PYRIDINE and ITS DERIVATIVES Part Five

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PYRIDINE AND ITS DERIVATIVES Part Five

Edired by George R. Newkome

Louisiana State University Baton Rouge. Louisiana

AN INTERSCIENCE "I PUBLICATION

John Wiley and Sons NEWYORK CHICHESTER BRISBANE TORONTO SINGAPORE

______I_ ----__ll____l______.__ __I____II___-_-.----c.__. I______X_I__._-.--.--_

PYRIDINE AND ITS DERIVATIVES

Part Five

This is the jourteetith iw/ut?ii, in the siviips THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS - - __- .-.-___*-l_ll_---.-----_ ___- --

TItE CHEMISTRY OF HETEROCYCLIC COMPOUSDS A SERIES OF MONOGRAPHS

ARNOLD WEISSBERGKR AND EDWARD C. TAYLOR

@ PYRIDINE AND ITS DERIVATIVES Part Five

Edired by George R. Newkome

Louisiana State University Baton Rouge. Louisiana

AN INTERSCIENCE "I PUBLICATION

John Wiley and Sons NEWYORK CHICHESTER BRISBANE TORONTO SINGAPORE

______I_ ----__ll____l______.__ __I____II___-_-.----c.__. I______X_I__._-.--.--_ An Interdencc " PUbllCdtioll Copyright @ 1984 hy John Wiley & Sons. Inc. All rights rewved. Puhlished simultaneously in Canada. Keproductioii or translalion of any part of this work beyond that permitied by Section 107 or 108 ofthe 1976 United States Copyright Act without the permission of ihe copyright owner is unlawful. Requests for permishn or further information should be addreshed to the Periniwons Department. John Wiley & Sons. Ins.

Library of Congrclr.5 catabging in Publication Data : ( Revid Ibr volume 5) Klingsberg. Erwin. Pyridine and it\ derivatives.

(The Cheniislr) of heteroc)clic ccimpound>: a ,cries of nionographs. v. 14) Vd. 5- edited hy George R. Newkoiiir Vd. 5- ha3 impriiir : New York : Wile! "An Interscience publication" -Val. 5. I p Include\ hihl iograph ics. I. Plridiiie. I. Ncwkoine. George R. (George Kizh.irdI II. Title. Ill. Serie\: Chemistry of heieroc?clic compound>.\. 14.

QD4Oi.K712 547'.5Y3 59-13038 ISBN 0-471-05072-5 (v. 5)

10 9 K 7 6 5 4 3 2 i Contributors

T. D. BAILEY J. D. SAUER Reilly Tar and Chemical Corporation Ethyl Corporation Indianapolis, Inilianu Baton Rouge, Louisiana

G. L. GOE E. F. V. SCRIVEN Reilly Tar and Chemical Corporation Reilly Tar and Chemical Corporation Indiunapolis, Indianu Indiarwpolis, Indiana

V. K. GUPTA R. P. THUMMEL Depa r ttnen t of' Clierii is try Depar frnent 01' Client istry Louisiana Stute Uniwrsity Unicersity of' Houston Baton Roicyr, Louisium Houston. Trsas

G. R. NEWKOME Department of Clietnistry Louisiana Stare Unioersitj Baton Rouge, Louisiarru

Tbe Chemistry of Heterocyclic Compounds

The chemistry of heterocyclic compounds is one of the most complex branches of organic chemistry. It is equally interesting for its theoretical implications. for the diversity of its synthetic procedures, and for the physiological and industrial significance of heterocyclic compounds. A field of such importance and intrinsic difficulty should be made as readily accessible as possible, and the lack of a modern detailed and comprehensive presentation of heterocyclic chemistry is therefore keenly felt. It is the intention of the present series to fill this gap by expert presentations of the various branches of heterocyclic chemistry. The subdivisions have been designed to cover the field in its entirety by monographs which reflect the importance and the interrelations of the various compounds, and accommodate the specific interests of the authors. In order to continue to make heterocyclic chemistry as readily accessible as possible, new editions are planned for those areas where the respective volumes in the first edition have become obsolete by overwhelming progress. If, how- ever, the changes are not too great so that the first editions can be brought up-to-date by supplementary volumes, supplements to the respective volumes will be published in the first edition.

