Nuclear chlorination of alkylpyrazines

摘要

J.C.S. Perkin INuclear Chlorination of AlkylpyrazinesBy A. F. Brarnwell, 1. M. Payne, G. Riezebos,' P. Ward, and R. D. Wells, Research Laboratories, ProprietaryPerfumes Limited, Ashford, KentA series of monoalkylpyrazines have been chlorinated specifically in the 3-position with sulphuryl chloride in thepresence of NN-dimethylformamide ; the nucleus of symmetrical 2.6-dialkylpyrazines is also readily chlorinated.The structures of the by-products from some of the reactions have been assigned. The reaction of isobutylpyrazinewith phosphoryl chloride and phosphorus pentachloride was also investigated and gave specifically 2-chloro-5-isobutylpyrazine in 25 yield.THE identification of a number of alkoxy(alky1)pyrazinesisolated from a variety of natural sources (such as oilof galbanum,l bell peppers,2 green peas,3 roasted coffee?and oil of petitgrain 5, has required the synthesis ofseveral groups of model compounds with unambiguousstructures.Halogeno-compounds are convenient start-ing materials for the preparation of such alkoxy-derivatives but until now their application has beenrestricted by the general lack of specific halogenatingagents. For this reason the halogeno-intermediatesrequired have often been derived from hydroxy- oramino-pyrazines.6-8 Amongst the agents suitable fordirect nuclear halogenation which have been investi-gated are chlorine in carbon tetra~hloride,~ bromine inacetic acidJ8* lo bromine in aqueous hydrobromic acid,lla mixture of phosphorus pentabromide and phosphorylbromide,12 phosgene,13 sodium hypoiodite,6 phosphorylchloride (for pyrazine N-oxides 14) , and chlorine orsulphuryl chloride in a number of s01vents.l~ In usingthe last-named reagents, the presence of water has beenshown to affect the position of substitution in thenucleus.For instance, the chlorination of chloro-pyrazine with chlorine in the presence of a water-solublepolar organic solvent containing at least 0.02 mol per-cent of water gives 2,6-dichloropyrazine, whilst lessthan this amount of water results in preferential form-ation of the 2,3-isomer.15 Similarly, the chlorinationof chloropyrazine with sulphuryl chloride in the presenceof NN-dimethylformamide affords specifically, 2,3-di-chloropyrazine; l5 in this instance the sulphurylchloride functions as both chlorinating and dehydrat-ing agent.We have investigated this last procedure for thechlorination of 2-alkylpyrazines and found it to leadspecifically to the 3-chloro-derivative (see Table 1) ;no other isomers were detected by g.1.c.under con-ditions which are known to separate the 2,3- and 2,6-1 A. F. Bramwell, J. W. K. Burrell, and G. Riezebos, Tetra-hedron Letters, 1969, 3215.2 ( a ) R. G. Buttery, R. M. Seifert, R. E. Lundin, D. G. Guad-agni, and L. C. Ling, Chem. and Ind., 1969, 490; ( b ) R. G.Buttery, R. M. Seifert, D. G. Guadagni, and L. C . Ling, J .Agric. Food Chem., 1969, 17, 1322.3 K. E. Murray, J. Shipton, and F. B. Whitfield, Chem. andInd., 1970, 897.4 P. Friedel, V. Krampl, T. Radford, J.A. Renner, F. W.Shephard, and M. A. Gianturco, J. Agric. Food. Chem., 1971,19, 530.R. J. H. Duprey and J. F. Janes, Amer. Perfumer, 1971, 86,No. 9, 53.A. Hirschberg and P. E. Spoerri, J . Org. Chem., 1961, 26,1907.isomers. The chlorination of some 2,6-dialkylpyrazineswas also studied but these were mainly of the sym-metrical type and specificity in these cases was therebyensured see, however, isopropyl(methy1)pyrazine below.The conversion of the chloro-derivatives cited inTable 1 