Acyl Anion Synthons: Benzotriazole Stabilized Compared to Classical

Issue in Honor of Prof. Armand Lattes ARKIVOC 2006 (iv) 119-151

Acyl anion synthons: benzotriazole stabilized compared to classical

Alan R. Katritzky*and Kostyantyn Kirichenko

Center for Heterocyclic Compounds, University of Florida, Department of Chemistry, Gainesville, Florida 32611-7200, USA E-mail: [email protected]

Dedicated to Professor Armand Lattes to celebrate his 50 years of great research and teaching activity

Contents

1. Introduction 2. Classical acyl anion synthons 2.1. Cyanohydrins 2.2. Azolium stabilized acyl synthons 2.3. Thioacetals 2.4. Alkyl vinyl ethers, vinyl sulfides and vinyl selenides 3. Benzotriazole stabilized acyl anion synthons 3.1. Alkyl vinyl ethers, vinyl sulfides and vinyl selenides 3.2. N-[Ethoxy(aryl)methyl]benzotriazoles - aroyl anion synthons 3.3. Bis(benzotriazolyl)methane derivatives 3.4. 1-(1-Methylsulfanylalkyl)benzotriazoles 3.5. 1-(Carbazolylalkyl)benzotriazoles 3.6. Application to the synthesis of 1,6-diketones 4. Propenoyl anion synthons 5. Propargoyl anion synthons 6. References and notes

1. Introduction

Increasing need for new methods to construct complex molecules, especially natural products with a variety of functionalities, promoted the development of strategies utilizing temporary reversal (“umpolung”) of the reactivity of functional groups. This important concept was first introduced in 1962–1965 by Froling and Arens,1 Truce and Roberts,2 and Seebach and Corey3,4 in their applications of thioacetals to the synthesis of carbonyl compounds.5-7

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The account provides a brief survey on applications of important classical acyl anion synthons to illustrate the advantages and limitations of the major methods available and then attempts to assess the utility of the diverse benzotriazole-stabilized acyl anion synthons, developed by our research group over the last 15 years. The benzotriazole moiety, which can be introduced easily to a molecule, possesses several properties that are relevant to an acyl anion synthon: especially regioselective stabilization of an α-carbanion and ease of removal in the final stage.8 The methodology has been applied to the synthesis of a large variety of simple and functionalized alkenyl, alkynyl, aryl/heteroaryl, and alkyl ketones plus alkenoyl-, alkynoyl-, aroyl-, and heteroaroylsilanes.

2. Classical acyl anion synthons

2.1. Cyanohydrins The venerable cyanide ion catalyzed dimerization of aromatic and heterocyclic aldehydes 1 to benzoins 3 by formation of key intermediates 2b, which are nitrile-stabilized acyl anion synthons (Scheme 1).

O O OH + CN RH RCN RCN 1 2a 2b O 1 HO O O OH H H RH R - CN- R R OH CN R 3

RCN EWG 2b OH EWG OEWG R NC R 4

1 1 EWG = COR , CO2R , CN

Scheme 1

Carbanions of type 2b add to double bonds by Michael type addition to give 1,4-diketones, 4-ketonitriles, and 4-ketoesters of general structure 4 (Scheme 1).9-11

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2.2. Azolium stabilized acyl synthons

It is known that vitamin B1 (thiamine) converts aliphatic aldehydes to acyloins. The catalytic activity is associated with thiazolium part 5 (Y = S) of the vitamin (Scheme 2).12-16

1 1 O R1 R R Y Y OH Y base RH E1 2 2 2 N R R R N R N 3 R3 3 X R R 6 5 (Y = S, NR)

1 R 1 Y OH R 1 O Y E + 2 N 1 R R cleavage RE 2 3 R N R 3 R

Scheme 2

Thiazolium and other azolium salts of structure 5, including imidazolium and benzimidazolium, were successfully employed as catalysts in benzoin – acyloin condensations of aliphatic and aromatic aldehydes 1 (Scheme 3).17

O 1 1 R Y OH O R Y O OH O RH OH H H + 6 5 6 2 N 2 N R H 1 R R R R R R R3 R3 R 3

Scheme 3

Addition of aldehydes 1 to α,β-unsaturated ketones, esters and nitriles of structure 7 (Scheme 4)9,11 and similar addition of acylsilanes to α,β-unsaturated ketones and esters18 in the presence of 5 provide access to carbonyl derivatives 8. Azolium 5 catalyzed syntheses of heteroaromatic ketones 10 and ketimines 12 (and subsequently 1,2-diketones 13) by the reaction of aldehydes 1 with heteroaryl halides 919 and imidoyl chlorides 11,20 respectively, have also been reported.

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EWG O 7 5, base R EWG 8

O Het-X 9 O Het RH 5, base R 10 1 R1 N 11 1 + O 2 R N O H O O R Cl 3 2 5, base R2 R R R 12 13

Scheme 4

2.3. Thioacetals21

1,3-Dithianes The nucleophilic acylation by reaction of carbanions 15, derived from 1,3-dithianes 14, with electrophiles followed by hydrolysis of the intermediates 16 forming a carbonyl compound 17 is still the most widely used umpolung method (Scheme 5).7,22

O base E1 O SS SS SS 1 RH 1 RE RH R RE 1 1415 16 17 equivalent to O C R

Scheme 5

1,3-Dithianes have been successfully used in reactions with (i) alkyl halides, sulfonates and triflates;23-28 (ii) oxiranes23,29-31 and three- to six-membered cyclic ethers;29 (iii) carbonyl compounds;23,32,33 (iv) acid halides34,35 and chloroformates;29,36,37 (v) imines;23 and (vi) electron deficient olefins38-40 (Scheme 6).

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O 1 2 ( )n R R CO S R2 S S (ii) (iii) S OH R 1 R ( )n R OH

1 1 S R X R COX SS O (i) SS (iv) S 1 RR R R1 R 15

2 EWG NR 2 R NH 1 S EWG R S R1 R (vi) (v) S S R

Scheme 6

Unfortunately, the hydrolysis of 1,3-dithianes under mild conditions has proved difficult. High yields of carbonyl compounds were reported in the presence of mercury (II),25-27,31,38 in few cases with copper (II) ions,32 or by oxidation (see later).

Bis(alkylthio)acetals Alkylation of bis(alkylthio)acetals 18 (Scheme 7) using an alkali metal amide followed by reaction with electrophiles occurs in low yields.1 However, an alternative approach involving initial addition of a Grignard reagent to a dithioester 19 followed by reaction of anion 20 with an electrophile (ketones, aldehydes and chloroformates) is a useful synthetic method. Thus α- hydroxy ketones and α-ketoesters were obtained in good yield but required mercuric ion promoted hydrolysis of thioketals 21.41

Et Et Et S 2+ S Et EtMgI S E1 S Hg O R Et Et S R S 1 SEt R S R E R MgI E1 18 19 20 21 17

Scheme 7

Bis(arylthio)acetals The use of bis(phenylthio) acetals 22 rather than bis(alkylthio) acetals 18 results in increased anion 23 stabilization (Scheme 8). Initial studies employed alkali metal amides in liquid ammonia and showed satisfactory results only with alkyl halides.1 Later, alternative procedures using lithiation of 22 with butyllithium in the presence of TMEDA42,43 and a copper derivative of

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2344 were introduced. Anions 23 were successfully reacted with alkyl halides,2,43,45 aldehydes and ketones,42,43,46,47 acid chlorides,42 and electron deficient olefins.44,48 ,49 However, butyllithium caused carbon – sulfur bond cleavage.43,50 Similarly with thioketals 16 and 21, hydrolysis of 24 to ketones 17 requires heavy metal catalysis (Hg2+, Cu2+, Ga3+).44,45,51 Hydrolysis intermediates 21 with TFA was also reported, but caused in some cases elimination of phenylthio group instead to give a vinyl sulfide.42

S Ph 1 base S Ph E1 E SPh O R R 1 SPh SPh R S Ph R E 22 23 24 17

Scheme 8

Oxidized thioacetals Oxidation of a dithioacetal sulfur atom facilitates generation of a carbanion. Methyl methylthiomethyl sulfoxide 25a, ethyl ethylthiomethyl sulfoxide 25b and 1,3-dithiane-1-oxide 25c have been employed as acyl anion equivalents for the preparation of ketones (Scheme 9). Acyl anion synthon 25a (R = H) was used for the preparation of symmetrical52,53 and cyclic54,55 ketones by reaction with excess base (NaH, KH) and an alkyl halide or a dihaloalkane, respectively. The preparation of α-hydroxyketones has been achieved by the reaction of 25a (R = alkyl) with LDA and aldehydes.56 Reagent 25b (R = H) enabled the preparation of unsymmetrical ketones 28 via sequential alkylation with a base (BuLi or LDA) and an alkyl halide.57 In the reactions with α,β-unsaturated ketones and esters, conjugate addition of lithiated 25b (R = alkyl) dominated to give 1,4-dicarbonyl systems.58 2-Substituted 1,3-dithiane-1-oxides 25c were readily deprotonated with LDA followed by reaction with a variety of electrophiles, including alkyl halides, aldehydes, and ketones.59 Adducts 26 and 27 were converted to ketones 17 and 28 by acidic hydrolysis using hydrochloric acid,52 or perchloric acid,57,59 and in the presence of a mercury salt to avoid formation of disulfides.57,58

1 O 1 R E O R S R1 1) base S 17 1 R R 1 E 2 2) E 1 SR SR2 1) base R O S O 2 1 2 2 1 E 25a R , R = Me 26 2) E E 1 2 (R = H) 2 E E 25b R1, R2 = Et SR 1 2 27 28 25c R , R = -(CH2)3- Scheme 9

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Hydrolysis of dithioketals Hydrolysis of the dithioacetal (ketal) group to a carbonyl group21,60 is the crucial stage and often extremely difficult to achieve, especially for compounds having complex structure and sensitive groups.61,62 The problem is that the equilibria of Scheme 10 favor the dithioketal by large factors and only methods which remove the thiol products irreversibly are suitable for the hydrolysis.

