Oxidation Trifluoride (DAST) Selectfluor™

Vol. 5 No. 1 Synthetic Methods Iodotoluene difluoride Diethylaminosulfur Oxidation trifluoride (DAST) Selectfluor™

Ishikawa’s Reagent

Other Reagents for Fluorination

Dess–Martin Periodinane

Bis(pyridine)iodonium tetrafluoroborate

Magnesium bis(monoperoxyphthalate) hexahydrate

Chloramine-T

Other Reagents for Oxidation

Advancing Science 2

Introduction Oxidation is one of the most common transformations in all of organic chemistry. As a result, the number of oxidizing agents and reactions at the research chemist’s disposal number in the hundreds; Sigma-Aldrich is proud to offer a new series of ChemFiles—called however, few provide extended utility across a broad range of Synthetic Methods—to our Organic Chemistry and Drug Discovery substrates while remaining able to selectively oxidize one group customers. Each piece will highlight a specific motif or selected over another. Fewer yet remain effective under mild conditions. At organic transformation, and the range of products Sigma-Aldrich Sigma-Aldrich, we are committed to being your preferred supplier offers in this area. Our first installment focuses on oxidation for reagents used in oxidation—and we’d like to highlight some chemistry. In the future, we will highlight other synthetic methods new, popular, and versatile oxidation reagents in this ChemFile. such as asymmetric synthesis and reduction. We trust you will find these pieces useful, and we welcome your comments for Listed on the following pages is a selection of oxidation reagents future installments. If you cannot find a product for your specific available from Sigma-Aldrich. For a complete listing of oxidation research in organic synthesis or drug discovery, we encourage your reagents, please visit sigma-aldrich.com/oxidation. For a regular input to help us increase our product range. “Please bother us” at update on the latest products from Sigma-Aldrich, please visit [email protected] with your suggestions. sigma-aldrich.com/newprod.

8 Iodotoluene difluoride F F The importance of selectively fluorinating I C H O compounds in medicinal chemistry, biology, and O tol-IF2 5 11 C5H11 organic synthesis is well appreciated and provides a I Et3N-5HF, CH2Cl2 major impetus to the discovery of new fluorinating F agents that can operate according to an efficient, safe, and mild criteria. Elemental fluorine, and many Scheme 1 electrophilic fluorinating agents have been used CH3 Iodotoluene difluoride in synthesis; however, most of these fluorinating agents are highly aggressive, unstable, and require special equipment and care for safe handling. By contrast, iodotoluene O O O O tol-IF2 R X difluoride (tol-IF2) is easy to handle, and is less toxic than many R X CH2Cl2, 40°C F fluorinating agents. Sigma-Aldrich is pleased to introduce this new X = R', OR', NR'2 reagent for oxidation and fluorination. Scheme 2 A new methodology for the synthesis of fluorinated cyclic ethers

was recently reported, which utilized tol-IF2 to achieve a fluorinative ring-expansion of four-, five-, and six-membered rings, an example 1 of which is illustrated in Scheme 1. O O S 1eq tol-IF2 S OR OR CH Cl , 0°C 2 2 F Selective monofluorination of b-ketoesters, b-ketoamides, and

diketones takes place without requirement of HF-amine complexes O O under mild conditions (Scheme 2). The formation of difluoro 1) 2eq tol-IF , CH Cl , 0°C S 2 2 2 F 2 O O products were not detected in these reactions. 2) H2O 3) toluene, ∆

When one equivalent of tol-IF2 is reacted with phenylsulfanylated esters, the a-fluoro sulfide results through a Fluoro-Pummerer Scheme 3 reaction. In contrast to diethylaminosulfur trifluoride, two equivalents produces the a,a-difluoro sulfide, and three equivalents

of tol-IF2 produces the a,a-difluoro sulfoxide. This behavior was exploited in the one pot synthesis of a 3-fluoro-2(5H)-furanone 3 (Scheme 3). O O

S 1eq tol-IF2 S CH N CH3 N 3 X CH2Cl2, 0°C Treatment of phenylsulfanylated lactams with one equivalent n n

of tol-IF2 results in the unsaturated heterocycle in moderate to X = H, PhS good yields. When two equivalents of the reagent were used, the O O

lactams were fluorinated in the a - and b-positions resulting in the S 2eq tol-IF2 S CH CH3 N 3 4 N F diastereomeric difluoride (Scheme 4). X CH2Cl2, 0°C n F n X X = H, PhS 4-Iodotoluene difluoride 65,111-7 1 g 31.50 5 g 108.00 Scheme 4