Researcli Lubornrories ARNOLDWEISSBERGER hsmmKoahk Compnny Roclrester, New York

Princeton Uiiiixvsify EDWARDC. TAYLOR Princeton, New Jersey

vii

Preface

The original four volumes of this pyridine series were published between 1960 and 1964 under the guidance of Dr. Erwin Klingsberg. In 1974-1975, Professor Rudy Abramovitch edited a four-volume supplemental series, which followed the general format of the initial work. These herculean tasks covered most of the important research in pyridine chemistry up to 1970-1972. As with most areas of organic chemistry, proliferation has occurred at an incredible rate, especially in heterocyclic chemistry. The need for a topical update in key research areas is essential ; thus, the supplemental series has changed format in order to keep the interest in pyridine chemistry as current as possible. In 1977, Professor Abramovitch and I discussed the creation of this expansion of Pyridine and Its Derivatiues and decided to abandon the difficuli- to-organize chapter order of the previous volumes in this series. Also, new topics and directions caused duplication and a need for new chapters to meet the ever-expanding field of pyridine chemistry. As the task started, Professor Abramovitch’s writing and editing obligations in other areas of interest pre- vented his devotion to this series; his efforts are sorely missed. This and all future supplementary volumes in the Pyridine and Its Derimriucs series will be devoted to specific areas of interest and will attempt to remain as the comprehensive repository of pyridine chemistry. I express my thanks to the authors for their contributions and patience as well as to Rudy Abramovitch for his initial guidanceand support in this project.

GEORGER. NEWKOME

Contents

I. SYNTHETIC AND NATURAL SOURCES OF THE 1 PYRIDINE RING

T. D. BAILEY,G. L. GOE,and E. F. V.SCRIVEN 11. CARBOCYCLIC ANNELATED PYRIDINES 253 R. P. THUMMEL

111. MACROCYCLIC PYRIDINES 447

G. K. NEWKOME,V. K. GUPTA,and J. D. SAUER IV. THE REVIEWS OF PYRIDINE CHEMISTRY-11968-1982 635 G. R. NEWKOME

AUTHOR INDEX 659

SUBJECT INDEX 703

PYRlDlNE AND ITS DERIVATIVES

Part Five

This is tl~efourttwi~liIohtnrc it1 [lie .seric.y

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

CHAPTER I

Synthetic and Natural Sources of the Pyridine Ring

T. D. BAILEY, G.L. COE, and E. F. V. SCRIVEN Reilly Tar and Chemical Corporation, Indianapolis, Indiona

I. Pyridines from Natural Sources ...... 3 1. Pyridines in Nature ...... 3 A. Enzymes, Vitamins, Amino Acids, and Their Biogenesis ...... 3 B. The Tobacco Alkaloids...... I C. Other Pyridine Alkaloids and Related Compounds ...... 11 a. Simple Pyridine Alkaloids ...... 11 b. Monoterpenoid Alkaloids ...... 12 c. Scsquiterpenoid Alkaloids ...... 16 i. Derivatives of Nicotinic Acid ...... 16 ii. Pyridone and Pyridinol Alkaloids...... 11 iii. Other Sesquiterpcnoid Alkaloids ...... 22 d. pCarboline and Related Alkaloids That Contain a Pyridinc Ring. .. 23 2. Degradation of Natural Products ...... 24 A.Coa1...... 24 B. Petroleum ...... 28 C. Shale...... 29 D. Degradation and Transformation of Alkaloids ...... 31 E. Flavors, Odors, and Volatile Constituents of Food and Beverages . .. 33 F. Miscellaneous Sources ...... 36 11. Pyridines by Synthetic Methods ...... 36 1. From Other Ring Systcms ...... 36 A. Carbocyclic Compounds ...... 31 B. Three-Membered Ring Heterocycles ...... 43 C. Four-Membered Ring Heterocycles ...... 46 D. Five-hlcrnbered Ring Heterocyclcs ...... 41 a. Five-Membered Rings Containing One Ileteroatom ...... 48 i. Furans, Dihydrofurans, and Tetrahydrofurans ...... 48 ii. Pyrroles ...... 55 b. Five-Membered Rings Containing Two Heteroatoms ...... 60 i. Oxazoles...... 60 ii. Miscellaneous Fivc-hlembered Ring Hetcrocycles ...... 68 E. Six-Mcmbered Ring Heterocycles...... I5 a. One Heteroatom ...... I5 i. Pyrones ...... I5

