Reactions of organolithium reagents with quinazoline derivatives

This review deals with directed and regioselective lithiation of various quinazoline derivatives by the use of alkyllithiums in anhydrous THF at low temperature. Reactions of the lithium reagents obtained from the lithiation reactions with a range of electrophiles give the corresponding substituted derivatives in high yields. The procedures are simple, efficient and general to provide derivatives which might be difficult to produce by other means. In some cases nucleophilic addition of alkyllithiums takes place to produce the corresponding addition products via 1,2-and 3,4-additions. In other cases nucleophilic substitution or halogen-lithium exchange reactions occur.


DMG
RLi For a successful deprotonation to occur, the DMG must possess the somewhat contrary properties of being a good coordinating site for the lithium reagent and a poor electrophilic site for attack by the lithium reagent.The rate and regioselectivity of ortho-lithiation seems to be controlled not only by coordination between the lithium reagent and the heteroatom of the DMG but also by the acidity of the proton at the ortho-position. 12It is not clear which factor is the principal driving force in ortho-lithiation.However, both of them could play a role for lithiation to be successful.For example, strong activators (DMG) tend to have a mixture of the basic requirements for good coordination to lithium reagent and the electron-withdrawing properties required to cause the ortho-protons to become acidic enough to encourage deprotonation efficiently and rapidly.
6][67] In particular, pyridine and quinoline undergo 1,2-addition on reaction with alkyllithiums. 68Also, some fluoroquinolines undergo exclusive addition with butyllithium (BuLi), but in the cases of 2-fluoro-and 7-fluoroquinolines competitive lithiation takes place at the 3 and 8-positions, respectively. 69However, these reactions become completely chemoselective for lithiation by the use of lithium diisopropylamide (LDA) at low temperature.The high reactivity of diazines towards nucleophiles makes the lithiation of such compounds even more difficult than that of most heterocycles.However, successful lithiation of diazines has been achieved by the use of less nucleophilic lithium reagents such as LDA or lithium 2,2,6,6-tetramethylpiperidine (LTMP). 56,703][84][85][86] Therefore, methods for the syntheses and/or modification of this ring system are always of interest.As part of our continuing interest in quinazoline chemistry [87][88][89][90][91][92][93][94][95][96][97][98][99][100][101] and in lithiation chemistry, [102][103][104][105][106][107][108][109][110][111][112][113] we have previously reported on the modification of the quinazoline ring system via lithiation and the organolithium reagents obtained from such reactions are very useful intermediates for the synthesis of substituted quinazoline derivatives that might be difficult to prepare by other means. 114This review will concentrate on the work published in the general area of directed and regioselective ring-lithiation of various quinazoline derivatives.Also, it will discuss the lateral lithiation of various 2-n-alkylquinoxalines and their thione derivatives as well as the nucleophilic addition of alkyllithiums at the imine bonds of such ring systems.

Directed Lithiation of 3-Acylamino-3H-Quinazolin-4-Ones
Directed lithiation of 3-acylamino-3H-quinazolin-4-ones 5 was achieved by the use of LDA in anhydrous THF at -78 C for 1 h under nitrogen and the lithiation reaction was regioselective at the 2-position (Scheme 2). 115Two molar equivalents of LDA were used, the first to remove the NH proton to give the monolithium reagents 6 as yellowish solutions and the second to remove the hydrogen from the 2-position to form the dilithium reagents 7 as yellowish brown solutions (Scheme 2).Reactions of the dilithium reagents 7 with various electrophiles in THF at -78 C for 4 hours afforded the corresponding 2-substituted 3-acylamino-3H-quinazolin-4-ones 8-19 in very good yields (Table 1). 115heme 2. Directed lithiation and substitution of 5.
No deprotonation of the methyl group occurred for the case of compound 5b (R = Me) despite the acidic character of the methyl protons. 123,124][19][20] Reactions with excess iodomethane resulted in excellent yields of 2-alkylated products, but as mixtures of 2-methyl-, 2-ethyl-, and 2-(1-methylethyl)-3H-quinazolin-4-ones. 115The authors concluded that the 2-methyl-3H-quinazolin-4-ones 8 and 14 initially produced underwent lithiation by the excess LDA present in the reaction mixture and were then methylated to give the 2-ethyl derivatives 20 and 22, respectively.These in turn reacted further to give the 2-(1-methylethyl) derivatives 21 and 23, respectively. 115The authors did not attempt to optimize the yield of any individual products from these reactions, but it is likely that control of the total amount of LDA and/or iodomethane would allow the production of 2-methyl derivatives 8 and 14 without formation of any other alkylated products 20-23 (Figure 1).Yield of isolated product after crystallization from ethyl acetate.b 2-Ethyl-3-pivaloylamino-3H-quinazolin-4-one 20 and 2-(1-methylethyl)-3-pivaloylamino-3Hquinazolin-4-one 21 (Figure 1) were produced as side products in 16 and 6% yields, respectively.Directed lithiation of 5a with three molar equivalents of LDA in THF at -78 C for one hour followed by reaction with carbon monoxide at 0 °C for two hours gave a 77% isolated yield of a mixture of azetidinone derivative 26 and indole derivative 27 (Scheme 4). 116Both products involved the incorporation of a diisopropylamide unit from the LDA used for lithiation as well as carbon monoxide.Compound 26 was obtained due to reaction of the lithium intermediate obtained with one molar equivalent of carbon monoxide, while compound 27 involved uptake of two molar equivalents of carbon monoxide.The mechanism of the formation of 26 and 27 has not been investigated.Scheme 4. Directed lithiation and carbonylation of 5a.

