GB2450682A - Use of benzyl protection in the synthesis of 5-n-alkylresorcinols - Google Patents
Use of benzyl protection in the synthesis of 5-n-alkylresorcinols Download PDFInfo
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- GB2450682A GB2450682A GB0712351A GB0712351A GB2450682A GB 2450682 A GB2450682 A GB 2450682A GB 0712351 A GB0712351 A GB 0712351A GB 0712351 A GB0712351 A GB 0712351A GB 2450682 A GB2450682 A GB 2450682A
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- Prior art keywords
- alkylresorcinols
- wittig
- grignard
- synthesis
- dibenzyloxyphenyl
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- 238000003786 synthesis reaction Methods 0.000 title claims description 12
- 230000015572 biosynthetic process Effects 0.000 title claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title abstract description 5
- KVVSCMOUFCNCGX-UHFFFAOYSA-N cardol Chemical compound CCCCCCCCCCCCCCCC1=CC(O)=CC(O)=C1 KVVSCMOUFCNCGX-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 8
- 238000007327 hydrogenolysis reaction Methods 0.000 claims abstract description 8
- 238000007239 Wittig reaction Methods 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- UFMJCOLGRWKUKO-UHFFFAOYSA-N cardol diene Natural products CCCC=CCC=CCCCCCCCC1=CC(O)=CC(O)=C1 UFMJCOLGRWKUKO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000018044 dehydration Effects 0.000 claims abstract description 3
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 3
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 claims abstract 4
- 238000005949 ozonolysis reaction Methods 0.000 claims abstract 2
- 230000003197 catalytic effect Effects 0.000 claims 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 abstract description 5
- 238000006722 reduction reaction Methods 0.000 abstract description 5
- CHUAMRVJSRBRHT-UHFFFAOYSA-N 3,5-bis(phenylmethoxy)benzaldehyde Chemical compound C=1C(OCC=2C=CC=CC=2)=CC(C=O)=CC=1OCC1=CC=CC=C1 CHUAMRVJSRBRHT-UHFFFAOYSA-N 0.000 abstract description 4
- AUIDIGHJWOLCEH-UHFFFAOYSA-N 8-[3,5-bis(phenylmethoxy)phenyl]octanal Chemical compound C(C1=CC=CC=C1)OC=1C=C(C=C(C1)OCC1=CC=CC=C1)CCCCCCCC=O AUIDIGHJWOLCEH-UHFFFAOYSA-N 0.000 abstract description 4
- 230000009467 reduction Effects 0.000 abstract description 4
- 244000226021 Anacardium occidentale Species 0.000 abstract description 3
- 235000020226 cashew nut Nutrition 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract description 3
- GDJMJAKVVSGNLA-UHFFFAOYSA-N 5-Pentacosyl-1,3-benzenediol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCC1=CC(O)=CC(O)=C1 GDJMJAKVVSGNLA-UHFFFAOYSA-N 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- 238000010531 catalytic reduction reaction Methods 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- WSULSMOGMLRGKU-UHFFFAOYSA-N 1-bromooctadecane Chemical compound CCCCCCCCCCCCCCCCCCBr WSULSMOGMLRGKU-UHFFFAOYSA-N 0.000 abstract 1
- VUJOPHOWGIMUIS-UHFFFAOYSA-N 7-[3,5-bis(phenylmethoxy)phenyl]heptanal Chemical compound C(C1=CC=CC=C1)OC=1C=C(C=C(C1)OCC1=CC=CC=C1)CCCCCCC=O VUJOPHOWGIMUIS-UHFFFAOYSA-N 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 150000001299 aldehydes Chemical class 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- NUJGJRNETVAIRJ-UHFFFAOYSA-N octanal Chemical compound CCCCCCCC=O NUJGJRNETVAIRJ-UHFFFAOYSA-N 0.000 description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 150000001336 alkenes Chemical class 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- -1 dibenzyloxyphenyl Chemical group 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 2
- BFDNZQUBFCYTIC-UHFFFAOYSA-N 1-bromotridecane Chemical compound CCCCCCCCCCCCCBr BFDNZQUBFCYTIC-UHFFFAOYSA-N 0.000 description 2
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical class COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 description 2
- VFZRZRDOXPRTSC-UHFFFAOYSA-N 3,5-Dimethoxybenzaldehyde Chemical compound COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 description 2
- UYEMGAFJOZZIFP-UHFFFAOYSA-N 3,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC(O)=C1 UYEMGAFJOZZIFP-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 240000005979 Hordeum vulgare Species 0.000 description 2
- 235000007340 Hordeum vulgare Nutrition 0.000 description 2
