US2659734A - Dehydrogenation of coumaranes - Google Patents
Dehydrogenation of coumaranes Download PDFInfo
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- US2659734A US2659734A US239375A US23937551A US2659734A US 2659734 A US2659734 A US 2659734A US 239375 A US239375 A US 239375A US 23937551 A US23937551 A US 23937551A US 2659734 A US2659734 A US 2659734A
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- Prior art keywords
- dimethylaniline
- khellinone
- solution
- aceto
- coumaranes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Definitions
- This invention relates to a new method of dehydrogenation of coumaranes and. substituted coumaranes to prepare coumarones and substi tuted coumaronesi
- This invention is useful in' that iticomprises a convenient, practical and efficientg methodof. preparing; coumarones from coumaranes involving, essentially, a process whereby the coumarane is dehydrogenated,
- the particular novelty and usefulness ofthis invention resides in the fact thatitiprovides greater yieldsgof the dehydrogenated coumarone than are ordinarily obtained withwthe... use, of well-:lmowm common; methods.
- the method of thisiinvent-ion possesses additional advantage in that materials and apparatus necessary to efiect the process are less expensive and easier. to handle, using ordinary laboratory. techniques.
- termediates and more. particularly, as inter mediates inthe v preparation .of compounds havm physiological. activity, such; as, khellin and visnagin.
- the method. according. to. this invention com: prises generally speaking, treatment, oi a con;- maraner. type. compound with. a ,halogenrcontain ing,. reagent which is ,capable.ofjinitiating a. free-,-
- R R R R may be selected from the group consisting of hydrogen, lower alkoxyy lower acyl, lower acyloxy radicals and. any two adjacent of which may together; comprise a pyrone radical, and X is a halogen which, preferably may be selected from the group consisting of chlorine and bromine:
- halogen-containing reagents capable of initiating; a freeradical halogen attack may be,.mentioned; N brcmphthalimide, N-bromacetamide and halogen derivatives of succinimide, such as" N-bromo- 3 succinimide and N-chlorosuccinlmide, whose structures appear below:
- CHa on CFN on As specifically illustrative of the bases which may be utilized to effect the dehydrohalogenation of the halocoumarane are tertiary amines as for example, dimethylaniline, collidine, quinoline and pyridine.
- the G-acetylvisnaginone product was then saponified by heating it with an aqueou solution of potassium hydroxide. Acidification of the basic solution precipitated visnaginone, which melted at 109 C., and was identical in every respect with visnaginone obtained by the degradation of visnagin.
- khellinone acetate is converted to khellinone, which in turn may be utilized to prepare khellin, a compound having physiological activity, as follows:
- the khellinone acetate prepared above was saponified to prepare khellinone by treating with a solution of 10 g. of potassium hydroxide and 150 g. of aqueous (1:1) methanol and heating on the steam bath for 30 minutes. Evaporation of the methanol was followed by addition of more water, and the solution was washed with ether and acidified. Ether extraction of the mixture followed by evaporation of the ether gave a slowly crystallizing oil. Purification of the khellinone was effected by a chromatographic technique using a column of alumina and benzene solution.
- the eluate contained khellinone which upon evaporation provided crystals melting at 92- 94 C.
- the conversion of the khellinone to khellin was effected by treating the khellinone with ethyl acetate in the presence of metallic sodium and heating the mixture on the steam bath for five hours. Methanol is then added to the reaction mixture to destroy traces of excess metallic sodium and the mixture is diluted with Water, followed by acidification by'acetic acid. A brown oil gradually solidifies, and is redissolved in a large quantity of light petroleum boiling from 70 to C. Distillation of the light petroleum leaves a saturated solution which upon cooling deposits a crystalline material. Recrystallization several times from benzene-light petroleum provides small yellow prisms melting at C. Ring closure of the diketone so obtained is efiected by boiling the acetoacetyl compound in alcohol solution acidified with 4 drops of concentrated hydrochloric acid. Cooling isolates crystalline khellin melting at 153 C.
- N-chloro succiniinide one; I com ollidine l CHaO-- 0 CHaO 4,6-dimethoxycoumarone was prepared from 4,6-dimethoxycoumarane by treating with an equimolar quantity of N-chlorosuccinimide and a trace of benzoyl peroxide to prepare the chlorocoumarane. Heating of thi material on a steam bath with an excess of collidine prepared the coumarone. using a procedure identical with that described in Example 1 above.
- the product was characterized as the 6-hydroxy derivativ which was obtained upon hydrolysis with an alcoholic potassium hydroxide solution.
- the crude, semi-crystalline product resulting was sublimed at 90-100" C./5 mm.
