§1. Definition of an alkaloid.

Originally the name alkaloid (which means alkali-like) was given to all organic bases isolated from plants. This definition covers an extraordinary wide variety of compounds, and as the study of “alkaloids” progressed, so the definition changed. Konigs (1880) suggested that alkaloids should be defined as naturally occurring organic bases which contain a pyridine ring. This definition, however, embraces only a limited number of compounds, and so the definition was again modified a little later by Ladenburg, who proposed to define alkaloids as natural plant compounds having a basic character and containing at least one nitrogen atom in a heterocyclic ring. Ladenburg's definition excludes any synthetic compounds and any compounds obtained from animal sources. One must admit that even today it is still difficult to define an alkaloid. The term is generally limited to organic bases formed in plants. Not all authors do this, and so they specify those alkaloids obtained from plants as plant alkaloids (or vegetable alkaloids). On the whole, alkaloids are very poisonous, but are used medicinally in very small quantities. Thus we find that the basic properties, physiological action and plant origin are the main characters which define plant alkaloids. Even so, the class of compounds known as the purines (Ch. XVI), which possess the above characters, are not usually included under the heading of alkaloids (some purines are also obtained from animal sources). It is interesting to note in this connection that Serturner (1806) isolated a basic compound from opium. Up to that time it was believed that plants produced only acids or neutral compounds.

§2. Extraction of alkaloids.
In general, the plant is finely powdered and extracted with ethanol. The solvent is then distilled off, and the residue treated with dilute inorganic acids, whereupon the bases are extracted as their soluble salts. The free bases are liberated by the addition of sodium carbonate and extracted with various solvents, e.g., ether, chloroform, etc. The mixtures of bases thus obtained are then separated by various methods into the individual compounds. More recent methods of extraction involve the use of chromatography. Lee (1960) has converted plant alkaloids into their reineckates, dissolved these in acetone, and passed this solution through an ion-exchange column, and thereby obtained the alkaloids in a high state of purity. (Reinecke’s solution is H[Cr(NH3)2(SCN)4].)

§3. General properties.
The alkaloids are usually colourless, crystalline, non-volatile solids which are insoluble in water, but are soluble in ethanol, ether, chloroform, etc. Some alkaloids are liquids which are soluble in water, e.g., coniine and nicotine, and a few are coloured, e.g., berberine is yellow. Most alkaloids have a bitter taste and are optically active. They are generally tertiary nitrogen compounds and contain one or two nitrogen atoms usually in the tertiary state in a ring system; most of the alkaloids also contain oxygen. The optically active alkaloids are very useful for resolving racemic acids. The alkaloids form insoluble precipitates with solutions of phosphotungstic acid, phosphomolybdic acid, picric acid, potassium mercuri-iodide, etc. Many of these precipitates have definite crystalline shapes and so may be used to help in the identification of an alkaloid.

§4. General methods for determining structure.
(i) After a pure specimen has been obtained it is subjected to qualitative analysis (invariably the alkaloid contains (carbon), hydrogen and nitrogen; most alkaloids also contain oxygen). This is then followed by quantitative analysis and thus the empirical formula is obtained; determination

of the molecular weight finally leads to the molecular formula. If the alkaloid is optically active, its specific rotation is also measured. (ii) When an alkaloid contains oxygen, the functional nature of this element is determined: (a) Hydroxyl group. The presence of this group may be ascertained by the action of acetic anhydride, acetyl chloride or benzoyl chloride on the alkaloid (acylation must usually be considered in conjunction with the nature of the nitrogen also present in the molecule; see iii). When it has been ascertained that hydroxyl groups are present, then their number is also estimated (by acetylation, etc.). The next problem is to decide whether the hydroxyl group is alcoholic or phenolic. It is phenolic if the alkaloid is soluble in sodium hydroxide and reprecipitated by carbon dioxide; also a coloration with ferric chloride will indicate the presence of a phenolic group. If the compound does not behave as a phenol, then the hydroxyl group may be assumed to be alcoholic, and this assumption may be verified by the action of dehydrating agents (most alkaloids containing an alcoholic group are readily dehydrated by sulphuric acid or phosphorus pentoxide). The behaviour of the compound towards oxidising agents will also disclose the presence of an alcoholic group. (b) Carboxyl group. The solubility of the alkaloid in aqueous sodium carbonate or ammonia indicates the presence of a carboxyl group. The formation of esters also shows the presence of a carboxyl group. (c) Oxo group. The presence of an oxo group is readily ascertained by the formation of an oxime, semicarbazone and phenylhydrazone. (d) Hydrolysis of the alkaloid and an examination of the products lead to information that the compound is an ester, lactone, amide, lactam or a betaine. (e) The Zerewitinoff active hydrogen determination may be applied to the alkaloid (see Vol. I). (f) Methoxyl group. The presence of methoxyl groups and their number may be determined by the Zeisel method. The alkaloid is heated with concentrated hydriodic acid at its boiling point (126°) ; the methoxyl groups are thereby converted into methyl iodide, which is then absorbed by ethanolic silver nitrate and the silver iodide is weighed. Only methoxyl groups have been found in natural alkaloids. (g) Methyleneiioxyl group ( — OCH 2 *0 — ). The presence of this group is indicated by the formation of formaldehyde when the alkaloid is heated with hydrochloric or sulphuric acid. (iii) The functional nature of the nitrogen. \a) The general reactions of the alkaloid with acetic anhydride, methyl iodide and nitrous acid often show the nature of the nitrogen. (b) Distillation of an alkaloid with aqueous potassium hydroxide usually leads to information regarding the nature and number of alkyl groups attached to nitrogen. The formation (in the volatile products) of methylamine, dimethylamine or trimethylamine indicates respectively the attachment of one, two or three methyl groups to a nitrogen atom; the formation of ammonia shows the presence of an amino group. Only iV-methyl groups have been shown to be present in alkaloids with one exception, viz., aconitine, which contains an iV-ethyl group. (c) The presence of iV-methyl groups and their number may be determined by means of the Herzig-Meyer method. When the alkaloid is heated

486

ORGANIC CHEMISTRY

[CH. XIV

with hydriodic acid at 150-300° under pressure, iV-methyl groups are converted into methyl iodide (cf. the Zeisel method, ii/). (d) The results of hydrolysis will show the presence of an amide, lactam or betaine (cf. iid). (e) Hofmann's exhaustive methylation method, (1881) is a very important process in alkaloid chemistry, since by its means heterocyclic rings are opened with the elimination of nitrogen, and the nature of the carbon skeleton is thereby obtained. The general procedure is to hydrogenate the heterocyclic ring (if this is unsaturated), then convert this compound to the quaternary methylammonium hydroxide which is then heated. In this last stage a molecule of water is ehminated, a hydrogen atom in the ^-position with respect to the nitrogen atom combining with the hydroxyl group, and the ring is opened at the nitrogen atom on the same side as the /S-hydrogen atom ehminated. The process is then repeated on the product; this results in the complete removal of the nitrogen atom from the molecule, leaving an unsaturated hydrocarbon which, in general, isomerises to a conjugated diene (see also Vol. I); e.g.,

H.-Ni.

pyridine

/\ 2

CH CH 2 CH.l CH 2 XJHj H piperidine (ii) AgOH /C H 2 CH2 *?Hjjf\ (CHsUfOH.CH2 ch 2 (i) CH. . heat (-H.0) CH.

(ii)AgOH N(CH 3 ) 2 CH 2 CH CH. heat (-H.(i) CH 3 . .O) CH 2 N(CH 3 ) 3 | + OH *-(CII 3 ) s N+ /C H. CH CH CH.

isoquinoline H 8 (ilCH. 1912) may be used.g..CH.^ NH (ii)AgOH l:2:3:4-tetrahydrof'soquinoline . e. In this method the quaternary ammonium halide is reduced with sodium amalgam in aqueous ethanol or catalytically hydrogenated. in such cases the Emde modification (1909. /°5 CH T!H II I CH 2 CH 3 piperylene Hofmann's method fails if there is no /3-hydrogen atom available for elimination as water.

N(CH 3 ) 2 l OH §4] (-H a O) Na-Hp HjO-C. + (CH 3 ) S N 487 . ALKALOIDS CH CHij-N(CH3) 2 KIT CK w " <K.

.nX oh„-nkih. r > X CH 2 -CH 2 / C N J Br . e.CH 2 . CH 2 'CH 2 \ H 2 N N-Rl + _ ™.u t CH 2 -N(CH 8 ) 3 i + I I' Examination of I shows that /3-hydrogen is absent . Other methods for opening heterocyclic rings containing nitrogen are: (i) Von Braun's method for tertiary cyclic amines (see also Vol.CH 2 \ CH 2 NR+BrCN CH 2 'CH 2 / CH. hence Hofmann's method cannot be used.. I).g.

•CH 2 "CHjgv CH. / CH 2 ..CH 2 Br-(CH 2 ) 4 -NH-R (ii) Von Braun's method for secondary cyclic amines (see also Vol.CH 2 NH + CgHs-COCl NaOH.g. I). •CH 2 "CH 2 CH 2 \/ CH 2 .CH 2 N-CO-C 6 H 5 .yCH. e.2 ' CHgBr CH 2 N CH 2 -CH 2 NRCN ->.

sodium and ethanol. In some cases. and hence milder methods of reduction are desirable.CH 3 -(CH 2 ) 3 -CH 3 + NH 3 (iv) The presence of unsaturation in an alkaloid may be ascertained by the addition of bromine and halogen acids. This often happens when catalytic reduction is used (ring cleavage occurs). e. reduction may decompose the molecule. Two particularly mild reducing reagents are lithium aluminium hydride and sodium borohydride.. Reduction by means of sodium amalgam. also may be used to show the presence of unsaturation. (v) Oxidation.g..CH 2 V CH 2 N-CBr 2 C6H 6 CIi2' CHg distil under reduced pressure *-Br-(CH 2 ) 5 -Br+C 6 H 5 -CN (iii) In a number of cases the ring may be opened by heating with hydriodic acid at 300°. hydriodic acid. -555**. or by the ability to be hydroxylated with dilute alkaline permanganate. tin and hydrochloric acid. This is one of the most valuable means of determining . etc. Sodium in liquid ammonia gives the Emde type of degradations (see iii).PBrj-Bt* yCHjj .

the " strength " of an oxidising agent depends to some extent on the nature of the compound being oxidised.488 ORGANIC CHEMISTRY [CH. (c) Vigorous oxidation is usually effected by potassium dichromatesulphuric acid. This classification is by no means rigid. By varying the " strength " of the oxidising agent. chromium trioxide-sulphuric acid. it is possible to obtain a variety of products: (a) Mild oxidation is usually effected with hydrogen peroxide. (vi) Fusion of an alkaloid with solid potassium hydroxide often produces . concentrated nitric acid. §3.0) -CHC1 I CH 2 More recently. ozone. VIII) . mercuric acetate has been used to dehydrogenate certain alkaloids. XIV the structure of alkaloids (cf. oxidation is readily effected at a double bond. or manganese dioxide-sulphuric acid. In those cases where it can be done. or alkaline potassium ferricyanide. — CHOH Ha so 4 — CH 2 (-H. terpenes. iodine in ethanolic solution. (b) Moderate oxidation may be carried out by means of acid or alkaline potassium permanganate. thereby introducing olefinic bonds. better results are sometimes achieved by first dehydrating the compound and then oxidising the unsaturated compound thus obtained. or chromium trioxide in acetic acid.

iiib). ultraviolet spectra are used to indicate the likely type of structure present . with the structures of so many known. depends on an unambiguous synthesis of the alkaloid. Members of the following groups are described in this book: (i) Phenylethylamine group. and X-ray analysis has offered a means of distinguishing between alternative structures that appear to fit equally well the alkaloid in question. (vi) MoQuinoline group. The final proof of structure. it is probably most satisfactory (chemically) to classify the alkaloids according to the nature of the nucleus present in the molecule. §5. Even today. Even so. in conjunction with chemical methods. the nature of which will give information on the type of nuclei present in the molecule (cf. the source of the alkaloid was considered the most important characteristic of the compound. (ii) Pyrrolidine group.g. (viii) Physical methods are also now being used. however. to elucidate structure. e. Long before the constitutions of the alkaloids were known. (v) Quinoline group. This usually gives the same products as (vi). (vii) Phenanthrene group. (ix) Synthesis. Classification of the alkaloids. Thus there could not be a rational classification. The foregoing analytical work will ultimately lead to the proposal of a tentative structure (or structures) for the alkaloid under consideration.. infra-red spectra studies are used to identify many functional groups. (iii) Pyridine group.relatively simple fragments. (vii) Zinc dust distillation. the classification of the alkaloids is still somewhat arbitrary owing to the difficulty of classifying into distinct groups. except that when the alkaloid contains oxygen the oxygen is removed. (iv) Pyrrolidine-pyridine group. §7] ALKALOIDS 489 .

and since on oxidation ephedrine forms benzoic acid. PHENYLETHYLAMINE GROUP Many compounds of this group are known.p. pVPhenylethylamine may be readily synthesised as follows: Wo C 6 H 5 -CH 2 C1 + KCN -+ C 6 H 5 -CH a -CN > C 6 H 5 -CH 2 -CH 2 -NH 2 pVPhenylethylamine is a colourless liquid. its action is similar to that of adrenaline (§12).It should be noted that in many cases different alkaloids obtained from the same plant often have similar chemical structures. therefore the compound is a secondary amine. b. Finally. an amino-acid). some natural and others synthetic. Since ephedrine forms a dibenzoyl derivative. (— )-Ephedrine. when heated with hydrochloric acid. and occurs in putrid meat (it is formed by the decarboxylation of phenylalanine. §6. the structure therefore contains a benzene ring with only one side-chain. Their outstanding physiological action is to increase the bloodpressure. that compounds of structure II undergo . ephedrine forms a nitroso-compound . C 6 H 5 -CHOH-CH 2 -CH 2 -NH-CH 3 C 6 H 5 -CHOH-CH-CH 3 NH-CH 3 I II It has been observed. and it can be taken orally. Physiologically. m. When treated with nitrous acid. (5-Phenylethylamine. one hydroxyl group must be present (one benzoyl group is accounted for by the imino group). hence they are often referred to as the pressor drugs. C 10 H 15 ON -^> CH 3 -NH 2 + C 6 H B -COCH 2 -CH 3 The formation of these products can be explained if the structure of ephedrine is either I or II. ephedrine forms methylamine and propiophenone. §7. and so sometimes the source of the alkaloids may indicate chemical similarity. however. This is the parent substance of this group of alkaloids. it is one of the most important drugs in Ma Huang (a Chinese drug). 197°. (— )-Ephedrine occurs in the genus Ephedra. The molecular formula of ephedrine is C 10 H 15 ON.p. 38-1°.

and so the replacement of the hydroxyl group by hydrogen should still give a compound that can be optically active. but is to be expected from II. Spath et al. e. ephedrine forms sym. C 6 H 5 -CHOH-CH(CH 3 )-NHCH 3 Jj^5jU II C 6 H 5 -CHOH-CH(CH 3 ).-CHO -^-> CH. Thus II is more likely than I. and so replacement of the hydroxyl 490 ORGANIC CHEMISTRY [CH.-CHBr-CHO CH 3 -CHBr-CH. III . . is optically active. deoxyephedrine. Structure I contains one asymmetric carbon atom. Experimentally it has been found that when this replacement is effected in (— )-ephedrine. Thus II agrees with all the known facts.g.N(CH 3 ) 3 }+OH.-CH. contains two asymmetric carbon atoms. This is supported by the fact that when subjected to the Hofmann exhaustive methylation method. and this structure has been confirmed by synthesis. -methylphenylethylene oxide.. however. this cannot be produced from I.^S C e H 5 -CH-CH-CH 3 + (CH 3 ) 3 N III Further support for II is afforded by the following evidence. (1920) : CH. Structure II.the hydr amine fission to form propiophenone when heated with hydrochloric acid. XIV group by hydrogen will result in the formation of an optically inactive compound. the product.

