Organic syntheses collective volume 10 jeremiah p freeman

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DOI:10.15227/orgsyn.077.0121 Organic Syntheses, Coll Vol 10, p.1 (2004); Vol 77, p.121 (2000) 7α-ACETOXY-(1Hβ, 6Hβ)-BICYCLO[4.4.1]UNDECA-2,4,8-TRIENE VIA CHROMIUM-MEDIATED HIGHER ORDER CYCLOADDITION [ Bicyclo[4.4.1]undeca-3,7,9-triene-2-ol, acetate, endo- (±)- ] Submitted by James H Rigby1 and Kevin R Fales Checked by Robert E Lee Trout and Amos B Smith, III Procedure A Tricarbonyl(η6-cycloheptatriene)chromium(0) An oven-dried complexation flask (Figure 1), fitted with an additional condenser (Note 1) and gas adapter, is charged with acetonitrile (300 mL) The solvent is heated to 40°C under argon (Ar) (Note 2), chromium hexacarbonyl is added (45 g, 0.2 mol) (Note 3), and the mixture is immediately heated to reflux for 24 hr (Note 4) Toward the end of this time period (i.e., after 20 hr), the cooling jacket attached to the flask is alternately filled with water and emptied to allow for complete digestion of the starting material After complete conversion of the chromium hexacarbonyl is evident, the free condenser is quickly changed to a 9"-Vigreux column connected through an acetone/solid carbon dioxide (CO2) condenser to a vacuum/argon line using a Firestone valve (Note 5) Vacuum ( 0.1 mm) is quickly and cautiously applied to the system while simultaneously removing the heating source (Note 6) The reaction mixture is evaporated to complete dryness by warming the reaction flask with a warm water bath as necessary (Note 7) The system is filled with argon and a previously prepared solution of cycloheptatriene (1.5 eq., 0.31 mol, 28.3 g, 32 mL) in tetrahydrofuran (THF) (50 mL) is added via syringe to the dry, bright yellow, solid tris (acetonitrile)chromium tricarbonyl intermediate This addition is best performed under a very strong flow of argon through the top joint of the reaction apparatus An additional 100 mL of THF is added to the mixture and the resulting solution is heated to reflux After 48 hr, additional cycloheptatriene (1.0 eq., 0.2 mol, 20.5 g, 23 mL) is added and the reaction is continued until complete digestion of the (CH3CN)3Cr(CO)3 intermediate is evident (Note 8) Solvent is removed under reduced pressure (Note 9), and the residue is dissolved in a mixture of hexanes (225 mL) and methylene chloride (225 mL) Celite (5.0 g) is added to the solution and the mixture is filtered through a Celite pad (5.5 cm × 1.0 cm) The filter cake is washed with methylene chloride (2 × 50 mL) and the filtrate is concentrated under reduced pressure to provide an oily red solid After the solids are dried briefly under vacuum ( hr, 0.1 mm), they are triturated with chilled hexanes (100 mL), and the chilled solids are collected via vacuum filtration and washed with chilled hexanes (50 mL) The solids are dried under vacuum (0.1 mm) to yield the dark red tricarbonyl(η6-cycloheptatriene)chromium(0) (34.4-39.9 g, 75-85%, (Note 10)) Figure B 7α-Acetoxy-(1Hβ, 6Hβ)-bicyclo[4.4.1]undeca-2,4,8-triene To a large, fully assembled photochemical reaction vessel (Figure 2) are added tricarbonyl(η6-cycloheptatriene)chromium(0) (10.0 g, 0.044 mol) and hexanes (4 L, (Note 11)) While the mixture is stirred it is purged with argon for 2030 and then 1-acetoxy-1,3-butadiene (1.5 eq., 7.4 g, 7.8 mL, 0.66 mol) is added via syringe (Note 12) The solution is irradiated (Note 13) using a Hanovia medium pressure 450W mercury vapor lamp (Note 14) for hr or longer (Note 15) until complete digestion of the starting chromium complex is noted by TLC (Note 16) The reaction mixture is transferred, portionwise, to a 2-L, round-bottomed flask using diethyl ether, and the solvents are removed under reduced pressure (Note 9) The residue is taken up in methanol (300 mL), with scraping as necessary, and the resultant slurry is stirred open to the atmosphere overnight At this time, flash grade silica gel (10.0 g, Merck 230-400 mesh) is added to the green slurry and stirring is continued as necessary for complete decomplexation of the intermediate cycloadduct complex, as noted by TLC (Note 16) The reaction mixture is filtered through a Celite pad (9 cm diameter by cm deep), using additional methanol (3 × 50 mL) to rinse the flask and filter cake until the filtrate runs clear (Note 17) Solvent is removed under reduced pressure and the residue is dried overnight under 0.1 mm vacuum to remove additional traces of solvent and unreacted diene (Note 18) The product is purified via flash column chromatography (Note 19) to yield 98% pure (Note 20), 7αacetoxy-(1Hβ, 6Hβ)-bicyclo[4.4.1]undeca-2,4,8-triene (7.7 g, 86%) (Note 21) as a white solid (mp 5457°C) Figure 2: Immersion well photochemical reactor Notes It is most convenient to attach cooling water in series to the free condenser first and then to the cooling jacket on the complexation flask The submitters used nitrogen at this point, but the checkers found that argon worked as well The checkers also recommend the use of an Oxiclear gas purifier Fresh reagent grade acetonitrile was purchased from Fisher Scientific Co and used without additional purification Chromium hexacarbonyl was purchased from Strem Chemical Co Celite and cycloheptatriene (90% technical grade) were purchased from Aldrich Chemical Company, Inc , and used without purification THF was distilled from sodium/benzophenone ketyl Once heating of the reaction is begun, any significant cooling or exposure to the atmosphere generally causes degradation of the tris(acetonitrile)chromium tricarbonyl intermediate The reaction initially turns greenish yellow, but then quickly forms a bright yellow to golden color that becomes dark green upon degradation Greenish, partially degraded intermediates can be carried through the sequence with a corresponding reduction in yield The total time of reflux ranged from 24-26 hr This item may be purchased from Ace Glass Inc., Vineland, N.J., catalog #8766-12 Vacuum must be applied carefully to avoid bumping, but must also be applied quickly and steadily to avoid degradation of the reaction intermediate Warning! Tris(acetonitrile)chromium tricarbonyl is highly pyrophoric and degrades rapidly when exposed to oxygen, but is reasonably stable in THF solution Best yields are obtained when this intermediate is as free of acetonitrile as possible while avoiding formation of the green colored [Cr(III)] decomposition product, which develops on contact with air The reaction is monitored by TLC (silica gel, 6:1 hexanes: ethyl acetate) Typical characteristics are Rf = 0.15, a yellow spot [tris(acetonitrile)chromium tricarbonyl intermediate], and Rf = 0.51, a red spot (product complex) Total reaction time averaged 180 hr Solvent is removed via rotary evaporator 10 This product was typically found to be ≥ 98% pure based on 1H NMR analysis, and it may be used without further purification However, the compound may be recrystallized from hexanes if necessary The complex exhibits the following characteristics: TLC: Rf = 0.51 (silica gel, 6:1 hexanes:ethyl acetate); 1H NMR (500 MHz, CD2Cl2) δ: 1.74 (d, H), 2.95 (dt, H, J = 9.0, 14.0), 3.40 (t, H, J = 7.5), 4.87 (bs, H), 6.09 (bs, H) ; 13C NMR (125 MHz, CD2Cl2) δ: 23.9 (CH2), 57.1 (CH), 98.4 (CH), 101.1 (CH) ; IR (CDCl3) cm−1: 3052, 2895, 2848, 1982, 1974, 1917, 1897, 1886, 1877 ; HRMS calcd for C10H8CrO3: m/e 227.9879, found 227.9881 ; LRMS [EI] (rel %): 227.9 (19), 199.9 (13), 172.0 (15), 144.0 (74) 11 Performing this reaction at higher concentrations (i.e., in 1-2 L solvent) results in significantly increased reaction times, incomplete reaction, and increased side product formation 12 The reaction conditions given were developed using (E)-1-acetoxy-1,3-butadiene prepared according to the procedure of McDonald, et al.2 with the following modifications (unchecked) Crotonaldehyde (105 g, 125 mL) is added by addition funnel over hr to a refluxing solution of isopropenyl acetate (2.5 mol, 250 g, 275 mL), p-toluenesulfonic acid (anhydrous, 2.0 g) and copper(II) acetate (0.5 g) The mixture is heated at reflux for 30 and then the reaction apparatus is set up for distillation Distillation (bath temp 110-130°C) is continued for 2.5 hr until acetone and nearly all unreacted isopropenyl acetate is collected The distillation residue is cooled to 25°C and crude product is isolated via vacuum distillation (bp 32°C, mm) This crude product typically contains traces of isopropenyl acetate and significant amounts of acetic acid The crude distillate is dissolved in diethyl ether (500 mL), and carefully mixed with saturated aqueous sodium bicarbonate solution, adding additional anhydrous sodium bicarbonate slowly to the stirring mixture until gas evolution ceases and the pH increases to 7.0 The layers are separated and the organic phase is washed with brine (300 mL) and dried with magnesium sulfate The solution is carefully concentrated, and the product is purified by distillation to yield nearly pure (E)-1-acetoxy-1,3-butadiene ( 35-50% yield) Frequently, sequential distillations of the product are necessary to ensure the purity of the product obtained Pure product exhibits the following characteristics: bp 32°/10 mm; TLC: Rf = 0.61 (silica gel, 6:1 hexanes:ethyl acetate); 1H NMR (500 MHz, CDCl3) δ: 2.14 (s, H), 5.08 (dd, H, J = 10.5, 0.5), 5.21 (d, H, J = 