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22
[CONTFKBUTION FROM THE ORGANIC CHEMISTRY DEPAETMENT, THEINSTITUTE O F SCIENCE]
Formylation of Benzopyrones. 11. Formylation of Hydroxycoumarins with N-Methylformanilide' R. M. NAIK
AND
V. M. THAKORZ
Received May 2.2, 1967 The formylation of 5,7-dihydroxy-Pmethyl-, 5-hydroxy-4methyl-, and 4,7-dimethyl-5-hydroxycoumarinswith N methylformanilide has been investigated for the first time and the resulting formylcoumarins have been subjected to Dakin oxidation to furnish the correspondjng o-dihydroxycoumarin derivatives. The formylation of 4methyl-5,6,7-trihydroxycoumarin met with a failure although 4methyl-5,6,7-trimethoxy-4-methylco~rin could be formylated to furnish the 8-formyl derivative in poor yield. The applicabfity of N-methylformanilide as a formylating agent to the coumarin series appears to be limited. With almost all coumarins a good amount of the unreacted substance was recovered.
In an earlier publication3 it was pointed out that the formylation of 5,7-dihydroxy- and 5,6,7-trihydroxy-4-methylcoumarins with hexamethylenetetramine met with failures. To find a suitable method of formylation, which could also be applicable to 5,7-dihydroxy- and 5,6,7-trihydroxy-coumarinsl Nmethylformanilide has been tried for the first time in the coumarin series and the findings are described in this communication. The f ormylation of 5,7-dihydroxy-4-methylcoumarin (I) with N-methyl-formanilide in the presence of phosphorus oxychloride furnished a monoformyl derivative m.p. >315", in a fairly good yield. This aldehyde smoothly underwent Dakin oxidation to give the known4 4-methyl-5,7,8-trihydroxycoumarin (111) which was methylated to 4-methyl-5,7,8-trimethoxycoumarin (IV). Hence H y . . $ J @
H
o
OH CHa H
OB
HO
OH CH3
I c
e
OH CH3
IS 3OCHa o w
CHIO
CHa
o
IT1 H
o
CHjO
e
CH3
Iv
V
the structure of 5,7-dihydroxy-8-formyl-4-methylcoumarin (11) has been assigned to the monoformyl derivative. The 6-formyl isomer does not appear to have been formed. The methylation of 5,7-dihydroxy-8-formyl-4-methylcoumarin(11) furnished 8formyl - 7 -hydroxy - 5-me thoxy - 4-me thylcoumarin (V) and 5,7-dimethoxy-8-formyl-4-methylcoumarin (VI), the former (V) of which afforded 7,S-dihydroxy-5-methoxy-4-methylcoumarin(VII) on Dakin oxidation. The reaction of N-methylformanilide with 5,7-dimethoxy-4-methylcoumarin(VIII) yielded two monoformyl derivatives, melting point 267" and 284". The aldehyde, m.p. 267", was identical with the above described 5,7-dimethoxy-B-formyl-4-methylcoumarin (VI) and hence the only other possible structure of 5,7-dimethoxy-6-formyl4-methylcoumarin (IX) has been assigned to the other isomer, m.p. 284". On warming with 10% sodium hydroxide on a steam bath, both the isomers (VI and IX) went into solution, but on gentle acidification the 8-formyl derivative (VI) furnished presumably 4,6-dimethoxy-3-formyl-/3-methylcoumarinic acid (X), whereas the 6-formyl isomer (IX)was recovered. The Elbs persulphate oxidation of 5,7dimethoxy-8-formyl-4-methylcoumarin (VI) afforded 5,7-dimethoxy 6-hydroxy-8-formyl-4-methylcoumarin (XI) in poor yield. The formylation of
cH30w0 CH30
CH3
VI11
I
CH90
VT
AHs
I
CHsO
I
CHI
VI1
(1) This paper comprises a portion of the thesis presented by R. M. Naik towards the requirement for the degree of Doctor of Philosophy of the University of Bombay and the work was carried out during the tenure of the Government of India Scholarship. (2) Present address: Department of Chemistry, Gujarat College, Ahmedabad. (3) R. M. Naik and V. M. Thakor, J . Org. Chem., 22, 1626 (1957). (4) V. D. Nageswara Sastri and Co-workers, Proc. Ind. A d . Sci., 37A, 681 (1953).
