diphenyl ether (5.0m1) was
refluxed for 10 minutes. The solvent was distilled off on oil bath
under vacuum. Column chromatography using methanol:chloroform
(1:9) as an eluent gave white coloured product (19c) (0.01g, 41%)
m.p.2220C (1it.106m.p.222-224°C).
