Organisilicon Compounds as Water Scavengers in Reactions of Carbonyl Compounds

REVIEW 3719 Organosilicon Compounds as Water Scavengers in Reactions of Carbonyl Compounds ODmitriy M. Volochnyuk,*a,b Sergey V. Ryabukhin,a Andrey S. Plaskon,a Oleksandr O. Grygorenkoa,c rganosilconCompoundsasWaterScavengers a Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103, Ukraine Fax +38(44)5024832; E-mail: D.Volochnyuk@enamine.net b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine c Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska Street 64, Kyiv 01033, Ukraine Received 16 July 2009; revised 6 August 2009 1 2 2.1 2.2 3 3.1 3.2 4 5 5.1 5.2 5.3 5.4 6 Introduction Reactions Leading to Carbon–Carbon Bond Formation Aldol-Type Condensations Other Reactions Reactions Leading to Carbon–Nitrogen Bond Formation Two-Component Condensations Three-Component Condensations Formation of Iminium Salts by Elimination Reactions Heterocyclizations Synthesis of O- and O,N-Containing Heterocycles Synthesis of Pyrimidines by Biginelli Reaction Synthesis of Other N-Containing Heterocycles Recyclization of 3-Formylchromones Conclusions Key words: carbonyl compounds, condensation, organosilicon compounds, water scavengers, chlorotrimethylsilane 1 Introduction The chemistry of carbonyl compounds has always attracted the attention of organic chemists because of their great synthetic potential that has not yet been exhausted despite the overwhelming amount of research performed in this area. Most of the reactions of these compounds (e.g., aldol-type condensations, imine synthesis, heterocyclizations) result in water formation. Therefore, the successful outcome of these reactions relies on the use of appropriate reagents that can act not only as catalysts but also as water scavengers. The early examples of the reagents of that type included concentrated inorganic acids (H2SO4, H3PO4, etc.) and alkalis [e.g., NaOH, KOH, Ba(OH)2].1 Despite the high catalytic and dehydrating activities of these systems, they lack efficiency as most of the substrates are unstable under the reaction conditions. One way to solve this problem is to use milder reagents such as SYNTHESIS 2009, No. 22, pp 3719–3743xx. 209 Advanced online publication: 22.10.2009 DOI: 10.1055/s-0029-1217066; Art ID: E24909SS © Georg Thieme Verlag Stuttgart · New York organic acids (e.g., acetic, formic or p-toluenesulfonic) or amines (triethylamine, piperidine, pyridine, etc.).2 However, the latter lack sufficient dehydrating activity, therefore they can be used only if the reaction equilibrium is shifted towards the products. Otherwise, additional tools should be applied to make the equilibrium state more favorable, such as azeotropic distillation of water and use of ceolytes or anhydrous inorganic salts. The methods mentioned above still find application; nevertheless, they cannot satisfy the growing demands of organic and medicinal chemistry. Therefore it is not surprising that water scavengers have evolved drastically since the 19th century (Figure 1). Some examples of these regents include Al2O3, MgO, TiCl4, cation-exchanged zeolites, SiO2, calcite, fluorite, modified Mg-Al hydrotalcite, and Lewis acidic ionic liquids.3–7 Several criteria for reagents that can be expected to be efficient as water scavengers are formulated from both the literature data and our own experience (the most critical are italicized): – stability to air exposure and long-term storage; – commercial availability and low cost; – wide applicability; – solubility in common organic solvents; – high activity under normal conditions and the possibility of use at elevated temperatures; – simple and efficient synthetic protocols; – high selectivity, conversion and yields in the reactions; – simple procedures for the separation of the products formed from the scavenger. Organosilicon compounds satisfy most of the requirements cited above. The chemical behavior of these compounds is determined primarily by the tendency of the silicon atom to expand its valence shell, giving rise to five- and six-coordinate intermediates, therefore, they can be considered as Lewis acids. Unlike many traditional metal-centered activators, silicon Lewis acids are compatible with most synthetically valuable nucleophiles and are not prone to aggregation, thus substantially simplifying the analysis of the reaction mechanisms.8 Most of the organosilicon compounds discussed in this review are halogenosilanes (in particular, chlorotrimethylsilane). Apart from increasing the Lewis acidity of silicon atom, the intrinsic role of the halogeno substituent is related to the high acceptability of Si–X bond towards hydrolysis which is explained by the strong preference of silicon Downloaded by: University of Chicago. Copyrighted material. Abstract: The literature data on the application of organosilicon compounds as water scavengers in reactions of carbonyl compounds is surveyed. The reactions leading to both carbon–carbon (in particular, aldol-type condensations) and carbon–nitrogen bond formation, the synthesis of iminium salts by elimination reactions and heterocyclizations are considered. 3720 to form silicon–oxygen bonds. In addition, an easily removable hydrogen halide is formed upon hydrolysis of halogenosilanes (Scheme 1), which increases the catalytic activity of the system further. The advantages that halogenosilanes have as water scavengers in reactions of carbonyl compounds are summarized in Figure 2. lCH 2 + O2)SMT( O2H + lCSMT 2 Scheme 1 REVIEW D. M. Volochnyuk et al. Hydrolysis of chlorotrimethylsilane The main goal of this review is to survey the literature data on the application of organosilicon compounds as water scavengers in the reactions of carbonyl compounds. The reactions leading to carbon–carbon and carbon–nitrogen bond formations, formation of iminium salts by elimination reactions, and heterocyclizations are all considered. In some cases, related transformations resulting in elimination of small molecules other than water are also discussed. It should be noted that the use of polyphosphoric acid trimethylsilyl ester (PPSE) and related compounds is beyond the scope of this review, as the properties of this water scavenger are defined by the P–O–P fragment and are not related to the silicon atom.9 Dmitriy M. Volochnyuk was born in 1980 in Irpen, Kiev region, Ukraine. He graduated from Kiev State University, Chemical Department in 2002 and was awarded an MS in chemistry. He recieved his PhD in chemistry in 2005 from Institute of Organic Chemis- try, National Academy of Sciences of Ukraine under the supervision of Dr. A. Kostyuk with research concentration in the chemistry of enamines. At present, he divides his time between the Institute of Organic Chemisty, as deputy head of the Organophosphorus Depart- ment, senior scientific worker, and Enamine Ltd (Kiev, Ukraine), as Director of Chemistry. His main interests are fluoroorganic, organophosphorus, heterocyclic and combinatorial chemisiry. He is co-author of 61 papers. Sergey V. Ryabukhin was born in Kirovograd in 1979. He received his MS in chemistry (2001) and PhD in organic chemistry (2007) from Kyiv National Taras Shevchenko University under the supervision of Prof. Dr. Sci. Andrey A. Tolma- chev. At present, he works in Enamine Ltd. (Kyiv, Ukraine) as a director of the Combinatorial Chemistry Department and lectures about combinatorial chemistry in Kyiv National Taras Shevchenko University. His scientific interests include combinatorial chemistry, molecular design, drug discovery, modern methods in organic synthesis, chemistry of heterocyclic compounds, bioorganic and medicinal chemistry. He is co-author of 30 papers. Andrey S. Plaskon was born in 1982 in Kalush, Ukraine. He received his MS in chemistry in 2004 and PhD in organic chemistry in 2009 from Kyiv National Taras Shevchenko University under the super- vision of Prof. Dr. Sci. Andrey A. Tolmachev. At present he divides his time between Kyiv National Taras Shevchenko University as scientific worker and as researcher in the Combinatorial Chemistry Depart- ment at Enamine Ltd (Kyiv, Ukraine). His scientific interests are focused on chemistry of heterocycles and combinatorial chemistry. He is co-author of 28 papers. Oleksandr O. Grygorenko was born in Brody in 1982. He received his MS in chemistry (2004) and PhD in organic chemistry (2007) from Kyiv National Taras Shevchenko University under the supervision of Prof. Dr. Sci. Igov V. Komarov. At present, he divides his time between Kyiv National Taras Shevchenko University as Assistant Professor, and Enamine Ltd. (Kiev, Ukraine) as researcher in the Custom Synthesis Department. His scientific interests include modern methods in organic synthesis, molecular rigidity concept, chemistry of amino acids and related compounds, bioorganic and medicinal chemistry. He is co-author of 8 papers. Synthesis 2009, No. 22, 3719–3743 © Thieme Stuttgart · New York Downloaded by: University of Chicago. Copyrighted material. Biographical Sketches REVIEW 3721 Evolution of water scavengers O O O O TMSCl + R1 H R2 O R2 20 °C, 72 h R1 R1 , = n-Bu, R2 = OEt , R1 = n-C7H15, R2 = OEt , R1 = Ph, R2 = OEt , R1 = n-Bu, R2 = Me d1 c1 b1 a1 Scheme 2 Figure 2 2 Advantages of chlorotrimethylsilane as water scavenger Reactions Leading to Carbon–Carbon Bond Formation In this section, silicon-promoted reactions of aldehydes and ketones with carbon nucleophiles such as carbonyl compounds, activated alkenes and aromatic compounds are considered. Most of the reactions discussed include the use of chlorotrimethylsilane itself, or as a reagent component, as water scavengers. 