Organosulphur chemistry Sul hur trioxide-pyridine complex A versatile organic reagen Dr Dirk Kusch, head of development at SF-Chem, looks at the use of the sulphur trioxide-pyridine complex in many applications pronson. siphon and subhamaon G rein it rau roperanur tc par Cre 1 aerator ase perc pee Toy sed wale bond ge of pets try ys pores eee Parc Cx igonenian nd op ees In gol sion is ome y sop scr cerant cles on ata serpy seo! end oocorporet Spr sod od te coreqedng a. Te tomes sly sary pod ce! Op feo vasa re GO) hs Sat Icon eof pce et poke pte cope subhorte Soy eam ecrone decree at: ay acre ay ppc ext oh ete anor goup Mast vei compo toma bint ron ci wi pre S0y oe tv ean snd heat eon? To de techy a 50 robe eaten vr Oued fome 50, ae ae oe D Inaasion Ie us of 25 8 SOs i ya sunset sihaeton on siphon process tig rote oes® ext o30y cm becanted win ses he spr one Sos ant gone cata ed chy co be roa by he eo ew een her aw bey SOs anne omg Thee compos apart vay vl and venus ds fey wah see propeies They have maple ues for te thnaon 22sec hres Shae tmatrix nr be span anon ewes sopranos? RH + So Reso R-OH + $0; —+ RO-SOH RANH + SO; —~R,N-SOW Ral ay = 50,1450, Hal + So, ——+ ciso,H HO + S05 = His Ny + $0; ——= nHSOH NR + $0; ——+ 504°N of sulphur trioxide RR-NGH Prine ee SE eed ‘The application of SOy amine complexes forthe syithess of sulphated polysacchariées as pharma- ceutical intermediates is breadly used to provoke the cleavage of glycosidic bonds and other lable functions, such as amides, esters and even ethers Recent the regicselecve sulphation of triethys IM cellulase, using diferent SO;-amine complexes, has aso been decribed > Numerous complexes of S03 with amines, such 25 Wimethylamine, viellamine, NINdimethytan: Ine, 2-methylpyridine or pyridine, are described in the iterature® Complexes of S03 with ather Lewis bases such as dioxane thioxane,cimethy!suiphide, imettyd sulphoxide oF NN-dimettyl formamide ‘ate also known The reactty of these complexes is inversely pro portional to thei stability, which in tum varies erect: |y according tothe stenat of base used® Diferent papers have described investigations ino the suihonation reactivity of different SOs-amine and other SOs-Lenis base complexes."® Even the weak- ‘st complex & 2 much milder reagent than tree ‘50s, It slo possible to maderate the reactivity of 505 to any desired degree by the comect choice of «8 complexing Lewis base’* Several methods have been descibed for the preparation of trary SOs-amine complexes? The processes may be performed by the reacion of 2 teriary amine (eg. trimethylamine, tethylamine, NNimethyantine o° pytiine) with SO, in the ‘gaseous phase or in an organic solvent or by reac- tion with chlorosuiphonic acd. ina chlorinated ‘organic solvent (e9. 1.2-pytdine complex is one of the most important SOsamine complexes used in ‘oxganie synthesis for diferent kinds f reaction. It is 8 cytaline white sod with 4 melting point of 15°C, which can be prepared by using one ofthe methods described above The complex is a corrosive compound, which reacts quantitatively with hot water to give pyridine and sulphuric acid Complexes with SOs-pyicine Toler ratios other than 1:1 (CAS 26412873) can algo be prepared: 2:1 (CAS §2922-34-6), 3:1 (CAS 5292235-7) and 1:2 (CAS 8281030. ‘Any addtional SOs in these complexes is much ‘more reactive than the fst equivalent For instance, 2 complex with a SOxpyridine molar ratio of 2:1 ‘an be used forthe «sulphonaton of butyric acd In general, however, the use ofthese complexes i very limited 3 Reprinted fom Specialty Chemicals Magazine December 2006eyecare lonley? ‘The SOspytidine complex can be used fr the suiphonation of poyeyic compounds and eciesen sive heterondes, for example the synthesis of sulphonated indoles under mid reaction canitons (Gigare 3.3.5" tis algo broadly used for sulphation ‘of yes, sterols, and especialy fr carbohyerates3¢ ‘The method can be used to minimise polsul phation, e9. for the preparation of glucose 6s phate Figure 4 Due tothe fact that there ae nat ‘rally occuring sulphated polysaccharides (eg. heparin, bearing atemating glucosamine and glu- ‘uronic acid units, the use of SO pyricine complex is ef general interest a5 a selective sulphonating reagent for amino groups in amino alcohols. © The sulphated products can be used as interme. ates for cferent subsequent reactions. For exam: ple, the pyridinium sulphate ester intermediates of subsituied benzyl alcohols can be eliminated, to form substituted siyrol compounds.” Pridinium sulphate esters can be used as inter- mediates for the deoxygenation of alyic and ber 2c alcohols for substitution by hydride. This rec- ‘tn is useful in reactions of alc or beneyli alco- hols which cannot be converted into halides 8 The preparation of carboxjic acid aries from foximes can aio be performed with the SOs pyti- ine complex Recent publications describe is use in the synthesis of sulphated alcohols as intermedt aes forthe production of functonalied?