CBHB .H.OH > HBr £>CH. Br CH. C. .OCH.OCH„ ch 3 -ch-c: <.-NH.MgBr > CH 3 -CHBr-CH: CH.

HI NH-CH.?'~ P > C„H B -CHOH-CH(CH 3 )-NH-CH 3 (±) -ephedrine The racemic ephedrine was resolved by means of mandelic acid. Since the ephedrine molecule contains two dissimilar asymmetric carbon atoms. CH 3 . CbH5 C 6 H 6 -CHOH-CH(CH ? )-NH-CH 3 ( ± ) -y-ephedr ine The racemic modification of y-ephedrine (see below) was resolved by means of tartaric acid. According to Freudenberg (1932). the configurations of ephedrine and y-ephedrine are: CH. (— )-Ephedrine itself has been synthesised by Manske et al. four optically active forms (two pairs of enantiomorphs) are theoretically possible.H B -COCOCH 3 + CH 3 -NH 2 -> C 6 H 6 -CO-C(=N-CH 3 )-CH s . Some (±)-V-ephedrine was also obtained in this synthesis. C. (1929) by the catalytic reduction of 1-phenylpropane-l : 2-dione (benzoylacetyl) in the presence of methylamine in methanol solution.

CH,

HH-

-NHCH 3 -OH

CH 3 -NHHO-

C6H5 (— ) -ephedrine

-H -H

CH 3 -NHH-

CeH s (+) -ephedrine

-H -OH CeH 5 (— )-4> -ephedrine

CH 3 -NH-CH 3 H

HHOC6H5 (+)-«J> -ephedrine

Various mechanisms have been proposed for the hydramine fission. Chatterjee et al. (1961) have suggested two different mechanisms according to whether the aryl nucleus contains (i) an electron-releasing group in the o and /or pposition, e.g., R = OMe, OH, Me:

c-ch 2 — nh 2 OH

C-'-OHj- NH 3 OH

^^ 0^-H

MeNH 2 HCl

CHO

ALKALOIDS

491

-NH, t

§10] (ii) R in the m-position: BH \__\ -C-CHjfNH. OH Thus hydramine fission gives an aldehyde or a ketone according to the nature and position of groups in the aryl nucleus. With a 4-nitro group the product is 4-nitroacetophenone (yield: very poor). §8. Benzedrine (Amphetamine) was originally introduced as a substitute for ephedrine, but it is now used in its own right since it apparently produces a feeling of confidence.

COMe

o

CH 2 -CH(CH 3 )-NH 2

m. occurs naturally in germinating barley. Anhaline).g. m. Since the methylation of .-COCHj "*) C 6 H 5 -CH 2 -CH(CH 3 )-NH-CHO -2^> C 6 H 5 -CH 2 -CH(CH 3 )-NH §9. and is produced by the putrefaction of proteins (by the decarboxylation of tyrosine). Hordenine (j5-^-hydroxyphenylethyldimethylamine. 160°.Benzedrine has been synthesised in many ways. Tyramine has been synthesised in various ways. The molecular formula of hordenine is C 10 H 15 ON.g. 117-118°.p. (S-p-Hydroxyphenylethylamine (tyramine). Mingoia (1940): CgHB-CH. occurs in ergot. the routine tests show that hordenine is a tertiary base and that it contains a phenolic group. e.p. •oO( anisaldehyde CH 3 0<^ ">CHO+ CH 3 -N0 2 W *°"> CH 3 <^_ _\ CH=CH-N0 2 -^-CH s O CH 2 CH 2 -NH 2 - -O CH 2 -CH 2 -NH 2 §10... e.

since the methylated compound gives ^>-vinylanisole. it therefore follows that the hydroxyl group is in the ^ara-position with respect to the side-chain. I. Furthermore. Barger (1909): (CH 3 ) 3 NH > ^^XcHijCHaOH -^^<^J>CH 2 CH 2 C1 . followed by oxidation (with alkaline permanganate)..g.hordenine. gives anisic acid. II. after the Hofmann exhaustive methylation. the structure of hordenine is probably III. CH 3 C0 2 H CH3O GH=CH 2 II HO CH 2 -CH 2 -N(CH 3 ) 2 III 492 ORGANIC CHEMISTRY [CH. e. XIV This has been confirmed by synthesis.

occurs naturally in " mezcal buttons ". 0CH .2-phenylethanol ^~^S CH 2 -CH 2 -N(CH 3 ) 2 HN ° 3 > N0 2 <f_J> CH 2 -CH 2 ^(CH^ g"> HO<^^>CH 2 OH 2 N(CH. The routine tests show that mezcaline contains a primary aliphatic amino-group and three methoxyl groups. C u H 17 3 N..3 . b. 0° H 3 OH 3 <f^\c0 2 H^^ CH 3 <(^y COC1 H 2 -Pd ^ BaS0 4 .) 2 §11.p. 180-180-5°/12 mm. 1919) : OCH. and thus the probable structure of mezcaline is I. mezcaline gives 3:4: 5-trimethoxybenzoic acid. (Rosenmund OCH3 OCH3 reduction) OCH. On oxidation with alkaline permanganate. Mezcaline (mescaline). OCH. CILjO ^ ^ >CH 2 CH 2 -NH 2 OCH 3 This has been confirmed by synthesis (Spath.

NO '> CH 3 0</ .\__/ OCH.r ^\cH=CH-N0 2 CH 3 0<f >CHO-^oh . OCH. (1952) . §12] ALKALOIDS 493 OCH 3 OCH 3 CH 3 0^^C0C1 SbSU. "*> CH.0<A^\cH 2 -CH 2 NH 2 .c "3.CH 3 0<^>C0CHN 2 " H ^°" S > OCH 3 OCH 3 diazoketone OCH 3 OCH 3 CH 3 0<^^>CH 2 CQ-NH 2 UA. this makes use of the Arndt-Eistert synthesis. 3:4:5-trimethoxyto-nitrostyrene OCH Na-Hg *■ CH 3 0< >CH 2 -CH 2 -NH 2 OCH 3 mezcaline A more recent synthesis of mezcaline is that of Banholzer et al.

Since adrenaline is optically active. the product is protocatechuic acid. adrenaline evolves methylamine. §12. it must contain at least one asymmetric carbon atom. The third hydroxyl group was shown to be secondary alcoholic by the fact that when adrenaline is treated with benzenesulphonyl chloride. 1904). is a non-steroid hormone. this led to the suggestion that adrenaline is a catechol derivative. 1901). On the other hand. and is used locally to stop haemorrhage. m. and dissolves in acids and alkalis (it is insoluble in water) . Now adrenaline contains three hydroxyl groups.p. C 9 H 13 3 N. Adrenaline was the first hormone to be isolated in a crystalline form (Takamine. it raises the blood-pressure. Aldrich. and trimethylamine (Jowett. 1901) . The formation of trimethylamine indicates that the nitrogen atom must occur at the end of the side-chain. II. when fused with potassium hydroxide. Since it gives a green colour with ferric chloride. gives veratric acid.OCH 3 OCH 3 iV-Methylmezcaline and iV-acetylmezcaline also occur naturally in mezcal buttons. it is also optically active. thus a methylamino group is probably present. The adrenal medulla is the source of the hormones adrenaline and noradrenaline. I (Takamine. a tribenzenesulphonyl derivative is obtained . two of which are phenolic (as shown by the formation of I and II). methylation. followed OH OCH 3 OH I OH 0" 0" C0 2 H C0 2 H CHOH-CH 2 -NH-CH„ I II III by fusion with potassium hydroxide. When boiled with aqueous potassium hydroxide. 1901. The phenolic character of adrenaline is indicated by its solubility in sodium hydroxide and its reprecipitation by carbon dioxide. 211°. Adrenaline (Epinephrine). Adrenaline is a colourless crystalline solid. having a lsevorotation. Adrenaline is active only when given by injection.

the — CHOH — group must be attached directly to the nucleus . on oxidation. XIV CH. with improvements by Ott (1926).-NH t> catechol Hj-Pcl . AH the foregoing facts are in keeping with structure III for adrenaline. then a phenylacetic acid derivative would have been obtained. gives a ketone (Friedmann. had it been — CH 2 -CH0H>.which. 494 OH + CH 2 C1-C0 2 H POC ' 3 > ORGANIC CHEMISTRY OH OH [CH. and this has been confirmed by synthesis by Stolz (1904) and Dakin (1905). To account for the oxidation of adrenaline to the benzoic acid derivative. 1906).

CO-CH 2 Cl io-chloro-3:4dihydroxyacetophenone GO-CH 2 -NH-CH 3 OH CHOH-CH 2 -NH-CH 3 (±)-adrenaline The racemic adrenaline has been resolved by means of (+)-tartaric acid. Nagai (1918) has also synthesised adrenaline as follows: OGO-CHj ^O-CO-CHj CHO diacetylprotocatechualdehyde + CH 3 -N0 2 -^ L >- 0-CO-CH 3 OCO-CH 3 .

the configuration of (—) -adrenaline is probably CH 2 -NH-CH 3 HO-C-H §12a.g.CHOH-CfI 2 -N0 2 O-CO-CH. C 8 H 11 3 N.. The structure of noradrenaline has been established by analytical work similar to that described for adrenaline. Zii-CH 3 CO a H^ HCHO * ^0-CO-CH 3 hci OH -0 OH CHOH-CH 2 -NH-CH 3 CHOH-CH 2 -NH-CH 3 (±) -adrenaline According to Dalgliesh (1953). The natural compound is laevorotatory. is also present in the adrenal medulla. e. and this (— )isomer is the most powerful pressor-compound known. Noradrenaline (Norepinephrine). . and has been confirmed by various syntheses.

hygrinic acid is formed. Furthermore. since the decarboxylation occurs very readily. hygrinic acid gives 2V-methylpyrrolidine . 193-195°. b. When subjected to dry distillation. Hygrine. hence hygrinic acid is an iV-methylpyrrohdinecarboxylic acid. C(C0 2 C 2 II 6 ) 2 CHa ' N " 2 > CH 2 G(C0 2 C 2 H 5 ) 2 Br Br ^N^ . l-methylpyrrolidine-2-carboxylic acid.§13] ALKALOIDS 495 OH OH OH OH — OH ^0 OH CHO CHOHCN CHOH-CHjfNHjj (±) -noradrenaline According to Dalgliesh (1953). and when oxidised with chromic acid. the configuration of (— )-noradrenaline is CH 2 -NH 2 HO— 0— H PYRROLIDINE GROUP §13. This structure. the carboxyl group was assumed to be in the 2-position (by analogy with the a-amino-acids). Br-(0H 2 ) 3 -Br+ [cH(C0 2 C 2 H 6 k] Na + — vBr(CH 2 ) 3 -CH(C0 2 C 2 H 5 ) 2> Br . for hygrinic acid was confirmed by synthesis (Willstatter. 1900). C g H 15 ONi°U 6 H u 2 N hygrinic acid Hygrinic acid was first believed to be a piperidinecarboxylic acid. C 8 H 15 ON. but comparison with the three piperidine acids showed that this was incorrect. > CHf-CH» ch CH— CH 2 *~GTI. is one of the coca alkaloids.p. Its reactions show the presence of a keto group and a tertiary nitrogen atom.

. the imino nitrogen is methylated and the secondary alcoholic is oxidised to a keto group. Hess (1913) claimed to have confirmed this structure by synthesis. XIV CH. This compound is then catalytically hydrogenated and then treated with formaldehyde. CH 2 (h)hci C h 2 CH -C0 2 H I CH 3 (+)-hygrinic acid 496 ORGANIC CHEMISTRY Thus a possible structure for hygrine is CH 2 — CH 2 II CH 2 CH-CH 2 -CO-CH 3 [CH.I CH 3 (i)Ba(OH) v ^H. his synthesis starts with pyrrylmagnesium bromide and propylene oxide to form pyrrylpropanol (note the rearrangement that occurs).

Flo MgBr H OH 2 -CHOH-CH. H 2 -Pt CHo — CHn II' CH 2 CHCH 2 -CHOHCH 3 H .CH 3 Mgflr H CHVCH-CH 3 .

it is the last stage of Hess's interpretation that has been shown to be incorrect. (1949) have also synthesised (i) -hygrine by condensing ymethylaminobutyraldehyde with ethyl acetoacetate in a buffered solution at a pK of 7 (physiological conditions).H-CHO II CH 2 CHCH 2 COCH 3 CH 3 (±) -hygrine Lukes et al. Anet et al. CH 2 -CH 2 C0 2 C 2 H 5 II+I GH 2 CHO CH 2 COCH 3 NH CH 3 pHl II . (1959) have repeated Hess's work and have shown that the product is not hygrine but the tetrahydro-oxazine (I).

CH 2 CHCH 2 COCH 3 I CH,

§13a. Cuscohygrine (Cuskhygrine), b.p. 169-170°/23 mm., occurs with hygrine. Its structure is established by the following synthesis (Anet et al., 1949) ; y-methylaminobutyraldehyde is condensed with acetonedicarboxylic ester:

§15] ALKALOIDS CH— CH 2 I I . COoEt C0 2 Et CH 2 CHO +| I +

N

NH I CH,

CH 2 -CO-CH 2

CH 2 — CH 2 CHO CH 2 HN I

CH,

497

PHT,

CH 2 — CH 2 CH 2 — CH 2 II II CH 2 6H-CH 2 -CO- CH 2 -CH CH 2

CH,

CH,

cuscohygrine

§13b. Stachydrine is obtained from the roots of Stachys tuberifa, from orange leaves, etc. It is the betaine (§4 C. XIII) of the quaternary ammonium compound of hygrinic acid.

CH 2 CH 2

CH 2 CH-COr

X 1T (CH 3 ) 2 §14. Gramine has been found in barley mutants; it raises the bloodpressure in dogs when administered in small doses. Gramine has been synthesised by allowing indole to stand in an aqueous solution containing formaldehyde and dimethylamine (Snyder et al., 1944).

