FUROPYRANS and FUROPYRONES

1967

INTERSCIENCE PUBLISHERS

a division of John Wiley & Sons

London - New York - Sydney

FUROPYRANS AND FUROPYRONES

TSa is tlrc twenty-thiM &me. in the a e r h

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

T H E CHEMISTRY OF HETEROCYCLIC COMPOUNDS A SERIES O F MONOBRAPHB

ARNOLD WEISSBERGER, Editor

FUROPYRANS and FUROPYRONES

1967

INTERSCIENCE PUBLISHERS

a division of John Wiley & Sons

London - New York - Sydney

Copyright @ 1967 by John Wiles and Som, Ltd.

All Rights Reserved

Library of Congrese Catalog Card Number: 67-16130

The 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 prooedures, and for the physiological and industrid significance of heterocyclic compounds.

A field of such importance and intrinsic difficulty should be made L ~ S

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 8ubdiViaiona 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 &uthors.

Research I.abomtories Eaatmn K&k Cmpany Rachim%w, New Ywk

ARNOLD WEISSBEWER

Preface

The furopyram, and -pyrones occupy a prominent position among the plant phenols, and comprise a body of organic substances of ex tm ordinary variety and interest. The use of certain planta 88 an aid in catching fish; the increasing use of derris products, including rotenone itself, aa insecticides; the recognition of the active principles of Kellah plant (Ammi visnaga L.) by Egyptians centuries ago, aa a home remedy against leucoderma, in relieving the pain of renal colic and uretral s p m s , and in facilitating the passing of uretral stones ; the production of antifungal compounds by host plants following the fungal infection, phytoalexins; and the isolation of metabolites from the mycelium of variant strains of mould, all present a rich field of scientific inquiry from which have come many interesting and important findings.

Them compounds occupy a close structural and chemical inter- relationship that appears to reflect a similarly close relationship in the processes by which they are formed in plants. The v&ed nomenclature was most confusing. It is not u n d to find

many names attached to each of the more widespread natural products, and two or three for each of the many plants. In general, the name given here is that apparently used most aften ; the u88 of trivial names has been adopted with the more complex ring systems in order to avoid unwieldy and cumbersome Sgstematic names. In all instances, however, alternative nomenclature and numbering have been indicated so that no confusion should result. The synonyms can usually be found in the Kowtetitution und Vorkommen den Orgcsnischen Pfkcnzenstoffe, compiled by W. Karrer, which also givea the important references to historical matters and details of isolation. A good source of analytical data is Moderns Hethoden der PJEanwmw&se, edited by K. P a c h and M. V. Traoey, and the Merck I d e a : is as convenient a source as any for references to the medical and clinical aapecta of many of the compounds to be dealt with. Finally, The Chemhty of FhuonoS Crnpound.9, edited by T. A. Geissman, Natumlly Owwring Oxygen Ring Cmppounda, compiled by F. M. Dew, the chapter on ‘Naturlich vorkommende Chromone’ by

vii

viii Preface

N. Schmid in F0rtsChritt-e der Chmde wganiwher Natur8k$e, edited by L. Zechmeister, and on ‘Compounds Containing Two Hetero-Oxygen Atoms in Different Rings ’ by W. B. WhaHey in €ZeterocycE%’c Conzpound~, edited by R. C. Eldefield, discuss not only chemical matters, but also a variety of related subjects of economic importance. Every effort has been made to include in the manuscript, papers

indexed by Amerhn ChmkaZ Abstracts, up to and including, 1964, and subsequent papers in the more important Journals up to Deoember 1965. The Chemkal Ab&wts reference is listed in addition to the primary reference for any article not consulted in the original. Steroid sapogenins (spiroshns), compounds, having a fused five-membered lactonic ring with a pyran nucleus, and those chmacterized by spiro rather than fused ring systems are outside the scope of this book.

It is an aim of t h i s contribution to bring together the knowledge of these compounds that hm 80 far been gained, iand to present a systematic survey and bibliography of the present position h m which further progress c&n be made. Present day studies on the eyntheeis, stereo- chemistry, physioiogical activity, and biosynthesis of furoppnes mntinue to add new information.

It is hoped that the arrangement and discussion of the closely related chases, included in the volume, will arouse greater inte& and impart a new viewpoint to the chemistry of the individual substanm.

