この論文は国立情報学研究所の学術雑誌公開支援事業により電子化されました。p-Coumar-, coniferyl- and sinap aldehydes were synthesized in good yields by new two synthetic methods. 1) The aldehydes were prepared by a two-carbon homologation of p-hydroxybenzaldehyde, vanillin and syringaldehyde with 2, 4, 4, 6-tetramethyl-5, 6-dihydro-1, 3-oxazine in the presence of n-butyllithium in anhydrous tetrahydrofurane at -77℃. 2) The aldehydes were also prepared by reduction of the corresponding p-hydroxycinnamic acid chlorides with lithium tri-t-butoxyaluminohydride in anhydrous diglyme at -77℃

HIGUCHI, Takayoshi

NAKAMURA, Yoshiki

NAKATSUBO, Fumiaki

Kyoto University Research Information Repository

Title Synthesis of p-Coumar-, Coniferyl- and Sinap AldehydesAuthor(s)NAKAMURA, Yoshiki; NAKATSUBO, Fumiaki; HIGUCHI,TakayoshiCitationWood research : bulletin of the Wood Research Institute KyotoUniversity (1974), 56: 1-6Issue Date1974-02-28URL http://hdl.handle.net/2433/53393RightType Departmental Bulletin PaperTextversionpublisherKyoto UniversitySynthesis of p-Coumar-, Coniferyl-and Sinap Aldehydes*Yoshiki NAKAMURA**, Fumiaki NAKATSUBO**and Takayoshi HIGUCHI**Abstract--p-Coumar-, coniferyl- and sinap aldehydes were synthesized in good yields by newtwo synthetic methods. 1) The aldehydes were prepared by a two-carbon homologation of P-hy-droxybenzaldehyde, vanillin and syringaldehyde with 2,4,4, 6-tetramethyl-5, 6-dihydro-1, 3-oxazine inthe presence of n-butyllithium in anhydrous tetrahydrofurane at -77°C. 2) The aldehydes werealso prepared by reduction of the corresponding p-hydroxycinnamic acid chlorides with lithium tri-t-butoxyaluminohydride in anhydrous diglyme at -77°C.IntroductionThe occurrence of lignin in woody plants has long been observed by botanists and wood che-mists using phloroglucinol-HCI color reaction!). The red color formed in this reaction with plantmaterials is attributed to p-hydroxycinnamyl aldehyde groups of lignin moleculesz), and in factconiferyl aldehyde has been obtained in the hydrolysis products of lignin3).On the other hand, p-hydroxycinnamyl aldehydes, especially coniferyl aldehyde, were detectedin the extracts of cambial zone and woods4-7), and tracer experiment suggested that coniferylaldehyde was an intermediate in reduction of ferulic acid to coniferyl alcohoI8).ZENK et at. recently established the enzymic mechanism of formation of coniferyl aldehydefrom ferulic acid9 ). The present authors also reported that ferulic and sinapic acids were reducedto the corresponding aldehydes which were further reduced to the alcohols in several plants IO ).Thus the p-hydroxycinnamyl aldehydes are believed to be obligatory intermediates in lignin bio-synthesis.While synthetic methods of the aldehydes have been reported l 1-l4), their yields are very low.In the present investigation, two synthetic methods have been applied for preparation of p-hydroxycinnamyl aldehydes, 1) a two-carbon homologation of p-hydroxybenzaldehydes by hydrolysisof a substituted six-membered heterocyclic ring, 2) reduction of p-hydroxycinnamic acid chlorideswith lithium tri-t-butoxyaluminohydride.Experimental1. Two-carbon homologation of p-hydroxybenzaldehydes2,4,4, 6-Tetramethyt-5, 6-dihydro-], 3-oxazine (2-methytoxazine) (l)--This reagent wasprepared from acetonitrile and 2-methyl-2,4-pentanediol by the method of MEYERS et at. 15) NMR(CCI4) 0 (ppm) : 1.07 (6H, s, Cr (CH3)z), 1.19 (3H, d, J***=6.0, C6-CH3), 1.76 (3H, s, CZ-CH3),4.03 (lH, m, C6-H).Tetrahydropyranyt ether (T H P) derivatives of p-hydroxybenzatdehydes (II a, lIb, IIc)-The THP derivatives were prepared by the usual method. A mixture of each of p-hydroxyben-zaldehydes (25-30 m moles) and 2,3-dihydropyrane (50--60 m moles) containing DL-camphor-10-sul-* Presented partly at the 23rd Annual Meeting of the Wood Research Society, Kyoto, April, 197:3.