Insight into the offbeat electrochemical methoxylation of isatin

Article abstract of DOI:10.1016/S0040-4039(00)01554-9

A claim by Kazimierczuk and co-workers to have synthesized the diene 1 by electrochemical vic-dimethoxylation of isatin 2 is wrong. The product is now shown by a careful analysis of spectral data and synthesis to be in reality methyl N-(methoxycarbonyl)an

Full text of DOI:10.1016/S0040-4039(00)01554-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8825–8827
Insight into the offbeat electrochemical methoxylation of
isatin
Giancarlo Cravotto,a Giovanni B. Giovenzana,b Giovanni Palmisanoc,* and
Bruno Vodopivecd
aDipartimento di Scienza e Tecnologia del Farmaco, Via Giuria 9, 10125 Turin, Italy
bDipartimento di Scienze Chimiche Alimentari Farmaceutiche e Farmacologiche, Viale Ferrucci 33,
28100 Novara, Italy
cDipartimento di Scienze Chimiche, Fisiche e Matematiche, Via Valleggio 11, 22100 Como, Italy
dDipartimento di Biotecnologie e Bioscienze, Piazza delle Scienze 1, 20100 Milan, Italy
Received 4 September 2000; accepted 14 September 2000
Abstract
A claim by Kazimierczuk and co-workers to have synthesized the diene 1 by electrochemical vic-
dimethoxylation of isatin 2 is wrong. The product is now shown by a careful analysis of spectral data and
synthesis to be in reality methyl N-(methoxycarbonyl)anthranilate 3. © 2000 Elsevier Science Ltd. All
rights reserved.
Kazimierczuk and co-workers1 recently showed that anodic methoxylation of isatin 2 gave a
stable and strongly fluorescent main product to which they assigned the structure of (Z)-3a,7a-
dihydro-3a,7a-dimethoxy-1H-indole-2,3-dione 1.2 Needless to say, this result is surprising as no
such oxidation pattern (i.e. 1,2-dimethoxylation across a fused double bond) has been previously
observed in any electro-oxidation of benzenoid systems.3 If confirmed, this reaction would
provide a one-step method for the synthesis of a novel class of compounds that have thus far
remained inaccessible by classical routes.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01554-9

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Because of our general interest in indole chemistry and intrigued by these findings, we were
prompted to reexamine this reaction. Thus, isatin 2 was oxidized at room temperature in an
undivided cell equipped with a nitrogen inlet using two Pt wire electrodes, a 0.9 M AcONa in
MeOH–AcOH (15:1) electrolyte solution and a constant current of 25.4 mA cm−2. The reaction
proceeds exactly as the Polish workers described and, after a total of 6 F mol−1 of charge has
passed, a 35% isolated yield of the methoxylation product was obtained. An increase in the
number of F mol−1 did not improve the yield of this product, but did reduce the amount of
starting material recovered.
Chemical behaviour and a careful analysis of this product raise questions about the proposed
structure. Accordingly, we were surprised to find the cisoid 1,3-diene subunit in 1 was reluctant
4
to give either h4(diene)–Fe(CO)3 complex with Fe2(CO)9 or [4+2]-cycloadducts with strong
dienophiles [i.e. 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD), tetracyanoethylene (TCNE)].
1
Of particular concern, upon examination of the H and 13C NMR data, was the downfield
1
shift (:6 ppm) noted for C(4) and C(7) resonances in 1 vis-a`-vis isatin 2.5 In the H NMR
spectra the chemical shifts for H(4)ꢀH(7) (between 7.1 and 8.2 ppm) are the most diagnostic
resonances, typically falling below 6.1 ppm in similar systems,2,6 with a noticeable (and
somewhat inexplicable) downfield shift. In order to clarify the issues raised above, we undertook
a thorough investigation of this product by 1D and 2D NMR experiments. Application of
H,H-relayed COSY, heteronuclear multiple bond correlations (HMBC) and INADEQUATE
experiments to the electro-oxidation product resulted in structure 3 as most consistent with the
spectral data.7
The probable course of the electro-oxidation process of 2 would involve the ring-opening of
the radical cation of 2, during or after electron transfer, followed by rapid nucleophilic capture,
whose product undergoes further oxidation.8
Quantum-mechanical calculations on 2 and its radical cation, the latter presumably formed in
the first step of the electrochemical oxidation, were performed using semiempirical methods
(AM1 and PM3) from the SPARTAN package.9 The optimised structure of 2+ indicated a
’
substantial weakening of the C(2)ꢀC(3) bond with most of the spin density confined to the
NHꢀC(2)ꢁO site. This could reasonably indicate that the fate of the radical cation is the
C(2)ꢀC(3) bond fission, without involving the aromatic ring.
Redox considerations further support these proposals suggesting that 2 would be readily
+
transformed into 3 (via 2 ) by metal-based oxidizing agents [e.g. Ce(IV), Pb(IV)].10 Gratifyingly,
’
treatment of 2 with 2.1 molar equiv. of Ce(NH4)2(NO3)6 (CAN) in 1:1 MeCN–MeOH at room
temperature for 1 h, followed by silica gel chromatography, led to clean formation of 3 in 45%
isolated yield.11
With the exception of the chemical shifts of the four C(sp2)H in the 1H and 13C NMR spectra,
which may be a result of inadvertent inversion in the assignment, all signals and coupling
constants for the alleged 11 are in agreement within experimental error with those obtained for
the authentic 312 (prepared by treatment of commercially available methyl anthranilate with
ClCO2Me in pyridine at room temperature). We are forced to conclude that the claim that isatin
2 could be converted into 1 was erroneous.
Acknowledgements
The help rendered by Drs L. Calabi and L. Paleari, Bracco S.p.A. (Milan) in the 2D NMR
studies is greatly appreciated.

