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Communication
Communication | Regular issue | Vol. 83, No. 6, 2011, pp. 1259-1265
Received, 14th February, 2011, Accepted, 24th March, 2011, Published online, 11th April, 2011.
DOI: 10.3987/COM-11-12172
Steric Effect on the Formation of 3H-Azepine Derivatives from o-Alkylphenylnitrene and Alcohol as a Nucleophilic Media

Siti Mariyah Ulfa, Hideki Okamoto, and Kyosuke Satake*

Department of Chemistry, Faculty of Science, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract
The cause of regioselectivity for the formation of 3-alkyl- and/or 7-alkyl-3H-azepine derivatives via the intramolecular insertion reaction of o-alkylphenylnitrene, which is generated by an action of Bu3P on o-alkylnitrobenzene, in the presence of alcohol found to be elucidated by the steric effects of an alcohol adduct on the dehydroazepine intermediate. Observed selectivity is confirmed both by changing the bulkiness of the o-alkyl group of phenylnitrene and that of alcohol as a nucleophile.

The behavior of a singlet phenylnitrene (1) has been studied theoretically1 and/or experimentally,2 that is, the intramoleculer insertion reaction of nitrogen atom leads to a labile benzoazirine 2 and subsequent ring opening reaction gives seven membered dehydroazepine 3. Typical synthetic application of this reaction is the synthesis of 3H-azepine derivatives. When phenylnitrene is generated in the presence of nucleophilic media (NuH) such as alcohol and amine, 2-alkoxy- or 2-amino-3H-azepine derivatives are obtained in practical yields. Reaction mechanism is often explained as in Figure 1, includes two possible reaction paths (path A and path B) before giving the final 3H-azepine 6. That is to say, nucleophile attacks on azirine 2 to give an aziridine 4 (path A) and thermally allowed ring opening occurs to form 1H-azepine 5 then isomerizes to stable 3H-azepine 6 by a rapid 1,3-prototropy.3 On the other hand, azirine 2 isomerizes into dehydroazepine 3 which is trapped by NuH to give 1H-azepine 5 and subsequent isomerization gives 3H-azepine 6 (path B).4,5 Thus far the reaction path giving 3H-azepine has not been clarified experimentally. We report here 2-alkoxy-3H-azepine is produced via path B based on the experimental results by modifying the substituent and solvent on the reaction of o-alkylphenylnitrene.

We have reported that the reaction of o-tert-butylnitrobenzene (7d) with Bu3P under the presence of methanol (Scheme 1) resulted in the selective formation of 7-tert-butyl-2-methoxy-3H-azepine (9d) in 58% yield,6 although, the formation of another isomeric product 3-tert-butyl-2-methoxy-3H-azepine (8d) can be expected as shown in Scheme 1. To elucidate this anomaly and to obtain the deeper insight into the mechanism of this reaction, we examined the reaction of several o-alkyl (methyl, ethyl and isopropyl) nitrobenzene derivatives (7a-c) with Bu3P in methanol.
A representative procedure for the reaction of
7a-c was as follows.6,7 A solution of o-nitrotoluene (7a) (10 g, 73 mmol), 2 equiv. of Bu3P and methanol (50 ml) was degassed for an hour with nitrogen flow then heated in a stainless sealed tube at 150 °C for 24 h. After cooling, the excess of solvent was removed and the resulted mixture was distilled under reduced pressure. The distillate was identified as a mixture of 3-methyl-3H-azepine 8a and 7-methyl-3H-azepine 9a by 1H NMR analysis and determined the ratio between 8a and 9a by integration values. Chromatographic separation of the mixture using silica-gel column at 0 °C (AcOEt : hexane (1 : 19 v/v)) gave pure 8a and 9a without decomposition.8 Similarly, reaction of o-ethylnitrobenzene (7b) and o-isopropylnitrobenzene (7c) also gave a mixture of 3-alkyl-3H-azepine 8b,c and 7-alkyl-3H-azepines 9b,c in respective ratio. The isomer 8a and 9a was appropriately characterized by 1H NMR chemical shift. Olefinic four protons of 8a were observed at δH-4 5.01, δH-5 6.16, δH-6 5.98, and δH-7 6.96 and three olefinic protons of 9a were observed at δH-4 5.18, δH-5 6.13 and δH-6 5.86. Olefinic signal for 9a suggest the lacking in the α-proton of nitrogen atom (H-7) which is expected for around 7 ppm, therefore, a methyl group is considered to be situated on C7-position on 3H-azepine 9a.