2.1 Aldol-Type Condensations One of the first literature examples of chlorotrimethylsilane-mediated aldol-type condensation was reported by Zav’yalov and co-workers.10a Aliphatic and aromatic aldehydes reacted with ethyl acetoacetate under mild conditions to give Knoevenagel adducts 1 in 70–75% yields (Scheme 2). The method was extended to some other carbonyl compounds.10b In particular, Knoevenagel adduct 1d was obtained in condensation of butyraldehyde and acetylacetone. Reaction of benzaldehyde with diethyl malonate or p-bromoacetophenone in the presence of chlorotrimethylsilane required the use of zinc chloride as cocatalyst; compounds 2a,b were obtained from these reactions in 60–70% yields. Reaction of benzaldehyde with acetylacetone, acetophenone and a-bromoacetophenone afforded the b-chloro ketones 3, 4a and 4b, respectively (Scheme 3). A chlorotrimethylsilane–N,N-dimethylformamide system was applied to the synthesis of 5-(arylmethylene)hexahydropyrimidine-2,4,6-triones 5 (from barbituric acid and the corresponding aromatic aldehydes) possessing immunosuppressive, fungicidal and anti-inflammatory activities (Scheme 4).11 Combinations of chlorotrimethylsilane with other Lewis acids (e.g., SnCl2,12–14 BF3·OEt2,13 TiCl415 or InCl316) were found to be efficient as promoters for the addition reactions of aldehydes, acetals and a,b-unsaturated ketones with p-donor alkenes (enol silyl ethers, dihydropyrans, styrenes) as well as for Knoevenagel-type condensations under very mild conditions.8 For example, adduct 6 was obtained in 64% yield by the reaction of 3-phenyl-1,1dimethoxypropane (7) and 3,4-dihydropyran in the presence of chlorotrimethylsilane and tin(II) chloride at 0 °C (Scheme 5).12 Synthesis 2009, No. 22, 3719–3743 © Thieme Stuttgart · New York Downloaded by: University of Chicago. Copyrighted material. Figure 1 Organosilicon Compounds as Water Scavengers 3722 REVIEW D. M. Volochnyuk et al. O O rA rA tEO + %09–97 h 5 ,FMD n O O lCSMT ,C/dP H rA 1 = n ,b8 0 = n ,a8 O O + tEO H OtE hP OtE O n O 2lCnZ lCSMT hP a2 O O O O O lCSMT ,C/dP rA %58–07 h 5 ,FMD + H O 2lCnZ lCSMT hP + H hP rB rB rA b2 O 9 lC Scheme 6 O lCSMT hP O O + H hP O )%95( 3 O lC 2lCnZ Reaction of acetophenones and aromatic aldehydes under the conditions described above allowed for the substituted alkylideneacetophenones 10 to be obtained, whereas the analogous transformation in the case of cycloalkanones and aliphatic aldehydes led to the 2-alkylidenecycloalkanones 11 (Scheme 7). These products were also obtained when a chlorotrimethylsilane–ytterbium(III) triflate system was used as reaction promoter.18 hP 1rA h 5 ,FMD O O + 2 H 1 rA rA H hP )%29( rB = X ,b4 )%44( H = X ,a4 O FMD–lCSMT NH 2rA hP X O O lCSMT ,C/dP O + X R O O ,lCSMT hP Scheme 3 H N O O NH + R H O H N O )%29–58( 5 01 O O Scheme 4 O lCSMT ,C/dP R h 5 ,FMD H + R eMO n 11 lC lykla = R eMO lCSMT n hP eMOSMT – eMO hP 7 Scheme 7 2lCnS a,a¢-Bis(benzylidene)cycloalkanones 8 were also obtained, in 70–95% yields, by the reaction of alicyclic ketones and aromatic aldehydes in the presence of iodotrimethylsilane, generated in situ from chlorotrimethylsilane and sodium iodide in acetonitrile (Scheme 8).19 eMO + 3lCnS + – eMO O hP 2lCnS – hP lC O lCSMT – eMOSMT O rA O rA IaN ,lCSMT + H n eMO O rA n hP eMO 8 Scheme 8 O 6 Scheme 5 Recently, a system of chlorotrimethylsilane, N,N-dimethylformamide and palladium-on-carbon was shown to be an efficient catalyst in the aldol condensation of aldehydes with cycloalkanones and acetophenones.17 In particular, the reaction of cyclopentanone and cyclohexanone with aromatic aldehydes led to the formation of the 2:1 adducts Synthesis 2009, No. 22, 3719–3743 © Thieme Stuttgart · New York The chlorotrimethylsilane-induced condensation of 2,5dihydro-2,5-dimethoxyfuran (12) and aromatic or heteroaromatic aldehydes led to the formation of the corresponding g-arylidene-a,b-butenolides 13 in 17–62% yields (Scheme 9).20,21 All of the procedures described above for Knoevenageltype condensations are limited in scope due to the volatil- Downloaded by: University of Chicago. Copyrighted material. 8 in high yields. In the case of cyclooctanone, the 1:1 adducts 9 were obtained exclusively (Scheme 6). REVIEW Organosilicon Compounds as Water Scavengers 3723 tic acid derivatives, hetaryl acetonitriles, cycloalkanones [in this case, a,a¢-bis(arylidene)cycloalkanones 8 were obtained] and cyclic methylene active compounds (Scheme 10). R O + O R H eMO )%26–71( 31 O 21 Scheme 9 1R O FMD ,lCSMT rA h 6–5.0 ,C° 001 2 R RHN The condensation proceeds in a stereoselective manner affording exclusively alkenes that possess a trans disposition of the aryl substituent and the possible silylation site (circled in Scheme 11) even if such a product is not the most thermodynamically stable of the two possibilities (as in the case of compound 18a).22 CN tEOOC H + rA CN NC 2R 1R CN O 3 O R CN 3R O S CN O 3R The method discussed above was successfully applied to less reactive substrates such as aryl methyl ketones and methyl derivatives of p-acceptor heterocycles (Scheme 12).22 N N NC NC NC N O 2eMN N N O NC X S R N Other methylene active compounds were also used as substrates in chlorotrimethylsilane-mediated Knoevenageltype condensations, including hydroxymethyl, chloromethyl and tosyloxymethyl derivatives of heterocycles (Scheme 13 and Scheme 14).23 The latter transformations allowed for the preparation of chlorovinyl derivatives 19 that are difficult to obtain by other methods. HN N NC NC N N N2H )C2H( 3 O N O HN 3R R O 3 O NH HN 3R n O X 3R X 3 R N O 3 O R R OO S O hP hP O O O 3 N O N R O O 3R O X N 3 R O Scheme 10 Selected examples of methylene active compounds R1CH2R2 are given ity of chlorotrimethylsilane (bp 57 °C). In the case of the substrates possessing low reactivity, a modification of the water scavenger is needed; for example, introducing a second Lewis acid as a co-reagent. An alternative approach22 includes performing the reactions in sealed reactors, which allows heating of the reaction mixture to the desired temperature without loss of chlorotrimethylsilane or hydrogen chloride from the reaction mixture. The optimized reaction conditions [TMSCl (3 equiv), DMF, 100 °C, 0.5–6 h] allowed for the execution of Knoevenageltype condensations of aromatic aldehydes with cyanoace- When o-dialkylamino aldehydes were used as carbonyl components in chlorotrimethylsilane-mediated Knoevenagel-type condensations, the reactions were accomplished by way of ring fusion; this is referred to as the T-amino effect (Scheme 15).24,25A set of methylene active compounds was successfully applied to this transformation under optimized reaction conditions [TMSCl (4 equiv), DMF, 100 °C, 12 h]. In the case of pyridine as a solvent, benzylidene derivatives were obtained as a result of the usual Knoevenagel reaction. Thus, free hydrogen chloride, which is formed in N,N-dimethylformamide and not in pyridine as a solvent, is essential for the T-amino effect. When aldehydes processing cyclic dialkylamino moieties were applied to these conditions, tricyclic fused heterocycles 20 were obtained. When Meldrum’s acid (21) was used as a substrate in the reaction described above, fused nipecotic acid derivatives 22 were obtained in a one-pot procedure (Scheme 16).26 In the latter reaction, moderate diastereoselectivity was observed (de ~60%). A system comprising chlorotrimethylsilane, sodium iodide, and acetonitrile–dichloromethane was successfully applied to promote a reductive Knoevenagel-type condensation.27,28 The reaction results in C-arylmethylation of the corresponding methylene active compound (e.g., Synthesis 2009, No. 22, 3719–3743 © Thieme Stuttgart · New York Downloaded by: University of Chicago. Copyrighted material. eMO O lCSMT The proposed mechanistic scheme for the reaction postulates a double function for chlorotrimethylsilane as activator for both the aldehyde and the methylene reaction components, owing to the formation of the silyl derivatives 14a–c and 15a–c (Scheme 11). The latter react to form intermediates 16a–c. In the next step, extrusion of hexamethyldisiloxane (HMDS) and elimination of hydrogen chloride occur from 16a–c, giving