1 2 'r . D . Bailcy, C . L . Goe. and E . F . V . Scriven ii . Pyrcins ...... 83 iii . Pyrylium Salts ...... 83 b . Two Hetcroatoms ...... 93 i . Pyriniidincs ...... 93 ii. Pyridazincs ...... 97 iii . Pyrazincs ...... 98 iv. Oxmincs ...... 99 v . Miscellancous Six-hiembered Heterocycles Containing Two ... lleteroatonis ...... 101 c . Six-Membcrcd Ring lleterocycles with Tluec tietcroatoms .... 102 F . Seven-Membered Ring lieterocycles ...... 104 a . Azepincs ...... 104 b . Diazepincs ...... 105 G . Pyridincs from Reduced Pyridines ...... 106 a . Dihydropyridines ...... 106 b . Tctrahydropyridincs ...... 111 c. Piperidines ...... 113 H . Condensed Kinps ...... 113 a . Oxidation ...... 113 b . Reductions ...... 117 c . RingOpcning Reaction ...... 117 2 . From Acyclic Compounds...... 118 A . Cyclization of a 5Carbon Chain ...... 119 a . 1 J-Dioxo Compounds and Derivatives ...... 119 b . Oxocarboxylic Acids and Derivatives ...... 125 c . 1 .5-Dicarboxylic Acids and Derivatives ...... 132 d . Conipounds Having Terminal Unsaturation ...... 136 e . Misccllaneous 1.5.Bifunctional Compounds ...... 139 B. 4-1 Condcnxitit>ns ...... 141 a . Dicncs with Nitrilcs ...... 141 b . Other Rc;ictions of Nitrilcs ...... 142 c . Reactionr of lsocyanates ...... 144 d . Reaction of Othcr Acid Derivativcs ...... 144 e . Miscellaneous ...... 146 C . 3-2 Condcnsations ...... 147 a . 1.3-Dicarbonyl Cumpounds and Their Derivatives wit11 Methylenic . . Compuunds ...... 147 b . a.@-Unsaturated Carbonyl Compounds and Their Derivatives with Met hy lenic Conipou nds ...... 166 c . Condcnsation of a.p.Unwturatcd Carbonyl Compounds with Ammonia . 172 d . Miscellancous 3-2 C'ondcnstions ...... 173 D . 1-3-1 Condensations ...... 175 E . 2-2-1 Condensations ...... 176 a . Acetylenes and Nitriles ...... 176 177 b . Aldehydes with Arniiionia ...... i . Acetaldehyde with Ammonia-Vapor Phase ...... 177 ii. Acctaldchydcwith Ammonia-Liquid Phase ...... 177 iii . Other Aldehyde3 uhh Ammonia-Liquid Phase ...... 178 c . Aldchydcs. Ketones . and Mixtures with Ammonia-Gas Phase ... 179 i . Acetaldehyde ;ind I~rmnaldchydcwith Ammonia ...... 179 ii . Other Mixtures of Aldchydcs and Ketones with Ainnionia ... 179 d . Other Oxygcnatcd Compounds with Ammonia-Vapor Phase .... 181 c . Miscellancous 2-2-1 Condcnsaticins ...... 181 F . 2-1 -2 Condensatlims ...... 185 Pyridines from Natural Sources 3 a. Mixtures of Aldehydes and Ketones with Ammonia ...... 185 b. Carbonyl Conipounds with Active Mcthylene Compounds .... 185 i. Aldehydes with Active hlethylene Coinpounds ...... 185 ii. Carbosylic Acid Derivatives with Active Methylene Compounds. . 186 c. Miscellaneous 2-1-2 Condensations ...... 187 G. Cyclization Not Involving the Ring Nitrogen ...... 188 a. Cyclization of Isocyanates ...... 188 b. Cyclization of Imines ...... 190 c. ReactionsRelated to theCould-JacobsReaction ...... 191 d. Miscellaneous Ring Closures ...... 193 Acknowledgment ...... 194 References ...... 194