O + RSH H2O R1 R2

R1 S R 2 R S R R3OH 3 R1 O R + RSH 2 R O R3

Scheme 10

Frequently utilized procedures for hydrolysis are (i) transition metal ion (Hg, Ag, Cd, Cu, Ga) induced hydrolysis, which involves metal thiolate formation; (ii) oxidation of sulfur to make it less nucleophilic; (iii) alkylation (typically with methyl iodide, trimethyl(or ethyl)oxonium tetrafluoroborate, methyl fluorosulfonate or trityl methyl ether) to a sulfonium salt followed by elimination of sulfide in the presence of base; and (iv) transacetalization to highly reactive carbonyl derivatives using formaldehyde, glyoxylic acid,62 ,63 or benzaldehydes.64 Trityl methyl ether in the presence of catalytic trityl perchlorate was reported to cleave selectively a diethyl thioketal in the presence of a diphenyl thioketal or 1,3-dithiane.65 Interestingly, gallium chloride mediated hydrolysis affords transformation of dithioketals into the corresponding ketones whereas dithianes and dithioacetals of aldehydes were unreactive.51

2.4. Alkyl vinyl ethers, vinyl sulfides and vinyl selenides Alkyl vinyl ethers 29 have been used as acyl anion equivalents (Scheme 11).66-71 Deprotonation of 29 requires the use of tert-butyllithium,66-73 in some cases in the presence of HMPA72 or TMEDA.66,67,71 The system n-butyllithium / KOBut has also been reported to be suitable for the deprotonation of 1,3-dienyl ethers.74 Reactions of carbanions 30 with alkyl halides,67,72,74 aldehydes,66,67,74 ketones,67,73 esters,67 benzonitrile,67 and alkyl silyl,68,69,71 alkyl germanium68,69 and alkyl tin69 chlorides yield intermediates 31, which can be hydrolyzed to the corresponding ketones 32 by aqueous acid,67-71 also in the presence of mercury ion.66

1 1 1 R1 O R O AlkbaseR O Alk E R OAlk hydrolysis R2 R2 Li R2 E R2 E 29 3031 32 Scheme 11

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In a similar manner, vinyl sulfides 33 (R3 = alkyl, phenyl) have been used as synthons for the preparation of ketones (Scheme 12).70,75-77 The base / solvent systems used for the generation of vinylanion 34 are: n-butyllithium in THF,70 sec-butyllithium75 in THF – HMPA and n- butyllithium / potassium tert-butoxide74,76,77 for alkyl vinyl sulfides (R3 = alkyl); and n- butyllithium – TMEDA,78 LDA,79-81 and LTMP82 for aryl vinyl sulfides (R3 = Ph). In some cases treatment of phenyl sulfides 33 with organolithium reagents resulted in side reactions involving addition to the double bond80,82,83 and ortho-lithiation82 of the phenyl ring. Vinyl anion 34 reacts with alkyl halides,74-77 aldehydes,74,75,81 acid chlorides,81 epoxides,75 trimethylsilyl chloride76,77 and iminium salts70 to give masked ketones 35 that may be hydrolyzed to ketones 32 by methods that have been used for the hydrolysis of thioacetals, using mercury salts,25,75,84 titanium tetrachloride,70,79,84-86 TFA79 or methyl iodide76,77 in aqueous acetonitrile. Hydrolysis of 35 sometimes proved difficult79 and in some cases the vinyl sulfides could not be hydrolyzed even using mercury salts.70

1 3 1 3 1 SR3 R1 O R SR baseR SR E R hydrolysis R2 R2 Li R2 E R2 E 33 3435 32

Scheme 12

1-(Phenylseleno)alkenes 36 on treatment with butyllithium at –78 ºC gave products of metalation, cleavage of the C–Se bond and addition (Scheme 13).87 LDA was found to be an effective reagent for metalation of 36, but depending on reaction conditions, elimination of phenylselenol with formation of acetylene was observed as well as metalation.87 Surprisingly, the treatment of 1-(phenylseleno)alkenes 36 with a mixture of potassium diisopropylamide – lithium tert-butoxide (KDA) gave selenium stabilized carbanions 37, which reacted with a variety of electrophiles including alkyl halides, epoxides, aldehydes, and ketones to give products 38 in good yields.88 Hydrolysis of vinyl selenides 38 to the corresponding ketones 32 was accomplished in the presence of mercury salts,88-91 strong mineral acids or TFA.92,93

R1 Se R3 R1 Se R3 R1 Se R3 2+ R1 O LDA or E Hg KDA R2 R2 Li (K) R2 E H2O R2 E 36 37 38 32

Scheme 13

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3. Benzotriazole stabilized acyl anion synthons

Over the last 15 years a range of benzotriazole–stabilized acyl anion synthons has been developed (Figure 1). These synthons, obtained by deprotonation of 39–43, combine the stabilizing influence of a benzotriazolyl group and α-phenoxy-, α-alkoxy-, α-mercapto-, α- carbazolyl-group, or a second α-benzotriazolyl group.

OPh OAlk SMe Cb Bt Cb = Bt = N RBtRBtRBtR Bt RBt N N N 39 4041 42 43

Figure 1. Conjugate acids of benzotriazole stabilized acyl anion synthons.

3.1. Alkyl vinyl ethers, vinyl sulfides and vinyl selenides 1-(1-Phenoxyalkyl)benzotriazoles 39 usefully combine the activating influence of the phenoxy- and benzotriazolyl- groups (Scheme 14).94 Compounds 39 are conveniently prepared in good yields (i) from 1-phenoxymethylbenzotriazole 4495,96 via lithiation with butyllithium in THF at –78 ºC followed by the reactions with alkyl halides,94,96,97 or (ii) by the O-alkylation of phenol with 1-(1-chloroalkyl)benzotriazoles 45 in the presence of a base.94,98-100 Compounds 39 can be deprotonated using butyllithium in THF at –78 ºC to give anions 46, which react with a wide variety of electrophiles to give simple alkyl 47, α-hydroxyalkyl 49, and α-aminoalkyl 51 masked ketones.94 Crude intermediates 47, 49 and 51 are then hydrolyzed with 5% sulfuric acid in aqueous ethanol under reflux to give good overall yields of ketones 48, 50 and 52, respectively.

Bt Bt O BuLi Bt Li H+ R R1 R THF H O 1 OPh o 2 -78 C OPh OPh R 44 47 48 (65-97%) 1 Bt O RX R X + R OH H OH 1 1 1 2 O R R R R C PhO H2O R Bt Bt Bt 2 2 PhOH BuLi Li R R R R 49 50 (41-76%) base THF R Cl OPh -78 oC OPh PhN 45 (R = Alkyl) 39 46 Ph Bt O + equiv. to R NHPh H NHPh R O PhO H2O C Ph Ph R 51 52 (74%)

Scheme 14

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1-Phenoxymethylbenzotriazole 44 was also applied to one-pot double-lithiation techniques. Successive treatment of 44 with one equivalent of butyllithium followed by one

equivalent of alkyl halide or trialkylsilyl chloride (R = Alk3Si), then with a second equivalent of butyllithium and finally, with the appropriate second electrophile (alkyl halide, aldehyde, ketone, trialkylsilyl chloride, etc) gave i good yields of ketones 48, 50 and acyl silanes 48 (R or R1 =

Alk3Si) after direct hydrolysis of crude products 47 and 49. With α,β-unsaturated ketone, 2-cyclohexenone, anion 53 gave exclusively the product of 1,4-addition 54 in 48% yield (Scheme 15). No 1,2-addition product was detected. Intermediate 54 was hydrolyzed to 55 in 90% yield under conditions similar with those used for 48.