the final products 17a–c.22 3724 REVIEW D. M. Volochnyuk et al. H –lC lC O N SMT SMT +O O rA rA O lC c41 O +N SDMH – 1R rA SMT 41 1 R rA lCH – 2 a41 O O SMT SMT H R rA SMT b41 O O– )sic era spuorg lyra( elbats ssel a81 H lCSMT rA 2 lCSMT 1 1R lC R O O 2 R lCH – 2 R R B: a71 a51 a61 O SMT SMT N SDMH – N rA X 41 X rA lCH – 2 SMT N H R R N lCSMT X lC 2 N X lCH – 2 2 R R B: O +N b51 b61 SMT O SMT O– N demrof TON elbats erom b81 lCH – SDMH – rA 2R rA N SMT 41 lC H 2 lCH – R 2 R B: c71 c61 N lCSMT N 2R c51 Mechanistic scheme for the chlorotrimethylsilane-promoted Knoevenagel-type condensation rA lCSMT N FMD S N O R O H rA h 42–51 ,C° 001 S HO N rA Y + FMD H O O O X X N N N O N 2 2ON N N N X lC S R N X lC N O hP N S lC O HN lC N N N N NH NH N lC N N N sTO O N lC S O N H N 2 rA O N O HN N SeM N R lC O R © Thieme Stuttgart · New York Scheme 14 S lC N O CN O N rA acetylacetone or ethyl acetoacetate) thus leading to the products 23. The proposed mechanism for this reaction is shown in Scheme 17. The postulate is supported by the isolation of intermediate 24a (68%) in the case where diethyl ether was used as the solvent.27 sTO N N X O O N lC S O sTO ,lC = X 91 HN eMR Y rA lC lC + Scheme 12 Selected examples of compounds RMe are given; X = O, S, NR1 Synthesis 2009, No. 22, 3719–3743 lC 1rA H HO N O lCSMT O FMD ,lCSMT 1rA + Scheme 13 Selected examples of heterocyclic derivatives are given Downloaded by: University of Chicago. Copyrighted material. b71 Scheme 11 REVIEW 3725 Organosilicon Compounds as Water Scavengers An example of a heterogeneous catalyst used in Knoevenagel-type condensations is represented by silica gel functionalized with amino groups; this catalyst was prepared by the treatment of silica gel with (3-aminopropyl)trimethoxysilane (Scheme 18).29 2R 2 R 3R 3R HO O h 21 ,C° 001 N N O N 1 R R hP 1 N 1R R O 4 O NC S NC rA O R N O O N O 4 R O N 4 R N N NC O N X NC N O N O R NC H N O 4 N 4R N S N 4R X NC O lCSMT + rBaN lCSMT + rBaN + rB O O + O O O O rB Aldehydes of the formula RCH2CHO formed self-condensation products 26 in 78–89% yields in the presence of iodotrimethylsilane. A mechanistic scheme of the reaction was suggested. The key step of the transformation was postulated to be the reaction between trimethylsilyliodohydrine 27 (formed by TMSI addition to the starting aldehyde) and trimethylsilyl enolate 28 (formed from 27 by HI elimination) (Scheme 20).13 O lCSMT R lCH – N O I NCeM –I+ ]HNCeM[ – SMTO R R 12 HOOC HOOC + N R N R R 1:4 ~ b22 a22 R H N O2H lCH O ISMT R O + O R R R O Scheme 16 72 82 SMT O SMT + SMTO R I – R SMTO I R SMTO O rA R SMTO + O IaN ,lCSMT O O + + NCeM I R H rA R O SDMH – I ISMT – R R O SMTO R 2)SMT(O + I ISMT – – O O2)SMT( – R O O R IH rA rA O 2I IH – R R 62 O eM = R ,b42 tEO = R ,a42 – R O eM = R ,b32 tEO = R ,a32 Scheme 17 Scheme 20 Synthesis 2009, No. 22, 3719–3743 © Thieme Stuttgart · New York Downloaded by: University of Chicago. Copyrighted material. 4R 1R N N 1 Scheme 19 – N Scheme 15 Selected examples of aromatic aldehydes and methylene active compounds are given SMTO R 1R O R In some cases, the Knoevenagel reactions discussed above were accomplished by self-condensation of the starting aldehydes.13,17,30,31 Analogous halogenosilane-promoted self-condensations of preparative significance were also reported in the literature. Thus, acetone and cyclohexanone underwent self-condensation smoothly, in the presense of a chlorotrimethylsilane–sodium bromide system, to give the corresponding b-bromo ketones (Scheme 19).30 O 1 + 3R 1R 1 HO O N O 2HN3)2HC(iS3)OeM( 2HN3)2HC(iS R 02 n 2 ) HC( HO O 1 N O FMD ,lCSMT 2R Scheme 18 REVIEW D. M. Volochnyuk et al. HO 3 R HO HO lCSMT 1R 1R + C° 4–0 ,6H6C ,21H6C 2 R 3 R )%77–04( 33 Complexes of chlorotrimethylsilane with Lewis acids appeared to be more efficient as promoters of aldehyde selfcondensations than iodotrimethylsilane. That can be explained by lower nucleophilicity of complex anion [LA·Cl]– (where LA is Lewis acid) comparing to iodide ion. Trimethylsilyl triflate (TMSOTf) appeared to be the most efficient among the reagents used for this reaction.13 23 Other Reactions HO Apart from the aldol-type condensations discussed above, the transformations considered in this section include reactions of C-electrophiles with activated alkenes and aromatic compounds. HO lCSMT + OeM OeM )%06( 53 43 Scheme 22 HO HO O lCH – SMTO lCSMT HO +C SMTO – O lC 2 rA lCH R HO 1 rA R 1rA ISMT 1rA R 92 1rA O + 2rA H R 2rA O lCH – + C O H –lC O O + 03 HO O rA 2 73 eMO O lC hP 83 63 lCSMT hP ).tac( 2lCnS eMO hP + hP eMO 13 Scheme 21 Scheme 23 Chlorotrimethylsilane is a convenient catalyst in Friedel– Crafts reactions.32,33 In particular, it was applied successfully in the condensation of alcohols 32 and substituted phenols that led to diarylmethanes 33. In an analogous reaction of o-cresol and secondary alcohol 34, compound 35 was obtained in 60% yield (Scheme 22).32 sations with secondary amines affording iminium salts are also discussed. 2HN FMD–lCSMT 2 R 1R R H ,eM = 1R eMOOC ,tEOOC ,eM ,H ,lC = 2R © Thieme Stuttgart · New York )%09–07( 93 1 O Synthesis 2009, No. 22, 3719–3743 1R In this section, two-component condensations of aldehydes and ketones with various nitrogen-containing compounds (e.g., primary amines, amides, ureas, and hydrazines) leading to the formation of imines or derivatives thereof are under consideration. Analogous conden- H N + Two-Component Condensations R 3.1 1 O Reactions Leading to Carbon–Nitrogen Bond Formation O 3 2R A chlorotrimethylsilane-promoted reaction of salicylic aldehyde and 1-methylfuran allowed (2-hydroxyphenyl)difurylmethane (36) to be obtained in 90% yield (Scheme 23).33 A chlorotrimethylsilane–N,N-dimethylformamide system was successfully applied in the reaction of cyclic b-diketones (cyclohexane-1,3-dione, dimedone) and aromatic amines to give N-arylenamino ketones 39, which are intermediates in the syntheses of some analgesics (Scheme 24).34 Scheme 24 Use of chlorotrimethylsilane as the reaction promoter allowed Schiff bases to be obtained, even from weakly basic amines. An example of this is shown in Scheme 25.35 Downloaded by: University of Chicago. Copyrighted material. O H The reaction of aliphatic aldehydes with 1,1-diarylethylenes led to the formation of complex mixtures that include 1,1-bis(2,2-diarylethylenyl)alkanes 29 and cyclic ketals 30 as the main products.13 In contrast, chlorides 31 were the only products formed, in 80% yield, in the reaction of acetals and styrene in the presence of chlorotrimethylsilane–tin(II) chloride (Scheme 21).12 HO 2.2 2R 3726 REVIEW 3727 Organosilicon Compounds as Water Scavengers O 2R N 2 X N 2X 3R 1 R 1X N h 2 ,C° 001 yp ,)viuqe 4( lCSMT 1 3R 2HN X )%57–84( 44 The proposed mechanistic scheme suggests silylated aminal 45 as a key reaction intermediate. A [1,6]-hydride shift in 45 accompanied by silicon–oxygen bond formation affords iminium salt 46, which undergoes fast cyclization into the final product (Scheme 29).38 1R R H H H N 2 X 1 X 2 N 2X SMTO 1 O R 1 X H lCSMT N N 4OlC – O 4 – OlC %07 N H lCSMT N O O + N N O O eM N H N 04 N O N O N N O 2HN eM 1R R N + N NCeM O O eM eM lCSMT 14 2 2HN SMT R 54 1 1R 1 R R N 2X SDMH – N 1 R H N N 1X SMTO – iS3eM 2 R 2X 2R Tetraethylorthosilicate [Si(OEt)4] was proven to be an efficient reagent in the synthesis of sterically hindered ketimines 42 and 43 (Scheme 27).37 This water scavenger does not form acidic products upon hydrolysis; thus, an excess of the amine is not needed in the reaction. 1X +H 64 .tac ,4)tEO(iS 2HNR + h 61 ,C° 061 Scheme 29 O RN 2hPHC )%09–27( 24 +H RN ,hPeMHC ,rA = R O .tac ,4)tEO(iS 2HNR hP hP )%89–26( 34 h 57–4 ,C° 061 + hP hP ,2)hP(HC ,rA = R Scheme 27 Reactions of o-(dialkylamino)anilines and aromatic aldehydes performed in sealed reactors at 100 °C resulted in the T-amino effect, thus leading to the formation of dihydrobenzimidazoles 44. To avoid the acid-catalyzed dis- Carbonyl compounds and amides or ureas were found to react with chlorotrimethylsilane–N,N-dimethylformamide at room temperature to afford the corresponding condensation products in good yields (67–92%). The reaction of benzaldehyde and benzamides allowed for arylidenebisbenzamides 47 to be obtained, whereas acetylacetone and ethyl acetoacetate led to enamine derivatives 48 (Scheme 30).39 This method was modified for the synthesis of tosylformamides 49 – substituted tosylmethylisonitrile precursors. It was shown that aromatic, heteroaromatic and aliphatic aldehydes reacted with formamide (or acetamide) and chlorotrimethylsilane in toluene–acetonitrile (1:1) at 50 °C to afford the corresponding condensation products. In Synthesis 2009, No. 22, 3719–3743 © Thieme Stuttgart · New York Downloaded by: University of Chicago. Copyrighted material. Scheme 28 1 N Scheme 26 1R + N 2HN The condensation of aromatic/heteroaromatic amines with 1-methylparabanic acid was studied extensively. In particular, reaction of 