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Diethylaminosulfur trifluoride (DAST) H O H O F 1) HCl , aq F HO2C CO2H DAST F dioxane O NO NO CH2Cl2 F DAST has proven itself to be an extremely NH 2) propene N CO2H F 2 H F F popular reagent for nucleophilic fluorination, F3C CF3 F3C CF3 oxide S due to its ease of handling and versatility. Scheme 5 N It has regularly been employed in a myriad selective fluorinations of alcohols, alkenols, carbohydrates, ketones, sulfides, epoxides, thioethers, and cyanohydrins. In addition some novel organic 5 OH F cyclizations are possible when DAST is employed as a reagent. DAST LHMDS F F

Ar CF3 CH Cl , -70°C Ar CF THF, 15°C 2 2 3 Ar F Fluorodeoxygenation was achieved using DAST in a preparatively simple synthesis of 5,5-difluoropipecolic acid from glutamic acid 6 (Scheme 5). Scheme 6

1,2,2-Trifluorostyrenes can be synthesized using a sequential reaction on the parent a-(trifluoromethyl)phenylethanol with DAST, followed by dehydrohalogenation with lithium bis(trimethylsilyl)amide Br Br Br Br (LHMDS). This method achieves the trifluorostyrene without requirement of palladium coupling (Scheme 6).7 N N DAST OH F CH2Cl2, 0°C trifluoride (DAST)

DAST was recently used to obtain fluorinated analogues of N N Diethylaminosulfur 3,6-dibromocarbazole piperazine derivatives of 2-propanol BocN BocN (Scheme 7). A series of these analogues are described as the Br Br first small and potent modulators of the cytochrome c release Br Br triggered by Bid-induced Bax activation in a mitochondrial assay.8 N N DAST O F CH Cl , 0°C The synthesis of a,a-difluoroamides via direct fluorination was 2 2 F recently reported using DAST as the fluorinating reagent in a one- N N BocN pot reaction (Scheme 8). Decreasing the molar ratio of DAST to BocN substrate resulted in the formation of the respective a-ketoamide.9

Scheme 7 a-Fluorosulfides and secondary alcohols were coupled by Yb(OTf)3 to generate O,S-acetals, which are key intermediates in the assembly of ciguatoxins. In their synthesis, hydrogen was directly converted to fluorine using DAST and a catalytic amount of SbCl to 3 O 10 O F F make the a-fluorosulfide (Scheme 9). DAST (1eq) DAST (2eq) NEt2 OH NEt2 CH2Cl2, rt CH2Cl2, rt O O O Diethylaminosulfur trifluoride (DAST)

23,525-3 1 g 20.30 Scheme 8 5 g 62.90 25 g 194.50 125 g 583.00 250 g 900.00

BnO F BnO Me H Me H O O PhS OBn DAST, SbCl3 PhS OBn

TIPSO OBn TIPSO OBn

BnO BnO OH Me H H O BnO O O OBn H H SPh O OBn BnO O Yb(OTf)3, DTBMP, MS 4Å H TIPS BnO H

Scheme 9

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Selectfluor™ ™ CH2Cl Selectfluor (1-chloromethyl-4-fluoro- + 1,4-diazoniabicyclo[2.2.2]octane Cl N Br Me Sn Cl + - bis(tetrafluoroborate), or F-TEDA) is a 3 N 2 BF4 N 1) n-BuLi, THF, 30min, -78°C N user-friendly, mild, air- and moisture- N 2) Me3SnCl, THF, 24h, rt F N N N stable, non-volatile reagent for H H electrophilic fluorination. Selectfluor™ is capable of introducing fluorine into organic substrates in one step, with a remarkably F NH2 broad scope of reactivity.11 Many of these reactions display excellent F Cl N SelectfluorTM N N regioselectivity. HO O N CH CN, 7h, rt 3 N N H CH3 Recently, the synthesis of a potent and noncytotoxic nucleoside HO OH inhibitor of Hepatitis C virus RNA replication was accomplished ™ ™ using Selectfluor (Scheme 10). This ribonucleoside shows a significantly improved enzymatic stability profile compared to the Scheme 10 parent 2’-C-methyladenosine.12

