1626
NAIK AND THAKOR
VOL.
[CONTRIBUTION FROM THE ORGANIC CHEMISTRY DEPARTMENT, THE INSTITUTE
OF
22
SCIENCE]
Formylation of Benzopyrones. I. Formylation of Hydroxycoumarins with Hexamethylenetetramine' R. M. NAIK
AND
V. M. THAKORa
Received May 22,1967 The applicability of hexamethylenetetramine as a formylating agent to some typical hydroxycoumarins has been systematically investigated. The successful Dakin oxidation of the formylcoumarins has offered a method of introduction of a hydroxyl group in the ortho position, thus constituting a method for the synthesis of polyhydroxycoumarins. It is significant that 5-hydroxy-4-methylcoumarin and 5-hydroxy-4,7-dimethylcoumarin yielded diformyl derivatives. The hitherto unknown 4methyl-5,6,7,&tetrahydroxycoumarinand its partially and completely methylated derivatives have been synthesized.
In connection with the work on the synthesis of some naturally occurring furanocoumarins we were interested in the preparation of hydroxyformylcoumarins, being the intermediates for the synthesis of these compounds. A perusal of literature revealed that no systematic work has been done in this direction.3 The formylcoumarins would also be important starting materials for the synthesis of a number of heterocyclic compounds and polyhydroxycoumarins, and therefore it was thought of interest to investigate the application of various methods of formylation to the coumarin series. Attempts were first made to formylate 7-hydroxy-4-methylcoumarin by the Gattermann reaction with zinc cyanide and hydrogen chloride. However, all the attempts-in ether a t 0", in nitrobenzene at room temperature (ca. 30") or applying the modifications of Adams, HinkeP and their co-workers using anhydrous aluminum chloride in o-dichlorobenzene at SOo-were unsuccessful. However, earlier Spath and Pailer6 and later Rangaswarni and Seshadri' had employed the Duff and Bills methods using hexamethylenetetramine in the formylation of 7-hydroxycoumarin and its 4methyl derivative, respectively. In the present communication, the application of this method to some typical hydroxycoumarins is described. The ortho-hydroxyformylcoumarins obtained smoothly underwent Dakin oxidation to the corresponding ortho-dihydroxycoumarins.
6-Hydroxy-4-methylcoumarin (I, R = CH3), on f ormylation with hexamethylenetetramine , furnished an aldehyde, m.p. 191", in poor yield. The reaction was found to proceed with difficulty and even after prolonged heating (36 hours) on a steam bath, a considerable amount of the original coumarin was recovered. The Dakin oxidation of the aldehyde afforded the known9 5,6-dihydroxy-4methylcoumarin (111, R = CH,). Hence the structure of 5-formyl-6-hydroxy-4-methylcoumarin(11, R = CHa) has been assigned to the aldehyde. 6Hydroxycoumarin (I,R = CHa)on similar formylation, gave a monoformyl derivative, m.p. 189", in fairly good yield, and the unreacted coumarin
HO
HO R
I
HO
OCH R I1
OH R I11
could not be isolated. The aldehyde, on oxidation with hydrogen peroxide, furnished a dihydroxycoumarin, m.p. 269", which considerably depressed the m.p. of 6,7-dihydroxycoumarin (m.p. 268'). The dimethyl ether of the dihydroxycoumarin obtained in the present case melted at 111", whereas the melting point of 6,7-dimethoxycoumarin has been reportedloto be 146". Hence the structures of 5-formyl-6-hydroxycoumarin (11, R ~(I)This paper comprises a portion of the thesis presented = H) and 5,6-dihydroxycoumarin (111, R = H) by R. M. Naik towards the requirement of the degree of have been respectively assigned to the aldehyde and Doctor of Philosophy of the University of Bombay, and its oxidation product. This is also confirmed by the t,he work was carried out during the tenure of the Govern- behavior of 6-hydroxy-4-methylcoumarinobserved ment of India research scholarship. earlier. (2) Present address: Department of Chemistry, Gujarat When the whole work was complete, a paper by College, Ahmedabad. (3) R. M. Naik and V. M. Thakor, Current Sci. (Znndia), Sastri and co-workers" appeared in which they re21, 349 (1952). ported the formylation of the above two coumarins (4) R. Adams and E. Montgomery, J . Am. Chem. Sac., by the same method. However, the melting points 46, 1518 (1924). (5) L. E. Hinkel, E. E. Ayling, and J. H. Beynon, J . of the substances reported by them are different Chem. Sac., 339 (1936). (9) V. J. Dalvi, R. B. Desai, and S. Sethna, J . Zndian (6) E.Spath and M. Pailer, Ber., 68, 940 (1935). (7)8. Rangaswami and T. R. Seshadri, Proc. Indian Chem. Sac., 28,366 (1951). (10) H. Simada, J . Pharm. Sac., 57, 618 (1937). Acad. Sci., 6A, 112 (1937). (11) V. D. Nagebwara Sastri and Co-workerp, Proc. (8) J. C. Duff and E. J. Bills, J . Chem. Soc., 1987 (1932); Indian Acad. Sei., 37A, 681 (1953). 1305 (1934). ~~
DECEMBER
1957
1627
FORMPLATION OF BENZOPYRONES. I
from those observed by us. Table I is'given for comparison of the melting points.