1-methylparabanic acid and preclathridin A (40) in the presence of chlorotrimethylsilane, triethylamine, imidazole and DMAP afforded alkaloid clathridin A (41) regioselectively in 73% yield (Scheme 26).36 2R + N Scheme 25 mutation of the final products, pyridine was used as solvent. This transformation was extended to include the use of acetophenones, cyclic ketones and heterocyclic aldehydes as the carbonyl components in the reaction (Scheme 28). The reaction scope showed its limitations in the case of electron-rich aldehydes; in this case, dismutation products were isolated from the reaction mixture. The T-amino effect was also not observed in the case of o-piperidinylanilines as amine components; usual imine formation was observed instead.38 REVIEW D. M. Volochnyuk et al. O 2R NH1R N lCSMT H O O O HOcA 2R + NH1R 2HN klA ,H = 1R rA O hP = rA ,b74 hP = rA ,a74 O 1R NH1R FMD–lCSMT 2 R H N O H N 2HN O O 2R 2HN = R ,tEOOC = R ,c84 2 1 hP = 2R ,tEOOC = 1R ,b84 hP = 2R ,cA = 1R ,a84 )%09–06( 15 OHC S S HOcA ,lCSMT .1 + 4HBaN .2 2HN R NH1R 2 R )%39–47( hPO ,tE ,rA = 1R ,35 )%56–05( H = 1R ,25 eMO ,uB-t = 1R O 2R 2R H N S2OloT h 6–5 ,C° 05 NCeM–eneulot Scheme 34 + 2 R 1 R H N2H Recently, tetraethylorthosilicate was used as a reaction promoter to obtain aromatic and heteroaromatic N-tosylaldimines 50 from p-toluenesulfonamide and corresponding aldehydes (Scheme 32).41 sT 4)tEO(iS N rA h 21–4 C° 061–041 O 2HNsT-p + H rA )%58–64( 05 Scheme 32 Reductive alkylation of unsubstituted and monosubstituted ureas by aromatic aldehydes was achieved using chlorotrimethylsilane in combination with sodium borohydride. It should be noted that monoalkylation products 51 were obtained only when a large excess (up to 20 equiv) of urea was used; otherwise, bis-alkylation occurred (Scheme 33). The reaction was carried out under mild conditions, and the products were easily isolated from the reaction mixture. However, the method was not successful for enolizable or a,b-unsaturated aldehydes.42 An analogous reaction of aromatic aldehydes with thiourea and chlorotrimethylsilane followed by sodium borohydride reduction of the intermediate products afforded monosubstituted thioureas 52. When N-monosubstituted thioureas were subjected to these conditions, N,N¢-disubstituted thiuoreas 53 were formed in good yields (Scheme 34).43 The chlorotrimethylsilane-mediated construction of hydrazones was used in the syntheses of various complex organic molecules, including the macrolide antibiotics rutamycin B (obtained via intermediate 54)44,45 and oligo© Thieme Stuttgart · New York mycin C (via 55),45,46 the spiroketal polyketide antibiotics spirofungins A and B (via 56),47 the polyether antibiotic X-206 (via 57)48 and the secondary metabolite ulapualide A (via 58)49 (Scheme 35). Reaction of aldehydes with primary or secondary amines, a-amino esters, O-trimethylsilylhydroxylamine and N,Ndimethylhydrazine in the presence of chlorotrimethylsilane and lithium perchlorate followed by reduction of the carbon–nitrogen double bond (BH3·NEt3) afforded amines 59, a-amino esters 60, N-substituted hydroxylamines 61 and hydrazines 62, respectively (Scheme 36).50 An approach to the synthesis of iminium salts that includes the reaction of carbonyl compounds with dialkylaminotrimethylsilane and chlorotrimethylsilane has been developed. The corresponding products 63 were stable enough to be isolated in 75–93% yields and characterized (Scheme 37, see also Scheme 41). The method was applied to non-enolizable and a,b-unsaturated aldehydes and dimethylformamide. The procedure can also be utilized in the case of aldehydes capable of enolization if trimethylsilyl triflate is used instead of chlorotrimethylsilane.51,52 Reaction of the dialkylaminotrimethylsilane–chlorotrimethylsilane system with 3,3-dichloroacrolein afforded a mixture of salts 64 and 65 (Scheme 38). Compound 66 was isolated in 75% yield as a perchlorate salt from a mixture obtained by the reaction of dimethylaminotrimethylsilane and the precursor dialdehyde in the presence of chlorotrimethylsilane (Scheme 39).51 A modification of the method discussed above relies on using dialkylamines and in situ generated iodotrimethylsilane.53,54 The first step of the reaction was amine silylation, leading to quantitative yield of the dialkylaminotrimethylsilane which then reacted with the Downloaded by: University of Chicago. Copyrighted material. )%39–26( 94 O O H2OSloT ,lCSMT Scheme 31 Synthesis 2009, No. 22, 3719–3743 2 1R + situ reaction of the latter with toluenesulfinic acid allowed for compounds 49 to be obtained in excellent yields (Scheme 31).40 H N hP H rA 2HN 4H6CN2O-2 4HBaN 2R + rA H N H N O O FMD–lCSMT Scheme 33 Scheme 30 1RHN 3728 Synthesis 2009, No. 22, 3719–3743 © Thieme Stuttgart · New York aldehyde to give the iminium salt. This approach was used in the synthesis of dialkylamino-9H-pyrrolo[1,2-a]indoles 68 obtained in 68–84% yields from 2-(pyrrolyl)benzaldehydes 67 and secondary amine hydrochlorides by action of chlorotrimethylsilane in combination with sodium iodide and triethylamine, followed by intramolecular cyclization of the iminium salts thus formed (Scheme 40).54 )%38–56( 26 rP ,uB-t ,rA = 1R 2eMN N H 56 2RN + N2R + 1R HO 2eMN-N2H SMTO-N2H 46 2 + RN lC –lC lC 1R )%88–56( 16 uB-t ,teH ,rA = 1R HN Scheme 38 –lC lCSMT lC O SMTN2R lC H lC Scheme 36 h 1 ,.t.r ,O2tE H 3 3HB )%09–58( 06 2HC2HCSeM ,rA = R 2 uB-t ,teH ,rA = 1R ⋅NEt lCSMT 1R O eMO eMO 2R O Downloaded by: University of Chicago. Copyrighted material. HN Scheme 37 R 1 O 2R 2HN O N , 36 H –lC N ,2eMN = 22RN 2 RN 2 1R )%59-08( 95 ro lC = X X H R 1 O2)SMT( – 2 RN 2 + lCSMT H 2 RNSMT 2 O 1R tE ,uB-t ,hP = 3R tE ,H = 2R rP-i ,uB-t ,rA = 1R R R N 1 2 3R R O 3 SMT H N R 2 Scheme 35 85 OBMP OBMP 2eMN O N 2eMN-2HN O O lCSMT O O 75 eMO eMO eM O 2eMN N O N eM O 2eMN-2HN OeM O O lCSMT N OeM O O 65 O 2eMN O 2eMN-2HN OSBT N OeM lCSMT OSBT O OeM 55 2eMN 2eMN-2HN N O lCSMT OSPDBT O O OSPDBT O O 45 2eMN O N 2eMN-2HN lCSMT OSPDBT SBTO nBO OSPDBT SBTO nBO Organosilicon Compounds as Water Scavengers REVIEW 3729 3730 REVIEW D. M. Volochnyuk et al. lCSMT 2HN 4OlCiL eMOOC2HCnZrB O + + + hP .t.r ,O2tE N2eM rA H N 2eMN N H eMO N H eMO 4 – OlC rA hP rA H O O lCSMT ,SMTN2eM .1 H N2eM 4OlCaN .2 hP 2 + H O O + 2eMN H N lC )%57( 66 hP )%09–57( 17 lCSMT 2HN 4OlCiL uN + .t.r ,O2tE O + hP – rA H X N 2 RN + 3 ro N3tE ,IaN ,lCSMT ,–lC2H+N23R N 2 RN 3 N H uN H uN + rA hP lC hP Scheme 39 N H 1R 1R rA H 2R 2R hP )%08–06( 27 O N .t.r/C° 0 ,NCeM lC HN3tE ,IaN – + ,lCSMT ,HN23R 1 86 76 klA = 3R ,H = 2R ,lC = 1R ,eMO = 2R = 1R ,H = 2R = 1R rBnZ rBnZ R 2R = uN , Scheme 40 Scheme 42 4OlCiL ,lCSMT .t.r ,O2tE rA 3) RO(P 2 O + 2HN R 1 + H rA tE ,eM = 2R ;uB ,hP = 1R )%89–58( 37 Scheme 43 A system comprising chlorotrimethylsilane, sodium iodide and triethylamine was used in the synthesis of b-amino ketones 74 from secondary amines, aldehydes and enamines (Scheme 44). The reaction resulted in high yields and diastereoselectivity; however, its use was limited to non-enolizable aldehydes.53 5 RN O 3 2 RN 1 R 4 3 R 2R )%89–86( 47 R 4 R 2 RN 1 + –I 2R .t.r ,NCeM ,N3tE lCSMT ,IaN O + H 2 RNH 1 2R H 2 RN 2 uN M-uN 1R 2R O 1R N Scheme 44 + R OiL ,iL3R ,rBgM3R ,nZ2tE = M-uN 2 RN 2 O H M-uN 1R 1 H 2R )%08–06( 96 uN 2 RNSMT 2 2R N 1R )%58–56( 07 2RHNSMT + H 1R tEOOC2HCnZrB ,iL3R = M-uN Scheme 41 Synthesis 2009, No. 22, 3719–3743 H Chlorotrimethylsilane–lithium perchlorate in diethyl ether is a mild reagent for Mannich-type three-component condensations, and has allowed for the corresponding products to be obtained in high yields.50,55–57 First, it was shown that aromatic and heteroaromatic aldehydes were aminoalkylated by trimethylsilylamines in the presence of lithium perchlorate.58–63 Imines or iminium salts formed in the first step of the reaction were trapped by the corresponding nucleophile to afford corresponding amines 69, 70 (Scheme 41). Later, the approach was modified in order to allow trimethylsilylamines to be generated in situ. In particular, reaction of aromatic aldehydes and (R)-aphenylethylamine in the precence of chlorotrimethylsilane–lithium perchlorate led to the formation of chiral imines which reacted with organozinc compounds to give chiral amino esters 71 or amines 72 (Scheme 42).55 It should be noted that moderate to high diastereoselectivities were achieved in these transformations (90% de for 71 and 40% de for 72). a-Aminophosphonates 73 were obtained in an analogous manner when trialkylphosphites were used as nucleophiles (Scheme 43).56 This was a one-pot procedure and resulted in high yields and diastereoselectivities of the products, even in the case of a,b-unsaturated and some enolizable aldehydes. 