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Mechanism of nitrenium ion cyclisations in the formation of N-acyl-3,4-dihydro-1H-2,1-benzoxazines and N-acyl-1,3,4,5-tetrahydro-2,1-benzoxazepines

Stephen A. Glover, Anthony P. Scott and Gregory J. Tarrant

Department of Chemistry, University of New England, Armidale, New South Wales 2351, Australia

Introduction

N-alkoxynitrenium ions are strongly resonance stabilised through the oxygen lone pair. The ¼-bond order is typically 0.9 reflecting significant double-bond character.1 Such stabilisation facilitates their generation from N-alkoxy-N-chloroamides through treatment with silver tetrafluoroborate and other Lewis acids and we have utilised this reaction to synthesise a variety of N-acyl-3,4-dihydro-1H-2,1-benzoxazines 1 and N-acyl-1,3,4,5-tetrahydro-2,1-benzoxazepines 2 (Scheme 1).2 Benzolactams can also be synthesised by this method.3,4

Scheme 1

In principle, two mechanisms could lead to the formation of 1 and 2.5 As an alternative to direct ortho attack followed by rearomatisation [pathway (i)], the electrophilic nitrenium ion could react at the ipso position to give 3 [pathway (ii)]. A 1,2-carbon or nitrogen migration would also afford the observed products. We were alerted to the possibility of both mechanisms by the formation of both the 7- and the 8-methylbenzoxazepines 5 and 4 in the ratio 2:1 from the cyclisation of N-chloro-O-3-(p-methylphenyl)propyl benzohydroxamate. In addition, cyclisation of substrates bearing a p-methoxyphenyl group led to ipso attack and formation of the dienones 6.3 Both methyl and methoxy substituents would, however, be expected to activate the ipso position to electrophilic attack.

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Deuterium labelling in cyclisation studies

Cyclisation of the deuteriated substrates 7 and 10 provided us with insights into the preferential modes of cyclisation in the absence of electron donor (activating) substituents.5 [reference NMR data for benzoxazines and benzoxazepine can be viewed here]

Cyclisations

In the case of 7, the sole product was shown by both 1H and 13C NMR to be the 7-deuterio-3,4-dihydro-1H-2,1-benzoxazine 8. 9 was absent in the product mixture. By way of example, in the product from 7 (R=Me), isotope effects in the aromatic region of the 13C NMR spectrum clearly showed that deuterium resided exclusively on the 7-position. This was deduced from the absence of C-7 near d 126, as well as the b isotope shifts of ca. 105 ppb for C-6 (d 124.7) and C-8 (d 121). In addition, H-8, which normlly resonates as a doublet at d 7.93 as a consequence of strong coupling to H-7 in the proton spectrum becomes a singlet in the deuteriated substrate. H-5 and H-6 form a clean AB spin system and H-7 is completely absent. Similar results were obtained for the N-benzoyl analogue.

In the case of the formation of the N-benzoylbenzoxazepine ring system from 10 (R=Ph), both the 1H and 13C NMR indicate the presence of mainly the 7-deuterio 11 together with some of the 8-deuterio product 12 indicating that ipso attack followed by 1,2-C migration was the major pathway. The proton spectrum in (CD3)2SO at 370 K (ring and amide conformational isomerism lead to extreme broadening in the aromatic region at room temperature) indicates the presence of the 7-deuterio product through strong doublets at d 6.94 (H-9) and d 7.05 (H-8). A weaker singlet at d 6.94 (H-9) and doublet at d 7.17 (H-8) are diagnostic of the presence of the 8-deuterio species. Some protio material was also regenerated in the cyclisation. In the carbon spectrum the presence of both isomers is indicated by two peaks at C-6 (d 129.6) and C-8 (d 126.2) as well as a major resonance with a b-shift of 99 ppb for C-8 (d 126.25) due to deuterium at C-7 and a minor peak with a b-shift of 95 ppb at C-9 (d 127.1) due to deuterium at C-8 (the shift for C-7 (d 127.5) is masked by the resonances for the benzoyl ring protons)

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N- vs. C-migration

The exclusive formation of the 7-deuterated benzoxazine is very likely a result of direct cyclisation onto the ortho position although ipso attack followed by a regiospecific 1,2-N-migration would have yielded the same result. 1,2-carbon migration would be favoured on simple thermodynamic grounds as the resultant carbocation in (e.g. 13, Scheme 2) would be stabilised by the nitrogen lone pair. Ipso attack followed by carbon migration is clearly the predominant process in the formation of the methylbenzoxazepines and deuteriobenzoxazepines5 above.