both of the above 5-hydroxycoumarins yielded the diformyl derivatives on reaction with hexamethylenetetramine. The simultaneous introduction of two formyl groups has been observed by Duff12 in TABLE I case of o-cresol and 6-chloro-mcresol. M.P., "C. Both these 5-hydroxycoumarins also gave rise t o Substance Observed Reported1* insoluble orange red complex products along with 5-Formyl-6-hydroxy-4methyl191 202-203 the diformylcoumarins. This tendency to form red, coumarin insoluble, complex products appeared to be general 5-Formyl-6-hydroxy coumarin 189 212-213 with 5-hydroxycoumarin derivatives. Thus, at5,6-Dihydroq~coumarin 269 256-258 5,6-Dimethoxycoumarin 111 132-133 tempts to formylate 5,7-dihydroxy4methylcoumarin and 5,6,7-trihydroxy-4-methylcoumarinmet with failure and only complex products were quanThe melting points of the aldehydes obtained in titatively formed. the present case could not be raised even after sevThe interaction of 7,8-dihydroxy4methylcoueral crystallizations. The aldehydes, on treatment marin (VII) with hexamethylenetetramine afforded with 10% sodium hydroxide, yielded the correa fairly good yield of the formyl derivative which sponding deep yellow insoluble sodium salts, underwent hydrogen peroxide oxidation to furnish whereas the original coumarins remained in solu- 4-methyl-6,7,8-trihydroxycoumarin (IX) identition under the same conditions. The sodium salts fied by direct comparison with the specimen prewere isolated but could not be crystallized. On pared according to Parikh and Sethna.I3 Hence the acidification with hydrochloric acid the aldehydes structure of 7,8-dihydroxy-6-formyl4-methylcouof unchanged melting points were obtained. On marin (VIII) has been assigned to the formyl derepetition of the reaction with 6-hydroxy-4-meth- rivative. This provided another convenient method ylcoumarin under the conditions (heating for 8 for the preparation of Pmethyl-6,7,8-trihydroxyhours on a steambath) described by Sastri and co- coumarin (IX). Similar formylation of 7,s-dihyworkers,ll mostly the unreacted coumarin was redroxy-5-methoxy-4-methylcoumarin met with covered along with only traces of the aldehyde, failure, the resultant product being a crimson red m.p. 191". complex product. This observation is in accordance &Hydroxy-4-methylcourin (IV, R = H) afwith the behavior of &hydroxycoumarin derivaforded a diformyl derivative (as shown by analysis) tives. The formylation of 7,8-dimethoxy-6-hydroxyon reaction with hexamethylenetetramine. The 4methylcoumarin (X) afforded an aldehyde, m.p. structure of 6,8-diformyl-5-hydroxy-4-methylcou156") in fairly good yield and the original coumarin marin (V, R = H) has been assigned to this prodwas not recovered, in contrast to the behavior of 6uct, as only two positions, viz., 6 and 8 being ortho and para to the hydroxyl group in 5 position, would be the most reactive. Moreover, the diformyl derivative on oxidation with hydrogen peroxide furnished a dihydroxycoumarin which gave green coloration with alcoholic ferric chloride and also afforded a 2,4dinitrophenylhydraaone. The structure of 5,6dihydroxy-%formyl Pmethylcoumarin (VI, R = H) has been assigned to the oxidation product as (i) with ferric chloride it gave a green coloration characteristic of o-dihydroxy compound, and (it] during this reaction, the ortho-carbonyl group is more easily oxidized than the para-carbonyl one.
