Bis[trimethylsilyl] Sulfate-Catalyzed Alcohol Protection with Dihydropyran, Deprotection, and Transesterification

November I981 Cttl‘lr7BI0t calc. C 57.3] H 4.54 Br 2l.l8 (377.2) lound 57.15 4.80 20.9I ‘H-N.M.R. (CDCI,): 5-3.74 (s. 3H): 3.81 (s, ZH): 4.42 (s, 1H): 5.28 (s. IH); 7.0-7.9 ppm (m. 8H). 4-(soc-a-rlnoaeyloxymethyl)-phenylaoetlc Acld (4-Metnotty).pberraeyl FAR: (4): Potassium fluoride (1.75 5. 30 mmol) is added with stirring to a solu- tion or 4-bromomethylphenylaoetic acid (4—methoxy)—phenacyI ester (3; 3.77 g. IO mmol) and Boo-amino acid (I5 mmol) in aceton' ‘I: (60 ml). The reaction mixture is stirred unlil T.LC. analysis oflhe mixture showed no further reaction (I6-72 h). on a thin layer chromatography plate (Silica Gel F M}. 200 microns; chlorofonn/uoelic acid-95 :5), the product appears as a UN. and ninhydrin-positive spot (after heat- ing) with a higher R, value than the corresponding Bo -amino acid. The precipitate is rrltered and washed with acetonitrile (1x20 ml), ethyl acetate (150 ml) and water (I50 ml) are added to the filtrate. After I vigorous extraction, the aqueous layer is re-extracted with ethyl acetate (3 X 30 ml). The com ed organic layers are washed with water (2)( 150 ml), saturated sodium hydrogen carbonate solution. (3 X150 ml), and water (2x lso ml), and dried with sodium sulrate. The drying agent is removed by rrltration and the nitrate is evaporated to dryness. The residue is erystallized either rrom ethyl acetate/ether or ethyl acetate/petroleum ether (b.p. 3s—oo°c) to give 4 as a white e material (Table l). satisractory analytical data (microanaly- si , T .c. purity, and ‘H-N.M.R. spectnrm) were obtained ror all the compounds listed. ntotolyrie Cleavage or etnooamlooaeylortymettryl)-pbenylar.-etie Add (4—Methoxy)~plIen|cyI Esters (4): All photolyses are done in a RPR I00 Rayonet photochemical reactor (The southern New England ultraviolet co., Hamden. Conn.) eq ped with Rrluso A lamps. Tlte temperature in the reactor is mar tained at 34°C by an electric ran. 4-(Boc-Iminoaeyloxymethyl)-phen- ylacetic acid (4»metlloxy)-phenacyl ester 4 (lo mmol) is dissolved in absolute ethanol (5% solution: w/v) in a glass vial with screw cap. For some amino acid derivatives, absolute dimethyllormamide is added to dissolve the sample. The solution is bubbled with dry argon ror L: h and irradiated at 350 nm until the cleavage is complete (4-12 h, Table 2). as shown by thin layer chromatography (silica Gel F so, 200 m . crons: chlorolorm/acetic acid—95 ts, except for arginine derivative: n-butanol/acetic acid/water-3 :I l). The solvent is removed under reduced pressure, and the product is obtained either as the free acid by crystalliration from ethyl acetate/petroleum ether or ether/petro- leum ether (b.p. 35—60°C), or its dicyclohexylammonium salt. Each compound in Table 2 was obtained in pure lorrn (T.LC.) and gave sa- tisiscrory microanalysis as well as the expeued ‘H-N.M. spec- tmm. Rate of Clelvlge of 4-(Bocdglycyloirylnelhyl)-phenylacefie Aeltl (4—Me- tboxy)-piteaacyl Ester lry notolysla: 4-(Boc-glycyloxymethyl)-phenylaoetic acid (4-methoxy)~phenacyI ester (300 mg, 0.64 