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email.gif - 0.3 K ECHET96 Article 107: Rzepa, Henry
email.gif - 0.3 K ECHET article 107 sglover@metz.une.edu.au

A dynamic NMR investigation of the conformational isomerism in novel 1,3,4,5-tetrahydro-2,1-benzoxazepines

Tony M. Banks, Gary J. Cowin, Stephen A Glover , Gregory J. Tarrant, Colleen A. Rowbottom, David J. Tucker and Yang Zengjia

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

Table of Contents

Introduction

N-acyl-1,3,4,5-tetrahydro-2,1-benzoxazepines are a novel member of the oxazepine family which, together with the analogous N-acyl-3,4-dihydro-1H-2,1-benzoxazepine, were synthesised quite recently by cyclisation of the N-chlorohydroxamates. 1,2 The reaction involves generation of an electrophilic alkoxynitrenium ion 3 which , in the case of seven-membered ring formation, cyclises onto the 3-phenylpropyloxy sidechain. Paper 102 of this conference deals in detail with the mechanism of these cyclisations. 4 A range of compounds bearing different acyl and methyl ring substituents (1-7) have been synthesised and, recently, the parent -1,3,4,5-tetrahydro-2, 1-benzoxazepine (8) has been made by base hydrolysis of N-benzoyl-1,3,4,5-tetrahydro-2,1-benzoxazepine. A naphthamide analogue (9) has also been made.

Benzoxazine structures

The NMR spectra of these compounds are characterised by an unusual degree of line broadening which we have discovered is attributable to two processes; slow E/Z-isomerism about the amide bond and conformational changes in the oxazepine ring.

N-benzoyl-1,3,4,5-tetrahydro-2,1-benzoxazepine was the first member of this group to be identified. An X-ray structure indicated a chair conformation for the aliphatic ring with the phenyl substituent folded back over the aromatic portion of the benzoxazepine skeleton (ring and carbonyl oxygens cis. AM1 calculations give a similar lowest energy structure.

Benzoylbenzoxazepine (1)
(X-ray structure)


(AM1 geometry
click to change display and rotate)

The 1H NMR spectrum showed extreme line broadening for almost all signals in the aliphatic and aromatic regions. Raising the temperature to 375K in D6-DMSO resulted in sharpening of all resonances and the aromatic region was readily assigned as shown. Line broadening at room temperature was therefore particularly evident in the o-protons of the benzoyl ring as well as H8 and H9 on the benzoxazepine skeleton. Full 1H and 13C NMR assignments in D6-DMSO are shown below.

Benzoylbenzoxazepine NMR data

Contents

Amide E/Z isomerism

Most acylated benzoxazepines exhibited some degree of line broadening in their NMR spectra at room temperature as a consequence of E/Z isomerisation about the amide bond. For the N-benzoyl compounds (1-3), isomerism is relatively slow on the NMR timescale leading to broadened signals. The 13C spectra exhibited single resonances for all the carbon resonances indicating that one isomeric state was predominant. Parent (1) and 7-methylbenzoxazepine (2) were fully characterised as part of an earlier study using high temperature NMR in D6-DMSO. The 8-methyl analogue (3) was characterised similarly in this study and at 370K it's spectrum was sharp indicating a clear ABX system in the aromatic region. Full assignments were possible using 1JCH correlated experiments, selective INEPT as well as decoupling experiments.

In contrast to theN-benzoyl derivatives,N-pivaloylbenzoxazepine (5) exhibited sharp resonances in both the aliphatic and aromatic regions and both proton and carbon spectra indicated the presence of only one isomer. E/Z isomerisation must be significantly slower in this case and the equilibrium is dominated by one isomer, presumably due to the bulk of thetert-butyl group.

