摘要:

J.C.S. Perkin I Quinones. Part 9.l Side-chain Alkylthiolation of Methyl-I ,4-naphtho- quinones By Ronald H. Thomson * and Roger D. Worthington, Department of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen A69 2UE, Scotland 2-Methyl-1,4-naphthoquinones react with an excess of sodium methanethiolate to give methylthiomethyl derivatives. Corresponding products were obtained, but in lower yield, using a-toluene- and toluene-p-thiolates. With 3-chloro-2-methyl-l,4-naphthoquinoneand methanethiolate, replacemsnt of chlorine occurs before reaction with the side chain, while the minor products formed provide evidence that the side-chain alkylthiolation proceeds by addition of thiolate to the tautomeric quinone methide form of the methylquinone. IN connection with previous work on the structure of caldariellaquinone we synthesisecl 6-methyl-5-methyl-tliiobcnzo[b] thiophcn-4,7-quinone (1) by the reaction of 5-bromo-6-methylbenzo[b]thiophen-4,7-quin~1newith a small excess (14%) of sodium methanethiolate.A minor product of this reaction was fouiid later to be 5-methyltliio- (6-methyl thiomet hyl)benzo[ b] thiophen-4,7-quinone (2). The structure of (2), CllH1002S3,was evident from the n.m.r. spectrum which comprised two S-methyl singlets at 6 2.63 and 2.18, a methylene singlet at 6 3.90,and two doublets at 6 7.62 and 7.54 arising from the thiophen-ring protons. As the formation of (2) in-0 0 0 0 (3) 0 0 0 0 (4) (5) HO (6) (7) volves both nuclear and side-chain metliylthiolation, which is new, the reaction was studied further using more readily available quinones.RESULTS 3-Chloro-2-methyl- 1,4-naphthoquinone reacted with so-dium methanethiolate (1.66 mol equiv.) at rooin temperature to give mainly 2-methyl-3-niethylthio-1 ,Cnaphthoquinone (3). The minor products did not include the di-methyl- tliiolated product (4) but this was detected (t.1.c.) when 2 md of sdium methanetliiolate were used. Using a large excess of niethanethiolate (10 mol equiv.) (4)was formed in 21y0 yield, better yields (51%) being obtained when 2-methyl-3-niethylthio- 1,4-naphthoquinone (3) was used as starting material. The structure of (4) was deduced from analytical and spectroscopic data (see Experimental section) and was confirmed by synthesis from 3-chloro-2- chloromethyl- 1,4-izaphthoquinone and the same reagent.The minor products formed in the above reactions in- cluded the dinieric compounds (5) and (6). The n.ni.r. spectrum of the biquinone (5), C,,H,,O,S,, displayed singlets at 6 3.21 (-CH,CH,-) and 2.40 (2 SMe) whereas the 0-methyl analogue 3 resonates at 6 2.88 and 4.00. The red xanthene (6), C,,H,,O,S, showed A,,,. 478 nm, w,,,. 3 360, 1702 (C-13 >GO), and 1 654 ciii-l, and 6 8.41 (H-7), 7.30 (HO), 2.32 (SMe), and 1.58 (C-13a Me), ancl was generally very similar to the xanthene (6; Me in place of SMe) [cf. A,,,,. 486 nm, v,,,,. 3 370, 1 709, ancl 1 650 cin-l, and for the acetate 6 7.95 (H-7), and 1.57 (C-13a Me)]. When a solution of 3-c~iloro-2-methyl- 1,4-naplithoquinone and a large excess of sodium niethanethiolate was left in a stoppered flask for two days, relatively little reaction ensued, giving low yields (< loo/) of (3) and (4).However another minor product was isolated which we regard as the dihydro- pentap1ienediquinr)ne (7). It showed characteristic 1,4-naphthoquinone U.V. and i.r. spectra (A,,,a,. 251 and 333 nni, wlnaY. 1675 and 1660 cm-l), and a typical 1,4-naphtho- quinone n.1n.r. spectrum at low field in addition to a singlet (4H) at 6 2.88 (CDCI,) or 3.03 (CF,CO,D) [cf. (5; Et in place of SMe), 6 (CDCl,) 2.80 (4 H, s) and (CF,CO,D) 3.051. In the mass spectrum the molecular ion is very weak with the base peak at vn/e 338 (Mf-2), corresponding to penta- plienediquinone, followed by successive losses of four mole- cules of carbon monoxide from M+-2. Easy aromatis- ation of the central ring of (7) is not surprising although it would be opposed by increased steric interaction between the C-13 and C-14 oxygens.Initially we considered that this biquiiione might be the isomer (S), as its dehydro- derivative, pentacene-5,14 : 7,12-diquinone, can be