Five-membered monoheterocyclic compounds

253

Chapter 14 FIVE-MEMBERED MONOHETEROCYCLIC

COMPOUNDS"

THE INDIGO GROUP

M. SAINSBURY

I ~ o ductio n The commercial importance of indigo (indigotin) has received a stimulus in the last decade through the increased popularity of certain types of clothing wherein part fading of the dyestuff is deemed fashionable. As a result interest in the chemistry of indigoid dyes has revived to a degree, and some of the structures long thought satisfactory have been re-examined and reassigned.

I. Indigo and i t s d e r i v a t i v e s (a) Methods of s y ~ h ~ ~ (i) Three new syntheses of indigo have been reported by J. Gosteli (Helv., 1977, 60:1980), the first of these utilizes isatoic anhydride (I, R=H) as starting material. This with dimsyl sodium in dimethylsulphoxide affords 2-amino-~-methylsulphinylacetophenone (2, R=H) which, when warmed with hydrochloric acid, undergoes a Pummerer rearrangement and loss of methylthiol to give indigo.

0 @

0 0

N C1)

MeSC

. . . .

Me

(2)

I--1(~

254

0 ( [ ~ ~ S M )H NNR (3)

0 Hf9 i:-~s.)

~N~ =

CHO R

(4)

A more satisfactory yield (77% uS 39%) is obtained by acetyfating the amine (2), and in this case the presence of the rearrangement product 2-acetamido-m-methylmercapto-~-acetoxyacetophenone (3, R=Ac) is detected in the mother-liquors. When the acetylation is conducted under vigorous conditions (not specified) the rearrangement product predominates. On treatment with hydrochloric acid (3) is transformed into indigo (4) (cf. M. von Strandtmann es ~s U.S. patent, 1976, 3,937704). In the second approach isatoic anhydride is reacted with nitromethane to give 2-amino-~-nitroacetophenone (5). This compound on warming with hydrochloric acid yields indigo. It is suggested that a Nef rearrangement is involved in this transformation, in the course of which the nitromethyl group of the nitroacetophenone is converted into a carboxaldehyde function. Again the synthesis is improved by the N-acetylation of the starting material (5), the final step then occurs in 88% yield.

0 ~NH2 NO2 (5)

OAc ~

NO2 (6)

Styrene reacts with acetic anhydride and nitric acid, together with a catalytic amount of concentrated sulphuric acid, to give

255

the dinitroacetate (6). Treatment of this with methanol and toluene-p-sulphonic acid gives the corresponding alcohol, which is a known compound having been made many years ago by J. Thiele (Ber., 1899, 32:1293). Incidentally, Thiele noted that this compound gives a blue colour when it is exposed to ferrous ion. The alcohol is converted into indigo (59% yield) by sodium dithionite in aqueous sodium hydroxide. (ii) N-Methyl- and N,N-dimethyl-indigo have been prepared by the oxidative dimerisation of indoxyl derivatives using the one electron oxidant 2-chloro-2-nitropropane. N-Methylindigo, for example, is obtained together with indigo, (molar ratio 2: i) by the reaction of 0-acetylindoxyl and N-methyl-0-acetylindoxyl with this reagent in methanol solution containing sodium methoxide (G. Kaupp, Ber., 1970, 103:990). N,N-Dimethylindigo results from a similar experiment, this time using as starting material N-methyl-0-acetylindoxyl. (iii) 1,3-Dimethyl-2,1-benzisoxazolium perchlorate (7) adds cyanide, azide or methoxide ion to give 3-substituted 2,1benzisoxazolines of the general type (8). Pyrolysis of the cyano derivative (8, X=CN) affords N-methylindoxyl (10) and N,N-dimethylindigo (11) (N.F. Haley, J. org. Chem., 1978, 43: 1233). It is considered that the exocyclic methylene compound (9), formed by elimination of hydrogen cyanide from 3-cyanoI ,3-dimethyl-2, 1-benzisoxazoline, rearranges to N-methylindoxyl, as a key step in this sequence of reactions. Air oxidation of the last product then yields N,N-dimethylindigo.