mmol) is dissolved in absolute ethanol (30 ml). The solu- lion saturated with argon for I.5 h and divided into 6 samples place in a glass vial with screw cap. ive or the samples are irradiated at 350 nm in the manner described above for the preparation of 5. At various time intervals, I sample is taken and applied to a reversed» phase uliondapak C-I8 column (30 cm x 0.4 cm), equilibrated with 0.0l molar N-methylmorpholine acetate in 35% acetonltrile/water (v/ v) at 3 ml/min. The column effluent is monitored at 214 nm. The prod- uct is eluted from the column with a retention of 2.4 min, while the phenacyl ester has a retention time of1l.3 min. The rate of decrease in pllenacyl ester content, compared to unphotolyzed sample, is taken as the rate of photolysis of the ester bond. ltednctsorr or 4—(Doc-Amllolcyloxylletllyl)-phellylacetlc Add (4.Me. ttroxy)-pbeaaeyl meter (4): HBot;-aminoacyloxymethyl)-phenylucetic aeid (4-lnelhoxy)-phenacyl ester 4 (1.0 mmol) is ssolved or suspended in acetic acid/water (20 ml: as~ 5 v/v) and zinc dust (I.3 g, 20.0 mmol) r added. The reaction mixture is stirred ror I3 h and altered. The precipitate is washed with water (30 ml) and the combined rrltrates are adjusted to pH is with 0.2 normal hydrochloric acid alter addition or ethyl acetate (so ml) and water (50 ml). Atter shaking the aqueous phase is separated and 0039-7331/81 /1 132-0898 S 03.00 899 Communications extracted with ethyl acetate (3x 50 ml). The combined organic layers are washed with water (5 X30 ml), dried with sodium sulfate. and fil- Iered. The filtrate is evaporated to dryness, the residue dissolved in ethyl acetate (is ml), and the solution adjusted to pH 7.0 with dicyclo- hexylamine. The dicyclohexylammonium aoetate salt is removed by filtration and the filtrate is evaporated to dryness. The residue is crys« tallized as described previously to give 5 as a white crystalline product (Table 2). The compounds are identical with the compounds prepared by photolysis cleavage as determined by thin layer chromatography. microanalysis, and ‘H-N.M.R. spectrum. Received: May l9. 1981 ‘ A. R Mitchell et aI...I. Am. chem. Soc. 93, 7356 (I976). 2 J. P. Tam, F. s. Tjoeng, R. B. Merrirreld, J. Am. chem. soc. ltn, 6117 (1930). * R. B. MerriI'leld,.l. Am. chem. Soc. 35. N49 (was). A. R. Mitchell, s. B. H. Kent, M. angelhard, R. B. Merrirreld, J. Org. chem. 43, 2345 (I978). l. P. Tam. s. E. H. Kent, T. w. Wong, R. B. Merrirreld, synthesis 1930, 955. s. l. sallay. K. s. L. srivastava, s. oroszlan, K v. Gilden. Proceed- rngr of the Sixlh American Peplide Symposium 1979. E. Gross. l. Meienhoter, Eds., pp. 377.331. ’ J. c. sheehan, K. Umezawu, J. Org. Chem. 38. 