into the corresponding methyl ethers is virtuallyquantitative and also facilitates the isolation of theproducts and by-products. For this reason the yieldsand n.m.r. data quoted in the Table are those of themethyl ethers. The n.m.r. spectra substantiated thestructures unambiguously and also confirmed that theisolated materials did not contain any noticeableamounts of other isomers.It may be seen that ingeneral the yield of 2-alkyl-3-chloropyrazine increaseswith increasing complexity of the 2-alkyl group. I tis interesting that the chlorination of an unsymmetrical2,6-dialkylpyrazine (vix. 2-isopropyl-6-methylpyrazine)results in the preferential formation of the chloro-derivative on the more hindered side.The chlorination and subsequent methoxylation ofisopropylpyrazine yielded, in addition to the 3-methoxy-derivative, by-products (I) and (11) (ca. 50 yield).On similar treatment, isobutylpyrazine gave the 3-meth-oxy-derivative and by-products (111) and (IV) (ca. 10yield) (see Table 2 for n.m.r.data). The formationof these by-products could account for the relativelylow yields of the 3-methyl ethers obtained starting withthese pyrazines.In many cases the crude chlorinated product con-tained a dark polymer-like material, from which thechloro-derivative could be easily separated by steam-distillation. The degree of by-product formation (e.g.,as a result of polychlorination of the nucleus or side-chainchlorination) seemed dependent upon the molar ratiosof reactants and, to a lesser extent, the temperature ofreaction (see later).7 A. E. Erickson and P. E. Spoerri. J. Amer. Chem. SOC.,1946, 48, 400.6 R. C. Ellingson and R. L. Henry, J. Amer. Chem. SOC., 1949,71, 2798.9 U.S.P.s 3,096,331, 1963 and 8,113,132, 1963, but see also W.B.Lutz, S. Lazarus, S. Klutchko, and R. I. Meltzer, J . Org.Chem., 1964, 29, 415.lo B.P.s 928,151, 1963 and 928,152, 1963.l1 H. Brachwitz, E.Ger.P. 66,877, 1969 (Chem. Abs., 969, 71,l2 K. H. Schaaf and P. E. Spoerri, J. Amer. Chem. SOC.,l3 B.P. 927,974, 1963.14 B. Klein, N. E. Hetman, and M. E. O'Donnell, J . Org. Chem.,16 U.S.P. 3,291,802, 1966.124,498d).1949, 71, 2043.1963, 28, 16821972The reaction of s-butylpyrazine with sulphuryl in the presence of NN-dimethylformamide gave com-chloride-NN-dimethylformamide was thoroughly in- pounds (ca. 50 total yield) to which structures ana-vestigated and the optimum conditions (with respect logous to those obtained with isobutyl- and isopropyl-to the yields based on pyrazine consumed) for the pyrazine see (IVa and b) and (11) were tentativelyformation of the 3-chloro-compound were ascertained. assigned by g.1.c.-m.s.By chlorination of 2,6-di-s-The most favourable molar ratio of the pyrazine to butylpyrazine, compounds (V) and (VI) (ca. 25 totalTABLE 1The chlorination of alkylated pyrazines with sulphuryl chloride and NN-dimethylformamide ; n.m.r. data forthe methoxy-derivatives of the principal products (6/p.p.m. ; J/Hz)J ( z t O . 1Yield 6 (ring Hz) (ring 6 6Starting material (yo) a protons) protons) (OMe) (Substituents other than OMe)2-Methylpyrazine 29 6 7.88 2-85 9-94 Me: 2.412-Isoprop ylpyrazine 21 b 7.83 2-85 3.94 Pri: 1-22 (6H, d, J 7), 3.31 (lH, sept, J 7)7.937.982-Isobutylpyrazine 26 b 7.837.962-s-Butylp yrazine 41 b 7-837.992-( l-Ethylpropy1)pyrazine 48b 7.838.022,6-Dimethylpyrazine 31 b 7.97 d2,6-Diethylpyrazine 17 b 7.662,6-Di-s-butylpyrazine 30 b 7-66'28b 7.67 2-Isopropyl-6-methylp~razine 14 7-682-Isopropyl-3-methoxy-6-methyl- 24 C2.85 3.932.75 3.942-70 3.933.913.933.913.913.91Bu': 0.93 (6H, d, J 