Me ~ ~ N / ) /0

~ ~ 'X~o

Me X ~N/O

Me C 1 0 2 (7,

Me

X = CN, N3 , 0 M e )

(8)

C/H2

0

Me

(9)

~ q PA"

,,0

Me

Me

(10)

(11)

256

(iv) 4,4' 5 5' 6 6' 7 7'-Octahydroindigo (13), m.p. >300 ~ , %max (log e ) n m 317 (4.60), 524 (4.05) (methanol) has been synthesised by G. Pfeiffer and H. Bauer (Ann., 1980, 564) by the oxidative coupling of the tetrahydroindoxyl (12) using potassium ferricyanide.

0 2

0 -.

H

K4Fe(CN) 6 , . ~._

H 0 (13)

(12)

(v) 4,4'-Dibutyl-5,5'-dimethylpyrrolindigo (14), m.p. >300 ~ , %max (log E) nm 317 (4.20), 529 (3.98) (methanol), and di(cyclopentan[b]pyrrolindigo) (15), %max 313.5, 505 nm, are prepared by similar reactions.

n

0 H Bu ~ i ~ n M e

0 (14)

0

H

0 (1.5)

(vi) Tetrahydroindigo (17), m.p. >300 ~ , %max (log E) nm 315 (4.47), 565 (4.32) is made by combining 3-methoxyindolin-3(2H)one (16) with tetrahydroindoxyl (12), and N-methyl and N,N-dimethyl derivatives of octahydroindigo and tetrahydroindigo have also been synthesised, l-Methyl-4,4' 5 5' 6 6' 7 7' octahydroindigo, m.p. 195 ~ (begins to decompose at ~140 ~ %max (log e ) n m 315 (4.28), 552 (4.00); 1,1'-dimethyl_4,4~,5 _ 5' , 6 , 6' , 7,7'-octahydroindigo, m.p. 90-92 ~ (decomp.), %max (log e) nm 328 (4.27), 621 (4.17); 1-methyl-4,5,6,7-tetrahydroindigo, m.p. 193 ~ , ~max (log c) m, 318.5 (4.28), 584 (4.13); 1'-methyl-4,5,6,7_tetrahydroindigo, m.p. 153~ %max (log E) nm 319 (4.23), 595 (4.15); 1,1'-dimethyl-4,5 6,7-tetrahydroindigo, m.p. 90-92 ~ (decomp.), Emax (log s) nm 330 (4.34), 582 (3.97).

257

O OMe

+

(12)

H

C e, FI6 60 ~

H

9

0

(16)

(17)

(vii) 4,5,6,7-Tetrahydroindirubin (20) m.p. >300 ~ , is the product of a reaction between isatin (18) and tetrahydroindoxyl (12). If acid is excluded the intermediate adduct (19) can be isolated as yellow solid, m.p. 145 ~ (decomp.). When the adduct is heated in benzene solution containing a catalytic amount of trifluoroacetic acid the colour of the reaction mixture turns red and tetrahydroindirubin is then formed.

H| 0

+

(12)

~

"H

-1420

0 (18)

(19)

0 (20)

(viii) The series of the six possible combination isomers of indigo has been completed by the synthesis of 3-oxo-2-(3-oxo1-isoindolinylidene)indoline (phthalorubin) (23) and 2-oxo-3(3-oxo-l-isoindolinylidene)indoline (phthalaurin) (25) (E. Wille and W. LHttke, Ber., 1973, 106:3257). These two compounds are prepared by the reaction of monothiophthalimide (21) with N,0-diacetylindoxyl (22) and oxindole (24) respectively. Phthalorubin sublimes at 275 ~ and melts between 310-320 ~ (decomp.),)'max (log e) nm 516 (4.16). Phthalaurin sublimes at 265 ~ and has m.p. 299-303 ~ , %max (log E) nm 455 (3.85).

