E h rodd rodds chemistry of carbon compounds volume 4 six membered heterocyclic compounds with a single nitrogen atom in the ring (rodds chemistry of carbon compounds 2nd edition) (1987)

Reader Emeritus, Department of Chemistry, Queen Mary College, University of London, Great Britain Supplement to VOLUME IV HETEROCYCLIC COMPOUNDS Part G: Six-Membered Heterocyclic Compou

R O D D ' S C H E M I S T R Y O F C A R B O N

C O M P O U N D S

,A,

Reader Emeritus, Department of Chemistry, Queen Mary College, University of London, Great Britain

Supplement to

VOLUME IV HETEROCYCLIC COMPOUNDS

Part G:

Six-Membered Heterocyclic Compounds with a Single Nitrogen Atom

in the Ring to which are Fused Two or More Carbocyclic Ring Systems, and Six-Membered Ring Compounds where the Hetero-Atom is Phosphorus, Arsenic, Antimony or Bismuth Alkaloids Containing a

Six-Membered Heterocyclic Ring System

ELSEVIER Amsterdam - Oxford - New York - Tokyo 1987

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CONTRIBUTORS TO THIS VOLUME Kenneth W Bentley, M.A., D.Sc., D.Phil., F.R.S.E Department of Chemistry, Loughborough University, Loughborough, Leicestershire LEII 3TU

John D Hepworth, B.Sc., Ph.D., C.Chem., F.R.S.C

Department of Chemistry, Lancashire Polytechnic,

Preston, Lancashire, PRI 2TO,

Robert Livingstone, B.Sc., Ph.D., F.R.S.C

Department of Pure and Applied Chemistry, The Polytechnic,

Queensgate, Huddersfield, HDI 3DH

A Reginald Pinder, D.Sc., Ph.D., D.Phil Department of Chemistry, The University, Clemson, South Carolina, U.S.A

Malcolm Sainsbury, D.Sc., Ph.D., C.Chem., F.R.S.C Department of Chemistry, The University,

P R E F A C E T O S U P P L E M E N T IVG

T h e p u b l i c a t i o n of this v o l u m e c o n t i n u e s the s u p p l e m e n -

t a t i o n of the s e c o n d e d i t i o n of R o d d ' s C h e m i s t r y of C a r b o n

C o m p o u n d s , t h u s k e e p i n g this m a j o r w o r k of r e f e r e n c e u p - t o - date In this v o l u m e C h a p t e r s 28 to 35 of the s e c o n d e d i t i o n are b r o u g h t u p - t o - d a t e and the s u p p l e m e n t c o v e r s the a d v a n c e s

d i a g r a m s I a l s o w i s h to t h a n k the s t a f f at E l s e v i e r for all

the h e l p t h e y h a v e g i v e n me and for s e e i n g the t r a n s f o r m a t i o n

of a u t h o r s ' m a n u s c r i p t s to p u b l i s h e d work

CONTENTS

V O L U M E IV G

Heterocyclic Compounds: Six-Membered Heterocyclic Compounds with a Single Nitrogen Atom

in the Ring to which are Fused Two or More Carbocyclic Ring Systems, and Six-Membered Ring C o m p o u n d s where the Hetero-Atom is Phosphorus, Arsenic, A n t i m o n y or Bismuth Alkaloids Containing a Six-Membered Heterocyclic Ring System

Preface Vll Official publications; Scientific journals and periodicals XIII List of c o m m o n abbreviations and symbols used XIV

Chapter 28 Polycyclic Compounds Comprising a Pyridine and Two or More

Carbocyclic Rings

by J.D H E P W O R T H

1 Acridine and its derivatives

(i) Acridines, l - - (ii) 9,9'-Biacridines, 12 m (iii) Reduced acridines,

14 - - (iv) Acridones, 20 - -

2 Phenanthridine and its derivatives

(i) Phenanthridines, 31 m (ii) P h e n a n t h r i d i n i u m salts, 35 m (iii)

Reduced phenanthridines, 38 m (iv) Phenanthridones, 4 0 -

3 Benzoquinolines

(i) Benzo[f]quinolines, 4 8 ~ (ii) Benzo[g]quinolines, 5 3 - (iii)