N-acetylbenzoxazepine (4) also exhibited extensive line broadening in its room temperature 1H NMR spectra in CDCl3 as well as the presence of major and minor isomers in the 13C and 1H spectra. Room temperature spectra were therefore recorded in the slow exchange region. Rigorous analysis of the effects of elevated temperature on the aliphatic regions of the proton and carbon spectra ofN-acetylbenzoxazepine (4) in CDCl3afforded coalescence data for the isomerisation process (Table 1)

Table 1. Coalescence data forN-acetylbenzoxazepine (4)
Position Spectrum Dfreq./Hz Tc/K kf/s -1 kb/s -1 DG ýkcal mol -1
Me 1H 119 325 113.3 239 14.8
Me 13C 102.5 324 99.1 205.9 14.9
C3 13C 124.3 327 120.4 250.0 14.9
C4 13C 19.6 308 19.0 39.4 15.1

In the slow exchange region, the proton integrals gave the relative proportions of the two isomers as 1:0.65. Detailed analysis afforded forward and reverse rate constants at each of the four coalescence temperatures from which EA fand EA bwere calculated to be 20.1 and 20.2kcal mol -1respectively. Approximating equal populations, DG ýwas calculated to be between 14.8 and 15.1 kcal mol -1(Table 1)

Like (4),N-2-methylpropanoylbenzoxazepine (6) exhibited two amide isomers at room temperature and all proton resonances were exceedingly broad ( 1H NMR spectrum at r.t. ).

In contrast to theN-benzoyl,N-acetyl and N-2-methylpropanoylbenzoxazepine derivatives above,N-acetylnaphthoxazepine (9) exhibited no line broadening in its 1H spectrum and both the proton and carbon spectra indicated the presence of two amide isomers. Elevation of the temperature in D6-DMSO resulted in time averaged environments for all aliphatic and aromatic resonances as a result of rapidE/Zisomerisation.

N-benzenesulfonylbenzoxazepine (7) exhibited no line broadening in the aromatic region of its 1H NMR spectrum/link. In addition, the carbon spectrum indicated one set of resonances. TheN­Sbond in sulfonamides is longer than theN­Cbond in amides. In addition, the barrier to rotation aboutN‹Sbonds is much smaller than that found for the analogous amides. Thus, the absence of broadening is most probably due to averaging of the chemical environments. A NOESY spectrum also indicated correlations from the benzenesulfonylorthoprotons to both the C9­H and the methylene protons adjacent to the ring oxygen.

Contents

Conformational isomerism in the oxazepine ring

When 1H NMR spectra of benzoyl derivatives, (1)-(3) were run at lower temperatures (220-230K), all three exhibited clearly defined axial and equatorial protons for the benzylic protons and the methylene adjacent to oxygen in the benzoxazepine ring. Below room temperature these molecules undergo a slowing down of a different form of isomerism resulting in separate chemical environments for all six aliphatic ring protons. The spectrum of (1) at 219K as illustrated below shows the axial protons at positions C3 and C5 resonating as triplets at d4.42 and d3.4 respectively while the associated equatorial protons are doublets at d4.6 and d3.0. The methylene protons at position 4 resonate at very similar chemical shifts and are not resolved at 300MHz.
benzoylbenzoxazine at 219K


It is clear that the slow isomerism at these temperatures involves flipping between energetically identical chair conformations similar to that observed in the solid state or predicted by AM1 calculations.

Chair isomerisation

The anisotropic shielding of aromatic protons at C8 and C9 adjacent to nitrogen in the benzoxazepine ring confirm that the oxygens arecis.

The pivaloyl substrate (5), in which only one isomer was prevalent at room temperature, also froze to a chair conformation below 250K as did the benzenesufonyl derivative (7) and in the latter case there was no evidence for slowing of isomerisation about theN‹Sbond although chemically distinct methylene protons were broader than in the case of the benzoyl substrates.

