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0040-4039(95)01455-1

Tetrahedron Letters, Vol. 36, No. 39, pp. 7027-7030, 1995 Elsevier Science Ltd

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Nucleophilic Aromatic Substitution by Paired Electrosynthesis: Reactions of Methoxy Arenes with 1H-Tetrazoles

Kai Hu, Murat E. Niyazymbetov and Dennis H. Evans"

Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716 (i./SA)

Abstract: Nucleophilic substitution reactions on 1,4-dimethoxybenzene and 1,3,5-trimethoxybenzene by the anions of 1H-tetrazole, 1,2,4-triazole and 5-phenyl-lH-tetrazole have been carried out effectively by paired eleetrosynthesis. An undivided cell with platinum anode and cathode was used and the solvent was acetonitrile containing the tetrabutylammonium salt of the heterocyclic anion as electrolyte.

Cathodic electrolysis can be used to generate reactive anions that can be subsequently introduced into a

number of synthetically useful reactions. ~ Usually no use is made of the reaction that necessarily occurs at the

anode and, in fact, the anode reaction is often regarded as a nuisance as products formed there can interfere

with the desired electrosynthetic reaction. An electrochemical synthetic method that makes use of both the

cathodic and anodic reactions is termed a "paired electrosynthesis"? In this paper we report the development

of a paired electrosynthesis in which anions of nitrogen-heterocycles are generated at the cathode and radical

cations &electron-rich aromatics are produced at the anode. Reaction between these two electrogenerated

species leads seriatim to products ofnucleophilic substitution on the aromatic substrate) The products

reported are derivatives oftetrazole and tfiazole which are members of important families of biologically active

compounds. ~

The prototype reaction is the nucleophilic substitution of hydrogen by tetrazole on 1,4-

dimethoxybenzene. 1,4-Dimethoxybenzene is an electron-rich and easily oxidized aromatic compound (anodic

peak potential, Er~ = +1.0 V vs. silver reference electrode, AGILE ~) that is an excellent candidate for the

contemplated paired electrosynthesis, lH-Tetrazole is easily reduced (cathodic peak potential, F_~ = -1.3 V vs.

AGILE) to produce the tetrazole anion. Initial attempts using electrolysis at platinum electrodes in an undivided

cell containing equimolar concentrations of 1,4-dimethoxybenzene and 1H-tetrazole in aeetonitfile containing

0.10 M tetrabutylammonium hexafluorophosphate or perchiorate as supporting electrolyte led to a variety of

products, of which the two desired substitution products (vide infra) were produced in minor amounts.

7027

7028

An outstanding improvement was obtained when the electrolyte was replaced with the

tetrabutylammonium salt oftetrazole. 6 Two products, la and lb, were formed in a total isolated yield of 88%

with the product ratio la : lb being about 3:2. TM The electrolysis required two Faradays per mole of

3 1

la lb

reactant(s) and it is suggested that the reaction proceeds

by the pathway shown in Scheme 1. The isomer-

determining step is attack of the tetrazole anion on the

radical cation. We suppose that the improved yield

results from more efficient capture of the radical cation

by the tetrazole anion due to the higher concentration of

the latter when it is used as the electrolyte.

Equally successful substitution on 1,3,5-trimethoxybenzene (Ep, = +1.25 V v s . AgP, E) was achieved.

Again the isomer ratio 2a:2b is about 3:2 and the total isolated yield was 92%. When 5-phenyl-lH-tetrazole

Cathode:

N + 2 e - 2 I N J H ) I. 2 NINON + H2

Anode:

N ~ N

- e - XX"N

3 3 3

- e -

= N 3 N ~ , N ~ N

OC-,It 3 ~ L ' r l 3 la

Scheme 1

+ I NH N ~ /

was used with 1,4-dimethoxybenzene, only the substitution product with attachment at the 2-position of the

tetrazote (3, 44%) was obtained, probably due to steric hindrance to attack at N-1.

When electrolysis of equimolar amounts of 1,2,4-tdazole and 1,4-dimethoxybenzene was carried out,

the principal product involved replacement ofmethoxy by the heterocycle producing 4 in moderate yield

7029

(40%). Clearly, a change in mechanism has occurred. In this case, the heterocyclic anion is slightly more

easily oxidized (E~ = +0.9 V vs. AgRE) than 1,4-dimethoxybenzene (E~ = +1.0 V) so the two reactants

CH30" ~ "OCH3 CH30" ~ ' ~ -OCH3

2a 2b

3 4

are co-electrolyzed at the anode which may

underlie the change in the nature of the principal

product.

The unusual nature of these

electrochemical preparations is that nueleophilic

substitution can be achieved at electron-rich

aromatic systems which ordinarily are immune to

such reactions. According to the suggested

mechanism (Scheme 1), this enhanced reactivity

is brought about by anodic activation by which

the aromatic is converted to the electrophilic

radical cation.

It is likely that successful nucleophilic

substitution requires an anion that is more

difficult to oxidize than the aromatic reactant. Attempts to achieve substitution on 1,4-dimethoxybenzene

using the following anions did not produce satisfactory yields: benzoate, trifluoroacetate, acetate, 2,4-

dinitrophenolate, and the anion of diethyl nitromalonate.

REFERENCES AND NOTES

1. (a) For a review see Niyazymbetov, M. E.; Evans, D. H. Tetrahedron 1993, 49, 9627-9688. (b) Niyazymbetov, M. E.; Evans, D. H. J. Org. Chem. 1993, 58, 779-783. (c) Laikhter, A. L.; Niyazymbetov, M. E.; Evans, D. H.; Samet, A. V.; Semenov, V. V. Tetrahedron Lett. 1993, 34, 4465-4468. (d) Niyazymbetov, M. E.; Laikhter, A. L.; Semenov, V. V.; Evans, D. H. TetrahedronLett. 1994, 35, 3037-3040.