Benzo[h ]quinolines, 58 - - (iv) Benzo[d,e]quinolines, 65 - -

4 Benzoisoquinolines

(i) Benzo[f]isoquinolines, 7 0 - (ii) Benzo[g]isoquinolines, 7 4 - (iii)

Benzo[h ]isoquinolines, 76 - - (iv) Benzo[d,e]isoquinolines, 78 - -

5 Benzacridines

(i) Benz[a]acridines, 81 - - ( i i ) Benz[b]acridines, 8 3 - (iii)

Dibenzo[c,h ]acridines, 91 m

6 Benzophenanthridines

(i) Benzo[c]phenanthridines, 9 4 - (ii) Benzo[a]phenanthridines and

benzo[b]phenanthridines, 9 9 - - (iii) Benzo[i]phenanthridines, 100

(iv) Benzo[k]phenanthridines, 101 - -

7 Naphthoquinolines and naphthoisoquinolines

(i) Naphtho[2,3-g]quinolines, 103 - - (ii) Naphtho[2,l-f]quinolines, 103

- - (iii) Naphtho[l,2-h]quinolines, 106 - - (iv) Naphtho[2,1-f]-

isoquinoline, 106m (v) Naphtho[l,2-h]isoquinolines, 108 - - (vi)

Naphtho[2,3-h ]isoquinolines, 108 - - (vii) Naphtho[ 1,8-fg]quinolines,

Chapter 29 Six-Membered Heterocycles Containing Phosphorus, Arsenic,

Antimony, and Bismuth as a Single Heteroatom

by R L I V I N G S T O N E

I n t r o d u c t i o n

1 P h o s p h o r u s c o m p o u n d s

(a) P h o s p h o r i n a n e ( p h o s p h a c y c l o h e x a n e , h e x a h y d r o p h o s p h a b e n z e n e ) a n d its d e r i v a t i v e s

(i) P h o s p h o r i n a n e s , 111 m (ii) P h o s p h o r i n a n o n e s , 116 m (iii) P h o s p h o r i n a n o l s , 1 1 9 m (b) D i h y d r o - a n d t e t r a h y d r o - p h o s p h o r i n s

(c) P h o s p h o r i n s , p h o s p h a b e n z e n e , p h o s p h i n i n e

(d) P h o s p h i n o l i n e s a n d d i b e n z o p h o s p h o r i n s

(i) Phosphinolines, p h o s p h a n a p h t h a l e n e s , b e n z o p h o s p h o r i n s , 135 ~ (ii) Dibenzo[b,e]phosphorins (9-phosphaanthracenes), 141 ~ (iii) Dibenzo- [ b , d ] p h o s p h o r i n s ( 9 - p h o s p h a p h e n a n t h r e n e ) , 144 ~ (iv) P h o s p h a p h e n a l e n e derivatives, 145 2 Arsenic c o m p o u n d s

(a) A r s a b e n z e n e (arsenin) a n d its d e r i v a t i v e s

(i) A r s a b e n z e n e s , 146 m (ii) D e r i v a t i v e s o f a r s a b e n z e n e possessing a functional group, 150 (b) A r s a n a p h t h a l e n e s ( b e n z o a r s e n i n s )

(c) D i b e n z o a r s e n i n s

(i) D i b e n z o [ b e ] a r s e n i n s ( a r s a a n t h r a c e n e s ) , 157 ~ (ii) D i b e n z o [ b d ] a r s e n i n , 160 (d) Miscellaneous heterocycles c o n t a i n i n g an a r s a b e n z e n e ring

3 A n t i m o n y c o m p o u n d s

(a) M o n o n u c l e a r c o m p o u n d s

(b) Fused ring c o m p o u n d s

4 B i s m u t h c o m p o u n d s

111 111 111 120 122 135 146 146 156 157 161 162 162 164 166 ~ 2 3 4 5 6 7 8 9 10 11 12 Chapter 30 Pyridine and Piperidine Alkaloids by M S A I N S B U R Y Alkaloids f r o m the Achillea a n d Piper g e n e r a

Miscellaneous N - a c y l p i p e r i d i n e alkaloids

Sedum alkaloids

T h e alkaloids o f Prosopis a n d Cassia species

Alkaloids o f t o b a c c o

Alkaloids f r o m p a p a y a

Nuphar alkaloids

Miscellaneous p i p e r i d i n e s a n d p y r i d i n e s f r o m plant sources