Finally, I wish to acknowledge the underahding of my wife, Professor Dr. W. Asker, who not only suffered patiently all the problems of writing a book, but helped me to eolve so many of them, by proof- reading and indexing,

Department of C&m&trg Faculty of Science Cairo University

A. MUSTAFA

Contents

I. Fumpyrans and -pyronea . I. Naturally Occurring Furopyrms .

1. Plumericin . 2. Anhydrotetrahydroaucubigenin

II. Synthetic Furopyrans and -pyrones III. ReferenMs.

II. purocoumorina . I. Isolation . II. PhysicalPropertiRs . Iu. Nomenclature . IV. Naturally Occurring Furocoumarh

1. Structure and Chemicd Properties A. Angelicin . B. Psoralen . C. Bergapten . D. Bergaptol . E. Isobergapten. . F. Bergamuttin. . G. Xanthotoxin . H. Xanthotoxol . I. Isoimperetorin . J. Oxypeucedanin .

K. ostruthol . L. Imperstorin . M. Alloimperatorin . N. Herdenin . 0. Isopimpinellin . P. Phellopterin , Q. Byekangelicol , R. Byakangelicin . S. Pimpinellin . T. Sphondin . U. Halfordin and Isohalfordm V. Nodakenetin. w. Peucedanin . X. Athamantin . Y. Discophoridin . 2. Edultin .

ix 1*

. 1

. 2

. 2

. 9

. 11

. 13

. 14

. 15

. 32

. 36

. 35

. 35

. 36

. 38

. 41

. 44

. 44

. 46

. 46

. 52

. 52

. 52

. 6 3 . 56

. 66

. 66 , 56 . 68 . 69 . 61 . 61 . 62 . 62 . 66 . 09

1 . 70 * 72 . 73

X contents

kA.Peulustrin . BB. Columbiansdin and Columbisnin .

DD. Archangelin. EE. Ppwmmcin. F'F. 4,5',8-Trimethylpralen. . W. Affstoxh Bmd G. .

cc. Archangelicin

2. Configuretion - . 3. Biosynthesia .

dihydrofuranB. A. a@'-Hydroxypropyl)dihydrofurans and a-Lsopropenyl-

B. a-hpmpyl-fi-hydroxyfimms and Relations. C. SimpleFurans .

4. Phyaiologiwl Activity . V. References.

III. Furochromonari . I. Isolation . II. PhysicelPraperties .

III. Nomenclature . IV. Naturally Occurring Furochromonea .

1. ChemioalF'ropertiee . A.Khellin .

(1) synthesis of wrellin . (2) Synthesis of khellin analogs . (3) Reactions .

B. Visnagin. (1) synthesis of vismgin . (2) Syntheeis of visnagin analogs and related transforma-

tions . (3) Rerrctions .

c. Khellinol. D.Khellinin . E. Khellol . F. -01 . Q. Vieaanminol .

8. ColorReactiona . 3. Physiologicel Activity .

v. R0f-m.

IV.Fpraxanthoner . I. Naturallp Ocourn'slg Furoxmthones .

1.sterigmetacystin . 11. SynthetioFuroxanthonee .

ICII. Referenme.

v,Ehroflrvonsll , I. Iaol~tion . II. PhyaimlPropertiw ,

73 76 77 78 78 79 79 80 82

83 84 85 87 90

102 102 103 104 104 104 104 107 112 112 133 134

136 138 143 144 145 147 148 150 161 153

160 160 180 189 174

175 176 176

Contents

III. Naturdy Occurring Furo&svonee. . 1. chemw&l Pmpertiee

A. B;ersnjin . B. LanoeohtinB . c. Pongapin . D. Kenjone. . E. Pongaglabrone. , F.Atamwin. . (3. Gamatin. H. pinrrcltin.

IV. Synthetiohfbvones . 1. LineaE-type . 2. Angular-type .

v. Referencee.

xi

183 183 183 186 186 186 188 190 190 191 192 192 196 198

v I . F l l r o ~ ~ n o i a B . I. Introduction . Ix. Furoisoflavanonee .

A. Nepseudin . B. Neotenone .

2. SyntheticMoaoflamonm . A. AngularFuroisoflavonea .

1. Naturally Ocourring Furoisofiavenonea .

(1) Introduction of a furan nucleus into an hflavone

(2) Ethyl orthoformate method (VenkstsMunan) . skeleton (T&’s method) .

B. Ljnw h ( 3 ’ , 2ff-6,7)mfhvonea . In. CQum~oahromSns. .

1. Introduction . 2. Naturally Oacurring Coumaranoahromans .

A. Homopterocarpin . B. Pteroasrpin . c.&aOu . D. Pisatin. E. Neodulin . F.PhslPeollin .

Iv. cOUmSronOfl8VSn-4-0h . 1. Na.twalIy &curring Coumamnofiavan -4-01s

2. Synthetic l~-benzofuro(3,2-b)-l-benzopyran-ll-onee . 1. Naturally Occurring Coumaronocoumarins .

. A. Gyanomaolurin .