ob-tained from 3-chloro-2-methyl- 1,4-naphthoquinone on treatment with N-methylcyclohexylamine but the observed methylene resonance is at too high field. When 2,3-dimethyl-1,4-naphthoquinonewas left for a few hours with a large excess of sodium methanetliiolate (30 mol) the di-methylthiolated product (10; iil = Me, R2 = H) was obtained in good yield.Using a smaller excess of reagent (10 mol) and restricted access of air led to the formation of a mixture of the mono- (9; R = Me) and di-metliylthiolated (10; R1= Me, R2= H) compounds. The structures of these quinones were confirmed synthetic- ally by nucleophilic substitution of 2,3-dichloromethyl- and 3-chloromethyl-2-methyl-1,4-naphthoquinones with sodium methanethiolate. Similarly, 2,3,6-trimethyl- 1,4-naphtho- quinone gave a good yield of the corresponding di-methyl- (10; R1= Me, R2 = H) was treated with piperidine (2 mol) 0 0 in order to obtain the bis(aminomethy1)quinone (12) or its more stable quinol.6 Five coloured products were formed, CH2SMe the major one being the pale yellow diformylquinol (13) large excess of sodium toluene-pthiolate was similar although yields of (9; R = p-MeC,H,) and (10; R1= p-MeC,H,, R2 = H) were somewhat lower and more by-products were observed.The two p-tolylthiomethyl derivatives were also prepared from the appropriate chloro- methylquinone by nucleophilic substitution by toluene-p- thiolate. In the mass spectrum of the bis-(p-tolylthio- methy1)quinone the base peak appears at vnle 273 (M+-C,H,S,) , probably corresponding to a tetracene derivative for which several structures can be written. It was desirable to relate the products from side-chain alkylthiolation to those obtained by side-chain amination.6 To this end 2,3-bis(methylthiomethyl)-l,Cnaphthoquinone 0 0 (10) (11) thiolated quinone (10; R1= R2 = Me) whereas 3-ethyl-2- methyl- 1,4-naphthoquinone reacted exclusively on the methyl side chain to give the methylthioniethyl derivative (11).Reactions with two other thiolates were examined briefly. 0 ?H OH (13) OH (15) 0 OH 0 (16) (17) 0 0 Ph (19) With sodium a-toluenethiolate, 2,3-dimethyl- 1,4-naphtho- quinone gave a mixture of (9; R = PhCH,) (mainly) and (10; K1 = PhCH,, R2 = H); even after heating at 55-60 "C with a 20-fold molar excess of reagent and then leaving overnight, some unchanged starting quinone remained.The reaction of 2,3-dimethyl-l,4-naphthoquinonewith a [vCo 1640 cm-l, 6 13.55 (HO) and 10.55 (CHO)]. Several routes to (13) are possible, one of which proceeds by hydroly- sis of the tetrasubstituted quinol (14).The analogue (15) was previously obtained by oxidation of (16) with a limited amount of chromic acid. The reaction of 2,3-bis(methylthiomethyl)-1,4-naphtho-quinone with dimethylamine was even more complex, but methylamine gave one major product identified as the iso- indolequinone (17) [VCO 1 657 cm-l, 6 7.36 (2 H, s, H-1 and -3)]. The reaction presumably proceeds by oxidation of the quinone (18) formed by nucleophilic displacement of both methylthio-groups in (10; R1 = Me, R2 = H). A similar intermediate compound is probably involved in the formation of the isoindolequinone (19) on treatment of 3-benzyl-2-inethyl-l,4-naphthoquinonewith t-butylan~ine.~ DISCUSSION This new side-chain alkyl(ary1)thiolation reaction bears an obvious resemblance to the side-chain amination of alkylated quinones,6p8 a reaction that is effected by leaving the quinone in contact with an excess of a second-ary aliphatic amine, with or without solvent, the product being the quinol, e.g.