377I (I973). E. P. serebryaltov, L. M. suslova, v. F. Kucherov, Tetrahedron 34, 345 (I978). ° B. Amit. u. Zehavi, A. Plllchornik, ltr. 1. chem. 12. I03 (1974). v. N. R. Pillai, synrnerlr rm. I. F. s. Tioeng, E. K. Tong, K s. Hodges, J. Org. chem. 43. mo (1973). D. H. Rich, 5. K. Gurwara. J. Am. chem. soc. 97, 1575 (I975). J. H. clarlr. l. M. Miller, Telrahedrorl Len. 1977, 599. t/laisltrimethylsilyll Sul{ate—Catalyzetl Alcohol Protection with Dihytlropynln. Deprotection. and Trunsesterificalion Yoshitomi MOIUZAWA, Icltiro MOI1I.Tamejiro HIYAMA‘, Hitosi NOZAKI Depantrtet-rt or Industrial Chemistry. Kyoto University. Yosltida. Kyoto 506. Japan We report that bisltrimethylsilyl] sulfate” (3) is an efficient catalyst both for tetrahydropyranylaiion of alcohols (I) as well as for removal of the protecting group“ from 4 under mild conditions as compared with those of the conventional protic acid catalysis‘. For example. the tetrahydropyran-2-yl ether 4 of an alcohol I is prepared at 0"C with l.l equiv of dihydropyran (2) in the presence of 2 mol% of 3 within 1 h. Isolation of the product is effected simply by adding pyridine, concentrating, and column chromatography of the residue, or alternatively by adding potassium carbonate to the reaction mixture and distillation. Deprotection is carried out at room temperature in methanol during ~1 h (Table). IN C) Sl0 ( 0(2)! ’ ‘ :501l3l ttt,ct,sro rt,t:—ottI:t R—0H 4 1 It is worth pointing out that even tertiary allyli alcohols can be protected without rearrangement or other side reactions 19 1931 Georg Thieme Verlag ~ Stuttgart - New York 900 Communications (lg, ll). The ether of testosterone (li) was prepared in a quan- titative yield in much shorter time as compared with the py- ridinillm tosylate catalysis‘. SYNTHESIS lated in 89% yield. Particularly this reaction is applicable to the alooholysis ofa glyceride as exemplified by the conversion of l,2.3-propanetriyl tris[decanoate] (5) into methyl decanoate The catalyst 3 is also userul for transesteritieation’-'“. For ex- (5) 3"‘ !'Y°"°‘ l7)‘ ample, when benzyl acetate was heated to reflux in methanol in the presence of 3 (I0 lllol“/0) for 2 h, benzyl alcohol was iso- Cllllllllyl Tetrlhydmpynllyl Ether (M); Typlcll T¢|I‘IlIytlf0p)’I'lll)'lI- tlon Procedure: A dichloromethane (10 ml) solution of cinnumyl alcohol (lc; L00 g, 7.5 mmol). dihydropyrart (2: 0.72 ml, 7.1; mmol) and 3 (1.0 molar di- chloroethane solution. 0.02 ml, 0.02 mmol) is stirred at 0°C. T.L.C. monitoring reveals that the reaction is completed in 10 min. At this point pyridine (~0.1 ml) is added to the reaction mixture and all the volatile material is evaporated under reduced pressure. Column chro- matography (silica gel, ~40 g; eluent: 20:1 hexane/ethyl acetate) 0 r H2c—o—E—c,1i.g-tr 11 tl,c—o1t,c N 11,4: 1 1 20 min 100-“ 101° 98-100” 1 h 95* 0 H,C ¢aHr1 "’C A l( - it 1 1 J 20 mm 98" 154° 150° " 30 min 98 - H) H A mixture of an alcohol 1 (1 mmol), dihydropyran (2; 1.1 mmol) and J (2 mol"/rt) is dissolved in diehloromethane (3 ml) and the whole is stir- red at 0°C. Distillation was elreoted with Kugelrohr (bath temperature given). Each product was homogeneous on silica gel T.LC. plate chromatogra- phy. The ether 4 (1 mmol) dissolved in methanol (7 ml) is stirred in the presence or 3 as catalyst (0.02 mmol) at room temperature. unless otherwise stated isolation was effected by addition or pyridine (more than one equivalent of 3) rollowed by concentration and column chromatography. satisractory micmanalyses obtained: c :0.22. 1-1 10.23. Products 4c. r were 100% pure by o.1.c. analysis (silicone SE 30, 5%. 