1RHN The transformations discussed in this section proceed in two steps: first, an imine or an iminium salt is formed, and this then reacts with a nucleophile to afford the three-component condensation product. © Thieme Stuttgart · New York 3-Functionalized indoles 75 were prepared in high yields by the three-component reaction of aliphatic aldehydes, O-trimethylsilylhydroxylamine and indole by action of chlorotrimethylsilane in 5 M ethereal lithium perchlorate solution (Scheme 45).53 a-(Hydroxylamino)alkyl/ arylphosphonates 76 possessing antibacterial properties were obtained in an analogous manner (Scheme 46).56 Downloaded by: University of Chicago. Copyrighted material. Three-Component Condensations 2) RO(OP 2 3.2 REVIEW silane or trichloro(methyl)silane and dialkyl(alkoxymethyl)amines, as well as dichlorodimethylsilane or trichloro(methyl)silane and aminals were detected by spectral methods. However, in the case of chlorotrimethylsilane and aminals, the iminium ion was not observed. SMTO h 2 ,.t.r ,O2tE lC2R+N 2HCN2R lCiS3eM + 2RN2HCN2R a97 3eMiS klA = R )%69–09( 57 HO R 2)eMO()O(P )%89–07( 67 2R eMN ,O = X –lC X 2RN lCiS3eM + HN2R 3eMiS-N2R – lCH – 18 – lC 3eMiS–+N2R R H R 3 N H 3 nim 5 ,.t.r NCeM R 3lCiSeM + N O1R 2R )%89–58( 77 a97 X H klA ,teH ,rA = R X 2RN 38 N2R lCH + 3eMiS–N2R 3 3 R 5R 4R SMTO O 4R N22R R 5R C° 0 – lC 2 RN 2 + H H 3lCiSeM C° 01 NCeM 2 RN 2 O1R 87 The approach was extended to other chlorosilanes (Me3SiCl, Me2SiCl2) and aminals.66,67 Formations of iminium salts from chlorotrimethylsilane, dichlorodimethyl- a28 h 1 ,.t.r ,O2tE + SMTO-N2H + Scheme 48 + lCH + O 3)eMO(P The method was successfully applied to the regioselective aminomethylation of ketones. Thus, Mannich bases 78 were obtained in the reaction of silyl ethers and pre-generated iminium salts (Scheme 48).65 3eMiS–N2R 4OlCiL–lCSMT NH Scheme 47 Scheme 49 In the case of dichlorodimethylsilane and trichloro(methyl)silane, the chlorine atom(s) present in the corresponding silylammonium salts 79b weaken the neighboring carbon–nitrogen bond, thus activating the compounds towards formation of iminium salts 80. On the other hand, (di)chloromethylsilylamines 82b are not basic enough to capture the hydrogen chloride formed. The latter protonates amines 81, thus preventing their further reaction with 80, hence monosubstituted heterocycles 81 are obtained as the final products (Scheme 50). Synthesis 2009, No. 22, 3719–3743 © Thieme Stuttgart · New York Downloaded by: University of Chicago. Copyrighted material. – R H H N The first example of an iminium salt synthesis by elimination reaction involving the use of organosilicon compounds was reported in 1986 and included the reaction of dialkyl(alkoxymethyl)amines and trichloromethylsilane (Scheme 47). The corresponding iminium salts 77 were isolated in 85–98% yields and characterized.64 X H N In the previous section, condensations of carbonyl compounds leading to the formation of iminium salts were mentioned. Another approach to the synthesis (or in situ generation) of iminium salts relies on the elimination of an alcohol or amine molecule from the corresponding aamino ethers or aminals. These transformations bear resemblance to those discussed in the previous section; hence they are considered herein despite their being beyond the main goal of this review. + O + SMTO-N2H + Synthesis of Iminium Salts by Elimination Reactions To explain the results obtained, a mechanistic scheme was proposed for the transformations (Scheme 49). The first step of the reaction is supposed to be reversible aminal silylation. In the case of chlorotrimethylsilane, the concentration of the silylammonium salt 79a is not high enough to generate iminium salt 80 due to the lowered stability of 79a. In the presence of a nucleophile, quaternary salt 79a reacts rapidly and irreversibly to give the product 81 and trimethylsilylamine 82a. The hydrogen chloride formed in this step of the reaction then protonates amine 82a, thus regenerating chlorotrimethylsilane; in other words, the latter acts as a catalyst. Compound 81 is a stronger nucleophile than the starting heterocycle, and hence reacts with quaternary ammonium salt 79 to give the 2,5-disubstituted heterocyclic derivatives 83 (Scheme 49). 08 + –lC2HC N2R 4OlCiL lCSMT Scheme 46 3eMiS–N2R NH R The reaction of chlorotrimethylsilane with aminals and electron-rich aromatic heterocycles (i.e., N-methylpyrrole, furans) led to the formation of 2,5-disubstituted derivatives 83, with chlorotrimethylsilane thus showing catalytic behavior. In the case of dichlorodimethylsilane and trichloro(methyl)silane, monosubstituted heterocycles 81 were isolated as hydrochlorides.66,67 Scheme 45 4 3731 Organosilicon Compounds as Water Scavengers 3732 REVIEW D. M. Volochnyuk et al. eM 2 R 3R N O 2 2R N + R lCSMT 1R 3lCiSeM ro + O NeM 3 1R O R HO hP = 3R ,eM = 2R = 1R ,c78 H= = 2R ,eM = 1R ,b78 H = 3R = 2R = 1R ,a78 hP = ,eM = 2R ,b68 H = 3R = 2R ,a68 3R 2lCXiSeM 2HCN2R b97 lCXeMiS + 2RN2HCN2R eM ,lC = X b28 lCXeMiS-N2R – eM ,H = 1R 3R – lC2HC Scheme 52 X + lCH + N2R 08 X eMN ,O = X 2RN 18 salt 89 was synthesized preliminarily. That fact could be explained by generation of iminium salt 92 from the secondary amine 90. For example, amine 91a (R = n-Bu) was obtained from N,N-bis(methoxymethyl)butylamine (88a; R = n-Bu), 2-methylfuran and trichloro(methyl)silane in 87% yield.70 X lC2RHN + – Scheme 50 R + MO N H lCSMT + eMO N N – O H –lC eMO O lC R 88 eMO N R eM N + –lC lCSMT SMT O O tEO lCSMT N )%68( 48 O O N + h 84 O 09 2 RN 1 lCSMT –lC R O eM N + N H N O R O O h 02 2 RO N21R + N eM )%98( 2tEN = 21RN ,a58 H 19 29 )%39( O N = 21RN ,b58 Scheme 53 Scheme 51 O 3lCSMT N 1R n 2 ) HC( )%09–65( 2 = n ,b39 )%99–57( 1 = n ,a39 tE2OC h 02 ,.t.r ,NCeM 1R 2 R N + n 2 ) HC( tEO OtE 2HC=HC-2HC- ,H = R 2 nB ,klA = 1R 2 ,1 = n © Thieme Stuttgart · New York 2R Synthesis 2009, No. 22, 3719–3743 Scheme 54 tE2OC N,N-Bis(alkoxymethyl)alkylamines such as 88 reacted with chlorosilanes to form a-alkoxymethyleneiminium salts 89 which are more reactive than their methyleneiminium counterparts.69,70 In particular, a mixture of amines 90 and 91 was formed from 89 and 2-methylfuran at ambient temperature (Scheme 53). When the reaction time was increased or when an excess of chlorosilane was used, tertiary amine 91 became the main product even if This approach was recently extended to cyclic b-keto esters71–73 and cycloalkanones.74 In the case of cyclic bketo esters, 3-azabicyclo[3.2.1]octanes 93a and 3-azabicyclo[3.3.1]nonanes 93b were obtained (Scheme 54);71,72 these were then used in the synthesis of the alkaloid methyllycaconitine and its analogues. The method was also applied to the chiral N,N-bis(ethoxymethyl)(1¢-phenylethyl)amine. Despite it not being possible to separate the diastereomers of the amino ketones obtained (93, R1 = 1¢phenylethyl), the presence of the chiral auxiliary in the molecules was exploited in their further transformations.73 O 1,3-Oxazolidines 86 were also shown to react with nucleophilic aromatic substrates in the presence of chlorotrimethylsilane, dichlorodimethylsilane or trichloro(methyl)silane. In particular, reaction of 3-methyl1,3-oxazolidine (86a), furan and trichloro(methyl)silane allowed monosubstitution product 87a to be obtained in 75% yield. Amino alcohol 87b was obtained in 73–87% yields from 86a, 2-methylfuran and either trichloro(methyl)silane or chlorotrimethylsilane. An analogous transformation of 3,4-dimethyl-5-phenyl-1,3-oxazolidine (86b) afforded the expected product 87c in 80% yield (Scheme 52).68 Downloaded by: University of Chicago. Copyrighted material. 98 R R eMO H Reaction of dialkyl(alkoxymethyl)amines with 1-methylpyrrole, 2-methylfuran and 1-methylindole afforded monosubstituted heterocycles as the main products (Scheme 51).66 REVIEW lCSMT 1RHN a)%59( eM = 3R ,H = 2R ,eM = 1R ,c99 )%09( H = 3R ,H = 2R ,eM = 1R ,b99 )%95( eM = 3R = 2R ,H = 1R ,a99 O 3R R HO Scheme 57 An analogous transformation involving salicylic acid amides or N-methylamides and paraform, paraldehyde or acetone led to the formation of benzo-1,3-oxazine[2H]-4ones 99 (Scheme 57).75,76 2R 4R 1R N O 2RHN lCSMT ,OC4R3R )%98( eM = 4R = 3R ,sT = 2R ,uB-i = 1R ,d001 )%68( H = 4R = 3R ,sT = 2R ,eM = 1R ,c001 )%06( H = 4R = 3R ,cA = 2R ,uB-i = 1R ,b001 )%07( H = 4R = 3R ,cA = 2R ,rP-i = 1R ,a001 4-Acetyl-2,2,5-trimethyl-2,3-dihydrofuran (101) was obtained in quantitative yield in a one-pot reaction involving acetylacetone, isobutyric aldehyde, a chlorotrimethylsilane–sodium iodide system and a stoichiometric amount of water. The overall process was a Knoevenagel condensation followed by cyclization (Scheme 59).27 O O IaN ,lCSMT O enaxeh )viuqe 1( O2H O N .t.r ,h 84 tEO N OtE O + 101 + R n 2 ) HC( O klA = R ;2 ,1 = n )%59–47( 2 = n ,59 1 = n ,49 O HO O R NCeM ,lCSMT 1R Scheme 58 Scheme 59 An analogous transformation of dimedone led to the formation of 1,8-dioxooctahydroxanthenes 102 (Scheme 60). The reaction steps included a Knoevenagel condensation, a Michael addition and a cyclodehydration.77 4-Iodo-2,6-disubstituted tetrahydropyrans 103 were obtained at first by Prins cyclization of homoallyl alcohols 