Directed lithiation of tert-butylsulfinyl-2-tert-butyl-3H-quinazolin-4-one
The position of a tert-butylsulfinyl group on the 3H-quinazolin-4-one ring system was found to have an effect on the position of lithiation.For example, lithiation of 5-tert-butylsulfinyl-2-tertbutyl-3H-quinazolin-4-one was not successful using excess LTMP at -78 C and starting material along with tarry material were recovered. 120On the other hand, lithiation of

Directed Lithiation of Quinazoline Derivatives
Directed lithiation and substitution of various quinazoline derivatives (see sub-sections below) has been achieved by the use of alkyllithiums followed by reactions with electrophiles to produce the corresponding substituted derivatives. 120,121
When the reaction was carried out with trimethylsilyl chloride (TMSCl) as the electrophile under conditions similar to those used in Scheme 11, 2-tert-butyl-5-(phenylsulfinyl)-6-(trimethylsilyl)quinazoline 60 and a cyclized product 61 (Figure 2) were obtained in 37% yield each. 120 Compound 61 was obtained as a result of a second ortho-directed lithiation on the orthoposition of the phenyl ring followed by a nucleophilic addition of the lithium derivative at the 4-position of the quinazoline ring and finally aromatization by air oxidation. 120
Similarly, lithiation of 7-chloro-4-methoxyquinazoline 62b (Scheme 12; X = H, Y = Cl, R = OMe) with LTMP in THF at -78 C for 0.5 hour gave the corresponding lithium derivative 63b which, on reactions with various electrophiles, gave the corresponding 8-substituted quinazolines 70-74 in 32-85% yields (Table 4). 121Starting material was recovered from reactions that gave low yields.Obtained with the in situ trapping technique in which 62a and trimethylsilyl chloride were simultaneously added to the LTMP solution.d 7-Chloro-8-ethyl-4-methoxyquinazoline 75 (Figure 4) was obtained as a side product in 8% yield due to lithiation and methylation of methylated product 72.
Compound 85 was obtained as a result of replacement of the methoxy group at the 2-position by a butyl group from n-BuLi.While compound 86 was obtained due to replacement of the two methoxy groups at the 2-and 4-positions by two butyl groups from n-BuLi followed by lithiation at the -position of the butyl group at the 4-position and finally reaction of the lithium reagent obtained with acetaldehyde.
On the other hand, treatment of 84 with t-BuLi (two molar equivalents) followed by reaction with acetaldehyde under conditions similar to those used in Scheme 14 gave a mixture of 87 and 88 in 32 and 39% yields, respectively (Scheme 15). 121heme 15.Reaction of 84 with t-BuLi in THF followed by reaction with acetaldehyde.
Compound 87 was obtained due to replacement of the two methoxy groups at the 2-and 4-positions by two tert-butyl groups from t-BuLi.While compound 88 was obtained due to replacement of the methoxy group at the 2-position by a tert-butyl group from t-BuLi followed by chlorine-lithium exchange to produce the corresponding 8-lithium derivative that reacted with acetaldehyde. 121

