Process lithiation

Lithiated indoles can be alkylated with primary or allylic halides and they react with aldehydes and ketones by addition to give hydroxyalkyl derivatives. Table 10.1 gives some examples of such reactions. Entry 13 is an example of a reaction with ethylene oxide which introduces a 2-(2-hydroxyethyl) substituent. Entries 14 and 15 illustrate cases of addition to aromatic ketones in which dehydration occurs during the course of the reaction. It is likely that this process occurs through intramolecular transfer of the phenylsulfonyl group. 

When lithiated, the ring strain of the three-membered heterocycle remains important, and this strain, combined with a weakening of the a-C-O bond, due to its greater polarization, make metalated epoxides highly electrophilic species [2], They react with strong nucleophiles (often the base that was used to perform the a-deprotonation) to give olefins following the elimination of M2O (Scheme 5.2, Path B), a process often referred to as reductive alkylation . 

Finally, metalated epoxides undergo isomerization processes characteristic of traditional carbenoids (Scheme 5.2, Path C). The structure of a metalated epoxide is intermediate in nature between the structures 2a and 2b (Scheme 5.2). The existence of this intermediacy is supported by computational studies, which have shown that the a-C-O bond of oxirane elongates by -12% on a-lithiation [2], Furthermore, experimentally, the a-lithiooxycarbene 4a (Scheme 5.3) returned cydo-pentene oxide 7 among its decomposition products indeed, computational studies of singlet 4a suggest it possesses a structure in the gas phase that is intennediate in nature between an a-lithiocarbene and the lithiated epoxide 4b [3],... 

Two important observations were made in this study of magnetite [101]. Firstly, the [Fe2]04 spinel framework remained intact during the lithiation process, and secondly, the interstitial space of 8a tetrahedra and 16c octahedra provided a three-... 

During electrochemical reduction (charge) of the carbon host, lithium cations from the electrolyte penetrate into the carbon and form a lithiated carbon Li rCn. The corresponding negative charges are accepted by the carbon host lattice. As for any other electrochemical insertion process, the prerequisite for the formation of lithiated carbons is a host material that exhibits mixed (electronic and ionic) conductance. 

The electrochemical performance of lithiated carbons depends basically on the electrolyte, the parent carbonaceous material, and the interaction between the two (see also Chapter III, Sec.6). As far as the lithium intercalation process is concerned, interactions with the electrolyte, which limit the suitability of an electrolyte system, will be discussed in Secs. 5.2.2.3,... 

Borole complexes ( 6.5.3), normally prepared from dihydroboroles by loss of hydrogen during the complexation process, are also available using a borole dianion via lithiation of dihydroboroles . ... 

OS 70] [R 25] [P 51] The total yield of a combined lithiation and alkylation of a ketone to a chiral alcohol was increased to 93% by micro-reactor processing, whereas the batch process gave only an 83% yield [83]. This increase in yield is related to reduced y9-elimination of the unstable Li intermediate. 

This ligand has also been used by the same authors to promote the addition of ZnMe2 to a functionalised a,(3-unsaturated ketone in the asymmetric key step of the first enantioselective synthesis of (-)-frontalin. This synthesis started with the naphthalene-catalysed lithiation of a chlorinated ketal (Scheme 4.15) that, after several transmetalation processes, was trapped by reaction... 

An unusual two-component domino Michael/aldol process was described by Tomioka and coworkers in which the initiating step is the formation of an a-lithiated vinyl-phosphine oxide [28] or vinyl phosphate [29]. 

As shown in Scheme 2.20, selective lithiation of substrate 2-87 by treatment with LDA in THF at -78 °C triggers an intramolecular Michael/intermolecular aldol addition process with benzaldehyde to give a mixture of diastereomers 2-90 and 2-91. 2-91 was afterwards transformed into 2-92, which is used as a chiral ligand for Pd-catalyzed asymmetric allylic substitution reactions [29]. 

Additions of stabilized carbanions to imines and hydrazones, respectively, have been used to initiate domino 1,2-addition/cyclization reactions. Thus, as described by Benetti and coworkers, 2-subshtuted 3-nitropyrrolidines are accessible via a nitro-Mannich (aza-Henry)/SN-type process [165]. Enders research group established a 1,2-addition/lactamization sequence using their well-known SAMP/ RAMP-hydrazones 2-308 and lithiated o-toluamides 2-307 as substrates to afford the lactams 2-309 in excellent diastereoselectivity (Scheme 2.72) [166]. These compounds can be further transformed into valuable, almost enantiopure, dihydro-2H-isoquinolin-l-ones, as well as dihydro- and tetrahydroisoquinolines. 

Taylor and coworkers also developed similar twofold intramolecular Li-mediated carboadditions [193]. In contrast to the aforementioned sequences, they were able to utilize functionalized triple bonds and to trap the intermediate lithiated species such as 2-352 with other electrophiles besides a proton. Such a 2.2.2 process will be discussed in the following section, which relates to threefold anionic domino processes. 

Leaving the (retro-)aldol addition-initiated threefold anionic domino processes, we are now describing sequences which are initiated by a SN-type transformation. In particular, domino reactions based on SN/1,4-Brook rearrangement/SN reactions are well known. For example, the group of Schaumann obtained functionalized cyclopentanols of type 2-461 by addition of lithiated silyldithioacetals 2-458 to epoxy-homoallyl tosylates 2-459 in 41-75% yield (Scheme 2.106) [248]. 

Recently, nitration of organolithiums and Grignards with N204 has been developed for the preparation of certain kinds of nitro compounds (Eqs. 2.14 and 2.15).31 The success of this process depends on the reaction conditions (low temperature) and the structure of substrates. For example, 3-nitrothiophene can be obtained in 70% overall yield from 3-bromothiophene this is far superior to the older method. 3-Nitroveratrole cannot be prepared usefully by classical electrophilic nitration of veratrole, but it can now be prepared by direct o>7/ o-lithiation followed by low-temperature N204 nitration. The mechanism is believed to proceed by dinitrogen tetroxide oxidation of the anion to a radical, followed by the radical s combination. 

The readily available, nonracemic indoloquinolizidine template 471 has been studied as a substrate for the construction of frameworks related to bioactive natural products. The lithiated dithiolane 472 served a dual role in its reaction with 471, both as a nucleophile giving the non-isolated intermediate 473, and, in the same pot, as an electrophile during the quench process. This reaction afforded compound 474 as a single diastereomer <2006TL1961>. 

Figure 6 shows the entropy curve obtained during the lithiation process. Starting from a high and positive value of 60J/(mol.K) at x 0, AS(x)... 

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