V,&-nocoumh . A. Coumestrol . B. WeddoIrtatone . C. Triioliol . D.Mediosgol . E. Psoralidin .

VI. 3-ArylfuroCO~~hS.

201 201 201 201 201 218 220 220

220 224 228 227 227 228 228 230 233 234 238 237 238 238 238 242 243 243 243 246 261 263 254 268

rii Contents

VII. Comnofurocoumsrins . IX. Physiologicd Activity .

V I E Furo( 3,2-0)-l-benzopynm-4-0n~.

x. References . MI. Chromanochromsnones (The Rotenoids) .

I. Introduction . 11. Nomenclature .

m. Rotenone . 1. Isolation . 2. Physicalhpertiee . 3. structure .

A. Dehydrorotenol . B. Roteno1 . A. Isomeric Carbony1 Derivatives of Rotenone B. Hydrogenation . C. Oxidation .

5. Synthesis . 6. Siemhemistry .

4. Immerizt~tion (The Isomtenones) . .

A. Optical Activity . B. Configuration .

7. Rotenolonee, RotenoIoIs, Isorotenolones, and Isorotenolola N. Sumatrol. v. Malaccol .

VI. Elliptone. .

Vm. Dolineone . IX. Pacbyxrhizone . X. References .

VII. Amoqhigenin .

Vm. Lese Common Furoppne Systems . I.Isog&llo~vin . Is. Enmein . III. Referenoes.

AuthorIndex . SubjectIndex .

259 261 262 266

272 272 272 277 277 277 278 283 289 290 292 292 293 295 300 300 301 305 309 312 314 318 321 322 324

328 328 330 335

337

357

CHAPTER I

Furopyrans and -pyrones

The furan ring is commonly found in plant products as furans ; a few are of fungal origin. Most of these compounds are terpenoids, whatever their source. The hydrofurans have rather complex structures; a few occur among the terpenes, and among the carotenoids. The lignans generally possess two fused tetrahydrofuran rings. Other hydrofurans are found in steroidal sapogenins, and yet others are found as complex alkaloids.

Whereas 8-methoxyfuran behaves 8s a true furan, 8-hydroxyfurans isomerize to butenolides (1) whose behavior is normally easily infer- preted solely in terms of lactone structures.1 3-Hydroxyfurans, which are in fact vinylogous lactones, show that their ketonic form (3) readily yield derivatives of the enolic forms, for example on acetylation, but the butenolides I and 2 resist even this type of conversion into true furam. Many examples among the terpenoids and the cardenolides carry the butenolide ring.

&though the parent pyran rings 4 and 5 am not known a t all, they give rise to a considerable number of important natural products. A we& defined group of dihydmpyrans forms a subdivision of the Rauwolfia alkaloids ; the plant a-pyrones include the cardadienolides whioh have a steroid nucleus attached to the 6-position in 6.

2 Chapter I

Fusion of the fwan ring and/or the benzofurano nucleus with the pyran and/or the pyrono ring is a common one in natural products and appem in many forms. Among the types of such compounds, which serve &B a guide to the chapters where they will be dealt with, are:

furopyrans and -pyrones furocoumarins furocbromones furoxanthones furoflavones and -flavanones the fmisoflavonoids the rotenoids lees common furopyran ring systems

Componnda having a f d five-membered lactone ring with a pyran nucleus, e.g. patulin, rubropunctstin, monascorubin, rotiorin, monaacin, and those characterized by spiro rtbther than fused ring systems, are outside the scope of this book.

Structural features of special interwt am displayed by plumericin, which is the sole representative of the fmpyran group known to occur naturally, and by anhydrotetrahydroaucubigenin which is not natural product in the rigorous sense, and may be considered as a furopyran. Synthesis of a few examples of furopyrms and -pyrones has been achieved (Table 1).

1. Naturally Occturring Furopyrrrns 1. Plum&

Plumericin (7), CIJXllOd, is a bactericide extracted from the roots of Ptwneriamdfi~aeandfrom theroots of Ptam&&avar. alba.s*4 The latter source also affords two related compounds, isopluericin (8) and &dihydroplumericin (9, R = CHs), together with ~-dihydroplumericinic acid (9, R = H), and fulvoplumierin (10).