6.5), 2.18 (lH, complex m), ca.2.64 (2H, complex d)complex m), 3-13 (IH, sext, J 7)Et,CH: 0.76 (6H, t, J 7), ca.14-2.0 (4H, complexm), 2.97 (lH, m, J 7)Me: 2.47, 2.57Et: 1.23 (3H, t, J 7), 1-26 (3H, t, J 7), 2.69 (2H, 9, J 7),2-76 (2H, q, J 7)B U ~ : 0.83 (6H, t, J 7), 1.22 (3H, d, J 7), 1-26(3H, d, J 7), ca. 1.4-2.0 (4H, complex m), 2.71(lH, sext, J 7), 3-14 (lH, sext, J 7)Me: 2-38; Pri: 1-23 (6H, d, J 7), 3.29 (lH, sept, J 7)Me: 2.40; Pri: 1.26 (6H, J 7), 2.95 (lH, sept, J 7)Me: 2.30; Pri: 1.17 (6H, d, J 7), 3.20 (lH, sept, J 7)Bu': 0.82 (3H, t, J 7), 1.19 (3H, d, J 7), 1.3-2.1 (2H,pyrazinec Product chlorinated at the 5-position.0 All reactions were carried out under comparable conditions (see experimental section).b Product chlorinated a t the 3-position.d Data are for the chloride.TABLE 2N.m.r. spectra of by-products (6/p.p.m., J/Hz)6(ringproton)7.878-077.998.0 18.038.097.307.648-208.538.158.4363.984.02sidechain3.25ring3-943.903-923-883.91(OMe)6(Substituents other than OMe)CHXMe-: 2.17 (3H, d, J 0.85; d, J 1.50), 5.52 (lH, m, J ca. 1.5), 6.05 (lH, m, J ca. 1.5)Me,C(OH): 1-49 (6H) 4.76 (1H)Pr'CH(0Me): 0.83 (3H, d, J 7), 0.90 (3H, d, J 7), ccc.2.03 (lH, m, 2-H), 3.94 (lH, d, J 6,l-H)Bu': 0.93 (6H, d, J 6.5), ca. 2.00 (lH, complex m), ca. 2.43 (2H, complex d)Bu': 0.90 (6H, d, J 6*5), ca. 2.03 (lH, complex m), ca. 2.53 (2H, complex d)CH,:CEt: 1-5 (3H, t, J 7), 2-63 (2H, q, J 7, m, J ca. 1.5), 5.29 ( l H , d, J ca. 1.5, t, J ca.Bu*: 0.85 (3H, t, J 7), 1-31 (3H, d, J 7), ca. 1-4-2.0 (2H, complex m), 2-78 (lH, sext, J 7)MeCHXMe: 1-87 (3H, d, J 7, m, J ca. 1.5), 2.08 (3H, m, J ca. 1.5), 6.49 (IH, q, J 7, q,1*5), 5.80 (lH, m, J l)f CU. 1.5)Bi8: 0-84 (3H, t , J 7), 1.28 (3H, d, J 7), ca. 1.4-2.0 (2H, complex, m), 2.77 (lH, sext)sulphuryl chloride appeared to be 1 : 1.2, and any amount yield) were isolated, and analogous products with anof NN-dimethylformamide in excess of 0.25 mol.equiv. unsaturated side-chain were also obtained from s-butyl-seemed to be superfluous but not detrimental to the pyrazine using an excess of sulphuryl chloride.reaction. It was also found that temperatures between Addition of aluminium chloride-sulphur mono-0 and 45" gave essentially the same yields (ca. 40 chloride (l), which is known to catalyse the nuclearbased on converted starting material over 1-3 h). chlorination of toluene by sulphuryl chloride,16 failed to*part from the main product, the Ofs-butylpyrazine with an excess of sulphuryl chloride 16 I. L. Finar, ' Organic Chemistry,' Vol. 1,3rd edn., Longmans,1959, p. 519J.C.S. Perkin Iincrease the yield of 2-chloro-3-methylpyrazine. At-tempts to retard that part of the side-chain chlorin-ation which might have resulted from a free radicalOMe OMe( IYa,b 1 ( 2 isomers 1 cm 1mechanism by the addition of sulphur or iron(II1)chloride had no apparent effect, as did performing thereaction in the absence of light.A further study of the mechanism of the chlorinationwas based on the work of Hasserodt,17 who suggestedthat the complex formed when sulphuryl chloride reactswith NN-dimethylf ormamide gave an equilibriummixture of the species (VII) and (VIII).Eliminationof sulphur dioxide to give the acid chloride (IX) isbelieved to progress via the cation of species (VII)by pyrolysis, which may be base-catalysed; a similarelimination of sulphur trioxide via the cation (VIII)is assumed to give the chloride (X).Although thetemperatures applied in our work were not conduciveto the reaction (VII) (IX), the presence of base(it?. the pyrazine derivative) means