Lateral Lithiation of 2-n-Alkylquinazoline Derivatives
Lateral lithiation of various 2-n-alkyl-3H-quinazolin-4-ones containing various groups at the 3-position, such as acylamino, methylamino, amino, aryl and a hydrogen, have been attempted by the use of BuLi or LDA at low temperature.The lithiation took place at the benzylic position of the n-alkyl group.These procedures provide efficient syntheses of more complex 2-substituted derivatives in high yields.Similar procedures have been applied to 3-unsubstituted 2-n-alkyl-3Hquinazolin-4-ones, their thiones and 4-substituted quinazolines.
The NMR spectra for compounds reported in Table 7 except for cases where the electrophile was D2O (i.e. products 122 and 127) showed that the two hydrogen atoms of the CH2 group at the 2-position occurred as independent, coupled signals, suggesting they are diastereotopic due to the barrier to rotation around the N-N bond.The crystal structure of compound 118 showed that the plane of the aromatic ring is orthogonal to the plane of the t BuCONH group.This renders the N-N bond as a chiral axis.Orthogonal conformations are known to be significantly more stable than their co-planar counterparts for N,N'-diacylhydrazines, which has resulted in measured barriers to rotation about the N-N bond. 129,130Barriers to rotation have been reported for di-and tetraacylhydrazines, where both nitrogen atoms are of amide type, [131][132][133][134] hydrazines, 135 triazines 136 and tetrazines. 137Also, hindrance to rotation about the N-N bond in 3-acylamino-and 3-diacylamino-3H-quinazolin-4-ones was found to be as high as for hydrazine derivatives (14.7-20.6Kcal mol -1 ). 138,139 4) were obtained as by products in 3-5% yields.Such compounds were produced due to lithiation and substitution on the methyl group of the acetylamino unit at the 3-position.
It was possible to remove the acyl group from products reported in Tables 7-9 under hot basic or acidic conditions to produce 2-n-alkyl-3-amino-3H-quinazolin-4-ones. 115,127For example, hydrolysis of compounds 20-23 with hydrochloric acid or aqueous sodium hydroxide in methanol under reflux removed the acyl group to give the corresponding 3-amino-derivatives in 75% yields. 115However, such forcing conditions for removal of the acylamino group were not always appropriate for some of the more complicated substituents at the 2-position.Yield of isolated product after crystallization from ethyl acetate.
The NMR spectra of products 149-163 (Table 10) showed the expected diastereotopic feature for all the CH2 groups and provided evidence for long-range asymmetric induction at the newly created asymmetric centre(s).This opens up possibilities for novel synthetic approaches to certain types of chiral compounds. 128
The ambient temperature 1 H NMR spectra of compounds 182-184 (Table 11) and 194 (Table 12) showed that the two hydrogens of the CH2 group adjacent to the newly created asymmetric center are diastereotopic, indicating a significant barrier to rotation around the N-N bond even at room temperature. 140learly the process represented in Scheme 23 was general, high yielding and accommodated various complex substituents at the -carbon at the 2-position.
Lateral lithiation of 164 with a lithium reagent (Scheme 24; n-BuLi for R 1 = H or LDA for R 1 = Me, Et) at -78 °C followed by reactions with two molar equivalents of iodomethane or phenyl isocycanate at -78 or 0 °C gave the corresponding disubstituted derivatives 195-201 in high yields (Table 13). 140Clearly, substitution at both the -carbon at the 2-position and the nitrogen attached to the 3-position had taken place.Scheme 24.Lateral lithiation and double substitution of 164.Yield of isolated product after crystallization, usually from diethyl ether.
1 H NMR spectra of compounds 257, 260, 269 and 272-274 showed that the two hydrogen atoms of the CH2 group at the 2-position occurred as independent, coupled signals, suggesting that they are diastereotopic.For compound 263, the two isopropyl methyl protons appear as two broad signals and two separated doublets in its 1 H NMR spectra recorded at room temperature and 100 °C, respectively.The 1 H NMR spectrum of 263 recorded at 150 °C showed significant line-broadening indicative of the onset of equilibration via rotation about the C-N and C-S bonds, thereby confirming the origin of the non-equivalence of the two isopropyl methyl protons.The NMR spectra of compounds 267 and 272 show the expected presence of two racemic diastereoisomers.