Plumericin (7), on hydrogenation in ethanol in the presence of a Pd/B&04 oataly&, gave a-dihydroplumericin (ll), showing its sensi- tivity toward alkalis; chromic acid oxidation of 11 afforded acetic acid, propionic acid, and some butyric, but no succinic acid. Similar hydrogen- ation of isoplumericin (8) also gave 11, which was converted with bromine in methanol into bromomethoxydihydroplumericin (12).4 Hydrogena- tion of 7 in ethanol in the presence of Pd/C produced a-tetrahydro- plumericin (IS), again showing ita eensitivity to alkali; appreciable

TABLE 1

. F

mp

yra

ns end

-pym

nm

Y.p

. or

B.p

. S

olve

nt*

for

Rem

arks

((a)o;

Com

poun

d (f

orm

ula

) ("C)

Cry

stal

lizat

ion

U.V

. ap

ectn

un

mex

mp

(loge))

Rde

mm

ceu

A. N

atu

ral

Fu

nyl

yran

a

Pl-ic

in

(7)

h$

hl

&O

~ (8

)

~-D

ihyd

rop1

um€a

.icin

(9

) a-D

ihyd

mp

lum

eri

oin

(11)

a-

T&

&y

hp

ld

i (18)

a-Herahpdroplumezioin (

15)

@-T

&x&

@t+

m&

cin

(16)

fl-Hexahydmplumericin (1

7)

Bmmometboxy-a-dihydroplwnecioin (

12)

Brornomethoxy-a-tetrahJrdroplumericin (14)

Anhy&vtetr&ydroaumbigenin

(29)

B. &n#

?a&

Fur

vpym

na and -

pyri

mea

211.5-

200.6-

la161

147.5-149

115-115.6

86.5

-88.

5 88.5-89; 95

148-150

(deo

.)

120-122.6

00.6 212.5

(dec

.)

201.5(dec.)

191-192

+ 197.6

(CH

Cla

); 214-215(4.24)

4

+ 216.4 (

CH

Cls

); 214-216 (4.23)

+208.9 (

CH

Cla

); 239-240 (3.976)

4 +9

2 (C

EC

ls);

237 (4.02)

4 -29.1 (CHCla);

4

210 (1.90) en

d s

bso

rpti

on

+ 123.5

(CH

Cls

); 235 (4.018)

4

E + 19.6 (

CH

cla)

; 210 (1.96) a

d

We&

ultr

avio

let e

nd a

bsor

ptio

n

Ace

tate

(b.p. 90-100°);

4 4f

+287.5 (

CH

Cla

); 2

40 (3.976)

i 4

sbso

rpti

on

p-ni

trob

enzo

ate (

m.p

. 131-132')

P

TA

BL

E 1

(cola

tinued

)

M.p

. or

B.p

. S

olve

nt fo

r R

emar

ks ((ah;

Com

poun

d (f

orm

ula

) ("

C)

Crg

Stsl

Liz

atio

n U

.V. epedr~m max

mp

(lo

ge))

R

efet

enea

a

136

138

178-

180

180

184

187

136

126

150

132

188-

170

112

12

12

12

12

12

12

12

12

0

12

12

v

12

H

12

s

12

TA

BL

E 1 (

co

nh

ue

d)

Compound (f

orm

ule

) M

.p.

or J

3.p.

S

olve

nt'

for

Rem

arks

WD

; ("C)

Cry

atal

iimtio

n U

.V. spectnun m

ax mp (l

og€)

) R

efer

enm

a

b.p-

m 81

-82

b.p.

m 7

6-78

b.p.

2086

-88

b.p

.208

7-88

b.

p.zo

86-8

6 b.

p-20

97-9

9 b.

p.20

83-8

4

b.p

.eoa

8-90

n8.I

1.48

30; d

l'.'

1.11

3

ng

1.47

72, d

y 1.

069

n2 1

.466

5; d

y 1

.016

1.

4690

; d:'.'

1.

068

np'

1.48

20; d

Fa 1.0

38

np6 1

,460

2; d

p'

1.01

6 ng

A 1.4

650;

dy

0.99

0

14

14

14

14

14

14

14

14 i E il. x f

A, d

iox

m; B, e

thyl

alc

ohol

; c, ether; D, ethyl a

ceta

te; &

, m

eth

yl aloohol; F, methylene c

hlo

rid

e; o,

pen

tan

e; H

, to

luen

e; I,

wat

er.

m

Ql

6 Chepter I

0+--1 CHa

COOCHI I Go

C H O I

amounts of acetic acid and propionic acid resulted from chromic wid oxidation of 13 and auociaic acid was obtained on boiling with chromic- sulfuric acids mixture. Similar hydrogenation of 8 gave 12, which

FWP- and -pyr~nee 7

upon bromination in methanol yielded bromomethoxy-a-tetrahydro- plumericin (14).