Fungal m e t a b o l i t e s

P i p e r i d i n e a n d p y r i d i n e bases f r o m insects

(a) A n t v e n o m s

(b) Bases f r o m bugs a n d beetles

T h e p u m i l o t o x i n s

P y r i d i n e s f r o m m a r i n e o r g a n i s m s

169

173

174

179

183

185

187

189

197

199

199

202

203

207

Chapter 31 The Quinoline Alkaloids

by M S A I N S B U R Y

1 K n o w n q u i n o l i n e s f r o m m i c r o - o r g a n i s m s a n d h i g h e r p l a n t s

2 N e w a l k a l o i d s

(a) S i m p l e q u i n o l i n e s a n d 4 - q u i n o l i n o n e s

(b) 2 - Q u i n o l i n o n e s

(c) N e w f u r o q u i n o l i n e a n d d i h y d r o f u r o q u i n o l i n e a l k a l o i d s

3 N o n - r u t a c e o u s m i s c e l l a n e o u s a l k a l o i d s

209 217 217 222 235 243 Chapter 32 The Acridine Alkaloids by M S A I N S B U R Y 1 N e w a l k a l o i d s

2 A c r o n y c i n e d i m e r s a n d t r i m e r s

247 257 Chapter 33 The Isoquinoline Alkaloids by K W B E N T L E Y 1 S i m p l e i s o q u i n o l i n e s , d i h y d r o - a n d t e t r a h y d r o i s o q u i n o l i n e s

2 B e n z y l i s o q u i n o l i n e s

3 B i s b e n z y l i s o q u i n o l i n e s

4 C u l a r i n e s

5 A p o r p h i n e s

6 P a v i n e s a n d i s o p a v i n e s

7 B e n z o p y r r o c o l i n e s

8 B e r b e r i n e s a n d t e t r a h y d r o b e r b e r i n e s

9 A z a b e r b e r i n e s

10 S e c o b e r b e r i n e s

11 P r o t o p i n e s

12 P h t h a l i d e i s o q u i n o l i n e s

13 S p i r o b e n z y l i s o q u i n o l i n e s

14 I n d a n o b e n z a z e p i n e s

15 R h o e a d i n e s

16 O t h e r m o d i f i e d b e r b e r i n e s

17 B e n z o p h e n a n t h r i d i n e s

18 I p e c a c u a n h a a l k a l o i d s

19 P h e n y l e t h y l i s o q u i n o l i n e s

20 C o l c h i c i n e a n d its a n a l o g u e s

259 265 271 280 283 295 297 298 306 307 311 313 318 321 326 328 332 340 344 345 Chapter 34 Diterpenoid Alkaloids by A.R P I N D E R I n t r o d u c t i o n

X - r a y d i f f r a c t i o n a n a l y s i s

M a s s s p e c t r o m e t r y

N m r s p e c t r o s c o p y

(a) P r o t o n m a g n e t i c r e s o n a n c e s p e c t r o s c o p y

(b) C a r b o n - I 3 m a g n e t i c r e s o n a n c e s p e c t r o s c o p y

349

350

353

356

356

357

Chapter 35 Steroidal Alkaloids

by A R P I N D E R

I n t r o d u c t i o n

1 Apocynaceae a l k a l o i d s

(a) 3 - A m i n o s t e r o i d s

(b) 2 0 - A m i n o s t e r o i d s

(c) 3 , 2 0 - D i a m i n o s t e r o i d s

(d) 3 - A m i n o c o n a n i n e s ( c o n e s s a n e s )

(e) M i s c e l l a n e o u s a l k a l o i d s

2 Salamandra a l k a l o i d s

3 Buxus a l k a l o i d s

4 Pachysandra a l k a l o i d s

5 Solanum a l k a l o i d s

(a) S p i r o s o l a n e a l k a l o i d s

(b) A l k a l o i d s r e l a t e d to 2 0 - p i p e r i d y l - 5 a - p r e g n a n e

(c) A l k a l o i d s r e l a t e d to 2 2 - p y r r o l i d y l - 5 c ~ - p r e g n a n e

