J. Org. Chem. 1982,47,4895-4899 (cyclohex-2-enyl)trimethylsilane, 40934-71-2; (trans-5-methylcyclohex-2-enyl)trimethylstannane,74089-89-7; (cis-5-methylcyclohex-2enyl)trimethylstannane, 74089-88-6; (cis-3,5-dimethylcyclohex-2enyl)trimethylstannane, 83269-39-0; (tra~-3,5-dimethylcyclohex-2enyl)trimethylstannane, 83269-40-3; (cis-5-methylcyclohex-2-enyl)trimethylgermane, 83269-41-4; (trans-5-methylcyclohex-2-enyl)tri-
4895
methylgermane, 83269-42-5; (5-methylcyclohex-1-eny1)trimethylgermane, 83269-43-6; (cis-3,5-dimethylcyclohex-2-enyl)trimethylgermane, 83269-44-7; (trans-3,5-dimethylcyclohex-2-enyl)trimethylgermane, 83269-45-8; 5-methylcyclohex-2-eno1, 3718-55-6; 3,5-dimethylcyclohex-2-enone, 1123-09-7;cis-3,5-dimethylcyclohex-2-enol, 32149-48-7; trans-3,5-dimethylcyclohex-2-enol, 83269-48-1.
New Aspects in the Chlorination of Indoles with 1-Chlorobenzotriazole and 1-Chloroisatin C. Berti,' L. Greci,*f R. Andruzzi,* and A. Trazzat Zstituto Chimico della Facoltd di Zngegneria della Universitd, Viale Risorgimento, 2-40136 Bologna, Italy, and Zstituto Chimico della Facoltd di Zngegneria della Universitd, Via del Castro Laurenziano, 7-00161 Roma, Italy Received February 11, 1982
2-Phenyl-, l-methyl-2-phenyl-, and 2-phenyl-3-methylindole react with 1-chlorobenzotriazole and 1-chloroisatin to form essentially 3-chloroindoles. The composition of the products, which depends on the solvent used, suggests an electron-transfer process for the reactions with 1-chlorobenzotriazole. This is supported by chemical experiments and electrochemical measurements. The reactions with 1-chloroisatin, which do not involve byproduct formation, is interpreted by classical electrophilic substitution. The different reactivities of 1-chlorobenzotriazole and of I-chloroisatin comes from the different mobility of their chlorine atom.
The chlorination of indoles, which normally occurs at C-3 of the indole nucleus, has been extensively studied,' and many reagents have been used for this reaction2 In 1972 an N-chloroindole was suggested as an intermediate in the chlorination of 2,3-dimethylindole with aqueous sodium hyp~chlorite.~More recently the formation and the stability of the N-chloroindole intermediate was detected and described by De RosaS4 In the present paper we describe the reactions of 2phenyl-, l-methyl-2-phenyl-, and 2-phenyl-3-methylindole with 1-chlorobenzotriazole (NCBT),which has been successfully used in the chlorination of indole alkaloids,6and 1-chloroisatin (NCI), which has been recently synthesized by us.6 Although much has been published in the way of mechanistic speculation, we now propose another possibility, which involves an electron-transfer process and which derives, above all, from the consistency of product composition.
Scheme I c
Ll
la, R = H b, R = Me
2
R
3a, R = R , = R, = H b, R = Me;R, = R, = H c , R = Me; R , = H; R, = C1 d, R = Me; R, = R, = C1
Results Each indole was reacted with NCBT and with NCI. All reactions were carried out in benzene, methanol, or Scheme I1 aqueous acetonitrile at room temperature with 20% excesa R Me reagent. 2-Phenylindole (la) and 1-methyl-2-phenylindole (lb) with NCI gave the corresponding 3-chloro derivatives 2a and 2b in very good yields, independent of the solvent used (Scheme I, Table I). 2-Phenylindole with NCBT gave the 5a, R = C1 HI 3-chloro derivative 2a in benzene and 2a together with b, R = OMe 4 c , R = OH 2-phenyl-2-(2-phenylindol-3-y1)-1,2-dihydro-3H-indol-3-one d, R = benzotriazol-1-yl (indoxyl; 3a) when it was reacted in methanol or aqueous acetonitrile (Scheme I, Table I). 1-Methyl-2-phenylindole (1b) with NCBT gave the corresponding 3-chloro derivaonly indoxyls 3b-3d were formed (Scheme I, Table I). tive 2b and indoxyls 3b-3d when the reactions were carried 2-Phenyl-3-methylindole reacted with NCI, forming out in methanol and produds 2b and 3b when benzene waa the reaction solvent, whereas when aqueous acetonitrile (1) (a) Powers, J. C. In 'Indoles"; Houlihan, W. J., Ed., Wiley-interwas the solvent the 3-chloro derivative was not isolated; science: New York, 1972; Part 11, pp 137-39,155-159. (b) Sundberg, R. t Bologna. 1 Roma.