CHO " H 3 9 o " CHsO
CHB
X
DECEMBER
1957
FORMYLATION OF BENZOPYRONES. I1
1631
4-methyl-5,6,7-trihydroxycoumarinwith N-meth- N-methylformanilide as a formylating agent to the ylformanilide did not succeed and the substance coumarin series is apparently very limited, 5,7-diwas either recovered almost quantitatively or de- hydroxy-4-methylcoumarin being the only one stroyed under drastic conditions. However, the which gave the aldehyde in a fairly good yield. The formylation of 4-methyl-5,6,7-trimethoxycoumarin rest of the coumarins could be formylated only (XII) succeeded partially to give the 8-formyl de- partially giving poor yields of the aldehydes or rivative (XIII) as a light yellow oil. It was charac- could not be formylated at all. The separation of terized by the preparation of a 2,4-dinitrophenyl- the unreacted substances and the formyl derivahydrazone which was found to be identical with tives or sometimes the mono-formyl isomers, eventthat of the methyl ether of 5,7-dimethoxy-6-hy- ually turned out to be difficult. droxy-8-formyl-4-methylcoumarin(XI),
R
p
R
/
W
EXPERIMENTAL'
6,7-Dihydroxy-8-formyE-4-methylcoumarin (11). To a mixture of 5.7 g. of 5,7-dihydroxy-4-methylcoumarin and 5.0 g. HO CH, HO CFI3 of N-methylformanilide in 15 cc. of distilled, dry o-dichlorobenzene, 5 cc. of phosphorus oxychloride was added and the XIV XV reaction mixture, fitted with a condenser and guarded from moisture, was heated on a steam bath for 0.5 hr. with interCHO mittent shaking. Vigorous fumes evolved for about 15 min. and then subsided. On adding about 100 cc. of saturated R W R / W sodium acetate solution and removing o-dichlorobenzene by / HO steam distillation, a pinkish brown amorphous product HO CH3 HO CH3 separated. It was filtered hot and the amorphous product XVII (3.5 9.) obtained was found to be very sparingly soluble in XVI boiling alcohol, acetic acid, benzene, chloroform, or acetone. The N-methylformanilide reaction with 5-hydroxy- A sample of this product was twice crystallized from 4-methylcoumarin (XIV, R = H) furnished a mono- acetone in thin white flocculent needles, m.p. >315". It formyl derivative, m.p. 220", in poor yield and gives a blood red coloration with alcoholic ferric chloride and dissolves in alkali giving light yellow solution. most of the unreacted coumarin was recovered. The Anal. Calcd. for C I ~ H ~ OC,~ :60.0; HI 3.6. Found: C, structure of 6-formyl-5-hydroxy-4-methylcoumarin 60.3; HI 3.8. The methylation of I1 afforded a mixture of 8-formyl-7(XV, R = H) has been assigned to the aldehyde as it furnished the known6 5,6-dihydroxy-4-methyl- hydroxy-5-methoxy-4-methylcoumarin(V) and 5,7-dimeth(VI). It was separated by coumarin (XVII, R = H) on Dakin oxidation. The oxy-8-formyl-4-methylcoumarin treatment with dilute alkali. The filtrate on acidification 8-formyl isomer could not be traced. The formyla- yielded 8-formyl-7-hydroxy-5-methoxy-4-methylcoumarin tion of 4,7-dimethyl-5-hydroxycoumarin(XIV, R (V) which crystallized from acetic acid (charcoal) as 1.8 g. = CH,) with N-methylformanilide afforded two of thin white needles, m.p. 224". It gives a red coloration monoformyl isomers, m.p. >315" and m.p. 218", with alcoholic ferric chloride and forms a yellow insoluble salt on treatment with alkali. both in poor yield, whereas most of the original sodium And. Calcd. for C&1006: C, 61.6; HI 4.3. Found: C, coumarin was recovered. The product, m.p. >315" 61.5; H, 4.3. was practically insoluble in boiling alcohol and The alkali-insoluble 5,7-dimethoxy-8-formyl-4-methylhence it could be conveniently separated. However, coumarin (VI) was crystallized from acetic acid (charcoal) the separation of the original coumarin and the as 0.8 g. of thin shining light yellow needles, m.p. 267". Anal. Calcd. for C13H1206: C, 62.8; HI 4.8. Found: C, product, m.p. 218", offered difficulty. The structure 62.7; HI 4.6. (XV, of 4,7-dimethyl-6-formyl-5-hydroxycoumarin $MethyZ-5,7,8-trihydroxycoumarin(111). Six ml. of 6 % R = CH,) has been assigned to the product m.p. hydrogen peroxide was added dropwise with stirring to a 218", since it gave a red coloration with alcoholic cooled solution (0") of 0.5 g. of 5,7-dihydroxy-8-formyl-4in 10 cc. of 1% sodium hydroxide, and the ferric chloride and underwent Dakin oxidation to methylcoumarin reaction mixture was kept a t 0" for 1 hr. The product furnish the knowna 5,6-dihydroxy-4,7-dimethyl- obtained on acidification was taken up in ether and the ether coumarin (XVII, R = CH3). The product, map. treated with activated charcoal and filtered. A bright yellow >315" did not give any coloration with alcoholic substance was obtained on evaporation of ether. It was ferric chloride and has been assigned the structure crystallized with difficulty from ethyl acetate as 0.3 g. of thin pale yellow plates, m.p. 273". With alcoholic ferric 4,7-dimethyl-8-formyl-5-hydroxycoumarin (XVI, R chloride it gives a light greenish yellow coloration which = CH,). soon turns brown. It is very soluble in methyl alcohol, The N-methylformanilide method met with fail- ethyl alcohol, acetic acid, acetone, etc. Sastri and coure in the case of 7-hydroxy-4-methylcoumarin and workers4 give m.p. 273-275". .4-Methyl-5,7,8-trimethoxycoumarin (IV) was obtained by its methyl ether, the unreacted substances being methylation of I11 and crystallized from methyl alcohol recovered almost quantitatively. (charcoal) in thin light yellow flakes, m.p. 174". Sastri and The present study shows that the applicability of co-workers4 give m.p. 173-174". 7,8-Dihydroxy-5-methoxy-4-methylcoumarin (VII). Three (5) V. J. Dalvi, R. B. Desai, and S. Sethna, J. Ind. Chem. ml. of 6% hydrogen peroxide was added dropwise a t 0" SOC.,28, 366 (1951). ( 6 ) R. J. Parikh and S.Sethna, J. Ind. Chem. Xoc., 27, (7) Melting points are uncorrected and were taken in 369 (1950). open capillary tubes. OHC
1632
NAIK AND THAKOR
with stirring, to a mixture of 0.2 g. of 8-formyl-7-hydroxy-
VOL. 22
It furnished an orange-red 2,Q-dinitrophenylhydrazone, crystallized from acetic acid in needles, m.p. 232". Anal. Calcd. for CZoHl8N408: N, 12.2. Found: XI 12.6. 8-Formyl-~-methyl-5,6,7-trimethoxycoumarin (XIII). A in small quantity, slowly reacted. The product obtained on mixture of 1.2 g. of 4-methyl-5,6,7-trimethoxycoumarin,6 a.cidification was crystallized from methyl alcohol to yield 1.7 g. of N-methylformanilide, 1.5 cc. of phosphorus oxy0.1 g. of thin light yellow needles, m.p. 231'. It gives a light chloride and 10 cc. of o-dichlorobenzene, was heated on a green coloration with alcoholic ferric chloride and dissolves steam bath for 1 hr. with intermittent shaking. Saturated in alkali giving an orange yellow solution. solution of