(d) A l k a l o i d s c o n t a i n i n g a n i n d o l i z i d i n e u n i t

(e) M i s c e l l a n e o u s a l k a l o i d s

6 Veratrum a n d Fritillaria a l k a l o i d s

(a) P i p e r i d y l p r e g n a n e a n d i n d o l i z i d i n e a l k a l o i d s

(b) C - N o r - D - h o m o s t e r o i d a l a l k a l o i d s

(i) A l k a m i n e s , 4 1 5 m (ii) E s t e r - a l k a l o i d s , 4 1 9 7 Asclepiadaceae a l k a l o i d s

8 M i s c e l l a n e o u s s t e r o i d a l a l k a l o i d s

9 B i o s y n t h e s i s o f s t e r o i d a l a l k a l o i d s

393

394

3 9 4

395

396

397

399

3 9 9

4 0 2

4 0 5

4 0 6

4 0 6

4 0 8

4 0 9

411

4 1 2

4 1 3

4 1 3

4 1 5

4 2 0

421

4 2 3

I n d e x 4 2 9

LIST OF COMMON ABBREVIATIONS

Bohr magneton

m i c r o g r a m (lO -6g) wavelength

frequency; wave n u m b e r magnetic, diamagnetic and p a r a m a g n e t i c

s u s c e p t i b i l i t i e s about

d e x t r o r o t a t o r y

l a e v o r o t a t o r y racemic negative charge positive charge

POLYCYCLIC COMPOUNDS COMPRISING A PYRIDINE AND TWO OR

MORE CARBOCYCLIC RINGS

J.D HEPWORTH

I Acridine and its derivatives

The widespread interest in acridine and its derivatives

T Brychcy, Mutat Res., 1979, 65, 261 and M.R Melamed

Horizons in Applied Biomedical Science' ed P.J Stoward and J.M Polak, Wiley, Chichester, 1981, p 237) and their occurrence in alkaloids (M.F Grundon, Nat Prod Rep., 1985, 2, 393)

(i) Acridines

formation of the C-9 - C-9a bond 7 to the heteroatom, although the exact nature and source of the immediate acridine precursor varies quite appreciably

obtained by the acid catalysed cyclisation of 2-

through protonation of the carbonyl group (J Rosevear and J.F.K Wilshire, Austral J Chem., 1981, 34, 839)

It is of interest to note that the presence of a meta- substituent in the arylamino moiety leads predominantly

to the 6-substituted 2-nitroacridine; only a small amount

substituents markedly decrease the rate of cyclisation in trifluoroacetic acid The effect of electron releasing groups is not as simple, for whilst a methyl group accelerates cyclisation, a dimethylamino or a methoxy group has a retarding effect It seems certain that

cyclisation the amine function is protonated and perhaps the methoxy group is similarly affected

NHAr

(i) ArNH2, DMSO, Et3N ; (ii) CF3COOH

Electron rich 2-arylaminoacetophenones cyclise readily on alumina (B Kasum and R.H Prager, Austral J Chem.,

1983, 36, 1455) and polyphosphoric ethyl ester effects the cyclodehydration of amides (I) to 9-aminoacridines (D Chambers and W.A Denny, J chem Soc Perkin I,

1986, 1055)

cyclisation in either sulphuric acid or methanolic hydrogen chloride to yield acridinequinones (3) (K Joos,

M Pardo and W Schafer, J chem Research (M), 1978,

Med Chem.-Chim Ther., 1981, 16, 24)

(3)

(4) by means of phosphorus oxychloride gives a mixture of 1- and 3-nitro-6,9-dichloroacridine The 1-isomer reacts selectively with pyridine to give the 9-pyridinium salt and hence separation of the isomers is possible (B Wysocka-Skrzela, K Biskup and A Ledochowski, Rocz

Chem., 1977, 51, 2411) The 9-chlorine atom in each isomer is exclusively displaced by phenol~ the resulting

9-phenoxy substituent is also labile For example reaction with mono-Boc-protected amines enables mono-, di- and tri- 9-acridyl derivatives (5, 6 and 7) of polyamines to be prepared (J.B Hansen and O Buchardt, Chem Comm., 1983, 162) and several 9-acridylamino acids have been obtained from l-nitro-9-phenoxyacridine (B Wysocka-Skrzela, G Weltrowska and A Ledochowski, Pol

affords a mixture of acridine and its 9,10-dihydro derivative, the composition of the product varying with the reaction temperature (M.G Hicks and G Jones, Chem Comm., 1983, 1277)

et al., J chem Soc Perkin I, 1978, 1211; 1981, 1132)