258

S [ ~ N

OAc H

~ N

+

O

0

Ac

(2t)

(21)

~ EtOH, piperidine " ~--

(22)

[ ~ ~

+

(23)

O

H

EtOH, piper'idine ........

0

H

Ft (24)

(25)

(ix) The synthesis of polymeric indigos has been extended by E. Ziegler ~ ~ . (Monatsh., 1970, 101:923) using a method previously described (Ziegler and Th. Kappe, Angew Chem., 1964, 76:921; Ziegler, H.G. Foraita and Kappe, Monatsh., 1967, 98: 324). The new compounds have structures (26), (27) and (28) (n unspecified).

m

0

FI

-t

o

- R-

FI o

H

R

--n

R --H (27) R : Me

(26)

(28)

259

(x) Minor amounts of thioindigo (36) are often observed in the reaction products of thiochromone and thiochromanone derivatives (R.M. Christie ~7~ as J. chem. Res., 1980, 8), but an 80% yield may be obtained when 2,3-dibromo (or chloro) thiochromone-S-oxide (29) is heated with sodium acetate (2 tool. equiv.) in boiling acetic acid. No thioindigo is formed if a 2,3-dihalogenothiochromone is used as starting material (N.E. MacKenzie and R.H. Thomson, Chem. Comm., 1980, 559). The following scheme is proposed to account for the generation of the dyestuff. Nucleophilic displacement of the halogen at C-2 affords the acetate (30) which rearranges via the intermediate (31) to the S-acetate (32). Intramolecular displacement of the acetate group then occurs to yield the thiiranium species (33) which reacts with water to give thioindoxyl-2-carboxylic acid (34). Decarboxylation generates 2-bromothioindoxyl (35) which is a known precursor of thioindigo.

O OOA c

O [~~~r

Br (29)

I Me

(30)

O~ Br (&Ac Me

(31)

(32)

0

O

0

. .H20 ..

~ B r co2H

@ (33)

(34)

O O (36)

--~'-

[ ~ (35)

Br

260

(b) Spectroscopy and E-Z ~omer2sm of indigo and thioindigo d~ivativ~ (i) The properties of the indigo chromophore have been the subject of much theorectical and experimental commentary in the last decade principally through the researches of groups lead by LUttke and by H. Bauer. Some of these studies are to be found in papers already cited, but a useful review is also available (Bauer and G. Pfeiffer, Chem. Zeit., 1976, 100"373). (ii) The electronic absorption maxima of indigo in various media have been compared (A.R. Monahan and J.E. Kuder, J. org. Chem., 1972, 37:4182). The lowest ~-~* transition occurs at 590 nm (CC14), 604 nm (CHCI3), 610 nm (EtOH), 640 nm (amorphous solid), 668 nm (crystalline solid). These differences are shown to be due to variations in hydrogen bonding interactions, and quantum chemical calculations support the conclusion that in the solid state associated species occur. It is pertinent to note that in related structures where the NH groups are replaced by O, S or Se similar changes in spectral properties are not observed and indigoid derivatives bearing bulky substituents at positions 4, 5 and/or 7 do not show hydrogenbonding shifts between solution and solid phases. In the latter case the size of the substituents inhibits interactions between NH and CO groups in neighbouring molecules. (iii) The photochemical c / S - ~ ~ 6 - i s o m e r i z a t i o n of N,N'-diacetylindigo (I, R=Me) has been studied extensively (W.R. Brode, E.G. Pearson and G.M. Wyman, J. Amer. chem. Soc., 1954, 76:1034; Wyman and A.F. Zenh~usern, J. org. Chem., 1965, 30: 2348) and thioindigo (D.A. Rogers, J.D. Margerum and Wyman, J. Amer. chem. Soc., 1957, 79:3464; A.J. Henry, J. chem. Soc., 1946, 1156). Although C~-thioindigo can be isolated by chromatography of the photostationary ci6-s ~-N,N'-diacylindigos are normally very unstable and readily change into the corresponding ~ ~ - i s o m e r s . However, Y. Omote, S. Imada and H. Aoyama (Chem. Ind., 1979, 415; Bull. chem. Soc. Japan, 1979, 52:3397) have observed that the gs of N,N'-diacetyl, distearoyl, dibenzoyl and 3,5-dinitrobenzoyl-indigo crystallise from solutions of the corresponding ~ ~ - i s o m e r s that have been irradiated with ultraviolet light. The relative rates of the c/s§ isomerism of these four c/S-N,N'-diacylindigos are 7.9, 11.0, 1.0 and 5.1 respectively. Physical data for the isomers are summarised in table i.