(20) from 2,3-dimethyl-1,4-naph- 0 0 II OH0 thoquinone, which is usually isolated by removal of solvent and the excess of amine. This difference in end- product is not of great significance as some of our reaction solutions showed relatively little colour prior to work-up, more colour developing, i.e. oxidation of quinols to quinones, during the isolation procedures. We regard the alkylthiolation as a three-step process (Scheme l),the thiolate acting first as a base to remove a proton from an a-carbon atom, and secondly as a nucleo-phile by conjugate addition to the quinone methide so formed to give the quinol dianion which is finally oxidised, mainly by air, although the starting quinone is no doubt involved to some extent.That oxygen is required for the oxidation step(s) was readily demon- strated by allowing the reaction to proceed in a stop-pered flask. Yields of thiolated products were invariably low, and when 2,3-dimethyl-1,4-naphtlioquinonewas treated with 10 mol of sodium toluene-fi-thiolate in that way scarcely any side-chain reaction occurred. How-ever, when the stopper was removed, allowing free access 0 0 0 / 0 0-0-repeat(9) -(10) SCHEMEI of air, the reaction continued in the normal way.The conversion Q-Me Q-CH,SR requires two mol of thiolate but in practice a substantial excess is required in order to obtain a good yield since quinone methide anions can react in other ways 899 (e.g. with themselves or with the protonated species), and some thiolate is inevitably consumed by oxidation (by air and starting quinone) to disulphide. This may be offset to some extent by a competing reaction, Q-CH,- + RSSR-RQ-CH,SR + RS-, but for $-tolylthiolation, at least, this is not important as very little of (9; R = $-MeC,H,) and (10; R1= $-MeC,H,, R1 = H) were formed when 2,3-dimethyl-l,4-naphthoquinonewas treated with so-dium niethanethiolate (1 mol) and di-$-tolyl sulphide (10 mol). Thus the thiolate anions are involved in three reactions, proton abstraction, nucleophilic addition, and oxidation, all of which relate to the electron density on sulphur.It is therefore not surprising that the side- chain reaction proceeds most efficiently with methane- thiolate and least with toluene-$-thiolate (cf. pK, values, MeSH 10.3, PhCH,SH 9.43, fi-MeC,H,SH 7.08).1° In the reactions of a-toluene- and toluene-fi-thiolate with 2,3-dimethyl-l,4-naphthoquinone,yields of dialkyl-(aryl) thiomethylquinones (10) were less than 15yo and much starting quinone remained at the end of the reaction period. If the reaction with toluene-fi-thiolate was prolonged the P-tolylthiomethylquinones (9; R =$-J.C.S. Perkin I MeC,H,) and (10; R1= p-MeC,H,, RZ= H) gradually disappeared with concomitant consumption of all the starting quinone and the appearance of two more polar products which have not bcen examined.The course of the side-chain reaction is also influenced by the redos potential of the alkylated quinone which affects the extent of thiolate oxidation, and by the nature of the alkyl side chains. In one example, methylthiolation of 3-ethyl-2-methyl-l,4-naphthoquinonegave the isomer (11) only, which is consistent with the greater acidity of the methyl compared to the methylene group, formation of the primary anion (Q-CH,-) being preferred. Similar observations have been made in other reactions involving quinone a-carbanions where ethyl groups are usually inert3*11 The participation of quinone methide tautomers in the reactions of alkylated quinones has frequently been invoked although they have never been directly detected in these reactions.Recently, Russian workers l2 have been able to isolate the diphenylmethylquinone (21) in both its quinone methide (22) and diketo (23) tauto- meric forms. However, this is a very favourable case, and the isolation of a quinone methide (24) derived from a simple methylquinone is unlikely. (4-Benzyl-1,2-naphthoquinone has also bcen isolated in a tautomeric form which in that case is a $-quinone nietliide.13) In-direct evidence for the participation of (24) or its anion, in our experiments comes from the minor products isolated from the reaction between 3-chloro-2-methyl- 1,4-naphthoquinone and sodium methanethiolate, namely (5) and (6).