+ HCHO+(CH 3 ) 2 NH

GH,-N(CH,)»

+^0

PYRIDINE GROUP §15. Trigonelline, C,H 7 O g N, m.p. 130°, is widely distributed in plants; the best source is the coffee bean. When boiled with barium hydroxide solution trigonelline produces methylamine; thus the molecule contains an iV-methylamino group. On the other hand, when heated with hydrochloric acid at 250° under pressure, trigonelline forms methyl chloride and nicotinic acid; this suggests that the alkaloid is the methyl betaine of nicotinic acid. This structure for trigonelline has been confirmed by synthesis (Hantzsch, 1886). When heated with methyl iodide in the presence of potassium hydroxide, nicotinic acid, I, is converted into methyl nicotinate methiodide, II. II, on treatment with " silver hydroxide " solution, forms nicotinic acid methohydroxide, III, which then spontaneously loses a molecule of water to give trigonelline (a betaine), IV.

^C0,H ch„i

e. (1923). CI CI CI KMnQ 4 . 201-5°.. it is not a very toxic alkaloid. [|\C0 2 •N' I CH 3 IV 498 ORGANIC CHEMISTRY [CH.p. Ricinlne. m. This has been confirmed by synthesis.g. C g H 8 2 N 2 .. XIV §16. Degradative and synthetic work led to the suggestion that I is the structure of ricinine. has been isolated from castor-oil seed. Spath et al.C0 2 CH 3 _AgOH_ CO g H -h 3 q.

4 -chloroquinoline CI (f\c0 2 H !iC0 2 H (CH 3 CO) 2 *)C0 2 H u CC-NH 2 4-chloropyridine2:3-dicarboxylic acid CI fjSc0 2 H V NH ° ~ Brj-KOH NaNOj H a S0 4 .

CO-NH 2 pocj^r II Jci " \ Jci 100° 2:4-dichloropyridine-3-carbonamide OCH 3 .CI C0 2 H poci 3 OH II HI 2-carbonamido-4-chloropyridine-3-carboxylic acid CI CI d^ScOCl NH . /A.

CI CI . and consequently III would have been Ilia. since II could have been 3-carbonamido-4-chloropyridine-2-carboxylic acid. CH S I heat in vacuo This is not an unambiguous synthesis.CH3OH PC1„ OCH3 CN :H s ON a> _ f ^ OCH. II«.

H U Jc0 2 H H ' so « I JcOoH XN ^N II a III a §17] ALKALOIDS 499 The structure of III was proved by the fact that on hydrogenation in the presence of Pd — BaS0 4 . . it gave 2-hydroxypyridine-3-carboxylic acid. IV.CI CI U JcO' l[ JC0.

NO. .S0' OCH.. O NO. CH. OCH OCH.Ha Pd -BaS0 4 A more recent synthesis of ricinine is that of Taylor et al. 227 H. (1956).

CO. 271-272° NN H N N^ I 0H 3 .g. Areca (or Betel) nut alkaloids.. The betel nut is the source of a number of alkaloids which are all partially hydrogenated derivatives of nicotinic acid.H C0 8 CH 3 C0 2 H guvacine.p. m. e.5|CONH 2 l'Cls POCl 3 §17.

on treatment with concentrated hydrochloric acid.p. Acraldehyde. 1907). 209° Let us consider arecaidine. forms 3-chloropropionaldehyde acetal. therefore this alkaloid is a pyridine derivative. This was proved to be so by synthesis. Since the alkaloid is a pyridine derivative. b. 1890) . I. an iV-methyl group and one double bond . The usual tests show that arecaidine contains one carboxyl group. on treatment with ethanol in the presence of hydrogen chloride. hence the formula for arecaidine may be written as C B H 7 N(CH 3 )'C0 2 H. and at the same time the positions of the double bond and carboxyl group were also established (Wohl et al.H4°/l3mm. II. When distilled with zinc dust. and consequently is also a pyridine derivative. 1888.. m. III.guvacoline. 223° C0 2 CH 3 arecoline.p. This gives the cyano compound V on treatment with hydroxylamine. II reacts with methylamine to form p^-methyliminodipropionaldehyde tetra-acetal. Now guvacine is converted into arecaidine on heating with potassium methyl sulphate and sodium methoxide (Jahns. and V is then converted into . ring closes to form 1:2:5: 6-tetrahydro-l-methylpyridine-3-aldehyde. followed by dehydration of the oxime with thionyl chloride. IV. the fragment C S H 7 N could be tetrahydropyridine. its molecular formula is C 7 H u 2 N. which. arecaidine . guvacine gives 3-methylpyridine. thus arecaidine is a methyl derivative of guvacine.p.

22 .500 ORGANIC CHEMISTRY [CH. XIV CHO CH + 2C 2 H 5 0H+HC1II CH 2 I CH(OC 2 H 5 ) 2 -CH 2 I CH 2 C1 II CH 3 NHj (C 2 H 6 0) 2 CH CH(OC 2 H 5 ) 2 CH 2 CII 2 .

CH CH 2 C-CHOjj) NH2 o H ^ CH 2 CH 2 CH 2 I CH 3 IV (ii) SOCIj . .CH 2 CH 2 CH 3 III HCl CHO CHO II CH 2 CH 2 CH 2 CH 2 CH.

Arecaidine is VI. ."cH.CH CH 2 N c-co 2 CH.X>CN CH 2 I CH 3 V CH 2 N C-C0 2 H I I or CH 2 CH 2 \/ NX I CH 3 VI . CH. . the dipolar ion structure (c/. or possibly Via. CH 3 Via arecaidine by hydrolysis. amino-acids and betaines).

C0 2 C 2 H 6 C0 2 C 2 H 5 CH +NH 3 + CH II II CH 2 CH 2 ethyl acrylate O C 2 H50 2 C COjAHs CH 2 CH 2 II Cxig XvXA2 \' NH A . (1946).coci .A more recent synthesis of arecaidine (and guvacine) is that of McElvain a al.C0 2 C 2 H 5 c 6 h.

H 3-carbethoxypiperid4-one C0 2 C 2 H 5 Hj-Ni CO-CgHs (Dieckmann reaction) SCO2C2H5 CO-C 6 H 5 dry HCl 180° iC0 2 H >C0 2 H H guvacine .

is the form that occurs in oil of hemlock. and it was actually shown to be rc-propyl by the fact that when heated with 'CH=CH-CH 3 Na ^_ 9 Ha I * 2-propenyl- . Oil of hemlock was drunk by Socrates when he was condemned to death in 399 B. The most important alkaloid of this group is coniine. (+)-Coniine. This side-chain must contain three carbon atoms. C 8 H 17 N. This side-chain is therefore either M-propyl or wopropyl. Thus coniine is probably a piperidine derivative with a side-chain in the 2-position. Since the oxidation of conyrine with permanganate gives pyridine-2-carboxylic acid (a-picolinic acid).C. When distilled with zinc dust. Hemlock alkaloids.p. it was the first alkaloid to be synthesised. coniine is converted into conyrine. since two are lost when conyrine is oxidised. C 8 H U N (Hofmann. 166-167°.CH 3 arecaidine §18] ALKALOIDS 601 §18. 1884). b. it follows that a pyridine nucleus is present with a side-chain in the 2-position.

Had the side-chain been isopropyl.pyridine I c„h 6 oh qjj^ CH-CH 2 -CH 2 -CH 3 H (±) -coniine hydriodic acid at 300° under pressure. then the expected product would be wo-octane. and the (+)-coniine so obtained was found to be identical with the natural compound. 1885). From this evidence it therefore follows that coniine is 2-M-propylpiperidine. The racemic coniine was resolved by means of (+) -tartaric acid. and this has been confirmed by synthesis (Ladenburg. coniine forms M-octane.HI CH 3 CHgCHgCHgCHj H 2 n -octane H . The reactions of coniine described above can therefore be formulated as follows: H2 CH 2 CH 2 .

CH^'CHs CHg KMnOi . 1932): EtBr CH. ^CM2"CIi2"Ofi3 conyrine J C0 2 H pyridine-2carboxylic acid Coniine has also been synthesised from 2-methylpyridine and phenyllithium as follows (Bergmann et al..Li EtOH .

rrw V-r^^n H./CH^ CH2* CH3 CH2 CH 2 " CH3 602 ORGANIC CHEMISTRY Other hemlock alkaloids are: H2H2 \ n 2 R0 \ r 2 2 V/^riimH.r!B . XIV CH2' CH2' OH3 . IT H H is CH2' Oxi2*Cri3 [CH.

The root bark of the pomegranate tree contains a number of alkaloids.Y-comceine conhydrine ^"Conhydrine §19. The last of these is related to atropine (§22). the most important of which is pelletierine. methyh'sopelletierine and pseudo-pelletierine. Pomegranate alkaloids. H CH 2 -CH 2 -CHO pelletierine o CH. methylzsopelletierine wopelletierine H H2 N CH 2 -COCH 3 -CH — CH 2 . three others are wopelletierine.

Spielman et al. also failed to obtain the free aldehyde. (1940) who attempted to hydrolyse it to the free aldehyde.II n-ch s co CH 2 CH 2 I2 CH 2 — CH — CH 2 pseudo-pelletierine Pelletierine acetal has been synthesised by Spielman et al. Beets (1943) has therefore suggested that pelletierine can. followed by catalytic reduction. they obtained only viscous oils. (1941) by the action of 3-bromopropionaldehyde acetal on 2-methylpyridine (a-picoline) in the presence of phenyl-lithium. CH(OC 2 H 5 ) 2 C 6 H B Li s CH 2 CH 2 -CH(OC 2 H 5 )2 ^CH 2 CH 2 CH(OC 2 H 6 ) 2 (±)-form Pelletierine acetal was also prepared by Wibaut et al. and probably does. exist as some bicyclic structure such as I. .

I H 2 C CH-CH 2 -CH 2 CH(OEt) 2 N H H.H. .C 2| HaC / Cja .C /$ CH. ■2 CH.

Piperine. the structure of piperine rests on the elucidation of that of piperic acid. occurs in pepper. m. especially black pepper {Piper nigrum). piperic acid gives first piperonal and then piperonylic acid. Hydrolysis of piperine with alkali gives C 17 H 18 8 N + N a O J-C^oO* + C 5 H U N piperic acid piperidine piperic acid and piperidine . C 8 H 6 4 + H 2 -^ piperonylic acid . Since piperidine is hexahydropyridine. The structure of the latter is deduced from the fact that when heated with hydrochloric acid at 200° under pressure.H CHCH 2 CH 2 CHO §20] ALKALOIDS 503 H 2 C CH 2 H 2 C CH N CH. C 17 H 1? 3 N.. II HOCH — CH 2 §20.p. thus the alkaloid is the piperidine amide of piperic acid (Babo et al. 1857). The routine tests show that piperic acid contains one carboxyl group and two double bonds. When oxidised with permanganate. 128-129-5°. piperonylic acid forms protocatechuic acid (3 : 4-dihydroxybenzoic acid) and formaldehyde.

and there are no free hydroxyl groups in piperonylic acid. i.HO(f\cO. this has been confirmed by synthesis: CH 2 I 2 -^> hut piperonylic acid Furthermore.e. since piperonal (an aldehyde) gives piperonylic acid on oxidation. piperonal is therefore 3 : 4-methylenedioxybenzaldehyde. .. the structure of this acid is probably the methylene ether of protocatechuic acid. piperonylic acid is 3 : 4-methylenedioxybenzoic acid.H 11+ H-CHO HO V protocatechuic acid Since one atom of carbon is eliminated. CH.

O-YXCHO KMn0<> c^. If we assume I as 504 ORGANIC CHEMISTRY [CH.CH' =CH-CH=CHC0 2 H I [o] C0 2 H . . XIV the structure of piperic acid.fV° H piperonal From these results of oxidative degradation. then all of the foregoing products of oxidation may be accounted for. and since the careful oxidation of piperic acid gives tartaric acid in addition to piperonal and piperonylic acid. the side-chain is a " straight " chain. It is this sidechain that contains the two double bonds (the ready addition of four bromine atoms shows the presence of two ethylenic bonds). it therefore follows that piperic acid is a benzene derivative containing only one side-chain.

NaOH CHO CH a(a NaOH % QIl£.+ H0 2 C-CHOH-CHOH-C0 2 II This has been confirmed by synthesis (Ladenburg et al. and the product (a cinnamaldehyde derivative) is then heated with acetic anhydride in the presence of sodium acetate (Perkin reaction).. piperonal (prepared via the Reimer-Tiemann reaction) is condensed with acetaldehyde in the presence of sodium hydroxide (Claisen-Schmidt reaction). CHO . 1894). + CHO.Q| catechol CH.

CH 2 -<AJ . CH.CH 2 v + HN. ^--O r r\cH=CHCH=CHCOCl .CH 2 .CHO ^-0 NaOH^-WzH I (CH 3 CO).CH 2 -CH 2 v. ^-°~( ^CH=CH-CH=CH-CON v . piperine is formed.G0 2 H When the acid chloride of piperic acid (prepared by the action of phosphorus pentachloride on the acid) is heated with piperidine in benzene solution. \/ Gfi2*CH 2 x^ / .CH=CH.:H * ch 1 ^r irNcH=CH.0 QH 2 JCH^COJsO CH 3 -C0 2 Nr !lCH=CH. thus pipeline is the piperidine amide of piperic acid.

at this point.. it occurs naturally as the (— )-form. When oxidised with dichromate— sulphuric acid (or permanganate or nitric acid). is the best known and most widely distributed of the tobacco alkaloids. 247°.p. Many alkaloids have been isolated from the tobacco leaf. nicotimine (anabasine). etc. Tobacco alkaloids. . C 10 H 14 N a .g. nicotine forms nicotinic acid (Huber. ^C0 2 H nicotinic acid §21] ALKALOIDS 505 It is instructive. to see how the orientations of the three isomeric pyridinecarboxylic acids have been elucidated. b. C 10 H 14 N 2 nicotine KWnO t . Nicotine. e. 1867).piperine PYRROLIDINE-PYRIDINE GROUP §21. nornicotine. nicotine.

. gives the dicarboxylic acid III which.p. 234-237° m. .p. 137° nicotinic acid. I). 1-Naphthylamine. is converted into 2-phenylpyridine. wonicotinic acid. i. when decarboxylated by heating with calcium oxide. IV. is converted into 7 : 8-benzoquinoline.e. when subjected to the Skraup synthesis (see Vol. II. be the 2-acid. from the structure of IV. m.NN 'COjH CO. on vigorous oxidation with alkaline permanganate.H C0 2 H w "N picolinic acid. I. This. on further oxidation with permanganate. II (this structure is established by its synthesis).p. picolinic acid. 317° Picolinic acid. V. gives a pyridinecarboxylic acid which must. m.

CO. CHjOH + GHOH NH 2 I CHjOH H a SO.H CO s H Co] H0 2 C Nicotinic acid. This has been shown to be pyridine-3-carboxylic acid by a similar set of reactions. CHjOH y 11011 C.NO.OH .NH. . CH.H. except that in this case the starting material is 2-naphthylamine.