Allylic fluorides can be prepared via a sequential cross-metathesis/ electrophilic fluorodesilylation route (Scheme 11). This route avoids Selectfluor TM R cross-metathesis Selectfluor R the formation of by-products that result from allylic transposition, R TMS TMS CH3CN, 48h, rt which is observed when nucleophilic displacement or ring-opening F reaction with DAST is attempted.13

Selectfluor™ is also capable of effecting other transformations. One Scheme 11 recent example uses Selectfluor™ as an alternative to silver or mercury salts in the rearrangement of iodides to alcohols (Scheme 12). In the case of an iodochloride (X=Cl), substitution only occurs at the 14 iodide and not the chloride. I OH CO Bn TM N 2 Selectfluor BnO2C R = H, Me R N X = F, Cl CH3CN / H2O, 48h, rt R Selectfluor™ has even been employed as an efficient catalyst for the X X preparation of b-hydroxy thiocyanates using ammonium thiocyanate under mild conditions (Scheme 13). In all cases, the reactions Scheme 12 proceed rapidly at room temperature without the formation of the corresponding thiiranes, which are generally the exclusive products 15 when Lewis acids such as Sc(OTf)3 and InCl3 are used.

O SelectfluorTM OH + NH4SCN SCN Selectfluor™ R CH3CN, rt R 43,947-9 5 g 17.80 25 g 61.60 Scheme 13

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Ishikawa’s Reagent HO F O O S Et NCF CHFCF F Ishikawa’s reagent (N,N-diethyl-1,1,2,3,3,3- CH3 2 2 3 CH S F F CH3 3 CH Et O, rt 3 F hexafluoropropylamine) has also CH N 2 N 3 CH3 demonstrated utility in fluorination. In a OTHP OTBS OTHP OTBS F N F recent example, Ishikawa’s reagent has O F been used in a clean and reproducible S fluorination protocol on an intermediate HO N in the total synthesis of 26-fluoroepothilone B (Scheme 14).16 O O OH O 26-Fluoroepothilone B

Ishikawa’s reagent also displays the ability to insert a fluoro(trifluoro- Scheme 14 methyl)methylene moiety in unsaturated alcohols (Scheme 15).17

O OH i-Pr2NEt Ishikawa’s Reagent + Et2NCF2CHFCF3 R NEt2 R F C F 56,499-0 25 g 63.70 3 100 g 217.00 Scheme 15

Poly[4-vinylpyridinium poly(hydrogenfluoride)] Other Reagents Other Reagents for Fluorination 37,705-8 5 g 40.60 for Fluorination 25 g 123.00 Ishikawa's Reagent Potassium fluoride, 99+%, a.c.s. reagent Cesium fluoride, 99% 40,293-1 5 g 16.40 19,832-3 25 g 33.90 100 g 36.70 100 g 98.40 500 g 109.60 Cesium fluoride, 99.9% 12 kg 1,939.10 28,934-528,934-5 5 g 20.50 Potassium fluoride, spray-dried, 99% 25 g 43.00 30,759-9 50 g 35.10 100 g 122.50 250 g 58.20 (Dimethylamino)sulfur trifluoride 1 kg 161.00 24,821-5 5 g 67.30 Tetrabutylammonium difluorotriphenylstannate, 97% 25 g 217.00 41,862-5 250 mg 18.40 N-Fluorobenzenesulfonimide, 97% 1 g 37.90 39,271-5 1 g 14.60 Tetrabutylammonium fluoride, 1.0M solution in THF 5 g 51.90 containing ca. 5 wt. % water 1-Fluoropyridinium tetrafluoroborate, 97% 21,614-3 5 mL 16.50 100 mL 42.10 37,726-0 1 g 40.60 500 mL 147.50 5 g 135.00 2 L 468.30 2.5 L 609.00 1-Fluoropyridinium triflate, 99% 20 L 4,865.00 32,365-9 1 g 52.20 Tetrabutylammonium fluoride, 75 wt. % solution in water 5 g 172.50 36,139-9 25 g 25.60 1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 95+% 100 g 85.50 43,931-2 1 g 24.80 500 g 273.00 5 g 82.20 Tetrabutylammonium fluoride, on silica gel 11-Fluoro-2,4,6-trimethylpyridinium triflate, tech., 85% 35,867-3 5 g 28.70 37,821-6 1 g 59.50 25 g 92.90 5 g 215.50 Triethylamine trihydrofluoride, 98% Hydrogen fluoride-pyridine 34,464-8 5 g 11.40 18,422-5 25 g 27.80 25 g 38.70 100 g 56.30 100 g 102.50 Morpholinosulfur trifluoride Tris(dimethylamino)sulfur (trimethylsilyl)difluoride, tech. 33,891-5 1 g 30.80 25,060-0 250 mg 18.60 5 g 98.70 1 g 50.90 5 g 167.50