(Minor products. were observed in most of the alkyltliiolation reactions but were not investigated.) The xanthene (6) arises (Scheme 2) by cycloaddi- tion 9b914915 of the quinone methide (26a; R = MeS) to the precursor quinone (25; R = C1 or MeS) followed by elimination of hydrochloric acid or methanethiol. The product described in tlie Experimental section is the xantliene (6) but on one occasion we also isolated a trace of the red chloroxanthene (6; C1 in place of MeS) (C,,Hl,C1O, by accurate mass measurement). The dimer (5)is most probably formed by Michael addition of the carbanion (26b; R = MeS) to the quinone methide, followed by oxidation tor which there is ample prece- dent.3316 It is not known whether this conjugate addition involves the quinone methide or its anion (as written), as (5) was isolated when the reaction with 3-chloro-2-meth yl- 1,4-n aph thoquinone was conducted with less than 2 mol of sodium methanethiolate, but it seems likely that the anion takes part in the preparative side- chain alkylthiolations (Scheme 1) where a large excess of thiolate was employed.Tlie formation of the dimeric compounds (5)and (6)could be detected when only 1mol of thiolate was used with 3-chloro-2-methyl-l,4-naphtlio-quinone showing that some attack had occurred on tlie methyl group, but subsequent addition of RS-to the quinone methide did not occur in the absence of an excess of reagent, the product being mainly 2-methyl-3- methylthio-I ,4-izaphthoquinone resulting from normal nucleophilic displacement.The other very niinor pro- duct (7) obtained from one of these reactions probably is not formed directly from a quinone methide, and we speculate that it derives from the biquinone (5)by further reaction with thiolate (Scheme 3) to give the penta- -RH Ia -(6) OH (25)+ 0 0-0 (a) (5) SCHEME2 phenediquinone (27). Reduction of the 6,7-double bond, which would relieve the steric interaction of the C-13 and C-14 carbonyl groups, could occur by a redox reaction with thiolate followed by rearrangement of the mono- quinol (or its dianion). EXPERIMENTAL Spectra were measured in ethanol (u.v.), KBr (i.r.), or deuteriochloroform (n.m.r.) unless stated otherwise.Sodiztm Methanethio1ate.-This was prepared by passing an excess of methanethiol gas through niethanolic sodium methoxide, and evaporating the solution to dryness in vacuo. The deliquescent white solid was stored in a desic-cator. 5-~lethylthio-6-(methylthiomet~~yl)benxo[b]thiophen-4,7-quinone (2).-The reaction of 5-bromo-6-methylbenzo[b]-thiophen-4,7-quinone and sodium methanethiolate to give 6-methyl-5-methylthiobenzo[b]thiophen-4,7-quinoneis de- scribed in ref. 2. Elution of the minor orange band which separated on preparative t.1.c. afforded the methylthio-(methy1thiomethyZ)quinoneas orange-red needles, m.p. 158- 159' (from ethanol) (3%) (Found: M+, 269.984 0. C,,H,,-O,S, requires M, 269.984 2) ; Amax.239, 275, 330, and 467 nm (log E 4.19, 3.88, 3.80, and 3.29); vmax. 1 660 and 1 638 cm-l; 6 7.64 and 7.54 (each 1 H, d, J 5 Hz, H-2 and -3), 3.90 (2 H, s, Q-CH,-S), 2.63 (3 H, s, Q-SMe), and 2.18 (3 H, s, CH,-SMe); m/e 270 (M', 50%), 255 (50),240 (47), 224 (45), 223 (50),222 (loo), 209 (€9, 190 (18), 139 (7), 111 (lo), and 110 (13). Reaction of 3-Chloro-2-methyl- 1,4-nafihthoquinone with Sodium Methanethio1ate.-(i) Sodium methanethiolate (0.56 g, 1.66 mol) in methanol (5 ml) was added to 3-chloro-2- methylnaphthoquinone (1 g) in benzene (20 ml) and methanol (10 ml). The mixture was stirred for 1h and then evaporated. The residue was separated on silica gel, eluting with benzene containing increasing amounts of MeS-(5) -0 /0 0 (27) SCHEME3 chloroform, to give 2-methyl-3-methylthio- 1,4-naphtho- I quinone (3) as yellow needles, m.p.91-92" (lit.,,' 91-92') (from ethanol) (0.55g); 6 2.66 (3 H, s, SMe) and 2.31 (3 H, s, Q-Me). Further elution with light petroleum (b.p. 60- 80')-ether gave a fraction which was separated by prepara- tive t.1.c. on silica gel in ethyl acetate-benzene (1 : 19), followed by ethyl acetate-light petroleum (1: 4), into 8,13- dihydro-5-hydroxy- 1 3a-methyl- 6-methyZthi0-8,13-dioxodi-benzo[b,h]xanthen (6) as red prisms, m.p. 190-191" (de-conip.) (from chloroform-light petroleum) (36 mg) (Found : M+, 338.076 5. C,,H,,O,S requires M, 338.076 9) ; A,,,. 