Metal-halogen exchanges

Metallation of 2 -(2-pyridyl)thiophen occurs almost exclusively at position 5 using butyl-lithium-THF or lithium di-isopropylamide, but predominantly at position 3 when ethereal butyl-lithium and short reaction times are used. This unusual and interesting p-metallation of a thiophen with a free a-position most probably depends on the chelating properties of the pyridinic nitrogen, and was also observed with 2 -(2-quinolyl)thiophen. 

Thienyl-lithium derivatives prepared through halogen-metal exchange and containing acetal-protected carbonyl groups have been used in the synthesis of di- and tri-formyl derivatives of thiophen, t-butoxy-sub-stituted thiophen aldehydes, and formylacetylthiophens. Symmetrical thienyl-substituted ketones have been obtained from thienyl-lithium derivatives and carbamates. Mixed heterocyclic carbinols have been obtained through the reaction of thienyl-lithium derivatives with heterocyclic aldehydes. Thienyl-lithium derivatives react with cyclohexanone, and various phenylthiophens have been made by aromatization of the intermediate cyclohexenyl derivative. The reaction of thienyl-lithium derivatives with NN-dimethylacetamide, which has been used for the synthesis of 

Decroix, J. Morel, C. Paulmier, and P. Pastour, Bull. Soc. chim. France, 1972, 1848. 

Gronowitz, J. Rehno, K. Titlest, M. Vadzis, B. Sjoberg, P. Bamberg, B. Ekstrom, and U. 

Kauffmann, J. Jackisch, A. Woltennann, and P. Rdwemeier, Angew. Chem., 1972,84,826. T. Kauffmann. J. Legler, E. Ludorff, and H. Fischer, Angew. Chem., 1972, 84, 828. 

Metalation and Halogen-Metal Exchange.—The direct metalation of thiophens with organolithium compounds and the halogen-metal exchange reaction between halogenothiophens and organolithium derivatives have 

186 p pirson, A. Schonne, and L. Christiaens, Bull. Soc. chim. beiges, 1970, 79, 575. 

Of fundamental importance is the recent discovery that 3-thienyl-lithium derivatives, such as 2,5-dimethyl-3-thienyl-lithium (87) or the three isomeric methyl-3-thienyl-lithiums, undergo a ring-opening reaction in refluxing ether to acetylenic derivatives such as (88), which are alkylated 

The t-butylsulphonyl group readily undergoes nucleophilic displacement by RS and RO groups, making this a preparatively useful route. t-Butyl 3-thienyl sulphone is also easily dimetalated in the 2- and 5-positions. The dialdehyde formed upon reaction with DMF does not, however, undergo nucleophilic substitution. 

JV7V-Dimethyl-2-thenylamine has been metalated with butyl-lithium in the 5-position the product reacted with benzaldehyde and benzophenone to give (91). When the 5-position is blocked, metalation occurs in the 

The halogen-metal exchange or interconversion reaction was independently discovered by us and by G. Wittig. In one of our initial reactions we observed that o-bromoanisole reacted with n-butyllithium to yield o-anisyllithium and -butyI bromide. 

In a series of studies over an extended period we found that this reaction is of uncommon synthetic and structural importance. Although it is best effected generally by the use of -butyllithium in ether, we showed that this exchange reaction proceeds with organometallic compounds of such metals as sodium, magnesium, barium, and aluminum. -In an examination of different solvents, we observed that low-boiling petroleum ether appears to be especially useful for reactions involving secondary and tertiary alkyl-lithium compounds which could not be prepared readily or used conveniently in ether solution. 

By this reaction, numerous organolithium compounds have been prepared from heterocycles. These heterocyclic lithium compounds can be those of pyridine, quinoline, carbazole, dibenzofuran, dibenzothiophene, etc. With some of these heterocyclic systems, there are made available organolithium compounds wherein the lithium is attached to carbon atoms otherwise inaccessible. We found them to be very helpful in our extensive heterocyclic investigations. 

Incidentally, from these studies there was developed an additional color test to differentiate between alkyllithium and aryllithium compounds, based on the ready exchange of bromine for lithiuift in bromodimethylaniline. 

Generally, the metal-metal exchange is more rapid than the halogen-metal exchange. The reaction of n-butyllithium with di-p-bromophenyl-mercury, for example, yields only di-n-butylmercury and -bromophenyl-lithium. 