Lateral lithiation of 4-substituted 2-n-alkylquinazolines
Lateral lithiation of 2-n-alkylquinazolines 276, substituted in the 4-position by a methoxy or methanethiyl group, have been achieved by the use of 1.1 molar equivalents of n-BuLi at -78 °C in anhydrous THF under nitrogen to produce the corresponding lithium reagents 277 (Scheme 32) as purple solutions. 147Reactions of 277 with various electrophiles afforded the corresponding 2-substituted derivatives 278-308 (Scheme 32) in high yields (Tables 18 and  19). 147cheme 32.Lateral lithiation and substitution of 276.
In some cases, a nucleophilic addition of n-BuLi took place at the C=N bond via 1,2-or 3,4addition to give side products 309-311 and 313 (Figure 6). 147Side product 312 (Figure 6) was formed due to 1,2-addition of n-BuLi followed by methylation at N-1 with iodomethane.Side product 314 (Figure 6) was obtained as a result of addition of n-BuLi at the imine bond at position 4, followed by elimination of the methoxy group and further addition of n-BuLi.Yield of isolated product after purification by column chromatography.b Compound 309 (Figure 6) was obtained in 3-5% yield.
e Compound (Figure 6) was obtained in 1-2%.The 1 H NMR spectra of compounds 278-281 and 294-297 showed that the two hydrogen atoms of the CH2 group at C-2 occurred as independent, coupled signals, verifying that they are diastereotopic. 147The NMR spectra of compounds 287, 291 and 303 showed the expected presence of two racemic diastereoisomers.In the cases of compounds 287 and 303 the two diastereoisomers were separated by column chromatography. 147
The equilibrium lies towards the side having the organolithium compound with the organic group better able to accommodate partial carbanionic character, and it is thus particularly useful for the preparation of aryllithiums by reaction of butyllithium with aryl bromides. 14Because bromine-lithium exchange takes place rapidly under mild conditions, potential side-products such as alkylation of the organolithium by the organic halide are not usually troublesome.However, when the desired organolithium reagent is warmed for subsequent reaction it can couple with the alkyl bromide, producing a coupled product (R-R 1 ). 14If alkylation is a problem, it can be minimised by use of two mole equivalents of t-BuLi as alkyllithium.In this case, bromine-lithium exchange is achieved by the first mole equivalent and the second reacts with the t-BuBr formed to produce isobutane and isobutene.
Bromine-lithium exchange may involve single electron transfer and radical intermediates (Scheme 34) or proceed through nucleophilic substitution at the bromine via ate complex formation (Scheme 35). 12It is believed that alkyl bromides react with alkyllithiums via the radical mechanism, while aryl bromides react via ate complexes as intermediates. 12,56heme 34.Bromine-lithium exchange of alkyl bromide via radical intermediate.

Scheme 35.
Bromine-lithium exchange of aryl bromide via ate complex intermediate.
Bromine-lithium exchange of 6-bromo-3H-quinazolin-4-one 315 was successful by the use of MeLi then t-BuLi at -78 C in anhydrous THF. 148Treatment of 315 with MeLi (1.1 molar equivalents) for 5 minutes gave the monolithium reagent 316 by removing the NH proton, followed by bromine-lithium exchange using t-BuLi (2.2 molar equivalents) to give the dilithium reagent 317 (Scheme 36) as a yellow solution.Reactions of 317 with a range of electrophiles at -78 C for 2 h gave the corresponding 6-substituted derivatives 318-326 (Scheme 36) in 81-91% yields (Table 20). 148heme 36.Bromine-lithium exchange of 315 followed by reactions with electrophiles.Yield of isolated product after crystallization from methanol or ethyl acetate.
No N-substitution was observed, even when excess iodoethane (2 molar equivalents) as electrophile was used. 148In the 1 H NMR spectrum of 326 the methyl and CH protons of the iso-propyl groups appeared as broad signals at room temperature and as doublet and heptet signals, respectively at 80 C. 148This confirms the restricted hindered to rotation about the C-S and C-N bonds at room temperature.