that at least fivespecies might have been responsible for the actualMe CLMe Hc1-0 so*c1-chlorination, viz. the cations of (VII) and (VIII), theacid chloride (IX), and the anions C1- and OSO,Cl-.The acid chloride (IX) was prepared,17 but did noteffect any detectable chlorination of s-butylpyrazineunder the given conditions. The cation of species(VIII) has been shown to be present in the complexformed between thionyl chloride and NN-dimethyl-formamide; however, the use of this complex underconditions identical to those of our experiments, gaveno chlorination.Species (VIII) represents an especiallyactive salt of chlorosulphonic acid, the anion of whichwas prepared by the neutralisation of chlorosulphonicacid with trimethylamine this base was selected togive a cation which would resemble that of the saltThis product however, did not chlorinate s-butyl-pyrazine and, since the chloride ion is unlikely to bethe chlorinating agent, it would appear reasonable thatthe cation of species (VII) is mainly responsible for thechlorination.During an investigation of the use of other dipolaraprotic solvents in place of NN-dimethylf ormamide forthe chlorination of s-butylpyrazine, it was shown that(a) no specific chlorination occurs in the absence of adipolar aprotic solvent, ( b ) N-methylpyrrolid-2-oneand acetic anhydride were less efficient (yielding 28and 15 of the 3-chloro-derivative respectively), and(c) with acetonitrile and NN-dimethylacetamide theconversions were extremely low.An interesting change in the selectivity of the reactionwith temperature was noticed with isobutylpyrazine.In this case an increase in the temperature of the re-action from 45 to 75" resulted in an increase in the yieldof the 2,5-isomer from 1 to 13, although the yield ofthe 2,3-isomer remained virtually unchanged (at 0"the 2,5-isomer was not detected).During the course of our investigation of otherpotentially-specific chlorinating agents, it was foundthat the reaction of isobutylpyrazine with a mixture ofphosphoryl chloride and phosphorus pentachloride gave2-chloro-5-isobutylpyrazine (25) with no detect ablequantities of the other isomers.A similar result wasobtained with s-butylpyrazine, but in this case theyield was very low (ca. 1) although the majority ofthe starting material was consumed. The scope of thisreaction has not yet been investigated but it couldprovide a means for the specific preparation of the2,5-isomers.The structures of the compounds were establishedfrom n.m.r. data (see Tables 1 and 2).(VIII).EXPERIMENTALN.m.r. spectra were obtained at 60 MHz with a VarianA60A instrument for carbon tetrachloride solutions.Analytical g.1.c. was performed with a Pye 104 instrumentwith 9 f t glass columns packed with Apiezon L (3 +0.3 FFAP on Chromosorb GI 100-120 mesh), FFAP(3 on Chromosorb G) or E.G.A.(3 on Chromosorb G).All solvents were reagent grade or better. Appropriatemass spectral data were obtained for all compounds,17 U. Hasserodt, Chew. Ber., 1968, 101, 1131972and are listed in Supplementary Publication No. SUP20444. *2-IsobutylpyrazineJ 2-s-butylpyrazine, 2-isopropylpyr-azine, and 2- ( 1-ethylpropy1)pyrazine were prepared by thealkylation of 2-methylpyrazine according to the generalmethod described in the literature.l8 2-Isopropyl-6-methyl- and 2,6-di-s-butyl-pyrazine were prepared by thealkylation of 2-methyl- and 2-s-butyl-pyrazine, respectively,with acetone and ethyl methyl ketone.l9The following experimental procedure may be regardedas typical of the technique employed for the chlorinationof alkylpyrazines.2-ChZoro-3-s-butyZfiyrazine.