75 em. 100°C). The product was isolated by addition ofexoess pyridine, washing the reaotion mixture with aqueous sodium hydrogen carbonate solution. con- centration, and column chromatography. 0.0 mom 3 used. 1.5 lI|0l"/11 2 used. 2 mmol 2 used. 1.5 mmol 2 used. ~s mol% 3 used. ‘the reset’ n was carried out at 55°C as the eholestereol ether was insoluble in methanol at room temperature. A homogeneous solution in ethanol/diehloromethane (1 : 1) was allowed to rucl at room temperature ror 20 h to produce eholestereol in 97% yield. November l98I Deprotectlon or 4c: ‘IV/rlcal Procedure: A methanol (5 ml) solution or 4c (150 mg, 0.69 mmol) and 3 (1.0 mo- lar dichloroethane wlution, 0.02 ml, 0.02 mmol) is stirred at room tem- perature for l h. Addition of pyridine (-lJ.l ml), concentration in va- cuo. and shon s ca gel column chromatography (eluent: 5 :1 hexane/ ethyl acetate) gives cirrrrarrryl alcohol (lc); yield: 93 mg (100%). rranseaterlllcaliorr or 1,2,3-Propaaetrlyl Trladecanoatel (5): A ‘xture or the glycerol triester 5 (15.0 g, 27 mmol), 3 (1.0 molar dichloroethane solution, 1.2 ml, 1.2 mmol) and methanol (25 ml) is heated under reflux ror 3.5 h. The catalyst 3 is hydrolyzed by adding water (0.024 ml, 1.3 mmol) and potassium carbonate (0.20 g, 1.4 mmol). concentration in vacuo results in the separation of two oily products. Distillation or the upper layer gives rrrerlryl detarloale (6); yield: 135 g (119%); b.p. I07-l08"C/3 torr. Distillation or the lower layer gives glycerol (7); yield: 2.0 g (32%); hp. I42-l53“C (Kugelrohr, bath temperature)/3 tort. Receive March 9, I981 (Revised form: May 6, I981) correspondence author. New address: sagami chemical Research center, Nishi-Ohnuma 44 1, sagamihara. Kanagawa 229, Japan. w. Patnode, F. c. schmidt, J. Am. Chem. Soc. 67, 2272 (1945). N. Durraut, R. calas, 1. Dunogues, Bull. soc. clnrn. Fr. 1963, 512. P. Bourgeois, N. Durraut, Bull. soc. Chim. Fr. 1900, 195. M. schmidt, 1-1. schmidbaur. Chem. Ber. 94, 244.5 (1961). L. 1-1. sommer, G. T. Kerr, F. c. whitemore, 1. Am. Chem. soc. 70, 445 (19413). 5 w. Kantlehner, E. 1laug,w. w. Mergen, synthesis 1900, 450. 1. F. w. Mcomie, Prvlecliue Groups in Organic Chemistry, Plenum Press, London and New York, 1973, p. 95. 1. 1-‘. w. Mc0mie, clrern. Ind, (Lmldan) m9, 603. M. Miyashrta, A Yosh'ltoshi, P. A. crieco, J. Org. chem. 42. 3772 (1977) and reierences d therein. C. E. Rehberg, Org Synlh. coll. Vol. 111, ltd (1955). 1. c. sauer, 13. E. liarn, P. w. Boulwell. Org. Syrllh. Coll. Val. 111, 605 (1955). '° K. Mori et al.,Syr1lIle:l'r rm. 790. " G. cardillo et al., Synlh¢.ri.r 1979, 6l8. '2 A. van der oen et al., Recl, Trav. Chirrl. Pay:-Ha: 911, 371 (1979). '= A. c. ott. M. 1:. Murray, 11. 