Indian Journal of Chemistry Vol. 40B, November 2001, pp. 1023-1028

Advances in Contemporary Research

6,7 -Dihydrobenzo[b ]thiophen-4(5H)one and 5,6-dihydrobenzo[b ]thiophen-7 (4H)-one: Versatile intermediates in the synthesis of sulphur heterocycles t

Sukanta Kamila & Asish De*

Department of Organic Chemi stry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032

Received 16 February 2001; accepted 4 July 2001

The title ketones, endowed with several reactive centres, are used as intermediates in the synthesis of a wide range of polycondensed systems incorporating a fused thiophene ring. The present review gives an account of the preparation of these ketones and their use in syntheses .

Introduction In the family of heterocyclic compounds, sulfur

heterocycles are presumably next in importance to nitrogen heterocycles. Among sulfur heterocycles, polycondensed systems incorporating a fused thiophene ring have, for quite some time, attracted attention of organic chemists active in this area. Initially, the idea was to synthesize these compounds as sulfur analogues of bioactive indole derivatives because of the bioisosteric relationship between indole 1 and benzo[b ]thiophene (2) leading to the syntheses2

.3 among others of benzo[b ]thiophene analogues of a number of indole alkaloids. Synthesis of sulfur analogues of bioactive furocoumarins and furochromones were also reported2

.3.

The methodology generally followed during the course of synthesis of these compounds was to start with a preformed benzo[b]thiophene core with subsequent construction of fused rings through suitable annelation reactions. Because of the greater reactivity of 2- and 3-positions in 2, it is easy to introduce substituents which can conveniently be used as handles for the purpose of annelating a ring in the thiophene moiety of benzo[b ]thiophene.

Regiocontrolled substitution in the benzene moiety of 2 is relatively difficult. Benzo[b]thiophenes carrying substituents in the positions 4-, 5- ,6-, and 7-were earlier synthesized from expensive thiols2

•3

.

However in more recent times two compounds, viz. 6, 7-dihydrobenzo[b ]thiophen-4(5H)one 3 and 5, 6-di­hydrobenzo[b]thiophen-7(4H) one (4) have shown

tDedicated to Prof. U R Ghatak on his 70'h birthday

Wi (VI H

2

0

Co W 3 o 4

their usefulness as versatile intermediates In the synthesis of benzo[b]thiophene derivatives, substi­tuted in the benzene ring, and of polycondensed systems with a fused thiophene ring.

Physical properties The ketone 3 is a low melting solid,m.p 37°C. IR:

1675(C=O) em-I; IH NMR. (CDCh): 87.37 (d, IH, 2-H), 7.03 (d, IH, 3-H), 3.02 (t, 2H, 5-H), 2.51 (t,2H, 7-H), 2.23 (m, 2H, 6-H). The ketone 4 is a low melting solid.b.p. (950CIO.l mm), m.p. 33-350C, IR: 1650 (C=O) em-I; IH NMR: 8 7.45 (d, IH, H-3, J=6Hz), 6.91 (d, lH, H-2, J=6Hz), 2.82 (m, 2H, CHr CO), 2.51-2.09 (m, 4H, other methylene protons)

Synthesis Of the two ketones 4 was synthesized much earlier.

It's synthesis was first reported by Fieser and Kennelly4 in 1935 (Scheme I)

An important modification of this synthesis was made by Nishimura et al.s who employed Huang­Minion reduction in obtaining 4-(2-thienyl) butanoic

1024 INDIAN J CHEM. SEC. B, NOVEMBER 200 l

(ii) n .. t.:..~/--

Reagents: (i) Succinic Anhydride/Anhyd. AICliC6HsN02: (ii) Zn/Hg,HCI; (iii) SOC12/Anhycl. AlCI)

Scheme I

5

o CO H

aCH=C~ 2

6

SH o

n t.:.. S/-- (CH

2)3 CO-0-COC~

7

o

~ S COCH3

9

acid and cyclised it with acetic anhydride in presence of catalytic amount of polyphosphoric acid (PPA). The reaction is cleaner and the yield is good, although the formation of a byproduct was overlooked (see later). An elegant albeit expensive synthesis of 4 was reported by Napier6. It consisted of acid catalysed cyclisation of the Michael adduct from cyclohex-2-enone and (EtO)2CH-CH2SH,followed by chloranil mediated dehydrogenation of the adduct 6. Napier also reported7 the synthesis of the ketone 3 carrying methyl substituents in the 6- or 7- position from the reaction between 3-mercapto cyclohex-2-enone and 1,2-dicarbonyl compounds R 'COCOR2. The ketone with a carboxylic acid function in the 2-position was obtained8 by heating 7, which is obtained by heating the trimethyl amine salt of the condensation product of dihydroresorcinol and 5-ethoxy-methylene-3-meth y 1-rhodanine.