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Dess–Martin Periodinane

O Dess–Martin Periodinane (DMP) is among the most widely used reagents for the O O mild oxidation of alcohols to aldehydes O and ketones.18 The neutral conditions of H N3 DMP, NaN3, CH2Cl2 I OAc the oxidation reaction make it a suitable X X AcO choice in syntheses of sensitive, functionally O 0°C, 1 to 4.5h O OAc 82-95% complex intermediates. When used in n H n N3 hydrophilic ionic liquids, DMP oxidations proceed even faster than in conventional solvents.19 Other advantages such as selectivity, avoiding the use of toxic (i.e. chromium-based) chemicals, using stoichiometric amounts of reagent, and ease of work-up make the Dess–Martin periodinane a reliable and easy-to-use oxidizer in Scheme 16 organic synthesis.

DMP has been employed in a practical and efficient route for the one-step conversion of aromatic and aliphatic aldehydes to acyl azides (Scheme 16). The acyl azides are able to be isolated OH O ON without rearrangement to the alkyl isocyanate due to the mild ON CH reaction conditions.20 Ph CH3 DMP, CH2Cl2 Ph 3 EtO2C CO2Et rt, 2h, 93% EtO2C CO2Et

H C Intramolecular competition between a dihydropyridine and H3C N CH3 3 N CH3 H H isoxazolyl alcohols has also been reported. When oxidation was performed using one equivalent of DMP, the keto-isoxazole- O ON dihydropyridine was produced in 93% isolated yield, with no OH ON CH detectable oxidation of the dihydropyridine (Scheme 17).21 Ph CH3 Ph 3 EtO2C CO2Et EtO2C CO2Et Dess–Martin Periodinane

A recent report describes a useful procedure for the removal of H3C N CH3 H3C N CH3 thioacetals and thioketals using DMP, displaying compatibility with a not formed wide range of functional groups (Scheme 18). A direct route to the corresponding acetals is also possible when the transformation is performed in the presence of an alcohol (Scheme 19).22

Rare, complex, and diverse polycycles and heterocycles can be rapidly obtained through DMP-mediated cascade cyclization (Scheme 20).23,24 Scheme 17

A slight modification in the reaction conditions allows for the genera- tion of p-quinones from anilides. This approach was then used as a key step in concise and efficient syntheses of epoxyquinomycin B (Scheme 21) and topoisomerase-II inhibitor BE-10988 (Scheme 22).25

O DMP, CH3CN, CH2Cl2, H2O SS Dess–Martin periodinane was found to be a superior oxidant for up to 99% R R' R R' the efficient preparation of epimerization-sensitive, optically active N-protected a-amino aldehydes with high enantiomeric excess (Scheme 23).26

Scheme 18 DMP-mediated oxidation also provides a convenient route to the preparation of highly reactive acyl nitroso compounds. These products can be trapped by dienes to form cycloadducts (Scheme 24).27

Dess–Martin periodinane, 97%

27,462-3 1 g 32.50 OR' DMP, CH3CN, CH2Cl2, R'OH 5 g 130.00 SS R H 74-91% R OR'

Dess–Martin periodinane, 0.3M solution in dichloromethane 55,987-3 1 mL 6.90 5 mL 23.20 25 mL 77.20 Scheme 19

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Ts H Ts N N 1) TBAF H O TBDMSO 2) DMP H

O R H 4 X N X R2 DMP N R5 R1 benzene, ∆ R R4 O R5 R3 1 O R2 R3

Scheme 20

OH OAc OAc O O H H H N N N DMP, H2O, CH2Cl2 O 25°C, 3h O OTBS O O O OTBS H O O Epoxyquinomycin B