17.0), 6.03 (dd, H, J = 12.0, 12.0), 6.26 (ddd, H, J = 21.5, 10.5, 10.5), 7.39 (d, H, J = 12.5) ; 13C NMR (125 MHz, CDCl3) δ: 20.7 (CH3), 116.0 (CH), 117.3 (CH2), 131.7 (CH), 138.6 (CH), 167.8 (C) ; IR (CDCl3) cm−1: 3091, 3074, 3041, 1660, 1097 ; HRMS m/e calcd for C6H8O2: 112.0524, found 112.0523 ; LRMS [EI] (rel %): 112.0 (57), 70.0 (100) Alternatively, 1-acetoxy-1,3-butadiene is available as a mixture of E,Z-isomers from Aldrich Chemical Company, Inc When using the commercial reagent, 3.0 eq (14.8 g, 15.6 mL) is necessary to ensure complete reaction, as the Z isomer does not react 13 Caution: UV radiation is harmful to eyes and skin; the reaction vessel may be wrapped with aluminum foil or the reaction conducted in a closed photochemical reaction cabinet to prevent exposure to the harmful UV rays 14 The photochemical lamp and power supply may be purchased from Ace Glass Inc., Vineland, N.J., catalog #'s 7825-32 or 7825-40 (lamp) and 7830-60 (power supply) 15 A solid buildup occurs on the immersion well that may slow the reaction considerably To help minimize this, the submitters suggest a constant purging of the reaction mixture with argon throughout the entire reaction time 16 Typical TLC data (silica gel, 6:1 hexanes:ethyl acetate) include Rf = 0.61 (1-acetoxy-1,3-butadiene); 0.51, a red spot [tricarbonyl(cycloheptatriene)chromium]; 0.45 a yellow spot (side product that often overlaps with the starting complex); and 0.31 a yellow spot (main intermediate chromium complex) 17 Prior to and between washes, the green filter cake cracks and should be "pushed down" with a spatula to form a uniform surface prior to any subsequent washes 18 TLC at this point (silica gel, 6:1 hexanes: ethyl acetate) shows three spots (UV): Rf = 0.76 (trace orange); 0.55 (side product); 0.47 (main product) 19 Chromatography is performed as follows: a 3.5-cm ID glass column is packed with 140 g of flash grade silica gel (Merck 230-400 mesh) in petroleum ether and the sample is loaded in minimal petroleum ether The checkers found that a 5.0-cm ID glass column packed with 170 g of Merck 70270 mesh silica gel gave slightly better separation Care must be taken during product application to minimize silica gel column separation The column is eluted, recycling solvent as necessary, until the front running orange band is collected This band is comprised of trace amounts of unreacted tricarbonyl (cycloheptatriene)chromium Elution then proceeds using 500 mL of 49:1 petroleum ether:diethyl ether followed by 19:1 petroleum ether:diethyl ether to obtain the product Prior to elution of the desired [6π+4π] cycloadduct, the side product, [6π+2π] cycloadduct (A) elutes, usually streaking into the desired product, but it is of little consequence All fractions containing the desired product are combined and the solvent is removed under reduced pressure The product sometimes solidifies during solvent removal, but may require seeding with authentic material to promote crystallization 20 The [6π+4π] cycloadduct exhibits the following characteristics: bp: 104-107°/1.3 mm; TLC: Rf = 0.47 (silica gel, 6:1 hexanes:ethyl acetate); 1H NMR (500 MHz, CDCl3) δ: 2.11 (s, H), 2.12-2.15 (m, H), 2.31 (bd, H, J = 14.0), 2.35-2.47 (m, H), 2.74 (bs, H), 2.92 (bs, H), 5.49 (bd, H, J = 11.0), 5.60-5.65 (m, H), 5.66-5.68 (m, H), 5.73-5.81 (m, H), 5.83-5.88 (m, H) ; 13C NMR (125 MHz, CDCl3) δ: 21.4 (CH3), 31.7 (CH2), 32.9 (CH2), 37.3 (CH), 42.7 (CH), 76.7 (CH), 124.9 (CH), 127.1 (CH), 128.7 (CH), 133.1 (CH), 135.3 (CH), 137.8 (CH), 170.5 (C) ; IR (neat) cm−1: 3011, 2924, 2905, 2884, 2872, 1737, 1447, 1430, 1368, 1241, 1199, 1055, 1020 ; HRMS calcd for C13H16O2: m/e 204.11503, found 204.1149 ; LRMS [EI] (rel %): 204.1 (2), 162.1 (2), 144.1 (20), 129.0 (11), 112.0 (6), 92.0 (100) Purity was determined by 500 MHz 1H NMR, with the main impurity being the [6π+2π] cycloadduct A This compound exhibits the following characteristics: TLC: Rf = 0.35 (silica gel, 19:1 hexanes:ethyl acetate); 1H NMR (500 MHz, CDCl3) δ: 1.58 (ddd, H, J = 13.5, 9.5, 3.5), 1.89 (d, H, J = 12.0), 2.01 (ddd, H, J = 13.5, 9.5, 9.5), 2.10 (s, H), 2.14-2.19 (m, H), 2.61 (dd, H, J = 12.0, 5.5), 2.69 (ddd, H, J = 16.5, 8.5, 4.0), 2.84 (ddd, H, J = 19.5, 9.5, 6.0), 5.58 (d, H, J = 10.0, 6.0), 5.62 (dd, H, J = 12.0, 9.5), 5.72 (dd, H, J = 12.0, 7.0), 5.83 (dd, H, J = 12.0, 6.5), 6.10 (dd, H, J = 10.5, 8.5), 7.09 (d, H, J = 12.0) ; 13C NMR (125 MHz, CDCl3) δ: 20.7 (CH3), 33.3 (CH2), 36.7 (CH), 42.3 (CH2), 46.3 (CH), 54.7 (CH), 115.5 (CH), 123.3 (CH), 126.6 (CH), 135.0 (CH), 135.2 (CH), 141.0 (CH), 168.2 (C) ; IR (neat) cm−1: 3019, 2950, 2931, 2863, 1755, 1370, 1219, 1094 ; HRMS calcd for C13H16O2: m/e 204.11503, found 204.1147 ; LRMS [EI] (rel %): 204.1 (2), 144.1 (20), 129.1 (7), 112.0 (6), 92.0 (100) 21 The yield reported is that of the submitters and is based on the use of the pure (E)-1-acetoxy-1,3butadiene It was found by the checkers that use of a mixture of the E, Z-isomers (as purchased from Aldrich Chemical Company, Inc.) led to an average yield of 73% Waste Disposal Information All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995 Wastes containing chromium, aqueous solutions as well as solids, were collected and disposed of separately Prior to washing, all glassware laden with chromium by-products, were soaked overnight in a solution composed of 15-20 g of copper beads dissolved in L of 50% aqueous nitric acid This solution may be kept loosely capped in a fume hood and reused several times prior to disposal Discussion Synthetic sequences that employ a cycloaddition step benefit from the convergency and stereoselectivity that characterizes these pericyclic transformations In recent years, several new methodologies for performing so-called higher-order cycloadditions [e.g., [6π+4π], [6π+2π], [4π+4π], [4π+3π], etc.] have appeared and are now being used as key transformations in the synthesis of a number of target molecules.3 For example, a number of reports have appeared in which the generation of specific examples of bicyclo[4.4.1]undecatriene ring systems are noted as useful intermediates in the synthesis of cerorubenate sesterterpenes6 as well as the ingenane diterpenes.7 In particular, the general utility of chromium-mediated [6π+4π] cycloaddition in the synthesis of several bicyclo[4.4.1]undecatriene systems as potential intermediates in natural product synthesis has been demonstrated,8 including the synthesis of members of the taxane and tigliane families.9 Furthermore, studies involving cleavage of certain functionalized members of these ring systems, allows for the generation of medium-sized carbocycles.10 With these synthetic opportunities in mind, presentation of the methodology used in large scale generation of tricarbonyl(η6-cycloheptatriene)chromium(0) as well as an example of [6π+4π] cycloaddition is timely Although a specific example of the submitter's higher-order cycloaddition methodology utilizing an electron-rich diene partner is presented, comparable results have also been obtained employing an electron-poor diene, methyl sorbate, with typical yields of 80-85% on a 10-g scale.11 Key to this large scale cycloaddition chemistry is the ability to generate large quantities of tricarbonyl(η6-cycloheptatriene)chromium(0) The submitters have found that the best results are obtained when the desired complex is generated with the highly reactive and pyrophoric complexation reagent (CH3CN)3Cr(CO)3.12 One drawback to this method, however, was the need to scrape solidified Cr(CO)6 from the reflux condenser during the early stages of the reaction, causing atmospheric exposure to the reactants For this reason, an engineering control was instituted through development of a reaction vessel (Figure 1) containing a built-in large bore condenser, thereby obviating the need to open the system for scraping and allowing, after subsequent complexation with cycloheptatriene, the isolation of highly pure product complex with little or no additional purification necessary References and Notes Department of Chemistry, Wayne State University, Detroit, MI 48202-3489 McDonald, E.; Suksamrarn, A.; Wylie, R D J Chem Soc., Perk Trans I 1979, 1893 Recent reviews in this area include: (a) Rigby, J H In "Comprehensive Organic Synthesis"; Trost, B M.; Fleming, I.; Eds.; Pergamon Press: Oxford, 1991; Vol 5, pp 617-643; Rigby J H In "Advances in Metal-Organic Chemistry"; JAI Press, Inc.: Greenwich, CT, 1995; Vol 4, pp 89-127; Rigby J H Org React 1997, 49, 331-425 Paquette, L A.; Hormuth S.; Lovely, C J J Org Chem 1995, 60, 4813, and references cited therein For an overview of synthetic approaches toward the ingenane diterpenes see: Rigby, J H In "Studies in Natural Products Chemistry"; Rahman, A.