-Sulphuryl chloride (397 g,2-94 mol) was added dropwise to a stirred mixture of2-s-butylpyrazine (400 g , 2-94 mol) and NN-dimethyl-formamide (249 g, 3.41 mol) during 2 h.The rate ofaddition was such as to maintain the temperature ofthe reaction a t 45 amp; 5". The reaction was exothermic anda cooling bath a t ca. 20" was employed. When the re-action was complete, the mixture was cooled to below40" and water (600 ml) was added cautiously, whilst keepingthe temperature below 40O.t The pH was adjusted to7.0-8.0 with aqueous sodium hydroxide (450 ml, 50w/w), the temperature again being maintained below 40".The alkaline mixture was steam-distilled and the distillatewas extracted with chloroform (3 x 50 ml).The com-bined extracts were dried and evaporated in vacuo to givethe crude product (350 g) which was shown (g.1.c.) to con-tain 2-chloro-3-s-butylpyrazine (173 g, 34) and un-changed s-butylpyrazine (80 g, 20). These componentswere easily separated by distillation, but in general thesteam-distilled product was methoxylated directly.2-Methoxy-3-s-butyZpyrazine.-The crude 2-chloro-3-s-butylpyrazine (350 g) was heated under reflux with asolution of sodium methoxide (3.1 mol) in methanol (500* For details of Supplementary Publications, see Notice toAuthors No. 7 in the index issue of J . Chem. SOC. ( A ) , 1970. t This method of quenching was found to be more convenientthan addition to water.Vigorous reaction is often preceded by a long inductionperiod when the mixture is poured cautiously into iced water.2007ml) for 6 h.The mixture was filtered to remove sodiumchloride and the excess of methanol was removed in vacuoprior to the addition of water (100 ml) and extractionwith light petroleum (3 x 50 ml). The combinedextracts were washed to neutrality with water(6 X 50 ml), dried, and, after removing the solvent, thecrude product (292 g) was obtained. This contained(g.1.c.) 2-methoxy-3-s-butylpyrazine (160 g, 33) and2-s-butylpyrazine (76 g, 19). Fractionation through acolumn (90 cm) packed with glass helices gave 2-s-butyl-pyrazine (64 g, 16) and 2-methoxy-3-s-butylpyrazine2-lsobutyZ-5-methoxy~yrazine.-2-Isobutylpyrazine (68 g,0.5 mol) was added dropwise to a stirred mixture of phos-phorus pentachloride (109 g, 0.55 mol) and phosphorylchloride (300 ml, 1.2 mol) and the mixture was heated a t95 f 5" for 8 h. The mixture was quenched by thecautious, dropwise addition of water (150 ml), whilstmaintaining the temperature at 20" with external cooling.The pH of the mixture was adjusted to 9-0 with aqueoussodium hydroxide (50 w/w) before steam-distillationand extraction of the distillate with ether. The combinedextracts were dried and the solvent was removed in vawoto give the crude product. G.1.c. showed that only onepositional isomer had been formed, i.e. 2-chloro-5-isobutyl-pyrazine.The crude chloro-derivative was methoxylated as de-scribed already. Fractionation of the crude product(145 g) through a column (100 cm, glass helices) gave2-isobutyl-5-methoxypyrazine (17 g, 2 1 yield) and 2-iso-butylpyrazine (1 7 g, 25 recovery).We thank Mr. D. A. Brown for helpful discussions,Mr. B. G. Clayson for assistance with some of the experi-ments, and Mr. R. A. Lucas for the measurement andinterpretation of the mass spectra.(151 g, 31).2/424 Received, 24th Februavy, 19721J. D. Behun and R. Levine, J . Org. Chem., 1961, 26, 3379.Is A. F. Bramwell, L. S. Payne, G. Riezebos, P. Ward, andR. D. Wells, J . Chenz. SOC. ( C ) , 1971, 1627