Since the o-substituted nitrobenzene 7 gave a mixture of 8 and 9, possible intermediates 10 to 14 can be considered and illustrated on Scheme 1. The initially formed phenylnitrene 10 is cyclizes at either away or toward to o-substituent and give two kinds of benzoazirine intermediates 11 and 13. Each of them is in equilibrium with dehydroazepine tautomer 12 and 14. Subsequent addition of methanol to C=N bond of 11 and/or 12gives 3-alkyl-3H-azepine 8 and that of 13 and/or 14provides 7-alkyl-3H-azepine 9.
The observed ratios of 3-alkyl isomer
8 to 7-alkyl isomer 9, noted as 8/9, in each reaction mixture are shown in Scheme 1. In the case of 7a whereas the alkyl size is relatively small, the ratio 8a/9a is 1.00, shows no selectivity in the formation of 3H-azepine, i.e. both sides reaction occurs almost even. In contrast, by modifying an o-alkyl group of 7 to the more bulky substituent, the ratio 8/9 decreases remarkably. When o-tert-butylnitrobenzene (7d) was employed as a starting material, exclusive formation of 7-tert-butyl isomer 9d was obtained. This selectivity suggests that the precursor for 3H-azepine 9d is azirine 13d or dehydroazepine 14d in the reaction of 10d, i.e. the reaction proceeds only on right side of Scheme 1. The product distribution gives us a clue to consider which path (see Figure 1, path A and B) is precedent to the final product. In the case of o-tert-butylphenylnitrene (10d), the possible structures of methanol adducts is considered to be methoxyaziridine 17 and methoxy-1H-azepine 18, both of which will be 7-tert-butyl derivative 9d (Figure 2). If this reaction proceeds via path A, it will includes the sterically unfavorable intermediate 17 because of vicinal steric hindrance between methoxy and bulky alkyl group on aziridine ring. In contrast, follows the path B, 14 can accept methanol without steric hindrance even though an alkyl group is bulky. Therefore, the favorable route to 3H-azepine should be considered as path B. In conformity with this view, small substituent as methyl group is allowable to attack intermediate 12 leads to 16 and finally give 3-methyl-3H-azepine 8a in even ratio with 7-methyl-3H-azepine 9a.

In order to confirm the steric effect on the formation ratio between 3-alkyl and 7-alkyl derivatives, nucleophilic media is modified in the reaction of o-methylnitrobenzene (7a) by methanol, n-hexanol, isopropanol and tert-butanol (Scheme 2). It has been found that phenylnitrene with small alkyl substituent (such as 7a) gave 3-methyl and 7-methyl-3H-azepine 19a/20a in 1:1 ratio when methanol was used as a NuH. However, reaction of 7a in the presence of n-hexanol gives 3-methyl and 7-methyl-3H-azepine 19b/20b in the ratio of 0.33 (Scheme 2).7 Furthermore, reaction of 7a using i-propanol gives a mixture of 19c and 20c in 0.05 ratio and no formation of 3-methyl-3H-azepine 19d were found in the reaction with tert-butanol. After all, the observed product distributions support that the regioselective formation of 7-alkyl-3H-azepine derivatives depends on the bulkiness of an alcohol used, the formation ratio is fully controlled by the steric features of alcohol adduct on dehydroazepine through path B.

The structure of 3H-azepine derivatives was characterized by an analysis of chemical shift and 3JH,H coupling constant for ring protons (Table 1). An eminent difference was observed in H-3 chemical shift between 3-alkyl- and 7-alkyl-3H-azepines. Usually, the methyne and methylene proton of general di-π-methane moiety are observed at around δ 3.0 and 2.6 ppm, respectively, however, assigned H-3 methyne proton for 3-alkyl-3H-azepines (8a,b and 19b) and methylene protons for 7-alkyl-3H-azepines (9a-c and 20c,d) are δ 1.95–1.98 and 2.34–2.62 ppm, respectively. This implies that the methyne proton of 3-alkyl azepine is observed by 1 ppm higher field shift compared to usual chemical shift value. To obtain theoretical information, GIAO chemical shift calculation9 for the structures 8aAx and 8aEq, which are correlated by ring inversion of seven-membered azatriene ring, were performed at HF/6-311+(2d, p)//B3LYP/6-31G(d) levels using GAUSSIAN0910 software package. Calculated chemical shift for 8aAx and 8aEq are included in Table 1 along with experimental data. By comparison between observed H-3 chemical shift for 8a and calculated values (8aAx and 8aEq), characteristic value of the methyne proton on 8a is considered to be rather the syn-axial situated proton of 8aAx than the anti-equatorial proton of 8aEq. Therefore, chemical shift data explains the equilibrium arises from the ring-inversion lies so far to the left (Figure 3), that is, 8aAx is a predominant conformer at under ambient conditions. Shielding effect on the proton which situated in the syn-axial position of seven-membered triene system has been explained as an anisotropic effect.11,12 In addition, optimized energy at B3LYP/6-31G(d) levels of 8aAx is more stable than 8aEq by 1.4 kcal/mol in gas phase.

ACKNOWLEDGEMENTS
This work was partly supported by the Grant-in-Aide for Scientific Research (C) (No. 20550044) of the Japan Society for the Promotion of Science (JSPS). The authors are grateful to the SC–NMR Laboratory of Okayama University for the NMR data collection.

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