248, 265sh, 312sh, 319, 350sh, and 478 nm (Iog E 4.37, 4.23, 4.10, 4.12, 3.74, and 3.82); vmax.3 360, 1 702, 1 654, and 1 590 cm-l; 6 8.41 (1 H, s, H-7), 8.56-8.16, 7.92-7.78 and 7.80-7.66 (total 8 H, m, ArH), 7.30 (1 H, s, exchanges with CD,OD, OH), 2.32 (3 H, s, SMe), and 1.58 (3 H, s, C-13a-Me); m/e 388 (M+,40./,), 373 (lo), 342 (40), 341 (loo), 312 (8), 105 (16), and 77 (14) ; and 1,2-bis-(3-methylthio-1,4-naphtho-quinon-2-yZ)ethnne (5)as yellow needles, m.p. 203' (from chloroforni-light petroleum) (10 mg) (Found: Mf,434.065 1. C,,H,,O,S, requires M, 434.064 7) ; S 8.12-7.96 and 7.75-7.60 (each 4 H, m, ArH), 3.21 (4H, s, Q-CH,), and 2.40 (6 H, s, SMe); m/e 434 (Mt, loo%), 387 (17), 372 (26), 371 (13), 218 (l6), 217 (32), 189 (5),184 (71, 115 (9), 105 (lo), 85 (13), 83 (23), and 76 (13). (ii) A mixture of 3-chloro-2-methyl- 1,4-naphthoquinone (0.2 g), sodiuni methanethiolate (0.7 g, 10 mol) in benzene (5 ml), and methanol (10 ml) was stirred under a drying tube for 4 h and poured into a mixture of ether (50 ml) and 10% w/v potassium dihydrogen phosphate-water (50 nil).The organic phase was dried (MgSO,) and evaporated, and the residue separated by preparative t.1.c. on silica in ben- zene. The upper orange band was removed to give 3- nzethyltl~io-2-(mnethylthiomethyJ)-1,4-naPhthoquinoneas orange needles, m.p. 128-129" (from ethanol) (48 mg) (Found: C, 59.3; H, 4.8; S, 24.6%; Mt, 264.027 7. Cl,Hl,O,S, requires C, 59.1; H, 4.6; S, 24.3%; M, 264.027 8); A,,, 250~11, 261, 323, and 434 nm (log E 4.16, 4.21, 3.56, and 3.36); v,lidlx.1 660, 1 650, and 1 590 cn-l; 8 8.15-8.0 and 7.76- 7.64 (each 2 H, ArH), 3.93 (2 H, s, CH,SMe), 2.67 (3 H, s, Q-SMc), and 2.18 (3 H, s, CH,SMe); wile 264 (loo%), 249 (63), 236 (5), 245 (8), 234 (loo), 218 (50), 217 (56), 216 (loo), 203 (ll), 189 (lo), 184 (13), 128 (8), 115 (14), 113 (14), 105 (lo), 104 (lY), ancl 76 (40).(iii) To a solution of 3-chloro-2-methyl- 1,4-naplitlio- quinone (0.5 g) in benzene (8 nil) was added sodium niethanethiolate (1.75 g, 10 mol) in methanol (18 ml). The flask, almost full, was left stoppered for 50 h. Benzene (80 nil) and 1Oo/, w/v potassium dihyclrogen pliosphate- water (100 nil) were added and the organic phase was washed with water, dried (MgSO,), and evaporated. The residue (264 nig) was separated by preparative t.1.c. on silica gel in benzene into 2-1iiethyl-3-1iietliyltliio-l,4-naplitlioquit~on~(3) (33 mg), 3-methylthio-2-( met1iylthiometliyl)- 1,4-napli tho- quinone (4) (55 mg), and 6,7-diJzydvopenta~I~ene-5,14: 8,13-diquinone (7) as yellow prisms, subl.250-260" (8 mg) (Found: A/l+ -2, 338.057 9. C,,HL,O, requires 111 -2, 338.067 9); Ar,l:ky, (CHC1,) 251, 270~11,295sh, and 333 nm (log E 4.38, 4.24, 4.11, antl 3.76); v,,;,,. 1 675, 1 660, and 1 694 ctii l; 6 8.20-8.08 and 7.82-7.70 (each 4 H, m, ArH), and 2.88 (4 H, s, H-6 and -7); m/e 342 (2%), 340 (M', 3.5),339 (14),338 (loo), 310 (35), 282 (28), 254 (16),226 (9), and 224 (8). Reaction oj 2-Methyl-3-~nethyZLJzio-1,4-naplztlaoquinone witlb Sodium iWetlzanethiolate .-2-Methyl- 3-niethylthio- 1,4-naph- thoquinone (120 nig) in benzene (3 ml) waLs stirred with sodium inetlirtnetliiolate (390 nig, 10 mol) for 4 h in a flask protected by a drying tube. Tlie mixture was poured into ether-aqueous potassium cliliydrogen phosphate and the ethereal layer was washed with water, dried (MgSO,), ancl evaporated. The residue was crystdlised from ethanol to give 3-methylthio-2- (methylthiomethy1)- l14-naphthoquin- one (4),m.p.128-129" (74 nig), identical with that obtained above. This compound was also obtained by stirring 2-chloro-3- chloromcthyl-l,4-naphthoquinone (34 ing) in benzene (2 ml) with sodium methanethiolate (19.4 ing) in methanol (1 ml) for 24 h. Tlie mixture was filtered atid evaporated, arid the residue purifietl by preparative t.1.c. on silica gel in chloroform.The main orange baiicl afforded 3-metliylthio- 2-(niethylt~iiomethyl)-l,4-naphthoquinone(4) as yellow needles, 11i.p. 128-129" (from ethanol) (15 mg), identical with tliat obtained above. Reaction of A llrylnled 1,4-Nnplathoqui~zonrs with Sodium Metlianethiolate.