- EXAlVIPLE 5 Preparation of 2-methyZ-(4',5',6,7)-jaranochromane-4 Dimethylaniline Ar mixtureeofi 8001 mg. of; Nebromosuccinimide; 800 mg. of the dihydrofuranochromonez;andza few m-gl of b'enzoyl, peroxide was refluxed. With 353ml; of carbon tetrachloride. Treatment of the refluxed product: with ;,dimethy1aniline.- yielded a crudezfcrystallineamaterial. which upon recrystaleliza'ti'oniromxmethanol.melted; at:1.75.-1818C;
- N-bromosuccinimide and the bromo derivative so prepared was dehydrohalogenated with dimethylaniline in a manner identical with that described for Example 5. Recrystallization of the crude crystalline product yielded khellin melting at 152-153 C.
- R R R R are selected from the group consisting of hydrogen, lower alkoxy, lower acyl, and lower acyloxy radicals and any adjacent two of which comprise together a pyrone radical, which comprises subjecting the coumarane to a free radical halogen attack to form a halocoumarane and reacting the thus formed halocoumarane with a tertiary amine base to form a. coumarone.
Description
l atented Nov. 17, 1953 UNITED; STATES PATENT 'OFFI JCE v 2;s59,7a4.i I
DEHYDROGENATION OEGOUMARANES;
e-Drawi a- Ann n -l l y 1951;. Serial No. 7539;3375r.
(3laimsz" (Cl. 260-3462) This inventionrelates toa new method of dehydrogenation of coumaranes and. substituted coumaranes to prepare coumarones and substi tuted coumaronesi This invention is useful in' that iticomprises a convenient, practical and efficientg methodof. preparing; coumarones from coumaranes involving, essentially, a process whereby the coumarane is dehydrogenated, The particular novelty and usefulness ofthis invention resides in the fact thatitiprovides greater yieldsgof the dehydrogenated coumarone than are ordinarily obtained withwthe... use, of well-:lmowm common; methods. of dehydrogenation, such: as the use of catalysts like platinum, palladium on carbon, Raney' nickel and others, at elevated temperatures. Further, the method of thisiinvent-ion possesses additional advantage in that materials and apparatus necessary to efiect the process are less expensive and easier. to handle, using ordinary laboratory. techniques.
The. compoundswhich are. the products offthe;
method .of this invention will find. utility as in:
termediates, and more. particularly, as inter mediates inthe v preparation .of compounds havm physiological. activity, such; as, khellin and visnagin.
The method. according. to. this invention, com: prises generally speaking, treatment, oi a con;- maraner. type. compound with. a ,halogenrcontain ing,. reagent which is ,capable.ofjinitiating a. free-,-
radical halogenattackuponthe. coumarane to,
effect halogenation oil that coumaranelreplacing one of the hydrogen atoms of the dihydro com: pound. The, halo derivative. isthen. dehydrohalogenatedin the presence of assuitable. basic reagent, preferably a tertiaryaminato efiect saturation of the 2,3 position or the. compound The ,exact. position of the, halogen. atom inthe. halo-ooumarane. structure. resulting. from; the, treatment. of. the. coumarane. with, Nf-ha fisllo cinimide; is not definitely established, although it, isrbelieyed to occur, in. the. 2-position, 11;..is. to,, be,.noted.that the, position of.theihalogenatommis. not-material. to; the. spirit. nor. the operation. of}; this;.invention since, as. itywill. beeppreciatedl, the. subsequent. dehydrohalogenation eliminating HX. collectively from the 2 and. 3.-positions.'
the. coumarane-to form the 2 ,3-unsaturatedcoumarone. is, effected with, equal case .from. either thez-rhalo-or the. 3 -halo isomer. Itis, there:
fore, not intendedthat this invention; shall be;
so. limited .asgtolexclude the use of either isomerI or even a mixture of both isomers.
The method in accordance with this invention can as applieditoiexemplarytcompounds is illustrated by way of example in the following scheme, in which R R R R may be selected from the group consisting of hydrogen, lower alkoxyy lower acyl, lower acyloxy radicals and. any two adjacent of which may together; comprise a pyrone radical, and X is a halogen which, preferably may be selected from the group consisting of chlorine and bromine:
4,7-dimethoxy-5-aceto-G-acetoxycoumarane;
Asspecifically illustrative ofithe halogen-containing reagents capable of initiating; a freeradical halogen attack, may be,.mentioned; N brcmphthalimide, N-bromacetamide and halogen derivatives of succinimide, such as" N-bromo- 3 succinimide and N-chlorosuccinlmide, whose structures appear below:
CHa on CFN on As specifically illustrative of the bases which may be utilized to effect the dehydrohalogenation of the halocoumarane are tertiary amines as for example, dimethylaniline, collidine, quinoline and pyridine.