** Division of Lignin Chemistry.*** J: Coupling constant (Hz).-1-WOOD RESEARCH No. 56 (1974)fonic acid (2-4 mg) was magnetically stirred for 1 hr (p-hydroxybenzaldehyde), 3 hr (vanillin)and/or 6 hr (syringaldehyde) at room temperature avoiding any moisture, respectively. The THPderivatives of aldehydes were obtained quantitatively.2-Substituted 4,4, 6-trimethyl-5, 6-dihydro-l, 3-oxazines (IlIa. IIIb, IIIc')--A 100mlflask equipped with a magnetic stirring bar and a rubber septum was evacuated and flushed withdry nitrogen gas by syringe needles through the rubber septum. Anhydrous tetrahydrofurane (6ml) and 776 mg (5.5 m moles) of 2-methyloxazine were added to the flask by a syringe throughthe septum. The stirred solution was cooled to -77°C with a dry ice acetone bath and 4.3 ml(6.0 m moles, 1.39 M) of n-butyllithium in hexane was added over a period of 30 min. Stirringwas continued for 30 min, in which yellow precipitates of the lithio anion of 2-methyloxazine wereformed. After additional 1 hr stirring, a THP derivative of aldehyde (5.0 m moles) dissolved in6 ml of anhydrous tetrahydrofurane was added to the mixture over a period of 15 min and thesolution was stirred for further 15 min. The reaction mixture was allowed to slowly warm upto room temperature, in which the yellow precipitates disappeared. The mixture was poured into30 ml of cooled water and it was extracted with ether (20 ml x 4). The ether extracts werewashed with saturated NaCI solution and dried over anhydrous K2C03 • The solvent was eva-porated and a 2-substituted dihydro-1, 3-oxazine was obtained (90-92 % yields). The data of NMRand MS of the compounds obtained were in good agreement with the structures of IlIa, Illb andI1Ie' in Scheme 1.Compound IlIa, NMR (CDCI 3 ) 0 (ppm): 1.24 (3R, d, J=6.4, C6-CR3), 2.40 (lR, d, J=6.6,I IT o,b,eBuLiill 0, b, e'NoBH4-5°C- -10°Cin MeOH(HO CHO ~~CH2-CHOHI IH( HC/I E' II E'CH CHR*R2* *R1::::-"'" RzR, 0-.. Rz OR3OH OR3VT 0, b VO,b, e' TV o,b,e'RI R2 R3a H H THP*b HOMe THPcOMe OMe THPc' OMe OMe H * THP; tetrahydropyranylScheme 1. Synthetic route of p·hydroxycinnamyl aldehydes by a two-carbon homologation ofp-hydroxybenzaldehydes.-2-NAKAMURA et at.: Synthesis of p-Hydroxycinnamyl AldehydesCrH), 2.44 (lH, d, J =6.6, Cp-H), 4.08 (lH, m, C6-H), 4.96 (lH, t, J =6.6, Ca-H), 5.42 (lH,broad s, Ca-OH), 7.03 (2H, d, J =8.8, Ar; Aromatic), 7.33 (2H, d, J =8.8, Ar). MS mje: 347(M+), 263 (MLDHP, DHP; 2, 3-dihydropyrane), 245 (263-HzO), 230 (245-CH3o), 147 (@*-CH=CH-C 0+), 141 (oxazine ion CH(CH3)-CHz-C(CH3)z-NH-C(=CHz)-01'+), 123 (@-CH=O+H),I I122 (@-CH=O'+), 121 (@-C_O+), 99, 85 (THP ion CH=0+-(-CHz-)3-CHZ, base ion), 43.I ICompound II Ib, NMR (CDCI3) 0 (ppm) : 2.42 (2H, d, J =6.4, CrHz), 3.87 (3H, s, Ar-OCH3),4.08 (lH, m, C6-H), 4.96 (lH, t, J=6.4, Ca-H), 5.39 (lH, broad s, Ca-OH), 6.98 (3H, m, Ar).MS mje: 377 (M+), 293 (MLDHP), 275 (293-HzO), 260 (275-CH3o), 177 (@*-CH=CH-C_O+),153 (@-CH=O+H), 152 (@-CH=O'+), 151 (@-C_O+), 141 (oxazine ion), 99, 85 (THP ion,base ion), 43.Compound II I c', NMR (CDCI3) 0 (ppm): 1.27 (3H, d, J =6.3, C6-CH3), 2.43 (lH, d, J =6.0,CrH), 2.47 (lH, d, J =6.0, CrH), 3.84 (6H, s, Ar- (OCH3)z), 4.23 (lH, m, C6-H), 4.93 (lH, t, J=6.0, Ca-H) , 5.38 (lH, broad s, Ca-OH), 6.62 (2H, s, Ar). MS mje: 323 (M+), 305 (MLHzO),290 (305-CH3o), 207 (@*-CH=CH-C-O+), 183 (@-CH=O+H), 182 (@-CH=O'+, base ion),181 (@-C 0+), 141 (oxazine ion), 99, 43.2-Substituted 4, 4, 6-trimethyl~2, 3, 5, 6-tetrahydro-l, 3-oxazines (IVa, IVb, IVc')-Analiquot (2 m moles) of a crude dihydrooxazine was dissolved in a minimum volume of methanol,and the solution was cooled to _5° __ lOoC with salt and ice. Sodium borohydride (2m moles)was added to the solution which was stirred for 30 min. The contents were poured into 20 mlof NaCI saturated water and the aqueous solution was extracted with ether (15 ml x 4). Thecombined ether extracts were dried over anhydrous KzC03, the ether was removed, and thecrude tetrahydrooxazine was obtained (about 90 % yields).p-Hydroxycinnamyl aldehydes (V I a, V Ib, V c') --The crude tetrahydro-1, 3-oxazine obtainedin the preceeding experiipent was dissolved in 1 ml of ethanol and then 1 ml of ammonium chloridesolution (6N) was added to the mixture, which was subsequently acidified (pH 5-6) with oxa-lic acid. The mixture was stirred for 24 hr at room temperature, in which the oxazine ringsof the compounds IVa, IVb, IVc' were hydrolyzed. All of p-coumar aldehyde and a part of con-iferyl aldehyde were obtained as THP derivatives (Va, Vb), but in the case of IVc' sinapaldehydewas directly obtained, since THP group had been removed during homologation reaction. To ob-tain free aldehydes of the two formers, ethanol solution (1 ml) of DL-camphor-10-sulfonic aCid(2 mg) was added to the mixture, which was stirred for additional 1-2 hr. The mixture was pouredinto 20 ml of NaCI saturated water and it was extracted with ether (15 ml x 4). The ether ex-tracts were dried over anhydrous NaZS04 and the ether was removed. The aldehydes wereobtained from dihydro-1, 3-oxazines (Ilia, I1lb, and I1Ie') in 67-73 % yields. The following ana-lytical data of the aldehydes were completely identical with those of authentic compounds.p-Coumar aldehyde VIa, Overall yield: 63 %. m.p. 134°C (liL1\) 134°C). Red coloration withphloroglucinol-HCI. IR l.i (KBr) cm- 1 : 1647 (-CHO) , 970 (C=C, trans), 810 (Ar). NMR (CD3COCD3) 0 (ppm): 6.56 (lH, dd, J = 16.0, 8.0, CrH), 6.83 (2H, d, J =8.8, Ar), 7.48 (2H, d, J =8.8,Ar), 7.53 (lH, d, J=16.0, Ca-H) , 9.48 (lH, d, J=8.0, Cr-H). UV ).EtOH m,u (s) : 324-325 (30000).maxMS mje: 148 (M+, base ion), 147 (M+-Ho), 131, 120, 119 (147-CO), 91 (119-CO), 65 (91-(CHCH». Metastable peaks: 146.01 (148--?147), 96.33 (147--?119), 69.59 (119--?91), 46.43 (91--?65).Coniferyl aldehyde VIb, Overall yield: 64 %. m.p. 80-82°C (liLIZ) 82SC). Red purple colo-ration with phlorogluclnol-HCI. IR l.i (KBr) cm-1 : 2850 (Ar-OCH3), 1682 (-CHO) , 1227 (Ar-OCH3) , 1028 (Ar~OCH3)' 967 (C=C, trans), 883 (Ar), 813 (Ar). NMR (CDCI3) 0 (ppm) : 3.92(3H, s, Ar-OCH3), 6.56 (lH, dd, J = 16.0, 7.8, CrH), 6.88-7.16 (3H, m, Ar), 7.38 (lH, d, J = 16.0,Ca-H) , 9.62 (lH, d, J=7.8, Cr-H). UV ).;~~H m,u (s): 340 (23800). MS mje: 178 (M+, baseion), 177 (M+-Ho), 163 (MLCH3o), 147 (l77-CHzO), 135 (163-CO), 119 (147-CO), 107, Metasta-ble peaks: 176.01 (178--?177), 122.08 (177->147),96.33 (147->119).