-( i) 2,3-Dimethyl- lf4-naphthoquinone (0.508g) in benzene (10inl)was stirred with sodium rnethane- thiolate (3.82 g, 20 mol) in methanol for 12 11 in a flask protected by a drying tube. The mixture was added to benzene (50 ml) arid aqueous potassium dihytlrogen plios-phate, and the organic phase was washed with water. drietl, J.C.S. Perkin I and evaporated to give a crystalline residue (0.67 g). Crystallisation from ethanol gave 2,3-bis(inethyZt,bziomet/Lyl)-1,4-naphthoquinone (10; R1= Me, It2= H) as orange-red needles, m.p.85-86" (0,43 g) (Found: C, 60.3; H, 5.3; S, 22.876; fW+, 278.043 2. C,,H,,O,S, requires C, 60.4; H, 5.05; S, 23.0.4; M, 278.043 4); 252.5, 267, 273.11, and 335 nrn (log E 4.19, 4.15, 4.14, and 3.50); 6 8.12-4.06 and 7.80-7.67 (each 2 H, A$,, ArH), 3.78 (4H, s, Q-CH,-S), and 2.19 (6 H, s, SMe); wz/e 278 (fV', 8?4), 231 (lG), 230 (28), 216 (lo),215 (loo), 184 (5), 128 (5),and 76 (6). (ii) The above experiment was repeated in a stoppered flask for 2 days using half the amount of sodium methane- thiolate (10 mol). Tlie residue after work-up was separated by preparative t.1.c. on silica gel in benzene followed by ethyl acetate-light petroleum (1: 9).The main bancl was passed clown a column of silica gel in etlier-petrol (1 : 9) to give 2-methyl-3-met~~yltliioinetl~yl-1,4-nap/~thoquinone(9; l< = Me) as yellow needles, m.p. 61.5-G2" (from light petroleum-ethanol) (48 mg) (Found: C, 67.2; H, 5.3; S, 13.8%); M+, 232.055 5. C,,H,,O,S requires C, 67.2; H, 5.2; S, 13.80/; M, 232.055 8); A,,,,,. 252, 265-272, and 329.5 nni (log E 4.16, 4.15, and 3.51); v,,,,~,. (KHr) 1660, 1614, and 1594 cm-l; 6 8.15-8.02 and 7.76-7.63 (each 2 H, m,ArH), 3.72 (2 H, s, Q-CH,-S), 2.24 (3 H, s, SMe), 2.15 (3 H, s, Q-Me);m/e 232 (M, 75%), 217 (as), 187 (7), 186 (loo), 185 (25), 158 (16), 157 (18), 129 (ll),128 (28), 127 (ll),105 (9), 77 (ll),and 76 (20); and 2,3-bis(metliyl- thiomethy1)- 1,4-naphthoquinone, n1.p.85-86" (97 rng), identical to that obtained in (i). Another fraction (159 mg) containing more (9; I< = Me) and (10; R1= Me, It2 = H) was not purified further. 2-Methyl-3- (methylthiornethyl ) -1,4-naphthoquinone was also prepared from 3-chloromctl~yl-2-niethyl-1,4-naphtho-quinone l8 (0.64 g) in benzenc (13 ml) by stirring with sodium metlianethiolate (0.2 g) in methanol (3 nil) for 24 h. After filtration and evaporation, the residue was purified by preparative t.1.c. on silica gel in benzene, the main yellow band (0.41 g) yielding the desired quinone, m.p. 61.5-62', identical to that obtained abovc. 2,3-Bis(methyltliio-rnetliyl)-1,4-naphthoquinone(10; R1= Me, 1<,= H) was obtained siniilarly from 2,3-bis(chloromethyl)-1,4-naphtho-quinone.18 The crude product crystallised from ethanol as orange-red needles, n1.p.85 -86', identical with those ob- tained in (i). (i ii) 2,3,6-'l'riniethyl- 1,4-naphthoqu inone (0.264 g) in benzene (7 nil) was treated with sodium inethanethiolate (1.84g, 20 mol) in the usual way. Work-up ancl preparative t.l.c., gave 6-naetlzyl-2,3-bis(tnethylthiol.netlzylo-quinone (10; lil = R2 = Me) (280 nig) as orange needles, 1n.p. 93-93.5" (from chloroform-liglit petroleum) (Found : C,, 61.8; H, 5.7; S, 22.0:4,; lWt, 292.059 2. C,,Hl,02S, requires C, 61.6; H, 5.5; S, 21.9%; &I, 392.059 1); 6 7.97(1H,d,J8Hz,H-8),7.88br(lH,s,H-5),7.49(1H,cld, J 8 and 2 Hz, H-7), 3.76 (4H, s, Q-CH,-S), 2.43 (3 H, s, 6-Me), and 2.18 (6 H, s, SMe); 192/e 292 (MA,7O/,), 246 (lo), 245 (53),244 (71), 231 (lo), 230 (37), 229 (loo), 199 (7), 198 (2l), 171 (LO), 119 (15), 118 (7), 115 (ll), and 89 (10).(iv) As in (iii), 3-ethyl-2-methyl-l,4-nxphthoquinone (0.19 g) l9 in benzene (4 ml) was stirred with sodium tnstlianethiolrtte (0.69 g) in methanol (8.5 nil) for 4 11. Work-up gave 2-etJzyl-3-(metkzyZtlzioi~etlzyl)-l,4-naphthoquin-one (11) (0.19 g) as crange-yellow needles, m.p. 63.5---64" (from light petroleum) (Found: C, 68.3; H, 5.9; S, 13.0%; Mt, 246.071 7. C,,H,,O,S requires C, 68.3; H, 5.7; S, 23.0°/,; AZ. 246.071 3); 8 8.14-8.02 and 7.75-7.62 (each 2 H, A,U, 111, ArH), 3.71 (2 H, s, Q-CH,-S), 2.70 (2 H, q, J 8 Hz, Q-CH,Me), 2.20 (3 H, s, SMe), and 1.18 (3 H, t, J 8 Hz, CH,Me); ln/e 246 (M+, 8%), 200 (21), 199 (17), 198 (loo), 197 (13), 128 (8), and 76 (12).'l'he identical quinone was obtained by leaving a mixture of 3-chloro-methyl-2-ethyl- 1,4-naphthoquinone l8 (78 mg) and sodium methanethiolate (24.5 nig) in benzene-methanol overnight. The product, needles, had m.p. 63.6-64". Reaction of 2,3-Di~izethyZ-l,4-naphtlioquinonewith Tliio-lutes.