Scheme 21 Dess–Martin Periodinane H3CO2C H3CO2C

H N N N 2 S O S DMP, H2O, CH2Cl2 BzHN BzHN N 25°C, 12h CH 3 N N CH3 O CH3

H2NOC

N O S NH3, THF H N -78 to 25°C, 48h 2

N O CH3

BE-10988

Scheme 22

H O N H HO Fmoc N DMP, wet CH2Cl2 H Fmoc rt, 25min

99%ee

Scheme 23

O O O DMP N R OH O R N R N O H

Scheme 24

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Bis(pyridine)iodonium

O R3 tetrafluoroborate 1) Ipy2BF4, HBF4 1) Ipy BF , HBF R3 2 4 4 CH2Cl2, 0°C to rt H CH2Cl2, 0°C to rt (Ipy BF , Barluenga’s Reagent) 2) R2 2 4 R2 R2 R3 2) R3 R2 I R O R This mild iodinating and oxidizing reagent is 1 1 capable of selectively reacting with a wide range Scheme 26 N of unsaturated substrates and tolerates a variety of functional groups. Ipy BF reacts with acetonides I+ BF - 2 4 4 derived from simple terpenes to accomplish O OR N selective iodofunctionalization with excellent regio- 1) Ipy2BF4, HBF4 H CH Cl , 0°C to rt and diastereofacial control (Scheme 25).28 2 2 O 2) ROH R1 R1 I

When added to 2-alkynyl-substituted benzaldehydes, Ipy2BF4 Scheme 27 produces substituted naphthalene products upon treatment with 29 either an alkene or alkyne (Scheme 26). Alternatively, subsequent I treatment with primary alcohols affords oxygen containing N heterocycles (Scheme 27).30 OH O Ipy2BF4 O Y CH2Cl2, rt, 10min Y Y X X X Recently, tetracyclic tetrahydrofurans were produced using Ipy2BF4 in a key step of the synthesis of a series of potential broad- Scheme 28 spectrum psychotropic agents (Scheme 28).31 tetrafluoroborate O Additionally, Ipy BF has been reported to be useful in general O I 2 4 Ipy2BF4 32 33 N Ph CH CH Cl , rt N iodinations (Scheme 29) and oxidation of alcohols to carbonyls. N 3 2 2 Ph N CH3 Bis(pyridine)iodonium CH Photolytic reactions of cycloalkanols produced ring-cleaved 3 CH3 products, while thermal reactions left the ring intact during oxidation (Scheme 30). Thermal reactions of primary alcohols were Scheme 29 capable of producing either aldehydes in dilute conditions or esters in more concentrated solutions (Scheme 31). OH O O Ipy2BF4, CsCO3 Ipy2BF4 , I2 I Bis(pyridine)iodonium tetrafluoroborate H CH2Cl2, rt, hν CsCO3, CH3CN, 60°C 53,163-4 1 g 45.60 Scheme 30

O O O O MeO O O Ipy BF , I , MS 4Å Ipy2BF4 , I2, MS 4Å Ipy2BF4, HBF4, MeOH 2 4 2 R OH K2CO3, CH3CN, 40°C R O R CH Cl , -60 - 30°C, 4h R H K2CO3, CH3CN, 60°C 2 2 24h I 14h

Scheme 25 Scheme 31

8 Safer, Amine-Stabilized BH3-THF Solutions for Hydroboration and Reduction

O o OH 65,039-0: 98%; 96.1%ee BH3-THF, 25 C CH3 CH3 65,041-2: 98%; 96.2%ee (R)-Me-CBS cat. Product Highlights: 1M in toluene 17,619-2: 97%; 90.3%ee (10 mol %) • Enhanced safety • Shipment for all pack sizes at OH room temperature providing 1 65,039-0: 90%; 93:7 (1:2) greater cost savings 1. BH3-THF + 65,041-2: 93%; 94:6 (1:2) 2. H2O2 • Excellent reactivity and selectivity 17,619-2: 92%; 94:6 (1:2) vs. BH3-THF (17,619-2; NaBH4- 2 OH stabilized)

8 65,039-0 BH3THF, 1.0M solution in THF, 1,2,2,6,6-Pentamethylpiperidine (PMP)-stabilized 8 65,041-2 BH3THF, 1.0M solution in THF, N-Isopropyl-N-methyl-tert-butylamine (NIMBA)-stabilized 17,619-2 BH3THF, 1.0M solution in THF, NaBH4-stabilized