In an analogous manner, 2,(phenylamino)phenylcarbenes ( I 0 ) , generated in the vapour phase from the

adjacent ortho-position although giving only the dihydro derivative (W D Crow and H McNab, Austral J Chem.,

Diels-Alder reaction gives only a 4% yield of acridine when heated with aniline However, the other products include the diphenylmethane ( 1 2 ) and the Mannich base (13) both of which yield the tricyclic compound upon pyrolysis (J.L Asherson, O Bilgic and D.W Young, J chem Soc Perkin I, 1980, 522)

phenylbenzoxazine (14) break down to the azaxylylene (15)

alumina the reaction temperature is reduced from 650~ to

dehydrogenation increasing at temperatures over 650~ (I Hodgetts, S.J Noyce and R.C Storr, Tetrahedron Letters,

1984, 5435)

alkoxyalkyl lithium compounds and subsequent oxidation of the resul ring 9,10-dihydroacridine derivative ( 16) Various functional group interconversions are possible

containing substituents at the 9-position (L Hornet and

W Hallenbach, Phosphorus and Sulphur, 1984, 20, 173)

1986, 2762)

An alternative approach to 9-substituted acridinium salts and thence the corresponding acridines involves the

trifluoromerhanesulphonyloxy acridinium salts (17), which react readily with halides, pseudohalides such as azide and isothiocyanate, and sulphur nucleophiles (B Singer and G Maas, Z Naturforsch., 1984, 39b, 1399) The free base results on reaction with diisopropylethylamine 9,9'-Bisacridine ethers are also available by this methodology

(CF3SO2)2 O .

It is well known that acridine reacts with dienophiles to yield the unbridsed dihydroacridines rather than the bridged adduct s However, N-methyl- N -proparEyl-9- acridinecarboxamide ( 1 8 ) undergoes an intramolecular Diels-Alder reaction, providinE the first example of a

thermal [4+2] cycloaddition of an acridine (E Ciganek,

J org Chem., 1980, 4_55, 1497)

The IH- and 13C- nmr data for acridine are shown below

aminoacridines has shown that the electron density is

significantly higher at the sites adjacent to the amino substituent in agreement with the observed pattern of

electrophilic substitution (R F Martin and D.P Kelly,

Austral J Chem., 1979, 32, 2637) The IH- and 13C- nmr

1 3 5 9 1 2 9 5

1 3 o 3

128.3

125.5

13C chemical shifts (6) for acridine

Acridine coordinates with the shift reagent Eu(thd)3 although the binding constant is much smaller than for pyridine or quinoline even though the pK a values are quite similar (D.M Rackham, Spectros Letters, 1980, I_33, 517) "

The radicals arising by X-ray irradiation of a single crystal of acridine are formed by the addition of a

been deduced from the proton hyperfine tensors determined

extensively delocalised but there is a large spin density

on C-9 (V P Chacko, C.A McDowe11 and B.C Singh, Molecular Physics, 1979, 38, 321)

Various electronic indices have been obtained for the five aminoacridines, several aminobenzacridines and the corresponding salts from molecular orbital calculations and these have been related to the pK a values and

molecules (N.F Ellerton and D.O Jordan, Austral J Chem., 1978, 31, 1463)

(ii) 9, 9 '-Biacridines

The redox reaction of benzaldehyde and acridine in the presence of 3-benzylthiazolium salts gives high yields of 9,9 ', 10,10'-tetrahydro-9,9 '-biacridine, (biacridan) (19)

by electron transfer from the activated aldehyde (H Inoue and K Higashiura, Chem Comm., 1980, 5 4 9 )

H (19)

