Carbamates directed lithiation

The preference for 8-metalation, seen with the 2-phenyl-, 4-pivalamido-, and 2-butyl-5-ethoxyquinolines, is continued, as shown by the absence of any 6-substituted products from the directed lithiation of 7-substituted derivatives. This type of preference is not seen with 6-substituted compounds, however, and a mixture of the 5,6,7-trisubstituted, and both possible disubstituted products, was obtained on treatment of the lithio derivative of the 6-carbamate with TMSC1 at -78°C [78JOM(336)l]. 

Directed ortho lithiation of 2-, 3-, and 4-pyridyl diethylcarbamates provides a route to a variety of polysubstituted pyridines. The 2- and 4-pyridyl carbamates are metallated at C-3, whereas the 3-pyridyl carbamate is lithiated at C-4. For example, 3-pyridyl diethylcarbamate (118) on treatment with sec-BuLi/TMEDA/THF (TMEDA = N,N,A, Af -tetramethylethylenediamine) at — 78°C followed by McjSnCI gives 3,4-disubstituted pyridine 120 in 83% yield via lithiated intermediate 119. On warming, the metallated pyridyl... 

An iterative directed-metallating approach to 4,5-substituted indoles starting from gramine was documented <05T6886>. Treatment of gramine 173 with tert-butyllithium and trimethylsilylmethylazide followed by Boc protection gave 4-aminoindole 174. Directed lithiation by the carbamate followed by treatment with DMF gave indole 175. 

Directed lithiation of (9-aryl carbamates provides a method for the formation of 2-substituted phenols. For example, quenching with dimethylformamide (DMF) gave the aldehyde 130 (1.120). Interestingly, if no electrophile is added but the mixture is allowed to warm to room temperature, then a rearrangement takes place, in which the aryllithium species undergoes attack on the carbamate group (1.121). 

For example, the 5-(tert-butyldimethylsilyloxy)pentyl carbamate 159a was converted to the enantiomerically emiched (>95% ee) stannane 159b via sparteine-mediated deprotonation. Then an aUyl chloride unit was elaborated, finally, the (S)-lithium intermediate 179 was generated by lithiodestannylation. The (li ,2S)-2-vinylcyclopentyl carbamate 180 was produced with essentially complete enantio- and diastereoselectivity [Eq. (46)] [98]. AUyl chloride (178,H for Bu3Sn) and epoxides do not survive direct lithiation [117]. 

In aromatic compounds, potent but frustrated (their ortho positions blocked) directing groups may lead to lithiations at positions other than ortho. For example, when the carbamate 610 is treated with LDA in refluxing THE, lithiation occurs at a remote position (not peri, note) and an anionic Fries rearrangement ensues to give 611 (see Section I.B.l.d). Lactonization gives 612 (Scheme 239). ... 

Carbamate 613 under the same conditions also undergoes remote lithiation and a remote anionic Fries rearrangement, and then the product amide 614 proceeds to direct a remote benzylic lithiation, even though it has a free ortho position. Finally, the benzylic organo-lithium 615 cyclizes onto the amide to form 616—all in one pot (Scheme 240) . 

A very attractive and convenient method to generate enantiomerically pure a-lithiated alcohol derivatives directly consists of the deprotonation of an achiral alkyl carbamate in the presence of (—)-sparteine (7,15-diazatetracyclo[7.7.1.02-7.01Ol5]heptadecane)42. 

Other examples of intramolecularly coordinated (by 0 as well as by N groups) organolithium compounds can be found in Setzer and Schleyer (2) and Seebach (4). Two recent reviews are also pertinent. Klumpp (34) deals with 0- and N-assisted lithiation and carbolithiation of nonaromatic compounds, and Snieckus (34a) deals with directed (by amide and carbamate groups) ortho metalation in polysubstituted aromatics. 

The starting point for the metallation sequence was /7-chlorophenol, whose directing power was first maximised by conversion to the carbamate 3. Ortholithiation and reaction with N,N-diethylcarbamoyl chloride gave the amide 4. The second ortho carbonyl substituent was then introduced simply by allowing the lithiated carbamate 5 to undergo an anionic ortho-Fries rearrangement to the bis-amide 6. The phenol was protected as its methyl ether 7. 

The simple compound 79 is an aggregation pheromone of the fruit fly Drosophila mulleri. Hoppe proposed to synthesise it by asymmetric deprotonation and retentive methylation of a carbamate derivative of n-dodecanol.8 Given that the carbamate group (required for directed oc-lithiation) must, at the end of the synthesis, be removed from the molecule, the best choice is the tetramethyloxazolidine-derived 81, readily formed by acylation with the carbamoyl chloride 80. Lithiation of 81 with excess s-BuLi-(-)-sparteine gives, by asymmetric deprotonation, a configurationally stable complex of organolithium 82 with (-)-sparteine. 

Sibi, M. P., Snieckus, V. The directed ortho lithiation of O-aryl carbamates. An anionic equivalent of the Fries rearrangement. J. Org. Chem. 1983,48, 1935-1937. 

An unprecedented O C 1,3-carbamoyl migration of the ortto-lithiated species 252 in the course of a directed metalation reaction of carbamates 251 to give the sahcy-lamides 253 was first reported by Sibi and Snieckus (equation 116) . This approach was afterwards developed in a series of investigations . ... 

Now comes the clever bit. Lithiation of 63 with LDA occurs next to Br at the only remaining free position 64 but the halogen dance (chapter 32) exchanges Br and Li so that Li is next to the excellent ortho-directing carbamate 65. Protonation with EtOH gives 66 ready for introduction of the fourth and last OH group. 

Direct ortho lithiation of O-aryl carbamates and 0 to C carbamoyl migration to give salicylamides. 

Heteroatom-facilitated lithiations , Gschwend, H. W. and Rodriguez, H. R., Org. React., 1979, 26, 1 Directed metallation of 7r-deficient azaaromatics strategies of functionalisation of pyridines, quinolines, and diazines , Queguiner, G., Marsais, F., Snieckus, V., and Epsztajn, J., Adv. Heterocycl. Chem., 1991, 52, 187 Metallation and metal-assisted bond formation in 7r-electron deficient heterocycles , Undheim, K. and Benneche, T., Heterocycles, 1990, 30, 1155 Directed ortho metallation. Tertiary amide and O-carbamate directors in synthetic strategies for polysubstituted aromatics , Snieckus, V., Chem. Rev., 1990, 90, 879. 

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