104 and aromatic aldehydes in the presence of in situ generated iodotrimethylsilane. The reaction was carried out in acetonitrile at ambient temperature for three to eight min- Synthesis 2009, No. 22, 3719–3743 © Thieme Stuttgart · New York Downloaded by: University of Chicago. Copyrighted material. In the case of N-acetyl a-amino acids, the reaction required harsher conditions: for example, N-acetylvaline or N-acetylleucine reacted with paraform in an acetic acid– chlorotrimethylsilane mixture only under reflux. On the other hand, corresponding N-tosyl derivatives easily underwent cyclization at ambient temperature to give oxazolidinones 100 (Scheme 58).76 3R O n 2 ) HC( An early example of chlorosilane-mediated heterocyclization goes back to 1985 when it was shown that hydroxy and amino acid derivatives undergo cyclization upon treatment with chlorotrimethylsilane and a carbonyl compound (e.g., formaldehyde, acetaldehyde or acetone).75 Thus, heating of paraform, lactic or mandelic acid and an excess of chlorotrimethylsilane afforded dioxolanone derivatives 96.76 Oxazolidines 97 and 98 were obtained from glycolic or lactic acid methylamides and acetone or formaldehyde (Scheme 56).75,76 N 2 Synthesis of O- and O,N-Containing Heterocycles 2R X O lCSMT ,OC3R2R HX O 3 R 3R 2R O 1R 1R .eMN = X ,eM = 3R = 2R ,H ro eM = 1R ,89 eMN = X ,H = 3R = 2R ,H ro eM = 1R ,79 O = X ,H = = ,hP ro eM = ,69 HO 2 eM ,H = 3R eM ,H = R 1 R hP ,eM ,H = 1R eMN ,HN ,O = X Scheme 56 O 5.1 ,OC3R2R In this section, chlorotrimethylsilane-mediated heterocyclizations are under consideration. Modifications of classical transformations, such as the Biginelli reaction, Hantzsch and Friedlander syntheses, are among those discussed. In a separate section, 3-formylchromone recyclizations are illustrated. Some of the heterocyclization reactions were also mentioned previously (Schemes 15, 16, 28, 54 and 55). O Heterocyclizations R Scheme 55 1 The method was also applied to some cycloalkanones, including cyclooctanone, cycloheptanone and substituted cyclohexanones. In particular, azabicyclo[4.3.1]decanones 94 and azabicyclo[5.3.1]undecanone derivatives 95 were obtained from the corresponding cyclic ketones by treatment with chlorotrimethylsilane in acetonitrile at ambient temperature (Scheme 55). The scope and limitations of the approach were established; it was shown that variation of the substituent at nitrogen in N,Nbis(alkoxymethyl)alkylamine as well as the ring size or alkyl substituents a to the ketone did not affect the reaction progress significantly, whereas introduction unsaturated substituents or heteroatoms at that position lowered the yield of the product.74 5 3733 Organosilicon Compounds as Water Scavengers REVIEW D. M. Volochnyuk et al. The reaction was also extended to N- and N,N¢-(di)substituted ureas. Thus, N-substituted 3,4-dihydropyrimidine2-(1H)-ones 107 were obtained in 77–97% yields using chlorotrimethylsilane (4 equiv) and N,N-dimethylformamide at room temperature for one to three days (Scheme 63).82 NCeM ,lCSMT h 01–8 ,xulfer + rA H O O )%48–27( 201 I H O HO IaN ,lCSMT 1 O + R nim 8–3 ,.t.r ,NCeM 2 1R 2 R R 401 )%69–07( 301 rA ,klA = 1R )eMO = 2R )4H6COH-4(2HC2HC = 1R( HnS3uB ,NBIA O O2R N 1 R 3R lCSMT .t.r ,FMD O O2HCrA + O + HN 4R NH 3 2RO O O 1R R OeM HO )%39( 501 )%79–77( 701 5.2 N O O Scheme 61 Scheme 63 Synthesis of Pyrimidines by Biginelli Reaction One of the prevalent applications of chlorotrimethylsilane as a water scavenger is related to the Biginelli reaction and involves a three-component condensation of b-dicarbonyl compounds, aldehydes and ureas leading to the formation of 3,4-dihydropyrimidine-2-(1H)-one derivatives 106. An original method included refluxing of a mixture of the starting matherials in ethanol in the presence of hydrochloric acid as a catalyst and allowed the condensation products to be obtained in 20–60% yields (Scheme 62).79 3 R H O O O H N + + xulfer ,+H O2R HN O O HOtE 2HN N2H 2RO O 1R 3 R 1R )%06–02( 601 Scheme 62 Synthesis 2009, No. 22, 3719–3743 © Thieme Stuttgart · New York Cycloalkanones can be used in the chlorotrimethylsilanemediated Biginelli reaction in place of the b-dicarbonyl compounds. Depending on the structure of the starting compounds, three types of products can be obtained in this reaction: fused heterobicyclic structures 108, benzylidene heterobicyclic compounds 109 or spiroheterotricyclic pyrimidines 110 (Scheme 64). In particular, cyclopentanone, urea and most aromatic aldehydes reacted in the presence of the chlorotrimethylsilane–acetonitrile–N,Ndimethylformamide system to afford pyrimidines 109. Under these conditions, p-fluorobenzaldehyde gave a mixture of 109 and 110 in an 87:13 ratio.83 Aliphatic aldehydes were less reactive in these transformations: the corresponding condensation products were formed in satisfactory yields only under reflux. Cyclopentanone reacted with aliphatic aldehydes and ureas or thioureas to give the products 110, whereas higher cycloalkanones afforded fused heterobicyclic pyrimidines 108.83 Condensation of butyric or valeric aldehydes and urea in a chlorotrimethylsilane–acetonitrile–N,N-dimethylformamide system led to the formation of 5,6-dihydropyrimi- Downloaded by: University of Chicago. Copyrighted material. It was found that 3,4-dihydropyrimidine-2-(1H)-one derivatives 106 could be obtained in high (76–97%) yields using chlorotrimethylsilane in a mixture of acetonitrile and N,N-dimethylformamide (2:1). The method was applied to various aromatic, aliphatic and a,b-unsaturated aldehydes, ureas and thioureas, acetylacetone and ethyl acetoacetate. The products were separated from the reaction mixture simply by filtration.81 O O utes to afford products 103 as mixtures of diastereomers. The all-cis isomer of 103 was the main product of the reaction, presumably due to its greater thermodynamic stability. The method appeared to be ineffective in the case of aliphatic aldehydes; however, it was successfully applied in the synthesis of the antibiotic (±)-centrolobine 105 (Scheme 61).78 rA rA O Scheme 60 In 1992, Zav’yalov and Kulikova showed that using a system of chlorotrimethylsilane and N,N-dimethylformamide allowed for the process to be carried out at ambient temperature. Products were obtained in 62–80% yields from aromatic aldehydes and in 32–37% from aliphatic aldehydes. The procedure included two steps: first, the b-dicarbonyl compound and the aldehyde underwent aldol condensation to give an a,b-unsaturated ketone, then urea was introduced into the reaction mixture to react with the product of the previous step. The final products were isolated and purified chromatographically.80 4R 3734 REVIEW 3735 Organosilicon Compounds as Water Scavengers rivative 114 predominating in the mixture, ortho- and meta-substituted benzaldehydes gave only the octahydroquinazolines 115 (Scheme 66).84 R R HN O NCeM–FMD lCSMT X + N2H 2HN n 2 ) HC( O H + 2 1 R O rA ,klA = 2R n )2HC( R R 901 801 H eM ,H = 1R O O X + O HN HN X R H N + n R NH 2 1 + N2H 2HN X 2R H N X 1R S ,O = X HN H N X )2HC( 2 O R O R 1R R R 511 n )2HC( 411 Scheme 66 NH HN 011 din-2-ones 111 in 53% and 62% yields, respectively. Under these conditions, isovaleric aldehyde and urea or thiourea afforded 3,4-dihydro-1H-pyrimidin-2-ones 112, whereas cyclohexanone and thiourea gave spirotricyclic product 113 in 78% yield (Scheme 65).83 b-Ketonitriles were used in a Biginelli-type reaction with aromatic aldehydes and thiourea in the presence of chlorotrimethylsilane–N,N-dimethylformamide at 25 °C to obtain 1:2:1 condensation products 116 (Scheme 67). In the case of cyanoacetamides, one-step fusion of 1,3-thiazine and pyrimidine cycles occurred to give hydrochlorides 117 (Scheme 68). The structure of the latter products was confirmed by single-crystal X-ray analysis.85 R O R O O rA rA HN lCSMT S N2H 2HN .t.r ,FMD NH + N NC R X NCeM ,FMD ,lCSMT HN X rA N S NH H N OHCrA 2 + 2HN NH + 2 N S NC R n 2 3RO ) HC( + HN h 6 ,xulfer R ,rA ,nB ,eM ,H = 1R ,3ROn)2HC( ,hP ,eM ,H = 2R S NCeM ,FMD ,lCSMT NH O 2HC 211 H N 1 R )%29–65( 711 N2H S ,O = X O 2 lC 2HN h 6 ,xulfer O + O lCSMT .t.r ,FMD rA H hP ,uB-t = R )%29–58( 611 S R O S 2HN N2H H N )%87( 311 Scheme 65 O N2H 2HN h 6–4 ,xulfer Scheme 67 1R H + )%26( rP-n = R ,b111 )%35( tE = R ,a111 O OHCrA 2 + NCeM ,FMD ,lCSMT R HN NC X X Scheme 64 Scheme 68 Condensation of cyclohexane-1,3-dione and urea or thiourea in the presence of chlorotrimethylsilane–acetonitrile–N,N-dimethylformamide led to the formation of either spiro (114) or heterobicyclic compounds (115) in high yields. Whereas benzaldehyde or para-substituted aromatic aldehydes afforded both products, with spiro de- When trifluoromethyl-substituted b-dicarbonyl compounds were used as substrates in the Biginelli reaction, 4-hydroxyhexahydropyrimidin-2-one derivatives 118a were obtained in 48–82% yields. It should be noted that a Synthesis 2009, No. 22, 3719–3743 © Thieme