* Abbreviations: @, p-Hydroxyphenyl; @, Guaiacyl, (3-Methoxy-4-hydroxyphenyl) ; @, Syringyl, (3,5-Dimethoxy-4-hydroxyphenyl).- 3 -WOOD RESEARCH No. 56 (1974)Sinapaldehyde Ve', Overall yield: 62 %. m.p. 106-10rC (liLl4) 109°C). Purple colorationwith phloroglucinol-HCI. IR).J (KBr) cm-l : 2854 (Ar-OCH3), 1660 (-CHO), 1259 (Ar-OCH3),975 (C=C, trans), 810 (Ar). NMR (CDCI3) a (ppm) : 3.94 (6H, s, Ar- (OCH3) 2)' 6.59 (lH, dd,J=16.0, 7.8, CrH), 6.82 (2H, s, Ar), 7.40 (lH, d, J=16.0, C,,-H), 9.67 (lB, d, J=7.8, Cr-H).UV AEtOH mfl (c): 345 (24300). MS m/e: 208 (M+, base ion), 207 (MLH.), 193 (M+-CH3 ·),max180, 177 (207-CH20), 165 (l93-CO), 137, Metastable peaks: 206.00 (208~207), 151.35 (207~ln).Method of analysis---HITACHI model 124 double beam spectrometer and JASCO model IR-Swere used for UV and IR spectra, respectively. NMR spectra were taken by the use of R22HITACHI high resolution NMR spectrometer (90 MHz) with TMS Internal standard. Mass spec-trometry was conducted by the use of SHIMAZU-LKB 9000 gas chromatograph-mass spectrometer.2. Reduction of p-hydroxycinnamic acid chlorides with lithiumtri-t-butoxyaluminohydrideLithium tri-t-butoxyaluminohydride--This reagent was prepared by the method of BROWNet al. l6 )Acetyl p-hydroxycinnamic acid chlorides--p-Coumaric, ferulic and sinapic acids were syn-thesized by condensation of the corresponding p-hydroxybenzaldehydes and malonic acidl7), andthese acids were subsequently acetylated in anhydrous acetic acid and pyridine (yields of theproducts for 2 steps; 81-85 %). The acetyl p-hydroxycinnamic aCIds were converted to their acidchlorides in refluxing with thionyl chloride for 3 hr, and the products were recrystallized fromxylene before use (about 90 % yields).p-Hydroxycinnamyl aldehydes--One of the p-hydroxycinnamic acid chlorides (7.0 m moles)was dissolved in 40 ml of anhydrous diglyme in a three-necked flask equipped with a stirringbar, a dropping funnel, a low temperature thermometer and a gas inlet glass tube. The flaskwas flushed with dry nitrogen and cooled to about -noc in a dry ice acetone bath. Lithiumtri-t-butoxyaluminohydride (7.0 m moles) in anhydrous diglyme (20 ml) was added over a periodof 1 hr with stirring, avoiding any major rise in temperature. The cooling bath was then re-moved and the flask was allowed to warm up to room temperature over a period of 1 hr. Thecontents were then poured into 100 ml of water, which was cooled and weakly acidified with dryice, and extracted with ether (30 ml x 4). The extracts were dried over anhydrous Na2S04 and thesolvent was evaported. The oily acetyl p-hydroxycinnamyl aldehyde was kept in a refrigerator,and the crude crystal obtained was washed with n-hexane. The acetyl aldehyde was deacetylat-ed with sodium methoxide in the conventional wayl4). Recrystallization was periormed withbenzene. A small amount of p-hydroxycinnamyl alcohols, which were identified by GC-MS, wasdetected in the mother liquor. The total yields of these aldehydes based on the corresponding p-hydroxybenzaldehydes were as follows; p-coumar aldehyde, 30 %; coniferyl aldehyde, 32 %; sina-paldehyde, 34 %. The analytical data of three aldehydes, which were obtained by IR, NMR,UV and mass spectrometry, were completely identical with those described above.Results and DiscussionIn