I

09 x' I CHs

0J-+---1 CHa

Hydrogenation of 7 with Rh/C in ethanol gave cr-hexahydroplumericin (15); chromic acid oxidation of the latter gave acetic, propionic, and succinic acids. Under the same conditions, 15 waxj also obtained by hydrogenation of 11 andlor 18.

Hydrogemtion of p-dihydroplumericin (9, R=CHs) yielded /3- tetrahyhplumericin (X6), which on further hydrogenation produced 8-hexahydropIumericin (17, R =CHs). The latter waa hydrolyzed to g-hexahyhphmericinic acid (17, R = H) ; on the other hand, hydrolysis of 15 led to 17 (R=H).

Treatment of 17 (R = CH,) with aluminum bromide in benzene erected ring A opening to yield 18 (R =C!H20H). The latter gave an acetate (18, R = CH,OAc); on oxidation it yielded the acid (18, R = COOH), whioh underwent thermal decarboxylation to yield 18 (R = H). Hydrogenation of the latter compound in presence of palladium black ikmished 19 (R-H). Similar treatment of 17 with aIuminium bromide in benzene gave 20 (R=CH,OH) which underwent oxidation to 20 (R=COOH), and the latter decarboxylated to 20 (R =H).

Refluxing a-hexahydroplumericin (15) with methanolia hydrogen chloride gave 21 (R = H), which waa converted by the u8wI method into 21 (R = Ao), and on hydrogenation in the presence of Rh/C gave 22 (R = a).

8 chapter I

( f l ) tzw

On oxidizing 21 (R = H) with chromic oxide in pyridine, 23 was obtained, which upon catalytic hydrogenation gave 24. In this dilactone (24) sodium methoxide induced two j3-eliminations which, after hydrolysis of

$ocHa $:OCHa

CHzCHa 0 CHaCRs 0 (28) (24)

(25) (26)

the ester functions, afforded the tribaaic acid (%), identical with degrada- tion product of plumieride (26). Taken with evidence derived h m ultra- violet, infrared, and nuclear magnetic resonance spectra, these facts show that plumericin has structure 7. The difference in reactivity between

Furopyrenrr and -pyrones 9

exocyclic and endocyolic unsaturation in 8 butenolide accounted for the fact that, whereas hydrogenation of plumieride (26) first afFected the oyalopentene link, leaving an unsaturated lactone, hydrogenation of 7 afforded the saturated lactone (11) which retained the cyclopentene system. Lactone (Il), a-dihydroplumericin, is epimeric with the naturally occurring p-compound (9); the difference involves only the stereochemistry at the starred position. This relation can be demon- strated by the fact (see above} that the /?-dihydro-9 affords the p- hexahydro derivative (17) which is isomeric with the a-derivative (1s) but is transformed into it when warmed with alkali and then reesbrified with diazomethane. The nucleax magnetic resonance spectrum is in accord with the suggested structureYs*

2. Anhydrobirahydroauoubigenin

Anhydrotetrahydroaucubigenin, C9HI4O9, is the dehydrated product of tetrahydroaucubigenin. The latter is obtained by hydrogenation of aucubin hexaacetate in nearly neutral medium, followed by hydrolysis to the aglyoone.e Fujise and coworker^,^*^ on the basis of their results, showed that aucubin, obtained from the seeds of A d a japonim L., and in at least seventy-five plants according to s ~ r v e y s , ~ could be represented by a structure of type 27, tetrahydroaucubigenin can be given structure 28, and anhydrohtrahydroaucubigenin 28. lo

OH OH OH

Structure 29 is consistent both with the inabiIity of the anhydro compound to react with triphenylmethyl chloride, and with its oxidation to a ketone having v,,, 1742 cm-l as do authentic cyclopentanones. Though no carbonyl bands appear in the spectnun of the anhydro

10 chspter I

-0

(W

l-.

compound, it doea remt with !2,4-dinitrophenylhydrazine under forced oonditions. The derivative is not a normal hydrazone, but ~ 0 8 0 m b h those obtained from hydroxy ketones that form ketds easiIy; thus anhydrotetrahydroaucubigenin may be regarded as having a ketal or an acetal grouping aa in 29. The anhydro compound has the appropriate characteristic bands of the OCHO sptem and thus the metal grouping ia preferred.

