Mendeleev Communications Electronic Version, Issue 5, 2001 1 Direct conversion of N-ethylamines into functionalised amides by S2Cl2 Lidia S. Konstantinova,a Oleg A. Rakitin*a and Charles W. Rees*b a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation. Fax: +7 095 135 5328; e-mail: orakitin@ioc.ac.ru b Department of Chemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY, UK.E-mail: c.rees@ic.ac.uk 10.1070/MC2001v011n05ABEH001504 Hunig¡�s base 1 is known to react extensively with S2Cl2 to give monocyclic, bicyclic and fused tricyclic 1,2-dithioles with the N-ethyl group intact, but with S2Cl2 and DABCO in chloroform at 0 ¡ÆC 1 is converted into dichloroacetamide 2 by selective reaction of the N-ethyl group in a new one-pot transformation; ethyl-substituted derivatives of 1, diethylisopropylamine 17 and triethylamine react similarly though the last, less bulky, amine also gives trichloroacetamide 20.We have recently shown that the complex reaction between Hunig¡�s base 1 and disulfur dichloride, S2Cl2, which gives bicyclic bis(1,2-dithiol-4-yl)amines1 and tricyclic bis[1,2]dithiolo- [1,4]thiazines2 can, with a deficiency of S2Cl2, also give intermediate monocyclic 1,2-dithioles in low to moderate yield.3 Since this reaction is an unusually mild route to 1,2-dithioles,4 we attempted to increase its synthetic utility by replacing that part of the Hunig¡�s base which neutralises the hydrogen chloride liberated, by another amine DABCO; also the reaction temperature was lowered to 0 ¡ÆC to minimise conversion of the second isopropyl group. Unexpectedly, these conditions led to an entirely different reaction in which the isopropyl groups are unchanged and the ethyl group is transformed into a dichloroacetyl group, which, as far as we are aware, is a new transformation. Thus, Hunig¡�s base with S2Cl2 (7 equiv.) and DABCO (7 equiv.) in chloroform at 0 ¡ÆC for 3 days followed by addition of formic acid1.3 and heating for 1.5 h gave (N-dichloroacetyl)diisopropylamine 2¢Ó (41%) (Scheme 1).This conversion of Hunig¡�s base into amide 2 is the first example that we have encountered, in many such S2Cl2 reactions, of attack at its ethyl rather than isopropyl group, in the presence or absence of other bases.1,2 The key reaction is presumably oxidation of the tertiary amine to an iminium ion by S2Cl2.DABCO complex 3,3 which is a potential source of Cl+ and Cl., and the outcome depends upon which iminium ion is formed.We assume that the present mild (0 ¡ÆC) conditions result in oxidative removal of the less hindered ¥á-hydrogen, i.e., from ethyl rather than isopropyl, to give kinetically controlled iminium ion 4 (Scheme 2) rather than the, presumably more stable, alternative.Ion 4 can isomerise to enamine 5, which can be oxidised further, as shown in Scheme 2, to give ultimately tetrachloro species 6, which is converted into product 2 by formic acid. Once the ethyl group has been oxidised (Scheme 2), the N-isopropyl groups will be deactivated to electrophilic attack.N-Dichloroacetyl diisopropylamine 2 is inert to the reaction mixture even at room temperature, and we have previously shown that N-acetyl- and N-cyanodiisopropylamine are inert to S2Cl2 under similar conditions.2 The formation of iminium ion 4 to the exclusion of its isomer has previously been demonstrated by Schreiber10 in the oxidation of Hunig¡�s base with trifluoroacetic anhydride in dichloromethane at 0 ¡ÆC; no attack at isopropyl was detected.In the Hunig¡�s base.S2Cl2 reactions, there is a relatively fine balance between conversion of the ethyl group into dichloroacetyl (Schemes 1 and 2) and the isopropyl group into dithioles,3 bisdithioles1 and bisdithiolothiazines.2 It could be instructive to see how substituents on the ethyl