O O Bt O H+ Li Bt C5H11 C H H2O 5 11 OPh C5H11 O OPh 53 Ph Ph 54 (48%) 55 (90%)

Ph O OPh Ph Ph + HO Ph Ph + H ,H, Ph O + Ph H2O Bt H2O OPh Bt OPh OH C5H11 C5H11 C5H11 C5H11 O 58 (23%) 56 57 59 (33%)

Scheme 15

However, when trans-chalcone was used as electrophile to react with anion 53, both the 1,2-addition 56 and the 1,4- addition products 57 were generated, probably as result of steric hindrance at the γ-position in chalcone (Scheme 15). The crude mixture of 56/57 was hydrolyzed with 5% sulfuric acid in aqueous ethanol to give ketones 58 (23%) and 59 (33%).

β-Alkoxy synthons from alkoxymethylbenzotriazoles and phenyl vinyl ether. α'-Functionalized β-alkoxy ketones An example of the double-addition of Bt-reagents to enol ethers is shown on Scheme 16. Thus, 1-(1-alkoxy-1-arylmethyl)benzotriazoles 60 (available from aromatic aldehydes and benzotriazole with the corresponding alcohol, or trimethyl or triethyl orthoformate)101-105 add via the ionized form, 61, to phenyl vinyl ether to give intermediate β-alkoxy acyl anion synthon 62,106 of type 39 (Figure 1) and discussed earlier (Scheme 14 and 15). Compounds 62 can be deprotonated with butyllithium in THF at –78 ºC and then reacted with a variety of electrophiles to give intermediates 64, 66, 68, and 70 (Scheme 16). Reaction of anions 63 with alkyl halides gave good yields of masked ketones 64. In the reactions with

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carbonyl compounds, aromatic, benzophenone and benzaldehyde, gave excellent (83–90%) yields of intermediates 66, while reactions with enolizable aliphatic ketones, acetone and 1 2 cyclohexanone, resulted in low yields of 66 (24–45%, R ,R = Me, –(CH2)5–) and recovery of about 50% of 62. Reactions of anion 63 (Ar = Ph, Alk = Et) with 4-methylbenzylideneaniline or TMS chloride produced masked α-anilino ketone 68 and acyl trimethylsilane 70, respectively.106

1 OAlk OEt R Ar O Bt HCl dilute Ar R Ar OPh o AlkO R1 Bt Bt 20-25 C 60 61 AlkO 64 (66-96%) 65 (76-96%) R1 = Alkyl R1X o OPh 70 C 1 R R1 Li R2 Bt OPh OPh 1 2 OH BuLi R R CO HO OPh HCl dilute O Bt 2 Ar THF, Ar Ar = Ph Bt 20-60 oC R Ph Ph -78 oC OAlk OAlk OAlk OAlk 62 63 TolCH 66 (24-90%) 67 (54-94%) NPh TMSCl Ar = Ph Alk = Et Tol Tol OTMS PhO Bt TMS O PhO NHPh HCl dilute NHPh HCl dilute Bt Ph Ph 50-60 oC Ph 20-25 oC Ph OEt OEt OEt OEt 68 (92%) 71 (67%) 70 (71%) 69 (64%)

Scheme 16

Hydrolysis of compounds 64 with dilute hydrochloric acid in aqueous ethanol (1:1) at room temperature produced β-alkoxy-substituted ketones 65 in 76–96% yields. Compound 70 under the same conditions gave 71, while hydrolysis at 50–60 °C resulted in partial deethoxylation. Unlike compounds 64 and 70, hydrolysis of intermediate 68 and some adducts 66 to ketones 69 and 67 required elevated temperature and was achieved with dilute hydrochloric acid in aqueous ethanol at 50–60 °C.106 Reactions of anion 63 (Ar = Ph, Alk = Et) with i-propyl isocyanate and phenyl isothiocyanate gave excellent yields of corresponding adducts 72 and 74 (Scheme 17). Hydrolysis of compounds 72 and 74 with diluted hydrochloric acid in aqueous acetonitrile gave carbonyl compounds 73 (75%, product of deethoxylation) and 75 (95%).106

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O O S S NHPri Bt Bt NHPh i HCl HCl dilute i-PrNCO PhNCS dilute O NHPr 63 NHPh O PhO PhO CH CN CH3CN 3 Ph /H2O /H2O Ph o Ph Ph 80 oC OEt OEt 20-25 C OEt 73 (75%) 72 (95%) 74 (93%) 75 (95%)

Scheme 17

3.2. N-[Ethoxy(aryl)methyl]benzotriazoles - aroyl anion synthons If an aryl- or heteroaryl- group together with a ethoxy group is already present at the α-position to benzotriazole, then the remaining hydrogen is sufficiently acidic to be deprotonated and replaced by a wide variety of electrophiles as shown in Scheme 18.101,107 Synthons 78 have been prepared in good yields (51–85%) either from aldehydes 76 or the corresponding acetals 77.101,107 Treatment of 78 with butyllithium in THF at –78 ºC for several minutes gave the anions 79; subsequent reaction with an appropriate electrophile, such as alkyl halides,101 aldehydes,101 ketones,101 and imines101 at the same temperature for few minutes followed by simultaneous hydrolysis of intermediates 80, 82, 85, and 87 with diluted hydrochloric or sulfuric acid during workup afforded ketones 81, 83, 86, and 88 in good yields. With anion 79 (Ar = 2-pyridyl), reactions with alkyl halides and benzaldehyde were accomplished at room temperature followed by normal hydrolysis of 80 (Ar = 2-pyridyl, R = alkyl) to ketones 81 (Ar = 2-pyridyl, R = alkyl) or hydrolysis / self-oxidation of 82 (Ar = 2- pyridyl, R = Ph) to diketone 84 in 78% yield.

Bt + O R H OPh Ar Ar O H2O 2 CH(OEt)3,BtH OEt R Py O Ar + 80 81 (65-99%) 84 (78%) H H , THF [O] 76 rt - reflux RX Bt OH H+ OR RCOH Ar H O OEt BtH, H+ Bt Bt R 2 BuLi OEt Ar OH Ar Ar Li 82 toluene, THF, Ar 83 (55-93%) OEt OEt RR1CO reflux -78 oC OEt 77 HO R 78 79 Bt 1 + O 1 R H R Ar = aryl, 2-furyl, Ar H2O 3-furyl, 2-pyridyl, PhCH=NPh OEt R Ar OH equiv. to thiophen-2-yl, 85 86 (55-81%) thiophen-3-yl. O Bt NHPh + C H O NHPh Ar Ar H O OEt Ph 2 Ar Ph 87 88 (54-83%)

Scheme 18

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Deprotonation of the methine group of 78 occurs immediately after the addition of butyllithium. The highly reactive anions 79 are of limited stability in solution, especially in the case of furan and thiophene systems, and therefore immediate quenching with electrophiles is necessary for satisfactory results. Prolonged lithiation times led to partial decomposition of the resulting anion 79 and subsequently to low yields. Two exceptions are the 2-pyridyl ketones 81 (Ar = 2-pyridyl, R = alkyl) and 84 since for these the precursor anion 79 (R = 2-pyridyl) was stable even at 20 °C. With trialkylsilyl chlorides anions 79 form intermediates 89; the direct hydrolysis of 89 with dilute hydrochloric or sulfuric acid in aqueous THF give good yields of aroylsilanes 90 (Scheme 19).107

Bt O RMe2SiCl SiMe2R HCl or H2SO4 79 Ar SiMe2R OEt THF / H2O Ar 20-25 oC 89 90 (57-97%)

Scheme 19

3.3. Bis(benzotriazolyl)methane derivatives Bis(benzotriazolyl)arylmethanes 43 (Figure 1, R = Aryl), available from either substituted benzaldehydes with benzotriazole in the presence of thionyl chloride107 or α,α-dichlorotoluenes with benzotriazole,108 on treatment with LDA109 or potassium tert-butoxide110 form carbanion stable at temperatures up to 0 °C. Reactions of anion 92 (generated from 91) with alkyl, benzyl, or allyl halides give alkylated intermediates 93 in good yields (52–95%, except for product of the reaction with sec- butyl bromide, 8%), as well as reactions with acid halides and cyclohexenone give good yields of masked diketones 99 and exclusive 1,4-addition product 101, respectively (Scheme 20).110 However, treatment of anion 92 with 4-vinylpyridine, chalcone, ethyl acrylate, and acrylonitrile gave no reaction. On the other hand, reaction of 91 with 4-vinylpyridine in the presence of catalytic potassium tert-butoxide (0.05 equiv) in THF at –10–(–5) °C gave addition product 103 in 75% yield.111