Pyrolpis of the methyl xanthate from 5i9, followed by hydrogenation of the o l e h produced by removal of the hydroxyl group, gives anhydro- tetrahydrodeoxyaucubigenin ($0) which still behaves aa an acetal.

Furopyrans end -pyronm 11

Oxidation of ipo with chromic acid gives a tricarboxylic acid,

Further degradation and nuclesr magnetic resonance spectral deter- minations permitted a definite choice of the structure 27 for aucubin.'* Treatment of aucubin hexaacetate (82) with bromine in aqueous tetrahydrofuran gave the bromohydroxy derivative (W), which when allowed to react with chromio oxide in acetic acid followed by reduction of the resultant a-bromolactone (34, R-Br), gave 84 (R=H)." Catalytic hydrogenation of the oily substance 85, obtained via action of methanoIic hydrogen chloride followed by alkaline hydrolysis, led to the formation of the lactone 86. The latter was also obtained from aucubin (27) via $7 and tls (Eq. 1).

C&g(COOH)s, oft- 81.

XI. Synthetic Furopyrans and -pyrones Schulte and coworkers12 have prepared a number of 3-propargyl-4-

hydroxy-(6-R1-6-RZ-sububstituted)-2-pyrone derivatives (89) according to the method of Boltze and Heidenbluthls by condensation of propargyl- malonic acid &chloride with fklicarbonyl compounds, e.g. acetoacetic ester, benzoylacetic ester, acetylacetone, and benzoylacetone. On heating 99 with zinc carbonate at the melting point, ring closure took p h to give the corresponding 3,4-(2-methylfuro)-2-pyrone derivatives (40) (Eq. 2). By reacting 39 (R1=OCgH6, R2=CHs) with aromatic aldehydes in the presence of piperidine, the corresponding styryl derivatives (41) were obtained. With salicylaldehyde, 3,4-(2-methyl- furct)-6-ethoxycarbonyl-6- (2-coumaranyl)-2-pyone (42) was produced. le

(W (44)

The condensation of a number of vinyl ether heterocycles with vmious dienes htw been thought to yield most probably lY7-diox&- 4,7,SY9-tetrahydroindanes (&).lo 2,3-Dihydrofuran reacts with acrolein and with crotonaldehyde to give the adducts having probable structures 48 (R=R1=H) and 48, (R=H, R1=CH,), respectively. The same is true with 5-methy1-2,3-dihydrohn, which yields the adducts 43

12 Chapter I

00, H&rOOC ~ T c H ' H S C ~ O O C ~ ~ ~ ~ '

\ 0

(R = CHS, R' = H) and 48, (R = Rf = CHs), respectively. Catalytic hydrogenation of these adducts in the presence of Raney nickel effects the formation of the corresponding l,?-hexahydroindanes (44) (Eq. 3).

RCH=CH

(42) (41)

R1

- R z.

(48) (W

Worthy of mention is the fact that 45 hias been isolated together with 48 (R=CH,, R1 =H); the formation of the former is attributed to the poaaible isomeriaztion of 5-methyl-2,3-dihydrofuran to methylene-2- tetrahydrofuran, which reacts with acrolein to give 45 (Eq. 4).

(45)

1,7-Dioxahexahydroindanes (44, R = R1 = H) and (44, R = R1 = CH,) are readily converted into the dialdehyde (46) and the monoaldehyde (47),14 respectively, by the action of dilute hydrochloric acid.

CHO I

HOCH&H~CHCHZC€K~CH~OH YHO

OHCCHgCHaCH \ CHnCHsOH

(46) (47)

1,5-Dioxahexehydroindane (50) is readily obtaJned by catalytic hydrogenation of p-furylacrolein (as), together with 3-tetrahydrofuryl- prop&n-l-oI (49).lS Treatment of 50 with hydrobromic acid effected pyran-ring opening to yield a dibromo compound, presumably having structure (51). The latter compound recyclizes to 50 via the action of a zinc-copper couple. Hydrogenation of 50 over nickel produced 49 (Eq. 5).

h p y r a a s and -ppnea 13

The fact that y-furylpropionaldehyde (52) gave 50 under the aame conditions which brought about transformation of 48 to 50 justses the conclusion that 50 ie formed primarily via 52.

