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PYRIDINE AND ITS DERIVATIVES
Part Five
Edired by
George R. Newkome
Louisiana State University Baton Rouge. Louisiana
John Wiley and Sons
NEWYORK CHICHESTER BRISBANE TORONTO SINGAPORE ______I_ ----__ll____l_________.__ __I____ II___-_-.----c.__. I_ __ ___X_I__._-.--.--_
A N INTERSCIENCE "I PUBLICATION
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
John Wiley and Sons
NEWYORK CHICHESTER BRISBANE TORONTO SINGAPORE ______I_ ----__ll____l_________.__ __I____ II___-_-.----c.__. I_ __ ___X_I__._-.--.--_
A N INTERSCIENCE "I PUBLICATION
An Interdencc " PUbllCdtioll Copyright @ 1984 hy John Wiley & Sons. Inc.
All rights rewved. Puhlished simultaneously in Canada.
Keproductioii or translalion of any part o f this work beyond that permitied by Section 107 or 108 o f t h e 1976 United States Copyright Act without the permission of ihe copyright owner is unlawful. Requests for p e r m i s h n or further information should be addreshed to
the Periniwons Department. John Wiley & Sons. Ins.
Library of Congrclr.5 catabging in Publication Data :
( R e v i d Ibr volume 5)
Klingsberg. Erwin. Pyridine and i t \ derivatives.
(The Cheniislr) o f heteroc)clic ccimpound> : a ,cries
Vd. 5- edited hy George R. Newkoiiir V d . 5- ha3 impriiir : New York : Wile! "An Interscience publication" - V a l . 5 . I p Include\ hihl iograph ics. I . Plridiiie.
o f nionographs. v. 14)
I . Ncwkoine. George R. (George Kizh.irdI I I . Title. compound>. \. 14.
I l l . Serie\: Chemistry of heieroc?clic
Q D 4 O i . K 7 1 2 547'.5Y3 59-13038 ISBN 0-471-05072-5 ( v . 5 )
10 9 K 7 6 5 4 3 2 i
Contributors
T. D. BAILEY Reilly Tar and Chemical Corporation Indianapolis, Inilianu
G . L. GOE Reilly Tar and Chemical Corporation Indiunapolis, Indianu
V. K . GUPTA Depa r ttnen t of' Clierii is try Louisiana Stute Uniwrsity Baton Roicyr, Louisium
G . R. NEWKOME Department of Clietnistry Louisiana Stare Unioersitj Baton Rouge, Louisiarru
J . D. SAUER Ethyl Corporation Baton Rouge, Louisiana
E. F. V. SCRIVEN Reilly Tar and Chemical Corporation Indiarwpolis, Indiana
R . P. THUMMEL Depar frnent 01' Client istry Unicersity of' Houston Houston. Trsas
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. I t 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 h s m m Koahk Compnny Roclrester, New York
ARNOLD WEISSBERGER
Princeton Uiiiixvsify Princeton, New Jersey
EDWARD C. TAYLOR
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 ex- pansion 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.
ix
GEORGE R. NEWKOME
Contents
I. SYNTHETIC AND NATURAL SOURCES OF THE PYRIDINE RING
T. D. BAILEY, G. L. GOE, and E. F. V. SCRIVEN
11. CARBOCYCLIC ANNELATED PYRIDINES
R . P. THUMMEL
111. MACROCYCLIC PYRIDINES
G. K. NEWKOME, V. K. GUPTA, and J . D. SAUER
IV. THE REVIEWS OF PYRIDINE CHEMISTRY-11968-1982
G. R. NEWKOME
AUTHOR INDEX
1
253
447
635
659
703 SUBJECT INDEX
xi
PYRlDlNE AND ITS DERIVATIVES
Part Five
This is t l~e four t tw i~ l i Iohtnrc 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 . . . . . . . . . . . . . 1. Pyridines in Nature . . . . . . . . . . . . . . . .