Scheme 2

Kikugawa has, however, argued that in competitions between alkoxyamine and carbon migration in dienone-phenol rearrangements, 1,2-N migration is strongly favoured through anchimeric assistance by the nitrogen lone pair; dienone 14 gives almost exclusively the 7-acetate 16 (Scheme 3).6,7 However, such rearrangements are different to those in Scheme 1 as the intermediate cyclohexadienyl cation 15 is resonance stabilised by the ether oxygen of the acetoxy group.

Scheme 3

In the case of benzoxazepine formation, while ipso attack appears to be the major pathway, ortho attack to give 12 directly cannot be ruled out.

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This study

In this study we have obtained unequivocal evidence for exclusive ortho attack in the case of formation of the 2,1-benzoxazines 1 by rearranging the 8-deuterio-2-oxa-1-azaspiro[4,5]deca-6,9-dien-8-ols 21, 22 and 23 with BF3. Evidence for dual cyclisation pathways and exclusive 1,2-C-migration in the formation of the 2,1-benzoxazepine 2 was obtained by rearranging the 9-deuterio-2-oxa-1-azaspiro[5,5]undeca-7,10-dien-9-ol 26. Both systems were synthesised by NaBD4 reduction of the corresponding dienones 19, 20 and 25 which were derived as previously described from cyclisation of the N-chloro-2-(p-methoxyphenyl)ethyloxy- or N-chloro-3-(p-methoxyphenyl)propyloxyamides 17, 18 and 24 with AgBF4 in diethyl ether.2

Formation of deuteriodienols

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Benzoxazine formation

Reduction of N-acetyl spirocyclohexadienone 19 afforded two diastereomers (21 and 22 which were separated by centrifugal chromatography and characterised by 1H and 13C NMR. Rearrangement of each isomer was effected quantitatively in diethyl ether using BF3 and the product exhibited a molecular ion of 178 corresponding to monodeuteriated benzoxazine. NMR spectra of either reaction mixture were identical in that both the resolution enhanced 300 MHz 1H NMR as well as the 75 MHz 13C NMR spectrum indicated that both the 7-deuterio and 6-deuterio products were present, the former in significantly greater proportion.

Scheme 4

Proton spectrum from rearrangement of (21)

In the resolution enhanced 300 MHz proton spectrum above, the major constituent, the 7-deuteriobenzoxazine (8, R=Me) is evident from the AB pattern for H-6 and H-5, the singlet at H-8 and the greatly reduced signal at H-7. The minor, 6-deuterio isomer (9, R=Me) has a weak doublet for H-7, a singlet (shoulder) for H-5 and a doublet at H-8. In the 13C NMR spectrum below, the 7-deuterio isomer results in 1:1:1 triplet at C-7 and a typical a-deuterium isotope shift of 0.2 ppm. In addition both C-6 and C-8 experience upfield b-isotope shifts of close to 90 ppb while C-5 is largely unaffected. The C-6­D isomer results in upfield b isotope shifts for C-5 and C-7 while C-8 is unaffected. The C-7­D isomer is clearly the most abundant.

Carbon spectrum from rearrangement of (21)

Reduction of N-benzoyl spirocyclohexadienone 20 gave a single isomer which was rearranged with BF3 to give a similar mixture of mainly 7-deuterio-3,4-dihydro-1H-2,1-benzoxazine (M+=240) (8, R=Ph) together with some of the 6-deuterio isomer (9, R=Ph). The carbon spectrum also shows major and minor resonances for C-8 as well as b-shifted signals for C-6 and C-7.

Rearrangement of the dienols 21-23 clearly proceeds through both 1,2-C and 1,2-N migration while nitrogen migration is the predominant process in this case. Neither the stereochemistry of the departing group in 21 and 22 nor the presence of different N-acyl substituents appear to influence the migratory tendencies. We conclude from this that alkoxynitrenium ion cyclisation, which affords only the 7-deuteriobenzoxazine must occur exclusively through direct ortho attack rather than through ipso attack followed by exclusive nitrogen migration.