sodium acetate was added and the contents were Anal. Calcd. for CllHloOs: C, 59.5; H, 4.5. Found: C, steam-distilled to remove o-dichlorobenzene. A brown pasty 59.4; HI 4.5. substance separated. It was atered, while hot, through & This product also furnished 4-methyl-5,7,S-trimethoxy- cotton wool, and the filtrate, on cooling, gave the unreacted coumarin on methylat,ion with dimethyl sulphate by the coumarin. The pasty material was taken up in ether and the ,ton-potassium carbonate method, m.p. and mixed map. extract treated with activated charcoal. On removing char174O. coal and evaporating ether, the light yellow oil was isolated. 5,r-Dimethoxy-8-form!/1-?-methylcoumarin (VI) and 5,7- Most of it decomposed when distilled under vacu~im.It di.~nethozy-9-fo~inyl-4-mEthylcoumarin (IX). To a mixture of was characterized by the preparation of a 2,4-dinitro2 2 g. of 5,7-dimethoxy-4-methylcoumarin and 1.6 g. of N- phenylhydrazone (m.p. 231-232") which did not depress the methylformanilide in 15 cc. o-dichlorobenzene, 1.5 cc. of melting point of the 2,4-dinitrophenylhydrazone obtained phosphorus oxychloride was added and the reaction mixture in the previous case. was heated on a steam bath for 2 hr. with intermittent 6-Formyl-5-hydroxy-4-methylcoumarin (XV, R = H). A shaking. On adding 100 cc. of sodium acetate solution and mixture of 1.8 g. of 5-hydroxy-4-methylcoumarin, 2.0 g. of romoving o-dichiorobenzene by steam distillation, the prod- N-methylformanilide, 2 cc. of phosphorus oxychloride, and uct, separated in the form of dark globules. It was refluxed 15 cc. of o-dichlorobenzene, was heated on a steam bath v4,bh excess of acetic acid and filtered. The filtrate gave 5,7- for 2 hr. After adding sodium acetate solution and steamdi1nethoxy-S-formyl-4-methylcoumari1i on cooling. It was distilling, the brown product which separated was found to purified by crystallization from acetic acid (charcoal), m.p. be the unreacted coumarin. The contents were filtered hot, ax:! mixed m.p. with the product obtained earlier, 267". and the filtrate afforded the aldehyde on cooling. It was The light green prodirct obtained as insoluble in boiling crystallized from alcohol to yield 0.2 g. of thin white needles, acetic acid, was crystaliized from nitrobeneene to yield 0.8 m.p. 220". I t gives a purple red coloration with alcoholic g. of thin pale yellow r,trndles of 5,7-dimethoxy-6-formyl-4- ferric chloride and dissolved in alkali giving an orange-red methylconmarin, m.p. 284-285". It is insoluble in almost solution. ail of the usual organic solvents. Anal. Calcd. for C1&04: C, 64.7; HI 3.9. Found: C, A.nal. Calcd. for C:SEY&: C, 62.8; H, 4.8. Found: C, 65.0; HI 3.8. 5,6-Dihydroxy-4-methylcoumarin (XVII, R = H). To a 62.4; f r , 4.8. An attempt to demethylate both the 8-formyl and the solution of 0.2 g. of 6-formyl-5-hydroxy-4-methylcoumarin 6-formvl isomers with livdriodic acid in acetic anhvdride in 2 cc. of 2% sodium hydroxide a t O", 1.5 cc. of 6% hydrome; with a failure, appa.&tly similar black complex"prod- gen peroxide was added dropwise, and the rcaction mixture was left at 0" for 1 hr. It was acidified and the product ucts being isolated. .