OH
OH
HO CH3
IX
VI1
OHC CH3 VI11
hydroxy-4-methylcoumarin. The structure of 5formyl - 7,8 - dimethoxy - 6 - hydroxy - 4 - methylcoumarin (XI) has been assigned to the formyl deriCHO CHO vative as it gave a red coloration with alcoholic ferric chloride and only one position, viz. 5, is vacant for the formyl group to enter. This aldehyde (XI) OHC HO underwent Dakin oxidation t o furnish 5,6-dihyOH CH3 6 H CH3 OH CH3 droxy-7,8-dimethoxy-4-methylcoumarin (XII) IV V VI which gave a characteristic bottle-green coloration with alcoholic ferric chloride. This was fully methyThe formylation of 5-hydroxy-4,7-dimethylcoulated with dimethyl sulfate to give Pmethyl-5,6,7,8marin (IV, R = CH3) similarly furnished 6,8-diformyl-4,7-dimethyl-5-hydroxycoumarin (V, R = tetramethoxycoumarin (XIII). On account of the CHa) which gave 5,6dihydroxy-4,7-dimethyl-8- (12) J. C. Duff, J . C h m . Soc., 547 (1941). formylcoumarin (VI, R = CH3) on oxidation with (13) R. J. Parikh and S. Sethna, J . Indian Chem. Soc., hydrogen peroxide. It is significant to note that 27,369 (1950).
1628
NAIR AND THAKOR
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22
low yield of XI1 during Dakin oxidation, the de- 1.1 g. A sample of this was twice recrystallized from alcohol, methylation was not carried out. On the other hand, m.p. 19io. Anal. Calcd. for C11H80a: C, 64.7; H, 3.9. Found: C, the Elbs persulfate oxidation of 4-methyl-5,7,864.9; H, 4.2. trimethoxycoumarin (XIV) furnished a fairly good Since Sastri and co-workersll gave m.p. 202-203", the yield of 6-hydroxy-5,7,8-trimethoxy-4-methylcou-product was treated with 10% sodium hydroxide. The marin (XV). The methylation of this product (XV) sodium salt of the formyl coumarin separated. The salt was furnished the above described 4-methyl-5,6,7,8- isolated but could not be crystallized. On acidification it the aldehyde which was crystallized from alcohol, m.p. tetramethoxycoumarin (XIII), while the demethy- gave 191'. It gives deep red coloration with alcoholic ferric chlolation of XV with hydriodic acid in acetic anhy- ride. dride gave 4-methyl-5,6,7,8-tetrahydroxycoumarin It was characterized by the preparation of the 2,4-dinitro(XVI) which gave with alcoholic ferric chloride, a phenylhydrazone, crystallized from acetic acid in orange crimson-red coloration which rapidly changed to yellow needles, m.p. 312' (dec.). Anal. Calcd. for CllHl2O7N4:N, 14.6. Found: N, 14.8. purple-violet and then to pale green. The color dis5,6-0ihydroxy-4-methylcoumarin (111, R = CHa). To a appeared completely on keeping. It dissolved in solution of 0.2 g. of 5-formyl-6-hydroxy-4methylcoumarin OCH3 I
CH3 X OCH3
in 5 cc. of 2% sodium hydroxide and 5 cc. of water at 0", 1.5 CC. of 6% hydrogen peroxide was added dropwise. The reaction mixture was kept at 0" for an hour with occasional stirring when some product separated out. The reaction mixture was acidified and the product which separated was crystallized from alcohol (charcoal) in thin shining yellow needles, m.p. 248" alone and when mixed with 5,6-dihydroxy4methylcoumarin prepared according to Dalvi, Desai, and Sethna.8 6-Formyl-6-hydroxycoumarin(11, R = H). Five grams of 6-hydroxycoumarin, 10 g. of hexamethylenetetramine and 100 cc. of glacial acetic acid were heated on a steam bath for 8 hr., and 75 cc. each of concentrated hydrochloric acid and hot water were added. After