2016 CLAYTON : THE COUMARIN CONDENSATION.

CC1.- The Cournarin Condensation.

By ARTHUR CLAYTON.
IN 1883 and 1884 von Pechmann (Ber., 1883, 16, 2119; Ber.,
1884, 17, 929, 1646) and others found that phenols condense
with ethyl acetoacetate and malic acid i n the presence of concen-
trated sulphuric acid to form members of the coumarin series.
Different phenols were found to condense with varying degrees of
readiness; thus phenol, 0- and p-cresols, quinol, and thymol gave
extremely poor yields (phenol furnished not more than 3 per cent.
of the theoretical quantity), but resorcinol, orcinol, and pyrogallol
condensed very readily. Later, Pechmann (Bey., 1899, 32, 3681)
showed that dimethyl-m-aminophenol condensed readily with ethyl
acetoacetate, whilst the corresponding ortho- and para-compounds
yielded only traces of coumerins. Still more recently Fries and
Klostermann ( Be y . , 1906, 39, 871) condensed m-cresol with malic acid
and ethyl acetoacetate, and showed that a plentiful yield was obtained
in each case.
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CLAYTON : THE COUMARfN CONDENSATION. 201 7
From the above, it is readily seen that meta-substituted phenols
condense readily with ethyl acetoacetate and malic acid, and
that,, on the other hand, the corresponding ortho- and para-compounds
are comparatively inert in this respect.
The influence of the nature of the substituent was indicated by the
experiments of Pechmann (Ber., 1899, 32, 3681), i n which he showed
that the negative groups NO, and C0,H prevented condensatiou.
The experiments described i n the present communication were
undertaken with the view of obtaining further knowledge of the
influence of the position and nature of the substituent group or
atom.
I n order to examine the influence of substituent groups which are
known to favour this condensation, 1 : 2 : 4-xylenol, 1 : 3 : 4-xylenol,
1 : 3 : 5-xylenol, and 1 : 4 : 5-xylenol were treated with a molecular pro-
portion of ethyl acetoacetate or malic acid i n the presence of concen-
tmted sulphuric acid. 1 : 2 : 4-Xylenol was found to yield about 60
per cent., 1 : 3 : 4-xylenol 50 per cent., and 1 : 3 : 5-xylenol 40 per cent
of the theoretical quantity of the corresponding cournarin, whilst
1 : 4 : 5-xylenol only condensed with extreme difficulty, not more than
1 pr cent. of the theoretical yield being obtained.
The substituents which appear to exert this peculiar influence are
the hydroxyl, dimethylamino-, and alkyl groups.
These results, taken i n conjunction with those obtained by von
Pechmann and his collaborators, shorn that the condensation of phenols
with ethyl acetoacetate or malic acid is facilitated by the presence of
one of the foregoing groups (hydroxyl, dimethylamino-, and alkyl) in
position 5 (formula I), position 2 being occupied by the carbon
atom taking part in the condensation. It is also seen tlintl,
x
X/)OH
\/
(1.1 (11.) (111.)
although the presence of the group in the position 4 or 6 does not
render phenol more reactive, the introduction of methyl or hydroxyl
i n both of these positions has the same effect as that produced by sub-
stituting the hydrogen atom i n position 5.
It would appear that there is some important connexioo between the
carbon atom taking part in the condenxition and that i n the para-
position to this atom, for only if position 5 is masked, either by direct
substitution (formula 11) or by a substituent on each side (formula
III), does condensation with ethyl acetoacetate readily take place,
I n order to study the influence exerted by other groups, the nitro-
phenols, chlorophenols, cyanophenols, and the esters of the three
hydroxybenzoic acid were examined.
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2018 CLAYTON : THE COUMARIN CONDENSATION.
The results obtained with the three nitrophenols confirmed those of
von Pechmann (Ber., 1899, 32, 3681), no condensation products being
obtained.
m- and p-Chlorophenols were found to yield respectively 3 and 6 per
cent. of the theoretical quantity of a chlorocoumarin. A coumarin
derivative was not isolated i n the case of o-chlorophenol.
The esters of the three hydroxybenzoic acids were examined in order
to ascertain whether the disappearance of the acidity of the group
would alter the inhibiting effect noticed by von Pechmann (Ber., 1899,
32, 3681), but since the formation of coumarins does not take place,
it mould appear that the acidic nature of the group is not the essential
condition which prevents condensation.