261

TABLE I Properties of ci6- and s

of N,N'-diacylindigo

mp (decomp) o

CH3

~KBr C =0

cm-Z

(37)

~C6H6 max

c~ ~nS

244-246 256-257

1720, 1690 1690, 1680

438 562

4500 7000

cs ~ ~

101-103 101-102

1720, 1690,

1700 1670

437 567

3900 7100

CBH5

~ s

246 256-257

1725, 1695,

1675 1660

460 574

3900 7700

3,5-(N02) 2C6H3

ci6 ~n6

205-210 249-252

1730, 1660 1700, 1680

436 552

2800 6200

CH3 (CH2)

16

~..

--

0 0::::~R

(37) cis-form

trans-form

(iv) R. Hasenkamp, V. Luhmann and LUttke (Ber., 1980, 113: 1708) have prepared a number of new thioindigo dyes with interrupted peripheral conjugation. As expected the electronic absorption maxima of these compounds occur at shorter wavelengths than those of the parent compound although the extinction coefficients are similar. Examples of these compounds are collected in table 2 where some of their spectral properties are compared.

262 TABLE 2 Some new derivatives of thioindigo

Structure

o

m.p.~

%max (l~

~)nm

v C=O

v C=C cm-1

>280

541 (4.19)

1658

235

477 (4.03)

1627

186

454 (3.96)

1658

213

388 (3.97)

1676, 1637 1500

o (thioindigo)

( c ) Tyrianpurple and i t s

b i o l o g i c a l precursors

The dyestuff Tyrian purple has a very long history. Members of the genera Mugtex from the families Muytic~dae and Thagsidae concentrate precursors of the dye in their hypobrachial glands. The occurrence of the dye or its precursors is not restricted to gastropod molluscs, however, since Tyrian purple has been

263

identified in the hemichorate Ps flava layangca Spengel( T. Higa and P.J. Scheuer, Heterocycles, 1976, 4:227). J.T. Baker and M.D. Sutherland (Tetrahedron Letters, 1968, 43) and Baker and C.C. Duke (Austral. J. Chem., 1973, 26:2153) have identified the precursor of Tyrian purple in Dieas orb~ Gmelin as tyrindoxyl sulphate (38) and the counter cation has been shown to be choline, or its ester, in ~. o r b ~ and Manc i n ~ a k~ngki Deshayes (Baker and Duke, Tetrahedron Letters, 1976, 1233). The %n v%v0 transformation of tyrindoxyl sulphate involves an enzymic hydrolysis to give tyrindoxyl (39) which in turn is oxidised to the corresponding dehydro derivative (40). This product and tyrindoxyl are assumed to form a quinhydrone-type complex (tyriverdin), i.e. a charge transfer complex with the elemental composition C18HI4Br2N202S2, 89 or C36H28BrN404S4, H20, which is the immediate precursor of Tyrian purple (Baker, Endeavour, 1974, 32: 11).