The following examples willfurther serve to illustrate the method in accordance with this invention:
1 g. of 4-methoxy-5-aceto-6-acetoxycoumarane (dihydrovisnaginon acetate) was treated with slightly more than an equimolar portion of N-bromosuccinimide and a trace-of benzoyl peroxide in boiling carbon tetrachloride solution. The completion of the reaction within a few minutes was indicated by the formation of succinimide and a nearly colorless reaction mixture. Filtration and evaporation resulted in the isolation of the crude bromodihydrovisnaginone acetate. The bromo derivative was then treated with an excess of dimethylaniline and was heated on a steam bath. The reaction mixture was then poured into dilute hydrochloric acid and extracted with ether to yield the G-acetylvisnaginone.
.The G-acetylvisnaginone product was then saponified by heating it with an aqueou solution of potassium hydroxide. Acidification of the basic solution precipitated visnaginone, which melted at 109 C., and was identical in every respect with visnaginone obtained by the degradation of visnagin.
EXAMPLE 2 Preparation of G-acetylkhellinone 0cm 9 CHJJ N-Bromo- CHaC O succinimide com OCH; OCH: g l
Dimeth lomhg CHaC Br CHaC-O onto-o 0 0 ton. 60H,
3.86 g. of dihydrokhellinone acetate (4,7-dimethoxy-5-aceto-6-acetoxycoumarane) 2.55 g. of N-bromosuccinimide and a trace of benzoyl peroxide were refluxed in 150 g. of carbon tetrachloride for 5 minutes. The succinimide was removed by filtration and evaporation isolated an oil. The oil was heated with 80 g. of purified dimethylaniline for 3 hours at 210 C. After cooling, the solution was added to ether and extracted several times with 3 N sulfuric acid. The ether solution was evaporated and the residue was recrystallized from alcohol and water to give khellinone acetate (4,7 dimethoxy 5 aceto- G-acetoxycoumarane) which melted at Pl-75 C.
As specifically illustrative of the utility of this invention is the following, in which khellinone acetate is converted to khellinone, which in turn may be utilized to prepare khellin, a compound having physiological activity, as follows:
EXAMPLE 2 (continued) 0 C H; O 0 Ha 7 if I? Sa on'fith 1 CH3C cgtioii CHQC a eta te (alkali) I Na C H; fi-O O H O O I J) CH: O C H: (Khellimone) O 0 Ha O O C H: I I! I g I euro-cure @Fgi- T l l H0 W cm- A o o 0 C C H: C H:
(Khellin) The khellinone acetate prepared above was saponified to prepare khellinone by treating with a solution of 10 g. of potassium hydroxide and 150 g. of aqueous (1:1) methanol and heating on the steam bath for 30 minutes. Evaporation of the methanol was followed by addition of more water, and the solution was washed with ether and acidified. Ether extraction of the mixture followed by evaporation of the ether gave a slowly crystallizing oil. Purification of the khellinone was effected by a chromatographic technique using a column of alumina and benzene solution.
' The eluate contained khellinone which upon evaporation provided crystals melting at 92- 94 C.
The conversion of the khellinone to khellin was effected by treating the khellinone with ethyl acetate in the presence of metallic sodium and heating the mixture on the steam bath for five hours. Methanol is then added to the reaction mixture to destroy traces of excess metallic sodium and the mixture is diluted with Water, followed by acidification by'acetic acid. A brown oil gradually solidifies, and is redissolved in a large quantity of light petroleum boiling from 70 to C. Distillation of the light petroleum leaves a saturated solution which upon cooling deposits a crystalline material. Recrystallization several times from benzene-light petroleum provides small yellow prisms melting at C. Ring closure of the diketone so obtained is efiected by boiling the acetoacetyl compound in alcohol solution acidified with 4 drops of concentrated hydrochloric acid. Cooling isolates crystalline khellin melting at 153 C.
ages-career 5 I EXAMPLE 3 Preraratiomofi4,6 aimeti omycoumarorie;
N-chloro succiniinide one; I com ollidine l CHaO-- 0 CHaO 4,6-dimethoxycoumarone was prepared from 4,6-dimethoxycoumarane by treating with an equimolar quantity of N-chlorosuccinimide and a trace of benzoyl peroxide to prepare the chlorocoumarane. Heating of thi material on a steam bath with an excess of collidine prepared the coumarone. using a procedure identical with that described in Example 1 above.