Oxidation of 10, I0 ' -dimethyl-9,9 ' -dihydro-9,9 ' -biacridine

methylacridanyl radical, (A.K Colter et al., Canad J Chem., 1985, 63, 445) This radical has been trapped by 2-methyl-2-nitrosopropane during the oxidation of 9,10- dihydro-10-methylacridine by 2,3-dicyano-l,4-benzoquinone (C.C Lai and A.K Colter, Chem Comm., 1980, 1115)

dimethyl-9,9'-biacridinium and two nitrate anions (20) affords 10,10 ' -dimethyl-9,9 ' -biacridylidene (21) on irradiation at the charge transfer band (> 510 nm) in deaerated solution However, irradiation at > 420 nm

k'l']diacridine ( 2 2 ) (K Moeda et al.j J chem Soc

proceeds via a cation radical to the acridylidene (21) (E Ahlberg, O Hammerich and V.D Parker, J Amer chem Soc., 1981, 103, 844)

conformation and are joined by an elongated C-C single bond of 1.58 ~ in 10,10'-dimethyl-9,9',10,10'-tetrahydro- 9,9'-biacridine (J Preuss, V Zanker and A Gieren, Acta Cryst., 1977, B33, 2317)

(iii) Reduced acridines

The reduction of acridine by water gas (CO + H20) synthesis gas (CO + H 2) or hydrogen alone is catalysed by transition metal carbonyls The reaction is highly regioselective, only the heterocyclic ring being hydrogenated (R.H Fish A.D Thormodsen and G.A Cremer,

3 Amer chem S o c 1 9 8 2 1 0 4 5234) A similar selectivity is not observed using (Ph3P)3RhC1 as catalyst and 1.2.3.4-tetrahydroacridine is formed in addition to the 9.10-dihy droacridine (R H F i s h J L Tan and A.D Thormodsen J org Chem.,1984 49 4500)

9.10-Dihydroacridines arise from the reaction of ketones with diarylamines at elevated temperatures and pressures Cyclic ketones lead to spirodihydroacridines (23) The 9-aryl spiro derivatives exist in a twisted boat

equatorial, as do the analogous symmetrical 9.9-diaryl dihydroacridines (W Tritschler et al., Bet 1984 117

Acridone is reduced by sodium in deuteriated butanol to

affords 9-deuterioacridine Acridinium salts are readily reduced by hydride ion donors, providing support for the

methylacridinium involves hydride ion transfer from the 9-position of the pseudo-base to the corresponding site

of the acridinium salt (J Clark and M Bakavoli, J chem S o c Perkin I, 1977, 1966) The kinetics of the

acridinium ions have been studied (J.W Bunting et al.,

(A.K Colter et al., Canad J Chem., 1984, 6 22, 1781)

The dehydration of formate to carbon dioxide by 10-

dehydrogenase (J.E.C Hutchins, D A Binder and M M

Kreevoy Tetrahedron, 1 9 8 6 , 42, 993 ) Whilst 10- methylacridinium iodide does not oxidise alcohols, the 3-

potassium t-butoxide, thereby behaving as an NAD + model oxidisin 8 agent (S Shinkai et al.j Chem Letters, 1980, 1235~ J org Chem., 1981, 46, 2333)

9,10-Dihydroacridine is efficiently ozidised to acridine under phase transfer conditions by oxygen (E Alneri,

G Bottaccio and V Carletti, Tetrahedron Letters, 1977,

2117)

5,10-Dihydroacridines are formed along with 5,6-diphenyl-

Gupta and R.C Storr, J chem S o c Perkin I, 1984,

2 8 2 7 )

A variation on the Pfitzinger acridine synthesis utilises the reaction between isatin, cyclohexanone and ammonia to

directly (J Bielavsky, Coll Czech chem Comm., 1977,

42, 2802) Hofmann desradation of the amides yields the partially reduced 9-aminoacridines

A number of 9-dimethylamino-l,2,3.4-tetrahydroacridines have been obtained by the reaction of methyl anthranilate

(A Osbirk and E B Pedersen, Acta Chem Scand., 1979,

acridone can be isolated and it seems likely that the dimethylamino function is introduced by the reaction of HMPT with the acridone at reflux temperature The use of

unsubstituted 9-aminoacridine, presumably v~a the nitrile (N.S Girgis and E.B Pedersen, Synthesis, 1985, 547)

1,2,3,4,5,6,7,8-Octahydroacridine results from the

cyclohexanone (R P Thummel and D.K Kohli, J org Chem., 1977, 42, 27 42)