Low temperature 1H NMR spectra of acetylbenzoxazepine (4) and 2-methylpropanoylbenzoxazepine (6) indicated the presence of chair conformers for both theEandZ-isomers. A spectrum of the acetyl compound (4) at 220K diplayed overlapping equatorial and axial benzylic resonances at d2.85 and d3.15 and in one isomer the methylene hydrogens adjacent to oxygen resonate normally at d4.2 (axial) and d4.4 (equatorial). The same protons in the other amide isomer also overlap at ~ d4.4.

Acetylbenzoxazepine at 220K


The 2-methylpropanoyl compound (6) displayed a similar spectrum at 230K but, in addition, separate methine and methyl resonances were evident. Two sets of diasteriotopic isopropyl methyls were evident. The upfield pair correlating with the methine at d2.5 and the downfield pair correlating with a methine overlapping the axial benzylic proton at d3.3. A NOESY spectrum at 230K indicated that the upfield methine correlated with aromatic protons and therefore corresponded to the isomer in which the isopropyl group was over the aromatic ring (oxygenscis)
isobutanoyl at 220K

The unsubstituted benzoxazepine (8) exhibited a chair conformation at lower temperatures than the other benzoxazepines and at 220K, only the benzyl protons were clearly resolved into distinctly different environments. Isomerisation in this substratewould be expected to be a faster process when compared toN-acylated derivatives.

Each of theEandZ-isomers ofN-acetylnaphthoxazepine (9) was conformationally stable at room temperature. Axial and equatorial benzylic and oxymethylenic hydrogens are clearly discernable for each isomer. Resonances for the major isomer (red) and minor isomer (blue) are depicted in the accompanying COSY spectrum of the aliphatic region.

COSY spectrum of naphthoxazine (9)

It is clear that relative to the benzoxazepines (1) to (8), the bay orientation of the acetyl substituent results in a strong steric barrier to ring inversion due to interference with the peri hydrogen. Though not measured, this barrier must be high as even at 398K in D6-DMSO the ring methylenes and acetyl methyls are still extremely broad .

Contents

Variable temperature NMR studies and energetics of ring isomerism

Variable temperature NMR studies were carried out for all benzoxazepines (1)­(8). Raising the temperature above the slow exchange range forN-benzoylderivatives (1)-(3),N-pivaloyl- (5) and benzenesulfonyl compound (7) in which only one isomer was present resulted in coalescence of methylenic protons at the 3- and the benzylic positions. Coaelscence temperatures, chemical shift differences rate constants and DG ýfor the ring inversion are provided in Table 2. TheN-acetyl (4) andN-2-methylpropanoyl (6) derivatives, each of which presented chair conformations for both theE- andZ-forms at low temperature displayed three coalescences two of which were for the benzylic protons and one for the oxymethylene of one isomer. In addition, the diastereotopic isopropyl methyls in each isomer of (6) also coalesced through the same dynamic process (Table 2).

The benzylic protons of the unsubstituted parent (8), which were the only methylene clearly resolved at low temperature, coalesced at 242K yielding a rate constant of 216.2 s -1indicating the fastest isomerisation of all the chair forms studied. The DG ýof 10.98 kcal mol -1for the ring inversion was correspondingly the smallest that we observed. Most typically, the DG ýwere in the region of 11.5-12.5 kcal mol -1and the reduced value for the unsubstituted benzoxazepine indicates that a strong contributor to free energy barrier to inversion is steric hindrance between the acyl substituent and the aromatic proton on the 9­position. In the case of the acetyl (4) and 2-methylpropanoyl (6) substrates, one isomer has an inversion barrier in the above range but the other has a measurably higher barrier to inversion. In the case of the isobutanoyl substrate, coalescence of one set of the benzylic protons ( DG ý=13.6 kcal mol -1) and the isopropyl methyls ( DG ý=14.0 kcal mol -1) are found for the isomer in which the amide and ring oxygens arecisie the isopropyl group over the aromatic ring (6B, Table 2). Similarly, one isomer of the acetyl substrate (4) has a higher barrier of 12.4 kcal mol -1and most probably corresponds to the isomer with methyl over the aromatic ring ie the methyl upfield (4B, Table 2). Thus, spacially demanding groups on theN­acyl substituent measurably slow the rate of ring inversion and particularly so if the acyl sidechain is trans to the ring oxygen. The extreme case of this is found for the naphthoxazepine where ring mobility is very slow, even at room temperature.