the usual treatment the ether extract gave a deep yellow product which crystallized from alcohol in clusters of yellow needles, m.p. 189", yield 2.2 g. A sample was twice recrystallized from alcohol, m.p. 189". Anal. Calcd. for CllH806: C, 60.0; H, 3.6. Found: C, 60.3; H, 3.7. Since Sastri and co-workersll give map. 212-213', an attempt was made to purify it by preparation of its sodium salt and acidification. The product even after repeated crystallization from alcohol and acetic acid melted at 189". It gave deep red coloration with alcoholic ferric chloride. Its I,~dinitrophenylhydraz~e was crystallized from acetic acid in orange yellow prates, m.p. >315". Anal. Calcd. for ClcHloNhO,: N, 15.1. Found: N, 15.4. 6,G-Dihydroxycoumarin(111, R = H). To 0.4 g. of 5formyl-6-hydroxycoumarin in 4 cc. of 2% sodium hydroxide solution at 0", 2 cc. of 6% hydrogen peroxide was dropwise added with stirring. The sodium salt of the aldehyde which separated slowly reacted and the color of the reaction mixture gradually changed from orange-red to light yellow. It was kept at 0" for 0.5 hr. with occasional shaking. It was worked up as usual and the product crystallized twice from alcohol to yield 0.2 g. of thin golden yellow prisms, m.p. 269". It gives a deep green coloration with alcoholic ferric chloride and depresses the melting point of 6,7-dihydroxycoumarin (m.p. 268'). Sastri and co-workers give m.p. 256258". Anal. Calcd. for C9H604: C, 60.7; H, 3.4. Found: C, 60.9: H, 3.5. 5,6-Dimethoxycoumarin obtained by methylation of 111 (R = H) was crystallized from alcohol in shining yellow needles, m.p. 111". Sastri and co-workers give m.p. 132133". Anal. Calcd. for CnHlo04: C, 64.1; H, 4.9. Found: C , 64.4; H, 4.9. 6,8-Dijorm~b6-hydroxy-~-methyk~murin (V, R = H). A mixture of 2 g. of 5-hydroxy-4-methylcoumarin,4.0 g. of hexamethylenetetramine and 50 cc. of acetic acid was heated on a steam bath for 5 hr. The solution turned red and an orange-yellow complex product separated. Hot concentrated hydrochloric acid (20 ml.) and water were then added and the contents heated for 2 hr. The complex which went into solution reseparated on cooling. Exhaustive ether
H3c0w0
HO
HjCO
,
OH CH3 XI1
I
CH3O
CH3
XI11
OCHa
OCHs
CH3b
CH3 XIV
CH30
CHa
XV
Howo OH I
HO
OH CH3 XVI
alkali but soon blue particles separated .indicating the great susceptibility to oxidation. EXPERIMENTAL'4
6-Formyl-6-hydroxy-~-methylcoumarin (11, 12 = CHa). To a solution of 5.0 g. of 6-hydroxy-4methylcoumarin in 100 cc. of hot acetic acid, 10.0 g. of hexamethylenetetramine was added and the reaction mixture was gently refluxed for 10 hr. A hot mixture of 75 cc. of concentrated hydrochloric acid and 75 cc. of water was added to the hot reaction mixture and the contents were further heated on a steam bath for 2 hr., cooled, and extracted with ether. The products obtained on removal of ether and residual acetic acid were found to consist of the formyl derivative and the original coumarin. The mixture was triturated with alcohol and filtered. The undissolved part melting over the range 205230" was found to contain mostly the unreacted coumarin with traces of the formyl derivative. The filtrate on cooling gave the formylcoumarin. It was crystallized from alcohol in clusters of shining yellow needles, m.p. 190-191', yield (14) Melting points are uncorrected and were taken in open capillary tubes.