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O O OR p-Tol H2SO4conc p-Tol 96 (84-96%) THF, r.t. R R = Alkyl, Bn p-Tol OH R = allyl 95 (75%) CH3 98 (91-95%) HCl (1-10M) O THF, r.t. HClconc THF, r.t. p-Tol HClconc Bt R TMS Bt OTMS THF, r.t. Bt RCHO/CsF Bt p-Tol Bt R = allyl Bt DMF, r.t. p-Tol CH3 93 (8-95%) p-Tol Bt R 94 (80%) l 97 l SC C /TM R = Ph, p-Tol, 60-76% RX S HO M olC R = Pr, 6% T p-T ) (68% Bt Bt OR LDA Bt O HCl p-Tol Li RCOCl conc Bt THF, p-Tol p-Tol THF, r.t. -78 oC Bt Bt R p-Tol O 91 92 99 (45-61%) 100 (88-92%) t R = Ph, CH3 KOBu cat O Py4 THF, o -10-(-5) C O O p-Tol HClconc p-Tol 4 p-Tol Py THF or Bt O Bt Bt Bt acetone 103 (75%) 101 (78%) 102 (85-92%)

Scheme 20

Unlike previously discussed synthons 39 and 78, reactions of anion 92 with aldehydes appear to be reversible and result in recovery of starting materials. However, reaction of 92 with p-tolualdehyde followed by the addition of trimethylsilyl chloride gave 68% yield of intermediate silyl ether 97 (R = p-Tol). Alternatively, compounds 97 were obtained by treatment of anion 92 with trimethylsilyl chloride followed by the reaction with aldehydes in the presence of caesium fluoride in DMF (Scheme 20).110 Hydrolysis of intermediates 93, 97, 99, and 101 (except 93, R = allyl) in THF in the presence of hydrochloric acid at 20–25 °C gives corresponding ketones 96, 98, 100, and 102 in good yields (Scheme 20). Hydrolysis of intermediate 93 (R = allyl) was accompanied by the addition of benzotriazole to allyl group resulted in formation of β-benzotriazolyl ketone 94 (80%). In the presence of concentrated sulfuric acid in THF at 20–25 °C, compound 93 (R = allyl) gave crotonophenone 95 (75%).110 Bis(benzotriazolyl)alkanes are also potential alkanoyl anion synthons. The presence of two benzotriazolyl groups in bis(benzotriazolyl)ethane 104 stabilizes carbanion 105 formed on treatment with butyllithium in THF at –78 °C (Scheme 21). At –78 °C, carbanion 105 reacts with ketones including enolizable to give, upon quenching with aqueous ammonium chloride at the same temperature, good yields of masked α-hydroxyketones 106. However, if the reaction

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temperature is allowed to rise to 20 °C prior to quenching with aqueous ammonium chloride, the reaction results in recovery of starting material 104.112

1 2 1 R R % Bt Bt 1 2 HO R BuLi Li R R CO Me Ph 90 H3C H C H3C 2 THF, 3 R Ph Ph 70 Bt -78 oC Bt Bt Bt -(CH2)4- 50 104 105 106 -(CH2)5- 75 Me i-Pr 80

Scheme 21

3.4. 1-(1-Methylsulfanylalkyl)benzotriazoles (Benzotriazol-1-yl)methyl methyl thioether 107 is conveniently accessible from dimethyl sulfoxide, acetic anhydride, and benzotriazole (98%) (Scheme 22).113 On treatment with butyllithium in THF at –78 ºC 107 gives the carbanion, which reacts smoothly with alkyl halides, including cyclic, benzyl, and allyl, to form intermediates 108 (55–85%). Compounds 108 can be deprotonated using butyllithium or in some cases LDA to form anions 109, which react further with various electrophiles, such as alkyl halides, carbonyl compounds (quenching of the reaction mixtures is advantageous at –78 °C due to reverse to starting materials at temperature approaching 20 °C), and phenyl isocyanate to give masked dialkylketones 110 (42–94%), α- hydroxyketones 112 (80–90%), and 2-ketoamides 114 (ca. 75%), respectively. With ethyl benzoate, anion 109 (R1 = Bu) gave product 116 (40%) instead of expected 117. With α,β- unsaturated esters, anions 109 either failed to give or gave low yields of the expected Michael addition products, except the adduct 118 formed in 40% yield.113 Hydrolysis of intermediates 110, 112, 114, and 118 under mild conditions, 20 °C, with dilute aqueous methanolic solution of sulfuric acid (hydrochloric acid for 114) provided corresponding ketones 111, 113, 115, and 119 (Scheme 22).113

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2 2 O R X Bt R H2SO4 BtH + Ac2O 1 2 1 MeOH/H2O R R DMSO R SMe 111 (72-83%) 100 oC 110 (42-94%) Bt O O 1 2 1 OH MeS Bt R R CO R OH H2SO4 1 C 3 R R3 107 MeS R MeOH/H2O R2 R2 1) BuLi THF 112 (80-90%) 113 (74-85%) 2) R1X -78 oC Bt O 1 Bt O PhNCO R NHPh HCl 1 NHPh 1 R R MeOH/H2O 1 C MeS O 108 SMe R O 114 (75%) 115 (48-55%) BuLi THF o -78 C SMe Bt O Bt O Bt PhCO2Et Li Bu 1 Bu Ph Ph R1 R = Bu SMe 116 (40%) 117 (0%) 109 CO2Bu 1 H SO R1 CO Bu R = Alkyl, Bn, Allyl CH2=CHCO2Bu MeS 2 4 2 1 MeOH/H2O R = Bu Bu O Bt 119 (69%) 118 (40%)

Scheme 22

3.5. 1-(Carbazolylalkyl)benzotriazoles 1-(Carbazolylmethyl)benzotriazole 120 on treatment with butyllithium readily formed anion 121, a versatile formyl anion equivalent,114 which reacts with variety of electrophiles, including alkyl halides, aldehydes, ketones, isocyanates, isothiocyanates, and esters, to give 71–96% yields of adducts 122 (Scheme 23). Hydrolysis of intermediates 122 with dilute sulfuric acid in aqueous THF at 20–25 °C gave corresponding aldehydes 123, which were trapped and characterized as 2,4-dinitrophenyl hydrazones.114

Bt Cb + O Bt BuLi E H Li E Cb THF E THF/H2O H 120 -78 oC Cb Bt 121 122 123

Scheme 23

Intermediates 122 (E = Alkyl) can be further deprotonated and the resulting anions again react with electrophiles. Thus compounds 124 (Scheme 24) with butyllithium in THF at –78 °C give anions 125, which further react with electrophiles.115 With alkyl halides, α,β-unsaturated

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ketones, and phenyl and tert-butyl isocyanates, anions 125 give corresponding alkylated products 126, exclusively 1,4-addition products 128, and amides 133. Reactions of 125 with aldehydes showed to be reversible and addition of trimethylsilyl chloride was necessary to trap products of addition as silyl ethers 130. Unlike isocyanates, reaction of anions 125 with phenyl isothiocyanate results in the addition followed by the elimination of benzotriazole to give unsaturated thioamides 135.115 Hydrolysis of compounds 126, 128, 130, and 133 (except adduct 130 of tert- butylcarbaldehyde, R2 = But) to corresponding ketones 127, 129, 131, and 134 was achieved under mild reaction conditions, at 20–25 °C, using dilute hydrochloric acid in THF (Scheme 24). Treatment of compound 130 (R2 = But) under these conditions resulted in elimination of benzotriazole and formation of product 132, which is resistant to further hydrolysis to α- hydroxyketone.115

O 2 HCl Bt R Bn O dilute Cb HCl 1 2 THF, r.t. 1 O dilute O R R R Cb Bt THF, r.t. Bn 126 (78-94%) ( ) ( ) 127 (63-89%) n n 128 (76-81%) 129 (51-67%) R2 = Me, Bu, Bn O R2X ( ) n = 1,2 n 1 O Ph R = Bn HCldilute r.t. Bn OH Bt 2 Bn OTMS HF, BuLi Bt Li R CHO T R1 131 (57%) THF 1 TMSCl Cb 2 Cb o R Cb 1 Bt R H 124 -78 C R = Bn Cl 130 (67-85%) di 1 125 2 t TH lute R = Bn, Bu R = Ph, Bu F, r.t. Cb OH R2NCO PhNCS t -BtH Ph Bu 132 (79%) R S Bt O O O HCldilute 1 R 2 THF, r.t. 1 Cb NHPh Cb NHR R NHPh 135 (87-91%) 133 (84-88%) 134 (62-82%) 2 t R = Ph, Pr R = Ph, Bu

Scheme 24

β-Aminoalkanoyl aanion synthons from N-vinylcarbazole and N- aminomethylbenzotriazoles Alkylaminomethylbenzotriazoles 137 exist in equilibrium with the corresponding immonium cation and add to vinyl group of N-vinylcarbazole 136 giving adducts 138 (Scheme 25), which are β-amino functionalized acyl anion synthons of type 124 (Scheme 24). Compounds 138 on the treatment with butyllithium form anions 139, which further react with alkyl halides, or aldehydes in the presence trimethylsilyl chloride to give intermediates 140 (69–86%) and 142 (57–68%), hydrolysis of which with dilute aqueous hydrochloric acid in THF at 20–25 °C provides