-U.; Ed.; Elsevier: New York, 1993; Vol 12 (Part H), pp 233-274 Rigby, J H.; de Sainte Claire, V Heeg, M J Tetrahedron Lett 1996, 37, 2553 Rigby, J H.; Niyaz, N M.; Short K M.; Heeg, M J J Org Chem 1995, 60, 7720 10 Rigby, J H.; Ateeq, H S.; Krueger, A C Tetrahedron Lett 1992, 33, 5873 11 For general experimental details see: Rigby, J H.; Ateeq, H S.; Charles, N R.; Cuisiat, S V.; Ferguson, M D.; Henshilwood, J A.; Krueger, A C.; Ogbu, C O.; Short, K M.; Heeg, M J J Am Chem Soc 1993, 115, 1382 12 Tate, D P.; Knipple, W R.; Augl, J M Inorg Chem 1962, 1, 433 Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number) 7α-Acetoxy-(1Hβ, 6Hβ)-bicyclo[4.4.1]undeca-2,4,8-triene: Bicyclo[4.4.1]undeca-3,7,9-triene-2-ol, acetate, endo- (±)- (12); (129000-83-5) Tricarbonyl(η6-cycloheptatriene)chromium(0): Chromium, tricarbonyl (1,3,5-cycloheptatriene)- (8); Chromium, tricarbonyl[(1,2,3,4,5,6-η)-1,3,5-cycloheptatriene]- (9); (12125-72-3) Acetonitrile (8,9), (75-05-8) Chromium hexacarbonyl: HIGHLY TOXIC: Chromium carbonyl (8); Chromium carbonyl (OC-6-11)- (9); (13007-92-6) Cycloheptatriene: 1,3,5-Cycloheptatriene (8,9); (544-25-2) Tris(acetonitrile)chromium tricarbonyl: Chromium, tris(acetonitrile)tricarbonyl- (8,9); (16800-46-7) (E)-1-Acetoxy-1,3-butadiene: 1,3-Butadiene-1-ol acetate, (E)- (9); (35694-20-3) Crotonaldehyde: Crotonaldehyde, (E)- (8); 2-Butenal, (E)- (9); (123-73-9) Isopropenyl acetate: 1-Propen-2-ol, acetate (8,9); (108-22-5) p-Toluenesulfonic acid (8); Benzenesulfonic acid, 4-methyl- (9); (104-15-4) Cupric acetate monohydrate: Acetic acid, copper(2+) salt, monohydrate (8,9); (6046-93-1) Copyright © 1921-2005, Organic Syntheses, Inc All Rights Reserved DOI:10.15227/orgsyn.077.0135 Organic Syntheses, Coll Vol 10, p.9 (2004); Vol 77, p.135 (2000) STILLE COUPLINGS CATALYZED BY PALLADIUM-ONCARBON WITH CuI AS A COCATALYST: SYNTHESIS OF 2-(4'ACETYLPHENYL)THIOPHENE Submitted by Lanny S Liebeskind2 and Eduardo Peña-Cabrera3 Checked by Jory Wendling and Louis S Hegedus Procedure A 200-mL, flame-dried Schlenk flask is purged with nitrogen and charged with 10.0 g (40.6 mmol) of 4-iodoacetophenone (Note 1), 770 mg (4.1 mmol) of copper(I) iodide (CuI) (Note 2), 2.5 g (8.1 mmol) of triphenylarsine (Note 3), and 150 mL of anhydrous 1-methyl-2-pyrrolidinone (Note 4) The dark solution is degassed for 15 (nitrogen sparge) and then 14.1 mL (44.7 mmol) of 2(tributylstannyl)thiophene (Note 5) is added The reaction flask is immersed in a preheated oil bath at 95°C and 215 mg (0.2 mmol) of 10% palladium on activated carbon (Note 6) is added under a positive nitrogen pressure The mixture is kept at 95°C for 24 hr (Note 7) and then allowed to cool to 25°C and diluted with 300 mL of ethyl acetate The dark mixture is poured into 200 mL of an aqueous saturated sodium fluoride solution (Note 8) and stirred vigorously for 30 The green-yellow heterogeneous mixture is passed through a sand pad contained in a medium-frit filter, aided by a water aspirator (Note 9) The filtrate is partitioned in a separatory funnel and the aqueous layer is extracted with two 100-mL portions of ethyl acetate The organic extracts are combined and stirred with 200 mL of fresh saturated aqueous sodium fluoride solution for 30 The mixture is then passed through a sand pad as described above The pad is rinsed with 50 mL of ethyl acetate The mixture is partitioned again and the aqueous layer is extracted with two 50-mL portions of ethyl acetate The organic extracts are combined and washed with five 100-mL portions of water and finally with 100 mL of brine (Note 10) The dark yellow solution is dried over anhydrous magnesium sulfate (MgSO4) (Note 11) and filtered The used MgSO4 is washed with 50 mL of ethyl acetate The solvent is removed under reduced pressure to give a dark yellow solid that is dissolved in the minimum amount of dichloromethane and adsorbed onto 20 g of silica gel (Note 12) The solvent is thoroughly removed under reduced pressure and the resulting solid is charged into a medium-pressure liquid chromatography column (silica gel, × 15 cm) (Note 13) The product (6.6 g, 80%) (Note 14) is purified as described by Baeckström et al.4 (Note 15) Notes 4-Iodoacetophenone was purchased from Aldrich Chemical Company, Inc , and used without purification Copper(I) iodide was purchased from Aldrich Chemical Company, Inc , and purified according to a literature procedure.5 Caution: Triphenylarsine is highly toxic and must be handled with gloves in a well-ventilated hood It was purchased from Aldrich Chemical Company, Inc., and used as received Anhydrous 1-methyl-2-pyrrolidinone was purchased from Aldrich Chemical Company, Inc , and used without further drying The water content was determined to be 117 ppm using a Coulomatric K-F Titrimeter 2-(Tributylstannyl)thiophene was purchased from Aldrich Chemical Company, Inc , and is used without additional purification 10% Palladium on activated carbon was purchased from Alpha Division The reaction can be monitored by quenching small aliquots with water and extracting with a small amount of diethyl ether The ethereal layer is spotted on an analytical silica gel TLC plate (0.25 mm thickness, from EM Separations Technology) ( 10% ethyl acetate in hexanes, using 254 nm UV light to visualize the spots) The following are the Rf's of the components of the mixture: 2-(tributylstannyl) thiophene (0.86), triphenylarsine (0.62), 4-iodoacetophenone (0.48), and 2-(4'-acetylphenyl)thiophene , (0.38 fluorescent) Trace amounts of 4-butylbenzophenone (Rf, 0.52) were observed at the end of the reaction Caution: Sodium fluoride is highly toxic and should be handled with gloves in a well-ventilated hood It was purchased from Spectrum Chemical Mfg Corp and used without purification If crystallization underneath the frit occurs during the filtration process, the sand pad is washed with 20 mL of ethyl acetate The sand pad was changed three times during the filtration of the whole mixture to avoid clogging 10 The washings are necessary to remove all the 1-methyl-2-pyrrolidinone 11 Anhydrous magnesium sulfate was obtained from EM Science 12 Silica gel 60, particle size 0.040-0.063 mm (230-400 mesh) was obtained from EM Separation Technology 13 The medium-pressure liquid chromatography system (MPLC) was purchased from Baeckström SEPARO AB 14 The product (a golden flaky solid) exhibits the following properties: mp 118-119°C; IR (CH2Cl2) cm−1: 1680, 1601, 1270 ; 1H NMR (300 MHz, CDCl3) δ: 2.6 (s, H), 7.1 (m, H), 7.3 (d, H, J = 5), 7.4 (d, H, J = 3.8), 7.7 (d, H, J = 8), 8.0 (d, H, J = 9) ; 13C NMR (75.5 MHz, CDCl3) δ: 26.5, 124.6, 125.6, 126.4, 128.3, 129.1, 135.7, 138.7, 142.9, 197.2 Anal Calcd for C12H10OS: C, 71.30; H, 5.00; S, 15.90 Found: C, 71.14; H, 5.03; S, 15.77 (The material obtained by the checkers was a very pale yellow flaky solid.) 15 The purification was carried out using a hexanes/dichloromethane gradient (200 mL of each gradient solution) The gradient started with hexanes at a flow rate of 25 mL/min and the concentration of dichloromethane was increased each time by 10% A total of fifty 30-mL fractions were collected Under these conditions, most of the triphenylarsine used was recovered and recycled (The checkers purified the material using conventional flash chromatography techniques The crude product adsorbed on 20 g of flash silica gel was dry packed on a 6-cm × 14-cm column of flash silica gel Elution with 750 mL of hexanes followed by 500 mL each of a hexane/dichloromethane gradient starting with 10% dichloromethane (CH2Cl2)/hexanes and finishing with 100% CH2Cl2 A total of fifty 100-mL fractions were collected The separation was monitored by analytical TLC as described in (Note 7).) Waste Disposal Information All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995 Discussion The rate-enhancing influence of Cu(I) salts (the so-called "Copper Effect") in normally nonproductive and sluggish Stille couplings was first pointed out by Liebeskind et al.6 in 1990 A greater insight into this phenomenon was obtained later by Farina and co-workers.7 A number of modifications of the Stille reaction have since been reported Among them are the cross-coupling of organostannanes with organic halides promoted by stoichiometric amounts of Cu(I) salts,8 10 and the Cu(I)- or Mn(II)-catalyzed cross-coupling of organostannanes with iodides in the presence of sodium chloride.11 It was also discovered that aryl and vinyl iodides, bromides, and triflates participated efficiently in cross-coupling reactions with organostannanes when catalyzed by palladium-on-carbon in the presence of Cu(I) as cocatalyst.1 The best conditions were found to be: Pd/C (0.5 mole%), Cu(I) (10 mole%), and AsPh3 (20 mole%) Besides the advantage of using a stable form of Pd(0), the yield of the products under these conditions was better than that obtained using tris(dibenzylideneacetone)palladium [Pd2(dba)3] as the source of Pd (0) Similarly, a slightly lesser amount of the homocoupled product was observed using the Pd/C protocol Although a significant amount of AsPh3 is necessary for cross-coupling to take place, it can be efficiently recovered (and recycled) at the end of the reaction by column chromatogaphy Other products prepared using the Pd/C protocol are: References and Notes The original report was published elsewhere: Roth, G P.; Farina, V.; Liebeskind, L S.; PeñaCabrera, E Tetrahedron Lett 1995, 36, 2191 Chemistry Department, Emory University, 1515 Pierce Dr., Atlanta, GA 30322 Facultad de Química, Universidad de Guanajuato, Col Noria Alta S/N, Guanajuato, Gto 36000, Mexico Baeckström, P.; Stridh, K.; Li, L.; Norin, T Acta Chem Scand, Ser B 1987, B41, 442 Kauffman, G B.; Teter, L A Inorg Synth 1963, 7, Liebeskind, L S.; Fengl, R W J Org Chem 1990, 55, 5359 Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L S J Org Chem 1994, 59, 5905 Piers, E.; Romero, M A J Am Chem Soc 1996, 118, 