A. Enzymes, Vitamins, Amino Acids, and Their Biogenesis . . . . B. The Tobacco Alkaloids. . . . . . . . . . . . . . C. Other Pyridine Alkaloids and Related Compounds . . . . . .
a. Simple Pyridine Alkaloids . . . . . . . . . . . . b. Monoterpenoid Alkaloids . . . . . . . . . . . . c. Scsquiterpenoid Alkaloids . . . . . . . . . . .
i. Derivatives of Nicotinic Acid . . . . . . . . . . ii. Pyridone and Pyridinol Alkaloids. . . . . . . . . iii. Other Sesquiterpcnoid Alkaloids . . . . . . . . .
d. pCarboline and Related Alkaloids That Contain a Pyridinc Ring.
A . C o a 1 . . . . . . . . . . . . . . . . . . . B. Petroleum . . . . . . . . . . . . . . . . . C. Shale. . . . . . . . . . . . . . . . . . . D. Degradation and Transformation of Alkaloids . . . . . . . E. Flavors, Odors, and Volatile Constituents of Food and Beverages . F. Miscellaneous Sources . . . . . . . . . . . . . .
11. Pyridines by Synthetic Methods . . . . . . . . . . . . . 1. From Other Ring Systcms . . . . . . . . . . . . . .
B. Three-Membered Ring Heterocycles . . . . . . . . . . C. Four-Membered Ring Heterocycles . . . . . . . . . . D. Five-hlcrnbered Ring Heterocyclcs . . . . . . . . . .
a. Five-Membered Rings Containing One Ileteroatom . . . . i. Furans, Dihydrofurans, and Tetrahydrofurans . . . . . ii. Pyrroles . . . . . . . . . . . . . . . .
. . . . i. Oxazoles. . . . . . . . . . . . . . . . ii. Miscellaneous Fivc-hlembered Ring Hetcrocycles . . . .
E. Six-Mcmbered Ring Heterocycles. . . . . . . . . . . a. One Heteroatom . . . . . . . . . . . . . .
i. Pyrones . . . . . . . . . . . . . . . .
2. Degradation of Natural Products . . . . . . . . . . . .
A. Carbocyclic Compounds . . . . . . . . . . . . .
b. Five-Membered Rings Containing Two Heteroatoms
3 3
. .
. . 3 I
. . 11
. .
. .
. . 11
. . 12
. . 16
. . 16
. . 11
. . 22
. . 23
. . 24
. . 24
. . 28
. . 29
. . 31
. . 33
. . 36
. . 36
. . 36
. . 31
. . 43
. . 46 41 . .
. . 48
. . 48
. . 55
. . 60 60 68 I5 I5
. . 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
104 a . Azepincs . . . . . . . . . . . . . . . . . . 104 b . Diazepincs . . . . . . . . . . . . . . . . . . 105
G . Pyridincs from Reduced Pyridines . . . . . . . . . . . . 106 a . Dihydropyridines . . . . . . . . . . . . . . . . 106 b . Tctrahydropyridincs . . . . . . . . . . . . . . . 1 1 1 c . Piperidines . . . . . . . . . . . . . . . . . . 1 1 3
H . Condensed Kinps . . . . . . . . . . . . . . . . . 1 1 3 a . Oxidation . . . . . . . . . . . . . . . . . . 113 b . Reductions . . . . . . . . . . . . . . . . . . 1 1 7 c . RingOpcning Reaction . . . . . . . . . . . . . . 117
2 . From Acyclic Compounds. . . . . . . . . . . . . . . . 118
a . 1 J-Dioxo Compounds and Derivatives . . . . . . . . . . 119
c . 1 . 5-Dicarboxylic Acids and Derivatives . . . . . . . . . . 132
F . Seven-Membered Ring lieterocycles . . . . . . . . . . . .
A . Cyclization of a 5Carbon Chain . . . . . . . . . . . . . 119
b . Oxocarboxylic Acids and Derivatives . . . . . . . . . . . 125
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 o f 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 . . . . . . . . . . . . 1 7 3
D . 1-3-1 Condensations . . . . . . . . . . . . . . . . 175 E . 2-2-1 Condensations . . . . . . . . . . . . . . . . 176
a . Acetylenes and Nitriles . . . . . . . . . . . . . . 176 1 7 7
i . Acetaldehyde with Ammonia-Vapor Phase . . . . . . . 177 ii . Acctaldchydcwith Ammonia-Liquid Phase . . . . . . . 177
178
b . Aldehydes with Arniiionia . . . . . . . . . . . . . .