1. Pederson. J. Am. Chem. soc. 74, 1239 (1952). Improved Synthesis of N-Substituted lsopropylidenenzlr‘ ines Joannes B. P. A. WIJNBERG, Petrus G. WIERING, Herbert STEINBERG' Laboratory ror organic chemistry, University or Amsterdam, Nieuwe Achtergracht 129, 1011; ws Amsterdam, The Netherlands 3-Bromo-2-methyl-ta]kylamino-2-butenes (4) are key inter- mediates in the synthesis of N-substituted isopropylideneazir- idines (5). Compounds 4 can he prepared from l,l-dihromo- 2,2-dimethylcyclopropane and excess amine”: however, the high temperatures (l30—Z00°C) and long reaction times re- quired for this transfon-rlation give rise to only moderate or poor yields of 4. especially when thermally labile or sterically hindered amines are used. For example, l,l-dibromo-2,Z-di- methylcyclopropane and cyclopropylamine gave ill-defined products when heated above l20°C for several hours. The reaction sequence described in the following provides a convenient route to the 4-aminobutenes 4 in high yields. 0039-7881/B1/1132-0901 $ 03.W 901 Communications 0 ll H3c\C_c/c"'c' LIAM‘ Irlher.- 25°C H3c\c_c/c"7'°H HJC/ \Br 95']: H3c/ \B' 1 2 H3C\ :N "35 \ R 5 a 12 =1-c,rt. d R - —crl,—c1c)1,), b R : H e R = cans c 17 e 1.c,t1, f R = 1-adarnantarrvl Our two-step method for the conversion 1—>3—>4 appears to be superior in terms of overall yield to an alternative proce- dure° reponed for the one-step conversion of allylic alcohols into the corresponding amines. Further, our method for the cyclization of 4 to 5 is more convenient than the known cycli- zation of 4 using sodium amide which generally gives rise to mixture of 5 and isomeric products‘'’. The starting material I is obtained in 80% overall yield from 3-methylcrotonic acid by bromination, t:lehydrobromina- lion“, and reaction with thionyl chloride‘. 2)-Bromo-3—netllyl-2)-butenoyl ch de (1): Prepared lrom 2-hromo-3-methyl-2-buranoic acid“ according to Ref.’; yield: 39%); b.p. 75—76"C/I8 torr. c,ll.1arclo calc. c30.4l (197.5) round 30.23 l.R. (cl-1cl,): v= 1750 cm-' (c=o). ‘H-N.M.ll. (cDcl,/TMs): 5-2.14 ppm (s, 6H). 2-Brorno-3-metlryl-2-lrirtenol (2): To a stirred suspension of lithium aluminium hydride (5.21 g. 0.l36 mol) in anhydrous ether (440 ml), cooled at — 25°C. is slowly added I solution of Z-bromo-3-methyl-2-butenoyl chloride (1; 26.4 g, 0.l34 mol) in anhydrous ether (60 ml). After 20 h, aqueous sodium sulfate is added, the mixture extracted with ether (2 x 50 ml), the ether solution washed with saturated sodium chloride solution (50 ml), dried with so- dium sulfate, the ether evaporated, and the residue distilled in VI¢IlD: yield: 2! g (95%): |>.p. 79°C/ll torr. CgHoBrO calc. C 36.38 H 5.50 Br 48.42 (165.0) found 36.30 5.58 48.20 'H-N.M.R. (CDCI,/TMS): 5- 1.88 (s. 3H); L92 (5, 3 H): 2.83 (s, 1H; disappears with D10), 4.42 ppm (5, ZH). 1,2-Dlltrorno-3-rnethyl-2-ltateue (3): To a stirred solution or triphenylphosphine (20.6 g, 0.079 mol) in dry carhcn tetrachloride (200 ml) is slowly added a solution or bromine (12.6 g, 0.079 mol) in dry caroon tetrachloride (50 ml) at 0°C. Then, a solution or the alcohol 2 (11.13 g, 0.071 mol) in dry oarhon tetrachlo. ride (50 ml) is added and the mixture refluxed ror 1 h. Alter cooling, the precipitate is filtered oil by suction and washed with a rew ml of cold carbon tetrachloride. The solvent is evaporated and the residue distilled in vacuo; yield: l4.8 g (91%); hp. 57.s0°c/3 torr(Re{.", b.p. 62-63 °c/3,5 torr). ‘H-N.M.R. (ccl./TMs): 5- 1.90 (s, 3 H); 1.93 (s, 3 H): 4.37 ppm (s, 2 H). H 3.06 2.97 to 1931 Georg Thieme Verlag ~ Stuttgart - New vorlt