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Magnesium bis(monoperoxyphthalate) hexahydrate OAc AcO OAc AcO Magnesium bis(monoperoxy- MMPP, H O O O 2 O O phthalate) hexahydrate AcO S CH2Cl2, 0.7h, MW AcO S - OAc O Mg2+ (mono peroxyphthalic OAc O acid magnesium salt, or CH3 CH3 OH MMPP) is a mild, general · 6H2O oxidizing agent which is a O suitable replacement for 2 Scheme 32 peroxycarboxylic acids. This versatile reagent is capable of effecting many types of general oxidation reactions.34 In addition, MMPP displays low toxicity, and is safer to use in larger-scale reactions, compared to common peroxycarboxylic acids. The reaction by-product, magnesium OH bisphthalate, is water soluble, and generally easy to separate O PPh3 O O O MMPP H CO CO Bn CO2Bn during work-up. H3CO CO2Bn 3 2 H3CO N R N(Boc)2 O N(Boc)2 O N(Boc)2

Recently, the difficult oxidation of glycosyl sulfides to the sulfoxide

has been achieved using moist MMPP and microwave irradiation Magnesium (MW) (Scheme 32). The yields using MMPP were superior to those Scheme 33 hexahydrate achieved using other oxidants such as oxone or sodium periodate, and no over-oxidation to the sulfone was observed.35

MMPP was also used in the formation of a unique alkenyl H3C H3C H ClO - OR 4 MMPP tricarbonyl, which was used as a common precursor in the synthesis + 36 N ultrasound N of a series of heterocyclic substituted amino acids (Scheme 33). H3C S H3C S H2O or ROH O O R1 R1 phthalate) bis(monoperoxy MMPP was used in conjunction with ultrasound stimulation to produce 2-aryl-3-hydroxysultams and 2-aryl-3-alkoxysultams in one step from the isothiazolium salt (Scheme 34).37 Scheme 34

Whereas most aromatic aldehydes are oxidized to the corresponding carboxylic acids, it has been reported that o- and p-methoxy- benzaldehydes can be converted to the analogous phenols in pres- O 38 OH ence of MMPP (Scheme 35). H MMPP MeOH OCH3 OCH3 Magnesium bis(monoperoxy phthalate) hexahydrate 28,320-7 5 g 18.00 100 g 37.00 Scheme 35

New Piperazine Building Blocks from Sigma-Aldrich

65,167-2 65,238-5 1-(3-Hydroxyphenyl)piperazine, 97% 1-Boc-4-(4-methoxycarbonylphenyl)piperazine, 97% OH O O MW 178.24 1 g $28.50 MW 320.19 N N 1 g $70.00 H3C O C H N O 5 g 100.50 C H N O O 5 g 245.00 10 14 2 N 17 24 2 4 H3C CH H3C 3 N H 65,237-7 65,142-7 1-Boc-4-(2-methoxycarbonylphenyl)piperazine 1-Boc-4-(4-Formylphenyl)piperazine, 97% O MW 308.38 O CH3 1 g $65.00 MW 290.36 O 1 g $41.50 O N N C H N O O 5 g 227.50 C H N O H O 5 g 145.00 16 24 2 4 N N 16 22 2 3 H3C CH3 O H3C H3C

CH3 H3C 65,192-3 65,015-6 4-(Boc-piperazin-1-yl)-3-nitrobenzoic acid, 97% 1-(2-Chloro-6-fluorobenzyl)piperazine, 98% NO2 H MW 351.35 O O 1 g $19.50 MW 228.69 N 1 g $17.50 C H N O N N 5 g 68.00 C H ClFN 10 g 98.50 16 21 3 6 HO O 11 14 2 N F H3C CH3 H3C Cl

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Chloramine-T Although the aziridinations39 and Cl aminohydroxylations40 of olefins using O N S Na chloramine-T as a commercially-available O and inexpensive nitrene source have been OR 1.5M Chloramine-T OR in CH3CN well documented, the use of chloramine-T O RO O H C RO OH 3 in other capacities as an oxidizing agent is RO SR' H2O, rt RO OR OR less well-known.

