Halogen-dance

Introduction of a 3-bromosubstituent onto thiophene is accompHshed by initial tribromination, followed by reduction of the a-bromines by treatment with zinc/acetic acid, thereby utilizing only one of three bromines introduced. The so-called halogen dance sequence of reactions, whereby bromothiophenes are treated with base, causing proton abstraction and rearrangement of bromine to the produce the most-stable anion, has also been used to introduce a bromine atom at position 3. The formation of 3-bromotbiopbene [872-31-1] from this sequence of reactions (17) is an efficient use of bromine. Vapor-phase techniques have also been proposed to achieve this halogen migration (18), but with less specificity. Table 3 summarizes properties of some brominated thiophenes. 

The route to 3-bromothiophene utilises a variation of the halogen dance technology (17). Preferably, 2,5-dibromothiophene [3141-27-3] is added to a solution of sodamide in thiophene containing the catalyst tris(2-(2-methoxyethoxy)ethyl)amine (l DA-1) (33) at temperatures marginally below reflux. On completion, quenching exothermically Hberates ammonia gas the organic phase is separated, washed, and distilled, and foremnning thiophene is recycled. Material of 97—98% purity is isolated. 

Rearrangement of polyhalobenzenes can also be catalyzed by very strong bases for example, 1,2,4-tribromobenzene is converted to 1,3,5-tribromobenzene by treatment with PhNHK." This reaction, which involves aryl carbanion intermediates (Sgl mechanism), has been called the halogen dance. 

Oxidation of thiophene with Fenton-like reagents produces 2-hydroxythiophene of which the 2(570 One isomer is the most stable (Eq. 1) <96JCR(S)242>. In contrast, methyltrioxorhenium (Vn) catalyzed hydrogen peroxide oxidation of thiophene and its derivatives forms first the sulfoxide and ultimately the sulfone derivatives <96107211>. Anodic oxidation of aminated dibenzothiophene produces stable radical cation salts <96BSF597>. Reduction of dihalothiophene at carbon cathodes produces the first example of an electrochemical halogen dance reaction (Eq. 2) <96JOC8074>. 

A New Improved Synthesis of Tricycle Thienobenzazepines Apphcation of chemistry recently developed by Knochel" combined with the well-described halogen dance (HD) reaction, allowed preparation of our key intermediate A in only three synthetic transformations (Scheme 6.4). In this respect, treatment of 2-bromo-5-methylthiophene with hthium diisopropylamide followed by dimethylformamide afforded aldehyde 11 in good yield, lodo-magnesium exchange with conunercial 4-iodo-3-nitro anisole followed by reaction with 11 afforded the thiophene catbinol 12. Dehydroxylation of 12 provided our key intermediate A which presented the requisite functionality to examine our approach to the construction of the seven-member ring system. 

In the total synthesis of 1-fluoroellipticine (56), 1-ethoxy-1-tributylstannylethene was once again used as a two-carbon building block. The 4-pyridylbromide 54 was assembled by applying a metalation/halogen-dance strategy starting from 2-fluoropyridine <92JOC565>. 

Examples exist of rearrangements in which a halogen atom migrates from annular nitrogen to carbon, or from one ring carbon to another ( halogen-dance or transmetalation). Such processes occasionally have preparative importance, and they will be covered in the appropriate sections. 

Indirect support for the above mechanisms is provided by the fact that treatment of di-, tri- and tetra-bromothiophenes with sodium alkoxide in DMSO results in partial debromination (72CC615). Replacement of DMSO by DMF results in bromine migration and polybromi-nation (Scheme 165). The same kind of halogen dance has also been observed on treatment of bromoiodothiophene with alkoxide (80JHC171). 

Schlosser and co-workers have reported the shift of lithium in lithiated l-bromo-3-(tri-fluoromethyl)benzene 2,fa Quenching at — 100 C gives exclusively the product derived from 2, whereas after 2 hours at — 75 C, arene 2 is completely converted into less basic 3. A lithium-iodine exchange takes place in lithiated 2-chloro-3-iodo-6-(trifluoromethyl)pyridine 4, which at —85 C is totally converted into the less basic isomer 5.7 These rearrangements have been discussed in terms of a base-catalyzed halogen dance or halogen-shuffling mechanism. 

While 5-chloro-l,2,3-triazole 1-oxide 467 reacted with sodium methox-ide with replacement of the chlorine (see Section 4.1.6.8), the corresponding bromo compound 468 under similar conditions afforded the cme-substitution product 483 as the main product (1987ACSA(B)724). A mechanism involving halogen dance and supported by control experiments is sketched in Scheme 142. The bromine in 468 is located at the less activated position with respect to nucleophilic displacement. On the other... 

Cochennec, C. Rocca, P. Marsais, F. Godard, A. Queguiner, G. Metalation of aryl iodides, part II directed ortho-lithiation of 3-iodo-N,N-diisopropyl-2-pyridinecarboxamide halogen dance and synthesis of an acyclic analogue of meridine. Synthesis 1995, 321-324. 

The halogen dance reaction with base on 2-thiazolamine systems has been reported giving access to 5-substituted 4-bromo-2-thiazolamine derivatives (Scheme 60). The dance reaction is a favoured process and prevention is only possible when optimized reaction conditions and selected electrophiles are applied.95... 

Oxidative dimerization of A,A-dialkyl-<9-(8-lithio-7-quinolyl)carbamates with anhydrous ferric chloride has been shown to be efficient for the preparation 1,1 -dioxygenated 8,8 -biquinolyls (Scheme 61) and it is anticipated that this tandem halogen-dance oxidative dimerization reaction will find further applications for the synthesis of other highly substituted biaryl molecules.96... 

The DE ring of camptothecin has been prepared enantioselectively in six steps from 2-fluoropyridine using a halogen dance reaction <95TL(36)7995>. The first total synthesis of dimethyl sulfomycinamate (47) was reported starting from 3-hydroxy-6-methylpyridine (48) <95TL(36)5319>. 

As with carbocyclic rings, the usual rules apply for avoiding deprotonation (and rearrangement) and promoting metallation low temperatures and t- orn-BuLi as base.94 LDA is used when deprotonation is required (the example below contrasts the deprotonation and halogen-metal exchange of 104) and the halogen dance reactions described in section... 

Halogen dance is more common in aromatic systems. Thus 1,2,4-tribromobenzene is rearranged in an intermolecular mechanism, by potassium anilide in liquid ammonia to give 40-60% of 1,3,5-tribromobenzene (equation 29)229. 

In contrast to the well known metal-halogen exchange of bromo and iodo aromatics, commercially available halopyridines are amenable, for all halogens, to DoM chemistry of considerable synthetic value [9d]. Recent results [9d, 41], have pointed to the additional feature of the halogen dance as a tool for the construction of unusually substituted pyridines. Illustrative are the conversion of 69 into 2,3,4-substituted pyridines 70 and, more interestingly, of 71 into the tetrasubstituted 72 bearing all but one of the theoretically possible halogens (Scheme 24) [42]. 

---