- 241000209056 Secale Species 0.000 description 2
- MHHXKZKHZMSINU-UHFFFAOYSA-N [3,5-bis(phenylmethoxy)phenyl]methanol Chemical compound C=1C(OCC=2C=CC=CC=2)=CC(CO)=CC=1OCC1=CC=CC=C1 MHHXKZKHZMSINU-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 230000017858 demethylation Effects 0.000 description 2
- 238000010520 demethylation reaction Methods 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229930003811 natural phenol Natural products 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 150000003333 secondary alcohols Chemical class 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 235000020985 whole grains Nutrition 0.000 description 2
- XPDQMUYGFQRKLQ-UHFFFAOYSA-N 1-phenylpentadecane-3,5-diol Chemical compound OC(CCC1=CC=CC=C1)CC(CCCCCCCCCC)O XPDQMUYGFQRKLQ-UHFFFAOYSA-N 0.000 description 1
- 229930188104 Alkylresorcinol Natural products 0.000 description 1
- 101100133006 Arabidopsis thaliana ndhT gene Proteins 0.000 description 1
- 101100448208 Human herpesvirus 6B (strain Z29) U69 gene Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 244000062793 Sorghum vulgare Species 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- XQFOQOGEHIMARN-UHFFFAOYSA-N [Br-].C1(=CC=CC=C1)C(CCCCCCCCCCCCCCCCC[PH3+])(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound [Br-].C1(=CC=CC=C1)C(CCCCCCCCCCCCCCCCC[PH3+])(C1=CC=CC=C1)C1=CC=CC=C1 XQFOQOGEHIMARN-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000005027 hydroxyaryl group Chemical group 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 235000019713 millet Nutrition 0.000 description 1
- WURFKUQACINBSI-UHFFFAOYSA-M ozonide Chemical compound [O]O[O-] WURFKUQACINBSI-UHFFFAOYSA-M 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
- C07C37/20—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms using aldehydes or ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
- C07C37/003—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain by hydrogenation of an unsaturated part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
- C07C39/08—Dihydroxy benzenes; Alkylated derivatives thereof
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
5-n-Alkylresorcinols, i.e. 5-N-alkyl-1,3-dihydroxybenzenes, are synthesised by Wittig or Grignard reactions of 8-(3,5-dibenzyloxyphenyl)octanal followed by dehydration (for Grignard reactions) and catalytic reduction/hydrogenolysis. 8-(3,5-dibenzyloxyphenyl)octanal is prepared by ozonolysis of the dibenzyl ether of cardol, which may be obtained by benzylating cardol from cashew nutshell liquid with benzyl bromide. Alternatively, 5-n-alkylresorcinols may be prepared by Wittig or Grignard-type reactions of 3,5-dibenzyloxybenzaldehyde followed by hydrogenolysis. Removal of the benzyl protection of the hydroxy groups is accomplished at the same time as the reduction step that completes the introduction of the alkyl group. 5-n-Pentaeicosylresorcinol may be synthesized from 7-(3,5-dibenzyloxyphenyl)heptanal by Wittig or Grignard reactions based on the use of 1-bromooctadecane.
Description
BRITISH PATENT SPECIFICATION
Syntheses of 5-n-alkylresorcinols (5-n-alkyl-1,3-dihydroxybenzenes) from 8-(3,5-dibenzyloxyphenyl)octanal, obtainable from the replenishable source, cardol derived from cashew nutshell liquid; and from 3,5-dibenzylozybenzaldehyde, a synthetic intermediate accessible from 3,5-dihydroiybenzoic acid, a transformation product of natural gallic acid, (3,4,5-trihydroxybenzoic acid).
The 5-n-alkylresorcinols, notably, the C15 to C25 homologues, are natural products which occur in the bran fraction of whole grain cereal seeds Graminac) such as rye (Cereale secale) wheat (Triticum aestivum), barley (Hordeum distichon), millet and other crops, (J H P Tyman and A Kozubek, Chem.Rev., 1999, 99, 1-27). Several studies have demonstrated the health-beneficial effects of whole grain cereals which have been attributed to the minor 5-n-alkylresorcinolic and other components (H.Adlercreutz and A -M Linko, Brit. J NuIr., 2004,92,1-4, A Kozubek and J H P Tyman, Bloactive Phenolic Lipids, in Studies in Natural Products Chemistry, Vol 30, part K, Elsevier Science, 2005). Methods for the synthesis of 5-n-alkylresorcinols are thus of topical interest (J H P Tyman, Sthetic and Natural Phenols, Elsevier Science, 1996).