III. References

1. W. Hiickel, Theore&& P&a&pk3s of C h b k g , Elsevier, Amatedarn,

2. J. E. Little and D. B. Jahhne, A&. Biochem. Bbphy8.. 30, 446 (1961);

3. 0. Albme-Sohbberg aad R. Schmid, Chi& (Awau), 14,127, (1960). 4. G. Albere-schLinberg aad H. Schmid, Helw. C h . Acta, 44,1447 (1961). 6. H. Schmid and W. Bencze, Hdw. China. Ada, 36.206,1468 (1953). 6. I?. Kawr snd H. Schmid, Hdv. C h h . A&, 29,626 (1946). 7. S. Fujise, H. Ude, T. khiJ.mwz~, H. O h and A. Fujino, C h . Id. (London), 289.984 (1960); C h m . Ab&., 54,2354 (1960).

8. S. Fujise, J . C h . Soo. Japan, Pure C h . S&., 74,726 (1963); Y. I d , Y. Hotta, T. Kubota, S. Fujise, T. Iahibwa and H. Uda, J . Ohem. Soc. Jaz~pn,

1966.

C k . A M . , 45,6136 (1951).

PUT6 c%ZB, 8&., 76, 77 (1956). 9. R. P& and M. Chmlot, A m . P k m . Fmm., 13,648 (1956). 10. W.Haegla,F.ICsplsn8ndH.Schmid,Te~Le#crs,(a) , llO(l961). 11. M. W. Wendt, W. Haegle, E. Simonitmh end H. Schmid, Helv. Chim. Ada,

12. K. E. Schulte, J. Rebh end K. H. Kmder, Arch. Pharrm., 295,801 (1962);

13. K. H. Boltze and K. Heidenbhth, C h . Ber., 91,2489 (1968). 14. R. Paul and S. Tchelitcheff, BUM. 800. C h . Frano~, 672 (1964); C h . Abetr.,

15. H. E. Burdick end H. Adkin~, J . Am. O h . 800.. 68, 438 (1934).

43, 1440 (1960).

C h . A M . , S, 11337 (1963).

49,9638 (1956).

CHAPTER II

Purocoumarhs

hocoumarins, discovered in plants, were for many years the only ones (Table 1) known, until synthetic methods were combined to produce virtually any furocoumarin desired. The natural product serves a power- ful purpose in directing further synthetic effect and on occmion with- standa the competition of its synthetic congeners, e.g. coumestrol and

TABLE 1& Naturslly Occurring Fumcoumarina

(=ID No. Name (8ynonyx-m) (Formula) (Solvent> O C ) References

1 2 3 4 6 6 7 8 B

10 11 12 13 14 16 16 17 18 I9 20 21 22 23 24 25 26 27

Angelioin (Isopsoralen) (1) Peorelen (Fiowin) ( W) Bergsptan (Herwlin, Majudin) (g6) Bergaptol (al) Ieobergaptm (44) Bergamottin (Bergaptin) (46) Xaathotorin (Ammoidin) (47) Xsnthotoxol (M) Ieoimperstoriu (70) o w - . (71) (+)-Oxgpenoedanin (Prangolstin) (71) Oatruth01 (76) Imperatorin (Marmeloah, Ammidin) (76)

Heraddn (PrSngenin) (78) Ieopimpinek (82) PhellopteFin (86) 8-H~sy-6.metaorjrpeoraIen (87) ( f )-B~skangeIicol(8@)

Pimpinellin (94)

Alloimperatorin (Prmgenidin) (77)

(&))-Byakengelioin (91)

Sphondin (95) Halfordin (108) Ieohalfordin (104a or 104b)

Nodakenia (11Ob) (-)-Nodakenetin (110~)

(+)-Malm& (1lOa)

61, 62, 64 6446,190

76-77,86,93,215 85,SQ, 139 94-95 97, 101,216 116,126-126 118,217

123s-124 94 115,127,183,219 128,130,280

91 77, 133,221 222 133, 135,221 6, 133,138 91 90,139 141 141 146-148,143, 161 140,148 144,181,223

77-78.214

i is-12a~, 218

131-132

hcoumar ins 16

TABLE la (&.n&)

4D) No. Name (Synonyms) (Formula) Solven&L 00) References

28 29 30 31 32 33 34 96 30 87 38 39 40 41 42

~

Marmesinin (Amejin) (110b) PEWdUAUl * (Oreowlone methyl ether) (119) Athamnutin (187) Omeelone (Kvanin) (I-) Disaophoridin (I#) Edultin (1&7) oohrmbienidin ( l a )

oolumbianetin (141) Admnpbim (146) Arcbngdin (14s) 8-Gerenyloxgpeoralen (119b) Peuhmtrin (1Ma) Iaopeuluutrin (14eC) ColumWdinoxide (IUb)

columbianin (146)