HO s C<* nicotinic acid isoNicotinic acid. XIV [o]. on oxidation with alkaline permanganate. woQuinoline.or -3-carboxylic acid. . gives a mixture of nicotinic and isonicotinic acids. produces cinchomeronic acid. Hence picolinic acid is pyridine-2-carboxylic acid. This. Oxidation of quinoline with alkaline permanganate gives quinolinic acid which. thus nicotinic acid must be either pyridine-2. This third isomer is therefore pyridine-4-carboxylic acid. by its method of preparation. An alternative proof for the orientations of these three acids is based on the structures of quinoline and isoquinoline (which have been established by synthesis). When quinolinic acid is heated to 190°. on gentle heating. and isonicotinic acid the 4-acid. 506 ORGANIC CHEMISTRY [CH. must be pyridine-2 : 3-dicarboxylic acid. thus nicotinic acid must be the 3-acid. one carboxyl group is lost to produce nicotinic acid. which must therefore be pyridine-3 : 4-dicarboxylic acid.C°] .

CO.H N quinoline to].H CO.H nicotinic acid CO>H . MOquinoline quinolinic acid C0 8 H C0 2 H cinchomeronic acid CO.

Thus the side-chain contains an iV-methyl group. this side-chain was originally believed to be piperidine. This suggests that the side-chain C 5 H 10 N is a pyrrole derivative. methyl iodide is formed. the products are pyridine. pyrrole and methylamine (Laiblin.wonieotinic acid Returning to the structure of nicotine. but its point of attachment to the pyridine nucleus could be either 2 or 3 on the evidence obtained so far: C B H 10 N CH 2 — CH 2 -CH CHg T CH. or \. Furthermore. . Thus we may write the formula of nicotine as C 5 H 10 N Because of its formula. but further work showed that this was incorrect. It therefore appears that the side-chain could be iNT-methylpyrrohdine. the alkaloid therefore contains a pyridine nucleus With a complex side-chain in the 3-position. since nicotinic acid is a product of oxidation. 1879). when nicotine is heated with concentrated hydriodic acid at 150° (Herzig-Meyer method). When nicotine ziocichloride is distilled.

C 10 H 10 ON 2 Br 2 . forms 3-acetylpyridine. 'I . on heating with a mixture of sulphurous and sulphuric acids at 130-140°.„N C-C + C-C ^N (oxalic acid) (3-acetylpyridine) . is converted into dibromocotinine. CinH^ONgBra-HBr-Brg. oxalic acid and methylamine. This. Treatment of nicotine with bromine in acetic acid gives. when treated with aqueous sulphurous acid.-CH— CH. among other products. Of CH 2 CH 2 a-/ I CH S The correct structure of nicotine was obtained by Pinner (1892. which. 1893). the hydrobromide perbromide. Thus the structure of nicotine must account for the following skeleton structures: C 5 H.

taken in conjunction with one another. on heating with barium hydroxide solution at 100°. are satisfied by the following skeleton for nicotine: C-C-C-C .I — N-CH 3 (methylamine) Now bromine. forms nicotinic acid. converts nicotine into dibromoticonine. C 10 H g O 2 N 2 Br s . Hence the structure of nicotine must also account for the following skeleton structures: §21] ALKALOIDS 507 C 5 H 10 N + C-C-C + — N-CH 3 N N' "N" (malonic acid) (methylamine) (nicotinic acid) These two sets of reactions. malonic acid and methylamine. in the presence of hydrobromic acid. which.

i.e. Hence the side-chain must be saturated.H if >~CBr -CHBr „x I 1 "V P H * (i) Br.-CH 3 -CQ 3 H^ (I J N (ii)H. m Rr . All the foregoing facts are satisfied by the following structure for nicotine.. rV< CHg CH 2 CH ^CHj nicotine On this basis. and forms two isomeric " methyl iodide addition products ". Pinner's work may be formulated: CH 2 -CH 2 CH 2 /\— CH CH.+ — N-CHs The problem now is : Where is the position of the N-methyl group? Nicotine behaves as a di-tertiary base. iNT-methylpyrrohdine (C 5 H u N=C 4 H8'NCHj^C 4 Hg). .-co. it is extremely difficult to reduce nicotine beyond hexahydronicotine (the pyridine part is reduced to piperidine)._cH. The presence of this pyrrolidine nucleus also accounts for the formation of pyrrole when nicotine zincichloride is distilled (see above).SO. and this can only be so if the sidechain is cyclic. Furthermore. Thus the nitrogen atom in the side-chain must be of the type — C— N(CH 3 )— C— .

•N' CII.CH CH.CH 2 . X 1T .fV. Y CO I CH 3 dibromocotinine H a SO» l0 OCH s+ CO 2 H + CO a H 3-acetylpyridine CHsr.

: X N' CH. dibromoticonine jCOoH + H0 2 C-CH 2 -C0 2 H + CH 3 -NH 2 508 ORGANIC CHEMISTRY .I CH S Brj HBr CO— CHBr || / \-CBr / CO B a(OH).

XIV The most direct analytical evidence for the presence of the pyrrolidine nucleus has been given by Karrer (1925. CH 2 -CO\ electroIytic CH 2 -CH 2 \ .cHJ. nicotine hydriodide forms nicotine isomethiodide when warmed with methyl iodide and this..g. on oxidation with potassium ferricyanide.™/ NaOH CH. e.[CH. gives hygrinic acid (§13). CH 3 }V nicotine /somethiodide CH 2 — CH 2 H0 2 CCH CH 2 V I CH 3 hygrinic acid Pinner's formula for nicotine has been confirmed by synthesis. is converted into nicotone which. 1926) . Spath and Bretschneider (1928).-CO / CH 2 -CO' succinimide .so t 9 H «"GH^ >/ nil. on oxidation with chromium trioxide.

HCl ..CH 2 CO ' 2-pyrrolidone (ii) || / \C0 2 C 2 H 5 + CH 2 -CH 2 C2 H 6 oNa > /\-0O-GH— CH S \r CO CH. i CHs \r CO CH 2 V I CH.

-CH. . CHOH CH 2 NH CH. — CH. II CO ^jCKt u a NH -^(X ^N Zn dust CjHjOH-NhOH CH.COCHCH 2 CH 2 NH-CH 3 C0 2 H (5-ketonic acid CH.

§22] Craig (1933). . NaOH CH 2 ov N CH 3 (+)-nicotine CH 2 I CH 2 This was resolved by means of (+)-tartaric acid. NH CH. the synthetic (— )-nicotine is identical with the natural compound.VN CH 2 — CH 2 II CHI CH.

J NH 2 OC 2 H 5 N .H 5 H.ALKALOIDS 509 nicotinonitrile NHjOH + BrMgCH 2 CH 2 CH 2 OC 2 H 5 Y -ethoxypropylmagnesium bromide CH 2 — CH 2 a CO CH 2 OC 2 H 5 3-pyridyI y-ethoxypropyl ketone GH 2 — * CH 2 C CH 2 „„ z " u > /\— CH CH 2 || | 2 CH 3 -CO a H ] | | NOH OC.

CH 2 — CH 2 CH 2 HBr 150-155° CHo CHg -a CHg 'CHo CH CH. H ^ 2 (i)CH 3 l (ii) NaOH (+)-nornicotine CH 2 — CI12 (f\— CH CH 2 .

and this.H CH 2 II gives benzoic acid. When heated strongly. 118°. atropine is hydrolysed to (i) -tropic acid and tropine (an alcohol). thus atropine is (±)-hyoscyamine. the usual tests show that it contains one carboxyl group and one alcoholic group. tropic acid loses a molecule of water to form atropic acid. hyoscyamine and scopolamine (hyoscine). Addition of a molecule of water to II would therefore give tropic . C 17 H 23 3 N. thus atropine is the tropine ester of tropic acid.VY N CH 3 (±) -nicotine Spath et al. C 9 H g 2 . is a saturated compound (it does not add on bromine) . but readily racemises to atropine when warmed in an ethanolic alkaline solution. This group includes atropine. (1936) have resolved ( r | r )-nornicotine. Atropine. §22. 117°. When warmed with barium hydroxide solution. m. Solanaceous alkaloids. It therefore follows that atropic acid could be either I or II.p. I is known to be cinnamic acid. II must be atropic acid. however. occurs in deadly nightshade (Atropa belladonna) together with hyoscyamine.p. Thus tropic and atropic acids contain a benzene ring with one side-chain. on oxidation. C 6 H 5 CH=CH-C0 2 H I C 6 H 5 -C-COi. Since. Hyoscyamine is optically active (laevorotatory). methylation of the (— )-form with formaldehyde and formic acid gave (—) -nicotine. m. C fl H 10 O 3 . (±) -Tropic acid. identical with the natural product.

. The above synthesis results in (±)-tropic acid. ° 6Hs \n ~ "cn. and this has been resolved by means of quinine. (1952) have synthesised tropic acid by boiling phenylacetic acid with tsopropylmagnesium chloride in ethereal solution. and then treat- . starting from acetophenone. consequently. had the addition been in accordance with the rule.g.-H CH 3 CH 2 OH III IV acid which. Blicke et al. Vol. C„H 5 ^^OH C 6 H 5 ^ OH heat JJ=0 *~ yk *" / \ reduced CHf CH 3 ^ XN GH " III COaH pressure atrolactic acid CH^^COgH HQS CH.^ dX 0H. It should also be noted that the addition of hydrogen chloride takes place contrary to Markownikoff 's rule (see unsaturated acids. Tropic acid has been shown to be IV by synthesis.510 ORGANIC CHEMISTRY [CH. I) . and its dehydration to II confirms the structure of atropic acid. e. XIV OH H II C e H 6 — C-C0 2 H C 6 H 5 — C— 00. must be either III or IV.01 K>c% CeH^^CH.OH CH2 * " ■j-r tropic acid III is atrolactic acid. then atrolactic acid would have again been obtained. It is tropic acid that contains the asymmetric carbon atom which gives rise to the optically active hyoscyamine. Mackenzie and Wood (1919).

natural tropic acid is (S)-(-) -tropic acid.H. H— Ph — C0 2 H CH-OH Tropine (tropanol). a Grignard reagent.CH 2 OH C.p.-OHr 2L£^C 6 H 6 -Ch( X C0 2 MgCl \:o 2 H Fodor etal. which is then replaced by hydrogen to form . 1887). II).N §22] ALKALOIDS 511 " Tropine iodide " is formed by the replacement of the alcoholic group in tropine by an iodine atom. m. According to the Cahn-IngoldPrelog convention (§5c. who showed that the molecule contained a reduced pyridine nucleus: Tropine > " Tropine iodide " >• Dihydrotropidine CgH 16 ON < Mowl60 °> C 8 H U NI C 8 H 15 N ->. 63°. The structure of tropine was investigated by Ladenburg (1883.CH3CI + wrDihydrotropidine *■ 2-Ethylpyridine hydrochloride C 7 H 1S N iml C 7 H.ing the product. (1961) have established the absolute configuration of (— )-tropic acid by its correlation with (— )-alanine. with formaldehyde. >MgCl . behaves as a saturated compound which contains an alcoholic group. C 8 H 16 ON.H 6 -CH 2 -C0 2 H (CH3) ' CHMgCI > O.

thus tropine is a secondary alcohol (c/. obtained (±)-tropinic acid. Thus tropinone contains the 'CH^CO'CHg' grouping. and a di-oximino derivative when treated with amyl nitrite and hydrochloric acid. and so it follows that Merling's formula is also untenable. and the isolation of 2-ethylpyridine shows the presence of this nucleus (in a reduced form)..dihydrotropidine (tropane). and so Merling proposed the following structures for tropine: I I I or I I I CH 3 -N fa* CH 2 CH S -N CHOH CH 2 Willstatter (1895-1901) then examined the oxidation products of tropine obtained as follows: Tropine > Tropinone '-*■ (±)-Tropinic acid C 8 H 16 ON C 8 H 13 ON C 8 H 1S 4 N Tropinone behaved as a ketone. The formation of methyl chloride indicates the presence of an iV-methyl group. Willstatter therefore proposed three possible structures for tropine. the hydroxy! group in tropine must therefore be in a ring system. C 8 H 15 ON-^V C 8 H 13 4 N tropine (^-tropinic acid Tropinic acid is a dicarboxylic acid. NCH 3 CHOH II CH 2 — CH — CH 2 . Willstatter (1897) also showed that tropinone forms a dibenzylidene derivative with benzaldehyde. and was left with the following (which contains a pyridine and a pyrrole nucleus with the nitrogen atom common to both): CH 2 — CH — OH. Merling's formula). Thus Ladenburg's formula is untenable. Ladenburg was led to suggest the following alternative formulae for tropine: Merling (1891). by the oxidation of tropine with chromium trioxide. Largely on this evidence. and since there is no loss of carbon in its formation. but eliminated two by the consideration of various reactions of tropine.

forms pimelic acid. on reduction...~~~ CP12 tropine Hr CH 2~~* C jFx GH2 NCH. (ii) Exhaustive methylation of tropinic acid gives an unsaturated dicarboxylic acid which.Not only did this fit the facts best. but it was also supported by the following evidence: (i) Exhaustive methylation of tropine gives tropilidene (cycloheptatriene). CHI Cri2^~ CH CH 2 ." "* CH. CH 2 — CH — CH 2 NCH 3 CHOH II CH2 . All the foregoing reactions of tropine can be readily explained on the Willstatter formula. XIV Formation of 2-ethylpyridine from tropine. C 7 H 8 . 512 ORGANIC CHEMISTRY [CH.

[H] HCI *-CH 3 Cl + CHg" . CH 2 — CH — CH 2 CH 2 — CH— CH 2 CH 2 — CH— CH 2 -C0 2 H NCH 3 .~CH — CHo 11 NH CH 2 OH 2 Cy£X'—' ™ CH2 NCH. CH 2 II CHg — CH CH 2 dihydrotropidine (tropane) /CHo'OHfl CH 2 CH 2 CH 2 Kordihydrotropidine 2-ethylpyridine Formation of tropinone and tropinic acid from tropine.

CH 2 — CH — CH 2 CH 2 — CH— CH 2 tropinone c«h b -cho NCH. ^ CH 2 — CH — CH 2 CHg— CH — CH CH 2 — CH=CH NCH 3 CH-|^> distillation MCH^CHCH 2 — CH CH .92 ^ 2 -CH-< CH 2 — CH-C0 2 *H tropinic acid CH 2 — CH — C=CHC 6 H5 NCH S CO CH 2 — CH — C=CHC 6 H 5 dibenzylidenetropinone Formation of tropilidene from tropine. CHOH. CHOH-g^. CH 2 — CH — CH„ CH 2 — CH — CH 2 NCH.

CHf.(i) CH 3 I (ii) AgOH (iii) vacuum distillation CH 2 — CH CH 2 -UI HON(CH 3 ) 2 CH CH 2 — CH CH CH 2 — CH=CH I CH II CH=CH — CH tropilidene Formation of pimelic acid from tropinic acid.CHCH 2 C0 2 H CH 2 — CH-CH 2 C0 2 H I NCH 3 CH 2 — CHC0 2 H (i) CH 3 I .