® and halo ‘erfree ionic lquids2 It can also be used for the ‘manufacturing of pigment cispersions forthe prepa- ‘ation of inkjet inks with spectc properties?” ‘The complex is suitable for sulphamation reac: ‘ons of primary amines" Is us in the preparation (of phenyethynesulpheryl sulphamates from alkyne- sulphenamides can also be considered as a su pPhamation reaction. Pherylthynesuipheny supha- ‘mates can be used forthe elecrophic adlion 9 dlefinic double bonds for the preparation of _acetlenic sulphides (Figure 5.23 ‘The oxidation of primary alcohols to aldehydes and the oxidation of secondary alcohols to ketones bby means of the SO;-pytidine complex and diet suiphoxide in the presence of rithylamine For mote information, please contact Dr Dirk Kusch, Head of Development ‘SF-Chom (GH-4133 Pratoln 1 ‘el: +41 61 825 32 12 E-mal: dik kuschd@ist-chem com Internet: wwewsf-chem com is known as Patkh-Doering oxidation2* This is brosaly used for the synthesis of pharmaceutical Intermediates, due © the mild reaction condtions ie In the fst step, ciety sulphoside fs activated by SOs, which in the second step reacs with an alcoho! under basie condtons to for the care sponding carbony! compound and dimety suk pide asa by-product (igure 6 Recent, unusual oxidation behaviour by ‘ropargylc alcohol by Parikh-Doering oxidation was described. The aldehyde formed in 1. EA. Krag, ML Nussbour 6 S. Shute in Ml. Grayson fed). Ki Dtkmer Ereyapeda of Chemie! Takndoy, an Woy & Sons, 1983, Nel 22,140 2 NC. Fost ia Slfonation & Silloton Processes, Chaithon [vmuchertoncom), 1-37 3. ely, St 200814, 7263- 68 4. 0. PapeGorcis et al, Macro: mous 2006, 38 (11,47 54 Asahi Kase Kogyo Kebushi Kaisha, EP 0053473, 1981; A Heche, USP 700520918, 72005; Endeavor Prammacsuials, Ire, WO 2003057167, 2003 5. Fiche 6D. Kern, Cato 2003, 1072, 193.198 6. £E. Giben hem Re. 1961, 589- 1991 75638, 1860 ams-a7e, 7. Caran & BN, Baer ia LA Paquette (ea) Eneyclpadia of Reagets er Ogi Sytoss, Jahn ey Sars, 1985, 699-4702 8.Y Auger, G Uses, JC. Fischer 6 M Witte, J Alectronal. Ohm 1860, 106, 48; TH. Lowry & K Schule ichadson in Mechanism & Toy in Organi Cons, Hope Pw 1987, rE, 297 8. Goal Air 6 Fim Capoten, sr 27080, 1956 10.2. Guba aa, WO 900082, 11, Aled Cherical Caran, USP 12. ciel Chica Corporation, USP 4640209, 1987; f. Bunce hom. fox 1970, 328:37: £6. Barua & GW. Crosby. Am. Cham Soe 1956 78, 5387-371 18. TL wl n LA. Pate (ed) Enoydopeda of Regents fr Organ Sess Job Wi & Sans, 1985, 14. GF Smith § DA. Tovar, Tented 1973, 29, 658672 15. KB Ghisly 6PM. Rot J Op ham 1981, 25, 1248-1154 539 16... Wane; LL Clean, Os am, 1958 23, 11331135 HLA, Barat 6K Sefer, Hoe Chim ‘Acts 208, 5), 724-796 164 18. EJ, Dowy # K Achine, Oop (he. 1968 24/17, 2867-368; EL Corey, DE. Cane 6 Ut, J Am hem Soc 1971, 9, 7016-7021; DS. Wet & EJ. Cy, Fvaieton Frunsaturated-f-methylsuiphany! aldehyde, pre- sumably formed by the adaition of dimety su hide 2* The Parikh Doering reaction wih SOs pyr- dine complex can ako be performed on a large scale” Dimethyl sulphide is ormed as a by-product of the ParikhDeering oxidation, using dimethyl sulphoxide. The general application of this side reac- tion i abo described by using the SOypytiine complex along with sodium iodide for the deoxy genation of sulphides to sulphides at room tem- erature wih high viele ?® ‘The activated dimethyl suiphoxide species formed by the reaction of SOypyridine complex vith cimethy sulphoxide as descibed above can aso be used as a dehydrating agent to obtain tres from primary amides in excellent yds? In concksion, the SOx-pyiine complex repre sents 2 very valuable and versatile frm of SO and ‘an be used for diferent types of reactions that have to be performed under mild conditions. SF-Chern produces it on a multitonne scale and has exper ence in the producion and use of SOsamine com- plexes for diferent kindof reactions. er 1972, 451-654, 18. BASF AG, OE 390510, 1988, 20. Sole lnoraton GBH, DE 10247578, 2004; P Wasserchi, Diessontsha, A. van Hel, HC Soofns 6 J. Zeeman, dhe Goran, 2008, 6, 238-2033 2 Sohent Imoraton GrtH, WO 203074894, 203 22. Toyo Ink Mandoctcing, CP 0894597, 1998; Seo Epson Caparica, USP 2003001599, 2008 23. OV. Dein, AG. Kuno, NM 2k & Zoey, Suir Corer 962 15), 3-106 24, 1 Pak YE. Down, J Am (ham. So 1967 9, 8505-5507 25, Meck & Ca, wo zmosa75337, 2005 26, MJ, Porte, NJ. Wht, GE Howels & OD? Lafn,Teatetan eters 2008, 4505), 65818543, 21. Gh, Slee Mi Rene 0. Tan LEN. Nay OA 2006, 101), 163 28. GA. Olah, YO. Vankar § M. ‘Aovenagh, yes 1979, 964806 28. N. Naja, ML Sato & M. Uadota, Tevahedon 2002.52 (18), 23581-2577 Reprinted fom Spedaly Chemicals Magazine December 2006