2. Baizer, M. M. Paired Electrosynthesis. In Organic Electrochemistry. An Introchwtion anda Guide, 3rd ed.; Lund, H.; Baizer, M. M. Eds.; Marcel Dekker, Inc.: New York, 1991; pp. 1421-1430.

3. (a) An analogous substitution of 3-nitro-1,2,4-triazole on 1,4-dimethoxybertzene has been reported earlier) b (b) Niyazymbetov, M. E.; Mikhal'chenko, L. V.; Petrosyan, V. A. Abstracts of papers of National Conference on Aromatic Nucleophilic Substitution, USSK, Novosibirsk, 1989, p. 91.

4. (a) For a review see, Wittenberger, S. J. Org. Prep. Proced 1994, 26, 499-531. (b) Symposium-in-print: Recent Advances in the Design and Synthesis of Angiotensin ILl Receptor Antagonists, Biomed Chem. Left. 1994, 4, 1-222.

5. Potentials are referred to a reference electrode comprising a silver wire in contact with 0.01 M AgNO3, 0.10 M Bu4NPF6 in acetonitdle. Its potential is about +0.3 V vs. the aqueous saturated calomel electrode.

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6. Procedure for preparation of the tetrabutflammonium salt of tetrazole: (The other electrolytes were prepared in an analogous fashion). I H-Tetrazole (10 mmol) and NaOCH3 (10 retool) were added to 50 mL methanol and mixed for 5 min. Tetrabutylammonium bromide (10 retool) was added to the solution, the methanol was evaporated and the residue was treated with acetonitrile, filtered and the acetonitrile was evaporated affording the tetrabutylammonium salt oftetrazole.

7. Procedure for the preparation of la andlb: (The other clectrolyses were conducted in an analogous fashion). 1,4-Dimethoxybcnzene (I retool), 1H-tetrazole (1 mmol), and tetrabutylammonium salt oftetrazole (0.5 retool) were dissolved in 20 mL of acetonitrile. The electrolysis was carried out in an undivided cell with vigorous stirring (magnetic stirbar), purging with nitrogen gas and using an applied voltage of 2.75-3.25 V which resulted in an initial current of 20 mA that decreased to about 4 mA after passage of 2 Faradays per mole of reactant(s). The ~rojected area of the platinum gauze anode was ca. 30 cm 2 while that of the platinum gauze cathode was 10 cm'. After electrolysis, the solvent was evaporated and the products were extracted from the residue with ethyl ether. The products were separated on silica gel (ethyl ether: hexane, 2:1) giving analytically pure ~,tmples of I I and lb. The remaining solid residue was mainly electrolyte which was easily recycled.

8. Product characterization: 'H NMR (250 MHz, CDCI3, ppm/TMS); 13C NMR (62.5 MHz, CDCI3, ppm). la: mp: 89-90 *C. ~H NMR: 3:76 (s, 3H, methyl), 3.84 (s, 3I-I, methyl), 6.91-7.03 (m, 2H, aromatic), 7.34- 7.35 (d, J = 2.8 Hz, IH, aromatic), 9.19 (s, IH, tetrazole); this isomer showed a significant (1.2%) NOE for the proton on tetrazole when the methoxy group closer to the tetrazole (3.84 ppm) was irradiated, t3C NMRg: tetrazole carbon, 143.0. Mass spectrum: M*, m/z = 206. Anal Calcd for CgH,0N402: C, 52.42; H, 4.89; N, 27.17. Found: C, 52.55; H, 4.86, N; 27.18. lb: tH NMR: 3.77 (s, 31--1, methyl), 3.78 (s, 3H, methyl), 7.00-7.08 (m, 3H, aromatic), 8.65 (s, 1H, tetrazole). t3C NMRg: tetrazole carbon, 152.6. Mass spectrum: M*, m/z = 206. 2a: IH NMR: 3.73 (s, 6H, methyl), 3,86 (s, 3H, methyl), 6.17 (s, 2H, aromatic), 8.57 (s, 1H, tetrazole). 13C NMRg': tetrazole carbon, 145.1. 2b: rap: 128-130 *C. ~H NMR: 3.71 (s, 6H, methyl), 3.85 (s, 3H, methyl), 6.18 (s, 2H, aromatic), 8.67 (s, IH, tetrazole). ~3C NMRg: tetrazole carbon, 152.7. 3: ~H NMR: 3.80 (s, 3H, methyl), 3.81 (s, 3H, methyl), 7.05 (m, 2H, aromatic), 7.42-7.57 (m, 3H, phenyl), 8.20-8.25 (m, 21-1, phenyi). ~3C NMRg: tetrazole carbon, 153.7. 4: ~H NMR: 3.82 (s, 31-I, methyl), 6.94-7.02 (m, 2H, aromatic), 7.50-7.56 (m, 2H, aromatic), 8.04 (s, 1H, triazole), 8.42 (s, 114, triazole), t3C NMR: only one type ofmethoxy carbon at 55.5. Mass spectrum: M*, m/z = 175.

9. (a) Begtrup, M.; Elguero, J.; Faure, g.; Camps, P.; Estop/t, C.; Ilavsk~, D.; Fruehier, A.; Marzin, C.; Mendoza, J.Magn. Reson, Chem. 1988, 26, 134-151. (b) Semenov, V. V.; Ugrak, B. I.; Shevelev, S. A.; Kanishchev, M. I.; Baryshnikov, A. T.; Fainzil'berg, A. A. lzv. Akad. Nauk SSSR, Set. Khim. 1990, 1827- 1837.

(Received in USA 9 June 1995; revised 25 July 1995; accepted 28 July 1995)