Addition of Alkyllithiums to Substituted Quinazoline Derivatives
Nucleophilic addition of alkyllithiums takes place at the imine bond of the quinazoline moiety to produce either 1,2-or 3,4-addition products.However, regioselective lithiation can take place by the use of less nucleophilic lithium reagents.
This result contrasts sharply with the situation of 3H-quinazolin-4-one, which does not react at all with alkyllithiums (n-BuLi, t-BuLi and MeLi) under similar conditions, which is an indication of the important role played by the sulfur atom in this reaction. 149The authors suggested that the reason for this difference could be due to the thiolate anion in 344 being less effective at donating negative charge to the ring than its oxygen counterpart.The acquisition of negative charge by the ring would be expected to deactivate the ring towards nucleophilic attack by alkyllithiums. 149

Addition of alkyllithiums to substituted quinazolines
0][151] For example, reactions of 4-substituted quinazolines 105 and 348 with 1.2 molar equivalents of alkyllithiums took place smoothly and cleanly at -78 C in anhydrous THF for 1 h. 149The lithium reagent reagents 349 were presumably obtained as intermediates and after quenching with aqueous ammonium chloride solution gave the corresponding 4-substituted 2-alkyl-1,2-dihydroquinazolines 350-357 (Scheme 42) in high yields (Table 22). 149Lithiation of 348 with LDA under similar reaction conditions was not successful. 149heme 42.Addition of alkyllithiums to 4-substituted quinazolines 105 and 348.Yield of isolated product after column chromatography.
Reaction of 4-methoxyquinazoline 105 with excess t-BuLi gave a mixture of 2-tert-butyl-4methoxy-1,2-dihydroquinazoline 356 and 2-tert-butyl-1,2-dihydro-3H-quinazoline-4-one 358 (Scheme 43) in proportions that depended on the molar equivalents of t-BuLi used (Table 23). 149ompound 358 was the very product that might have been expected from the reaction of 3H-quinazolin-4-one with t-BuLi, but, of course, this direct reaction of 3H-quinazolin-4-one with t-BuLi did not occur. 149Compound 358 was obtained due to nucleophilic addition of t-BuLi at the 2-position of 105 followed by a C=O formation at the 4-position.Scheme 43.Reaction of 4-methoxyquinazoline 105 with excess t-BuLi.Yield of isolated product after column chromatography.
Reactions of 4-substituted 2-phenylquinazoline 359 with one molar equivalent of alkyllithiums (n-BuLi and MeLi) at -78 C in anhydrous THF for one hour gave 4,4-dialkyl-3,4dihydro-2-phenylquinazolines in moderate yields along with significant quantities of starting material 359. 149Use of 2.2 molar equivalents of alkyllithium (n-BuLi, t-BuLi and MeLi) at -78 C in THF for one hour gave 360-362 (Scheme 44) in high yields (Table 24). 121,149Products 360-362 were obtained via 3,4-nucleophilic addition of alkyllithiums followed by displacement of the substituent (SMe, OMe or O(CH2)2OMe) as an anion and further addition of alkyllithium.Reaction of 359 with t-BuLi gave only a modest yield of product 362 due to formation of byproducts which were not identified. 149heme 44.Addition of alkyllithiums to 4-substituted 2-phenylquinazoline 359.Yield of isolated product after column chromatography.

