Substitution 2- substituted 2-lithio-1,3-dithianes

The possibility of activating the indole nucleus to nucleophilic substitution has been realized by formation of chromium tricarbonyl complexes. For example, the complex from TV-methylindole (215) undergoes nucleophilic substitution with 2-lithio-l,3-dithiane to give a product (216) which can be transformed into l-methylindole-7-carbaldehyde (217) (78CC1076). 

The dibromobutene 149 could be monosubstituted using 2-lithio-l,3-dithiane as a carboxylic acid precursor, followed by substitution of the remaining bromide with sodium azide as the amine precursor (Scheme 32). The azide was reduce under Staudinger conditions and acy-lated. After separation of the EIZ isomers, further functional group transformations gave the dimethyl-substituted Gly-Gly alkene isostere 152J123 ... 

Carbon nucleophiles of type (iii) add to the arene ligand and do not rearrange examples include the very reactive anions, such as 2-lithio-2-methyl-l,3-dithiane, and the less sterically encumbered anions, such as lithio acetonitrile and /-butyl lithioacetate. In these cases, the anion adds to an unsubstituted position (mainly ortho or meta to Cl, as in 22) and does not rearrange. Then iodine quenching, even after a long period at 25 °C, gives almost exclusively the products from formal substitution for hydrogen, as from (22) in Scheme 8. 

An impressive example is the reaction of [(2,6-dimethyl-1 -fluorobenzene Cr(CO)3] with 2-lithio-2-methyl- 1,3-dithiane at -78 C followed by treatment with trifluoroacetic acid at -78 C.69 Loss of HF leads to the 1,2,4-substitution (tele) product (29) in 62% yield (equation 18).70... 

Activation of aromatic compounds by transition-metal complexes was initially studied with Cr(CO)3 complexes. Nucleophilic addition of 2-lithio-l,3-dithianes to arene-chromium(O) complexes 185 followed usually by iodine-promoted decomplexation affords the corresponding 2-arylated 1,3-dithianes 186. The reaction of //-(toluene)- and (anisole)tricarbonylchromium (185) with compound 161 gave mixtures (52 46 and 10 90, respectively) of ortho and meta substituted derivatives (186) (Scheme 54)244. The meta directing effect was also observed (mainly better than 95%) with amino and fluoro substituted complexes245. 

Vinyl epoxides can be regioselectively opened depending on the substitution at the 2-position of the 2-lithio-l,3-dithiane. Thus, the Sw2 adducts anti-204 were obtained with unencumbered dithiane anions, whereas Sa 2 adducts 205 were produced with sterically encumbered ones (Scheme 58)293. 

Multicomponent linchpin couplings can be carried out with 2-trialkylsilyl substituted 1,3-dithianes 207 and epoxides and was successfully used in the synthesis of natural products182. Tietze and coworkers303 found out that 2-lithio-2-trimethylsilyl-1,3-dithiane 208 reacted with two equivalents of a chiral epoxides in the presence of a crown ether to give first the monoadduct 209, which suffered 1,4-Brook rearrangement304 generating a new dithiane anion 210. Final reaction with an epoxide afforded products 211, which are equivalents of acetone aldol products (Scheme 60). 

The ring opening of enantiopure IV-tosyl aziridines 215 with 2-substituted 2-lithio-l,3-dithianes takes place at the less substituted carbon atom in good yields (59-92%)321. The corresponding adducts gave /9-tosylamino carbonyl compounds after reaction with methyl iodide under acetone reflux. 

Aldehydes react very fast with 2-lithio-l,3-dithiane (161) even at very low temperatures, whereas ketones need higher temperatures175-181. Stereochemical control of the new stereocenter can be achieved with a-substituted aldehydes or conveniently with 2-substituted... 

Lithio-l,3-dithiane and 2-lithio-l,3,5-trithiane have been transformed into 2-substituted benzylamines 273 and 274, respectively, by reaction with a mixture of benzaldehyde and lithium hexamethyl disilazide449. In the case of compound 266, the corresponding derivatives 275 and 276 have also been prepared. Related compounds were used for the preparation of photolabile molecular hosts. 

The lithiation of 1,3-oxathiane (296) takes place with s-BuLi at —78 °C to give 2-lithio-1,3-oxathiane (315), an analogue of 2-lithio-l,3-dithiane (161), but with lower stability487. This intermediate reacts with different electrophiles, such as alkyl halides, carbonyl compounds, benzonitrile, dimethyl disulfide, dimethyl diselenide, trimethylplumbyl acetate and trimethylsilyl, germyl and stannyl chlorides488,489. However, further deprotection of 2-substituted 1,3-oxathianes has not been reported yet. 

The efficient trapping of the cyclohexadienyl anionic intermediates with protons raises the possibility of qnenching with carbon electrophiles. The process is not as general as the proton quench. However, when the nucleophile adds essentially irreversibly, quenching with a limited set of carbon electrophiles is successful. For example, addition of 2-lithio-l,3-dithiane to benzene-Cr(CO)2T, followed by addition of ethyl iodide and then oxidation or addition of a donor ligand (CO, PhsP), produces a cyclohexa-l,3-diene substituted by both acetyl (Me + CO) and the nucleophile (Scheme 47).134,209 insertion of CO occurs, without... 

The reaction usually occurs at the less substituted carbon of the oxirane ring (Scheme 62 and Scheme 67) 293,297 However regioisomeric dithianyl alcohols are obtained from 2-lithio-1,3-dithianes and the protected 3, y-epoxy alcohols shown in Scheme 66 (entry b). The observed regioselectivity is very different when methoxymethyl or benzyl protecting groups are used. This has been explained by the different... 

The methylations of l,3-dilithio-5,7-dimethyl-2,4,6,8-adamantane and of 1,3,5,7-tetrathiacyclooc-tane tetraanion- are of theoretical value only. 1,3,5-Trithiane and both mono- and 2,4,6-trialkyl-substituted derivatives have been metallated - with n-butyllithium and alkylated - with reactive alkylating agents such as primary alkyl iodides or bromides and benzyl bromide (Scheme 73, entries a and b). The metallation of monoalkylated trithianes occurs at one of the two unsubstituted sites and leads eventually to the product having both substituents in the equatorial position. - Thus the high equatorial preference for lithium in 2-lithio-l,3-dithiane is also present in 2-lithio-2-methyl-l,3,5-trithiane. Mer-... 

The commonly encountered C-2 anions derived from 1,3-dithiane and 1,3-oxathiane and their derivatives can be generated by treatment with any of a wide range of bases, but typically n-butyllithium (for 1,3-dithianes) or yec-butyllithium (sometimes necessary for 1,3-oxathianes). There are many instances where the deprotonated heterocycles have been used in synthesis, usually as acyl anion equivalents <8977643, b-95MI 608-05>. Use of 1,3-dithiane derivatives is by far the most common, and the derived anions react with with a very wide variety of electrophiles <69AG(E)639, 8977643), whether or not the dithiane system is initially substituted at C-2. For example, 2-lithio-... 

Substitution m- to the methoxy group, established earlier for arene/chromium tricarbonyl systems (ref. 119), has been used to prepare the 1-(2-dithianyl) derivative of estrone (ref.120). A solution of 2-lithio-1,3-dithian in tetrahydrofuran at -78°C treated with the chromium tricarbonyl complex of HO-protected estrol (from the protected steroid with chromium hexacarbonyl by refluxing in... 

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