-(a) Sodium a-toluenethiolate was prepared by adding cr-toluenethiol (9.87 g) to sodium niethoxide (from 1.744 g sodium, 15 rnol) in methanol (60 ml). This solution was aclded quickly to 2,3-dimethyl- 1,4-naphthoquinone (0.94g) in benzene (20 nil). The mixture was stirred under a drying tube for 8 11, and then poured into ether-aqueous potassium dihydrogen phosphate. Evaporation of the dried ethereal layer left a yellow oil (4 g) which was chroma- tographed on dry silica eluting with ether-light petroleum (1 to 10%) to give dibenzyl disulphide; unchanged dirnetliyl- naphthoquinone ; 3-benzyltl~ion~ethyl-2-nzethyl-1,4-nufilztlzo-quinone (9; R = PhCH,) as yellow needles, 11i.p.89.5-91" (from chloroform--light petroleum) (0.5g) (Found : C, 74.1 ; H, 5.3; S, 10.2%; M+, 308.086 9.C19H1602S requires C, 74.1; H, 5.2; S, 10.4./; M, 308.087 0); Amax. 247sh, 251, 264, 269s11, and 331 nm (log E 4.18, 4.20, 4.12, 4.12, and 3.47); 6 8.15-7.09 and 7.74-7.62 (each 2 H, ni, ArH), 7.37-7.18 (5 H, m, Ph), 3.83 (2 H, s, -CH,-S-), 3.67 (2 H, s, -CH,-S-), and 2.16 (3 H, s, Q-Me); nz/e 308 (Mi,5%), (log E 4.40, 4.29, and 3.62); 6 8.12-8.0 and 7.77-7.63 (each 2 H, m, ArH), 7.22 and 7.04 (each 4 H, d, J 8 Hz, MeC,H,), 3.53 (4 H, s, Q-CH,-S), and 2.31 (6 H, s, ArMe); nq/e 430 (Mt, a%), 309 (18), 308 (84), 307 (84), 274 (32), 273.091 4 (100) (Cl,H1,O, requires 273.091 5), 246 (el), 215 (33), 184 (23), 159 (9), 128 (17), 127 (7), 125 (8),124 (79), 123 (89),92 (ll),91 (79), 79 (28),78 (8),77 (26), and 76 (13).Starting quinone (211 nig) and two unidentified coloiirIcss bands were also obtained. 2-Methyl-3-fl-tolyltliiomethyl-l14-naph thoquinone was also prepared from 3-chloromethyl-2-nietliyl-l14-naphtho-quinone (68 mg) and toluene-p-thiol (40 mg) by heating under reflux in benzene (5 ml) for 3 11, followed by addition of more thiol (20 ing) and further heating for 2 h.The mixture was then evaporated to dryness and the residue crystallised from methanol to give tlie desired quinone as orange needles, m.p. 93-94' (21 nig), identical with that obtained above. Similarly, 2,3-bis(chloronietliyl)-1,4-naplitlioquin~n~(195 nig) in benzene (15 ml) was stirred overnight with toluenc- p-thiol (205 in&. Ailore thiol (109 mg) was then added, and tlie niixture was heated under reflux for 6 11 and then worked up. The main orange band on preparative t.1.c. afforded 2,3-bis-(~-tolyltliionietliyl)-1,4-naphthoquinone which crys- tallised from methanol as orange-red needles, m.p. 112 -113" (200 ing), identical with those described above. Reactiovts of 2,3-L3is(vnetlzylthio1~etl~yl)-1,4-?zaphthoquinone.-(i) With piperidine. 2,3-Bis(methyltli iomethyl) -1,4-217 (,56), 187 (11), 186 (loo), 128 (ll), 123 (22), 92 (5), naI'litIioquiIioiie (]!I6rng) in benzene (4 ml) was stirred with dry piperidine (0.15 ml) for 36 11. The mixture was91 (7!1), 77 (lo), and 76 (8); ancl 2,3-bis(ben~yZmet~~yZtl~io)-1,4-naphthoquinone (10; Iil = PliCH,, R2 = H) as yellow needles, m.p. 88-89' (from ethanol) (0.28 g) (Found: C, 72.3; H, 5.3; S, 14.9%; M', 430.106 0. C,,H,,O,S, requires C, 72.5; H, 5.2; S, 14.9y0; M, 430.1060); hlllilX. 247~11, 253, 264, and 336 nm (log E 4.28, 4.29, 4.19, ancl 3.58); 6 8.11-7.99 antl 7.74-7.62 (each 2 H, m, ArH), 7.36-7.13 (10 H, br s, Ph),3.76 (4 H, s, -CH,-S-), and 3.58 (4 H, s, -CH,-S-); vn/e 430 (M+,1.5y0),339 (28), 217 (9), 216 (13), 215 (75), 184 (19), 128 (13), 121 (12), 92 (25), 91 (loo), 77 (7), and 76 (8). A further fraction (0.183 g) contained (9; R = PhCH,) and (10; R1= PhCH,, R2 = H).