As mentioned above, the Japanese workers5

overlooked the formation of a byproduct during the cyclisation of 4-(2-thienyl) butanoic acid. The mixed anhydride 7 undergoes acid catalysed cleavage to resulting in the ion 8 which affords 3 upon cyclisation. However acetyl cation CH3CO+, obtained by PPA mediated splitting of acetic anhydride and present in the reaction mixture, attacks the ketone to

afford the diketone 9 which can be separated from 3 by steam distillation. It was demonstrated9 by monitoring the cyclisation that the ketone 3 is initially formed and is subsequently attacked by the CH3CO+ ion. Cyclisation of the butanoic acid derived from 2-methyl thiophene takes place with no byproduct formation9 since the reactive a-posi tion to the ring su lfur atom is blocked.

Unlike 3, the isomeric ketone 4 was synthesised by earlier workers through lengthy and uneconomical routes. Macdowell and Greenwood1o first synthesized this ketone from 3- acety l thiophene (Scheme II) .

Later Cagniant and Cagniant" reported another synthesis using 3-methyl thiophene as starting material (Scheme III).

The first high yielding synthesis of this ketone was reported by De l2 (Scheme IV). The synthesis uses commercially available starting materials, the number of steps is fewer in comparison to the earlier reported synthesis, and the overall yield is excellent.

Reactions As stated above, the ketones 3 and 4 have been

widely used in the synthesis of a number of benzo­[b]thiophene derivatives and polycondensed systems incorporating a fused thiophene ring. Although both the ketones have identical structural features which make them useful synthetic intermediates, systematic exploitation of 4 is only recent, presumably because preparation of this compound in reasonably large quantities through lengthy syntheses reported earlier, was tedious.

Both the ketones have several reactive centres, viz. the a-position to the ring sulfur atom, the carbonyl group and the methylene group adjacent to the carbonyl function . Drewry and Scrowston 13 were the first to report a systematic study on the substitution reactions of 6,7 -dihydrobenzo[b ]thiophen-4(5H) one.

Bromination and formylation of this ketone were extensi vely studied by these authors. Reaction conditions are established to give exclusive bromination in 2- or 5-position. Further bromination

KAMILA el al .: VERSATILE INTERMEDIATES IN THE SYNTHESIS OF SULPHUR HETEROCYCLES 1025

Sr o s (i) •

CN

ro-;( (ii) ~-jJ-....

S

COCH3 o (iii).

s

~(W) o

~CH(COB) S 2 2

rTn y~S/

o

Reagents: (i) CuCN; (ii) MeMgl, then H+; (iii) Br2/AICI3: (iv) diethylmalonate/NaH;(v) KOH, (vi) LV 170 DC; (vii) Huang-Minion reduction; (viii) SOCl2. then AICI3.

Scheme II

CH2Sr

O~ S (iii)

R I

OCH

2CHCOC1

(iv) I I (v) ---. s ---.

~ (vi)

W o

Reagents: (i) N-Bromo succinimide; (ii) RCH(C02Et)2/Base; (iii) KOHlLl ; (iv) SOCI2: (v) Amdt-Eistert via diazoketone; (vi) Cyclisation via acid chloride.

Scheme III

of the 2-bromo compound led to either 2,3-dibromo or 2,5-dibromo derivatives. Spectroscopic evidences show that the 5-formyl derivative 10 obtained by treating the ketones with ethyl formate in the presence of sodium ethoxide, exists predominantly as hydroxymethylene tautomer.

It undegoes various reactions affording, inter alia, a fused pyrazole. Later De9 reported several electro­philic substitutions in the a-position to the ring sulfur atom in 3. When this position is occupied by a methyl

group, the substituent enters into the 3-position. The carbonyl group undergoes facile Knoevenagal condensation with active methylene compounds9

,14.

The condensed products can be further elaborated for annelating a third ring on to the existing benzo[b]­thiophene core (see later).