group influence this balance.We therefore treated N-(2-chloroethyl)diisopropylamine 7 with S2Cl2, DABCO and formic acid under the same conditions as for 1. Two products were isolated: the same dichloroacetyl compound 2 (21%) as from 1 and 1,2-dithiole-3-one 83 (34%) (Scheme 3). The chloroethyl group has been oxidised like the ethyl group but presumably more slowly, thus allowing competing oxidation of isopropyl to give dithiolone 8.On the above ¢Ó General procedure for the reaction of tertiary amines with S2Cl2. Disulfur dichloride (0.8 ml, 10 mmol) was added dropwise at .15.20 ¡ÆC to a stirred solution of a corresponding amine (2 mmol) and DABCO (10 mmol) (in the case of N-ethyldiisopropylamine without DABCO) in chloroform (25 ml). The mixture was stirred at 0 ¡ÆC for 72 h.Formic acid (3.75 ml, 100 mmol) was added, the mixture was refluxed for 1.5 h and filtered; and the solvents were evaporated. The residue was separated by column chromatography (Silica gel Merck 60, light petroleum and then light petroleum.CH2Cl2 mixtures). All new compounds were fully characterised by elemental analysis, 1H and 13C NMR, IR and mass spectra, and HMRS. Dichloroacetamides 2, 18, 19, trichloroacetamide 20 and compound 11 are identical with the known compounds.5.9 9: an oil prepared from 7 and sodium azide in DMSO at room temperature in 88% yield. 10: yellow oil. 1H NMR (CDCl3) d: 1.10 (d, 6H, 2Me, J 6.5 Hz), 3.10. 3.45 (m, 5H, CH, 2CH2). 13C NMR (CDCl3) d: 187.42 (C=O), 154.87 and 137.02 (2sp2 tertiary C), 54.33 and 50.80 (2CH2), 44.98 (CH), 21.50 (Me).IR, n/cm.1: 2980 (CH), 2120 (N3), 1660 (C=O). MS, m/z (%): 278 (M+, 11%), 222 (69), 180 (100). 13: yellow oil. 1H NMR (CDCl3) d: 1.12 (d, 6H, 2Me, J 6.6 Hz), 3.51 (q, 1H, CH, J 6.5 Hz), 4.01 (s, 2H, CH2). 13C NMR (CDCl3) d: 187.17 (C=O), 155.97 and 136.12 (2sp2 tertiary C), 117.15 (CN), 53.59 (CH), 35.93 (CH2), 21.17 (Me). IR, n/cm.1: 2980 (CH), 2140 (CN), 1660 (C=O). MS, m/z (%): 248 (M+, 74%), 233 (47), 206 (61), 179 (33). 14: yellow crystals, mp 75.78 ¡ÆC. 1H NMR (CDCl3) d: 1.35 (d, 6H, 2Me, J 6.2 Hz), 1.57 (d, 6H, 2Me, J 6.2 Hz), 4.26 (br. s, 2H, 2CH). 13C NMR (CDCl3) d: 163.74 (C=S), 113.02 (CN), 51.86 (CH), 21.42 and 18.53 (2Me). IR, n/cm.1: 2980 (CH), 2150 (CN). MS, m/z (%): 170 (M+, 87%), 127 (86), 113 (14), 101 (43). N i, S2Cl2, DABCO, 0 ¡ÆC ii, HCO2H 1 N CHCl2 2 O N N S S Cl Cl. 3 Scheme 1 1 R2N R2N R2N Cl Cl. 5 4 R2N Cl Cl R2N Cl Cl R2N Cl Cl R2N Cl Cl R2N CHCl2 O Cl Cl. R2N Cl Cl Cl Cl 6 HCO2H 2 Scheme 2 R = PriMendeleev Communications Electronic Version, Issue 5, 2001 2 mechanism (Scheme 2) formation of isopropyl-functionalised product 8 should be favoured by a higher reaction temperature and formation of ethyl-functionalised product 2 by a lower reaction temperature.Some evidence for this was obtained by running the reaction exactly as before but in boiling chloroform (61 °C) when several products, all of which were cyclic 1,2-dithiole derivatives,1–3 were formed in low yields, and only traces of compound 2 were seen (TLC). When the same reaction was run at –20 °C, all transformations were much slower and only a low yield (12%) of compound 8 could be isolated.N-(2-Azidoethyl)diisopropylamine 9 treated similarly also reacted by both pathways to give corresponding dithiolone 103 (12%) and an acyldiisopropylamine; the latter was not the analogous 2-azidoacetyl derivative but cyanoformyl derivative 11 (19%) (Scheme 4) obtained as a yellow oil. This product could arise readily by the general mechanism of Scheme 2 with a late diversion, caused by elimination of nitrogen and formation of the cyano group, as shown in Scheme 4.Formation of cyanoformamide 11 from azidoethyl compound 9 prompted similar treatment of N-(cyanomethyl)diisopropylamine 12,11 