J. 'The Chemistry of Indoles"; Academic Press: New York, 1970; pp 14-17. (2) De Rosa, M.; Triana Alonso, J. L. J. Org. Chem. 1978,43,3639 and references reported therein.
0022-3263/82/1941-4895$01.25/0 0 1982 American Chemical Society
4896 J . Org. Chem., Vol. 47, No. 25, 1982
Berti et all. Scheme I11
Table I. Reactions of l a , l b , and 4 with NCBT and NCIa compd reagent solvent products (% yields) la la la la la la lb lb
NCBT NCBT NCBT NCI NCI NCI NCBT NCBT
C6H, MeOH MeCN/H,O
lb
NCBT
MeCN/H,O
lb lb
NCI NCI NCI NCBT
MeOH MeCN/H,O C6H6
lb 4 4
4 4 4 4
NCBT NCBT NCI NCI NCI
C6H6
MeOH MeCN/H,O C6H6 MeOH
C6H6
MeOH MeCN/H,O 2 3 H MeCN/H@
2a (92) 2a (64), 3a (22) 2a (60), 3a (25) 2a (98) 2a (97) 2a(100) 2b ( 9 5 ) 2b (40), 3b (lo), 3c (15), 3d (22) l b (35), 3b (5), 3c (16), 3d (15) 2b (86) 2b (77) 2b (94) 5a (50), 5d (21), 5c (trace) 5b (75), 5c (trace) 5c (56), 5d (38) 5a (85) 5b (82) 5c (87)
r
(3)Gassman, P.G.; Campbell, G. A.; Metha, G. Tetrahedron 1972,28, 2749. (4)De Rosa, M.; Carbognani, L.; Febres, A. J . Org. Chem. 1981,46, 2054. (5)Lichman, K. V.; J . Chem. SOC.C 1971,2539. (6)Berti, C.; Greci, L. Synth. Commun. 1981,12(9),681. (7)Gross, E.A.; Vice, S. F.; Dmitrienko, G. I. Can. J.Chem. 1981,59, 635. (8)Colonna, M.; Greci, L.; Marchetti, L. Gazz. Chim. Ztal. 1975,105, 985. (9)Colonna, M.; Greci, L.; Marchetti, L.; Andreetti, G. D.; Bocelli, G.; Sgarabotto, P.J. Chem. SOC.,Perkin Trans. 2 1976,309. (10)Witkop, B.; Patrick, J. B. J. Am. Chem. SOC. 1961,73,713. (11)Hiremoth, S. P.;Hooper, M. Adu. Heterocycl. Chem. 1978,22, 123. (12)Berti, C.; Greci, L.; Marchetti, L. J. Chem SOC.,Perkin Trans. 2 1979,233.
Or
2b
6
/ h
OH
I
8
R
9
a NCBT = N-chlorobenzotriazole, NCI = N-chloroisatin, indole/reagent ratio = 1 : l . Z .