When a solution of chloramine-T in acetonitrile was added to thioglycosides, it resulted in their chemoselective hydrolysis into glycosyl hemiacetals under neutral conditions (Scheme 36). The Scheme 36 reaction is carried out without requiring any additive, and is tolerant of a variety of functional groups. Furthermore, neither oxidation of sulfur atoms, nor formation of aziridines was observed during the course of the reaction.41

Chloramine-T is also capable of oxidative cyclization to produce Cl ArCHO Cl Chloramine-T Cl various heterocycles. A recent report details the synthesis of DMF, MW N N NHNH2 EtOH, MW N N N N N N N 1,2,4-triazolo[4,3-a][1,8]naphthyridines using chloramine-T under H Ar N Chloramine-T for Oxidation microwave irradiation (Scheme 37). The reaction proceeds cleanly Ar Other Reagents in minutes, and requires a simple mild work-up to obtain the desired product.42

Scheme 37 Fused cyclic ethers have been obtained through oxidation by chloramine-T. Pyranocyclohexane derivatives were synthesized starting from 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose, using chloramine-T in a key step on an oxime derivative (Scheme 38).43

HO N O N Chloramine-T hydrate, 98% O O H O O Chloramine-T O O O H H MeOH, ∆ ,8h O 85,731-9 5 g 16.20 O O HO O O 100 g 17.60 H O 1 kg 53.00 Chloramine-T trihydrate, 98% 40,286-9 100 g 21.50 1 kg 91.90 Scheme 38

Other Reagents for Oxidation

N-Bromosuccinimide, 99% 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone, 98% B8,125-5 5 g 8.10 D6,040-0 5 g 16.70 100 g 18.70 10 g 25.40 500 g 51.60 100 g 212.40 1 kg 80.00 2.5 kg 201.40 Dithiothreitol 1,1’-Carbonyldiimidazole 15,046-0 250 mg 13.60 1 g 31.40 11,553-3 5 g 17.40 5 g 72.40 10 g 28.90 25 g 286.50 25 g 58.00 100 g 813.00 100 g 173.70 1 kg 7,410.00 1 kg 572.00 5 kg 25,100.00 25 kg 9,140.00 10 kg 33,400.00 3-Chloroperoxybenzoic acid, 77% Max. Osmium tetroxide, 99.8% 27,303-1 25 g 22.50 20,103-0 250 mg 46.70 100 g 53.70 500 mg 74.90 500 g 191.40 1 g 123.50

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Osmium tetroxide, 98+%, a.c.s. reagent References 41,949-4 250 mg 52.30 (1) Inagaki, T. et al. Tetrahedron Lett. 2003, 44, 4117. 1 g 144.70 (2) Yoshida, M. et al. ARKIVOC 2003, (vi) 36. Osmium tetroxide, 4 wt. % solution in water (3) Motherwell, W. B. et al. J. Chem. Soc. Perkin Trans. 1 2002, 2809. 25,175-5 2 mL 48.60 (4) Greaney, M. F. et al. Tetrahedron Lett. 2001, 42, 8523. 5 mL 77.40 (5) For a review of recent highlights: Singh, R. P. and Shreeve, J. M. 10 mL 121.50 Synthesis 2002, 2561. Osmium tetroxide, 2.5 wt. % solution in 2-methyl-2-propanol (6) Golubev, A. S. et al. Tetrahedron Lett. 2004, 45, 1445. 20,886-8 1 mL 25.00 (7) Anilkumar, R. and Burton, D. J. Tetrahedron Lett. 2003, 44, 6661. 5 mL 68.80 (8) Bombrun, A. et al. J. Med. Chem. 2003, 46, 4365. 25 mL 213.50 (9) Singh, R. P. and Shreeve, J. M. J. Org. Chem. 2003, 68, 6063. Oxalyl chloride, 98% (10) Inoue, M. et al. Tetrahedron Lett. 2004, 45, 2053.

O8801 25 g 17.40 (11) For a review of recent highlights: Singh, R. P. and Shreeve, J. M. 100 g 44.90 Acc. Chem. Res. 2004, 37, 31. 1 kg 320.30 (12) Eldrup, A. B. et al. J. Med. Chem. 2004, 47, 5284. 2.5 kg 601.10 50 kg 4,690.00 (13) Thibaudeau, S. and Gouverneur, V. Org. Lett. 2003, 5, 4891. (14) Krow, G. R. et al. Org. Lett. 2004, 6, 1669. OXONE®, monopersulfate compound (15) Yadav, J. S. et al. Tetrahedron Lett. 2004, 45, 1291. 22,803-6 5 g 18.20 (16) Koch, G. et al. Synlett. 2004, 693. 100 g 25.60 1 kg 32.70 (17) Ogu, K-i. et al. Tetrahedron Lett. 1998, 39, 305. for Oxidation