The cyanophenols were found to be converted into the corresponding
amides of the hydroxybenzoic acids under the conditions of the experi-
ments. I n the case of o-cganophenol, this conversion took place with
great ease, about 90 per cent. of the theoretical quantity of
salicylamide being obtained.
t,h-Cumenol was also condensed with ethyl acetoacetate and malic
acid, but owing to the difficulty of isolating the products, the yields
obtained could not be taken as significant. From the results obtained
with 1 : 3 : 5-xylenol and +-cumenol, a substituent i n position 3 appears
to inhibit condensation to some extent.
I. Phenols of the types shown i n formuls I and I1 (where X is
an alkyl, hydroxyl, or dialkylamino-group) condense readily with
malic acid and ethyl acetoacetate to form derivatives of coumarin.
11. Chlorine as a substituent has an effect similar to that of the
above groups, but its influence is very much less marked,
111. The introduction of such substituents as NO,, CO,H, and
C0,Et prevents condensation.
EXPERIMENTAL.
Coumarins derived from 1 ; 2 : 4-Xylerrol.
( i ) 6 : 7-Dimethylcoumarin was obtained by heating a mixture of
2.5 grams of 1 : 2 : 4-xylenol and 2.7 grams of malic acid with 6 C.C. of
concentrated sulphuric acid until the evolution of carbon monoxide
ceased. When cold, the liquid was poured on to crushed ice, and
yielded a solid product, which, when crystallised from alcohol, formed
white needles, melting at 148-149' :
0.1309 gave 0.3638 CO, and 0.0676 H,O.
(ii) 4 : 6 : 7-5"~immthyZcoumctrin was prepared by mixing 3 grains of
C = 75-80 ; H = 5.74.
Cl,HloO, requires C = 75-86 ; H = 5.75 per cent.
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CLAYTON : THE COUMARIN CONDENSATION.
2019
1 : 3 : 4-xylenol with an equal weight of ethyl acetoacetate, a d adding
4 C.C. of concentrated sulphuric acid. After twenty hours, the liquid
was poured on to ice, and yielded a solid which crystallised from
alcohol i n white needles melting at 169-170, the yield being 1. 8
grains of the pure product :
0.1815 gave 0.5064 CO, and 01048 H,O.
C12Hl,0, requires C = 76.60 ; H = 6.38 per cent.
(iii) 3 : 4 : 6 : 7-Y'etra~~~etl~ylcoumarin.-This compound was obtained
by mixing 2.5 grams of 1 : 2 : 4-xylenol with 2.7 grams of ethyl methyl-
acetoacetate and treating the mixture with cold concentrated sulphiiric
acid. 2.4 Grams of the crude product were obtained, which, on crystal-
lisation from alcohol, yielded 1.9 grams of white needles melting at
134-1 35' :
C = 76-08 ; H = 6.41.
0.1661 gave 0.4679 CO, and 0.1041 H,O. C= 76.83 ; H= 6.97.
C,,HI,O, requires C = 77-33 ; H = 6. 93 per cent.
Coumurins derived from 1 : 3 : 4-Xylertol.
6 : 8-DinzetAyZcoumarin, the condensation product of 1 : 3 ; 4-xylenol
and malic acid, was prepared in the usual manner. These substances
were heated with concentrated sulphuric acid, and he cold mixture
poured on to crushed ice, when a black tar was deposited, which, after
stirring for some time, became solid. This was extracted with
petroleum, and the solution yielded well-defined, white needles, melting
at 95". About 30 per cent. of the theoretical yield was obtained, but
the difficulty of isolating the product probably caused a consideiable
loss of material :
0.1692 gave 0.4689 CO, and 0.0888 H,O.
C,,HloO, requires C= 15-86 ; H=5. 75 per cent.
4 : 6 : 8-Trimethylcournarin was obtained by condensing equal weights
of ethyl acetoacetate and 1 : 3 : 4-xylenol i n the presence of cold
concentrated sulphuric acid. The solution was allowed to remain for
two days, and was then poured on to crushed ice. The resulting solid
crystallised from alcohol i n white needles, melting at 116-117. The
yield was about 50 per cent. of the theoretical amount :
C = 75.56 ; H= 5.54.
0.1808 gave 0.50'70 CO, and 0,1079 H,O.
C,,H1,O, requires C = 76.60 ; H = 6.38 per cent.
3 : 4 : 6 : 8-lretramethylcoumal.in.-This compound resulted from the
condensation of 1 : 3 : 4-xylenol and ethyl methylacetoacetate in
molecular proportion. The product was obtained withouc difficulty,
and crystallised from alcohol in white needles melting at llO-lllo.