Stuttgart · New York Downloaded by: University of Chicago. Copyrighted material. NH HN In an analogous transformation involving dimedone, aromatic aldehydes and a chlorotrimethylsilane–acetonitrile– N,N-dimethylformamide system, octahydroquinazolines 115 (R2 = Me) were also obtained.77 REVIEW D. M. Volochnyuk et al. ortho-substituted aldehydes and was efficient in the case of sensitive substrates (e.g., those containing nitro, hydroxy, alkoxy or chloro groups) due to the milder reaction conditions.89 O 1R O 2RO + OHC1R h 8–6 ,.t.r IaN–lCSMT O 2RO O O hP 1R O2R HO O H N NCeM ,IaN–lCSMT 021 X N N 3FC 2 H X + OHC1R h 3–2 ,.t.r N2H O N N 1R + 4R 2HN O2HCO-5,4 ,2ON-5 ,lC-5 ,H = 2R hP ,eM = 1R 121 1 O R 1R 3R 3R 4 N 2R R N 4 S R 321 221 O 3R R N N N 5 R 521 eM O O 3 R 4R N O 421 Scheme 71 4 2R © Thieme Stuttgart · New York N O Downloaded by: University of Chicago. Copyrighted material. R N HO 3FC N eM X eM )%65–14( b811 )eM = 3R = 2R ,hP ,tEO = 1R( 3FC In situ generated iodotrimethylsilane has been found to be an efficient condensing reagent in Hantzsch pyridine synthesis. The 1,4-dihydropyridines 120 were obtained from aromatic aldehydes, ethyl acetoacetate and ammonium acetate. An analogous result was obtained under modified reaction conditions starting from aldehydes and aminocrotonate (Scheme 70). Unlike the classical Hantzsch procedure or its newer modifications, the method described above afforded better yields of the products in the case of h 01–4 ,C° 59 ,FMD 1 Pyridines 2R )H = 3R ,hP = 2R ro eM = 3R = 2R( )%06–84( 911 hP 5.3.1 O X 2R ,hP ,tEO = 1R Synthesis of Other N-Containing Heterocycles Heterofused pyridines were also synthesized by this method. In particular, thieno[2,3-b]pyridines 122, [1]benzofuro[3,2-b]pyridines 123, 5H-chromeno[2,3-b]pyridin-5ones 124 and pyrido[2,3-d]pyrimidin-2,4(1H,3H)-diones 125 were obtained (Scheme 71).92 3R O 3R 3FC 5.3 Chlorotrimethylsilane was successfully applied in the Friedlander quinoline synthesis. In this case, o-aminoacetophenones reacted with a set of methylene active compounds [e.g., b-dicarbonyl compounds, acetophenones and other alkyl (het)aryl ketones, tert-butyl methyl ketone, cycloalkanones, 4-piperidones, ethyl 2-oxobutyrate, laevulinic acid, 1,3-dichloroacetone, ethyl 4-chloroacetoacetate, 2-chlorocyclohexanone] in the presence of chlorotrimethylsilane–N,N-dimethylformamide in a pressure tube to give various quinoline derivatives 121 in 76– 97% yields (Scheme 71).90,91 )viuqe 5( lCSMT eM ,H = 3R hP ,eM ,H = 2R S ,O = X Trimethylsilyl triflate is another effective catalyst in the Biginelli reaction. In this case, the reaction was complete within 15 minutes of the addition of 0.01 equivalent of trimethylsilyl triflate to the mixture of starting compounds (i.e., aldehyde, urea and b-dicarbonyl compound) in acetonitrile at ambient temperature. The corresponding products 106 were formed in 80–95% yields.88 Quinolines and Heterofused Pyridines 1R R O C3F 2 3 hP 3FC R NH + 1R OHChP + HN )H = 2R( )%28–65( a811 tE ,eM = 2R rP-i ,teH ,rA = 1R O Other organosilicon compounds have also been used as water scavengers in Biginelli reactions. For example, iodotrimethylsilane generated in situ from chlorotrimethylsilane and sodium iodide was successfully applied in the condensation of aromatic, heterocyclic, aliphatic or a,bunsaturated aldehydes, urea and acetylacetone or ethyl acetoacetate, leading to the formation of dihydropyrimidine-2(1H)-ones 106. The reaction was carried out for 30– 50 minutes and afforded compounds 106 in 82–98% yields.87 5.3.2 R .t.r ,FMD R 2RO Scheme 70 3 lCSMT Scheme 69 Synthesis 2009, No. 22, 3719–3743 NCeM ,cAO4HN different diastereoselectivity (compound 118b) was observed when N,N¢-dimethyl(thio)urea was used instead of the unsubstituted or monosubstituted derivatives. The only exception was represented by 1,1,1-trifluoropentane2,5-dione, which afforded classical dihydropyrimidine products 119 under these conditions (Scheme 69).86 4R 3736 REVIEW 3737 Organosilicon Compounds as Water Scavengers In an analogous reaction, fused heterocyclic compounds 126 were obtained in 45–98% yields from o-aminothiophenecarbaldehydes 127a–c and creatinine in the presence of bis(trimethylsilyl)acetamide (Scheme 72).93 the reaction of acetylacetone and urea that led to the formation of 1,2-dihydropyrimidin-2-ones 129 (Scheme 74).39 O N N R O FMD ,lCSMT O O h 21–6 ,.t.r RHN SMTO eM + N2H N eM N SMTN N )%99( eM = R ,b921 )%67( H = R ,a921 N R 2R 3R)O(CN N + 3R 1R )%31–0( 231 2R N 1R lC)O(C3R 721 N N S a621 eM eM S N N 2HN N S N N c621 2R OHC N 1R N3tE ,lCSMT 2HN O eM 2HN N b621 2HN OHC 2HN HN 1R )%79–36( 031 OHC 2HN 131 OHC S S Scheme 75 c721 b721 S a721 Scheme 72 A chlorotrimethylsilane-induced dehydrative cyclization of diamides 133 in the presence of N,N-dimethylethylamine (DMEA) afforded 3H-quinazolin-4-ones 134 (Scheme 76). The reaction appeared to be insensitive to the nature of the acyl substituent (R3) and was also effective in the case of compounds containing OH and NH groups.96 O O 2 AEMD ,lCSMT R NH O N h 07 ,C° 03 ,NCeM 3R N R R 1 R 431 3R NH 2 1 OSMD ,lCSMT h 5–3 ,C° 09 OHC2HC4R + 1R N 331 2R Scheme 76 4 3 R 1R R N 2 R 821 Scheme 73 5.3.3 R 3 Another approach to quinoline synthesis involved the chlorotrimethylsilane-promoted cyclization addition of enolizable aldehydes to arylimines, under an air atmosphere in dimethylsulfoxide, that afforded 2-arylquinolines 128 (Scheme 73). The clean and mild reaction conditions, high yields of the products and simple workup protocol are attractive features of the procedure described above which thus enable a facile preparation of the quinoline derivatives.94 Analogues of an alkaloid vasicinone 135a–c were obtained in quantitative yields by subsequent reduction of the corresponding N-(2-azidobenzoyl)lactams 136 and iodotrimethylsilane-promoted reductive cyclization, with iodotrimethylsilane acting both as reaction promoter and as reducing reagent (Scheme 77).97 Pyrimidines and Quinazolines In addition to the chlorotrimethylsilane-mediated Biginelli reaction discussed in section 5.2, several examples of other pyrimidine syntheses have been reported. In particular, Zav’yalov and Kulikova successfully applied the chlorotrimethylsilane–N,N-dimethylformamide system in 5.3.4 Azoles 2-Substituted 2,3-dihydro-3-phenyl-1,3,4-thiadiazoles 137 were obtained in high yields from N¢-phenylthioformic hydrazide 138 and aldehydes by treatment with chlorotrimethylsilane (Scheme 78).98 Synthesis 2009, No. 22, 3719–3743 © Thieme Stuttgart · New York Downloaded by: University of Chicago. Copyrighted material. 3R)O(CHN N 821 2HN 1R + h 2 ,C° 041 )%89( c621 )%89( b621 )%54( a621 Pyrimidine derivatives 130 were obtained in the reaction of azadienes 131 and acyl chlorides in the presence of chlorotrimethylsilane and triethylamine. N,N¢-Diacylazadienes 132 were also formed as by-products; nevertheless, the use of chlorotrimethylsilane decreased the yield of 132 significantly (Scheme 75).95 1 2HN 2HN 2HN Scheme 74 3738 REVIEW D. M. Volochnyuk et al. 4R O N O 3R O O + 1R lCSMT _ R 1 N 2R O 1 R N 2 O )2HC( N n R 1 IaN ,lCSMT 2R N n 2 ) HC( NCeM 4R 3R 4R 1R N 3R 631 3 = n ,c531 2 = n ,b531 1 = n ,a531 141 2R O 3N SMT 341 R N 3–1 = n lC ,H = 2R eM ,H = 1R 1R N + 2 R HOOC N N 2 HOOC Scheme 77 R sic )hP = 1R( 5:59 = sic/snart )%87–06 ( 241 snart N 1R N S eMOOC2HC ,rA ,nB = 4R tEOOC ,teH ,hP = 3R teH ,hP ,eM = 2R nB ,hP = S O lCSMT N H + H H N R R 831 )%78( eM = R ,b731 )%69( hP = R ,a731 Scheme 80 Recently, it was shown that some endothiopeptides 139 were transformed into thiazoles 140 by treatment with a chlorotrimethylsilane–sodium iodide system and microwave irradiation (Scheme 79).99 N-Aryl diamines, as well as diamines with a bulky substituent on the nitrogen, behaved poorly in the reaction: the products were formed in 10–25% yields. Only aldehydes that are sufficiently stable under reaction conditions (e.g., aromatic aldehydes) actually gave the desired products. The target products (namely, benzoxazoles) were also not formed in the case of o-aminophenols.102 R O N )viuqe 2( lCSMT 1 R h 2 ,C° 59 ,FMD X N 2HN S OHC1R + HX R RN ,S = X N OeM S R R 931 4R rB 2HN 4 R N 3RHN 5R 2HN O 3 N RHN 2HN 2HN N 2HN HS N2H N 3R O 2-(Chloromethyl)indolizine-1-carbonitrile 144 was obtained from pyridin-2-ylacetonitrile and 1,3-dichloroacetone (Scheme 82). It is interesting to note that other condensing reagents used did not allow for compound 144 to be obtained.103 NC O lCSMT + N lC lC NC N 441 © Thieme Stuttgart · New York 2HN Synthesis 2009, No. 22, 3719–3743 O Selected examples of the substrates are given Benzo- and Heterofused Azoles The chlorotrimethylsilane–N,N-dimethylformamide system has been applied successfully to the synthesis of benzimidazoles, 3H-imidazo[4,5-b]pyridines, purines, xanthines and benzothiazoles from the corresponding (hetero)aromatic o-diamines or o-aminothiophenols and aldehydes (Scheme 81). The