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corresponding β-amino-functionalized dialkyl- 141 (84–96%) and α΄-hydroxy- 143 (82–89%) ketones (Scheme 25).116

1 1 R 3 O Cb R N Bt R + + N Bt 1 H / H2O 1 2 R R 3 R2 R Bt N Cb THF, r.t. N R 136 137 2 R2 R 140 (69-86%) p-TsOH 141 (84-96%) 3 3 80-85 oC R X R = Bn, Alkyl OH R1 1 TMSO R3 O N Bt R R3 BuLi 3 + 2 N Bt R CHO 1 H / H2O R 2 Li R Bt THF R TMSCl N THF, r.t. Cb o 138 -78 C Cb 3 2 Cb R = Ar R 1 N 2 1 2 R R R , R = -(CH2)2O(CH2)2- 139 142 (57-68%) -(CH2)4- 143 (82-89%)

Scheme 25

3.6. Application to the synthesis of 1,6-diketones An example of the application of benzotriazole mediated acyl anion synthons is shown in the preparation of symmetrical and unsymmetrical alkyl, aryl, alkenyl and alkynyl 1,6-diketones 146 and 150 in Scheme 26.117 1,4-Dibromobutane is reacted with two equivalents of the anion derived from the Bt-reagent 144 to give intermediates 145, which on hydrolysis form the 1,6- diketones 146 in high yields. Alternatively, 1,4-dibromobutane is reacted with a single equivalent of the anion of 144, to produce intermediates 147, and then with the anion of the second Bt-reagent 148 to give upon hydrolysis unsymmetrical diketones 150 in good yields. Reaction conditions for hydrolysis of intermediates 145 and 149 depend from nature of groups R1 and R3: dilute hydrochloric acid in aqueous methanol at room temperature was used for preparation of alkyl diketones, and mixture of oxalic acid, water and silica gel in dichloromethane at room temperature was applied for mild hydrolysis of sensitive alkenyl or alkynyl derivatives.117

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OR2 O Bt 1) BuLi (2 equiv) R1 Bt 1N HCl / MeOH R1 R1 R1 OR2 2) Br(CH2)4Br Bt R1 OR2 O (2 equiv) (81-83%) 144 145 146

Bt 3 Br Bt R3 R 148 Bt 1) BuLi (1 equiv) R3 OR2 OR2 O 1N HCl / OR2 1 2 2) Br(CH2)4Br BuLi (1 equiv) MeOH R OR OR2 144 R1 O Bt R1 Bt 1 3 147 R1 R , R = Ph, Bn, CH2=CH, PhC≡C 149 150 (74-86%) R2 = Me, Et, Ph

Scheme 26

4. Propenoyl anion synthons

N-(α-Ethoxyallyl)benzotriazoles 151 are excellent propenoyl-anion synthons.97,107,118–121 The starting materials 151a,b are easily accessible from the corresponding acetal and benzotriazole.118–121 The lithiated derivatives 152a,b (R1 = H, Pr) react regiospecifically with alkyl halides to form compounds 153119 (Scheme 27), which undergo (without further separation) facile hydrolysis under very mild conditions, such as oxalic acid on wet silica (for R1 = H)119 or dilute hydrochloric acid (R1 = Pr),121 both at 20 ºC to give a variety of vinyl ketones 154 (48–82%). The lithiated derivatives 152a,b react with α,β-unsaturated ketones and esters in reactions which are doubly regiospecific α to the benzotriazole and β in the α,β-unsaturated ketones (esters) to give intermediates of type 163.118,119,121 The minor (ca. 20%) products of 1,2-addition were detected only for addition to β-substituted vinyl ketones (2-cyclohexenone and hex-4-en-3- one).119 The intermediates 163 can be hydrolyzed under the same mild conditions to give vinyl- ketoesters and 1,4-diketones of common structure 164 in overall 40–70% yields.118,119,121 Unlike α,β-unsaturated ketones, α,β-unsaturated aldehydes, e. g. cinnamaldehyde, with anion 152b gave exclusively the product of 1,2-addition 155 (R2 = PhCH=CH-), the hydroxy group of which can be oxidized with chromic oxide / pyridine to carbonyl followed by hydrolysis to give divinyl 1,2- diketone (not shown) in 39% yield.97

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OEt + O + OH H O OH H 2 Bt R 2 1 2 1 R 2 R R R Bt 1 R R OEt 1 153 R 156 (30-74%) 154 (48-82%) 155 2 2 R X R CHO 3 3 R HO R Bt 2 + R OH R2 H OEt 2R3CO OEt EtO R OEt O BuLi Li OEt BtH 1 Bt THF, R R1 o Bt Ph 1 1 -78 C C 157 158 (48-81%) R R R1 H= 1 NPh 151a R = H 152a,b Bt OEt O 1 R + 151b R = Pr EWG 2 Ph Ph C H O 2 R 1 NHPh NHPh R2 R R1 159 160 (71%) O EWG O Bt OEt O + EtO H 2 + 2 R2 EWG R H R 1 2 R 1 R Bt R 163 1 1 O 164 (40-70%) R R 161 EWG = CO2Alk, COAlk. 162 (41-61%)

Scheme 27

The lithiated derivatives 152a,b react respectively with aldehydes119,121 and ketones (except some enolizable or bulky examples, such as heptan-3-one, benzophenone or fluorenone discussed next)120.121 to form alcohols 155 and 157, with benzalaniline – to give amine 159,121 and with esters of alkyl- or aryl-carboxylic acids – to generate masked diketones 161.97 Hydrolysis of these intermediates provides access to α-hydroxy vinyl ketones 156 and 158,119– α- anilinomethyl vinyl ketones 160,121 and vinyl 1,2-diketones 162,97 respectively. Reaction of anion 152a (R1–R3 = H), derived from 1-(1-ethoxyallyl)benzotriazole, with trimethylsilyl chloride results in the formation of α- and γ-substituted products 165 and 166 in ratio 3:1 (Scheme 28).119 Reactions of trialkylsilyl halides with R1–R3 substituted anions 152 followed by hydrolysis with dilute hydrochloric acid in aqueous THF give exclusive formation α,β-unsaturated acylsilanes 167.107,122

EtO O EtO Li OEt TMS 3 4 3 TMSCl R 1) R Me2SiX R 4 + Bt + SiMe2R TMS Bt Bt 2) H R1 R2 R1 R2 166 (ca.14%) 165 (43%) 152 167 (66-80%) 1 2 3 4 R ,R = Me, R = H, R = C8H17 R1= H, R2 = Ph, R3,R4 = Me 1 2 3 4 R ,R = Bu, R = H, R = C8H17

Scheme 28

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Reactions of anion 152a with benzophenone, fluorenone, dicyclohexyl ketone and diisopropyl ketone resulted in exclusive formation of γ-adducts 168 (Scheme 29).120 Treatment of the crude products 168, derived from alkyl ketones, with dilute hydrochloric acid in DMF or methanol at 70 °C, and products from aryl ketones in DMF at 90 °C gave hydrolysis / cyclization to lactones 169 and hydrolysis / dehydration to unsaturated acids 170, respectively, in good yields.

1 R O 1 2 Bt HCl-H2O O R ,R = c-C6H11 R2 EtO OEt DMF or i-Pr Li R1R2CO MeOH 169 (75-76%) 70 oC Bt R1 2 O 152a R OH 2 HCl-H O R 2 R1,R2 = Aryl 168 OH DMF 1 90 oC R 170 (67-74%)

Scheme 29

Unlike 152a,b, reactions of phenylallyl anion 152c with electrophiles (alkyl halides and carbonyl compounds) produce mixtures of α- and γ- products 171 and 172 (Scheme 30). Treatment of these mixtures with dilute hydrochloric acid at 20 °C gave vinyl ketones 173 while compounds 172 (which are masked acids) appeared to be stable under these conditions.121 Alkyl halides and aldehydes gave predominantly α-products 173 (55–79%) whereas benzyl bromide gave a major γ-product 172 (E = Bn).121

O OEt OEt BtH BuLi H E 172 (%) 173 (%) Bt THF, Bt (EtO)3CH Et 19 79 -78 oC Ph C H Ph Ph Li 152c 5 11 23 70 151c C8H17 20 68 E PhCH(OH) 20 73 4-TolCH(OH) 24 65 Bt Bt O E C7H15CH(OH) 27 55 HCldil Me C(OH) + OEt 2 43 45 1 20 oC OEt R E PhCH2 86 13 173 Ph Ph E 171 172

Scheme 30

Further applications of the propenal acetal- derived Bt-reagent 151a are shown in Scheme 122 31. Treatment of 151a with catalytic ZnBr2 causes incipient ionization of the benzotriazole anion, which then adds to the ethoxy-stabilized allyl cation, but because of the steric situation

undergoes rearrangement to give 174. Compound 174 can be lithiated α-to the benzotriazole and then alkylated regiospecifically α-to the benzotriazole to give 175. Intermediates 175 undergo

both hydrolysis to α,β-unsaturated aldehydes 178 or SN2' reaction with Grignard reagents to give allyl ethers 176. This process can be repeated with 175 loosing another proton followed by alkylation α-to the benzotriazole to give 177. Intermediates 177 on hydrolysis or reaction with a Grignard reagent give compounds 181 and 179, respectively. Finally, if compound 177 is treated

with a small amount of a weak Lewis Acid (SiO2) it will also undergo reversible ionization and an isomerization to form 180. Compounds 180 contain one further acidic proton that can be removed and replaced by an electrophile (alkyl or trialkylsilyl halide) and finally hydrolyzed to give α,β-unsaturated carbonyl compounds 182. Thus we have five different synthons as shown in Scheme 31.