I. PYRIDINES FROM NATURAL SOURCES

1. Pyridines in Nature

A. Enzynzes, Vitamins, Amino Acids. anti Their Biogenesis

The wealth of information derived from isotopic labeling studies over the last few decades has established pathways for the biogenesis of many pyridines. Only the ones that lead to some iniportant pyridines will be outlined. The pyridine ring of nicotinic acid and the pyridine nucleotides is synthesized by two routes. In the tissues of higher animals and Neurospora it is derived from tryptophan, but another pathway starting from aspartic acid and a C3-fragnient is preferred in bacteria (e.g., E. coli and E. subtilis), green algae, and higher plants (e.g., corn or tobacco). The yeast S. cerevisiae has the ability to synthesize pyridine nucleotides by both routes. Under aerobic conditions the tryptophan pathway is favored, but in the absence of oxygen the aspartic acid route (deNovo pathway) predominates. The two pathways, which converge at a common intermediate, quinolinic acid, are illustrated in Scheme 1-1. Quinolinic acid is decarboxylated and converted to nicotinic acid mononucleotide by phosphoribosyltransferase to provide entry into the Pyridine Nucleotide Cycle (Scheme 1-2). Conversion of tryptophan to nicotinic acid has been well studied in both animals, principally the rat (1,2) and, fungi (3). The Pyridine Nucleotide Cycle is responsible for the production of nicotinic acid adenine dinucleotide, NAD, nicotinamide and nicotinic acid, and the alkaloids (1-1) and (1-2) in plants. Several reviews are available on biosynthesis (4-9) and other aspects (10-12) of pyridine nucleotides. The importance of this cycle in tlie generation of pyridine enzymes and vitamins has excited interest in its control mechanism (13-18). Before giving examples of isolation of members of the cycle from specific sources, the biogeneses of the B6 vitamins, pyridoxine (1.31, pyridoxal (1-4), and pyridoxamine (1-5) are mentioned. Evidence from comprehensive 14C labeling work indicated that all the carbon 4 '1. D. Bailey, G. L. Goe, and E. F. V. Scriven Tryptoplian pathway Condensation of aspartic acid (Nertrosporcr pathway) and a C,-fragment (dr. Novo pathway)

co;I

CH2OI-I CHzCO2H I I CHOW + CHCO; I CHzOH +AH3 0 II 50; I CCH2CH fkH, NHCHO

HCO,H COIH co,WrPyridine CycleNucleotide 0 qo; CCH,CtI (Scheme 1-2) +NH, a NH 2 OH T

OH MeCOSCoA + CO, Glutaric acid pathway QCO2H

Scheme 1-1. Two pathways for the biogenesis of quinolinic acid. Pyridines from Natural Sources 5

Scheme 1-2. Pyridine Nucleotide Cycle. (i) Quinolinic acid phosphoribosyltransferase. (ii) Nicotinic acid mononucleotide adenyltransferase. (iii) NAD + synthetase. (iv) NAD f glycohydrolase. (v) Nicotinaniide deaniidase. PRPP = phosphoribosyl pyrophosphate.

1-3 1-4 1-5 6 T. D. Bailey, G. L. Goe, and E. F. V. Scriven TABLE 1-1. SYNTHESIS OF NICOTINIC ACID AND B, VITAMINS BY MICROORGANISMS Organism Rcfcrence

Hydrogenomonas rittropha 47,48 Hydi-ogetiotrionas pantorroptia 47 Ifvdrogetionionas ttieriiiophilits 47 Azorobacter chroococcuni 49 Bacillits megateriicm 49 Urobactcria 50 Arthrobacter sitriplex 51 Arthro bac ter raria bilis 51 Art liro bacter t it iiiesceiis 51 Rhizobial bacteria 52 Spiriilina platerisis 53 Rtsariir~iirnoniliforriis 54 1:irsariitin gib bosirrii 54 Actinoniycctes 55,56 Proinyxohacterium lolinsoirii 51 hficrocoi~cirsfreiiderireictiii 58 Klocckera apicitlata 59 Saccliaroniyces ellipsoideits etc. 60 %I.Rosaccliarotri~cesbailii etc. 61 Candida tropicalis 62