~,6-D~m,eth,ozy-3-fomz~~~~-methylcoumar~nic acid (X). One which separated was crystallized from alcohol in thin shinand 10 ing yellow needles, m.p. 248'. It did not depress the melting gram of 5,7-di1nethox~-8-formyl-4-methylcoumarin cc. of l0qh sodium hydroxide were heated together on a point of 5,6-dihydroxy-4-methylcoumarin prepared accordsteam bat,h for 0.5 hr. when the substance slowly went into ing to Dalvi, Desai, and Sethna.6 solution. The mixt,ure m s cooled, carefully acidified, and ~,7-Dimethyl-8-formyl-5-hydroxycoumurin (XVI, R = the substance which sepxrated was crystallized from alcohol CHs) and ~,7-dinzethyl-6-formyl-5-hydroxycoumrin (XV, R to yield 0.8 g. of white necdles, m.p. 212' (dec.). It gives a = CH,). The mixture of 1.9 g. of 4,7-dimethyl-5-hydroxypurple red coloration :.rit,halcoholic ferric chloride, and dis- coumarin, 2.0 g. of N-methylformanilide, 2.0 cc. of phossoiveli in sodium bicarbonate with faint effervescence. phorus oxychloride, and 15 cc. of o-dichlorobenzene, was R7ial. Calcd. for C13111406: C, 58.6; H, 5.3. Found: C, heated on steam bath for 2 hi. The crude product obtained 58.9; B , 5 , 5 . on working up as in earlier cases was refluxed with alcohol 5.7-I)iinethcxy-6-forrny!-4-methylcoumarin was recovered and filtered. The product left over as insoluble was crystalon ilissohing the product in sodium hydroxide on a steam lized from acetic acid (charcoal) as 0.15 g. of thin white bath, cooling, and then acidifying. flocculent needles of 4,7-dimethyl-&lormyl-5-hydroxycou6,T-Dimelhozy-6-hydrozy-8-formyl-4-methyl-coumarin (XI). marin, m.p. >315'. It does not give any coloration with 5,7-L)irr;ethosv-8-formyl-4-methylcoumarin (1.25 g. ) was alcoholic ferric chloride and dissolves in sodium hydroxide dissolved in 10 cc. of 10% sodium hydroxide by warming on to give a yellow solution. a steam bath and the solution was cooled to 0'. A solution Anal. Calcd. for C12€IloO~: 6, 66.1; H, 4.6. Found: C, of 1.35 $5. of Imtassium persulfate in 27 cc. of water was then 66.4; H, 4.9. e while the reaction mixture was mechanically The filtrate on cooling gave a product which was frarleft overnight in a refrigerator, just acidified, tionally crystallized to give a small quantity of 4,7-dimethyland thc co1,iinarinic acid, m.p. 212', which separated was 6-formyl-5-hydroxycoumarin, m.p. 218", along with a large removed b:, filtration. The filtrate was heated on a steam amount, of the unreacted coumarin. It gives a blood-red bath for 1 hr. with more hydrochloric acid. The contents coloration with alcoholic ferric chloride and dissolves in were cooleil and extracted with ether (charcoal), and the alkali giving an orange yellow solution. ether was eiraporated bo furnish a product which crystalAnal. Calcd. for ClzHloO~:C, 66.1; HI 4.6. Found: C, p. 225-226'. It does 66.0; H, 4.4. rric chloride and dis,$,7-l>zmethyI-8-formyl-5-methoxycoumarin was obtained ' giving ~n orange yellow solution. by methylation of XVI (R = C€18) and crystallized from H, 4.6. Found: C, acetic acid in thin white needles, m.p. 262". Anal. Calcd. for C1?H1204: .. .~ C, 67.2:. EX, . 5.2. Found: C, marin (XIII), was 67.5; I-I, 5.0. 6,6-Dihydroxy-4,7-dimethylcoumarin (XVII, R = CHa). 3btained i!.s i~ light yeilow oil on methylation of XI. It did One ml. of 6% hvdrogen Deroxide was added dropwise to a n o t Rolidify eithtr in a refrigerator or in a desiccator under solution of 0.1" g." 4,7-ldim~thyl-6-formyl-5-hydroxycoumarin vacuum. 3-methoxy-4-methylcoumarin,4 cc. of 2% sodium hydroxide, and 10 cc. of water, and the reaction mixture was kept at 0" for 2 hr., when the sodium salt, which separated