1215, Takeda, T.; Matsunaga, K.; Kabawasa, Y.; Fujiwara, T Chem Lett 1995, 771, 10 Allred, G D.; Liebeskind, L S J Am Chem Soc 1996, 118, 2748 11 Kang, S-K; Kim, J-S.; Choi, S-C J Org Chem 1997, 62, 4208 Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number) 4-Iodoacetophenone: Acetophenone, 4'-iodo- (8); Ethanone, 1-(4-iodophenyl)- (9); (13329-40-3) Copper(I) iodide (8,9); (7681-65-4) Triphenylarsine: HIGHLY TOXIC: Arsine, triphenyl- (8,9); (603-32-7) 1-Methylpyrrolidinone: 2-Pyrrolidinone, 1-methyl- (8,9); (872-50-4) 2-(Tributylstannyl)thiophene: Stannane, tributyl-2-thienyl- (9); (54663-78-4) Sodium fluoride (8,9); (7681-49-4) DOI:10.15227/orgsyn.075.0161 Organic Syntheses, Coll Vol 10, p.707 (2004); Vol 75, p.161 (1998) 2-TRIMETHYLSILYLETHANESULFONYL CHLORIDE (SES-Cl) [ Ethanesulfonyl chloride, 2-(trimethylsilyl)- ] Submitted by Steven M Weinreb1 , Charles E Chase1 , Peter Wipf2 , and Srikanth Venkatraman2 Checked by Geoffrey R Heintzelman and Robert K Boeckman, Jr Procedure Caution! Although tert-butyl perbenzoate is one of the safest peresters/peroxides to handle, one should remain aware of the inherent shock sensitivity and instability of these compounds Users should exercise appropriate caution during concentration procedures A Sodium β-trimethylsilylethanesulfonate (1) To a 500-mL, round-bottomed flask (Note 1) flushed with argon and equipped with a magnetic stirring bar is added vinyltrimethylsilane (28.0 mL, 18.2 g, 181 mmol), methanol (70 mL), and tert-butyl perbenzoate (0.70 mL, 0.70 g, 3.6 mmol) (Note 2),(Note 3),(Note 4) To this solution is added a solution of sodium bisulfite, NaHSO3, (36.1 g, 347 mmol) in 70 mL of water (Note 5),(Note 6),(Note 7) The flask is equipped with a Claisen adapter bearing an immersion thermometer and reflux condenser, and the resulting suspension is heated in an oil bath at 50°C under argon for 48 hr (Note 8) The suspension is concentrated on a rotary evaporator (Note 9) and (Note 10) followed by azeotropic removal of the residual water with methanol (2 × 25 mL) Methanol (200 mL) is added to the resulting white solid, and the resulting suspension is stirred vigorously for 10 The mixture is filtered through a pad of Celite into a 500-mL, round-bottomed flask, and the filtrate is concentrated on a rotary evaporator (Note 11) The filter cake is resuspended in 200 mL of methanol and stirred vigorously for 10 min, filtered into the vessel containing the original filtrate, and further concentrated (Note 11) The preceding operations are repeated again on the filter cake After the final concentration of the combined filtrates (Note 11), the resulting white solid is dried (100°C and 0.1 mm) for 12 hr (Note 12) to give 29.0-31.9 g ( 78-86%) of crude sodium β-trimethylsilylethanesulfonate as white flakes with mp >310°C (Note 13) B 2-Trimethylsilylethylsulfonyl chloride (2) The 500-mL, round-bottomed flask containing sulfonate salt (29.0 g) is equipped with a magnetic stirring bar and a pressure-equalizing addition funnel fitted at the top with a silicone oil bubbler connected through a rubber septum The apparatus is purged with argon The sodium sulfonate is cooled to 0°C in an ice-water bath and the addition funnel is charged with 80 mL (1.10 mol) of thionyl chloride (SOCl2) (Note 14) The slow, dropwise addition of SOCl2 to is accompanied by generation of sulfur dioxide, SO2 (Note 15) After addition of the SOCl2 is complete, the addition funnel is removed, and the flask is fitted with a rubber septum and bubbler N,N-Dimethylformamide (DMF) (0.40 mL, 0.38 g, 5.2 mmol) (Note 16) is slowly added via syringe resulting in a substantial increase in the evolution of SO2 (Note 17) The solution is stirred for an additional 20 at 0°C during which time evolution of SO2 ceases The reaction mixture is warmed to room temperature and stirred overnight, resulting in a white precipitate (Note 18) The reaction flask is fitted with a short path distillation head and excess SOCl2 is distilled off at reduced pressure (Note 19) Twice the resulting white paste is diluted with 50 mL of hexanes and the residual SOCl2 and hexanes are removed under reduced pressure The resulting pale tan slurry is once again diluted with 50 mL of hexanes and the slurry is filtered through a pad of Celite The filter cake is washed with an additional 50 mL of hexanes and the combined filtrate and washings are concentrated to afford 23.5 g of a light brown oil (Note 20) Short path distillation of the crude oil using an oil bath as heat source (7075°C at 0.2 mm) affords 19.3 - 22.0 g ( 68-77% yield, or 53-66% overall yield from vinyltrimethylsilane) of the sulfonyl chloride (Note 21) and (Note 22) as a pale tan oil Notes The submitters employed a 250-mL flask The checkers found that use of a larger vessel (500 mL) minimized problems associated with bumping during removal of volatile material (see (Note 10) below) Vinyltrimethylsilane was purchased from Aldrich Chemical Company, Inc , and used without further purification Spectrophotometric grade methanol was purchased from Fisher Scientific Company and used without further purification tert-Butyl perbenzoate (98%) was purchased from Aldrich Chemical Company, Inc , and used without further purification Increasing the concentration of both the methanolic and aqueous solutions results in a 20-30% decrease in the yield of sodium salt Increasing the ratio of NaHSO3 : vinyltrimethylsilane from 1.9:1 to 4:1 results in lower yields of A fine suspension of NaHSO3 forms immediately Although the reactants are soluble in 22% (v/v) aqueous methanol , no improvement in the yield of is observed The reaction should be conducted behind appropriate shielding Maintaining the internal temperature of the reaction mixture at 50°C is imperative in order to obtain good yields of [the bp of vinyltrimethylsilane (55°C) should not be exceeded] Alternatively, the submitters employed a sand bath and the whole assembly was insulated with glass wool The checkers found that temperature control was more easily achieved with an oil bath and did not employ glass wool insulation Caution! Peroxides may be present The checkers observed a negative test for peroxides on the filtrate using acidified starch/iodide test paper prior to the final concentration and drying The checkers recommend testing for peroxides prior to the final concentration and drying 10 The mixture tends to bump upon concentration 11 Do not concentrate to dryness After the third extraction, removing the last 25 mL of methanol on a rotary evaporator at atmospheric pressure and 70°C prevents bumping 12 The 500-mL flask should be tared in advance, and after breaking up the large chunks of salt 1, the product can be dried sufficiently in the flask by placing the flask in a vacuum oven, or by applying heat directly to the flask with a sand bath at the same temperature and pressure 13 NMR spectral data for are as follows: 1H NMR (300 MHz, DMSO-d6) δ: −0.05 (s, H), 0.76-0.82 (m, H), 2.25-2.31 (m, H) ; 13C NMR (75 MHz, DMSO-d6) δ: −1.6, 12.1, 46.6 14 SOCl2 was purchased from Aldrich Chemical Company, Inc , and used without further purification 15 The addition is carried out at a rate that maintains the reaction temperature between 0-10°C (20-30 min) If the temperature is increased beyond this range prior to dissolution of 1, substantial formation of the sulfonyl anhydride occurs 16 DMF was purchased from J T Baker Inc and used without further purification 17 Caution! Do not add DMF to the reaction mixture through the pressure equalizing addition funnel 18 The reaction can be monitored by 1H NMR spectroscopy by removing 0.1-mL aliquots, filtering through glass wool, and diluting with CDCl3 The diagnostic peaks are: δ 3.55-3.63 (m, H) (2); 3.423.51 (m, H) (sulfonic anhydride); 2.26-2.35 (m, H) (salt 1) 19 Using a water aspirator and a warm water bath is sufficient Recovered SOCl2 can be recycled 20 1H NMR spectrum indicates that the crude product is comprised of a mixture of the sulfonyl chloride and the sulfonic anhydride in an 11:1 ratio Pure sulfonyl chloride is obtained by distillation Alternatively, the crude sulfonyl chloride can be chromatographed ( 60 g of silica gel per g of sulfonyl chloride) eluting with hexane to provide pure in equivalent yields 21 Caution! If a sufficiently high vacuum is not maintained, the increased temperature (pot temperatures >100-110°C) required for distillation may cause thermal decomposition of and evolution of hydrogen chloride The checkers observed that had bp 95-100°C at 0.5 mm Kugelrohr distillation (85-100°C at 0.3-0.5 mm) of the product in two batches can also be employed 22 NMR spectral data for are as follows: 1H NMR (300 MHz, CDCl3) δ: 0.13 (s, H), 1.30-1.36 (m, H), 3.60-3.66 (m, H) ; 13C NMR (75 MHz, CDCl3) δ: −2.3, 11.7, 63.2 Waste Disposal Information All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995 Discussion Sodium sulfonate has previously been prepared from NaHSO3 and vinyltrimethylsilane using sodium nitrite/sodium nitrate as the radical initiator.3 In the submitters hands this protocol resulted in salt as a pale tan powder in only 15-53% yield if 50% (v/v) aqueous methanol is employed as solvent The yield of could be increased to 63% if 22% (v/v) aqueous methanol is employed An advantage of this method is the elimination of a potentially explosive perester