atoms in pyridoxal biosynthesized by E. coli (B iiiutant WG2) originate from glycerol (19-23). Nicotinic acid is believed to be the precursor of pyridoxine from a feeding study of a pyridoxine-less mutant of Aspcrgilhis tiidirluns (24). The yeast Rhodofonila glufitzis is able to convert ti-alkanes to nicotinic acid (25 ). The tryptophan pathway is followed in this organism (26-28) and Clzlar?iydotizonas ezigumetos (29). Nicotinic acid has also been produced by soil rnicroorganisnis (30). baker's yeast (3 1). the funps Penicillirim digitarum (32), and cotton seeds Gossy- piitni burhadense (33). A review has appeared on the biogenesis of nicotinic acid in plants and microbes (34). Other reviews concerning its cheniical properties, phar- niacology and nutritional aspects as well as occurrence and synthesis have more gencral interest (35-37). Pyridoxal phosphate is the coenzyme responsible for trsnsarnination and is the chief form of the B6 vitamins in aninial tissues (38). Pyridoxine, the form in which pyridoxal is stored, has been found among the products of the fermentation of methanol, with Mcrkurwmonas nzelhj*bvora, which has been claimed to have industrial potential (39). Pyridoxal phosphate has also been synthesized by symbiotic bacteria of nonleguminous plants (40), aerobic cellulose bacteria (41), and all six strains of Rlrizobiiim legiiminosarum (42). The synthesis of both pyridoxine and nicotinic acid by bacteria from soils has been studied extensively (43-45). Some of these bacteria have been found to produce pyridoxine and nicotinic acid when ethanol is the sole carbon source (46). Other microorganisms producing nicotinic acid and pyridoxine are listed in Table 1-1. Pyridines from Natural Sources 7

kH CHCO; CH , CH 2 CH 2 AH3 kH3I ,CHz~ I -0,CCWCH CH 2CH2CHC0i +/ 1 AHI CH,CH,CH2CH2CHCO; 1-6

AH3 AH3I -0,CCHCHI ?CH CH,CH2CHCO;

+/ ,uI kHI CH2CH2CH2CH2CHCO; 1-7

The unusual amino acids desmosine (1-6) and isodesmosine (1-7) have been isolated from the protein elastin, in which they act as crosslinking centers of peptides (63).

I kH3I %(CH2)4 +NH3I CH &H ,CH ,CH ,CHCO; CHCo;I ,CH ,CH~CH,CHCO; + NH3 & 1-8 1-9

Recently, two more pyridine-containing amino acids, N(5-amino-5-carboxy- penty1)pyridinium chloride (I-8) and anabilysine (1-9), have been found important in the crosslinking of proteins by glutaraldehyde (64).

B. Thc Tobacco Alkuloids

Several new methods for the extraction and separation of these alkaloids have appeared (65,66).Separations on alumina sintered glass plates have been described (67) and new TLC solvent systems have been found which allow the separation of 10 to 13 component mixtures on a semiquantitative basis (68). T, Bailey, C. L. Goe, and E. F. V. Scriven 8 D.

1-10 1-1 1

Two new terpenoid alkaloids have been isolated from Burley tobacco (Nicoriana fabacunt), 1,3,6,6-tetramethyl-5,6,7,8-tetrahydroisoquinolin-8-one(1-10) and 3,6,6- trimethyl-5,6-dihydr0-7W-pyrindan-7-oiie (1-1 1) (69). Remarkably, 1-1 0 may be obtained froin the scent gland of the Canadian beaver (astor fiber) (70), or by a synthetic method (71). 1-10 has also been used to improve the aroma of tobacco! New variants of nicotine isolated from N. tabamin, apart from 2,3’-bipyridyl, have been shown to be N-acylated derivatives of the pyrrolidine ring (1-12)(72). The roots and stems of A! tabacunz, N. affinis, and N. sslvestris have all been found to contain cis or trans nicotine N-oxide, which may be reduced to the parent alkaloid with titanous chloride (73). The leaves of Aiithocercis tasmanica provided a new nontobacco source of nicotine (74). Nicotine has been observed spectroscopically in extracts of the plant Sehrrn acre (75).

