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The Royal Society of Chemistry"

Sandmeyer isonitrosoacetanilide isatin synthesis

SyntheticPage 464

Submitted: August 10, 2010, published: August 10, 2010

Authors

Christopher Cooksey (rsc@chriscooksey.demon.co.uk)

A contribution from 

Reaction Scheme

Chemicals

Chloral hydrate (Aldrich)

3-Bromoaniline (Aldrich)

Hydroxylamine hydrochloride (BDH)

Procedure

A 5-litre flask was charged with (i) a solution of chloral hydrate (45 g, 0.27 mol) and Na2SO4.10H2O (320 g) in water (600 cm3), warmed 30 °C to dissolve the solids, (ii) 3-bromoaniline (43 g, 0.25 mol) dissolved with warming in water (150 cm3) and conc HCl (25 cm3) and (iii) a solution of hydroxylamine hydrochloride (55 g, 0.79 mol) in water (250 cm3). A thick white suspension formed. The mixture was heated. At 60 – 70 °C a thick paste formed. After heating for 2 h at 80 – 100 °C the mixture was cooled to 80 °C and filtered. The filtrate yielded more solid (2.4 g) after cooling. The pale brown product (3-bromoisonitrosoacetanilide) was washed by stirring with water (400 cm3) followed by filtration. Drying in air for 2 d gave the product (81.2 g). The expected yield was 61 g, so still wet.

With mechanical stirring, conc H2SO4 (200 cm3) was heated to 60 °C in a flask which was then removed from the heating mantle. 3-bromoisonitrosoacetanilide (15 g) was added over 20 m in portions so that the temperature remained between 60 and 65 °C. The mixture was then heated to 80 °C, then cooled to 70 °C and poured on to crushed ice (2.5 litres). After standing 1 h, the orange precipitate was filtered and washed with water (2 x 60 cm3), drying at 40 °C to give the mixture of 4-bromo- and 6-bromo-isatin as a pale orange powder (8.9 g).

Some of the bromoisatin mixture (10.5 g) was dissolved in hot (60 °C) NaOH solution (2M, 35 cm3) to give a dark brown solution. This solution was acidified with acetic acid (3.6 cm3) and the resulting orange-brown crystals filtered and washed with hot water to give 4-bromoisatin (5.7 g). The combined filtrates were warmed to 80 °C and conc HCl (5 cm3) added. After cooling overnight in a fridge, the bright orange crystals were filtered to give 6-bromoisatin (3.3 g).

Author Comments

The 3-bromoisonitrosoacetanilide synthesis went well, probably in high yield, and was used directly for the second part. Holt et al 1958 report refluxing for 15 min gave a 55% yield of 3-bromoisonitrosoacetanilide.

The temperature of the sulfuric acid used in the second step is critical – too cold and no reaction occurs, too hot and decomposition occurs.   Holt et al 1958 report a yield for 4-bromoisatin (46%) and 6-bromoisatin (21%).    7-Bromoisatin was prepared in the same way in 74% yield (lit: 29%).

A nice (Sandmeyer T, Helv Chim Acta, 1919, 2, 237) almost 19th century bucket chemistry synthesis.

An alternative separation of 4-bromo- and 6-bromo-isatin using high-speed counter-current chromatography (HSCCC) has been suggested: Almeida MR, Leitão GG, Silva BV, Barbosa JP, Pinto AC, J Braz Chem Soc, 2010, 21(4), 764-769; doi: 10.1590/S0103-50532010000400025.

Data

4-bromoisatin:

δH (dmso-d6) 11.18s (1H), 7.44t (1H, 7.9), 7.20dd (1H, 0.8, 8.1), 6.87dd (1H, 7.7, 0.7)

6-bromoisatin:

m.p. 268.1 °C (lit. Holt et al 1958, 270 °C)

δH (dmso-d6) 11.15s (1H), 7.42d (1H, 7.9), 7.24dd (1H, 8.4, 1.6), 7.06d (1.6)

δC (dmso-d6) 183.21s, 159.28s, 151.65s, 131.73s, 126.15d (169), 125.67dd (173, 5.0), 115.04dd (171, 5.3), 116.96s

Lead Reference

Clark RJH, Cooksey CJ, New J Chem, 1999, 3, 323-328; DOI: 10.1039/a808562e

Other References

Holt SJ, Sadler PW, Proc Roy Soc Lond B, 1958, 148(933), 481-494; PMID: 13542639; doi: 10.1098/rspb.1958.0040

(isomer separation) Sadler PW, J Org Chem, 1956, 21, 169-170: doi: 10.1021/jo01108a004

(isatin) Marvel CS, Hiers GS, Org Syn, 1925, 5, 71, Coll. Vol. 1, 1941, 327

Keywords

bromoisatins, bromoisonitrosoacetanilide, Sandmeyer

Comments

Cl3CH(OH)2?
Hello, Chloral hydrate, as Cl3CH(OH)2 in the scheme, may be Cl3"C"CH(OH)2 ???
By HIROSE YOICHIRO on August 16, 2010
ID: #464
Thanks, yes, of course. A missing carbon. Well spotted !
By Chrisc on August 17, 2010
I don't understood how to ring colusre? please can you tell me the mechanism? Thanks!
By Rob on July 11, 2014
sandmeyer reaction
About the mechanism, I would not know, being essentially a 19th century chemist. But I see that there are words in a text book which says it is ... Nucleophyllic attack by the aromatic ring, electron withdrawing substituents, especially in the meta-position, lead to decreased reactivity. Hope that helps !
By Chrisc on July 11, 2014
Ring closure
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532013000500001 Take a look at this article. It might help. Cheers from Brazil!
By Vitor on August 24, 2017