2- and 3-Hydroxybenzo[6]thiophens and Related Systems.—During this period, a marked increase in interest in the properties and reactions of these compounds is evident. The composition of the keto-enol equilibrium in some chlorinated 

3- hydroxy-benzo[6]thiophens has been studied by n.m.r. Russian workers have studied tautomeric equilibria, spectra, and chelating properties of the imines of 3-hydroxy-2-formylbenzo[Z ]thiophen, 2-hydroxy-3-formylbenzo[ ]thio-phen, of 2-formyl-3-mercaptobenzo[A]thiophens and of 3-formyl-2-mercaptobenzo[Z ]thiophen. i Benzo[6]thiophen-3(2/T)-ones have been transformed into 3-(l-pyrrolidinyl)- and 3-(l-morpholinyl)benzo[6]thiophens. These 

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There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

Carbocyclic substitution can also be achieved by first introdueing a reactive organomelallic substituent. Preparation of organolithium reagents can be done by one of the conventional melhods. especially halogen-metal exchange or directed lithiation. Table 14.2 gives examples. 

Each of these intermediates can be hthiated in the 2-position in good yield. The reactivity toward hthiation is due to the inductive effect of the nitrogen atom and coordination by oxygen from the N-substituent. A wide variety of electrophiles can then carry out substitution at the 2-position. Lithiation at other positions on the ring can be achieved by halogen—metal exchange 3-hthio and 5-hthioindoles have also been used as reactive intermediates. 

The 6a-halo- and 6,6-dihalo-penicillanates have been shown to undergo halogen-metal exchange to form enolates which can then react with acetaldehyde to form 6-(l-hydroxyethyOpenicillanates (Scheme 34) (77JOC2960, 79TL3805). From (41) the isomeric products were obtained in the ratio (48) (49) (50) = 24 49 27. From (42) the isomeric products were obtained in the ratio (51) (52) (53) = 39 1.5 60. Product ratios were very... 

Pyran, 4-arylimino- C NMR, 3, 585 Pyran, 4-arylimino-2,6-dimethyl-synthesis, 3, 762 Pyran, 2-aryloxytetrahydro-X-ray studies, 3, 621 Pyran, 4-benzyl-isomerization, 3, 666 Pyran, 3-bromodihydro-synthesis, 3, 769 Pyran, -bromodihydro-halogen-metal exchange with t-butyllithium, 1, 474 Pyran, 2-bromotetrahydro- H NMR, 3, 579... 

The halogen-metal exchange reaction was pioneered by Gilman and co-... 

The halogen migration is completely suppressed by halogen-metal exchange when the chloroethynyl group is in position 5 of the pyrazole ring. The concentrations of 3-pyrazolyl and 4-pyrazolyl anions are probably small, and they cannot compete with NH2 anions for chlorine bonded to the acetylenic carbon. 

Dialkylquinolinyl boranes 83 and 86 were prepared from halogen/metal exchange of 3-bromoquinoline (70) with n-BuLi followed by quenching with Et2BOMe and Br-9-BBN, respectively. They are then coupled with bromides 84 and 87 to give 3-substituted quinoline derivatives 85 and 88, respectively (85H2375). 

An example of intramolecular conjugate addition of aryllithium generated by halogen metal exchange reaction of 92 is illustrated in equation 7966. 

It seems likely that the mechanism of the Wurtz reaction consists of two basic steps. The first is halogen-metal exchange to give an organometallic compound (RX -(- M —+ RM), which in many cases can be isolated (12-36). Following this, the organometallic compound reacts with a second molecule of alkyl halide (RX + RM —> RR). This reaction and its mechanism are considered in the next section (10-94). 

Preparation of both a- and p-substituted thiophenes can be achieved by halogen-metal exchange. The synthesis of 3,4-bis(isopropylthio)thiophene is achieved in 60-70% yield from... 

Scheme 7.2. Preparation of Organolithium Reagents by Halogen-Metal Exchange... 

Several examples of intramolecular additions to carbonyl groups by organo-lithium reagents generated by halogen-metal exchange have been reported, such as the two examples shown below. What relative reactivity relationships must hold in order for such procedures to succeed ... 

Section D illustrates formation of carbenes from halides by a-elimination. The carbene precursors are formed either by deprotonation (Entries 14 and 17) or halogen-metal exchange (Entries 15 and 16). The carbene additions can take place at low temperature. Entry 17 is an example of generation of dichlorocarbene from chloroform under phase transfer conditions. 

Silicon linker 76 was used for direct loading of aromatic compounds to supports for the assembly of pyridine-based tricyclics (Scheme 39) [87], Following the initial coupling of an aromatic bromide to the resin by halogen/metal exchange in the presence of tert-butyl lithium, a... 

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