R = CHO, Ac, COCSH,,, COC7Hlw

1-12

Biosynthesis and nietabolisrn of the pyridine alkaloids have been reviewed (76). Many studies of the biosynthesis of nicotine have utilized ”N and 14C labeled precursors (77-79), but more recently 13C labeling has found increasing favor because of the ease of site determination of the label in the product by 13C NMR (80-81 ). Abnormal synthetic reactions that occur in biological systems, referred to as “aberrant biosynthesis” (8 l), are currently of particular interest (76). Aberrant biosynthesis may be divided into two types. Tvpe I is dcpicrcd by fhefonirariorlof a natural conipound from an unmtural precursor, such as production of nicotine when 6-N-methylornithine (not normally a component of tobacco) is administered to N. tabaciun plants (82). TvpeN itzvolves thc coiircrsion of an unnatirral prccirrsor to an unnatural product. Examples of this type are provided by the conversion of 5-fluoronicotinic acid to either 5-fluoronicotine in N. fabaczim (83) or 5-fluoroanabasine in A! glaiica (8 1). Pyridines from Natural Sources 9

TABLE 1-2. SIMPLE PYRIDINES FOUND IN TOBACCO LEAF AND SMOKE Reference

Pyridine Bases Leaf Smoke Pyridine 108 108 2-Picoline 109 108 3-Picoline - 108 4-Picoline 109 108 Lutidines (only 2,6-) 109 108 2,4,6€ollidine - 110 2,3,6€ollidine 109 - 2-Ethylpyridine 109 - 3-Ethylpyridine - 108

Meth ylethylpyridine(s) I 111 2-Methyl4 4sopropylpyridine 112 111 2,4-Dimethyl-S 4sopropylpyridine - 111 2-Pheny lp yridine - 108 3-Phenylpyridine 113 108 2-Vinylp yridine - 111 3-Vinylp yridine - 108 3-Propenylpyridine 113 - 3-Form ylpyridine 113 108 2-Acetylp yridine 113 - 3-Acet ylpyridine 108 11 1 3-Propionylp yridine 113 108 3-But yr ylpyridine 108 - 6-Methyl-3-h ydroxyp yridine - 41 Nicotinic acid 108 114 Methyl nicotinate 115 - Nico t ins rnide 108 114 N-Methylnicotinamide 116 - 3Cyanopyridine 113 108 Methylcyanopyridine(s) - 111 - 111 Dimethylcyanopyridine(s) 3-Methylarninopyridine - 108

Regulation of the nicotine content of tobacco has been of great importance to the tobacco industry and has been reviewed (84). Such interest has led to the determination of alkaloid content during the course of ontogeny of N. tabacitm, N. glutinom, and N. sylvestris (85-88). Studies have been made of the alkaloid spectrum during germination of seeds (89,90) and in the roots of seedlings (91,92). Genetic effects on alkaloid content have also received attention (83-96). Flue- curing and aging of Virginia tobacco have been found to lower nicotine content but increase the amount of simple pyridine components (97). It has been claimed that nicotine may be removed from tobacco by rapid drying of an aqueous alkaline tobacco dispersion (98). Various aspects of smoking concerned with the occurrence and role of nicotine have been reviewed (99-1 04). Various metabolites of nicotine have been reported. 10 T. D. Bailey, G. L. Goe, and E. F. V. Ssriven TABLE 1-3. ALKALOIDS FOUND IN TOBACCO LEAF AND SblOKE