DECEMBER
1957
1633
NITROHYDROXY CHALCONES AND FLAVANONES
in 2 cc. of 2% sodium hydroxide at Oo, and the mixture was left for 1hr. It was acidified and the product which separated was crystallized from alcohol in light yellow needles, m.p. 260". It did not depress the melting point of an authentic specimen of 5,6-dihydroxy-4,7-dimethylcoumarin prepared according to Parikh and Sethna.1
[CONTRIBUTION FROM
THE
Acknowledgment. The authors thank Dr. R. C. Shah, National Chemical Laboratory, poena, for his keen interest in this BOMBAY, INDIA
QRQANIC CHEMISTRY INSTITUTE O F SCIENCE]
Stabilities of Nitrohydroxy Chalcones and Flavanones. Role of Hydrogen Bonding S. SESHADRI
AND
P. L. TRIVEDI
Received March 10, 1057 The cyclization of nitro-substituted chalcones to the flavanones has been studied for the first time. 'The effect of the nitro group on the reaction has been studied and it has been shown that the chelation of the nitro group with the 2'-hydroxyl group is an important factor in determining the stability of the chalcone. The properties of the chalcones and the flavanones have been studied and discussed.
The isomerization of nitro-substituted chalcones to flavanones does not appear t o have been studied a t all. The present work was, therefore, undertaken with a view to investigating the influence of the nitro group on the reaction. A number of new chalcones as well as a few known chalcones were prepared from nitro derivatives of 2,4-dihydroxyacetophenoneand 2,6-dihydroxyacetophenone. The chalcones, prepared by the "cold alkaline condensation" method, were of four types, I-IV. NOS
reacidifying. The flavanones from chalcones Ia-Ih were very unstable towards strongly acid solution, being completely converted to the chalcones in fifteen minutes. The flavanones of typi-:I11 were more stable since only a part of the flavanone had reverted to the chalcone after boiling for an hour. The Group IV flavanones were unaffected by strongly acid solution. The results obtained shorn that the nitro group has a profound influence on the behavior of nitrochalcones. The slow rate of cyclization of Group I chalcones and the high instability of the flavanone I a towards acid solution indicate that the nitro group has a stabilizing effect on the chalcone. This effect is probably exerted in the manner shown.
O"'o'F &02$H-C~H5
0,
,o.
&%"'?H-
CsHa
-,AH
ill
0
111
m
OH
IV
The cyclization of the chalcones was carried out by refluxing in aqueous alcoholic hydrochloric acid (3%). The flavanones were separated from the chalcones by fractional crystallization from suitable solvents. The times of refluxing and the yields of flavanones are set out in Table 11. All the flavanones were readily reconverted t o the chalcones by warming with alkali solution and
The chelation of the ortho nitro group will prevent proton elimination at the last stage and retard the cyclization. On the same basis, the t>endencyof (4) to take up a proton will be much greater than the tendency of (3) to lose one and this accounts for the instability of the flavanone ring in acid niediunl. Crawford and Rasburn' have observed a similar stabilizing effect of the nitro group in 3-nitrocouma(1) M. Crawford and J. W. Rasburn, J . C h e m Soc., 2155 (1956).