Conclusions
Directed ortho-lithiation of 3-acylamino-3H-quinazolin-4-ones with LDA at -78 C in anhydrous THF is regiospecific and reactions of the lithium regents obtained with various electrophiles provided access to a broad variety of 2-substituted derivatives in high yields.Similar procedures have been developed for directed lithiation and substitution of 3-aryl-, tert-butylsulfinyl-3Hquinazolin-4-ones, phenylsulfinyl-, chloro-and methoxyquinazolines.Such procedure provided derivatives previously unavailable or that might be difficult to prepare by other means.
Lateral lithiation of 3-acylamino-2-n-alkyl-3H-quinazolin-4-ones, at the benzylic position of the n-alkyl group, has been achieved by use of n-BuLi or LDA at low temperature.Also, lithiation of 3-amino-and 3-methylamino-2-n-alkyl-3H-quinazolin-4-ones at low temperature in THF followed by reactions with several electrophiles provides various 2-substituted derivatives in high yields.The procedure is particularly useful in that there is no protecting group to be removed in another step from the amino function.A similar procedure has been developed for the side-chain lithiation and substitution for 3-aryl-and 3-unsubstituted 2-n-alkyl-3H-quinazolin-4-ones and their thione derivatives.
A simple and convenient method for the side-chain substitution of 4-substituted 2-n-alkylquinazolines, with a methoxy or methylthio group at position 4, has been reported and allows synthesis of various 2-substituted derivatives in high yields.Also, lithiation and substitution of several other quinazoline derivatives have been achieved to provide a range of substituted derivatives.
Bromine-lithium exchange of 6-bromo-3H-quinazolin-4-one has been achieved by the use of MeLi and t-BuLi at -78 C in THF.Reactions of the dilithium reagent thus obtained with electrophiles give the corresponding 6-substituted 3H-quinazolin-4-ones in high yields.
university would permit it, Keith invited him back to the UK as a postdoctoral researcher and found support funding.Keith did the same on two more occasions and the latter has been continuous for the last 11 years.During these periods he has formed a very close working relationship with Keith's group and they have collaborated extensively.Together they have over 50 joint publications, including ones in all of the major areas of research in which Keith's group is involved and several reviews.They have recently started up a spin-out company to commercialise some of their innovations in the area of catalysis.He has acted as the Technical Director for the Company since August 2006.His research interests are primarily in the development of novel organic synthetic methods, especially ones that are "greener" than traditionally, and synthesis of compounds with interesting properties.Particular current research projects involve use of zeolites and solid-supported reagents and catalysts to gain selectivity in organic reactions; lithiation reactions, which they have used to devise novel heterocyclic ring syntheses and to introduce selectivity into aromatic and heterocyclic substitution reactions; heterocyclic chemistry and design and synthesis of novel compounds with interesting chemiluminescent or other photoactive properties.He is currently a Professor of Organic Chemistry since 2006 at Tanta University, Faculty of Science, Department of Chemistry, Egypt (on sabbatical leave to the UK).Dr Amany S. Hegazy Amany S. Hegazy received her B.Sc. degree in Chemistry from Tanta University, Egypt.She received her MPhil degree from Swansea University, UK in 2006 and her Ph.D. degree from Cardiff University, UK in 2009.She carried out her postgraduate studies under the supervision of Professor Keith Smith.Her research focused on the green synthetic methods of heterocycles and aromatics via use of organolithium reagents as intermediates.

Table 4 .
121thesis of 8-substituted quinazolines 64-74 according to Scheme12121 a Yield of isolated product after column chromatography.bYield after purification by column chromatography and sublimation.c

Table 5 .
121thesis of 7-substituted quinazolines 78-83 according to Scheme 13121 a Yield of isolated product after column chromatography.b Obtained with the in situ trapping technique in which 76 and Me3SiCl were simultaneously added to the LTMP solution.

Table 7 .
127hiation and substitution of 115 (R 1 = H; R 2 = Me, t-Bu) using n-BuLi as the lithium reagent according to Scheme 22127 a Yield of isolated product after crystallization from ethyl acetate.

Table 8 .
115hiation and substitution of 115 (R 1 = Me, Et; R 2 = t-Bu) using LDA as the lithium reagent according to Scheme 22115 a Yield of isolated product after crystallization from ethyl acetate.

Table 9 .
115hiation and substitution of 115 (R 1 = Me, Et; R 2 = Me) using LDA as the lithium reagent according to Scheme 22115 a Yield of isolated product after crystallization from ethyl acetate.b-d Compounds 146-148 (Figure

Table 11 .
140hiation and substitution of 164 (R 1 = H, Me, Et; R 2 = H) using n-BuLi or LDA according to Scheme 23140 a Yield of isolated product after crystallization, usually from diethyl ether.Table 12.Lithiation and substitution of 164 (R 1 = H, Me, Et; R 2 = Me) using n-BuLi or LDA a

Table 13 .
140hiation and double substitution of 164 according to Scheme 24140

Table 14 .
141hiation and substitution of 203 according to Scheme 26141

Table 16 .
143hiation and substitution of 221 (R = Me, Et) according to Scheme 28143 a Yield of isolated product after crystallization.

Table 17 .
146hiation and substitution of 255 according to Scheme 31146

Table 18 .
147hiation and substitution of 276 (X = S) according to Scheme 32147

Table 19 .
147hiation and substitution of 276 (X = O) according to Scheme 32147

Table 23 .
149lds of 356 and 358 from reaction of 105 with t-BuLi according to Scheme 43149