Reference

Alkaloid Leaf Smoke N'-Acetylnornicotinc 117 - Ana hasine 108 108 Anata binc 108 108 - Anatalline (I-IS) I18 2,2'-Bipyridyl - 119 N'Carbomethoxyanabasinc - 120 N'Carbometlioxynornicotine - 120 Cotininc 108 108 2',3'-Dehydronicotine - 108 Dihydromctanicotine - 108 Dihydronicotyrine (N-mcthylmyosminc) - 116 N'-Formylnornicotinc 117 - N'-Hexanoylnornico tine 12 - Isonicoteinc (2,3'-bipyridyl) 108 108 Mctanicotinc 108 108 N'-Mcth ylanahasinc 122 119 N'-Mcthyhnatabine 116 - 5-Mcthyl-2,3'-hipyridyl 117 - N-Methylnicotonc 123 124 Myosminc (1-16) 123 123 Nico t cllinc 125 - Nicotine 108 108 Nicotyrinc 108 108 N'-Nitrosonicotinc 126 126 Nornico tine 108 108 Nor nicot yrinc 108 108 N'Octanoylnornicotine 12 - Osynicotinc (nicotinc .&'+side) 108 127 1.3,6,6-Tetraniethyl-S .6,7.8-tetratiydroisoqitinolin- 9+nc (1-10) 69 - 3,6,6-Trimcthy1-5,64ihydro-711-pyrindan-7-onc (1-1 1) 69 -

1-16 Pyridines from Natural Sources 11 such as: hydroxycotinine (1-13) from urine of smokers (1 05) and diastereomeric N-oxides (1-14) from hepatic supernatants of mice, rats, hampsters, rabbits, and guinea pigs (1 06). H

.. 1-1 3 1-14

Work on the contents of tobacco leaf and smoke has been reviewed (107), and thus will be dealt with here in a cursory way. F‘yridine bases that have been found in tobacco and tobacco smoke are listed in Tables 1-2 and 1-3. Although bases isolated from tobacco smoke are not strictly speaking alkaloids, they are con- sidered alongside those found in leaf for comparative purposes. A few points of general interest regarding tobacco smoke are mentioned below. Cigar smoke contained a higher amount of pyridines relative to total alkaloids than did cigarette smoke (1 28). Cigar butt “head-space-vapors” contained some of the tabulated pyridines (1 29). Puff frequency has been found to have a greater effect than puff volume on the alkaloid content of smoke (130). Smoke from Cytrel smoking products has been compared with that from flue-cured tobacco (131,132); nicotine could not be detected in the smoke from 100%Cytrel samples (132).

C Other Pyriditie Alkaloids and Related Conipounds

A great expansion in the knowledge of pyridine alkaloids has taken place in the last decade since the appearance of two reviews on the subject (133, 135). Current work is reported in Alkaloids (London) in the Chemical Society Specialist Periodical Report Series (442), and another review has appeared (134). a. SIMPLE PYRlDlNE ALKALOIDS Ricinine (1-17) is a well-known 2-pyridone derivative that is found in the castor bean Ricinus committiis. Recent interest has been centered on the relationship between the pyridine nucleotide cycle and ricinine biogenesis (136, 137). The isomeric pyridones ricinidine (1-18) and nudifluorine (1-19) have been isolated from the leaves of Trcivia rzctdiflora (1 38, 139). OMC

1-17 1-1 8 1-19 12 T. D. Bailey, G.L. Goe, and E. I:. V. Scriven

1-20 1-2 1

1-22

Fusaric acid (1.20). a systemic wilt toxin found particularly in cotton plants (140,141), was produced by different species of Frrsaria (142-148)and other fungi (149). Dehydrofusaric acid (1-21) and (+)-S-fusarinolic acid (I-22), metabolites of fusaric acid, have been obtained from the mycelium of various Fusaria, S. cerevisiae, and Gibberellafiijikuroi (149-151). Dipicolinic acid was produced by aerobic spore-forming bacteria during spom- lation and its calcium salt is a major constituent of endospores. Its biosynthesis and occurrence have been a popular field of study; sources of dipicolinic acid include: Bacillus nieateritint (152-1 531, B. sicbtilis (1 53-1 57), B. sphaericirs (1 58), B. cereus (I 59 - 16 1 ), B. srearorhermop/iiltts (1 62, 163), Penicilliunr NRKL 3 1 14 by patented processes (1 64, 165). and Chlostridium roscunt (166, 167). An iron complex of pyridine-2,6-di-(rnonothiocarboxylic acid), which has reported antibiotic activity, has been isolated from a culture medium of a Pseudontoiias strain (168). Some other naturally occurring simple pyridine alkaloids and their source of origin are listed in Table 1-4. b. MONOTERPENOID ALKALOIDS A great deal of progress has been made on the isolation and structure determination of pyridine monoterpenoid alkaloids. These alkaloids have been sub- divided into those related to actinidine, mainly pyrindanes Table 1-5; and those resembling gentianine which usually have a lactonc ring annelated to pyridine Table 1-6. Indicaine and boschniakine were thought originally to differ in stereochemistry at C-7 but have now been shown to be identical (189). The confusion arose because of the formation of a diethylacetal during the preparation of a picrate derivative in ethanol. Indicaine has been found as its A’-ethyl quaternary salt, indicainine, in Pedicularis olgae (1 87). Actinidine (R = H) and tecostidine (R = OH) occur as their N-[P-(4-hydroxyphenyl)-ethyl)quaternary salts (1.44) in Valeriaria officinalis (2 16). Cantleyine has been shown to be an artifact formed during the treatment of the extraction of the trunk bark of C. corniculafa with ammonia (198). Gentianine is now known to be an artifact and has been attributed to the rcac- tion of ammonia, used in extraction, with swertiamarin (1-56) or gentiapicrin (1-57) found in the plant sources (7- 15). Pyridines from Natural Sources 13