H RR1 R1 R2 H CC C C H OEt OEt R OEt OEt 176 (60-71%) 179 (76-78%) 2 R1MgBr R MgBr Bt OEt RBt 1) BuLi Bt OEt 1) BuLi SiO2 Bt OEt R 1 2) RBr 2) R1Br R1 R OEt 174 R 175 177 180 + 1) BuLi + H /H O 2 ZnBr2 H /H2O 2 2) R Br + 3) H /H2O H OEt R H RR2 R O 1 Bt R O R1 O 151a 178 (40-82%) 181 (72-78%) 182 (50-66%)

H H C C C C H O O O

Scheme 31

5. Propargoyl anion synthons

Propargoyl anion synthons 183 are useful for the preparation of various functionalized alkynyl ketones, not easily accessible by other methods (Scheme 32). Readily available propargals are activated by the easy replacement of one of the ethoxy groups to give 183.122 In 183 the proton α to benzotriazole can be replaced by lithium using n-butyllithium. Anions 184 undergo regioselective alkylation with alkyl halides to give masked ketones 185.123,124 Hydrolysis of 185 with dilute hydrochloric acid provides the corresponding acetylenic ketones 186.123,124

Anions 184 can also react with a wide variety of electrophiles.97,107,123 ,124 In each case the electrophile reacts regiospecifically α to the benzotriazole group. Thus, the corresponding adducts 187, 189, 191, 193, 195, and 197 were obtained with aldehydes, ketones, imines, esters,97 ethyl carbonate and isocyanates, respectively.123 All these intermediates can be isolated and characterized in high yields. However, for the preparation of acetylenic carbonyl derivatives it is not necessary to isolate the intermediates, and hydrolysis can be carried out under mild conditions (typically, dilute hydrochloric acid in acetone (methanol or ethanol) for 10–20 min at 5–20 ºC) to give acetylenic hydroxy ketones 188 and 190, amino-ketones 192, diketones 194, keto-esters 196, and keto-amides 198, respectively, all in high yields (Scheme 32).97,123 This kind of compounds were previously little known and requiring rather complex procedures.

OEt EtO 1 O R1CHO R + 1 R R H R OEt 1 188 (84-98%) R = Ph, Tol Bt OH R OH BtH 187 (73-75%)

OEt 1 O 1 R 1 R R CO EtO 1 + R 2 R H 1 183 Bt 1 R 190 (98-100%) R = Me, Ph Ph Bt OH Ph OH BuLi o THF -78 C 189 (66-77%) O Bt EtO Tol TolCH=NTol H+ Ph R Li Tol 192 (90%) OEt Ph Bt NHTol TolHN 184 191 (85%) 1 1 O R Br EtO R R1CO R2 H+ R 2 1 OEt R R 194 (60-84%) R 1 1 Bt O O R R = Ph, Me, C8H17 Bt 193 (63-65%) 185 EtO OEt O + + H CO(OEt) H Ph 2 OEt 196 (90%) O Ph Bt O O R 195 (35%) 1 R O 186 EtO NH(t-Bu) + t-BuNCO H NH(t-Bu)

R = Ph, C6H13 Ph Bt O Ph O 198 (99%) 197 (54%)

Scheme 32

A general approach to functionalized acetylenic ketones 202 and propargoyl silanes 204 from 1-(1-ethoxy-propargyl)benzotriazole 199 via synthon 200 is shown in Scheme 33. Successive treatment of 199 with butyllithium / electrophile E1 and again butyllithium / electrophile E2 (TMSCl / butyllithium for 203) followed by hydrolysis of intermediates 201 and 203 provides compounds 202 and 204.107,123

OEt + O 1) BuLi 1 H E 2 1 2 E E 2) E 2 Bt E OEt 1) BuLi OEt 1 201 202 (10%) 1 E Bt 2) E Bt THF OEt + O o 1) TMSCl H 199 -78 C 200 E1 E1 2) BuLi TMS Bt TMS 1 3) H+ E : aldehydes, ketones, TMSCl 203 204 (10%) E2: alkyl bromides, aldehydes, imines

Scheme 33

Reactions of anions derived from compounds 183 with trialkylsilyl chlorides followed by acidic hydrolysis with dilute hydrochloric or sulfuric acid in aqueous THF at 20–25 °C resulted in propargoyl silanes 206 for TMS chloride, or mixture of products 207–209 for octyldimethylsilyl chloride (Scheme 34). Formation of mixture of products 207–209 is presumably caused by steric hindrance of octyldimethylsilyl group and presence of anion 184 in equilibrium with allenic form 205.107

OEt + O R H R OEt SiR3 SCl TMS TM Bt R Li Bt 206 R = Ph, 51% BuLi 184 R = C6H13, 69% 183 THF, 1) R 1 Me o 2 Si OEt O OEt -78 C R OEt 2) H + Cl O • 1 ++Ph • Bt Ph Li Bt SiMe2R 205 Ph 1 1 SiMe2R SiMe2R 207 (38%) 208 (10%) 209 (25%)

Scheme 34

Attempted preparation of acetylenic 1,2-diketones of type 194 (where R1 is vinyl) by using α,β-unsaturated esters and α,β-unsaturated acid chlorides as electrophiles in the reactions with anions 184 resulted in complicated mixtures (Scheme 32).97 On the other hand treatment of anions 184 with trans-cinnamaldehydes gave 1,2-addition products 210 (Scheme 35); oxidation of the hydroxy group in 210 with chromium trioxide / pyridine125 and subsequent hydrolysis of 211 with dilute sulfuric acid at 0–25 °C afforded 1,2-diketones 212 in moderate yields.97

1 Ph Ph 1 R 1 R Ph R 1 Bt Ph O R O R Li CrO3 + EtO EtO H OEt OH pyridine 184 O O Bt R Bt R = C6H13, Ph, R R 1 R = H, Me 212 (83-85%) 210 (51-52%) 211 (92-93%)

Scheme 35

Faust and Weber utilized propargoyl synthon 184 for the synthesis of dialkynyl-1,2-diones 215 (Scheme 36).126 This approach involves Dess-Martin127,128 oxidation of intermediate alcohols 213 to 214 and affords diketones 215 in good yields except for the trimethylsilyl- substituted series (R1 = TMS).

AcO OAc 1 1 1 R R I OAc R O Bt O R1 R Li CO HCl O EtO EtO OEt CH2Cl2 acetone 184 OH O 5-20 oC O R = Ph, Bt Bt R R R1 = Ph, t-Bu, TMS, i-Pr Si R 3 215 (15-75%) 213 (17-55%) 214 (15-80%)

Scheme 36

Inverted regioselectivity of 1,2,4-triazole stabilized allenic anions. Unlike benzotriazole analog 183, triazole derivative 216 have two acidic protons and on treatment with butyllithium produces allenic dianion 217 (Scheme 37). This dianion reacts with two equivalents of methyl iodide or only one equivalent of less active alkyl bromides to give adducts 218 and 220, direct hydrolysis of which with dilute hydrochloric acid in aqueous ethanol (these compounds undergo hydrolysis even on silica gel) provides α,β-unsaturated esters 219 and 221, respectively, as mixtures of E and Z isomers.129

OEt Li Me EtO EtO EtO OEt MeI HCl Ph O N N N N Ph • • EtOH/H O Ph Ph N 2 N 20 oC Me Triazole Me toluene Li 217 218 (100%) 219 (87%) E / Z = 1:4 reflux RX N Li EtO N BuLi Ph OEt N HCl Ph O N (2 eq) EtO • N EtOH/H O THF, RTr 2 OEt o N o -78 C Li 20 C R 220 221 (79-93%) Ph Ph R = Et, C5H11, E / Z = 1:2 - 1:3 216 (76%) allyl

Tr = [1,2,4]triazol-1-yl

Scheme 37

Reactions of dianion 217 with two equivalents of carbonyl compounds gave adducts of type 222 with aldehydes, cyclohexanone, and cyclohex-2-enone (exclusively product of 1,2- addition) and adduct 224 with one equivalent of benzophenone, which under acidic conditions gave lactones 223, 225–227 (Scheme 38).129 Treatment of dianion 217 with imines at –78 °C for several minutes produced adduct 228, which on quenching with water at the same temperature and subsequent hydrolysis gave product 229 (Scheme 38). In contrast, prolonged keeping of 228 at –78 °C resulted in cyclization by intramolecular substitution of triazole giving pyrrole 230.129