In UK Patent Application GB 2,429.455 A (25thAug., 2005) a novel method of synthesis ofCl 5-C 25, homologous 5-n-alkylresorcinols was proposed based on the reaction of 8-(3,5-dthydroxyphenyl)octanal with C7- C 17, triphenyl-n-alkyiphosphonium salts in the Wittig reaction.
Although in this method the use of OH protective groups was dispensed with, minor side reactions of the hydroxyaryl cardol ring to ozone at the first stage and the requirement for excess base and possibly of the triphenylalkyiphosphonium salt at the fmal stage, were slightly disadvantageous.
Thus, to counter these conditions it is proposed to employ certain benzyloxy intermediates. The advantage of the benzyl group as a protective group in systems also containing unsaturated groups, finally requiring reduction, is that the reductive methods can be chosen to simultaneously remove the benzyl group by hydrogenolysis, and thus two steps can be accomplished in one. By contrast, with for *.. example the methoxy protective group an additional demethylat ion step is involved because demethylation does not accompany hydrogenolyis Syntheses of C15-C23, 5-n-alkylresorcinols from 8-(3,5-r dibenzyloxyphenyl)octanal : : The proposed route to 5-alkylresorcinols is depicted in Scheme 1.
In this, cardol (1) is separated from technical or natural cashew nutshell liquid by the known phase distribution method, (J H P Tyman,I E Bruce and P Payne, Natural Product Letters, 1992, 1, 117-120); base/solvent extraction (R Paramashivappa, P P kimar, P J Vithayatvil and A S Rao, J. Agric. Food Chem., 2001, 49.2548) or by macroscale column chromatography (S K Sood, J H P Tyman, A A Durrani and R A Johnson, Lipids, 1986, 21, 241-246). It is then benzylated with benzyl bromide by the phase transfer method or by reaction in acetone containing potassium carbonate to give 3,5-dibenzyloxycardol (2) which is ozonised in ethyl acetate solution at low temperature as. described for cardol (M B Graham and J H P Tyman, J.Am. Oil Chem.Soc., 2002, 79, 725-732). Selective chemical reduction of the ozonide to avoid removal of the benzyl groups, which occurs in catalytic-type reductions, affords 8-(3,5-dibenzyloxyphenyl)octanal (3). Reaction with triphenyl n-heptylphosphoniuin
I
bromide in dimethylformamide (DMF) containing sodium ethoxide would give the dibenzyloxyalkene (4, R = C6H13). then reduced and hydrogenolysed to yield 3,5-dihydroxypentadecylbenzene (5, R = C6H13), By the use of homologous triphenyl aEkyiphosphonium salts from, commercially available I -bromononane, I- bromoundecane, I -bromotridecane, and I -bromopentadecane the homologous 5-alkylresorcinols having C17, C19, C21, and C23, alkyl side chains respectively, could be obtained. Generally I -bromoalkanes having odd C chains are more available than those with even C chains, with the exception of 1-bromotridecane. Grignard reaction of the aldehyde (3) with the appropriate alkylmagnesium bromide followed by acidic dehydration is an alternative sequence to (4).
Scheme 1 HOCh31 BnOCh31-BnO,(CH2) ,CHO
III -II -y iii
* SflO7ÁCH2)7CHCHR HO-(CH2)9R
-III
11] iv óBn OH 4 5 Reagents:-(i) BnBr, Me2CO, K2C03, (ii) EtOAc, 03, Zn,AcOH, 0 C, (iii) DMF, NaOEt, C7H15Ph3PBf, (iv) Pd-C/H2, EtOH.