TABLE 14. SlMPLE NATURALLY OCCURRING PYRlDlNE ALKALOIDS

Pyridine Source Reference

Phenopicolinic acid 0-23) Paecilomny ces AF2 5 6 2 169 Melochinine (1-24) Melochia pyraniidata 170 Anibine 0-25) Aniba duckei 171 Duckein (I-26) Aniba duckei 171 Proferrorosaniine 0-27) Pseudomonas roseus flitorescens 172 Uvitonic acid (1-28) Pseudomonas roseus fluorescens 173 Caerulomycin (1-29) Streptomyces caerulus 174 1-Methylpyridinium iodide Vandopsis Iongicaulis 175 1-Methylpyridinium' The oyster, Oassostrca gigas 176 l-Methyl-2-picoliniuma The oyster, Crassostrea gigas 176 3-Butylpyridine Fusariuni species 145 2-Hepty lpyridinc Bontebok, Damaliscus dorcas dorcas 177

1-23 1-24

OMe OMe

1-25 1-26

co211 I

-CO2H Mefico*H 1-27 1-28

OMe I

1-29

'Counterion not quoted 14 T. D. Bailey, G. L. Goe, and E. F. V. Scriven TABLE 1-5. ACTINIDINE AND RELATED ALKALOIDS

Alkaloid Species IaID Reference

Actinidine (1-30) Actiriidia polygama - 7.2" 178-180 A. argirta 181 Noractinidine (1-31) Tcconia staris + 3.0 182 Pediciilaris rtiacrocliila 183 Valerianine (1-32) Valeriaria officirialis - 10.5 184 Tecostidinc (1-33) Teconia statis - 4.0 185,186 Indicaine (1-34) Pedicularis algae 4- 21.02 187 (boschniakine) Tecortia stans 182 Bosclttiiaka rossica 189 Plan tagonine (1-35) Platitago iridica + 30.8 190 P. psylliitrti 191 Pedicularis olgae 192 Verrbasciini songaricutn 193 Pedicularis niacrochila 183 Venoterpine (1-36) A lsto ti ia vetienaia + 27.0" 194,19S (RW47) Raii wolfia wrticillata 196 Unnamed (1-37) Jasminuni sp. NGF29929 - 34O 197 Cantleyine (1-38) Catitlq-a cortiicitlata -40 t 2 198 Lnsiarithcra austrocaledoriica 199 Pedicularidine (1-39) Pediciilaris olgae 200 Pedicularine (1-40) P. olgae - 15.3 201 Pediculine (1-4 1 )" P. olgae + 615 207, Yediculidine (1-42) P. oIKac 20 3 Pediculinine (1-43) P. dgae 204

011 /

1-30 R = 1-36 K = tl Me 1-39 K =CHO 1-31 K=H 1-37 H = C'0:Me 1-40 H = C02ti 1-32 K ('H:OMt.

1-33 K 7: ('H:OH 1-34 R ('HO 1-3s K - "O:tl .-.'Y5) 1-38

aTI~cproposcd structure 1-4 I appcars unlikely.