Later De and his coworkers systematically exploited the highly reactive nature of the two methylene protons adjacent to the carbonyl function for introducing substituents and, as will be shown

1026 INDJAN J CHEM. SEC. B, NOVEMBER 2001

(iii) nTl (iv) ~ ~~S/ A ,,~s) lCOOH HOOC COOH

~ (v)

W o

Reagents: (i) 12/Ph3P/imidazole: (ii ) diethylmalonate: (iii) KOH : (iv) 6: (v) PPA

Scheme IV

= ... =:----' ....... HO~ 10

o 0

~o .. dY'0" o 0 11 12

o S 0

oeY's .. ... ~s .. S - S /" 13

O'I_fS

0

~s,"-- ... ~s .. o S O'H',S

14

o SMe

cCfs .. ~SMe S

o SMe 15 16

later in this paper, the products readily reacted with bifunctional nucleophiles resulting in the annelation of a third heterocyclic ring.

Following Drewry and Scrowston's method, De brominated the ketones 3 and 4 in 5- and 6- positions respectively 15 . Careful maintenance of the reaction conditions ensures exclusive monobromination. Dehydrobromination 16 with lithium carbonate and lithium bromide afforded 417_ and 7 18-hydroxybenzo­[b ]thiophene respectively in good overall yields from the starting ketone. The earlier one step preparation of 4-hydroxybenzo[b ]thiophene from 3 by heating with sulfur gave lower yield and the reaction was less clean. Synthesis of 7 -hydroxybenzo[b ]-thiophene, as reported earlier in the literature, required larger number of steps and the overall yield was less. The ketone 3 was chlorinated9 in the 5- position with N­chlorosuccinimide.

Following Drewry and Scrowston l 3, De also pre­

pared '9 the 5-formyl derivatives of 2-methyl- and 2-bromo-6, 7 -dihydrobenzo[b ]thiophene-4(5H)-one, the products existed predominantly as hydroxymethylene tautomers. De also converted l2

.2o the ketones 3 and 4

into 5-methoxycarbonyl 11 and 6-methoxycarbonyl 12 derivatives through reaction with dimethyl carbonate in dry benzene in the presence of sodium hydride_ Similarly methyl 4-oxo-4, 5, 6, 7-tetrahydro­benzo[b ]thiophene-5-carbodithioate 13 and methyl-7-oxo-4, 5, 6, 7-tetrahydrobenzo[b]thiophene-6-carbodi­thioate 14 were prepared by reacting the ketones 3 and 4 respectively with dimethyltrithiocarbonate in the presence of potassium tert-butoxide. Methylation of the dithioesters 13 and 14 afforded 5-bis(methyl­sulfamyl)methylidene-6, 7 -dihydrobenzo-[b ]thiophen-4(5H)-one 1520 and 6-bis(methyl sulphamyl)-methyli­dene-5, 6-dihydrobenzo[b ]thiophen-7(6H)-one 1618

respectively. Oxoketenedithioacetals like 15 and 16, which are

masked ketoaldehydes, have been utilised as versatile synthetic intermediates21

. These compounds possess electrophillic centres in 1,3 positions and, as such, undergo facile reaction with suitable bifunctional nucleophiles resulting in the annelation of five or six membered heterocycles.

Base catalysed condensation of hydrazine hydrate with the B-keto esters 11 and 12 afforded the tricyclic fused pyrazolones 17 and 18, while the B-keto dithioesters 13 and 14, under similar raction conditions, afforded 19 and 20 respectively.

KAMILA et al. : VERSATILE INTERMEDIATES IN THE SYNTHESIS OF SULPHUR HETEROCYCLES 1027

HN--N oBH ~NH \ OH S SH & II --olt

S S 19 S

nrl __ .. 'S~O

N-NH

nrl 'S~OH

HN-N

N-NH

oCt sMe I I

S

21

NH2

~N ~ ~sJlJ OMe

23

18

nrl "S~SMe

N-NH

22

24

dS~ NC N~

~S NC N~

r.Os

25 26 27

802Cf(N3 R

~ 100 ~ I I S

28 29

Spectroscopic evidence indicates that the compounds 17-20 exist almost exclusively as enol or enethiol tautomers.The oxoketene dithio acetals 15 and 16 reacted with hydrazine hydrate in the presence of methanolic sodium methoxide to afford the fused pyrazoles 2120 and 2221 and with guanidine the fused pyrimidines 23 and 24.

nrl 'S~S - -QC)"SH

N-NH 20 HN-N

During the formation of the last two compounds the methylthio group was in situ converted to methoxy.

Knoevenagal condensation of malononitrile, ethyl cyanoacetate or cyanoacetamide with 3 afforded 25 (R=CN,C02Et, CONH2)14. Upon reacting with elemental sulfur in methanolic solution of 25 (R=CN) in the presence of catalytic amount of morpholine the tricyclic compound 26 was formed which was aromatised to 27 with DDQ. Presence of nitrile and amino functions on adjacent carbon atoms in both the dihydro- as well as on the fully aromatised compounds was utilised in annelating a pyrimidine ring 22 on to the existing thienobenzo[b ]thiophene core. MM2 calculations were carried oue2 on the tetracyclic compounds.