products 5a in benzene, 5b in methanol, and 5c in aqueous acetonitrile. However, when it was reacted with NCBT it gave products 5a, 5c, and 5d in benzene, products 5b and 5c in methanol, and products 5c and 5d in aqueous acetonitrile (Scheme 11, Table 11). Compound 5a underwent methanolysis or hydrolysis, quantitatively forming compounds 5b and 5c, respectively, either in acid or alkaline solution, as has been described for the corresponding 3-bromo d e r i ~ a t i v e . ~Compound 5a also reacted with benzotriazole, forming product 5d in good yield. The 3-chloro derivatives 2a and 2b were identified by their analytical data and the absence of the H-3 in the 'H NMR spectra. Products 3as and 3b9 were identified by comparison with authentic samples. Products 3c and 3d were identified by the PhNC and >C=O IR absorptions, which were typical for the indoxyls structure.1° The indolenines 5a-d were identified by the N=C< group absorption at ca. 1535 cm-' in the IR spectra and the multiplet at 6 8.4-8.6 corresponding to two ortho hydrogens of the C-2 phenyl group in the 'H NMR spectra. This attribution is in agreement with the literature.'J' Compound 5c was identified by comparison with an authentic sample.12 Compound 5b showed spectroscopic data similar to that reported by Gross et al.7 Analytical and spectroscopic data for all new compounds are reported in Table 11. In the anodic oxidation, carried out in the concentration MI, la,b, 3a,b, and 4 in acetonitrile range [104-(9 X (with Et4NC104 as supporting electrolyte) exhibit at a
2a
3a
or
3b
3~
+
3d
pulsed platinum electrode (ppe) an oxidation step at potential between 0.6 and 0.8 V (Table 111). A comparison of the parameter value (il/C) reported in Table I11 with the one found for the first one-electron reversible anodic step of 3-(arylamino)indole~'~ under identical experimental conditions allowed us to conclude that the electrode process of compounds la, lb, 4 and 3a, 3b involves one and two electrons, respectively (see nappvalues, Table 111). The cyclic voltammetric measurements at the scan rates 0.1-250 V s-' showed that the primary oxidation product is rather unstable in every case. In fact, at a stationary platinum electrode the oxidation process of the studied indoles is characterized by the following features: (i) an initial voltage scan from zero toward positive potentials (up to 1.2 V) showed an anodic peak, which corresponds to the oxidation step observed at the ppe; (ii) reversal of the scan showed that the corresponding complementary cathodic peak appears only at scan rates faster than 100 V s-', as expected for a reversible electrol transfer followed by a very rapid chemical rea~ti0n.l~ Thus, on increasing scan rates the reaction rate is no longer able to keep up with the electrode polarization rate and the system tends to become reversible. Unfortunately, the normal diagnostic aid,14 i.e., the variation of peak current with scan rate, was not useful in these studies, since all compounds exhibited both adsorption and product filming. On addition of increasing quantities of water (molar ratio water/reactant, 0-1000) to the solutions of indoles la,b, 4, and indoxyls 3a,b in MeCN-Et4NC104, the oxidation step of 3a,b and 4 was unaffected, whereas that of la,b increased in height until it about doubled the original step recorded in anhydrous acetonitrile (i.e., it became bielectronic, see Table 111). Controlled-potential electrolyses at 0.8 V of indoles la and lb in anhydrous or in aqueous acetonitrile involved about 2 faraday/mol of reactant in each case. Nevertheless, it should be noted that in both media (aqueous and nonaqueous) the current was higher that the background current; furthermore, in anhydous acetonitrile it decays (13)Andruzzi, R.; Trazza, A. J. Electroanal. Chem. 1978,86, 201. (14)Nicholson, R. S.; Shain, I. Anal. Chem. 1964,36,706.
J,Org. Chem., Vol. 47, No. 25, 1982 4897
Chlorination of Indoles
Table 11. Analytical and Spectroscopic Data of New Compounds compdQ
solvente
mp, "C
2a 2b 3c
A A B
80 78 23 5
3d
B
236
5a
IR
(v),
cm-I
'H NMR, 6
33902
oil
1705: 1625 1705: 1610 153OC,'
5d
A
160
1535'
10b
B
185
3340f 1690; 1615
3.62 (1 H, s, NMe), 7.1-7.9 ( 9 H, m, arom) 2.76 ( 3 H, s, NMe, indolinic), 3.44 ( 3 H, s, NMe, indolic), 6.4-7.4 ( 1 7 H, m, arom) 3.26 ( 3 H, s, NMe, indolinic), 3.45 ( 3 H, s, NMe, indolic), 6.4-7.6 (16 H, m, arom) 2.02 ( 3 H, s, Me), 7.3-7.9 ( 7 H, m, arom), 8.4-8.7 ( 2 H, m, arom) 2.50 ( 3 H, s, Me), 6.45-6.60 (1H, d, arom), 7.1-8.1 (12.H, m, arom) 7.1 (1H, d, H-7, J = 9.7 Hz), 7.3-7.6 (12 H, m, arom)d
a Satisfactory analytical data (r0.4% for C, H, N) were obtained for all.compounds. d,. e A, n-heptane; B, ligroin, 100-135 "C. f NH. C=O. PhNC. ' N=C