An alternative approach to the synthesis of.5-atkylresorcinols is proposed by the use of 3,5-dibenzyloxyphenylbanzaldehyde. Previous syntheses of 5-n-alkylresorcinoi s have used the starting material, 3,5-dimethoxybenzaldehyde (J H P Tyman and A Kozubek, Chem. and Phys. of Lipids, 1995,78, 29-36; E. Wenkert, E -M Loeser, S N Mahapatra, F Schenker and E M Wilson, .1 Org. Chem., 1964, 29, 435-440) and for other phenolic lipids, methoxybenzaldehydes have been generally employed (J H P Tyman, Synthetic and Natural Phenols, Chap. 13, Elsevier Science, Amsterdam, 1996). The advantage of benyloxybenzaldehydes is firstly that for 5-n-alkylresorcinols the processes of hydrogenolysis and side chain double bond saturation can be combined in one reductive step. Secondly in cases where a required intermediate 1-bromoalkane is costly, for example the C13, 1-bromotridecane in the synthesis employing the octanal (3), the alternative C20 intermediate, I - bromoeicosane is more available.and is used in the proposed route starting with 3,5-dibenzyloxybenzaldehyde Syntheses of C1S-C25, 5-n-alkylresorcinols from 3,5-dibenzyloxybenzaidehyde In this procedure, ethyl 3,5dthydroxybenzoate (6) from the esterification of 3,5-dihydroxybenzoic acid in ethanol solution containin& sutphuric acid, is benzylated with benzyl bromide in acetone solution containing anhydrous potassium carbthIate to give ethyl 3,5-dibenzyoxybenzoate. This compound is reduced with lithium aluminium hydride to 3,5-dibenzyloxybenzyl alcohol (7) which is then oxidised with pyridinium chrornate or other selective procedures to afford 3,5-dibenzyloxybenzaldehyde (8), a crystalline compound, mp 74-76 C. Reaction of the aldehyde with I -bromoeicosane in tetrahydrofuran (THF) containing lithium would give upon acidic work-up, the secondary alcohol (10) which upon catalysed hydrogenolysis in ethanol with hydrogen at atmospheric pressure containing palladium/carbon would then afford the C21 alkylresorcinol (11, R = C19H39).
In the alternative Wittig approach, the aldehyde (8) with the salt, triphenyleicosylphosphonium bromide from I -bromoeicosane and triphenylphosphine in dimethylformamide containing sodium ethoxide would give the intermediate alkene (9) which by mild reduction and hydrogenolysis would then afford the required compound (11, R C19H39). Grignard reaction of the aldehyde (8) is an alternative approach.
The scheme of reactions is depicted in Scheme 2 for 5-alkyiresorcinols having C15 -C23 side chains Scheme 2 CO2Et BnO,çC H2OH BnO.1C HO BnO7CH=CRRJ 6 8 (a) iv 9 BnO-CH (OH) CH2R HO..y-..CH2CH I! I -....... ii I óBn V 11 Reagents: (i) BnBr, Me2CO, K2C03:LiAIH4,THF, (ii) Py,Cr03, (iii) Ph3RCH2PBr-,NaOEt, (a)iv, Pd-C, H2, EtOH; (b)iv, RCH2Br, Li,THF, (v) Pd-C, H2,EtOH.
Synthetic route to C25 5-alkyiresorcinol By the use of Schemes I and 2, 5-n-alkylresorcinols having side chains in the range Cl 5 to C23 could be synthesised from commercially available 1 -bromoalkanes. In the instance of the C25 resorcinol, the required bromoalkane to accomplish either route is not yet commercially available and in this case the route shown in Scheme 3 would have to be employed.
Scheme 3 In this approach, 3,5-dibenzyloxybenzaldehyde is reacted in THF containing lithium with 6-chlorohexano-I -ol protected at the OH group to give the 2-tetrahydropyranyl (Thp) compound (12, R = Thp). After acidic removal of the protective group hydrogenolysis affords (13) which by oxidation with pyridinium chioroformate would give the aldehyde (14). Wittig reaction of this aldehyde with triphenyloctadecyl phosphonium bromide in dimethylformamide containing sodium ethoxide would give the alkene (15) which by catalytic reduction affords the required C25, 5-n-pentaeicosylresorcinol.(16, R C171-135). Grignard reaction of the aldehyde (14) as with Schemes I and 2 is an alternative.
The use of 6-chiorhexanol (HO-protected), with methoxybenzaldehydes in the presence of lithium has been described in a number of publications (J Caplin and JH P Tyman, J. Chem. Res., 1982, (S),34-35; C J Baylis, S W D Odle and J H P Tyman, J Chem. Soc., Perkin Trans 1, 1981, 132-141; S K Lam and J H P Tyman, J Chem. Soc, Perkin Trans 1, 1982, 1942-1952. Some preliminary unpublished work has established the formatiom of (13) and the feasibility of the Wittig reaction procedures. The oxidation of side chain primary alcohols has been effected (AA Durrani, S C Goh and J H P Tyman, Lipids, 1982, 17, 56 1-569).