. . . . . . . iii . Other Aldehyde3 u h h Ammonia-Liquid Phase c . Aldchydcs. Ketones . and Mixtures with Ammonia-Gas Phase . . . 179
i . Acetaldehyde ;ind I~rmnaldchydc with Ammonia . . . . . . 179 179
d . Other Oxygcnatcd Compounds with Ammonia-Vapor Phase . . . . 181 c . Miscellancous 2-2-1 Condcnsaticins . . . . . . . . . . . 181
F . 2-1 -2 Condensatlims . . . . . . . . . . . . . . . . 185
ii . Other Mixtures o f Aldchydcs and Ketones with Ainnionia . . .
Pyridines from Natural Sources 3
a. Mixtures of Aldehydes and Ketones with Ammonia . . . . . . 185 b. Carbonyl Conipounds with Active Mcthylene Compounds . . . . 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. Aldehydes with Active hlethylene Coinpounds . . . . . . . 185
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 t o 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 (Nertrosporcr pathway)
Condensation of aspartic acid and a C,-fragment
(dr. N o v o pathway)
co; I
CH2OI-I CHzCO2H I I
I CHOW + CHCO; I CHzOH +AH3
0 50;
fkH,
II CCH2CH
NHCHO
HCO,H COIH a c o , W r P y r i d i n e Cycle Nucleotide
0 qo; CCH,CtI (Scheme 1-2)
NH 2
+NH,
T OH
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. G o e , and E. F. V . Scriven
TABLE 1-1. SYNTHESIS OF NICOTINIC ACID A N D B, VITAMINS BY MICROORGANISMS
Organism Rcfcrence
Hydrogenomonas rittropha Hydi-ogetiotrionas pantorroptia Ifvdrogetionionas ttieriiiophilits Azorobacter chroococcuni Bacillits megateriicm Urobactcria Arthrobacter sitriplex Arthro bac ter raria bilis Art liro bacter t it iiiesceiis Rhizobial bacteria Spiriilina platerisis Rtsariir~ii rnoniliforriis 1:irsariitin gib bosirrii Actinoniycctes Proinyxohacterium lolinsoirii hficrocoi~cirs freiiderireictiii Klocckera apicitlata Saccliaroniyces ellipsoideits etc. %I.Rosaccliarotri~ces bailii etc. Candida tropicalis
47,48 47 47 49 49 50 51 5 1 5 1 52 5 3 54 54 5 5 , 5 6 51 58 59 6 0 61 6 2
atoms in pyridoxal biosynthesized by E. coli (B iiiutant WG2) originate from glycerol (19-23). Nicotinic acid is believed t o be the precursor o f pyridoxine from a feeding study of a pyridoxine-less mutant o f Aspcrgilhis tiidirluns (24).
The yeast Rhodofonila glufitzis is able t o 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 f u n p s Penicillirim digitarum ( 3 2 ) , and cotton seeds Gossy- piitni burhadense ( 3 3 ) . 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 o f 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 AH3 CH 2
kH3 I I -0,CCWCH , C H z ~ CH 2CH2CHC0i
+ / AH
1 I CH,CH,CH2CH2CHCO; 1-6
AH3 AH3 I
-0,CCHCH I ?CH ,u CH,CH2CHCO;
kH + /
I I 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 k H 3 I % (CH2)4 +NH3 I
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).