CHg— CH-C0 2 H tropinic acid CH 2 -CH=CH-C0 2 H (i)CHsI C^-CH^H-COi-H CH 2 -CH 2 CH 2 -C0 2 H N(CH 3 ) 2 CH 2 — CHC0 2 H (ii) AgOH^ (iii) heat % CH=CHC0 2 H CH 2 -CH 2 -C0 2 H piraelic acid §22] ALKALOIDS 513 .(ii)AgrOH HONtcHs).

and the other by Robinson (1917).The structure of tropine has been confirmed by synthesis. WiUstatter's synthesis.K ° H . CH2" CH2 " CH2 \so^m+ CH2 # CH2" CHg (ii) HI CHg* GHg'GHg CHI .> CjH B OH suberone CH 2 " CHg* OHg CH ~^^ . one by Willstatter (1900-1903).

CH 2 -CH2-CH-N(CH 3 )2 ..CIV CH II CH exhaustive s methylation GHo " Oxxg * GxX II CH Br a .CH 2 -CH 2 -CH cycloheptene 0x12*0x12" CH 2 CHI I CHjj-CHj-CHBr CHBr (£^2V CH.

CH 2 .CHBr I CH II CHjj-CHBr-CH (l:4-addition) CH r -CH=CH quinoline 150° I HBr CH *- CH=CH— CH cyc/oheptatriene (tropilidene) CH2-CHBrCH2 CH II CH=CH— CH .CH=CH cyc/oheptadiene CH 2 -CH 2 .

CH2— CH- -CH igmrv CIT (QW.-C.-HBr ^ CH 2 -CH=CH CH 2 — CH CH 2 N(CH 3 )2 I warm in „ Br yH* ether CHj— CH CHBr CH.-CH CH 2 II Br"N + (CH 3 )2 CH 2 ~^^ CH 2 — CH- -QH.H. .(CH 3 ) 8 NH .OH JN(OH 3 ) 2 yti (ii)Br.

CH*— CH- -CHBr BrN(CH3) 2 CH CH 2 — CH CH (•)Kl(Br->.I) (ii)AgCl(I-*C1) CH»— CH- -CH2 ClN{CHs)2 CH heat > CHg^GH"" — ■ CH2 CH.— CH- -CH CHj— CH CH .

tropidine CH 2 — CH CH 8 NCH 3 CHBr II CHg — CH — — GHg Cxi2~~ * CH~~~ GH2 H3SO4. 200° NCH 3 C< H -^V Zn | x OH CH 2 — CH — CH 2 iji -tropine CH 2 --CH — CH 8 NCH 3 GO HI CH 2 — CH — CH 2 .

-OH NCH 3 C I |Sl CH2 — GH — CHg tropine 514 ORGANIC CHEMISTRY [CH. methylamine and acetone is allowed to stand in water for thirty minutes. tropinone is produced in very small yield. CH 2 — CHjO H —h + NCH 3 + . —I.tropinone CHj— CH — CH. XIV Robinson's synthesis. I I .*l . When a mixture of succinaldehyde.

J.g.CH 2 — OHIO H HiCHj HiCH 2 . the calcium salt or ester so produced is converted into tropinone by wanning with hydrochloric acid.Ah. (ca = Ca/2) : CH 2 -CHO CH 2 -C0 2 ca + CHs-NHjj + CO >- .- CH 2 • CH— CH 2 NCH 3 CO . A much better yield (40 per cent. e. CO -*-2H 2 + CH..) is obtained by using calcium acetonedicarboxylate or ethyl acetonedicarboxylate instead of acetone.' -CH.

by carrying out Robinson's synthesis at a pB. (1958) have also synthesised tropinone using methylamine hydrochloride. acetonedicarboxylic acid and generating succinaldehyde in situ by the action of acid on 2.CHO .CH 2 -CHO CH 2 -C0 2 ca CH— CH CH-C0 2 ca II NCH 3 CO II C%. of 7.CH — CH-C0 2 ca HCI CHjj— CH — CH 2 NCH 3 CO Ii CH 2 — CH — CH 2 Schopf et al. (1935) have obtained a yield of 70-85 per cent. Elming et al.5-dimethoxytetrahydrof uran : ^? H.

CH 2 — CH— CH 2 / •C0H5 . II NCH 3 CO CH— CH CH.. this has been done by heating the two together in the presence of hydrogen chloride (Fischer-Speier esterification. ■2 The yield was 81 per cent. but in this case " physiological conditions " were not necessary (see §28). see Vol.CH 3 NH 2 HCI CH3OI ^OCH 3 "s° CH 2 -CHO co(CH s co 2 H) 2 XT CHj-CH CH. I). The final problem is to combine tropine with tropic acid.

X CH 2 — CH — CH 2 CH. 13 II gi — CH — CH 2 atropine .CIJ2 NCH 3 CHO-CO-CH CbHr CH.NCH 3 CHOH + HO.OH OH2 — OH-^ .C-CH HCI.

CH- . A larger yield of the former (69 per cent.) is obtained with sodium borohydride. 1 shows the two possible forms. Neither of these forms is optically CH. On the other hand.). 54 per cent. and reduction with sodium and wobutanol (in toluene) gives the maximum yield of y-tropine (88 per cent."t!H 2 OH Stereochemistry of the troplnes. reduction with sodium amalgam converts tropinone into y-tropine. by means of a metal and §22] ALKALOIDS 515 acid. Tropinone can be reduced to tropine. of tropine are obtained. and the other isomer has this hydrogen atom on the opposite side (cf. VIII) . or by means of electrolytic reduction. lithium aluminium hydride reduces tropinone quantitatively to y-tropine. Fig. According to Mirza (1952). but according to Beckett et al. one isomer having the hydrogen atom on C 3 on the same side as the nitrogen bridge. the borneols. of y-tropine and 45 per cent. the best combination being zinc dust and hydriodic acid. (1957). §23b. Tropine and y-tropine are geometrical isomers. together with a small amount of y)-tropine.

.CH.OH 1 . / CH' CH- NCH. ^ CH 2 I . CH./ CH NCH.

however. C ± and C 6 are asymmetric. Fodor (1953) has given evidence to show that y-tropine is the sy«-compound (nitrogen bridge and . §23a. 1) is tropine and which is y-tropine. camphor. C 3 is pseudo-asymmetric (see §8. The problem now is to decide which geometrical isomer (of the two forms shown in Fig. VIII. this. is not possible (cf. and so each isomer is a meso-iorm.1.HO' CH' (a) ^ CH 2 . but the molecule is optically inactive by internal compensation (see §7b. CH(b) Fig. §23). active.cT ^CH. 14. II). also cocaine. IV). since the molecule has a plane of symmetry. It should also be noted that another pair of optically active forms would exist if the fusion of the nitrogen bridge were trans.

hydroxyl group are in the ct's-position; Fig. 1 b), and that tropine is the anticompound (nitrogen bridge and hydroxyl group are in the iraws-position; Fig. la). The problem, however, is more involved than this, since the conformation of the piperidine ring has also to be considered. Fodor gives the configuration of the piperidine ring as the boat form in both isomers (Fig. 2).

•CH 3 ho N V- H

/CH 3 H N >— i

(b) tropine

Fig. 14.2.

Zenitz et al. (1952) and Clemo et al. (1953) support these configurations from evidence obtained by measurements of the dipole moments of these two isomers ; y-tropine has been shown to have a higher dipole moment than tropine. Zenitz et al. have also shown from infra-red absorption spectra measurements that y-tropine has intramolecular hydrogen bonding; this is only possible in the sy«-form. Bose et al. (1953), however ^ have assumed the chair form for the piperidine ring by analogy with the chair conformation of cyc/ohexane compounds and pyranosides (see §11. IV). Thus these authors have suggested that y-tropine is Fig. 3 (a), in which the hydroxyl

516 ORGANIC CHEMISTRY [CH. XIV group is equatorial, and that tropine is Fig. 3 (6), in which the hydroxyl group is axial.

/CH 3 /CH 3 NN

(a) <]i -tropine Fig.

(b) tropine 14.3.

If these be the configurations, then it is difficult to explain Fodor's work (which involves rearrangements), and also the fact that there is intramolecular hydrogen bonding in ^-tropine. Sparke (1953) has suggested that the chair form can readily change into the boat form ; this would then explain the intramolecular hydrogen bonding. Archer and Lewis (1954) also adopt this explanation, but make the assumption that the bond energy involved in the hydrogen bond is sufficient to transform, at least partially, the more stable chair form into the less stable boat form; in ^-tropine the chair and boat forms are in mobile equilibrium, the latter being the predominant form. §22a. Tropeines and pseudotropeines. These are synthetic esters formed respectively from tropine and y-tropine with various organic acids. The tropeines (including atropine itself) are powerful mydriatics (pupil dilators) and feeble anaesthetics; the y-tropeines are the reverse. One of the most important tropeines is homatt 'opine (mandelyltropeine) , which is prepared by combining tropine with mandelic acid. Cxio — CH — CHo |I NCH 3 CHO-0O-CHOH-C 6 H 6 1I CH 2 — CH — CH 2 homatropine

§22b. Hyoscine (scopolamine), C 17 H 21 4 N, is a syrup and is laevorotatory; it is obtained from various sources, e.g., Datura Metel. Hyoscine is a constituent of travel sickness tablets, and when administered with morphine, produces " twilight sleep ". Hyoscine is the (—) -tropic ester of the aminoalcohol scopine; these two compounds are produced by the hydrolysis of hyoscine with ammonia. CH— CH CH 2 CH 2 0H

\

NCH 3 CHO-CO-CH — ^CH— CH CH 2 C6Hs

<

li3'oscine CH— CH CH,

/

CH 2 OH

NCH 3 CHOH + C 6 H 5 CH CH-CH— 0H 2 COzH scopine tropic acid

CH 2 CH CH — CH 2 Io scopine oscine It is interesting to note.§23] ALKAtOIDS 517 More vigorous hydrolysis of hyoscine with acids or alkalis produces oscine (scopoline). in this connection. which is formed by the isomerisation of scopine. O .CH— CH— CH 2 CHOH— CH CH. NCH 3 CHOH acid > \ II I m_ ch— c i NCH 3 CH-. that the action of ethanolic sodium hydroxide on (—) -hyoscine at room temperature causes the latter .

it follows that ecgonine contains the tropane structure and that the alcoholic group must be in the same position as in tropine (§22).. R = COCHPh-CH 2 OH). occurs in coca leaves. further hydrolysis occurs. cuscohygrine (§13a). m. Fodor et al. and so benzoylecgonine is the benzoyl derivative of a hydroxycarboxylic acid. C 16 H 19 4 N + H 2 7MSSB)t > C 9 H 15 3 N + C 6 H 5 -C0 2 H benzoylecgonine ecgonine Ecgonine shows the reactions of an alcohol.p. ecgonine contains a carboxyl group). it is sparingly soluble in water. cocaine is hydrolysed to methanol and benzoylecgonine. and benzoylecgonine a carboxyl group. C 17 H 21 4 N + H 2 -> C 16 H 19 4 N + CH 3 OH cocaine benzoylecgonine Thus cocaine contains a carbomethoxyl group. Coca alkaloids. viz. (1959) have carried out a total synthesis of (±) -hyoscine and shown its conformation to be (I. The structure of ecgonine has been deduced from the nature of the products obtained by oxidation. In this group occur cocaine. Now in the formation of tropinone from ecgonine. Thus the carboxyl group is in a position such that the oxidation of the secondary alcoholic group in ecgonine to a keto group is accompanied by the elimination of the carboxyl group. the products obtained being benzoic acid and ecgonine.NMe to racemise to (±) -hyoscine. 98°. When heated with water. C 17 H 21 4 N. When benzoylecgonine is heated with barium hydroxide solution.Tropinic acid + Ecgoninic acid C 9 H 15 3 N C 8 H 13 ON C 8 H 13 4 N C 7 H u 3 N From these results. etc. Ecgonine V Tropinone ^>. §23. benzoylecgonine. but its hydrochloride is quite soluble and is used as a local anaesthetic. hygrine (§13). tropacocaine. (— )-Cocaine. a carboxyl group is lost (as we have seen. This type of elimination is characteristic of .

CH— CH 2 cocaine H. Thus ecgonine is: CH 2 — CH— CH-COJI III NCH 3 OHOH III GH2— CH — CH 2 ecgonine On this basis. the foregoing reactions may therefore be written: CH 2 .CH— CH-COjCHs NCHj CHO-COC 6 H5 II CHr. (1898) actually observed the formation of an unstable /?-ketonic acid which lost carbon dioxide to give tropinone. and this interpretation of the results is confirmed by the 518 ORGANIC CHEMISTRY [CH./?-ketonic acids. XIV fact that Willstatter et al.o CH 2 — CH— CH-C0 2 H CH3OH + NCH 3 CHO-COC 6 H 5 II CH 2 -CH— CHj .

benzoylecgonine Ba(QH)» CHj— CH CH-C0 2 H NCH 3 CHOH + C 6 H 5 -C0 2 H-^II CHj.CH— CH.! ecgonine CH— CH— CHCOjH NCH 3 CO II CHj—CH— CHz CH*. CH 2 - NCH 3 COII CHj— CH— CH 2 .CH— CH 2 CHj— CH-CH 2 -C0 2 H CrO.

tropine. C x and C s therefore have only one configuration (the cis-form).*CHOH Is /I CHr. the starting point is tropinone (see §22 for its Synthesis) . and so there are only eight optically active forms (four pairs of enantiomorphs) actually possible (cf. and so there are 2 4 = 16 optically active forms (eight pairs of enantiomorphs) possible (cf. VIII) . only the cis fusion of the nitrogen bridge is possible in practice. Since. it will be seen that there are four dissimilar CHa— CH— 3 CH-COjjH NCH. let us first examine the structure of ecgonine from the stereochemical point of view. camphor. §22).. three pairs of enantiomorphs have been . 1901) . §23a. however. Before describing this synthesis.CH— 4 CH 2 asymmetric carbon atoms present {*).tropinone NCH 3 CH 2 — CH-C0 2 H tropinic acid -CH-CH 2 -C0 2 H I ^CHj CHj— CO ecgoninic acid The structure of ecgonine has been confirmed by synthesis (Willstatter et al.

prepared synthetically. but its chemical properties were the same. the racemic ecgonine obtained was not identical with the (— )-ecgonine from (— )-cocaine. In the original synthesis of Willstatter. §23] II NCH3CO II CHj— CH— CH 2 tropinone CHj— CH — CH-C0 2 Na NCH 3 CO II CH— CH— CH 2 ALKALOIDS CHg— CH— CH 519 NCH 3 CONa -^ .

(1921) synthesised ecgonine by means of the Robinson method (see §22): CH 2 CHO H CH 2 C0 2 C 2 H 5 II + NCH 3 + CO CH 2 -CHO H CHj-COaH KOH .CHj— CH— CH 2 Na-Hg acid CH 2 — CH— CH-C0 2 H II NCH 3 CHOH II CH— CH — CH 2 a (±)-ecgonine sodium tropinonecarboxylate Later. GHz— CH— CHC0 2 C 2 H 5 . Willstatter et al.