DECEMBER 1957
FORMYLATION OF BENZOPYRONES. I
1629
extraction of the contents afforded a yellow product which hydrogen peroxide were dropwise added with stirring to a crystallized from acetic acid in thin light yellow needles, solution of 0.4 g. of 7,8-dihydroxy-6-formyl-4-methylcoum.p. 242", yield 1.1 g. A sample of it was twice recrystal- marin in 10 cc. of 2% sodium hydroxide a t 0". After keeping for an hour a t 0", it was acidified, The product obtained lized, m.p. 242". Anal. Calcd. for ClzH80.6 (based on 2-formyl groups): was crystallized from alcohol, m.p. 274-275" alone and when mixed with an authentic specimen prepared according to C, 62.1; H, 3.5. Found: C, 62.1; H, 3.6. It gives a deep blood-red coloration with alcoholic ferric Parikh and Sethna.I3 7,8-Dimethoxy-6-hydroxy-6-formyl-~-methyl (XI). chloride and forms a crimson red 8,44initrophenylhydrazone, A mixture of 3 g. of 7,8-dimethoxy-6-hydroxy-4-methylalmost insoluble in boiling acetic acid, m.p. >315". Anal. Calcd. for Cl8H1d4O8(monohydrazone): N, 13.6. coumarin,,6 g. of hexamethylenetetramine, and 20 cc. of acetic acid was heated on a steam bath for 5 hr. On working Found: N, 14.1. The complex product which remained in the aqueous layer up as in the previous case, a deep yellow pasty product was was collected. It is insoluble in ether, ethanol, acetic acid obtained, which solidified on keeping overnight in a desicand could not be crystallized. It contains nitrogen but is cator. It was crystallized from alcohol, in shining needles, insoluble in hydrochloric acid. It dissolves in alkali and re- m.p. 156", yield 0.8 g. It gives a deep red coloration with precipitates on acidification. It was recovered unchanged alcoholic ferric chloride and dissolves in alkali giving an after keeping with cold concentrated sulfuric acid or boiling orange solution. Anal. Calcd. for C13H1206: C, 59.1; H, 4.5. Found: C, with hydrochloric acid alone or in acetic acid. It does not 58.9; H, 4.4. melt but chars and leaves a residue. 5,6-Dihydroxy-~,8-dimethoxy-~-meth~lcoumarin (XII). A 5,6-Dihydro~-8-formyl-4-methyleoumarin (VI, R = H). A solution of 0.2 g. of 6,8-diformyl-5-hydroxy-4-methylcou- solution of 0.3 a. of 7,8-dimethoxv-6-hvdroxv-5-formvl" marin in 3.0 cc. of 201, sodium hydroxide a t 0" was treated 4-methylcoumarin-in 1.5 cc. of 2% sodium hydroxide and with 2.0 cc. of 6% hydrogen peroxide as usual. The product 3 cc. of water at 0' was as usual treated with 1 cc. of 6% crystallized from glacial acetic acid (charcoal) as light hydrogen peroxide and then worked up. The substance which separated after acidification was collected and yellow plates, m.p. 295" (dec.). Anal. Calcd. for CIIH80~: C, 60.0; H, 3.6. Found: C, 60.4; crystallized from dilute alcohol to yield 0.1 g. of thin light pink flakes, m.p. 190". H, 3.9. Anal. Calcd. for C12H1~0a:C, 57.2; H, 4.7. Found: C, It gives a deep green coloration with alcoholic ferric chloride and forms a 1,44initrophenylhydrazone almost 57.0; H, 4.3. 4-Methyl-5,6,7,8-tetramethoxycoumarin (XIII). I t was insoluble in boiling acetic acid, m.p. >315". DreDared bv methvlation of 5.6-dihvdroxv-7,8-dimethoxvAnal. Calcd. for C1,H12N408: N, 14.0. Found: N, 14.3. 6,8-Difoimyl-~,7-dirnethyL5-hydroxycoumrin (V, R = &methylco;marin "and crystallized from methyl alcohol in CH3). Two grams of 4,7-dimethyl-5-hydroxycoumarin, 4 g. white needles, m.p. 65-66'. It is insoluble in alkali and does of hexamethylenetetramine, and 50 cc. of glacial acetic acid not give any coloration with ferric chloride. Anal. Calcd. for Cl4H1606: C, 60.0; H, 5.7. Found: C, were heated on a steam bath for 5 hr. The reaction mixture was worked up as in the previous case. The ether extract 60.1; H, 5.7. 