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Benzoxazepine formation

Scheme 5

Proton spectrum of 11 (R=Ph)Reduction of dienone 25 afforded a mixture of dienols 26 which could not be separated. The mixture was rearranged by conversion to the trifluoroacetates in situ and treatment with BF3 The 2,1-benzoxazepine was isolated by centrifugal chromatography and had a molecular ion of 254 in its mass spectrum indicating complete retention of deuterium.

In the resolution enhanced proton spectrum in (CD3)2SO at 370 K (ring and amide conformational isomerism lead to extreme broadening in the aromatic region at room temperature) it can clearly be seen that the sole migration product arises by a 1,2-C shift leading to the 7-deuterio product 11; the triplet for H-7 at d 7.2 is completely absent while H-8 and H-9 form a clean AB spin system. In contrast to the cyclisation process described above where H-9 appears as a singlet and a doublet, no 8-deuterio species is formed in the rearrangement.

In contrast to the five-membered ring, it is clear that the rearrangement is regiospecific in this case. Since cyclisation yields a mixture of 7- and 8-deuterio species, the 8-deuterio isomer 12 must arise through direct cyclisation in that case.

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Why different mechanisms?

We have argued that the difference in mechanisms arises from the incipient NO ¼-bond character. Since the double bond character is endocyclic in the cyclisation process, ipso attack in the formation of benzoxazines would invoke more strain in the transition state (five-membered ring) than in the transition state for ortho attack (six-membered ring).3,5 In the case of benzoxazepine formation, the difference would be less important. AM1 calculations support this assertion; d-H÷ for ipso attack leading to TS2 ( Table 1) is predicted to be larger than that for ortho approach (TS1, Table 1) by 6.3 kcal mol-1 (1 cal = 4.184 J) and the d-S÷ would be expected to be similar for the five- and six-membered ring formation. The difference in the case of the seven-membered ring formation is smaller ( TS6-TS5 = 4.4 kcal mol-1, Table 1) and ortho attack via a seven-membered ring would be characterised by a more unfavourable d-S÷. Thus, rates of cyclisation are most probably similar and both modes of cyclisation would be expected.

AM1 also predicts the relative migratory trends. The barriers to C- and N-migration are predicted to be identical in the formation of benzoxazines from the ipso intermediate (TS3 andTS4, Table 1) and both processes should occur in accordance with what is observed experimentally. In the case of the seven-membered ring formation, the transition state for 1,2-C migration is predicted to be lower in energy than that for 1,2-N migration by 4.6 kcal mol-1 (TS7 and TS8, Table 1).

AM1 also predicts that in each case, the product from carbon migration is thermodynamically more stable in keeping with qualitative predictions (GS4 and GS8 are more stable than GS2 and GS6 by 18 and 16 kcal mol-1, respectively)

Table 1 AM1 heats of formation for cyclisation reactions of N-formylalkoxynitrenium ion
Structure d-Hf/kcal mol-1 Structure d-Hf/kcal mol-1
GS1 GS1

209.8 GS5 GS5 203.0
GS2 GS2 190.1 GS6 GS6 180.8
GS3 GS3 203.1 GS7 GS7 191.1
GS4 GS4 171.8 GS8 GS8 164.8
TS1 TS1 217.2 TS5 TS5 209.8
TS2 TS2 223.5 TS6 TS6 214.2
TS3 TS3 221.5 TS7 TS7 211.3
TS4 TS4 221.1 TS8 TS8 206.7

The results presented here clearly suggest that migratory preferences in these systems cannot be generalised. Kikugawa's assertion that N-migration is the preferred mode is valid in the cases he has studied, namely that of the dienone-phenol rearrangements.7 Our results show that even in systems as similar as 23 and 26, migratory aptitudes can be very different indeed.

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References

  1. Glover, S. A.; Scott, A. P. Tetrahedron, 1989, 45, 1763.
  2. Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad, J. L. J. Chem. Soc., Perkin Trans. 2 , 1984, 2255.
  3. Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad, J. L. Tetrahedron, 1987, 43, 2577.
  4. Y. Kikugawa; M.Kawase J. Am. Chem. Soc., 1984, 106,5728.
  5. Glover, S. A.; Rowbottom, C. A.; Scott, A. P.; Schoonraad, J. L. Tetrahedron, 1990, 46, 7247.
  6. M.Kawase; T.Kitamura; Y. Kikugawa J. Org. Chem., 1989, 54, 3394.
  7. Y. Kikugawa; T.Kitamura; M.Kawase, J. Chem. Soc., Chem. Commun., 1989, 525.