BnOCHO (CH2) 6CH2OH (CR2) 6CHO RO'_(CH2)6CRCHR Roy..(CH2) 8R
Y
Reagents; (i) Li, Cl (Cl 12)oOThp, THF, (ii) HCI; Pd-C, H2,EtOl-1, (iii) Py, Cr03, (iv), Ph3C18H37PBr-, NaOEt, DMF, (v) Pd-C, H2, EtOH
Claims (2)
1. The use of 8-(3,5-djbei yIoxyphenyI)oc',, from the ozonolysis of the dibenzyl ether of cardol, by Wittig or Grignard reactions, followed in the latter case by dehydration and catalytic reductionlhydrogenolysjs for the synthesis of 5-n-alkylresorcjno
2. The use Of 3,S-dibeflyloxybenzaldehydc by Wittig or Grignard-type reactions followed by hydrogenolysis, for the synthesis of S-n-alkyfresorcino 3 The synthesis of C25, S-n-pentaeicosylresorcjnol from 7-(3,5-dihydroxyphenyJ)hepaJ by the Wittig or Grignard reactions based on the use of I -bromooctadecane * .* * * * * *S. * U S...
S * ** *
I
I..... * .
S
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0712351.6A GB2450682B (en) | 2007-06-26 | 2007-06-26 | Syntheses of 5-n-alkylresorcinols (5-n-alkyl-1,3-dihydroxybenzenes) from 8-(3,5-dibenzyloxyphenyl)octanal, obtained by ozonolysis from dibenzylcardol |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0712351.6A GB2450682B (en) | 2007-06-26 | 2007-06-26 | Syntheses of 5-n-alkylresorcinols (5-n-alkyl-1,3-dihydroxybenzenes) from 8-(3,5-dibenzyloxyphenyl)octanal, obtained by ozonolysis from dibenzylcardol |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB0712351D0 GB0712351D0 (en) | 2007-08-01 |
| GB2450682A true GB2450682A (en) | 2009-01-07 |
| GB2450682B GB2450682B (en) | 2012-01-25 |
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| GB0712351.6A Expired - Fee Related GB2450682B (en) | 2007-06-26 | 2007-06-26 | Syntheses of 5-n-alkylresorcinols (5-n-alkyl-1,3-dihydroxybenzenes) from 8-(3,5-dibenzyloxyphenyl)octanal, obtained by ozonolysis from dibenzylcardol |
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| GB (1) | GB2450682B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150018569A1 (en) * | 2012-02-13 | 2015-01-15 | Banor Universiity | Method for preparing a herbicidal compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2429455A (en) * | 2005-08-27 | 2007-02-28 | John Henry Paul Tyman | Synthesis of 5-(C15-25-alkyl/alkenyl)resorcinols via 8-(3,5-dihydroxyphenyl)octanal, the ozonolysis product of cardol, using Wittig & Grignard methodology |
| WO2008028098A2 (en) * | 2006-09-01 | 2008-03-06 | The United States Of America, As Represented By The Secretary Of Agriculture | A novel o-methyltransferase gene from sorghum cloning, expression, transformation and characterization |
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2007
- 2007-06-26 GB GB0712351.6A patent/GB2450682B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2429455A (en) * | 2005-08-27 | 2007-02-28 | John Henry Paul Tyman | Synthesis of 5-(C15-25-alkyl/alkenyl)resorcinols via 8-(3,5-dihydroxyphenyl)octanal, the ozonolysis product of cardol, using Wittig & Grignard methodology |
| WO2008028098A2 (en) * | 2006-09-01 | 2008-03-06 | The United States Of America, As Represented By The Secretary Of Agriculture | A novel o-methyltransferase gene from sorghum cloning, expression, transformation and characterization |
Non-Patent Citations (5)
| Title |
|---|
| Acta Pharmaceutica Suecica Vol. 16, No. 1, 1979, pages 21-33 * |
| Bulletin of the Chemical Society of Japan Vol. 56, No. 6, 1983, pages 1889-1890 * |
| Helvetica Chimica Acta Vol. 63, No. 8, 1980, pages 2508-2514 * |
| Journal of Organic Chemistry Vol. 29, No. 2, 1964, pages 435-440 * |
| Justus Liebigs Annalen der Chemie No. 7, 1977, pages 1132-1140 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150018569A1 (en) * | 2012-02-13 | 2015-01-15 | Banor Universiity | Method for preparing a herbicidal compound |
| US9447010B2 (en) * | 2012-02-13 | 2016-09-20 | Bangor University | Method for preparing a herbicidal compound |
Also Published As
| Publication number | Publication date |
|---|---|
| GB0712351D0 (en) | 2007-08-01 |
| GB2450682B (en) | 2012-01-25 |
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