The yield was about 25 per cent. of the theoretical amount :
C1,H1,O, requires C= 77-33 ; H = 6. 93 per. cent.
C = 76.47 ; H = 6.63.
0.1332 gave 0.3754 CO, and 0.0832 H,O. C = 7 6 6 5 ; H = 6-94.
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2020 CLAYTON : THE COUMARIN CONDEKSATION.
Coumarim derived f r o m 1 : 3 ; 5-Xyleszol.
4 : 5 : 7-~rinzethylcourr~arin.-l : 3 : 5-Xylenol and ethyl acetoacetate
mere condensed together in the usual manner. The crude product
crystalliscd from alcohol in brilliant flakes, having a pearly lustre and
melting at 175-176'. From 35 to 40 per cent. of the theoretical
quantity was obtained :
0.0964 gave 042690 GO, and 0.0562 H,O.
C12H1202 requires C 2= 76.60 ; H = 6.38 per cent.
3 : 4 : 5 : 7-Tetm?netlLyZcoumo,rin was prepared from ethyl methyl.
acetoacetate and 1 : 3 : 5-xylenol in the presence of cold concentrated
sulphuric acid. A pink product was obtained, but on repeated
crystallisation from alcohol this colour grew fainter, and finally
disappeared. One gram of 1 : 3 : 6-xylenol yielded 0'16 gram of
crystals melting at 154' :
C= 76.10 ; H= 6.48.
0.0667 gave 0.1SSO CO, and 0.0427 H,O. C = 76.32 ; H = 7. 1 1.
C13H1402 requires Cf 77. 23 ; H = 6. 93 per cent.
Coumcwin derived f rom 1 : 4 : 5-Xplenol.
6 : 8-Dtnaet~~~Z~~ouma?.in.--Twelve grams of 1 : 4 : 5-xylenol and 13
grams of malic acid mere ground together and treated with 30 C.C. of
concentrated sulphuric acid, the mixture being heated until the
evolution of carbon monoxide ceased. After twenty hours, the liquid
was poured on to crushed ice, The tar which separated did not solidify
for several days, but, on dissolving i t in a 15 per cent;. solution of
sodium hydroxide and subsequently acidifying with hydrochloric acid,
a light brown powder was obtained. This was very impure, and mas
therefore extracted with petroleum, the extract yielding about 0. 2
gram of fine, white needles, melting at 122-123' :
0,0542 gave 0,1504 CO, and 0.0296 H,O. C= 75.59 ; I3 = 6.03.
CllH1,O, requires C = 75-86 ; H = 5.75 per cent.
Coumarins derived from $-CumenoZ.
5 : 6 ; 8-Trimethylcoumarin.--Three grams of q-cumenol and 3 grams
of malic acid were heated with 8 C.C. of concentrated sulphuric acid
i n the usual manner. After crystallising the product from alcohol,
about 40 per cent. of the theoretical yield of crystals was obtained.
When pure, the crystals melted at 114-115O:
0.1890 gave 0.5302 CO, and 0.1087 H,O.
C12H1202 requires C = 76.60 ; H = 6-38 per cent.
4 : 5 : 6 : 8-27etranaeth?/lcoumarin was obtained by the condensation
of $-cumenol and ethyl acetoacetate, but there appeared to be a side
C = 76.50 ; H = 6*39.
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CLAYTON : THE COUMARIN CONDENSATION. 2021
reaction taking place, the mixture frothing continually. After
fmenty hours, the solution was poured on to crushed ice, and yielded
a quantity of an oily product, which set into an almost solid mass
after forty-eight hours. The substance so obtained was extracted
with benzene, and crystallised from the same medium. Subsequent
crystallisation from alcohol yielded pure white needles, melting at
114-115O. About 12 per cent. of the theoretical yield was
obtained :
0.0775 gave 0.2200 CO, and 0.0485 H,O.
3 : 4 : 5 : 6 : 8-Pentamet~yZcozLm~~~. -This coumaxin resulted from
the condensation of equal weights of ethyl methylacetoacetate and
+-cumenol. The solution of these two substances in concentrated
sulphuric acid was allowed to remain for twenty hours, and was
then poured on to crushed ice. The oil which separated could not
be made to solidify after two weeks, but by cooling i t to - 15O it
was obtained sufficiently viscous for removal from the aqueous
liquid. The product resisted all attempts at crystallisation, but it
was found that by rubbing i t with a few drops of ether, a white.
and perfectly solid substance was obtained. This was immediately
drained on a porous tile, and then crystallised from petroleum.