5 kg 118.20 (18) Dess, D.B and Martin, J. C. J. Org. Chem. 1983, 48, 4155. Other Reagents 25 kg 246.00 (19) Yadav, J. S. et al. Tetrahedron 2004, 60, 2131. Peracetic acid, 32 wt. % solution in dilute acetic acid (20) Bose, D. S. and Reddy, A. V. N. Tetrahedron Lett. 2003, 44, 3543. 26,933-6 5 mL 22.20 (21) Nelson, J. K. et al. Synlett 2003, 2213. 100 mL 26.90 (22) Langille, N. F. et al. Org. Lett. 2003, 5, 575. 500 mL 75.00 (23) Kitamura, T. and Mori, M. Org. Lett. 2001, 3, 1161. Phosphorus pentachloride, 95% (24) Nicolaou, K. C. et al. J. Am. Chem. Soc. 2002, 124, 2212. 15,777-5 5 g 19.20 (25) Nicolaou, K. C. et al. J. Am. Chem. Soc. 2002, 124, 2221. 100 g 32.40 (26) Myers, A. G. et al. Tetrahedron Lett. 2000, 41, 1359. 1 kg 39.40 (27) Jenkins, N. E. et al. Synth. Commun. 2000, 30, 947. Phosphorus tribromide, 99% (28) Barluenga, J. et al. J. Org. Chem. 2003, 68, 6583. 25,653-6 5 g 19.60 (29) Barluenga, J. et al. Org. Lett. 2003, 5, 4121. 100 g 48.20 (30) Barluenga, J. et al. J. Am. Chem. Soc. 2003, 125, 9028. 500 g 126.50 (31) Fernández, J. et al. J. Med. Chem. in press. Phosphorus tribromide, 97% (32) Campos, P. J. et al. Tetrahedron Lett. 1997, 38, 8397. 15,778-3 5 g 18.90 (33) Barluenga, J. et al. Chem. Eur. J. 2004, 10, 4206. 100 g 40.00 (34) Brougham, P. et al Synthesis 1987, 1015. 500 g 84.00 (35) Chen, M-Y. et al. J. Org. Chem. 2004, 69, 2884. Phosphorus trichloride, ReagentPlus™, 99% (36) Wasserman, H. H. et al. Tetrahedron Lett. 2002, 43, 3351. 32,046-3 1 L 65.80 (37) Taubert, K. et al. Synthesis 2003, 2265. Phosphorus trichloride, ReagentPlus™, 99% (38) Heaney, H. and Newbold, A. J. Tetrahedron Lett. 2001, 42, 6607. 15,779-1 50 g 21.20 (39) Some recent examples: (a) Kumar, G. D. K. and Baskaran, S. Chem. 250 g 25.30 Commun. 2004, 1026; (b) Minakata, S. et al. Angew. Chem. Int. Ed. 1 kg 42.50 Engl. 2004, 43, 79; (c) Kantam, M. L. et al. Tetrahedron Lett. 2003, 44, 9029; (d) Kano, D. et al. J. Chem. Soc. Perkin Trans. 1 2001, 3186; Pyridinium chlorochromate, 98% (e) Brandt, P. et al. J. Am. Chem. Soc. 2000, 122, 8013–8020; (f) 19,014-4 25 g 18.00 Jeong, J. U. et al. J. Am. Chem. Soc. 1998, 120, 6844. 100 g 39.70 (40) (a) Rudolph, J. et al. Angew. Chem. Int. Ed. Engl. 1996, 35, 2810; (b) 500 g 136.50 Li, G. et al. Angew. Chem. Int. Ed. Engl. 1996, 35, 451; (c) Li, G. and Sharpless, K. B. Acta Chem. Scand. 1996, 50, 649. Triphosgene, 98% (41) Misra, A. K. and Agnihotri, G. Carbohydrate Research 2004, 339, 885. 33,075-2 5 g 36.80 (42) Mogilaiah, K. and Reddy, G. R. J. Chem. Res. 2004, 145. 25 g 116.50 100 g 318.30 (43) Pal, A. et al. Tetrahedron 1999, 55, 4123.

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