(h) Toluene-p-thiol (8.45 g) was added to sodium meth- oxide (from 1.456 g sotliuni, 20 niol) in methanol (45 ml). This solution was added quickly to 2,3-dimethyl-l,4-naphthoquinone (0.6 g) in benzene (45 nil). After stirring for 4 11, the mixture was poured into benzene-aqueous potassium dihydrogen phosphate. The dried benzene layer was evaporated, and the crude product was separated by preparative t.1.c. on silica in benzene to give di-fl-tolyl clisulphide (1 74 mg) ; 2-vnetlzyZ-3-p-folythiol.netlzyl-1,4-napl~-tkoquinone (9; 11 = p-MeC,H,) as orange needles, n1.p.93-94' (from methanol) (207 mg) (Found: C, 73.8; H, 5.4; S, 10.4y0; iW+, 308.086 9. C,,H,,O,S requires C, 74.0; H, 5.2; S, 10.4%); M, 308.087 0); A,,,, 251, 262, and 333 nni (log E 4.27, 4.20, and 3.45); 6 8.13-8.0 and 7.75-7.63 (each 2 H, m, ArH), 7.34 and 7.06 (each 2 H, d, J 8 Hz, MeC,H,), 4.04 (2 H, s, Q-CH,-S), 2.31 (3 H, s, ArMe), ancl 1.88 (3 H, s, Q-Me); rn/e 308 (M+,400/,),293 (8), 157 (8), 128 (13), 124 (loo), 123 (91, and 91 (19); and 2,3-bis-(p-toZyZt/iiowzet/zyl)- 1,4-nl;rphthoquinone (10; R1= p-MeC,H,, It2 = H) as orange-red needles, n1.p. 112-113" (from methanol) (174 mg) (Found: C, 72.6; H, 5.5; S, 15.2%; Ill+, 430.106 0. C,,H,,O,S, requires C, 72.5; H, 5.2; S, l4.9"/b; M, 430.106 0); A,,,. 253.5, 268~11, and 335 nm separated by preparative t.1.c. on silica gel in chloroform.The band of second highest value yielded 2,3-diformyZ- 1,4-napJzthoquinol( 13) which separated from aqueous ethanol as pale yellow crystals, m.p. >165" (cleconip. ; gas evolved at 183") (30mg) (Found: C, 66.5; H, 3.7y4; Mf, 216.041 8. C,,H,O, requires C, 66.65; H, 3.7%; M, 216.042 2); Ar,,Lhx. 249, 278sh, 401, 419, and 450sh nin (log E 4.28, 3.95, 3.75, 3.75, and 3.37); v,,,,,~. 1 640, 1 610, 1 580, and 1 500 cm-l; 6 13.53 (2 H, s, OH), 10.55 (2 H, s, CHO), and 8.50-8.38 and 7.83-7.72 (each 2 H, dd, J 6 and 3 Hz, ArH); wz/e 216 (M+,loo%), 188 (35),187 (13), 131 (9), 105 (lo),and 77 (10). (ii) With methylamine. 2,3-Ris(niethylthiomethyl)-1,4-naplithoquinone (195 mg) in benzene (4 ml) was stirred over- night with methylatnine (33% w/w in EtOH; 1 nil).2-MethyZbenzo[f]isoindole-4,9-quinone (17) (73 ing) was de-posited after 2 days. It sublimed at >325O to give fine needles, 1n.p. 340-350' (Found: C, 74.0; H, 4.0; N, 6.7%; Mb, 211.063 6. C1,H,NO, requires C, 73.9; H, 4.3; N, 6.60/,; M, 211.063 3); A,,, (MeOH) 245, 263, 272~11, 330sh, ancl 354 nm (log E 4.40, 4.21, 4.13, 3.68, and 3.69); vrllnx. 1 657, 1595, and 1 585 cm-l; 6 8.30-8.18 and 7.74-- 7.62 (each 2 H, ni, ArH), 7.36 (2 H, s, H-1 and -3), and 3.82 (3 H, s, NMe); nz/e 211 (M+, looyo),183 (lo), 182 (5), 170 (17), 154 (5), 142 (8), and 114 (10) {cf. isoindole-4,7-quinone,20Y,,,~~.1 647 and 1 582 cm-l; 8 ([2H,]!h!te,CO) 7.50). We thank the S.R.C. for a Studentship (to R.L). W.) antl Beecham Research Laboratories for financial support. [9/394 Received, 12th Mavch, 19791 REFERENCES Part 8, A. R. Burnett and R. I-I. Thornson, J. Chenz. Soc. (C), 1967, 1261. M. De Rosa, S. Dc Rosa, A. Gambacorta, L. Minale, R. H. Thomson, and K. D. Worthington, J.C.S. Perkin I, 1977, 653. 288 K. Chandrasenan and R. H. Thomson, Tetrahedron, 1971,27, 2529. F. M. Dean and L. E. Houghton, Tetrahedron Letters, 1969, 3579. 5 I. Baxter, D. W. Cameron, and R. B. Titman, J. Chew Soc., (C),1971, 1253. D. W. Cameron, P. M. Scott, and Lord Todd, J. Chem. SOC., 1964, 42; D. W. Cameron, R. G. I;.Giles, and R. B. Titinan, J. Chem. SOC.(C),1969, 1245. 7 I. Baxter and J. K. M. Sanders, J.C.S. Chem. Comm., 1974, 143.* I;. M. Dean, L. E. Houghton, and R. B. Morton, J. Chem. SOC.(C),1967, 1980; 1968, 2065. 9 F. M. Dean and L. E. Houghton, J. Chem. SOC.(C),(a)1968, 2060; (b) 1970, 722. lo M. R. Cranipton in ' The Chemistry of the Thiol Group,' ed. S. Patai, Wiley, London, 1974, vol. 1, p. 398. l1 L. I. Smith and J. W. Opie, J. Amer. Chem. SOC.,1941, 63, 932, 937. J.C.S. Perkin I l2 A. M. Detsina, V. V. Russikh, and E. P. Fokin, J. Ovg. Chem. U.S.S.R., 1978, 2230. l3 L. F. Fieser and M. Fieser, J. Amer. Chem. Soc., 1939, 61, 596. l4 L. I. Smith, R. W. H. Tess, and G. E. Ullyot, J. Amer. Chem. SOC.,1944, 66, 1320. l5 K. Chandrasenan and R. H. Thomson, J. Chem. SOC.(C), 1966, 123. l6 F. M.Dean, P. G. Jones, R. B. Morton, and P. Sidisunthorn, J. Chem. SOC.,1963, 5336. l7 K. Miyaki and N. Ikeda, J. Pharm. SOC.Japan, 1954, 74, 655. I* R. H. Thomson, J. Chem. Soc., 1953, 1196. l9 N. Jacobsen and K. Torssell, Annalen, 1972, 763, 135. 2o G. M. L. Cragg, R. G. F. Giles, and G. H. P. Koos, J.C.S. Perkin I, 1975, 1339.

ISSN:1472-7781    

DOI:10.1039/P19800000282

出版商:RSC    

年代:1980

数据来源: RSC