8827
References
1. Niedzwiecka-Kornas, A.; Bojarska, E.; Kaminski, J.; Kazimierczuk, Z. Z. Naturforsch. 1998, 53b, 620–624
(Chem. Abstr. 1998, 129, 136058).
2. Search of database (Beilstein CrossFire) using the substructure A provided only one representative and rather
unstable compound (i.e. 4) (Kro¨ner, M. Chem. Ber. 1967, 100, 3162–3171).
3. The anodically promoted 1,4-addition of two OMe groups across a benzenoid system represents a well
documented behaviour. See: Yoshida, K. In Electro-oxidation in Organic Chemistry (The Role of Cation Radicals
as Synthetic Intermediates); Wiley: New York, 1984; pp. 174–203.
4. For a review, see: Donaldson, W. A. In Comprehensive Organometallic Chemistry II; Abel, E. W.; Stone, F. G.
A.; Wilkinson, G., Eds.; Elsevier Science: Oxford, UK, 1995; Vol. 12, pp. 623–637.
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Magn. Res. Chem. 1979, 13, 101–102.
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7. Compound 3: mp 57–58°C (hexane) (lit.1 54.5°C; lit.12b 56–58°C); IR (KBr) 3300, 3010, 2960, 1743, 1695, 1610,
1
1599, 1588, 1535 cm−1; H NMR (600 MHz, CDCl3) 3.77 (3H, s, OMe), 3.88 (3H, s, OMe), 6.99 (1H, t, J=7.6
Hz, H-5), 7.54 (1H, ddd, J=8.7, 7.9, 1.7, H-6), 7.96 (1H, dd, J=8.0, 1.7, H-7), 8.41 (1H, d, J=8.5 Hz, H-4),
10.49 (1H, br s, N-H); 13C NMR (150 MHz, CDCl3) 52.6 (2s, C-8 and C-9), 114.9 (C-3a), 119.1 (C-7), 121.9
(C-5), 131.2 (C-4), 134.9 (C-6), 142.1 (C-7a), 154.4 (C-2), 168.8 (C-3). HMBC C-2/H-4, H-9; C-3/H-4, H-5, H-8;
+
’
C-4/H-6, H-7; C-5/H-6, H-7; C3a/N-H, H-5, H-6, H-7; C7a/H-4, H-5, H-6, H-7. EI-MS 209 (M , 52%), 177
(M−MeOH), 146 (M−MeOH-MeO, 100%) (for the sake of comparison, we retained the numbering scheme of the
parent compound 2).
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Miranda, M. A. Angew. Chem., Int. Ed. Engl. 1987, 26, 797–798.
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10. The peak oxidation of isatin 2 measured at a Pt anode in 0.1 M LiClO4–MeCN (scan rate 50 mV s−1) was +0.43
V versus SCE, whereas the reduction potential of Ce(IV) was ca. +1.7 V.
11. For the Ce(IV)-promoted bond fission of a-dicarbonyl compounds, see: Danieli, B.; Palmisano, G. Chem. Ind.
(London) 1976, 565–566.
12. (a) Erdmann, E. Chem. Ber. 1899, 32, 2159–2172; (b) Hoesch, L.; Dreiding, A. S. Helv. Chim. Acta 1975, 58,
980–1001.
.