as radical initiator However, lower yields of and the subsequent lower yield of the sulfonyl chloride (53% for the sulfonylation, 35% overall from vinyltrimethylsilane) make this procedure less desirable than the method presented The use of tert-butyl perbenzoate as the radical initiator4 not only provides in a higher yield, but the subsequent conversion to also proceeds in better yield Sulfonyl chloride has previously been prepared from salt and phosphorus pentachloride, PCl5 in carbon tetrachloride, CCl4 The disadvantage of this procedure is the difficulty in avoiding sulfonic anhydride formation Using this method, the 1H NMR spectrum of the crude reaction mixture prior to distillation indicates a 2-4:1 mixture of and the corresponding sulfonic anhydride Although the sulfonic anhydride can also serve as an efficient sulfonylating agent (sulfonylation of ammonia resulted in the corresponding sulfonamide in 99% yield), and for most purposes the crude mixture of and the sulfonic anhydride can be used directly, limiting the formation of the sulfonic anhydride is economically desirable Sulfonyl chloride can be synthesized from β-trimethylsilylethanesulfonic acid (obtained from salt by ion exchange chromatography) and PCl5 in CCl4 , although there seems to be no advantage in using the acid.3 Both sodium salt and the corresponding triethylammonium salt, when treated with triphenylphosphine, PPh3 , and SO2Cl2 , provide in 62% and 79% yields, respectively.6 Sulfonyl chloride has also been prepared from β-trimethylsilylethylmagnesium chloride and sulfuryl chloride in 50% yield.3 The use of a catalytic amount of DMF in SOCl2 here is based on the work of Bosshard.7 The advantage of this procedure is the ability to minimize the formation of the sulfonic anhydride At 0°C is reasonably soluble and unreactive in SOCl2 , thereby minimizing local high salt concentrations Upon slow addition of DMF to the mixture, the resulting Vilsmeier-Haack reagent efficiently catalyzes the formation of from Sulfonyl chloride can be stored in a freezer at −15°C for months without any significant decomposition Sulfonyl chloride is used to protect primary and secondary amines as the corresponding sulfonamide.8 The SES-protected amines are stable compounds that can be readily cleaved by fluoride sources to regenerate the parent amine References and Notes Department of Chemistry, The Pennsylvania State University, University Park, PA 16802 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260 Tiers, G V 1964, U.S Patent 141 898; Chem Abstr 1964, 61, P9527c Harman, D 1950, U.S Patent 504 411; Chem Abstr 1950, 44, P5897f Weinreb, S M.; Demko, D M.; Lessen, T A.; Demers, J P Tetrahedron Lett 1986, 27, 20992102 Huang, J.; Widlanski, T S Tetrahedron Lett 1992, 33, 2657-2660 Bosshard, H H; Mory, R.; Schmid, M.; Zollinger, H Helv Chim Acta 1959, 42, 1653-1658 Weinreb, S M.; Ralbovsky, J L "β-Trimethylsilylethanesulfonyl Chloride," in Encyclopedia of Reagents for Organic Synthesis; Paquette, L A., Ed.; Wiley: Chichester, U.K., 1995, Vol 7, p 5255-5256 Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number) 2-Trimethylsilylethanesulfonyl chloride: Ethanesulfonyl chloride, 2-(trimethylsilyl)- (12); (106018-85-3) tert-Butyl perbenzoate: Peroxybenzoic acid, tert-butyl ester (8); Benzenecarboperoxoic acid, 1,1-dimethylethyl ester (9); (614-45-9) Sodium β-trimethylsilylethanesulfonate: Ethanesulfonic acid, 2-(trimethylsilyl)-, sodium salt (9); (18143-40-3) Vinyltrimethylsilane: Silane, trimethylvinyl- (8); Silane, ethenyltrimethyl- (9); (754-05-2) Thionyl chloride: (8, 9); (7719-09-7) N,N-Dimethylformamide: CANCER SUSPECT AGENT: Formamide, N,N-dimethyl- (8, 9); (68-12-2) Copyright © 1921-2005, Organic Syntheses, Inc All Rights Reserved DOI:10.15227/orgsyn.079.0001 Organic Syntheses, Coll Vol 10, p.712 (2004); Vol 79, p.1 (2002) SYNTHESIS OF TRIS(2-PERFLUOROHEXYLETHYL)TIN HYDRIDE: A HIGHLY FLUORINATED TIN HYDRIDE WITH ADVANTAGEOUS FEATURES OF EASY PURIFICATION [ Stannane, tris-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)- ] Submitted by Aimee Crombie, Sun-Young Kim, Sabine Hadida, and Dennis P Curran1 Checked by Peter Ranslow and Louis S Hegedus Procedure A (Perfluorohexyl)ethylmagnesium iodide A 500-mL, three-necked flask equipped with a stirring bar and a reflux condenser is dried in an oven overnight and then cooled under argon Dry ether (20 mL) and 2-perfluorohexyl-1-iodoethane (1 mL) are added to magnesium (2.91 g, 120 mmol) in the dried flask equipped with a reflux condenser, thermometer and an outlet to argon gas (Note 1) The reaction is initiated by sonication for 30 Additional dry ether (70 mL) is added to the mixture while stirring In a separate, dry, 100-mL, round-bottomed flask cooled under argon, dry ether (45 mL) is combined with 2-perfluorohexyl-1-iodoethane (13.70 mL, total of 60 mmol) This separate mixture is slowly added to the reaction mixture over hr with stirring The addition rate is adjusted to keep a constant temperature of about 30°C The reaction mixture is heated at reflux for 2.5 hr in an oil bath at 50°C and allowed to stand after removal from the bath until it reaches room temperature B Tris(2-perfluorohexylethyl)phenyltin Phenyltin trichloride (2.46 mL, 15 mmol) is dissolved in dry benzene (30 mL) in a 100-mL, round-bottomed flask under argon at room temperature The solution is slowly added to the 500-mL, three-necked flask containing the Grignard reagent at room temperature over hr while stirring The addition rate is adjusted to keep a constant temperature of about 25°C The reaction mixture is heated at reflux overnight in an oil bath at 50°C, removed from the bath, and allowed to stand at ambient temperature for 4.5 hr with stirring The reaction mixture is diluted with ether (100 mL), vacuum filtered into a 1-L Erlenmeyer flask, and hydrolyzed with saturated ammonium chloride solution (300 mL) Excess magnesium solid is also hydrolyzed with saturated ammonium chloride (100 mL) separately (Note 2) The mixture is transferred to a 1-L separatory funnel The water layer is removed, and the organic layer is washed three times with 3% sodium thiosulfate (3 × 200 mL) The organic layer is dried over magnesium sulfate and filtered under vacuum The solvent is evaporated to dryness under reduced pressure using a rotovap The impure product is redissolved in ether (20 mL) and transferred to a 50-mL pear-shaped flask The ether is removed under reduced pressure Kugelrohr distillation is peformed to remove a dimer impurity of (C6F13CH2CH2CH2CH2C6F13) at 0.02 mm, 100-120°C for hr (Note 3) The residue is further purified by column filtration over silica (30 g) under pressure with hexane (1 L) (Note 4) The solvent is evaporated under reduced pressure to leave 17.2 g (13.9 mmol, 93%) of pure compound as a colorless oil (Notes and 9) C Bromotris[2-(perfluorohexyl)ethyl]tin The fluorous phenyltinproduct (17.2 g, 13.9 mmol) and dry ether (80 mL) are transferred to a 250-mL, three-necked flask that had been dried in an oven and cooled to 0°C under argon Bromine (0.71 mL, 14 mmol) is added dropwise over 30 to the mixture The addition rate is adjusted to keep the temperature between 0° and 1°C The mixture is warmed to 25° C and stirred for hr The reaction mixture is transferred to a 250-mL, round-bottomed flask The ether and excess bromine are removed under reduced pressure to leave a yellow oil The oil is dissolved in FC-72 (75 mL) and transferred to a 250-mL separatory funnel The bromine and bromobenzene byproducts are removed by washing three times with methylene chloride (3 × 75 mL) leaving the fluorous layer colorless The FC-72 is removed under reduced pressure to provide 15.8 g (12.7 mmol, 92%) of a colorless oil (Note 6) D Tris[(2-perfluorohexyl)ethyl]tin hydride (Note 7) A 1-L, three-necked flask and a stirring bar are dried in an oven The fluorous tin bromide (13.8 g, 11.1 mmol) is dissolved in dry ether (275 mL) and transferred to the dried three-necked flask equipped with a thermometer, stirring bar, and an outlet to argon The solution is cooled to 0°C A M solution of lithium aluminum hydride (LAH) in ether (11.1 mL, 11.1 mmol) is added dropwise over 45 to the solution The addition rate is adjusted to maintain a temperature between 0° and 1°C The reaction mixture is stirred for hr at 0°C Water (75 mL) is slowly added (initially dropwise) with stirring to the ice-cold mixture Sodium potassium tartrate (20%) (250 mL) is added and the mixture is transferred to a 1-L separatory funnel The ethereal layer is separated and the aqueous layer is extracted three times with ether (3 × 100 mL) The combined extracts are dried with magnesium sulfate and vacuum filtered into a 1-L, round-bottomed flask The solvent is evaporated under reduced pressure The crude product is distilled under a reduced pressure of 0.02 mm at 133-140°C to provide 11.3 g (9.69 mmol, 87%) of the pure product as an oil (Notes and 9) Notes Ether and benzene were distilled with sodium/benzophenone prior to use The 2-perfluorohexyl-1iodoethane was purchased from Lancaster and the FC-72 was purchased from 3M Magnesium (powder, 50 mesh) and all other reagents were purchased from Aldrich Chemical Company, Inc The mixture can be hydrolyzed without filtration However, it is more convenient to remove the solid magnesium and hydrolyze the