The ketones 3 and 4 were utilised in regio­controlled introduction of functionalities like CHO I8.23 , CN23, COMeI2,20,23, C02MeI2.20,23 or

CH2CN25 in the benzene ring of benzo(b ]thiophene. Benzo(b ]thiophene-5-carboxaldehyde was condensed with ethyl azidoacetate and the resulting vinyl azide was thermally cyclised23 to afford the thienoindole 29 (R=C02Et) which was hydrolysed and decarboxylated to afford 29 (R=H).

Conclusion The two ketones 3 and 4 are versatile intermediates

in the synthesis of a number of condensed sulfur heterocycles. Both the compounds are readily available through synthesis from inexpensive commercially available starting materials.

Acknowledgement Thanks are due to late R M Scrowston, who

introduced A D to the chemistry of sulfur hetero­cycles, to the Council of Scientific & Industrial Research (New Delhi), Royal Society of Chemistry (U.K) and British Council for providing financial

1028 INDIAN J CHEM . SEC. B. NOVEMBER 200 1

assistance in different times, to the dedicated young collaborators of A.D whose names are given in appropriate references, and to Prof. H Junjappa and H lI a for helpful discussions. S K thanks the Council of Scientific & Industrial Research (New Delhi ) for a Junior Research Fellowship.

References I Langmu ir I, j AIIl Chelll Suc, 41.1919, 869 2 Campaigne E, Kn app 0 R, Neiss E S & Bosin T R, Adv ill

Drug Res (Academ ic Press, New York). 5. 1970. 3 Bosin T R & Campaigne E, Adv ill Drug Res, (Academic

Press. New York ). (Academi c Press. New York). 12. 1977, 19 1.

4 Fieser L F & Kennell y R G. j Alii Chelll Suc. 57. 1935. 1611. 5 Nishimura S, Nakamura K. Suzu ki M & Imoto E, Nippoll

Kagaku Zasshi. 83, 1962. 343: Chelll Abstr. 59. 1963,3862. 6 Napier R P. Kaufman H A, Drisco ll P R, Glick L A, Chu CC

& Foster H M, j Heterocyl Chem. 7. 1970,393. 7 Napier R P & Chu C C, lilt j Slilfur Chel1l Part A. I . 1971.

62. 8 Behringer H & Falkenberg K. Chelll Ber. 99, 1966, 3309. 9 (a) Asprou C M, Brunski ll J S A. Jeffrrey H & De A, j

Heterocycle Chem , 17, 1980,87. (b) Jeffery H. PhD Thesis. Uni versity of Wales, 1982.

10 Mac Dowell , 0 W H & Greenwood T D. j Heterocycle Chem, 2, 1965, 44.

II (a) Cagniant P, Merle G & Cagniant D, Bull Soc Chim France, 1970, 308. (b) Cagniant P, Merle G & Cagniant D, Bull Soc Chilli France, 1972. 322.

12 Samanta S S. Mukherjee S & De A, j Chell1 Res, 1990, (S) 128, (M) 0785 .

13 Drewry 0 T & Scrowston R M, j Chern Suc (C), 1969,2750. 14 De A, Brunsk ill J S A & Jeffery H, Indian j Ch el1l , 23 B.

1984,9 18. IS (a) Mukherjee S & De A, j Chern Res,S, 1994, 238.

(b) Ghosh S c. PhD Thesis, Jadavpur Univers ity, 1999. 16 Kasturi T R & Arunachalam T , Can j Chelll. 46, 1968, 3625 . 17 Cf reference 15(a) . 18 Samanla S S, Ghosh S C & De A, j Chelll Soc Perkin

Trance, 1, 1997,3673. 19 Cf Reference 14. 20 Samanla S S. Mukherjee S & De A, j Chem Res, 1995, (S )

429, (M) 2518 . 2 1 Junj appa H, lI a H & Asokan C V, Tetrahedron, 43 , 1987,

5367. 22 Bhattacharya S, De A & Ewi ng 0 F. j Chell1 Soc Perkin

Trans, 1, 1994.689. 23 Datta S & De A, j Chelll Soc Perkin Trans, I, 1989.603. 24 Ireland R E & Marshall J A, j Org Chefl/ . 27, 1962, 1615. 25 Datta S, De A & Brunskill J S A, Sulfur Lelfers, 4, 1986, 37.