earlier investigations, PAULY and WASCHERl!) synthesized p-coumar and coniferyl aldehydesby aldol condensation of methoxymethyl ether derivatives of p-hydroxybenzaldehydes with ace-taldehyde. In their method, cr, j3-unsaturated aldehydes were formed by the two-carbon homolo-gation of p-hydroxybenzaldehydes. The yields, however, were very low (p-coumar aldehyde, 26 % ;coniferyl aldehyde, 18 %) because of the alkaline condition at high temperature and the prolongedreaction time. In addition to the condensation reaction, the step of synthesis of methoxymethylether derivatives of p-hydroxybenzaldehydes also caused a decrease of overall yields of the endproducts (p-coumar aldehyde <12 %, coniferyl aldehyde <10 %). Although they prepared coni-feryl aldehyde in 24 % overall yield by a modified method 12), the yield of sinapaldehyde was only12 %13).-4-NAKAMURA et at.: Synthesis of p-Hydroxycinnamyl AldehydesFREUDENBERG and HDBNERI4) obtained acetyl sinapaldehyde from acetyl sinapic acid chloridein 36 % yield by the ROSENMUND reduction, and the overall yield of sinapaldehyde based onsyringaldehyde was only 22 %. The present authors prepared coniferyl aldehyde in a similaryield by this method. The low yield of the products was due to a strong acid condition and hightemperature. Furthermore, several by-products formed during the reduction made difficult iso-lation and purification ot the aldehydes. In the ROSENMUND reduction it is difficult to reproducethe precise poisoning of catalyst, that is, reduction of acid chloride does not proceed in thepresence of excess catalyst poison, but the chloride is overreduced to the alcohol in the absenceof the poison.Thus, it is desired that reduction is carried out in neutral condition at low temperaturewith a selective reducing reagent. It has recently been established that lithium tri-t-butoxyalu-minohydride is very effective for reduction of acid chlorides to the corresponding aldehydes 18 ).This reagent possesses the following advantages: 1) it is a far milder reducing agents thanlithium aluminum hydride, 2) the yield of reduced product is favored in low temperature, 3)the procedure is exceedingly simple and then it provides a valuable synthetic route of alde-hydes. In this experiment, the p-hydroxycinnamic acid chlorides were reduced to the correspond-ing aldehydes with lithium tri-t-butoxyaluminohydride in 45-50 % yields, which were higher thanthose in the ROSENMUND reduction by 10-15 %. As the synthetic routes other than the reduc-tion step of acid chlorides are common to the both methods, the overall yields of the aldehydesincreased from 22 % to 30-34 %. Since it was reported that cinnamic acid chloride gave cin-namaldehyde in the yield of 50 %, the overall yields of p-hydroxycinnamyl aldehydes wereregarded to be reasonable. The p-hydroxycinnamyl alcohols detected in the mother liquors ofthe corresponding aldehydes might be due to the occurrence of minor amounts of lithium alumi-num hydride, which is the parent compound of lithium tri-t-butoxyaluminohydride.As one of the synthetic methods of aldehydes, the hydrolysis of six-membered heterocyclicrings was reported I9 ). This synthesis is due to the fact that dihydro-l,3-oxazine is convertedinto anion and that the reaction of the anion with. a carbonyl compound results in the desiredaldehyde after hydrolysis. The synthetic method