two components separately A cooled collection flask and a guard collection flask were used during the Kugelrohr distillation so that the dimer impurity (white solid) would not contaminate the vacuum pump Periodic heating of the neck of the guard flask was performed with a heat gun to prevent any blockage from the impurity A high vacuum pump was used to reduce the pressure Although simple distillation has been used in the past, the Kugelrohr distillation is more advantageous and more convenient Short column chromatography can be performed to purify the compound further if desired The spectral properties of product are as follows: 1H NMR (CDCl3) δ:1.31 [t, H, J = 8.3, 2J(119SnH) = 53.4], 2.31 (m, H), 7.41 (s, H) ; 119Sn NMR (CDCl3) − 11.7 ppm; IR (thin film) cm−1: 3100, 2950, 1238, 1190, 1144, 655 ; MS (m/z) 1161 (M+ - Ph), 891 (M+ - CH2CH2C6F13) The spectral properties of product are as follows: 1H NMR (CDCl3) δ: 1.56 [t, H, J = 8.3, 2J(119SnH) = 53.4], 2.42 (m, H) ; 119Sn NMR (hexane-C6D6) 109.2 ppm; IR (thin film) cm−1: 3600, 1250, 1227, 1145, 534 ; MS (m/z): 1161 (M+ - Br), 893 (M+ - CH2CH2C6F13) Reactions on a smaller scale tended to give better yields for the reduction of the fluorous tin bromide to fluorous tin hydride The spectral properties of product are as follows (Note 10): 1H NMR (CDCl3) δ: 1.16 [t, H, J = 8.1, 2J(119Sn-H) = 53.4], 2.35 (m, H), 5.27 (s, H) ; 119Sn NMR (CDCl3) − 84.5 (1J(119Sn-H) = 1835) ; IR (thin film) cm−1: 1842, 1197 ; MS (m/z)1161 (M+ - H), 813 (M+ - CH2CH2C6F13) Thin layer chromatography was performed using silica plates and eluting with hexane Potassium permanganate was used to visualize the spots The Rf values for products and were 0.38 and 0.37, respectively 10 All NMR samples were dissolved in chloroform The fluorous tin hydride is only slightly soluble in chloroform Therefore it is necessary to saturate this NMR sample The NMR spectrum must be recorded quickly since the tin hydride reduces chloroform on standing in the light Waste Disposal Information All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995 Discussion Trialkyltin hydrides represent an important class of reagents in organic chemistry because of their utility in radical reactions.2 However, problems of toxicity and the difficulty of product purification made trialkyltin hydrides less than ideal reagents.3 Several workup procedures4 and structurally modified trialkyltin hydrides5 have been developed to facilitate the separation of tin residues from the reaction mixture Tris(trimethylsilyl)silicon hydride 6a has also been synthesized and is often used successfully in radical reactions However, its reactivity is different from that of trialkyltin hydrides in a number of important respects Other tin hydride surrogates are also available.6b On the heels of work by Zhu7 and Horváth and Rábai,8a perfluorocarbon solvents and fluorous reagents have been used increasingly in organic syntheses.9 Fluorous compounds often partition preferentially into a fluorous phase in organic/fluorous liquid-liquid extraction, thus providing easy separation of the compounds Tris[(2-perfluorohexyl)ethyl]tin hydride 9b-e combines the favorable radical reaction chemistry of trialkyltin hydrides with the favorable separation features of fluorous compounds Tris[(2-perfluorohexyl)ethyl]tin hydride has three perfluorinated segments with ethylene spacers and it partitions primarily (> 98%) into the fluorous phase in a liquid-liquid extraction This feature not only facilitates the purification of the product from the tin residue but also recovers toxic tin residue for further reuse Stoichiometric reductive radical reactions with the fluorous tin hydride have been previously reported and a catalytic procedure is also well established.9b-9e The reduction of adamantyl bromide in BTF (benzotrifluoride) 10,11 using 1.2 equiv of the fluorous tin hydride and a catalytic amount of azobisisobutyronitrile (AIBN) was complete in hr (Scheme 1) After the simple liquid-liquid extraction, adamantane was obtained in 90% yield in the organic layer and the fluorous tin bromide was separated from the fluorous phase The recovered fluorous tin bromide was reduced and reused to give the same results Phenylselenides, tertiary nitro compounds, and xanthates were also successfully reduced by the fluorous tin hydride Standard radical additions and cyclizations can also be conducted as shown by the examples in Scheme Hydrostannation reactions are also possible,9e and these are useful in the techniques of fluorous phase switching.10 Carbonylations are also possible.9p Rate constants for the reaction of the fluorous tin hydride with primary radicals and acyl radicals have been measured; it is marginally more reactive than tributlytin hydrides.9c,e Scheme The preparation method reported here can be applied to the synthesis of a variety of related fluorous tin compounds Seven more fluorous tin hydrides with the general formula of [CF3(CF2)n(CH2)m]3SnH (n = 3, m = 2,3, n = 5, m = 3, and n = 9, m = 2) and [CF3 (CH2)m CH2CH2]SnMe2H (m = 5, 7, 9) were synthesized using this method and used for radical reactions.9e The fluorous phenyl tin compound and related compounds have been successfully reacted in Stille coupling reactions9f-k demonstrating the easy purification feature of fluorous compounds Fluorous tin bromide is an important intermediate for the synthesis of various reagents including tin azide and allyl tin compounds.9g,h Fluorous silanes are made by similar routes.9m-o Recently, the submitters have developed new separation procedures based on fluorous silica gel,12 and the separation of fluorous compounds by solid phase extraction has become another option for compounds that are not easy to separate by liquid-liquid extraction References and Notes Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, 15260 (a) Kuivila, H G Acc Chem Res 1968, 1, 299; (b) Neumann, W P Synthesis 1987, 665; (c) Curran, D P Synthesis 1988, 489 Pereyre, M.; Quintard, J -P.; Rahm, A "Tin in Organic Synthesis"; Butterworths: London, 1987 (a) Berge, J M.; Roberts, S M Synthesis 1979, 471; (b) Curran, D P.; Chang, C -T J Org Chem 1989, 54, 3140; (c) Crich, D.; Sun, S J Org Chem 1996, 61, 7200 (a) Gerlach, M.; Jördens, F.; Kuhn, H.; Neumann, W P.; Peterseim, M J Org Chem 1991, 56, 5971; (b) Light, J.; Breslow, R Tetrahedron Lett 1990, 31, 2957; (c) Rai, R.; Collum, D B Tetrahedron Lett 1994, 35, 6221; (d) Clive, D L J.; Yang, W J Org Chem 1995, 60, 2607 (a) Chatgilialoglu, C Acc Chem Res 1992, 25, 188; (b) Walton, J C Acc Chem Res 1998, 31, 99 Zhu, D.-W Synthesis 1993, 953 (a) Horváth, I T.; Rábai, J Science 1994, 266, 72; (b) Cornils, B Angew Chem., Int Ed Engl 1997, 36, 2057; (c) Horváth, I T Acc Chem Res 1998, 31, 641 (a) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf, P.; Curran, D P Science 1997, 275, 823; (b) Curran, D P.; Hadida, S J Am Chem Soc 1996, 118, 2531; (c) Horner, J H.; Martinez, F N.; Newcomb, M.; Hadida, S.; Curran, D P Tetrahedron Lett 1997, 38, 2783; (d) Hadida, S.; Super, M S.; Beckman, E J.; Curran, D P J Am Chem Soc 1997, 119, 7406; (e) Curran, D P.; Hadida, S.; Kim, S -Y.; Luo, Z J Am Chem Soc 1999, 121, 6607; (f) Curran, D P.; Hoshino, M J Org Chem 1996, 61, 6480; (g) Curran, D P Hadida, S.; Kim, S Y Tetrahedron 1999, 55, 8997; (h) Curran, D P.; Luo, Z Med Chem Res 1998, 8, 261; (i) Curran, D P.; Luo, Z.; Degenkolb, P Bioorg Med Chem Lett 1998, 8, 2403; (j) Hoshino, M.; Degenkolb, P.; Curran, D P J Org Chem 1997, 62, 8341; (k) Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D P.; Hallberg, A J Org Chem 1997, 62, 5583; (l) Spetseris, N.; Hadida, S.; Curran, D P.; Meyer, T Y Organometallics 1998, 17, 1458; (m) Studer, A.; Curran, D P Tetrahedron 1997, 53, 6681; (n) Studer, A.; Jeger, P.; Wipf, P.; Curran, D P J Org Chem 1997, 62, 2917; (o) Curran, D P.; Ferritto, R.; Hua, Y Tetrahedron Lett 1998, 39, 4937; (p) Ryu, I.; Niguma, T.; Minakata, S.; Komatsu, M.; Hadida, S.; Curran, D P Tetrahedron Lett 1997, 38, 7883; (q) Ryu, I.; Niguma, T.; Minakata, S.; Komatsu, M.; Luo, Z Y.; Curran, D P Tetrahedron Lett 1999, 40, 2367 10 (a) Curran, D P In "Stimulating Concepts in Chemistry"; Stoddard, F.; Reinhoudt, D.; Shibasaki, M., Ed.; Wiley-VCH: New York, 2000; p 25; (b) Curran, D P Angew Chem., Int Ed Engl 1998, 37, 1175; (c) Curran, D P Chemtracts: Org Chem 1996, 9, 75 11 (a) Ogawa, A.; Curran, D P J Org Chem 1997, 62, 450; (b) Maul, J J.; Ostrowski, P J.; Ublacker, G A.; Linclau, B.; Curran, D P In "Topics in Current Chemistry: Modern Solvents in Organic Synthesis"; Knochel, P., Ed.; Springer-Verlag: Berlin, 1999; Vol 206; pp 80 12 (a) Curran, D P.; Hadida, S.; He, M J Org Chem 1997, 62, 6714; (b) Curran, D P.; Hadida, S.; Studer, A.; He, M.; Kim S -Y.; Luo, Z.; Larhed, M.; Hallberg, M.; Linclau, B In "Combinatorial Chemistry: A Practical Approach"; Fenniri, H., Ed.; Oxford University Press: Oxford, 2001; Vol Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number) Tris[(2-perfluorohexyl)ethyl]tin hydride: Stannane, tris(3,3,4,4,5,5,6,6,7,7,8,8,8,-tridecafluorooctyl)- (13); (175354-32-2) 2-Perfluorohexyl-1-iodoethane: Octane, 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluoro-8-iodo- (9); (2043-57-4) Tris[(2-perfluorohexyl)ethyl]phenyl tin: Stannane, phenyltris(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)- (13); (175354-30-0) Phenyltin