Ph Ph OEt R • HCl R N OH R O 223 (61-70%) THF/H2O O R = Ar, Alk OH N N 20 oC 222 RCHO (2 eq) Ph OEt Ph • HCl O O Ph2C Ph Tr Ph O OH EtOHaq. Ph reflux Ph 217 224 225 (78%)

Ph 1) Cyclohex-2-enone ArCH=NPh 2) HCl, EtOH , reflux O aq. O Ph OEt 226 (64%) • Li Ar N Ph N Li N N 1) Cyclohexanone Ph O 228 2) HCl, EtOHaq., reflux O o 1) -78 C, 10 min, o -78 C, 15h 227 (98%) 2) H2O; 3) HCl, EtOHaq., reflux Ph Ar Ph OEt Ph N O Ph OEt NHPh 229 (70%) 230 (82-86%)

Scheme 38

Reactions of alkyl acetylene derivative 231 with two equivalents of butyllithium followed by treatment with hexyl bromide, or benzophenone, and hydrolysis gave pairs of products 234 / 235 and 236 / 237, respectively (Scheme 39). Treatment of dianions 232 233 with benzylideneaniline produced exclusively pyrrole 238.129

OEt C H 6 13 O O OEt 1) C6H13Br C6H13 OEt + + C H Triazole toluene 2) H 6 13 C H reflux 6 13 C6H13 234 (65%) 235 (15%) Tr C6H13 OEt O 231 (70%) O OH 1) Ph CO C H + 2 6 13 O Ph BuLi (2 eq) THF, + 2) H Ph C6H13 Ph -78 oC Ph 236 (49%) 237 (16%) C6H13 C6H13 Li Et • O Ph Li OEt PhCH=NPh Li Ar N N Li o N -78 C, 15h 238 (83%) NN N N Ph OEt 232 233

Scheme 39

6. References and Notes

1. Froling, A.; Arens, J. F. Recl. Trav. Chim. Pays-Bas 1962, 81, 1009. 2. Truce, W. E.; Roberts, F. E. J. Org. Chem. 1963, 28, 961. 3. Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4, 1075. 4. Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4, 1077. 5. For a review, see: Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239. 6. Ager, D. J. In Umpoled synthons: a survey of sources and uses in synthesis; Hase, T. A., Ed.; Wiley: New York, 1987; p. 19. 7. Yus, M.; Nájera, C.; Foubelo, F. Tetrahedron 2003, 59, 6147. 8. Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem. Rev. 1998, 98, 409. 9. Stetter, H.; Kuhlmann, H. Organic Reactions 1991, 40, 407. 10. Stetter, H.; Schreckenberg, M. Ger. Pat. 2262343, 1974; Chem. Abstr. 1974, 81, 505015. 11. Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639. 12. Jencks, W. P. Catalysis in Chemistry and Enzymology; McGraw-Hill Book Company: New York, 1969. 13. Breslow, R. J. Am. Chem. Soc. 1957, 79, 1762. 14. Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719. 15. Breslow, R.; McNelis, E. J. Am. Chem. Soc. 1959, 81, 3080.

16. Kuebrich, J. P.; Schowen, R. L.; Wang, M.-s.; Lupes, M. E. J. Am. Chem. Soc. 1971, 93, 1214. 17. Stetter, H.; Rämsch, R. Y.; Kuhlmann, H. Synthesis 1976, 733. 18. Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004, 126, 2314. 19. Miyashita, A.; Matsuda, H.; Iijima, C.; Higashino, T. Chem. Pharm. Bull. 1992, 40, 43. 20. Miyashita, A.; Matsuda, H.; Higashino, T. Chem. Pharm. Bull. 1992, 40, 2627. 21. Review: Gröbel, B.-T.; Seebach, D. Synthesis 1977, 357. 22. Smith, A. B., III; Adams, C. M. Acc. Chem. Res. 2004, 37, 365. 23. Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231. 24. Seebach, D.; Wilka, E.-M. Synthesis 1976, 476. 25. Seebach, D.; Bürstinghaus, R.; Gröbel, B.-T.; Kolb, M. Liebigs Ann. Chem. 1977, 830. 26. Orsini, F.; Pelizzoni, F. J. Org. Chem. 1980, 45, 4726. 27. Mori, M.; Chuman, T.; Kohno, M.; Kato, K.; Noguchi, M.; Nomi, H.; Mori, K. Tetrahedron Lett. 1982, 23, 667. 28. Enders, D.; Schüßeler, T. Tetrahedron Lett. 2002, 43, 3467. 29. Fang, J.-M.; Chen, M.-Y. Tetrahedron Lett. 1988, 29, 5939. 30. Smith, A. B., III; Lodise, S. A. Org. Lett. 1999, 1, 1249. 31. Jiang, B.; Chen, Z. Tetrahedron: Asymmetry 2001, 12, 2835. 32. Araki, K.; Suenaga, K.; Sengoku, T.; Uemura, D. Tetrahedron 2002, 58, 1983. 33. Bio, M. M.; Leighton, J. L. J. Org. Chem. 2003, 68, 1693. 34. Sauers, R. R.; Valenti, P. C.; Crichlow, C. A. J. Am. Chem. Soc. 1982, 104, 6378. 35. Erni, B.; Khorana, H. G. J. Am. Chem. Soc. 1980, 102, 3888. 36. Berryhill, S. R.; Price, T.; Rosenblum, M. J. Org. Chem. 1983, 48, 158. 37. Reimer, L. M.; Conley, D. L.; Pompliano, D. L.; Frost, J. W. J. Am. Chem. Soc. 1986, 108, 8010. 38. Ziegler, F. E.; Schwartz, J. A. J. Org. Chem. 1978, 43, 985. 39. Funabashi, M.; Kobayashi, K.; Yoshimura, J. J. Org. Chem. 1979, 44, 1618. 40. Forns, P.; Diez, A.; Rubiralta, M. J. Org. Chem. 1996, 61, 7882. 41. Meyers, A. I.; Tait, T. A.; Comins, D. L. Tetrahedron Lett. 1978, 19, 4657. 42. Blatcher, P.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1979, 1074. 43. Ager, D. J. J. Chem. Soc., Perkin Trans. 1 1986, 183. 44. Mukaiyama, T.; Narasaka, K.; Furusato, M. J. Am. Chem. Soc. 1972, 94, 8641. 45. Alvarez, F. M.; Vander Meer, R. K.; Lofgren, C. S. Tetrahedron 1987, 43, 2897. 46. Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097. 47. Blatcher, P.; Grayson, J. I.; Warren, S. J. Chem. Soc., Chem. Commun. 1978, 657. 48. Villa, M.-J.; Warren, S. Tetrahedron Lett. 1989, 30, 5933. 49. Capilla, A. S.; Sánchez, I.; Caignard, D. H.; Renard, P.; Pujol, M. D. Eur. J. Med. Chem. 2001, 36, 389. 50. Ikehira, H.; Tanimoto, S.; Oida, T. J. Chem. Soc., Perkin Trans. 1 1984, 1223. 51. Saigo, K.; Hashimoto, Y.; Kihara, N.; Umehara, H.; Hasegawa, M. Chem. Lett. 1990, 831.