- 00(~,26) - + 90(~,22)

+ 20.4(cBm) + 41.6@,10.7) +26.6(~,27) + 118(~,23) + 20(~,27) + 112.7(~,26)

-

- +278(~,26) + 273(~,26) + 306(~,28)

146,162 121,163,224 166,168, 167, 226 139.166,167 169 100 161 101 101 167 124,106 21 123b 1230 123c

A, chloroform; 8, &ran; a, ethyl almhol; D, methyl alcohol; E, pyridine; r, wafer.

psoralen. hocoumarins are found especially in the Umbelliferae, Rutaceae, Leguminosae families and also in other families of lesser importance.

Spgth,' Dean,z* a and Reppel* have written comprehensive reviews about the chemistry of the naturally occurring coumarins. Mention should also be made of Karrer's6 review in 1968 in which he lists the h o - coum&liDs that had been isolated from natural sources up to the date of publioation.

The selection of the proper plant parts is of great importance, for the furocoumarin may be present in one part and completely absent or present in minor percentage in another; for example phellopterin is present in the f t u i t ~ and not the seeds of Phdbpterw lettoruth Benths (Table 2).

I. Isolation

For the moat part, isolation procedures depend upon successive extraction with solvents of increasing polarity. Thus, petroleum ether is hquently used rt8 the initial solvent and has the advantage that most of the oxygenated coumarinic materials are not particularly soluble in it. Petroleum ether may be omitted, and often is, and direct ether extraction employed. This, followed by the use of methanol or ethanol as the solvent often results in the fortuitous crystallization of coumarhic glycosides. Advantage may be taken of the alkali solubility and acid insolubility of

TABLE

lb.

Nat

ural

md

Syn

tJ~e

tio

ha

o-

8ub

etit

uen

td

(“C

) cr

yete

lliee

tion

’ U

.V. S

pect

rum

(L

x

(mp

) (lo

g€)

) R

efer

ence

s Y

.p.

hlv

en

t for

A. P

som

len

Typ

e

Un

sub

stit

uce

d ( + 4

- + f

)

162,

167,

171

3, =

246(

4.37

), 2

90{4

.03)

, 328

(3.0

8)

32,6

6,69

, 14

0,30

6,

317

&M

e 18

8.6

I)

2444

.39)

. 28

9(3.

99),

329

(3.8

5)

32,3

17

6‘-C

Hbf

es (enhydronodslrenetin,

135-

136,

0

, J

211(

3.89

), 2

61(4

.60)

, 294

(4.0

6), 3

34(3

.84)

14

4, 1

46,

.o

4-P

h

178-

179

I)

225(

4.43

), 2

48(4

.41)

, 298

(4.0

6). 3

3113

.83)

32

, 317

4,4’

-Di-

Me

( f f +

) 22

0,22

2 a

71,3

18

4,6’

-Di-

Me

+ + +

) 16

2.16

B, 1

71

H

245(

4.28

), 2

90(3

.82)

, 340

(3.6

8)

67,

73. 7

6 8,

6’-D

i-Me

176

S

250(

4.39

), 3

00(4

.12)

, 335

(3.8

3)

67

3-E

t.4-

Me

179-

180

g

2464

4.42

). 29

0(4.

06),

329

(3.9

9)

32,7

0 8-

n-P

r,4-

Me

1oQ

-101

a

244(

4.30

), 2

9q4.

04).

328

(3.8

3)

32

3-M

es4-

Ph

16

0 I

225(

4.36

6), 2

47(4

.38)

, 296

(4.0

6),

32

3-E

ts4-

Ph

17

8 H

226(

4.28

), 2

47(4

.32)

, 296

(3.9

0), 3

28(3

.84)

32

4-

MeD

4’-E

t 17

7 -

4-M

e94‘

-PC

17

6 -

4-M

e,4’

-Bu

168

-

4-M

eB4’

-Ph

(-)

186

a 22

4( --

}, 2

50( - ), 2

98( -

),

325 id

=.(

-)

72

8 4‘

-Ah(

+ + + )

16

7 H

71

z 3,

4-D

i-M

e 23

5-23

8 H

248(

4.38

), 2

90(4

.02)

. aZ

iI(3

.96)

32

.70

t4 de

oxyo

reos

elon

e)

138-

139

147,

162

3-Is

o-P

r, 4

-Me

146-

147

3

246(

3.59

), 2

90(3

.96)

, 329

(3.9

4)

az, ‘

10

328(

3.92

]

319

320

a19