has the following advantages: 1) 2-methyldihydro-l,3-oxazine is readily prepared as starting material, 2) lithio carbanion of 2-methyloxazine, generated by the use of n-butyllithium, is very stable in low temperature, 3) thereaction of the carbanion with electrophiles is rapid and irreversible, and then alkylation ofoxazine ring proceeds quantitatively. On the other hand, since all oxazine derivatives are oilyand difficult to be isolated and purified, crude products are forced to be subjected to subse-quent reactions without purification. Moreover phenolic hydroxyl group inhibited the formationof lithio anion of 2-methyloxazine, and then the hydroxyl group was protected as tetrahydro-pyranyl ether with 2, 3-dihydropyrane. The dihydropyrane easily reacted with phenols by thecatalytic action of acids (DL-camphor-l0-sulfonic acid or p-toluenesulfonic acid), affording theTHP derivatives of p-hydroxybenzaldehydes. The derivatives were basic and stable under thecondition, where oxazine derivatives were prepared and reduced with sodium borohydride. Inspite of quantitative conversion of p-hydroxybenzaldehydes to their oxazine derivatives, overallyields of p-hydroxycinnamyl aldehydes were limited to about 60 %. This may be ascribed partlyto overreduction of the dihydro-l,3-oxazines to open-chain amino alcohols through tetrahydro-oxazines during borohydride reduction and to prolonged standing in the cleavage of the tetra-hydrooxazines to the aldehydes.AcknowledgmentThe authors are grateful to Dr. ]. OKABE at SANYO-KoKUSAKU Pulp Co., Ltd. for the gift ofsyringaldehyde which has been lIsed for the synthesis of sinapaldehyde.- 5 -Literature1) K. FREUDENBERG and A. C. NEISH, Molecular Biology Biochemistry and Biophysics II (Constitutionand Biosynthesis of Lignin), p. 1, Springer-Verlag (1968).2) E. ADLER, K. J. BJORKVIST and S. HAGGROTH, Acta Chern. Scand., 2, 93 (1948).3) F. NAKATSUBO, M. TANAHASHI and T. HIGUCHI, Wood Research, No. 53, 9 (1972).4) R. A. BLACK, A. A. ROSEN and S. L. ADAMS, J. Am. Chern. Soc., 75, 5344 (1953).5) C. M. STEWART, Tappi, 40, 244 (1957).6) O. GOLDSCHMID and H. L. HERGERT, Tappi, 44, 858 (1961).7) K. FREUDENBERG and J. M. HARKIN, Phytochern., 2, 189 (1963).8) T. HIGUCHI and S. A. BROWN, Can. J. Biochern. Physio!., 41, 621 (1963).9) G. G. GROSS, J. STOCKIGT, R. L. MANSELL and M. H. ZENK, FEBS Letters, 31, 283 (1973).10) Y. NAKAMURA, H. FUSHIKI and T. HIGUCHI, Phytochern., in press.11) H. PAULY and K. WASCHER, Chern. Ber., 56, 603 (1923).12) H. PAULY and K. FEUERSTEIN, Chern. Ber., 62, 297 (1929).13) H. PAULY and L. STRASSBERGER, Chern. Ber., 62, 2277 (1929).14) K. FREUDENBERG and H. H. HUBNER, Chern. Ber., 85, 1181 (1952).15) A. 1. MEYERS, A. NABEYA, H. W. ADICKES, 1. R. POUTZER, G. R. MALONE, A. C. KOVELESKY, R. L. NOLENand R. C. PORTNOY, J. Org. Chern., 38, 36 (1973).16) H. C. BROWN and B. C. SUBBA RAO, J. Am. Chern. Soc., 80, 5377 (1958).17) S. A. BROWN and A. C. NEISH, Can. J. Biochern. Physio!., 33, 948 (1955).18) H. C. BROWN and R. F. McFARLIN, J. Am. Chern. Soc., 80, 5372 (1958).19) C. A. BUEHER and D. E. PEARSON, Survey of Organic Syntheses, p. 592, Wiley-Interscience (1970).-6-

Synthesis of p-Coumar-, Coniferyl- and Sinap Aldehydes

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Synthesis of p-Coumar-, Coniferyl- and Sinap Aldehydes

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