1,2,3,4,5,6,7,8-Octahydroacridine is reduced by sodium in ethanol to the trans-syn-trans perhydroacridine (25), the

13

C- nmr spectrum of which has been fully assigned All three rings exist in the chair form in this rigid molecule (R.W Vierhapper and E Eliel, J org Chem.,

1975, 40, 2734; 1976, 41, 199)

(25)

Treatment of 3-aminocy cl ohex-2-enone ( 26; R=H) with

hexahydroacridine-I (2H), 8 (7H)-dione; the spiran (28), which is formed as a side-product, becomes the major

cyclising medium, and the exclusive product from dimedone

also readily converted into a mixture of acridinedione and spiran (I Chaaban, J.V Greenhill and P Akhtar, J chem Soc Perkin I, 1979, 1593)

The use of acetaldehyde and benzaldehyde in place of the formaldehyde leads to the 9-methyl and 9-phenyl acridinedione, respectively, whilst 3-methylamino- cyclohex-2-enone gives the 10-methyl derivative

as formic acid 7,8-Dihydroquinolin-5(6H)-ones are also formed ( J V Greenhill et al., J chem Research (M),

1981 0821)

piperidine acetate IIO~

A 1 3 C - n m r study of 9,10-dihydroacridines indicates that there is very little delocalisation of the nitrogen lone pair of electrons into the aromatic rings in the case of the 10-acetyl derivative (E Ragg et al., J chem Soc

tetrahydroacridine exists predominantly as the acridone, there is no evidence from 1 3 C - n m r spectral data for the presence of the tautomeric imine of 9-(N-methylamino)- 1,2,3,4-tetrahydroacridine (R Faure et al., J Chim- phys., 1981, 78, 527)

(iv) Acridones

The cyclodehydration of 2-arylaminobenzoic acids, which are readily available from anilines and 2-halobenzoic

formation of the bond X to the hereto-atom ( C - 9 - C-ga),

is the most versatile and important route to 9-acridones and it continues to attract attention

The effectiveness of a number of dehydrating agents for the cyclisation of some N-arylanthranilic acids has been

reagent of choice (J.M Kauffman and I.B Taraporewala,

J heterocyclic Chem., 1982, 19, 1557)

Whilst electron-withdrawing groups on the amine component

Acheson, Wiley-lnterscience, New York, 1973), anthranilic acid reacts quantitatively with 2-halobenzoic acids to

give N-(2-carboxyphenylamino)benzoic acid and thence 9,10-dihydro-9-oxoacridine-4-carboxylic acid

Of course, cyclisation of substituted examples of the intermediate benzoic acids can lead to two different products An investigation of the factors affecting this cyclisation recognised that the direction of ring closure could be explained in terms of electronic and steric

carbocation (G.M Stewart, G.W Rewcastle and W.A Denny

precursors having electron withdrawing substituents yield the acridone (29) in which the substituent and carboxyl

releasing substituents favour formation of the isomer

cyclodehydrating agent Steric effects dominate when the substituent is adjacent to the carboxyl group and often result in almost exclusive formation of (30)

Despite these guidelines, the problem of isomer formation remains This difficulty has been overcome by using a 2- haloisophthalic acid (31) as the acid component (G.W Rewcastle and W.A Denny, Synthesis, 1985, 217), although

aniline is used in the reaction

diphenyliodonium carboxylates The esters which result after cyclisation with polyphosphoric ethyl ester undergo ready alkaline hydrolysis to the acid (G.W Rewcastle and W.A Denny, Synthesis, 1985, 220)

When the synthesis of the appropriately substituted anthranilic acid cannot be achieved by the usual Jourdan-

(D Chambers and W.A Denny, J chem Soc Perkin I,

1986, 1055)

carboxyl can act as precursors of acridones, though not

examples include the thiobenzoate (3 2) (J Martens, K Praefcke and U Schulze, Synthesis, 1976, 532) and the Schiff's base (33)

The cyclisation of N-arylanthranilamides into acridones

is effected by prolonged boiling with heptafluorobutanoic acid (M Iwao, J.N Reed and V Snieckus, J Amer chem Soc., 1982, 104, 5531) The particular significance of this work lies in the regiospecific o r ~ o - a r y l a m i n a t i o n