chloride: Aldrich: Phenyltin trichloride: Stannane, trichlorophenyl- (8,9); (1124-19-2) Bromotris[(2-perfluorohexyl)ethyl]tin: Stannane, bromotris(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)- (13); (175354-31-1) Bromine (8,9); (7726-95-6) Lithium aluminum hydride: Aluminate (1-), tetrahydro-, lithium; aluminate (1-), tetrahydro-, lithium, (T-4)- (9); (16853-85-3) Magnesium (8,9); (7439-95-4) Copyright © 1921-2005, Organic Syntheses, Inc All Rights Reserved DOI:10.15227/orgsyn.076.0275 Organic Syntheses, Coll Vol 10, p.718 (2004); Vol 76, p.275 (1999) VITAMIN D2 FROM ERGOSTEROL [ 9,10-Secoergosta-5,7,10(19),22-tetraen-3-ol,(3β)- from Ergosta-5,7,22-trien-3-ol, (3β)- ] Submitted by Masami Okabe1 Checked by Gilles Chambournier and David J Hart Procedure Caution! Light from a mercury lamp is damaging to the eyes and skin Suitable precautions, such as wearing an appropriate face shield, UV radiation protective eyewear and gloves, and surrounding the reaction vessel with aluminum foil, should be taken It is recommended that one work in a hood and that the hood sash be covered with aluminum foil A 3,5-Dinitrobenzoate of vitamin D2 (3) A 2-L photo-reaction vessel equipped with a quartz immersion well, a thermometer, an argon-inlet tube, a mineral oil outlet-bubbler, a mechanical stirrer, and supported in an adequately sized Dewar (Note 1), is charged with 13.5 g (34 mmol) of ergosterol (1) (Note 2), 1.31 g (6.8 mmol) of ethyl p-dimethylaminobenzoate , and 1.7 L of tert-butyl methyl ether (tert-BuOMe) (Note 3) The mixture is stirred at room temperature overnight with gentle bubbling of argon (Note 4) A 450-watt Hanovia medium-pressure mercury lamp is inserted into the well, through which a fast stream of water is continuously passed (Note 5) The solution is cooled in a dry ice-ethanol bath and stirred vigorously (Note 6) When the temperature of the solution reaches 0°C, the lamp is turned on, and irradiation is continued at 0°C to −20°C for hr (Note 7) The lamp is turned off, a solution of 75 mg (0.34 mmol) of 9-acetylanthracene (Note 8) in mL of tert-BuOMe is added to the solution, and a uranium filter (Note 9) is inserted into the arc housing (Note 10) After 10 min, the lamp is started again, and the mixture is irradiated at 0°C to −20°C for hr through the uranium filter (Note 11) The cold, pale yellow solution of pre-vitamin thus obtained (Note 12) is transferred to a 3L, round-bottomed flask and concentrated at 20-25°C under reduced pressure The residue is transferred again to a 500-mL, round-bottomed flask using tert-BuOMe to allow quantitative transfer The solution is concentrated and dried at room temperature under high vacuum (1 mm) for 30 to give approximately 15.4 g of a yellow resin The flask is filled with argon and equipped with a magnetic stirrer Methanol (100 mL) is added, and the mixture is shaken to give a stirrable suspension The suspension is then stirred for 45 at room temperature and stored in a freezer overnight After the mixture is stirred at −30°C (Note 13) for 30 min, it is quickly filtered through a 60-mL sintered-glass funnel of coarse porosity The collected solid is washed with 20 mL of cold methanol (Note 14) Ergosterol (1.83 g, 14% recovery, mp 145-151°C, 99.4% pure) is recovered by washing this solid with absolute ethanol (30 mL at room temperature) The filtrate and cold-methanol wash are transferred to a 500-mL, round-bottomed flask equipped with a magnetic stirrer, an argon-inlet tube, and a reflux condenser The flask is flushed with argon, and the orange solution is heated under reflux for hr (Note 15) and then stirred at 35-40°C overnight (Note 16) The mixture is concentrated at 30°C under reduced pressure, and the residual methanol is removed by coevaporation with 50 mL of toluene at 30°C to give approximately 14.6 g of an orange-tan oil The flask is filled with argon and then equipped with a magnetic stirrer The residue is dissolved in 40 mL of pyridine , and the solution is cooled in an icewater bath Solid 3,5-dinitrobenzoyl chloride (9.0 g, 39 mmol) (Note 17) is added in small portions over followed by 20 mL of pyridine to rinse the walls of the flask, and the mixture is stirred at 0°C for 20 The very thick suspension obtained is shaken and then allowed to stand at 0°C for a further 20 min, whereupon methanol (30 mL) is added to the cold mixture The mixture is allowed to stand at 0°C for min, and then it is shaken for about to give a stirrable suspension After the orange suspension is stirred at 0°C for 1.5 hr, it is diluted by the dropwise addition of 150 mL of methanol over 15 and stirred at 0°C for another hour The yellow solid is collected by filtration, washed with 50 mL of ice-cold methanol , and dried at room temperature under high vacuum for hr The yelloworange solid is transferred to a 250-mL, round-bottomed flask equipped with a magnetic stirrer and an argon-inlet tube The flask is flushed with argon, and the solid is suspended in 50 mL of absolute ethanol The suspension is stirred at room temperature for 15 and at 0°C for 45 The solid is collected by filtration, washed with 20 mL of cold methanol , and dried at room temperature under high vacuum overnight to give 8.3-10.1 g (41-50%) of as a yellow solid, mp 139-141°C (lit.2 147-149°C) (Note 18) and (Note 19) B Vitamin D2 (4) A 500-mL, round-bottomed flask equipped with a magnetic stirrer and an argoninlet tube is charged with 10.1 g (17.1 mmol) of and 171 mL of absolute ethanol The flask is flushed with argon, and 1.88 mL (18.8 mmol) of 10 N sodium hydroxide is added After the purple suspension is stirred at room temperature for 45 min, it is cooled with an ice-water bath Then, 75 mL of ethanolwater (EtOH-H2O)(2:5) is added over min, and the mixture is stirred for hr with ice-water cooling To the resulting rose-colored suspension is added 100 mL of EtOH-H2O (2:5) dropwise over 30 The mixture is stirred at 0°C for 30 and then stored in a refrigerator overnight The precipitate (Note 12) is collected by filtration using a 60-mL sintered-glass funnel of coarse porosity, washed quickly with 50 mL of cold EtOH-H2O (3:2) (Note 20), and dried at room temperature under high vacuum to give 6.55 g of an off-white solid This material is transferred to a 500-mL, round-bottomed flask equipped with a magnetic stirrer and an argon-inlet tube The flask is flushed with argon, and the solid is dissolved in 200 mL of methanol (MeOH) at room temperature The solution is cooled with an ice-water bath, and 15 mL of methanol-water (MeOH-H2O) (4:6) is added to give a cloudy solution After stirring at 0°C for hr, the resulting white suspension is diluted by the dropwise addition of 85 mL of MeOH=H2O (4:6) over 45 After hr at 0°C, the solid is collected by filtration using a 60mL sintered-glass funnel of coarse porosity, washed with 50 mL of cold MeOH=H2O (4:1) (Note 20), and dried at room temperature under high vacuum overnight to give 5.9-6.2 g (87-91%) of as a white solid, mp 112-114°C (lit.2,3 114.5-117°C) (Note 21) and (Note 22) The overall yield of vitamin D2 from ergosterol is 44% (51% based on the recovered ergosterol) (Note 2) Notes The reactor is available from Ace Glass Inc [reaction vessel (#7851-17), immersion well (#7854-28, 290 mm), Teflon bearing (#8066-24), and stirring shaft (#8068-303)] It is similar to that shown in Figure (Org Synth., Coll Vol V 1973, p.529) with an additional stirring chamber The submitter used a 4-mm I.D tube for an argon-inlet in order to avoid clogging; the tube should reach near to the bottom of the vessel The checkers used a 20 × 45-cm (ID × height) Dewar, available from Cole-Parmer Instrument Co #H-03774-54) Ergosterol (1), obtained from Aldrich Chemical Company, Inc (mp 134-142°C, ε 8,030 at 282 nm in EtOH), was purified before use as follows: 24.4 g of was suspended in 200 mL of ethanol (EtOH), and the mixture was stirred at room temperature for hr prior to filtration The collected solid was washed with 40 mL of EtOH and dried under high vacuum (1.0 mm) to give 19.3 g (79% recovery) of as a white solid (mp 147-153°C, ε 11,900 at 282 nm in EtOH) The submitter observed that when purchased from Kaneka Co (mp 147-153°C, ε 11,560 at 282 nm in EtOH) was used as received, a better quality of vitamin D2 (4) (mp 114-115°C, 99.8% pure) was obtained in a better overall yield of 48% (55% based on the recovered ergosterol) The checkers used ergosterol obtained from Acros Organics (mp 156-158°C), which was purified as described above (mp 154-158°C) Ethyl p-dimethylaminobenzoate and tert-butyl methyl ether (HPLC grade) were obtained from Aldrich Chemical Company, Inc , and used as received The overnight stirring with bubbling of argon to remove oxygen is probably too long, but was done simply for convenience, thereby allowing the irradiation to be carried out the next day The checkers found that hr was sufficient Water flow must be very fast to avoid freezing, which could result in breakage of the photochemical reactor and generation of a hazardous situation Water flow should be monitored continuously during the course of the reaction Efficient stirring is necessary to achieve relatively homogeneous temperature distribution throughout the reaction mixture The submitter recommends that the mixture be kept below 0°C to prevent