Table 2. Coalescence data for benzoxazepines (1)­(8)
Benzoxazepine Coalescence DFreq./Hz J/Hz Tc/K DG ý/kcal mol -1 kc/s -1
benzoyl (1) benzylic CH2
O­CH2

O­CH2Tw-bt 		103.0
38.0

81.3 		13.2
12.2

- 		274
260

247 		12.42
12.19

11.30 		238.9
107.4

180.6
7-methylbenzoyl (2) benzylic
O­CH2

O­CH2Tw-bt 		112.3
40.8

78.3 		13.44
11.74

- 		283
265

247 		12.82
12.42

11.32 		259.9
110.8

173.9
8-methylbenzoyl (3) benzylic
O­CH2Chair

O­CH2Tw-bt 		102.2
39.1

80.6 		13.23
11.74

11.31 		275
260

245 		12.49
12.19

11.19 		238.2
107.7

189.4
Acetyl alt. (4) A benzylic
O­CH2 		72
63.2 		12.6
11.0 		255
253 		11.71
11.68 		174.0
152.6
Acetyl (4) B benzylic 72.0 12.6 270 12.42 174.0
Pivaloyl (5) benzylic
O­CH2 		103.0
34.0 		12.6
11.5 		254
241 		11.50
11.31 		238.9
98.1
Methylpropanoyl alt. (6) A benzylic
O­CH2
methyls 		68.0
80.0
21.0 		14.5
12.38
- 		256
254
240 		11.76
11.61
11.62 		170.5
190.1
46.7
methylpropanoyl (6) B benzylic
methyls 		63
47.3 		15.2
- 		294
297 		13.62
14.02 		162.4
105.1
benzenesulfonyl (7) benzylic
O­CH2 		144.0
62.0 		-
- 		270
260 		12.10
12.07 		319.9
137.7
hydro (8) benzylic 97.3 13.87 242 10.98 216.2

Contents

Low temperature conformations and AM1 studies

The chair conformation

Chair conformer stereo view
Stereo view of chair conformation of (1)
(To animate see Table 3)

All low temperatures NMR shifts and coupling data accord with a chair conformation and isomerism involves interchange between two such forms, a process that interchanges protons between equatorial and axial environments. As outlined above, this is the structure in the solid state as well as that predicted by semiempirical AM1 calculations. Table 3 below gives AM1 optimised energies and geometries in rotatable form for various conformations of both parent benzoxazepine (8) andN-benzoylbenzoxazepine (1). In both cases the chair form is certainly the lowest energy structure. A search of the geometrical surface located two other local minima higher in energy than this chair form. These are the boat and the twist-boat forms. In both cases, the boat conformation turned out to be the highest in energy although the difference between boat and twist-boat forms for (1) was small whereas for the parent benzoxazepine (8) the twist-boat was only marginally higher in energy than the chair form.


Table 3. AM1 optimised geometries and Heats of Formation (kcal mol -1) for benzoxazepines (1)­(8)
AM1 Geometries
Benzoylbenzoxazepine (1) 		DHf AM1 Geometry
Benzoxazepine (8) 		DHf

(click to change display and rotate)
Chair
24.83

(click to change display and rotate)
Chair
13.36

(click to change display and rotate)
Twist-boat
27.06

(click to change display and rotate)
Twist-boat
13.90

(click to change display and rotate)
Boat
27.83

(click to change display and rotate)
Boat
18.39


The twist-boat and boat conformations

Twist-boat conformer stereo view
Stereo view of twist-boat conformation of (1)
(To animate see Table 3)

Boat conformer stereo view
Stereo view of boat conformation of (1)
(To animate see Table 3)

In the low temperature NMR spectra of benzoyl derivatives (1)-(3), and particularly in the 8-methylderivative (3), a second low temperature conformer is evident. A low temperature COSY spectrum at 220K is shown below and satellite resonances for axial and equatorial hydrogens of the oxymethylene ( d3.75 and d4.05) as well as the benzylic methylenes ( d3.05 and d2.80) are evident and correlated through the methylene at C4.