8 T, D. Bailey, C. L. Goe, and E. F. V. Scriven
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 ( a s t o r 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 fhefonirariorl of 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). Tvpe N itzvolves thc coiircrsion of an unnatirral prccirrsor to an unnatural product. Examples of this type are provided by the con- version of 5-fluoronicotinic acid to either 5-fluoronicotine in N . fabaczim ( 8 3 ) 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
4-Picoline 109 108 Lutidines (only 2,6-) 109 108
3-Picoline - 108
2,4,6€ollidine - 110 2,3,6€ollidine 109
Meth ylethylpyridine(s) I 111 2-Methyl4 4sopropylpyridine 112 111 2,4-Dimethyl-S 4sopropylpyridine - 111
2-Vinylp yridine - 111
- - 2-Ethylpyridine 109
3-Ethylpyridine - 108
2-Pheny lp yridine - 108 3-Phenylpyridine 113 108
3-Vinylp yridine - 108 3-Propenylpyridine 113 3-Form ylpyridine 113 108 2-Acetylp yridine 113
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
-
- 3-Acet ylpyridine 108 11 1
-
-
-
Methylcyanopyridine(s) - 111
Dimethylcyanopyridine(s) - 111 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 deter- mination 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 Ana hasine Anata binc Anatalline (I-IS) 2,2'-Bipyridyl N'Carbomethoxyanabasinc N'Carbometlioxynornicotine Cotininc 2',3'-Dehydronicotine Dihydromctanicotine Dihydronicotyrine (N-mcthylmyosminc) N'-Formylnornicotinc N'-Hexanoylnornico tine Isonicoteinc (2,3'-bipyridyl) Mctanicotinc N'-Mcth ylanahasinc N'-Mcthyhnatabine 5-Mcthyl-2,3'-hipyridyl N-Methylnicotonc Myosminc (1-16) Nico t cllinc Nicotine Nicotyrinc N'-Nitrosonicotinc Nornico tine Nor nicot yrinc N'Octanoylnornicotine Osynicotinc (nicotinc .&'+side) 1.3,6,6-Tetraniethyl-S .6,7.8-tetratiydroisoqitinolin-
3,6,6-Trimcthy1-5,64ihydro-711-pyrindan-7-onc (1-1 1) 9+nc (1-10)
117 108 108 I 1 8 - - -
108 - - -
117 1 2
108 108 122 116 117 123 123 125 108 108 126 108 108
1 2 108
6 9 69
- 108 108
119 120 120 108 108 108 116
-
- -
108 108 119 - -
124 123
108 108 126 108 108
127
-
-
- -
1-16
Pyridines f rom Natural Sources 1 1
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 cot ton 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 deter- mination 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 t o pyridine Table 1-6.
Indicaine and boschniakine were thought originally t o differ in stereochemistry a t C-7 but have now been shown to be identical (189). The confusion arose because of t h e formation o f 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 t h e extraction of the trunk bark of C. corniculafa with ammonia (198).
Gentianine is now known to be a n artifact and has been attributed t o 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
1-27
OMe I
M e fico*H 1-28
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)
Noractinidine (1-31)
Valerianine (1-32) Tecostidinc (1-33) Indicaine (1-34) (boschniakine)
Plan tagonine (1-35)
Venoterpine (1-36) (RW47) Unnamed (1-37) Cantleyine (1-38)
Pedicularidine (1-39) Pedicularine (1-40) Pediculine (1-4 1 )" Yediculidine (1-42) Pediculinine (1-43)
Actiriidia polygama A. argirta Tcconia staris Pediciilaris rtiacrocliila Valeriaria officirialis Teconia statis Pedicularis algae Tecortia stans Bosclttiiaka rossica Platitago iridica P. psylliitrti Pedicularis olgae Verrbasciini songaricutn Pedicularis niacrochila A l s t o ti ia vetienaia Raii wolfia wrticillata Jasminuni sp. NGF29929 Catitlq-a cortiicitlata Lnsiarithcra austrocaledoriica Pediciilaris olgae P. olgae P. olgae P. oIKac P. dgae
- 7.2"
+ 3.0
- 10.5 - 4.0
4- 21.02
+ 30.8
+ 27.0"
- 34O -40 t 2
- 15.3 + 6 1 5
178-180 181 182 183 184 185,186 187 182 189 190 191 192 193 183 194,19S 196 197 198 199 200 201 207, 20 3 204
011 /
1-30 R = Me 1-36 K = tl 1-31 K = H 1-37 H = C'0 :Me 1-32 K ('H:OMt. 1-33 K 7: ('H:OH 1-34 R ('HO 1-3s K - "O:tl .-.'Y5)
1-38
1-39 K =CHO 1-40 H = C 0 2 t i
aTI~c proposcd structure 1-4 I appcars unlikely.