The white needles obtained in this manner melted at 127"
The yield was very small, owing to loss during tbe isolation of the
compound :
C = 77.42 ; H = 6.82.
C,,H,,O, requires C = 77-23 ; H = 6.93 per cent.
0.1036 gave 0,4387 CO, and 0,1036 H,O. C.= 77.37 ; H= 7. 44.
C14H1602 requires C = 77-78 ; H = 7.41 per cent.
CousnaAns derived from I 1 1-Chlorophenol.
7-ChZorocoumar.in was obtained by treating a mixture of 5 grams
of m-chlorophenol and 5 grams of malic acid with 13 C.C. of
concentrated sulphuric acid. The liquid was heated until the
evolution of carbon monoxide ceased, and was then allowed to cool,
After two hours, the acid solution was poured on to crushed ice in
order to precipitate the chlorocoumarin. 'Ilhe semi-solid product
was extracted three times with petroleum, and, on evaporating the
latter, white needles (0. 3 gram) were obtained, which, after further
crystallisation from alcohol, melted at 129' :
0.0607 gave 0.0481 AgCl. C1=19.60.
0.0856 ,, 0.1873 CO, and 0.0208 H,O. C = 59.67 ; H = 2.57.
C,H,02C1 requires C1= 19.67 ; C = 59.83 ; I3 = 2.77 par cent.
7-Ci~Eoro-4-methyZcoumarin was obtained by condensing 5 grams of
m-ohlorophenol with 5 grams of ethyl acetoacetate in the presence of
12 C.C. of cold Concentrated sulphuric acid. After twenty hours, the
VOL. XCIII. 6 s
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2022 CLAY TON : THE COUMARlN CONDENSATION.
liquid was poured into ice-water, and the solid product separated by
filtration. Cry stallisation from alcohol yielded 0.45 gram of white
needles, or about 6 per cent. of the theoretical amount. The substance
melted at 144' :
0-0956 gave 0.0747 AgCl. C1=18.38.
0.1073 ,, 0.2627 CO, and 0-0365 H20. C = 61.69 ; H = 3.78.
C,,H70,C1 requires C1=18.25 ; C = 61.70 ; H = 3.60 per cent.
Coumarinna derived from p-ChZoyophen ol.
6-G'hZo~*ocoumarin resulted from the condensation of 13 grams of
p-chlorophenol and 14 grams of malic acid in the presence of 30 C.C. of
concentrated sulphuric acid, the solution being heated as usual. After
cooling the liquid and pouring it into ice-water, a black tar was
deposited. This product, on extraction with petroleum, furnished a
white solid, which crystallised from alcohol in tiny, white needles,
melting at 161-162'. The yield was about 2.5 per cent. of the
theoretical amount.
The substance has a well-marked odour of coumarin, and is possibly
identical with the " P-chlorocoumarin " obtained by Basecke (Annulen,
1870, 154, 84), the melting point of this substance being given as
162' :
0.0686 gave 0.0547 AgC1. C1=19.81.
0.1048 ,, 0.2316 CO, and 0.0285 H,O. C= 60.26 ; H = 3.02.
C,H,O,Cl requires C1=19-67 ; C = 59.83 ; H = 2.77 per cent.
6-ChZoro-Cmethylcozlmari~. -This substance was prepared by mixing
5 grams of othyl acetoacetate, 5 grams of p-chlorophenol, and 12 C.C. of
cold concentrated sulphuric acid, the mixture being allowed to remain
for twenty hours. After that period, the liquid was poured into ice-
water. The white solid which separated was crystallised from alcohol,
from which it separated in white needles, melting at 184-185'. The
yield was about 2.7 per cent. of the theoretical quantity :
0,1406 gave 0.1032 AgC1.
0.1779 ,, 0.4016 CO, and 0.0568 H,O. C = 61.60 ; H = 3.55.
C = 61.70 ; H = 3.60 per cent.
Experiments with o-chlorophenol did not result in the isolation of
any coumarin, the oils and tars which resulted proving to be uncrys-
tallisable. The odour of these products, however, showed that con-
dehsation had taken place to some slight extent.
Cl = 18.16.
C,,H70,Cl requires C1= 18.25.
ROYAL COLLEGE OF SCIENCE, LONDON,
SOUTH KENSINGTON, S. W.
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