Benzene lithiation

However, addition of (+ )-(7 )-l-methyl-4-(mcthylsulfinyl)benzene, to aldehydes and ketones proceeds with low stereoselectivity. An improvement of the 3-syn diaslereoselectivity was found with the zinc reagent obtained by transmetalation of the lithiated sulfoxide with anhydrous zinc chloride38. An improvement of the stereoselectivity was also attained by exchange of the 4-methylphenyl substituent for a 2-methoxyphenyl or 2-pyridinyl substituent. Thus, the introduction of an additional complexing site into the aromatic part of the sulfoxide reagent enhances the stereoselectivity35. 

Lithiated (5)- or r c-(tm-butylsulfinylmethyl)benzene adds to acetone68, benzophenone69, or other symmetrical carbonyl compounds8- 70, respectively, to yield a single diastereomeric alcohol. 

In one case, the addition of lithiated 1,3-dithiane to ( )-l-nitropropene gave an adduct in modest enantiomeric excess (43% ee). In an independent study chiral lithium [(S)-(l-(dimethylamino)-ethyl](methyl)phenylcupratc and lithium mcthoxy(methyl)eupratc were reacted with ( )-(2-ni-troethenyl)benzene to give adducts in 1-2% enantiomeric excess36. 

Cryoscopic measurements in benzene with different concentrations have demonstrated that the compounds remain undissociated. However, 8 and 9 undergo dissociation in solution as shown by means of NMR and cryoscopic measurements. A relatively strong deshielding of the 7Li nuclei has been observed for 8 and 9 but also in the case of the incompletely lithiated clusters 3a and 4a. 

DIRECTED ALDOL CONDENSATIONS threo-4-HYDROXY-3-PHENYL-2-HEPTANONE, 54, 49 DIRECTED LITHIATION OF AROMATIC COMPOUNDS (2-DIMETHYL-AMINO- 5-METHYLPHENYL) DI-PHENYLCARBINOL, 53, 56 DIRECT IODINATION OF POLYALKYL-BENZENES IODODURENE, 51, 94 Disiamylborane, 53, 79 Disodium hydroxylaminedisulfo-nate, 52, 83... 

Benzotellurophene (R = H) is stable only in benzene solution at low temperature, but the diester and disulphonyl derivatives (obtained by the bis-lithiation and subsequent reaction with alkyl chloroformates and p-toluenesulphonic anhydride) as well as the nitroderivative are more stable. 

Geurink and Klumpp measured the protodelithiation enthalpies of 3-lithiopropyl methyl ether, 3-lithiobutyl methyl ether, 5-lithiopentyl methyl ether and 7-5yn-methoxy-2-exo-lithionorbornane in the same study that was discussed in an earlier section for the non-oxygenated compounds n-propyl lithium, n-butyl lithium, 5ec-butyl lithium and 2-norbornyl lithium. The reaction enthalpies for the oxygen-containing lithium species with 5ec-butyl alcohol in benzene were —190 2, —199 4, —190 3 and —199 2 kJmoU, respectively, where all of the lithiated ethers purportedly exist as tetrameric species. 

Klumpp and Sinnige proceeded similarly, using ec-butyl alcohol to protodelithi-ate the anisoles and other lithiated aryl ethers in di-n-butyl ether. The protodelithiation enthalpies for all the lithiated aryl ethers, as monomers, from the latter study are listed in Table 3. The reaction enthalpies for the o- and p-lithioanisoles are ca 20 kJmop more negative from Reference compared to the ones from Reference, presumably due to differences in the reaction media. From the exchange reaction, equation 17, and the enthalpies of formation of phenyl lithium, benzene and the relevant aryl ether, the enthalpies of formation of the lithiated aryl ethers can be derived. The calculated values are shown in Table 3. 

Ethyl phenyl sulphide is lithiated mainly in the ortho position, but with significant amounts of meta and para lithiation and substitution products. Superbases, on the other hand, prefer to deprotonate afkylthio benzenes at benzylic or a-positions, rather than on the ring ... 