52. Schill, G.; Jones, P. R. Synthesis 1974, 117. 53. Song, J.; Hollingsworth, R. I. J. Am. Chem. Soc. 1999, 121, 1851. 54. Ogura, K.; Yamashita, M.; Suzuki, M.; Tsuchihashi, G. Tetrahedron Lett. 1974, 15, 3653. 55. Ogura, K.; Yamashita, M.; Furukawa, S.; Suzuki, M.; Tsuchihashi, G. Tetrahedron Lett. 1975, 16, 2767. 56. Fujiwara, K.; Takaoka, D.; Kusumi, K.; Kawai, K.; Murai, A. Synlett 2001, 691. 57. Richman, J. E.; Herrmann, J. L.; Schlessinger, R. H. Tetrahedron Lett. 1973, 14, 3267. 58. Herrmann, J. L.; Richman, J. E.; Schlessinger, R. H. Tetrahedron Lett. 1973, 14, 3271. 59. Fang, J.-M.; Chou, W.-C.; Lee, G.-H.; Peng, S.-M. J. Org. Chem. 1990, 55, 5515. 60. Protective Groups in Organic Synthesis; Greene, T. W. and Wuts, P. G. M.; John Wiley & Sons: New York, 1999. 61. Rieger, D. L. J. Org. Chem. 1997, 62, 8546. 62. Deprez, P.; Mandine, E.; Vermond, A.; Lesuisse, D. Bioorg. Med. Chem. Lett. 2002, 12, 1287. 63. Muxfeldt, H.; Unterweger, W.-D.; Helmchen, G. Synthesis 1976, 694. 64. Ravindranathan, T.; Chavan, S. P.; Tejwani, R. B.; Varghese, J. P. J. Chem. Soc., Chem. Commun. 1991, 1750. 65. Ohshima, M.; Murakami, M.; Mukaiyama, T. Chem. Lett. 1986, 1593. 66. Schöllkopf, U.; Hänßle, P. Liebigs Ann. Chem. 1972, 763, 208. 67. Baldwin, J. E.; Höfle, G. A.; Lever, O. W., Jr. J. Am. Chem. Soc. 1974, 96, 7125. 68. Soderquist, J. A.; Hassner, A. J. Org. Chem. 1980, 45, 541. 69. Soderquist, J. A.; Hassner, A. J. Am. Chem. Soc. 1980, 102, 1577. 70. Tietze, L. F.; Brill, G. Liebigs Ann. Chem. 1987, 311. 71. Schinzer, D. Synthesis 1989, 179. 72. Gould, S. J.; Remillard, B. D. Tetrahedron Lett. 1978, 19, 4353. 73. Paquette, L. A.; DeRussy, D. T.; Rogers, R. D. Tetrahedron 1988, 44, 3139. 74. Everhardus, R. H.; Gräfing, R.; Brandsma, L. Recl. Trav. Chim. Pays-Bas 1978, 97, 69. 75. Oshima, K.; Shimoji, K.; Takahashi, H.; Yamamoto, H.; Nozaki, H. J. Am. Chem. Soc. 1973, 95, 2694. 76. Bibang Bi Ekogha, C.; Ruel, O.; Julia, S. A. Tetrahedron Lett. 1983, 24, 4825. 77. Ruel, O.; Bibang Bi Ekogha, C.; Lorne, R.; Julia, S. A. Bull. Soc. Chim. Fr. 1985, 1250. 78. Yus, M.; Gutiérrez, A.; Foubelo, F. Tetrahedron 2001, 57, 4411. 79. Cookson, R. C.; Parsons, P. J. J. Chem. Soc., Chem. Commun. 1976, 990. 80. Harirchian, B.; Magnus, P. J. Chem. Soc., Chem. Commun. 1977, 522. 81. Isobe, K.; Fuse, M.; Kosugi, H.; Hagiwara, H.; Uda, H. Chem. Lett. 1979, 785. 82. Cabiddu, M. G.; Cabiddu, S.; Cadoni, E.; Cannas, R.; Fattuoni, C.; Melis, S. Tetrahedron 1998, 54, 14095. 83. Parham, W. E.; Motter, R. F. J. Am. Chem. Soc. 1959, 81, 2146. 84. Trost, B. M.; Hiroi, K.; Kurozumi, S. J. Am. Chem. Soc. 1975, 97, 438. 85. Sato, M.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1981, 22, 1609.

86. Takai, K.; Sato, M.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1984, 57, 108. 87. Sevrin, M.; Denis, J. N.; Krief, A. Angew. Chem., Int. Ed. Engl. 1978, 17, 526. 88. Raucher, S.; Koolpe, G. A. J. Org. Chem. 1978, 43, 3794. 89. Corey, E. J.; Shulman, J. I. J. Org. Chem. 1970, 35, 777. 90. Krief, A. Tetrahedron 1980 , 36, 2531. 91. Petragnani, N.; Rodrigues, R.; Comasseto, J. V. J. Organomet. Chem. 1976, 114, 281. 92. Piquard, J. L.; Hevesi, L. Tetrahedron Lett. 1980, 21, 1901. 93. Hevesi, L.; Piquard, J.-L.; Wautier, H. J. Am. Chem. Soc. 1981, 103, 870. 94. Katritzky, A. R.; Lang, H.; Wang, Z.; Lie, Z. J. Org. Chem. 1996, 61, 7551. 95. Katritzky, A. R.; Rachwal, S.; Caster, K. C.; Mahni, F.; Law, K. W.; Rubio, O. J. Chem. Soc., Perkin Trans. 1 1987, 781. 96. Katritzky, A. R.; Serdyuk, L.; Xie, L. J. Chem. Soc., Perkin Trans. 1 1998, 1059. 97. Katritzky, A. R.; Wang, Z.; Lang, H.; Feng, D. J. Org. Chem. 1997, 62, 4125. 98. Katritzky, A. R.; Ji, Y.; Fang, Y.; Prakash, I. J. Org. Chem. 2001, 66, 5613. 99. Katritzky, A. R.; Kirichenko, K.; Ji, Y.; Steel, P. J.; Karelson, M. ARKIVOC 2003, vi, 49. 100. Katritzky, A. R.; Kirichenko, K.; Hür, D.; Zhao, X.; Ji, Y.; Steel, P. J. ARKIVOC 2004, vi, 27. 101. Katritzky, A. R.; Lang, H.; Wang, Z.; Zhang, Z.; Song, H. J. Org. Chem. 1995, 60, 7619. 102. Katritzky, A. R.; Rachwal, S.; Rachwal B. J. Chem. Soc., Perkin Trans. 1 1987, 791. 103. Katritzky, A. R.; Rachwal, S.; Rachwal, B. J. Org. Chem. 1989, 54, 6022. 104. Katritzky, A. R.; Bayyuk, S. I.; Rachwal, S. Synthesis 1991, 279. 105. Katritzky, A. R.; Xie, L.; Serdyuk, L. J. Org. Chem. 1996, 61, 7564. 106. Katritzky, A. R.; Feng, D.; Qi, M. J. Org. Chem. 1998, 63, 1473. 107. Katritzky, A. R.; Wang, Z.; Lang, H. Organometallics 1996, 15, 486. 108. Katritzky, A. R.; Kuzmierkiewicz, W.; Rachwal B.; Rachwal, S.; Thomson, J. J. Chem. Soc., Perkin Trans. 1 1987, 811. 109. Katritzky, A. R.; Wu, H.; Xie, L. Tetrahedron Lett. 1997, 38, 903. 110. Katritzky, A. R.; Kuzmierkiewicz, W. J. Chem. Soc., Perkin Trans. 1 1987, 819. 111. Unpublished results by present authors. Treatment of bis(benzotriazolyl)(4- methylphenyl)methane 91 with 4-vinylpyridine (1.1 eq.) in anhydrous THF in the presence of catalytic potassium tert-butoxide (0.05 eq.) at –10–(–5) °C for 30 min (deep blue-purple color of the reaction mixture was observed and reaction was complete upon color disappearance) gave 1-[3-(pyridin-4-yl)-1-(4-methylphenyl)-1-(benzotriazol-1- yl)propyl]benzotriazole 103 in 75% yield (purified by column chromatography on silica gel using ethyl acetate / hexanes 1:1), as white prisms from ethyl acetate / hexanes, mp 129−131 °C; 1H NMR δ 8.49 (d, J = 6.0 Hz, 2H), 8.04 (d, J = 8.1 Hz, 2H), 7.31–7.17 (m, 8H), 7.14 (d, J = 6.0 Hz, 2H), 6.91 (d, J = 8.3 Hz, 2H), 3.91–3.85 (m, 2H), 2.81–2.76 (m, 2H), 2.43 (s, 3H); 13C NMR δ 149.8, 149.3, 146.5, 139.9, 132.2, 132.0, 129.4, 128.2, 127.8, 124.5, 123.8,

120.3, 111.7, 85.7, 42.8, 30.5, 21.1. Anal. Calcd for C27H23N7: C, 72.79; H, 5.20; N, 22.01. Found: C, 72.43; H, 5.48; N, 21.99.

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7. Authors’ biographical data

Kostyantyn Kirichenko was born in Severodonetsk (Ukraine) in 1970. He received his MSc degree (1993) in Chemical Technology of Organic Compounds from Ukrainian State Chemical- Technological University (USCTU, Dnipropetrovsk, Ukraine) and PhD degree (Advisor: Prof. Mati Karelson; 2003) in Organic Chemistry from the University of Tartu (Tartu, Estonia). He worked as a research associate (1993–1996) and later as Assistant Professor (1996–2001) at the Department of Chemical Technology of Organic Compounds at USCTU. In 2001 Dr. Kirichenko joined the research group of Prof. Alan R. Katritzky at the University of Florida with whom he is working on development of new synthetic methodologies for the preparation of heterocyclic

compounds, homologation – functionalization of carbonyl compounds, and development of Ionic Liquids based on Energetic Azoles.

Alan Katritzky was born in London, U.K. and educated at Oxford. He was a Founder Fellow of Churchill College, Cambridge, and then Professor/Dean School of Chemical Sciences at the University of East Anglia before crossing the Atlantic to become Kenan Professor and Director of The Center for Heterocyclic Compounds at the University of Florida in 1980. He has researched, published, lectured, and consulted widely especially in heterocyclic chemistry, synthetic methods, and QSPR. In 2000 he created the non-for-profit foundation ARKAT which publishes “Archive for Organic Chemistry” (Arkivoc) completely free on the Internet.