EXAMPLE 4 Preparation of 5-acetyl-6-acetoxycoumarone A mixture of 9'76 mg. of 5-acetyl-6-acetoxycoumarane, 840 mg. of N-bromosuccinimide, a trace of benzoyl peroxide and 40 ml. of carbon tetrachloride was refluxed for 75 minutes. The mixture was then cooled and filtered and the filtrate was evaporated in an air stream. The
crystalline residue was refluxed with ml. of
dimethylaniline for 3 hours, and after extraction, evaporation and recrystallization there was obtained the product, 5-acetyl-6-acetoxycoumarone.
The product was characterized as the 6-hydroxy derivativ which was obtained upon hydrolysis with an alcoholic potassium hydroxide solution. The crude, semi-crystalline product resulting was sublimed at 90-100" C./5 mm. and
was recrystallized from dilute methanol to provide 5-acetyl-G-hydroxycoumarone melting at 94-95.5 C.
EXAlVIPLE 5 Preparation of 2-methyZ-(4',5',6,7)-jaranochromane-4 Dimethylaniline Ar mixtureeofi 8001 mg. of; Nebromosuccinimide; 800 mg. of the dihydrofuranochromonez;andza few m-gl of b'enzoyl, peroxide was refluxed. With 353ml; of carbon tetrachloride. Treatment of the refluxed product: with ;,dimethy1aniline.- yielded a crudezfcrystallineamaterial. which upon recrystaleliza'ti'oniromxmethanol.melted; at:1.75.-1818C;
EXAMPLE. 6"-
Preparation of visnagin O 0 CH1 l N-bromo- O L succinimide II I Dimethylaniline 2 methyl 5 methoxy 2,3 dihydro- (4',5,6,'7) furanochromone 4 was halogenated with N-bromosuccinimide in a manner identical with that described in Example 5 above. Dehydrohalogenation with dimethylaniline of the bromo derivative so prepared yielded crystalline visnagin which was purified by recrystallization to provide a product melting at 142-143" C.
N-bromosuccinimide and the bromo derivative so prepared was dehydrohalogenated with dimethylaniline in a manner identical with that described for Example 5. Recrystallization of the crude crystalline product yielded khellin melting at 152-153 C.
What is claimed is:
l. The method of forming the corresponding coumarone from a coumarane having the following formula:
where R R R R are selected from the group consisting of hydrogen, lower alkoxy, lower acyl, and lower acyloxy radicals and any adjacent two of which comprise together a pyrone radical, which comprises subjecting the coumarane to a free radical halogen attack to form a halocoumarane and reacting the thus formed halocoumarane with a tertiary amine base to form a. coumarone.
2. The method of preparing G-acetoxy-E-aceto- 4 methoxycoumarone which comprises reacting 6 acetoxy 5 aceto 4 methoxyc-oumarane with N bromosuccinimide and reacting the bromocoumarane thus formed with dimethylaniline.
3. The method of preparing 6-acetoxy-5-aceto- 4,7-dimethoxycoumarcne which comprises react- 10 ing 6 acetoxy 5 aceto 4,7 dimethoxycow marane with N-bromosuccinimide and reacting the bromocoumarane thus formed with dimethylaniline.
THEODORE A. GEISSMAN.
References Cited in the file of this patent Baxter et a1.: J. Chem. Soc. (1949), (Supp. Issue No. 1), 830-3.
Barnes: J. Am. Chem. Soc. (1948), 70, 145-147.
Claims (1)
1. THE METHOD OF FORMING THE CORRESPONDING COUMARONE FROM A COUMARANE HAVING THE FOLLOWING FORMULA:
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US239375A US2659734A (en) | 1951-07-30 | 1951-07-30 | Dehydrogenation of coumaranes |
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US239375A US2659734A (en) | 1951-07-30 | 1951-07-30 | Dehydrogenation of coumaranes |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3474171A (en) * | 1964-01-23 | 1969-10-21 | Fmc Corp | 2,2-dimethyl-2,3-dihydrobenzofuranyl-7-n-methylcarbamate |
US4150042A (en) * | 1977-07-29 | 1979-04-17 | Hoffmann-La Roche Inc. | 6-Hydroxy-7-methoxy-5-benzofuran carboxaldehyde and 2,3-dihydro-7-methoxy-6-benzofuranol |
-
1951
- 1951-07-30 US US239375A patent/US2659734A/en not_active Expired - Lifetime
Non-Patent Citations (1)
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3474171A (en) * | 1964-01-23 | 1969-10-21 | Fmc Corp | 2,2-dimethyl-2,3-dihydrobenzofuranyl-7-n-methylcarbamate |
US4150042A (en) * | 1977-07-29 | 1979-04-17 | Hoffmann-La Roche Inc. | 6-Hydroxy-7-methoxy-5-benzofuran carboxaldehyde and 2,3-dihydro-7-methoxy-6-benzofuranol |
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