6-Hydroxy-5,7,8-trimethoxy-~-methylcoumrin (XV). To a afforded the product which crystallized from acetic acid well stirred solution of 2.5 g. of 4-methyl-5,7,8-trimethoxyas light yellow needles, m.p. 196", yield 0.7 g. Anal. Calcd. for C13H1005 (based on 2-formyl groups): coumarin in 20 cc. of 10% sodium hydroxide obtained by warming on a steam bath was dropwise added a t 0", a soluC, 63.4; H, 4.1. Found: C, 63.6; H, 4.3. It gives a blood-red coloration with alcoholic ferric chlo- tion of 2.7 g. of potassium persulfate in 55 cc. of water during the course of 2 hr. The reaction mixture was kept ride and forms a crimson red $,4-dinitrophenylhydrazone overnight and then just acidified. The original substance almost insoluble in boiling acetic acid, m.p. >315". Anal. Calcd. for C19H14N~08 (monohydrazone): N, 13.1. which separated was removed and the filtrate was heated with excess of hydrochloric acid when a brown product Found: N, 12.6. The orange-red complex product obtained from the separated. It crystallized from methanol (charcoal) as 0.1 aqueous layer showed behavior similar to the product g. of thin long shining yellow needles, m.p. 212'. It does not give any coloration with alcoholic ferric chloride. obtained in the previous case. Anal. Calcd. for C13H1406: C, 58.6; H, 5.3. Found: C, 5,6-Dihydroxy-~,7-dimethyl-8-formylcoumarin (VI, R = CHa). The Dakin oxidation of V (R = CH3) was carried 58.4; H, 5.3. The product was methylated to furnish the same 4out under the same conditions as in the case of 6,8-diformylm.p. 65-66' as de5-hydroxy-4-methylcoumarin (V, R = H). The product methyl-5,6,7,8-tetramethoxycoumarin, obtained was crystallized from acetic acid (charcoal), in scribed above. 4-Methyl-5,6,7,8-tetrahydroxycoumrin (XVI). A mixture thin light yellow plates, m.p. 282-283" (dec.). Anal. Calcd. for ClzHloOa:C, 61.5; H, 4.2. Found: C, of 0.2 g. of 6-hydroxy-5,7,8-trimethox~-4-methylcoumarin, 5 cc. of acetic anhydride and 5 cc. of hydriodic acid was 61.6; H, 4.3. It gives a deep green coloration with alcoholic ferric refluxed for 3 hr. in an oil bath a t 135-140". It was then chloride and forms a 2,Q-dinztrophenylhydrazone crystallized poured into sodium bisulfite solution and the bright yellow from acetic acid in thin crimson red needles, m.p. 298-299' substance which separated was crystallized from alcohol in (dec.). grey-colored prisms, m.p. 278-27Q0, yield 80 mg. It disAnal. Calcd. for Cl8HI4N4o8: N, 13.5. Found: N, 13.1.. solved in alkali giving an orange-yellow solution, but soon 7,8-Dihydroxy-6-formyl-4-methylcoumarin (VIII). A mix- blue particles separated. With alcoholic ferric chloride, it ture of 5 g. of 7,8-dihydroxy-4-methylcoumarin,5 g. of gives a crimson red coloration which rapidly changes to hexamethylenetetramine and BO cc. of acetic acid was purple-violet and then to pale green. The color disappears heated on a steam bath for 5 hr. It was then further heated completely on keeping. with dilute hydrochloric acid for an hour, cooled, and Anal. Calcd. for CloH&: C, 53.6; H, 3.6. Found: C, extracted with ether. Ether and residual acetic acid were 53.3; H, 3.4. evaporated and the greenish yellow product which separated Acknowledgment. The authors thank Dr. R. C. was crystallized from acetic acid in thin light yellow needles, m.p. 268", yield 2.1 g. It gives a deep bottle-green colora- Shah, National Chemical Laboratory, Poona for tion with alcoholic ferric chloride. his keen interest in the work. Anal. Calcd. for CllH806: C, 60.0; H, 3.6. Found: C, 60.3; H, 3.7. MAYOROAD,FORT, BOMBAY, INDIA 4-MethyE6,7,8-trihydroxycoumrin (IX). Two ml. of 6%