II NCH 3 CO II CH 2 — CH— CH-C0 2 H CH 2 — CH— CH-C0 2 C 2 H 5 NCH 3 CO II CHg — CH — CH2 CH 2 — CH— CH-C0 2 H II NCH 3 CHOH (ii) hydrolysis | I CH 2 — CH — CH 2 (0 [H] The final product was shown to be a mixture of three racemates. (±)ecgonine.. 1923). CHg— CH— CH-C0 2 H II . the product was (— )-cocaine. The racemic ecgonine was resolved. (ij-y-ecgonine and a third pair of enantiomorphs (Willstatter et al. and the (— )-form esterified with methanol and then benzoylated.

NCH 3 CHOH

(OCH3OH-HC1 .

(ii)C«H»-COCl

CH 2 — CH — CH2 (-) -ecgonine

CH 2 -CH — CH-C0 2 CH 3 II NCH 3 CHO-CO-C 8 H 5 CHr-CH — CH 2 (-)-cocaine

In a similar way, the (+)- and (— )-y-cocaines were obtained from the corresponding y-ecgonines. An interesting point in this connection is that Einhorn et al. (1890) showed that the prolonged action of 33 per cent, aqueous potassium hydroxide converts ecgonine into y-ecgonine, and Findlay (1953) has found that cocaine gives y-ecgonine methyl ester by the action of sodium methoxide in hot methanol. Fodor et al. (1953, 1954) and Findlay (1953, 1954) have established the conformations of ecgonine and y-ecgonine (R = CO a H; R' = H) and the corresponding cocaines (R = COjMe; R' = COPh) (c/. §22):

Nil*

OR

cocaine (and ecgonine)

y-cocaine (and y-ecgonine)

520 ORGANIC CHEMISTRY [CH. XIV Hardegger et al. (1955) have correlated (— )-cocaine with L-glutamic acid and have shown that the formula represents the absolute configuration of l(— )cocaine. §23a. Tropacocaine, C 15 H 19 O a N, m.p. 49°, occurs in Java coca leaves. When heated with barium hydroxide solution, tropacocaine is hydrolysed to y-tropine and benzoic acid; thus the alkaloid is benzoyl-y-tropine.

CHs— CH— CH 2 CHa -CH— CH 2 NCHsCHO-CO-Cft^^ 1 — lM CH— CH— CH 2 CHj CH— CH 2 tropacocaine t{<-tropine

NCH 3 <X* + CeHs'CO^I \ I OH

§23b. Cocaine substitutes. Cocaine is a very good local anaesthetic, but has certain disadvantages. The anaesthetic properties are lost if either the benzoyl group or the methyl ester group is removed; removal of the iV-methyl group has no effect. A number of synthetic drugs have now been introduced to replace cocaine as a local anaesthetic; their anaesthetic pro-

perties are as good as those of cocaine, and they are less toxic. Two important substitutes are p-eucaine and procaine (novocaine). j8-Eucaine has been synthesised by treating acetone with ammonia and then treating the product, diacetonamine (see Vol. I), with diethyl acetal. The piperidone thereby produced is then reduced and finally benzoylated to give /3-eucaine. H HCH 2 2CH3-CO-CH3+NH3— ^H^O+NH CO ch 3 -ch(qc 8 h 5 ) 3 ^ II (CH 3 ) 2 C CH 2 n yn 3 CH 3 -CH— CH 2 CH — CH Z 2C 2 H 5 OH + NH io i;;^. coc? ^ )cHO-CO-C 6 H 6 (CH 3 ) 2 C CH 2 C-— CH, p-eucaine Procaine has been synthesised from ^>-nitrobenzoic acid. y0 2 ^ 7 ~^>C0 2 H+HOCH 2 -CH 2 Cl ^ N0 2 <f^\cO-OCH 2 -CH 2 Cl (c ' HB)aNH >ISrO 2 <^^>CO-OCH 2 -CH 2 ^(0 2 H 5 ) 2 % > NH 2 <^_^>CO-OCH 2 CH 2 -N(C 2 H 5 ) 2 procaine QUINOLINE GROUP §24. Angostura alkaloids. A number of alkaloids have been isolated from angostura bark, e.g., cusparine, galipine, galipoline, etc.

§24]

ALKALOIDS

19 H 17 O 3 N KOH . and when fused with potassium hydroxide. controlled oxidation of cusparine gives piperonylic acid and 4-methoxyquinoline-2-carboxylic acid. has been shown to contain one methoxyl group (Zeisel method). C0 2 H Consideration of this information led to the suggestion of the following structure for cusparine. 90-91°.H On the other hand. C 19 H 17 3 N -^i*.521 Cusparine.p. C 19 H 17 3 N. OCH 3 .OH CO. m. protocatechuic acid is obtained.

. 1924). 1 ^~f 2 OCH.O — CH 2 SHa-CHr^f ^-0 cusparine This has been confirmed by synthesis (Spath et al. OCH3 CH.. OCH O— CH 2 O -^V 4-methoxy-2methylquinoline piperonal OCH.

XIV OCH. OCH 3 N /-CH— CHr-/^\oCH 3 . 113°. galipine produces 4-methoxyquinoline-2-carboxylic acid and veratric acid. m. C 20 H 21 O 3 N. ■CH 2 — CH 2 cusparine Galipine. contains three methoxyl groups (Zeisel method). When oxidised with chromic acid. Thus the formula of the alkaloid is probably: 522 ORGANIC CHEMISTRY [CH.p.O — CH.

galipine This has been confirmed by synthesis (Spath et al. OCH 3 OCH3 >CH 3 + OCH^^OCHr^^ veratraldehyde OCH. NCH-^V CH=CH- OCH3 CHf-CH : galipine o 0CH3 .. 1924).

occur in the bark of various species of Cinchona.V 7 "^ c^-chK7och s je ^ §25. U^CH^^>C€h7\A n ^ CTI=CH -^3 >OCH3 O-CHj-CeHs (i)C. 193°.H t CH 8 QNa (ii)H 2 -Pd-C OCH.p. Galipoline. Cinchona alkaloids. together with many other alkaloids. rcH. Cinchonine and quinine.. §25a] . Cinchonine may be regarded as the parent substance of the cinchona alkaloids. 1924). Thus one of the methoxyl groups in the latter is a hydroxyl group in the former. C 19 H 19 3 N. contains two methoxyl groups and one phenolic group. m. When methylated with diazomethane.OCH. galipoline is converted into galipine. The position of this phenolic hydroxyl was shown to be in the quinoline nucleus by synthesis (Spath et al.

II. cinchoninic acid. C^HgaONg. Thus cinchonine CO. 264°. is obtained (Konigs.H . Cinchonine has been shown to contain one ethylenic double bond by the fact that it adds on one molecule of bromine or halogen acid. I.H lg ON I contains a quinoline nucleus with a side-chain in position 4 (III) . the molecule contains one hydroxyl group. 1894). Fusion of cinchonine with potassium hydroxide gives lepidine (4-methylquinoline).p. m. cinchonine forms the ketone cinchoninone. Since cinchonine forms a mono-acetate and a monobenzoate.ALKALOIDS 523 but quinine is the most important member of this group. Furthermore. since on oxidation. (+)-Cinchonlne. its main use being in the treatment of malaria. The hydroxyl group in cinchonine must be in this " second-half ". adds on two molecules of methyl iodide to form a di-quaternary compound. §25a. thus the alkaloid is a di-tertiary base. since if . this hydroxyl group is secondary alcoholic. and on vigorous oxidation with chromic acid in sulphuric acid solution. one molecule of hydrogen being added on. and that it is readily catalytically reduced. this sidechain was referred to by Skraup as the "second-half" of the molecule.

we may formulate the work of Konigs as follows: / OH N CH=CH 2 cinchonine . then a hydroxy derivative or a carboxy derivative (sjnce the hydroxyl is alcoholic) of cinchoninic acid would have been obtained. 1879). when heated with 25 per cent. + H-C0 2 H cinchotenine This suggests that there is a — CH=CH S group in the side-chain in the " second-half ".it were not. cinchonine is converted into cinchene which. When treated with phosphorus pentachloride. followed by ethanolic potassium hydroxide. 1884). phosphoric acid. forms lepidine and a compound Konigs named meroquinene (Konigs et ah. Oxidation of cinchonine with permanganate gives cinchotenine and formic acid (Konigs. > C 18 H ao 3 N ! . With the information obtained so far. C 19 H M ON s + 4[0] KMnO.

wjien cinchonine is oxidised with chromic acid (Konigs. . XIV Meroquinene (meroquinenine) is also obtained. together with cinchoninic acid.KOH CjH„OH PCI„ ! 8 H 11 N-CH=CH i! H 3 PO« ( + 2H a O) + C 9 H 16 2 N meroquinene cinchene lepidine 524 ORGANIC CHEMISTRY [CH. 1894).

1879). the latter being a dicarboxylic acid (Konigs.?\ CioIImON /\ COJI 1 ^ Jsu CI [ ] + C 9 H 15 2 N v^V \sy\K / y meroquinene cinchonine cinchoninic acid Thus the key to the structure of the " second-half " is the structure of meroquinene. The formation of formic acid confirms the presence of the — CH=CH 2 side- . Oxidation of meroquinene with cold acid permanganate produces formic acid and cincholoiponic acid. The routine tests showed that meroquinene contains one carboxyl group and one double bond. the presence of the latter indicates that the — CH=CH 2 side-chain is still present in meroquinene.

1890). this suggests that the latter contains at least a side-chain — CH 2 -CO a H. and since it contains one methylene group less than its precursor cincholoiponic acid. H a SO t heat (iii) Loiponic acid -. The presence of this group has also been demonstrated by the ozonolysis of meroquinene. that they all contained a piperidine ring is shown by the following reactions. C 7 H 11 4 N (Konigs. The reactions of the above three acids indicated that they were all secondary bases . : — >- . (i) Meroquinene Hcl -. formaldehyde is produced (Seekles. ^ 240° * (ii) Cincholoiponic acid C2H5 CH. Oxidation of cincholoiponic acid with acid permanganate produces loiponic acid. 1923).C 9 H 15 O a N ™*S C 8 H 13 4 N + H-C0 2 H meroquinene ' * cincholoiponic acid chain in meroquinene. This is also a dicarboxylic acid.

Consideration of the above results shows that a possible skeleton structure of meroquinene is: C I . CH. §21).CH CH 2 x CH-C0 2 H CH.isomenses co s H . II hexahydrocin chomeronic acid §25a] alkaloids 525 The structure of hexahydrocinchomeronic acid is known from its synthesis (cf.

All the foregoing facts can be explained on this basis. A possible position for the extra carbon atom is the side-chain containing this unsaturated group. and the presence of such a group has already been inferred (see above)./°\ C C— C— \N/ } +c The problem then is to find the position of the remaining carbon atom. the side-chain is an allyl group. meroquinene contains a — CH=CH 2 group in the side-chain. i. All the reactions of meroquinene can therefore be explained on the following structures : CH 2 -C0 2 H CH 2 -C0 2 H CH A ?H 2 X CH-CH=CH 2 „" * . since all three acids are secondary bases. viz. a compound which contains one carboxyl group and one ethyl group.CH 2 N CH-CH 2 -CH 3 CH 2 CH 2 CH 2 CH 2 HH meroquinene cincholoipon .. As we have seen. — CH a -CH==CH 2 .. this would give a — CH a -C0 2 H group at this position. 4. C 9 H 17 2 N.. that reduction of meroquinene gives cincholoipon. This carbon atom cannot be an JV-methyl group. the side-chain is therefore vinyl. Thus the unsaturated side-chain cannot be allyl (this should have given a propyl group on reduction) .e. viz. but the following fact cannot. This leaves only one possible position for the extra carbon atom.

1907. §17) (see next page). 526 GH(OC 2 H 5 ) 2 2 0H 2 ■ + NH S 0H 2 C1 p-chloropropionacetal CHO I CH 2 CHO I CH 2 . cf.i CO] CH 2 -C0 2 H C0 2 H /( U + H-C0 2 H-I°1^ /( !3 H CH 2 X!H-C0 2 H CH 2 X CH-C0 2 H II 'I HH cincholoiponic acid Ioiponic acid This formula for meroquinene is supported by the synthesis of cincholoiponic acid (Wohl et ah.

CH / "^ CH 2 C-CN ■I I CH 2 CH 2 \N/ H .CH 2 CH 2 CH 2 / CH 2 NH iminodipropionacetal [ch. XIV HCI y CH CH 2 C-CH O (i)NHgOH CH 2 CH 2 W*** : H .\V H ORGANIC CHEMISTRY (C 2 H s O) 2 CH CH(OC 2 H 6 ) 2 ->.

cincholoiponic acid The racemic cincholoiponic acid was acetylated. the carbon atom of the carboxyl group in meroquinene will be the point of linkage to the " quinoline-half " at which scission of the " second-half " occurs.CH(C0 2 C 2 H 5 ) 2 CH 2 CH'CN CH a ( CQ 3 C 3 H») a . Since meroquinene is obtained from cinchonine by oxidation. and then this derivative was resolved by means of brucine. Since .C a H»ONa {Michael condensation) rrrr PTT H (i)Ba(OH)a (ii) HCI CH 2 -C0 2 H A CH 2 N CH-C0 2 H »-l I CH 2 CH 2 H (+) . the (-j-)-form was identical with the acid obtained from meroquinene.

CH 2 3-vinylquimielidine CH. But meroquinene is a secondary base. CH H. A possible explanation for this behaviour is that the tertiary nitrogen atom is a part of a bridged ring. one C — N bond being broken when cinchonine is oxidised: . the " second-half " therefore contains a tertiary nitrogen atom.CH 7 ?H* CH-CH-CH=CH 2 ^ 8 CH 2 6 CH*j.cinchonine is a di-tertiary base. a carboxyl group also being produced at the same time. and it therefore follows that in its formation the tertiary nitrogen atom is converted into a secondary nitrogen atom.S0 4 CH L I II C0 2 H CH 2 ^CH 2 I .

a methyne group adjacent to a carbonyl group: . Rabe et al. on treatment with amyl §25a] ALKALOIDS 527 nitrite and hydrogen chloride. gives cinchoninic add and an oxime. The remaining problem is to ascertain the position of the secondary alcoholic group in the " second-half ". in cinchonine. The formation of an acid and an oxime indicates the presence of the group -CO Ah-. the " quinoline-half " must be joined via its side-chain at position 4 to the " quinuclidine-half " at position 8.. i. This ketone.e. 1908) converted cinchonine into the ketone cinchoninone by gentle oxidation (chromium trioxide). in which both nitrogen atoms are still tertiary. meroquinene Thus. (1906.CH'CH=CH.

then the foregoing reactions may be written as follows.R-CO— i HO- -CHR 2 -NO ^r__CO + CHR 2 -^^CR OH NO 2 II NOH The structure of the oxime obtained from cinchoninone was shown to be 8K)ximino-3-vinylquinuclidine by its hydrolysis to hydroxylamine and meroquinene. If we assume that the secondary alcoholic group connects the " quinoline-half " to the quinuclidine nucleus. on the assumption that the structure of cinchonine is as given. /CH CH 2 ch 2 CH-CH=CH 2 III IHOH— CH CH. CH 2 \\7 .