reaction scope and limitations were also established. In the case of N-unsubstituted phenylenediamines, diimines were obtained as by-products, resulting in lowered yields of the desired products. N 5.3.5 Scheme 81 lC O The chlorotrimethylsilane-initiated [3+2]-cycloaddition reaction of imines and oxazolones 141 was shown to be a convenient method of obtaining highly substituted imidazolines 142. The first step of the reaction was the reversible N-silylation of 141 leading to the formation of ylide 143 (so-called ‘munchnone’), which acted as a 1,3-dipolar compound in the cycloaddition (Scheme 80). The diastereoselectivity of the reaction was determined by steric interactions of the bulky silyl group in 143 and the Csubstituent of the imine, and led to preferential formation of the trans-isomer. It should be noted that in the case of R = Me or Bn instead of R = Ph, the stability of cationic center is lowered, thus resulting in diminished stereoselectivity.100,101 2HN WM eMO 041 2 )%99–7( R R N H IaN ,lCSMT N Scheme 79 Scheme 82 Other examples of chlorotrimethylsilane- and/or hexamethyldisilazane-promoted dehydrative cyclizations leading to the formation of heterofused azoles are illustrated in Scheme 83.104,105 Downloaded by: University of Chicago. Copyrighted material. Scheme 78 REVIEW 3739 Organosilicon Compounds as Water Scavengers HOOC O N N HOOC lCSMT ,SDMH NC O N NC 4OS2)4HN( N O N ,SDMH 2HN O H N eMO O OH eMO OH O H O H eM O H N N H h 05 ,C° 041 O H N N 2HN O h 63 ,xulfer ,+H O H N N H O N H N H HOeM ,lCSMT N eM N N OeM h 1 ,C° 01 N OeM N NC O NC N H hPHN HN O S lCSMT O O C° 001 ,FMD O N 2R 1 841 R O 1R NH + 2R O 741 eMOC ,3RHNOC ,NC = GWE eMO ,eM ,lC ,F ,H = 1R O O HO O O O 641 541 The first expedient method for the preparation of the compound 145 was reported in 1973,106 and this chromone derivative has been widely applied in heterocycle synthesis since then.107 Nevertheless, the first example of using chlorotrimethylsilane as a promoter of the recyclization of 3-formylchromones was reported only in 2004. Specifically, the reaction of 3-formylchromones 147 and electron-withdrawing-group-substituted acetamides, in the presence of a chlorotrimethylsilane–N,N-dimethylformamide system, led to the formation of pyridone derivatives 148 as a result of a Guareschi–Thorpe condensation (Scheme 85).108 GWE Scheme 84 HO The condensation of 1,3-dicarbonyl compounds is one of the most widely used reactions in the synthesis of heterocycles. In many cases, these electrophiles possess several non-equivalent reaction centers, thereby presenting a regioselectivity problem. Hence, one of the major tasks in this area is to find the substrates and the conditions that allow for single regioisomers to be obtained. 3-Formylchromone (145), a molecule which possesses three electrophilic centers, is that type of substrate (Scheme 84). The tendency of the chromone fragment to undergo recyclization reactions allows one to consider 145 as a synthetic equivalent of 2-(2-hydroxybenzoyl)malonic aldehyde (146). O Recyclization of 3-Formylchromones GWE 5.4 Scheme 85 In the chlorotrimethylsilane-promoted reaction of 3formylchromone and primary hetarylmethylamines, (5-hetaryl-1H-pyrrol-3-yl)(2-hydroxyphenyl)methanones 149 were obtained in 68–91% yields (Scheme 86). With a 2:1 ratio of the reagents, fused chromonepyrroles 150 were formed in moderate yields. When secondary hetarylmethylamines were used as substrates in this reaction, only pyrrole derivatives 149 were isolated in 65–99% yields. An analogous transformation was also observed in the case of glycine derivatives 151 (Scheme 86). The chlorotrimethylsilane-mediated pyrrole synthesis appeared to be also applicable to the fusion of the pyrrole and the dihydroquinoxaline rings (compounds 152). However, in the case of prolinamide and N,N¢-dimethylglycinamide, imidazolinones 153 and 154 were obtained (Scheme 87).109 Unexpected results were obtained in the reaction of 3formylchromone with aromatic amines. In many cases, the target 3-(2-hydroxybenzoyl)quinolines 155 were synthesized in 35–87% yields, indicative of the amine acting first as a C-nucleophile. However, in the case of aniline derivatives possessing an electron-withdrawing group in the meta-position, or any para-substituted anilines, the fused chromenoquinolines 156 were formed in 39–67% Synthesis 2009, No. 22, 3719–3743 © Thieme Stuttgart · New York Downloaded by: University of Chicago. Copyrighted material. Scheme 83 3740 REVIEW D. M. Volochnyuk et al. HO OH O O O O )%19–86( 941 O R + lCSMT 541 O R O 2HN C° 001 ,FMD + C° 001 ,FMD teH N O O RHN lCSMT teH R )%78–53( 551 N O N O 2HN lCSMT teH + C° 001 ,FMD teH 2 O O O O O O )%46–45( 051 R OH )%76–93( 651 N O O O O 4)2HC(N ,2tEN ,2eMN O N H O R N R 2R 1 O OH N 2HN N N )%48( 351 NH O N O 1R O 251 O 2HN C2OtE S ,eMO ,HO = X + )%78–53( 751 N 2HN 151 R R O 2HN C2OeM O O N H R R N O O 2 NH 2HN O H N O O H N O N 2HN SeM N 2HN O O 1 R Scheme 89 Examples of amino heterocycles are given H eM N H N eM eM O N O N C° 001 ,FMD N 1R HN + O )%59–55( 851 HO O CN N H N CN C2OtE N 2HN H N O 2HN H N H N 2HN 2R 2R GWE N H N N N N 2HN N H N © Thieme Stuttgart · New York Scheme 90 2HN N O eM )%97( 451 Heteroaromatic amines lacking a carbon atom at the position a to the amino group showed NCN-binucleophilic behavior in the reaction with 3-formylchromone, thereby affording pyrimidines 158 (Scheme 90). An analogous H N O An analogous transformation was observed in the case of heteroaromatic amines capable of acting as CCN-binucleophiles, which thus led to the formation of fused pyridines 157 (Scheme 89).111 2HN O 2HN lCSMT and no traces of 155 were detected, thus the amine was acting first as an N-nucleophile (Scheme 88). In the case of 3,4-disubstituted anilines, the products 155 or 156 were obtained, depending on the electronic effects of the substituents.110 Synthesis 2009, No. 22, 3719–3743 1R Scheme 87 Examples of amino heterocycles are given transformation was observed in the case of amidines (Scheme 91).112 Downloaded by: University of Chicago. Copyrighted material. lCSMT S + NH C° 001 ,FMD 2HN C° 001 ,FMD 2HN O Scheme 86 N O lCSMT O N 251 HO O X X Scheme 88 REVIEW Organosilicon Compounds as Water Scavengers 3741 thus prevents any nucleophilic attack from taking place at that site.116 HO O 2 N 2 1 R 4)2HC(N ,hP = R O 1 NH R O C° 001 ,FMD lCSMT O 2R Scheme 91 The reaction of 3-formylchromones 147 and 1-aminoimidazoles 159 in the presence of chlorotrimethylsilane and N,N-dimethylformamide led to the formation of imidazo[1,5-b]pyridazines 160 (Scheme 92). However, 1-aminobenzimidazole and 4-amino-1,2,4-triazoles did not undergo an analogous heterocyclization under these conditions; only hydrazone formation was observed.113 Conclusions Organosilane compounds, in particular chlorotrimethylsilane, act as very efficient water scavengers in many common reactions of carbonyl compounds, including the Knoevenagel condensation, imine and enamine syntheses, the Mannich reaction, and heterocyclizations such as the Biginelli and Friedlander reactions. The procedures developed for these syntheses are applicable to a vast range of substrate molecules. Taking into account the simplicity and generality of the methods based on organosilane-promoted condensations of carbonyl compounds, one should expect further progress in this area with regard to other reactions for which the outcome depends on the use of a water scavenger. 1R N O O N lCSMT 1 N O 2HN N 2 741 2R HS = 2R ,b951 = ,a951 2HN R )%69–18( 061 R + C° 001 ,FMD R 2 O N hP OH hP Acknowledgment The authors thank Prof. A. A. Tolmachev for the great encouragement and support. Scheme 92 References Finally, in the reaction of 3-formylchromone with compounds 161 (imidazole, benzimidazole,114 quinazolone and thieno[2,3-d]pyrimidin-4(3H)-one115 derivatives), fused polycyclic heterocycles 162 were obtained (Scheme 93). HO O O N O R lCSMT N C° 001 ,FMD N O )%89–04( 261 R 161 N H ,hPO ,hPOCHN2HC ,hPOCHN ,lC ,H2OC2HCS ,hP ,lylozaihtozneb-2 ,hP2OS ,eM2OS ,2HNSC ,O4)2HC(NOC ,nBHNOC ,2HNOC ,)lyneiht-2(OC ,hPOC ,NC = X O H N X O4)2HC(N ,eMN4)2HC(N ,HN4)2HC(N ,H2OC2)2HC( ,H2OC2HC ,lC ,H ,NC = X HN X O eMS N O O hP HN HN + N HN N S NC N S H N Scheme 93 Selected examples of methylene components are given It should be noted that the use of chlorotrimethylsilane in most of the 3-formylchromone condensations discussed above significantly improved the regioselectivity of the reaction. This is presumably due to the preliminary silylation of the carbonyl group of the chromone ring, which (1) (a) Claisen, L.; Claparède, A. Chem. Ber. 1881, 14, 2460. (b) Fehnel, E. A. J. Org. Chem. 1966, 31, 2899. (c) Conard, C. R.; Dolliver, M. A. Org. Synth. 1932, 12, 22. (d) Noland, W. E. Org. Synth. 1961, 41, 67. (e) Kyriakides, L. P. J. Am. Chem. Soc. 1914, 36, 530. (2) (a) Newkomel, G. R.; Fishe, D. L. Org. 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