thermal isomerization of to vitamin D2, which produces a variety of photoproducts upon irradiation The checkers monitored the reaction temperature at 5-min intervals and added dry ice to the bath each time the temperature approached 0°C Approximately 30 pounds of dry ice are required over the 4-hr irradiation period Using 1H NMR analyses, the submitter judged the conversion to be 80-85% after hr of irradiation with the apparatus described After hr, a 1:2:1 mixture of 1:2:tachy-isomer (see Discussion) was obtained The diagnostic peaks in the 1H NMR spectra are listed in Table The Rf values on silica gel TLC using 1:4 EtOAc-hexane are as follows: (0.29), (0.34), tachy-isomer (0.34), (0.42), ethyl p-dimethylaminobenzoate (0.47), and 9-acetylanthracene (0.53), using short wave UV detection TABLE THE CHEMICAL SHIFTS OF DIAGNOSTIC PEAKS IN 1H NMRa Ergosterol (1) Pre-isomer (2) Tachy-isomer a 18-CH 3-H olefinic protons 0.62 (s) 0.71 (s) 0.69 (s) 3.62 (m) 3.92 (m) 3.92 (m) 5.39 (m), 5.57 (m) 5.48 (m), 5.67 (d, 11 Hz), 5.93 (d, 11 Hz) 5.67 (m), 6.00 (d, 16 Hz), 6.71 (d, 16 Hz) The chemical shifts are reported in ppm relative to CHCl3 (7.25) in CDCl3 as an internal standard 9-Acetylanthracene was purchased from Aldrich Chemical Company, Inc and used as received A cylindrical uranium filter (31-mm O.D., 2.5-mm thickness) was obtained from Houde Glass Co., Inc 10 Caution! The lamp is very hot The lamp should be allowed to cool for 10 before restarting to prevent damage 11 Based on 1H NMR analyses, the photosensitized isomerization of the tachy-isomer into was complete after 40 of irradiation (see Discussion) 12 The submitter recommends that pre-isomer (2) and vitamin D2 (4) not be exposed to air at room temperature for more than 30 min, since these compounds are relatively easily oxidized by air 13 The checkers used a dry ice-ethylene glycol bath at −25°C 14 The checkers cooled the methanol to −70°C in a dry ice-acetone bath 15 After hr of reflux, the ratio of to was ca 1:3, whereas after hr, it reached about 1:5 16 At this point, the ratio of to was greater than 1:6 17 3,5-Dinitrobenzoyl chloride was purchased from Aldrich Chemical Company, Inc and pyridine (A.C.S certified) was obtained from Fisher Scientific Co They are used as received 18 The elemental analysis and spectral properties of are as follows: Anal Calcd for C35H46N2O6: C, 71.16; H, 7.85; N, 4.74 Found: C, 71.05; H, 7.89; N, 4.58; IR (KBr) cm−: 1733, 1546, 1342 ; 1H NMR (CDCl3) δ: 0.56 (s, H), 0.82 (d, H, J = 6.5), 0.84 (d, H, J = 6.5), 0.92 (d, H, J = 6.8), 1.02 (d, H, J = 6.6), 1.25-2.17 (m, 16 H), 2.32 (m, H), 2.50 (m, H), 2.59 (dd, H, J = 12.2 and 6.8), 2.73 (dd, H, J = 12.2 and 4.5), 2.80 (dd, H, J = 8.8 and 3.5), 4.91 (bs, H), 5.13 (bs, H), 5.20 (m, H), 5.31 (m, H), 6.06 (d, H, J = 11.1), 6.28 (d, H, J = 11.1), 9.13 (d, H, J = 2.1), 9.22 (t, H, J = 2.1) ; 13C NMR (CDCl3) δ: 12.2 (q), 17.5 (q), 19.5 (q), 19.8 (q), 21.0 (q), 22.1 (t), 23.5 (t), 27.7 (t), 28.9 (t), 31.7 (t), 32.0 (t), 33.0 (d), 40.3 (d and t), 41.9 (t), 42.7 (d), 45.8 (s), 56.3 (d), 74.8 (d), 113.2 (t), 117.1 (d), 122.1 (d), 123.0 (d), 129.3 (d), 131.9 (d), 133.1 (s), 134.3 (s), 135.4 (d), 143.1 (s), 143.8 (s), 148.5 (s), 161.8 (s) (one doublet was not observed) 19 The submitter indicates that HPLC analysis of the product shows its purity to be 97.3% (with 0.3% of ergosteryl 3,5-dinitrobenzoate) HPLC conditions for this unchecked analysis are as follows: column: Chromegasphere SI-60 (3μ,15-cm × 5-mm) (purchased from ES Industries); mobile phase: 5% EtOAc in heptane (1 mL/min); detection: 275 nm The retention times of and ergosteryl 3,5-dinitrobenzoate are 4.90 and 3.83 min, respectively Those of the other impurities are 4.20, 4.55, 6.17, and 8.67 The checkers observed traces of pyridine in the 1H NMR spectrum of the product 20 The checkers cooled this solution in an ice-water bath 21 The elemental analysis and the spectral properties of are as follows: Anal Calcd for C28H44O: C, 84.79; H, 11.18 Found: C, 84.89; H, 11.17 UV (EtOH) λmax 264 nm (ε 18,450); 1H NMR (CDCl3) δ: 0.55 (s, H), 0.82 (d, H, J = 6.5), 0.84 (d, H, J = 6.5), 0.91 (d, H, J = 6.5), 1.01 (d, H, J = 6.7), 1.2-2.5 (m, 19 H), 2.57 (dd, H, J = 11.6 and 3.5), 2.81 (broad d, H, J = 9.0), 3.95 (m, H), 4.82 (bs, H), 5.04 (bs, H), 5.20 (m, H), 6.05 (d, H, J = 11.2), 6.23 (d, H, J = 11.2) ; The OH hydrogen was not observed; 13C NMR (CDCl3) δ: 12.2 (q), 17.5 (q), 19.5 (q), 19.8 (q), 21.0 (q), 22.1 (t), 23.4 (t), 27.7 (t), 28.9 (t), 31.8 (t), 33.0 (d), 35.0 (t), 40.3 (d and t), 42.7 (d), 45.6 (s), 45.8 (t), 56.3 (d), 69.1 (d), 112.3 (t), 117.4 (d), 122.3 (d), 131.8 (d), 134.9 (s), 135.5 (d), 142.1 (s), 144.0 (s) (one doublet was not observed) 22 The submitter indicates that HPLC analysis of the product shows the purity to be 99.7% (with 0.1% of ergosterol) The HPLC conditions for this unchecked analysis are as follows: column: Chromegasphere SI-60 (3μ, 15-cm × 5-mm) (purchased from ES Industries); mobile phase: 5% EtOAc in heptane (2 mL/min); detection: 275 nm The retention times of and are 19.54 and 16.27 min, respectively The checkers observed signals due to a trace olefinic contaminant in the 1H NMR of the product at δ 6.47 and 5.95 Waste Disposal Information All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995 Discussion The overall yields of vitamin D derivatives4 via the photolyses of pro-isomers (such as 1) are, generally only 15-30% (typically on a few milligram scale) Difficulties in obtaining higher yields arise from the fact that the photolysis of the pro-isomer gives a photostationary state where the distribution of the products (pro-, pre-, lumi-, and tachy-isomers) depends on the photolyzing wavelength6 (see Scheme) A shorter wavelength (300 nm) promotes the ring-closure reaction to the proand lumi-isomers Furthermore, the pre-isomer and vitamin D are in thermal equilibrium in which the ratio is dependent on the temperature (Scheme).10 11 Higher yields of the pre-isomer have been achieved in the past by irradiating the pro-isomer with a narrow band of approximately 250 nm light (using a low pressure mercury lamp or a laser) and then selective isomerization of the tachy-isomer thus formed into pre-isomer, either by irradiation at approximately 350 nm7,8 or by photosensitized isomerization.12 13 Vitamin D3 was then isolated in 50% yield after thermal isomerization.8 However, the use of high-intensity light sources with narrow band spectra, for large scale applications is prohibitive because of their high cost; moreover, such sources require the use of specialized equipment The present procedure uses a medium pressure mercury lamp, which is an inexpensive, highintensity light source commonly used in a synthetic laboratory The 300-315 nm light that promotes the ring-closure reaction is effectively removed by adding a small amount of ethyl pdimethylaminobenzoate which has a strong, relatively sharp absorption at 305 nm (ε 32,500) After the photosensitized isomerization and thermal equilibration, vitamin D2 is isolated as the 3,5dinitrobenzoate 3.2,3 Hydrolysis of this relatively stable derivative furnishes crystalline vitamin D2 in high purity This procedure, which uses readily available and inexpensive photolysis equipment, proceeds in good yields and does not require chromatographic purification of the product References and Notes Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110 The author would like to thank Mr M J Petrin and Mr R C West for the HPLC analyses For the original preparation of vitamin D2, see: (a) Askew, F A.; Bourdillon, R B.; Bruce, H M.; Callow, R K.; Philpot, J St L.; Webster, T A Proc Roy Soc (London) 1932, B109, 488; Windaus, A.; Linsert, O.; Lüttringhaus, A.; Weidlich, G Justus Liebigs Ann Chem 1932, 492, 226 For reviews, see: (a) Havinga, E Experientia 1973, 29, 1181; Norman, A W "Vitamin D: The Calcium Homeostatic Steroid Hormone"; Academic Press: New York, 1979; pp 37-69 Havinga, E.; de Kock, R J.; Rappoldt, M P Tetrahedron 1960, 11, 276; Malatesta, V.; Willis, C.; Hackett, P A J Am Chem Soc 1981, 103, 6781; 10 11 12 13 Dauben, W G.; Phillips, R B J Am Chem Soc 1982, 104, 355; Dauben, W G.; Phillips, R B J Am Chem Soc 1982, 104, 5780 Hanewald, K H.; Rappoldt, M P.; Roborgh, J R Rec Trav Chim 1961, 80, 1003; Okamura, W H.; Elnagar, H Y.; Ruther, M.; Dobreff, S J Org Chem 1993, 58, 600 Eyley, S C.; Williams, D H J Chem Soc Chem Commun 1975, 858; Stevens, R D S U.S Patent 686 023, 1987; Chem Abstr 1987, 107, 237124j Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number) Vitamin D2: Ergocalciferol (8); 9,10-Secoergosta-5,7,10 (19), 22-tetraen-3-ol, (3β)- (9); (50-14-6) Ergosterol (8); Ergosta-5,7,22-trien-3-ol, (3β)- (9); (57-87-4) Vitamin D2 3,5-dinitrobenzoate: Ergocalciferol, 3,5-dinitrobenzoate (8,9); (4712-11-2) Ethyl p-dimethylaminobenzoate: Benzoic acid, p-(dimethylamino)-, ethyl ester (8); Benzoic acid, 4-(dimethylamino)-, ethyl ester (9); (10287-53-3) tert-Butyl methyl ether: Ether, tert-butyl methyl (8); Propane, 2-methoxy-2-methyl- (9); (1634-04-4) 9-Acetylanthracene: Ketone, 9-anthryl methyl (8); Ethanone, 1-(9-anthracenyl)- (9); (784-04-3) 3,5-Dinitrobenzoyl chloride: Benzoyl chloride, 3,5-dinitro- (8,9); (99-33-2) Copyright © 1921-2005, Organic Syntheses, Inc All Rights Reserved
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