OSO? ~~---

SMe

OH . s_,u.Iph ata se ___

~

S

M

H (38)

[0]

(39) 0

0 SMe

Br

e

H

N

~Br

(40)

H 0 Tyrian purple

Tyriverdin can be isolated (Baker, Pure appl. Chem., 1976, 48"38), but it fails to exhibit a molecular ion peak in conventional mass spectrometric analysis. However, field desorption techniques can be applied and lead to the molecular formula CI8HI4Br2N202S2 (C. Christopherson es al., Tetrahedron Letters, 1977, 1747; Tetrahedron, 1978, 34:2779). On this basis tyriverdin is allocated structure (42), a conclusion supported by the fact that it is formed when 2,2'-diacetoxy6,6'-dibromoindigotin (41) reacts with methanethiol in pyridine solution containing triethylamine.

264 0 Ac

.

0 Me N

Br

H

.Br

Br

U 11 Ac 0 (41)

(42 ]

5,5' 7 7'-Tetrabromo-6,6'-dimethoxyindigotin (43) m.p >300 ~ , and 5,6',7-tribromo-6-methoxyindigotin (44), m.p. >300 ~ also occur in P. fs (Higa and Scheuer, loc. c ~ . ) accompanied by 5,7-dibromo-6-methoxyindole (45).

0

H

0

H

ooBr

Br [43)

Ibr (4,4)

Br (45)

(d) Deoxyindigo (structural reassignment) Deoxyindigo, obtained by treating indigo with hydrazine and sodium hydroxide in ethanol followed by aeration, was assigned structure (46) by W. Borsche and R. Meyer (Ber., 1921, 54:2854). A secondary product given the name dehYdrodeoxyindigo and thought to have the orthoquinonoid structure (47) was also isolated in a similar reaction conducted by P. Seidel (ibid., 1944, 77:788; 1950, 83:20). These compounds have been re-examined by J. Bergman, B. Egestad and N. Eklund (Tetrahedron Letters, 1978, 3147). Since deoxyindigo was isolated directly from an alkaline medium, it was argued that an anionic form would be favoured. Such a salt should be very susceptive to oxidative coupling and a high resolution mass spectrometric study of deoxyindigo showed that in reality deoxyindigo has the molecular formula C32H20N402. The structure has been reformulated as (50, R-H) and confirmed by an independent synthesis: the 3,3'-biindoyl lithium (49) reacts with dehydroindigo (48) to form the di-N-sulphonyl derivative of deoxyindigo (50, R=SO2Ph). This, when hydrolysed,

265

affords deoxyindigo.

0

H

H (46)

(47)

R

o (48)

R

(49)

0

R

i

OAc

H

(57) o

R (50)

The 0-monoacetate (51) of the structure originally proposed for deoxindigo is obtained by the addition of acetic anhydride (air being excluded) to Borsche's reaction mixture. Whereas addition of allyl chloride gives the allyl derivative (52), m.p. 171-173~ the isomer (54) has been obtained by the addition of allyl bromide to an alkaline solution 2(3-indolyl)indoxyl assumed to contain the anion (53) (E. Houghton and J.E. Saxton, J. chem. Soc. (C), 1969, 595).

O

H

(52)

(53)

(54)

266

( e) Reaction between indigo and hydrazine When indigo reacts with anhydrous hydrazine at 35 ~ a product Ci6Hi3NsO, m.p. 227-229 ~ , is formed, whereas at 100 ~ a compound Ci6HI2N~O, m.p. 218-220 ~ , is obtained. An X-ray diffraction analysis shows that the latter compound has structure (55, R=NH2). Treatment of this compound or the lower temperature product with Raney nickel gives the N-deamino derivative (55, R=H), m.p. 318-320 ~ The product of the low temperature reaction is assumed to be the zwitterion (56).

HN e

(55)

U H2N/ (56)

0

(f) I n . g o ~imine "Indigo diimine" (W. Madelung, Ber., 1913, 46:2259; Ann., 1914, 405:58) does not exist as the symmetrical form (57), but rather as the tautomeric structure (58), both in solution and in the solid state (H. Sieghold and LHttke, Angew. Chem. internat. Edn., 1975, 14:52). Nil

H

NH2

NH

(57)

(58)