H acid •N' cinchoninic acid .CH H 2 nwNH-CH= .CrQ 3 CH CH 2 C H^CH-CH=CH 2 III CO — CH CH 2 CH 2 cinchonine Tf cinchoninone CO.

CH 2C H 2 III 0=C CH. the latter isomerises (Rabe et al . 1913). 4. One pair of enantiomorphs is (±)-cinchonine. and the carbon atom of the CHOH group (see 3-vinylquinuclidine for numbering). I«I HON=C ch 2 CH 2 X N^ oxime .. which is prepared by the prolonged action of acetic acid on cinchonine. 8. since both give the same 8-oximino-3-vinylquinuclidine (see §25b). 3. CH. viz. A partial synthesis of cinchonine has been carried out by Rabe (1911. the configurations of C 3 and C 4 are the same in both.CH CH 2 CH 2 CH-CH=CH 2 CO. This starts from cinchotoxine. amide CH=CH 2 CH 2 ch^CH-CH^H.jH CH 2 CH 2 HN^^ meroquinene The above structure of cinchonine contains four dissimilar asymmetric carbon atoms. and another pair is (±)-cinchonidine.

CH V^N CH. ch7 chch=ch 2 CO-CH 2 CH 2JC1I 2 HIT VAn .1909). XIV CH 2 CH^OH-CH=CH 2 III CHOH-CH CI^CH 2 CH3CO2H ^ . 528 ORGANIC CHEMISTRY [CH.

O— CH 2 CH 2/ cH 2 HN NaOBr CH 2 CH. CII-OH=CH 2 I 'I CO— CHBr CI *^CH 2 HN cinchotoxine NaOH {-HBr) OH 2 ci^CH-CH=CH 2 III .cinchonine cinchotoxine This isomerisation is an example of the hydramine fission (see §7). The conversion of cinchotoxine into cinchonine was carried out as follows: CH 2 CH 2 CH-CH^H.

Cr0 C 20 H M O a N 2 h>.C ao H 2a O a N a quinine quininone §25b] ALKALOIDS 529 Quinine also contains one ethylenic double bond. etc. as is shown by the fact that it adds on one molecule of bromine. 177°. (— )-Quinine. it is therefore a di-tertiary base. quinine eliminates one carbon atom as methyl chloride. one hydroxyl group must be present. Since quinine forms a mono-acetate and a mono-benzoate.CO— CH ^^CHj Al C 2 HjONa-CjH 5 OH cinchoninone CH CH 2 CH^CH-CH=CH 2 CHOH-CH 9 H 2^CH 2 (±) -cinchonine §25b. is used as a febrifuge and as an antimalarial. Since quinine adds on two molecules of methyl iodide to form a di-quaternary salt. cinchonine). and that this is secondary alcoholic is shown by the fact that oxidation of quinine with chromium trioxide produces quininone. C 20 H 2 4O 2 N 2> m.p. quininic acid. When heated with hydrochloric acid. a ketone. among other products. . therefore there is one methoxyl group present in the molecule. (cf. Oxidation of quinine with chromic acid produces.

The position of the methoxyl group was ascertained by heating quininic acid with hydrochloric acid and then C0 2 H C0 2 H quininic acid [Q] > H0 2 C H0 2 CH . and so the problem is to elucidate the structure of quininic acid. H. the methoxyl group must be a substituent in the benzene ring (of quinoline). >CuH93N quininic acid On the other hand.SO. quininic acid forms pyridine-2 : 3 : 4-tricarboxylic acid. and the carboxyl group at position 4 (Skraup.20 H 24 O 2 N 2 quinine CrO. When heated with soda-lime. and since. on oxidation with chromic acid. quininic acid is decarboxylated to a methoxyquinoline. controlled oxidation of quinine with chromic acid gives quininic acid and meroquinene. Thus the " second-half " in both quinine and cinchonine is the same. 1881).

6-hydroxyquinoline (a known compound) was obtained. Thus quininic acid is 6-methoxycinchoninic acid. C0 2 H CH s O ^CH 3 C1+ C0 2 H HOrNf ^ _co. HO W quininic acid 6-hydroxyquinoline This structure for quininic acid has been confirmed by synthesis (Rabe .pyridine -2:3:4tricarboxylic acid decarboxylating the demethylated product.

1931). CH. CHjO )qI CH 3 -COjH . + CH 3 -CO-CH 2 C0 2 C 2 Hb- pocu OH PC1 < CHjO.0.. 0H 3 0. CH3O.a at. • CH.

on the basis of the foregoing evidence. XIV The direct oxidation of 6-methoxy-4-methylquinoline to quininic acid is extremely difficult. CH3O C0 2 H ■If 630 ORGANIC CHEMISTRY [cH. the structure of quinine is: CH 2 c H2 N CH-CH=CH 2 GHOH-CH °Hs CH 2 CH.CH^-CHO^ CH 3°| ZnCU CH — CH' C0H5 KMnQ 4 .0^ w xx . oxidation of the methyl group is accompanied by the oxidation of the benzene ring. Thus. the final product being pyridine-2 : 3 : 4tricarboxylic acid (see §26).

V. and from this to quinine is Rabe's work. which is prepared by heating quinine in acetic acid (c/. This. and so we now have a total synthesis of quinine. This. The complex formed (IV) is converted into 7-hydroxy-8-methyh'soquinoline (V) by heating with methanolic sodium methoxide at 220°. followed by hydrolysis. on heating with 16 per cent. on condensation with ethyl quininate (XII). Rabe et al. after esterification and benzoylation. Woodward and Doering (1944) have synthesised (-f-)-quinotoxine. on reduction. Exhaustive methylation of IX. is hydrolysed and decarboxylated to (±)-quinotoxine (XIV). cinchotoxine). quinidine. cinchonine and cinchonidine. produces XIII. the configurations of C 3 and C 4 are the same in quinine. hydrochloric acid. which may now be written more conveniently as shown. VII is a mixture of cis. X. w-Hydroxybenzaldehyde (I) is condensed with aminoacetal (II) and the product. gives 2V-acetyl-7-hydroxy-8-methyl1:2:3: 4-tetrahydrowoquinoline (VI). on catalytic reduction (platinum) followed by acetylation. and another pair is (±)-quinidine . IV for conventions) then treated with ethyl nitrite in the presence of sodium ethoxide to give the homomeroquinene derivative VIII. One pair is (±)-quinine. on further catalytic reduction by heating with a Raney nickel catalyst under pressure and then followed by oxidation with chromium trioxide. is treated with formaldehyde in methanol solution containing piperidine. is converted into 2V-acetyl-7-keto-8methyldecahydroMoquinoline (VII). gives m-(±)-homomeroquinene (X). these were separated and the cw-isomer (Vila. (1918) carried out a partial synthesis of quinine starting from quinotoxine. see §11 vii. which. The following is Woodward and Doering's work up to (+)-quinotoxine. gives IX. gives XI which. since all four give the same 8-oximino-3-vinylquinucHdine (see §25a). thus the same number of pairs of enantiomorphs is possible. The conversion of (±)-quinotoxine into quinine had already been accomplished by Rabe et al. (the equations for this conversion are also given below). 7-hydroxy*'soquinoline (III).and transisomers. This was resolved via its dibenzoyltartrate (tartaric acid proved unsuccessful for resolution).quinine This formula contains the same four asymmetric carbon atoms as cinchonine. §25b] u+ I .

ALKALOIDS 531 NH 2 -OH 2 -CH(OC 2 H B ) 2 II H.SQ 4 III CH 2 -C5H 10 N axo—- (ii) (CH 3 -CO).0 IV CH 3 CHs .

f)f f CO-CH.CH 3 _ CH2 ^ CH-CH-CHs .RM . (i) H . y N. I' OH VIII COAH5 J N ' C ° . t °YN / f CO- separated ^ VI CH 3 H VII *r Vr H ° VY N-CO-CHs CjHtONO C0 2 C 2 H 5 f N-CO-CH 3 Jh]_ Vila CH..

CH 2 OH.CH CH 2 CH 2 CH'CH=CH 2 (i)CaH 8 OH-HCl. A J ~~ CH. CH 2 V IX . .CH CHs CH 2 CH 2 C0 2 C 2 H B N^ CO-CHj IX exhaustive ^ methy lotion CH 2 CH 2 CHCH=CH 2 CH 2 CH 2 CH 2 C0 2 H HN X .CH.

0 XII ORGANIC CHEMISTRY !OOC 2 H 5 CH 2 — CH 2 — CH I |\ C0 2 C 2 H 5 CH 2 CH-OH=CH 2 + CH 2 L I/ . (ii)C.H 6 -COCI J"* I C0 2 C 2 H B f COC 6 H 6 XI 532 CH 3 CH 3 CH. CH 2 ch."CH.

CH-CH=CH 2 II*I CO— CH 2 9 H 2 CH 2 HIT C 3 H e ONa HC1 resolved ■>.W I COC 6 H 5 XI CH.(+)-isomer . XIV CO-CH— CH 2 -CH C0 2 C 4 H 5 C!^CH-CH=CH 2 f xni C °-° 6H5 /\\ CH 2 c H .

CH CHac^CH-CH^CH.CH CH 2 CH^CH-CH=CH 2 co— ch C ^y^h Al C2H 5 ONa-C 2 H 5 OH CH.(i)NaOBr (ii)'NaOH XIV (±)-quinotoxine CHjO . .0 (+)-quininone .

Since papaverine adds on one molecule of methyl iodide to form a quaternary iodide. and they are divided into two groups according to the nature of their structure : (i) isoQuinoline group.CHOH — CH CH 2 C h 2 (±)-quinine resolved *-(-)-quinine •W §26] ALKALOIDS 533 ISOQUINOLINE GROUP Opium alkaloids. e. §26. it does not contain any asymmetric carbon atom. is oxidised to the ketone . The structure of papaverine was established by Goldschmiedt and his co-workers (18831888). This.. is one of the optically inactive alkaloids .p.g.. papaverine. Papaverine. laudanosine. m. on more vigorous oxidation with hot dilute permanganate. C 20 H 21 O 4 N. Many alkaloids have been isolated from opium. the nitrogen atom in the molecule is in the tertiary state. the demethylated product is known as papaveroline. e.g. C 20 H 2l O 4 N + 4HI -> 4CH 3 I + C 16 H 13 4 N papaverine papaveroline When oxidised with cold dilute permanganate. C 20 H 21 O 5 N. The application of the Zeisel method shows the presence of four methoxyl groups. (ii) Phenanthrene group. morphine (see §27). papaverine is converted into the secondary alcohol papaverinol. 147°. etc.

(C 19 H 19 4 N)CH 2 -£L> (C 19 H 19 4 N)CHOH -£L> (C 19 H 19 4 N)CO papaverine papaverinol papaveraldine When oxidised with hot concentrated permanganate. veratrole is formed. This acid is a dibasic acid and still contains the keto group present in its precursor — it forms an oxime. Metahemipinic acid. but I can give rise to two . Furthermore. the prolonged action of hot permanganate oxidises papaveraldine to papaverinic acid. the two carboxyl groups must be in the ortho-position. viz. metahemipinic acid. When decarboxylated. veratric acid forms veratrole. since the acid forms an anhydride when heated with acetic anhydride. papaverine (or the oxidised products mentioned above) is broken down into smaller fragments. C 20 H 19 O 5 N (it is the formation of this ketone that shows that papaverinol is a secondary alcohol). veratric acid. Thus metahemipinic acid is either I or II. thus metahemipinic acid contains two methoxyl groups in the ortho-position. Since this is o-dimethoxybenzene. C 16 H 13 7 N. The position of the carboxyl group with respect to the two methoxyl groups (in the or^/w-position) is established by the following synthesis. etc. C0 2 H C0 2 H C0 2 H C0 2 H ch 3 i ^ 0H NaOH „ A 0CHs OCH3 veratric acid Thus veratric acid is 3 : 4-dimethoxybenzoic acid. This is a dicarboxylic acid. Let us now consider the evidence for the structures of these compounds. The foregoing reactions lead to the conclusion that papaverine contains a methylene group. and when decarboxylated by heating with calcium oxide..papaveraldine. Finally. veratric acid is therefore a dimethoxybenzoic acid. papaverinic acid also contains two methoxyl groups. pyridine-2 : 3 : 4-tricarboxylic acid and 6 : 7-dimethoxyj'soquinoline-l-carboxylic acid. . Veratric acid. II permits the formation of only one monoester. Now metahemipinic acid forms only one monoester.

hemipinic acid CH 3 CH.o CH 3° I C0 2 H CHp' . CO-0 I CO C0 2 H (CH. Thus II is metahemipinic acid. I is actually hemipinic acid (this isomer was known before metahemipinic acid).0 CQj H ( cH 3 co).-CO) l0 ^ do/V-. XIV different monoesters.534 ORGANIC CHEMISTRY [CH.

G0 2 H km„o v HO^ H0 2 Cll pyridine-2: 3: 4tricarboxylic acid 6 : 7-Dimethoxyisoquinoline-l-carboxylic acid. The usual tests showed that this compound contains one carboxyl group and two methoxyl groups. this acid forms pyridine-2 : 3 : 4-tricarboxylic acid. . and since decarboxylation gives pyridine. On oxidation. the acid forms a dimethoxywoquinoline which.P<K. :o n metahemipinic acid Pyridine-2 : 3 : 4-tricarboxylic acid. gives metahemipinic acid. The routine tests showed that this contains three carboxyl groups. on oxidation. when decarboxylated. the acid must be a pyridinetricarboxylic acid. The positions of the three carboxyl groups are established by the fact that this pyridinetricarboxylic acid is produced when lepidine (4-methylquinoline) is oxidised. thus the structure is established.

O.KMnO. CI^o/Sco.. The presence of these two groups also accounts for the isolation of the .!! CH 3 ol|JcG 2 H metahemipinic acid §26] ALKALOIDS 535 We may now deduce the structure of papaverine as follows: (i) The isolation of veratric acid indicates the presence of group III in papaverine. (ii) The isolation of 6 : 7-dimethoxy/soquinoline-l-carboxylic acid indicates the presence of group IV in the molecule. C0 2 H pyridine-2:3:4tricarboxylic acid C0 2 H 6:7-dimethoxyisoqainoline1-carboxylic acid CaO^ KM.

a — CH 8 — group present. with this formula.other two fragments. XIV [O] CH 3 CH 3 [O] . (iii) The total carbon content of III (9 carbon atoms) and IV (12 carbon atoms) is 21 carbon atoms. the carbon atom of the CH a group. There is. and if we assume that C" and C* are one and the same carbon atom. But papaverine contains only 20. however.. then the following structure of papaverine accounts for all the facts: papaverine Thus. viz. we can formulate the oxidation of papaverine as follows: 536 ORGANIC CHEMISTRY [CH.