Lithium homoenolates derived from carboxylic acids were generated from the corresponding /3-chloro acids by means of an arene-catalyzed lithiation. Chloro acids 186 were deprotonated with n-butyllithium and lithiated in situ with lithium and a catalytic amount of DTBB (5%) in the presence of different carbonyl compounds to yield, after hydrolysis, the expected hydroxy acids (187). Since the purification of these products is difficult, they were cyclized without isolation upon treatment with p-toluenesulfonic acid (PTSA) under benzene reflux, into substituted y-lactones 188 (Scheme 64) . 

Dichlorobenzenes 502 were lithiated in the presence of a catalytic amount of naphthalene (3%) in THF at -78 °C, being then successively treated with two electrophiles, so difunctionalized benzenes 503 were obtained (Scheme 140) . 

The corresponding catalytic version of this reaction was performed using either naphthalene- or biphenyl-supported polymers 594 or 595, respectively, which were prepared by cross-coupling copolymerization of 2-vinylnaphthalene or 4-vinylbiphenyl with vinyl-benzene and divinylbenzene promoted by AIBN in THF and polyvinyl alcohoP . These polymers have been used as catalysts (10%) in lithiation reactions involving either chlorinated functionalized compounds or dichlorinated materials in THF at —78°C and were re-used up to ten times without loss of activity, which is comparable to the use of the corresponding soluble arenes. 

After the optimization of the conditions for the production of o-bromophenyl-lithium to —78°C with a 0.8 s residence time, the scope was extended to sequential Br-Li exchange of both bromine substituents on the benzene ring and the reaction with electrophiles to form o-disubstituted benzene rings. This was done in a four-step reaction in one flow using four-linked microreactors (MRi ). For the second lithiation, the temperature of 0°C was sufficient, which was expected since the aryllithium intermediate is more stable than o-bromophenyllithium. 

A similar difference in product distribution, between ether and THF as solvent, was seen with l,4-di(I-pyrazolyl)benzene (80CB2740), but in this cast either exclusive benzene or pyrazole lithiation could be achieved, depending upon the reaction conditions (Scheme 36). 

Attempts to lithiate the benzene moiety of 1,4-dimethoxyphthalazine and of l-methoxy-4-phenylphthalazine were unsuccessful. However, treatment of 6-chloro-l,4-dimethoxyphthalazine with Bu"Li results in the regioselective lithiation at C-7 <1999T5389>. 

The synthesis of substituted quinazolin-4(. 7/)-ones and quinazolines via directed lithiation has been reviewed <2000H(53)1839>, and the topic has also been briefly discussed in a more general review on the synthesis of quinazolinones and quinazolines <2005T10153>. For example, the lithiation of 4-methoxyquinazoline 312 with LiTMP followed by reaction with acetaldehyde gave only a minor amount of the 2-substituted product 313, with the major product 314 being the result of lithiation at the 8-position in the benzene ring <1997T2871>. 

Directed ort o-metalations are also applied to quinoxalines possessing 2-chloro, 2-methoxy, and pivaloylamino substituents <1993JHC1491>, but successful syntheses via the lithio intermediates are far fewer compared to pyrazines. In fact, no example of metalation on aromatic carbons can be found in the literature since 1994. However, lithiation on benzene carbons of 6-chloro-2,3-dimethoxyquinoxaline was reported <1999T5389>. 

In the introduction of exp. 3 it is mentioned that lithiated acetylenes react very slowly at 70 C with dimethylfonnamide. However, lithiated benzene derivatives in most cases add very quicldy to DMF at these low temperatures. This difference in basicity may explain the specific reaction of the ortho-aryl negative center in dilithiated phenylacetylene with dimethyl-formamide. 

Like their sulfur counterparts (Section 3.2.4.4.2.), 1 -lithiocyclopropyl selenides 1, as generated by reductive lithiation of bis(selanyl)cyclopropanes 173 with butyllithium in diethyl ether or tetrahydrofuran, react with aldehydes or ketones to give /Lhydroxy selenides 2, which rearrange to cyclobutanones 3 on treatment with p-toluenesulfonic acid in wet benzene.174 175 The method was used in a total synthesis of a-cuparenone.175... 

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