COSY spectrum of 8-methylbenzoylbenzoxazepine (3)


Variable temperature studies indicated that the the C3 hydrogens coalesced at very low temperature and that the resultant signals ultimately coalesced with the respective coalesced methylenes from the chair conformation. Thus this minor conformation can clearly convert into the chair conformation but itself isomerises with a lower barrier. (Table 2, Tw-bt DG ý= 11.2 kcal mol -1). Careful analysis of models and AM1- optimised geometries indicates that this must be an intermediate twist-boat conformation. The twist-boat structure results in distinctly axial and equatorial proton environments at both the benzylic and 3-positions. In the boat structure, the benzylic protons and the 4-methylene protons are however largely eclipsed (Table 3). Axial and equatorial environments are interchanged through interconversion between equivalent forms.
Twist-boat isomerisation

Pseudo-rotation

Models indicate that a twist-boat to twist-boat interconversion can proceed through a pseudo-rotation via one boat conformation.

Twist-boat isomerisation

In seven-membered rings, this is normally extremely facile but fusion with the benzene ring slows this process and the high EApseudorotation also involves an energetically unstable transition geometry in which the nitrogen substituent is coplanar with the aromatic ring. A representation of this transition state is shown below.


(click to change display and rotate)

Chair-to-chair interconversion involves a comparatively strained flipping to the nearest boat conformer (but with minimal change at nitrogen), a high EApseudo-rotation via one twist-boat form to the alternative boat followed by flipping once again.

Twist-boat isomerisation

Contents

Conclusions

This novel class of benzoxazepines has a comparatively strained seven-membered ring which adopts a chair conformation as its lowest energy form. Where anN-benzoyl substituent is present there is evidence that they also adopt a twist-boat conformation. Isomerisation between equivalent chair conformations (and equivalent twist-boat conformations) is slowed at low temperatures (220-260K) and results in chemically distinct axial and equatorial proton environments in their 1H NMR spectra. The energetics of the isomerisation processes (Table 2) indicate that bulk of theN-acyl group is an important factor in determining ease of isomerisation which involves a pseudorotation through a transition state in which this group interferes strongly with the adjacent aryl hydrogen. In the case of the isobutanoyl and acetyl sidechains, chair conformers forE- andZ-amide isomers are clearly evident at low temperature. The greatest isomerisation barrier is found for the chair form in which the methyl and isopropyl groups are over the aromatic ring (oxygenscis). Where severe steric interference to isomerisation is present, as in the case ofN-acetylnaphthoxazepine, the ring assumes a chair conformation even at room temperature and isomerisation is still comparatively slow at 398K. AM1 calculations predict chair and twist-boat conformations to be the most stable and the isomerisation processes have been analysed. Finally, slow amideE/Z-isomerisation is evident inN-acetyl-,N-(2-methylpropanoyl)- andN-benzoylbenzoxazepines and the barrier ( DG ý=15 kcal mol -1, EA=20 kcal mol -1) has been determined for theN-acetyl derivative.

Contents

References

  1. Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad, J. L.J. Chem. Soc. Perkin Trans. 2, 1984, 2255.
  2. Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad, J. L.Tetrahedron, 1987,43, 2577.
  3. Glover, S. A.; Scott, A. P.Tetrahedron, 1989,45, 1763.
  4. Glover, S. A.; Rowbottom, C. A.; Scott, A. P.; Schoonraad, J. L.Tetrahedron, 1990,46, 7247.