CH 2 Cl H a -Raney Ni CH 2 -CH 2 -NH 2 (i)HCl (ii)PCl. but Bide and Wilkinson (1945) carried out a simpler one. CH 3 (. CH 3 v.H0 2 C H0 2 C OCH 3 OCH3 papaveraldine papaverinic acid This structure for papaverine has been confirmed by synthesis. . and it is this that is described here. The first synthesis was by Pictet and Gams (1909). (i) CH s o/%.

GH 2 .or Y CH.iOjjXcHii-COCl V homoveratrylamine homoveratroyl chloride papaverine §27] ALKALOIDS §26a. . Some other alkaloids of the woquinoline group are: 537 CH 3 CH 3 .

These are three important opium alkaloids which contain the phenanthrene nucleus. and this is reconverted into morphine by the action of carbon dioxide . C I? H 21 3 N. Morphine. CH3O1/Y laudanosine laudanine narcotine hvdrastine PHENANTHRENE GROUP §27. as is shown by the following reactions. . and was the first alkaloid to be isolated (Serturner. and dissolves in aqueous sodium hydroxide to form a monosodium salt. 254°. two hydroxyl groups are therefore present in the molecule.p.. Halogen acids convert morphine into a monohalogeno derivative. 1806). 155° (Grimaux.CH. m. m. The second hydroxyl group is secondary alcoholic. C 17 H 19 3 N. When heated with methyl iodide in the presence of aqueous potassium hydroxide.p. (-)-Morphine. The usual tests show that the nitrogen atom is in the tertiary state. 1881). 1869). morphine is methylated to give (-)-codeine. one hydroxyl group being replaced by a halogen atom. Since codeine is no longer soluble in alkalis. Furthermore. is the chief alkaloid in opium. codeine and thebaine. Morphine gives the ferric chloride test for phenols. and since morphine forms a diacetate and a dibenzoate. thus one of the hydroxyl groups is phenolic (Matthiessen et al. it therefore follows that it is only the phenolic hydroxyl group in morphine that has been methylated.

1881). a ketone (Hesse. and forms codeinone (Knorr. produces two molecules of methyl iodide when heated with hydriodic acid (Zeisel method). thebaine 538 ORGANIC CHEMISTRY [CH. The foregoing work can thus be summarised by assigning the following formulae to the compounds described: -OH f— OCH 3 C 16 H 16 ON<. XIV eliminates one methyl group as methyl hydrogen sulphate. When heated with sulphuric acid. . 193°.codeine can be oxidised by chromic acid to codeinone. m. hence thebaine is a dimethoxy derivative. and so codeine is the monomethyl (phenolic) ether of morphine. C 19 H 2 i0 3 N. 1884). 1906). C 16 H 16 ON CHOH I— CHOH IA. (-)-Thebaine. we have accounted for the functional nature of two of the oxygen atoms. The formation of a ketone led Knorr to suggest that thebaine is the methyl ether of the enolic form of codeinone.I morphine codeine f— OCH3 f— OCH3 C 16 H 16 ON^ C la H 15 ON —co L— 00CH3 I II codeinone thebaine So far.p. the unreactivity of the third oxygen atom suggests that it is probably of the ether type (Vongerichten. Thus the hydroxyl group in codeine (and this one in morphine) is secondary alcoholic.

C 17 H 17 2 N. and this has been confirmed as follows. morphothebaine. the quinone is converted into phthalic acid. fEEENCH 3 }+I. when heated with dilute hydrochloric acid. under the same conditions. then the formation of a primary base could be expected. morphol. IV (some of II isomerises to jS-methylmorphimethine). When codeine methiodide.All three alkaloids are tertiary bases (each combines with one molecule of methyl iodide to form a methiodide). therefore the two hydroxyl groups are in the same ring. this shows that both §27] . forms methylmorphol. Codeine.. and with concentrated hydrochloric acid. and ethanoldimethylamine. Thus in the formation of thebenine from thebaine. is obtained and this. When heated with hydrochloric acid at 140° under pressure morphine loses one molecule of water to form apomorphine. Since the fusion of morphine with alkali gives protocatechuic acid. phenanthrene and a number of bases are produced (Vongerichten et al. a tertiary nitrogen atom is converted into a secondary one. II. 1869). On further oxidation (permanganate). on heating with acetic anhydride. C 18 H 19 3 N (a secondary base). C 18 H 19 3 N (a tertiary base). forms thebenine. had the nitrogen been in the group — NR 2 . also gives apomorphine (and some other products). a-methylmorphimethine. III. however. Oxidation of diacetylmorphol gives a diacetylphenanthraquinone. This suggests that a phenanthrene nucleus is probably present. For this change to occur. is boiled with sodium hydroxide solution. methyl chloride and a dihydroxyphenanthrene. Thebaine. I.Na0H f=NCH 3 C 16 H 16 0^-OCH 3 J^C 16 H 15 0i-0CH 3 > I— CHOH L— CHOH i 1 'n C 16 H 12 2 + (CH 3 ) 2 N-CH 2 -CH a OH III IV The structure of methylmorphol (III) was ascertained by heating it with hydrochloric acid at 180° under pressure. thus positions 9 and 10 are free. where the nitrogen is in a ring system. When morphine is distilled with zinc dust. were obtained. the tertiary nitrogen must be of the type >N*R.

(1900) showed by synthesis that dimethylmorphol is 3 : 4-dimethoxyphenanthrene (c/. Pschorr et al. Finally.ALKALOIDS 539 hydroxyl groups in morphol are in the ortho-position. CH 3 CII3O . Pschorr synthesis. §2 via. X).CH« HOjjC V CHO (CH 3 -C0) 2 O N0 2 3 : 4-dimethoxy-2-nitrobenzaldehyde .

.phenylacetic acid (sodium salt) 3:4 -dimethoxy-2-nitroa-phenylcinnamic acid CH 3 0( (0 M CH3 °^ (ii) NaN0 2 -H 2 S0 4 ^ C0 2 H heat ^ CH3O CH3O (iii) Cu powder dimethylmorphol Then Pschorr et al. and showed it to be 4-hydroxy-3-methoxyphenanthrene (in this synthesis Pschorr used 3-acetoxy-4-methoxy-2-nitrobenzaldehyde). (1902) synthesised methylmorphol (III).

it has also been shown above that this nitrogen is in a heterocyclic ring). Furthermore.. the products obtained are trimethylamine.Ill methylmorphol The formation of ethanoldimethylamine (IV) from a-methylmorphimethine indicates that there is a >NCH 3 group in codeine (only one methyl iodide molecule adds to codeine to form codeine methiodide. 1912). The structure of this compound was shown by the synthesis of 3 : 4 : 5-trimethoxyphenanthrene. 1896). 1898). On fusion with potassium hydroxide. ethylene and methylmorphenol (Vongerichten. the reduction of morphenol with sodium and ethanol gives morphol (Vongerichten. These results can be explained by assuming that morphenol has a structure containing an ether linkage in positions 4 : 5 (of the phenanthrene nucleus). which was found to be identical with the product obtained by methylating the trihydroxyphenanthrene obtained from morphenol (Pschorr et al.. a compound which contains one phenolic hydroxyl group and an inert 540 ORGANIC CHEMISTRY [CH. Demethylation of this compound with hydrochloric acid produces morphenol. XIV oxygen atom. morphenol gives 3:4: 5-trihydroxyphenanthrene (Vongerichten et al. 1906). When j8-methylmorphimethine is heated with water. CH 3 .

Gulland and Robinson (1923. on heating with acetic anhydride. 1925) have proposed the following structures. Based on the foregoing evidence. and a large amount of other experimental work.CO)2O > CH 3 -NH-CH 2 -CH 2 OH + codeinone The position 3 of the methoxyl group and the position 4 of the hydroxy group have already been accounted for .*-0 methylmorphenol morphenol morphol Codeinone. C 18 H 19 3 N (CH3. §28] ALKALOIDS 541 . gives ethanolmethylamine and the diacetyl derivative of 4 : 6-dihydroxy-3-methoxyphenanthrene. the hydroxyl group in the 6-position must therefore be produced from the oxygen of the keto group in codeinone.

>H 15 . o/N .CH 3 o \ XJ" CH \ /|\14/ N I CHrl— OH.CH 16 7 morphine codeine CH. CH o/\ CH.

(1956) have now synthesised morphine.o / \/ thebaine Gates et al.o HO O CEfc /NCHs Y Y^ / NOH 3 "CHj CHj CHj CH codeinone {keto form) codeinone (enol form) . .

amines and amino-aldehydes. and from this Robinson .(1948) deduced the structure of emetine which was later confirmed by the synthetic work of Battersby et al. mezcaline. e. (1950). The general technique has been to administer labelled precursors to plants and to isolate the alkaloid after some time has elapsed for the growth of the plant. ephedrine. it became increasingly probable that the precursors in the biosynthesis of alkaloids were amino-acids and amino-aldehydes and amines derived from them. Alkaloids containing a benzene ring are believed to be products of the shikimic acid route (§18. Thus amino-acids. XIV HO HO<T_\cH 2 -CH(NH 2 )-C0 2 H H0 \ ^CH 2 C-H(NH 2 )-CO. The following examples of biosynthesis illustrate the principles outlined above. A particularly interesting point is that the consideration of biosynthesis has led to deductions in structure.§28. XIII) how keto-acids may be converted into amino-acids. There are also enzymes which bring about the decarboxylation of amino-acids to amines and the decarboxylation of a-keto-acids to aldehydes.2 H phenolase HO ° 2 HO HO^_\cO-CH(NH 2 )-C0 2 H HO<^J%CO-CH 2 -NH 2 HO HO . we may describe the biosynthesis of adrenaline (§12) from tyrosine. e. As an example. etc. and vice versa.g. As more and more structures of alkaloids were elucidated. together with formaldehyde (or its equivalent) are believed to be the units involved in the biosynthesis of alkaloids. We have already seen (§18.. the amino-acids phenylalanine and tyrosine are the starting points for the biosynthesis of.. hordenine. Biosynthesis of alkaloids. XIII). the route is possibly: 542 ORGANIC CHEMISTRY [CH. Woodward (1948) proposed a biosynthesis of strychnine.g.

VIII).4-dihydroxyphenylalanine are precursors for the alkaloids of the phenylalanine and woquinoline groups (see also later). A study of the formulae of hygrine (§13) and cuscohygrine (§13a) shows that the two most reasonable units are acetone and pyrrolidine. that phenylalanine. which could undergo the following reactions to give 4-methylaminobutanal (see also later): CH 2 i -CH 2 CH 2 12 -CH 2 i CH 2 I -CH 2 . but the precursor of the pyrrolidine fragment is less certain. The biosynthesis of acetone occurs via acetoacetic acid (see §32a. (1952-) have shown.HO^^ScHOH-CHg-NHa HO<f ^>CHOHCH 2 -NH-CH 3 noradrenaline adrenaline Leete et al. tyrosine and 3. using labelled compounds. The most likely aminoacid precursor appears to be ornithine.

1 CH 2 I -CH 2 1 CH a CH-NH 2 1 ■CH a 1 CO 1 -^CH 2 CHO -» 1 CH 2 .

13a). §§13.| CHO NH 2 CO a H NH 2 CO a H NH 2 CH. 5 -NH This compound may then be imagined to condense with acetone (or acetoacetic acid) to form hygrine and cuscohygrine (cf. HoC CHo H^C CHo II 2 2 | I 2 H 2 C X CHO + CH 3 CO • CH 3 + CHO CH 2 .

one possible mode of biosynthesis of tropinone could be via hygrine as the precursor: .. CH 2 C0 2 H x CH 2 COOH 3 n CH 2 CH 2 CH 3 wpelletierine coniine Now let us consider tropinone. (1949) have condensed this aldehyde with acetoacetic acid at pH 11 to give wopelletierine. The amino-acid precursor of 5-aminopentanal is most likely lysine (the homologue of ornithine). It should also be noted that conversion of the keto group in wopelletierine into a methylene group gives coniine : §28] ALKALOIDS 543 /\ 2 cr H 2 C V CHO + CO NH. and 5-methylaminopentanal with acetoacetic acid at pK 7 to give methyh'sopelletierine.g. the pelletierine group of alkaloids (§19) may all be imagined to be formed from 5-aminopentanal. Anet et al. Since this compound contains the hygrine skeleton.NH H 2 C CH 2 ^ H 2 C CH 2 ^ H 2 C CH 2 H 2 C CHCH 2 COCH 3 CH 2 CH-CH 2 CO-CH 2 -CH y CH 2 III CH 3 CH 3 CH 3 hygrine cuscohygrine In the same way. e.

methylamine and acetonedicarboxylic acid under physiological conditions (§22). Leete (1960) has shown that phenylalanine is a . Mannich (1942) has suggested that arecoline (§17) is formed as follows: /CHO CHO CH 3 CH3CHO H 2 C CH 2 CHO CHO CH 2 H 2 C CH 2 NH„ 7 0H 3 CH 3 Mannich obtained I by carrying out the condensation with a mixture of acetaldehyde. and succinic acid is another. using labelled ornithine. Marion el al. (1960). glutamic acid and proline are incorporated into the pyrrolidine ring. formaldehyde and methylamine at room temperature at pB. Leete (1955-1958) has shown. possibly via acetoacetate. In this case. but are less efficient precursors than ornithine. Kaczkowski et al. 3. Glutamic acid is one possibility. and has also suggested that putrescine. The biosynthesis of cocaine (§23) is similar to that of tropinone.CH a — CH CH 2 CH 2 — CH CH 2 CH 2 — CH CH 2 tf-CH 3 CO — ► N-CH 3 CO — >. that this aminoacid is a good precursor for the pyrrolidine ring in nicotine. have found that acetate is incorporated into the tropane ring in hyoscyamine. (1954) have also shown that labelled ornithine is incorporated into hyoscyamine (§22). the problem is the nature of the precursor of succinaldehyde.N-CH 3 CO CH 2 — CH 2 CH 3 CH 2 — CHOH CH 3 CH 2 — CH CH 2 On the other hand. The biosynthesis of some alkaloids containing a piperidine ring has already been discussed. tropinone has been synthesised from succinaldehyde. using labelled compounds.

It has been pointed out above that phenylalanine..OH. The origin of the pyridine ring is still obscure. It appears that alanine and aspartic acid are precursors of nicotinic acid. e.. are precursors for the woquinoline alkaloids. [CH. Some suggestions have been described above. and experiments using tritium-labelled nicotinic acid support the hypothesis that it is converted into nicotine via a 6-pyridone derivative (Dawson el al. Thus. 1958). XIV CH-NH 2 OCH Q OCHo Support for the plausibility of this mechanism is given.g. by the formation of the tetrahydrowoquinoline from the condensation between 3 : 4-dihydroxy- .. e. etc.precursor of tropic acid. papaverine (§26) might possibly undergo biosynthesis as follows: 544 ORGANIC CHEMISTRY .g.

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