which was expected to give the same product 11 but possibly in higher yield. However, cyanothioformyl derivative 14 (24%), mp 75–77 °C, was formed instead, together with dithiolone 133 (20%) (Scheme 5).Formation of thioamide 14 instead of carboxamide 11, after formic acid treatment, suggests that a different mechanism is operating. It seems reasonable that S2Cl2 could be reactilfur, with the activated methylene group of 12. This could be through its ketenimine tautomer 15 as shown in Scheme 5 or by a radical mechanism induced by the enhanced stabilisation of captodative radical 16.12 When one of the isopropyl groups of Hünig’s base was replaced by ethyl, the same conversion of ethyl into dichloroacetyl by S2Cl2 was observed. Thus, diethylisopropylamine 17 with S2Cl2 and DABCO in chloroform at 0 °C for 3 days, followed by the formic acid treatment, gave dichloroacetamide 18 (34%); when run at 20 °C for 3 days, the yield was 54% (Scheme 6).When both isopropyl groups of Hünig’s base were replaced by ethyl, the same reaction was observed, to give dichloroacetamide 19 in 51% yield; however, at lower temperatures (0 °C and –20 °C), the yield of 19 is much reduced (to 8% and to traces, respectively) and the major product is now trichloroacetyl derivative 20 (22%). The direct transformation of N-Et to N-COCCl3 also appears to be new.Formation of 20 in addition to 19 could result from reduced steric hindrance by the ethyl groups in the chlorination sequence of Scheme 2, before the formic acid reaction. The established formation of monocyclic, bicyclic and fused tricyclic 1,2-dithioles from ethylisopropylamines and S2Cl2 requires attack at the isopropyl groups.We have now shown that the presence of DABCO in the cold reaction mixture favours selective attack at the ethyl group to give N-dichloroacetyl derivatives such as 2, 18 and 19, probably by the mechanism of Scheme 2. Ethyl-substituted diisopropylamines behave similarly, by minor variations of this mechanism, to give 2, 11 and 14, and the less bulky triethylamine also gives some of trichloroacetyl derivatives 20.This work was supported by the Russian Foundation for Basic Research (grant no. 99-03-32984a), the Royal Society, MDL Information Systems (UK) Ltd and an RSC Journals Grant to O.A.R., and we thank the Wolfson Foundation for establishing the Wolfson Centre for Organic Chemistry in Medical Science at Imperial College.References 1 S. Barriga, L. S. Konstantinova, C. F. Marcos, O. A. Rakitin, C.W. Rees, T. Torroba, A. J. P. White and D. J. Williams, J. Chem. Soc., Perkin Trans. 1, 1999, 2237. 2 (a) C. F. Marcos, C. Polo, O. A. Rakitin, C. W. Rees and T. Torroba, Angew. Chem., Int. Ed. Engl., 1997, 36, 281; (b) C. W. Rees, A. J. P. White, D. J.Williams, O.A. Rakitin, C. F. Marcos, C. Polo and T. Torroba, J. Org. Chem., 1998, 63, 2189; (c) C. F. Marcos, O. A. Rakitin, C. W. Rees, L. I. 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Rabjohn, John Wiley, New York–London–Sydney, 1973, coll. vol. 5, p. 387. 9 W. G. Phillips and K. W. Ratts, J. Org. Chem., 1972, 37, 1526. 10 S. L. Schreiber, Tetrahedron Lett., 1980, 21, 1027. 11 D. B. Luten, J. Org. Chem., 1938, 3, 588. 12 D. J. Pasto, J. Am. Chem. Soc., 1988, 110, 8164. N Cl N Cl i, S2Cl2, DABCO, 0 °C ii, HCO2H S S Cl O N CHCl2 O Scheme 3 7 8 2 N N3 N N3 i, S2Cl2, DABCO, 0 °C ii, HCO2H S S Cl O N CN O Scheme 4 R2N Cl H N3 9 10 11 [Cl+] R2N Cl H N Cl N2 – N2 – H+ R2N CN Cl Cl R = Pri HCO2H N CN N CN i, S2Cl2, DABCO, 0 °C ii, HCO2H S S Cl O N CN S Scheme 5 R2N C H 12 13 14 R2N S H R2N CH R = Pri N H Cl S SCl SCl CN CN 15 16 – HCl – "S" Scheme 6 N N CHCl2 O i, S2Cl2, DABCO ii, HCO2H 17 18 Et3N i, S2Cl2, DABCO ii, HCO2H Et2N COCHCl 2 Et2N COCCl3 19 20 Received: 18th July 2001; Com. 01/1830