Synthesis of 8-substituted 5H,9H-6-oxa-7-azabenzocyclononene- 10,11- dione- 11-O-methyloximes, a new [1,2]-oxazonine ring system

Article abstract of DOI:10.1016/S0040-4020(99)01076-5

Reaction of (2-bromomethyl-phenyl)-methoxyimino-acetic acid methyl ester 4 with oximes 1 in the presence of NaH/DMF yields 8-substituted 5H,9H-6-oxa- 7-aza-benzocyclononene-10,11-dione-11-O-methyloximes 3 together with the expected open chain compounds 2. Some spectroscopic data as well as synthetic and mechanistic aspects of the formation of the novel compounds 3 are discussed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(99)01076-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1381–1384
Synthesis of 8-substituted 5H,9H-6-oxa-7-aza-
benzocyclononene-10,11-dione-11-O-methyloximes, a new
1
[1,2]-oxazonine ring system
a,∗
a
a
b
c
Alfons Pascual, Hugo Ziegler, Stephan Trah, Peter Ertl and Tammo Winkler
a
Research, Chemistry Projects, Novartis Crop Protection AG, CH-4002 Basel, Switzerland
Research, Lead Discovery, Novartis Crop Protection AG, CH-4002 Basel, Switzerland
b
c
Research Support, Novartis Crop Protection AG, CH-4002 Basel, Switzerland
Received 15 November 1999; accepted 13 December 1999
Abstract
Reaction of (2-bromomethyl-phenyl)-methoxyimino-acetic acid methyl ester 4 with oximes 1 in the presence
of NaH/DMF yields 8-substituted 5H,9H-6-oxa-7-aza-benzocyclononene-10,11-dione-11-O-methyloximes 3 to-
gether with the expected open chain compounds 2. Some spectroscopic data as well as synthetic and mechanistic
aspects of the formation of the novel compounds 3 are discussed. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: carbanions; cyclic ketones; cyclisation; deprotonation; oximes; substitution.
2
In the course of our research on pesticidal oxime ether compounds 2, we observed the unexpected
formation of a new compound, to which the [1,2]-oxazonine ring structure 3 was assigned (Scheme 1).
We report herein some examples of the synthesis of this novel heterocyclic system 3, together with its
spectroscopic characterisation as well as some considerations on the reaction mechanism and the ring
conformation.
The reaction of oximes 1 (for R see Table 1) with the bromides 4 in the presence of 1.1 equiv.
NaH in DMF usually yields the oxime ether derivatives 2 in good yields. In some cases, however, an
additional compound was formed that was assigned the [1,2]-oxazonine structure 3 (see Table 1, entry
3
a). Increasing the amount of NaH favoured the formation of 3 (Table 1, entries b–d).
Compound 2 is not an intermediate in the formation of 3, as shown by treatment of 2 with NaH in
DMF, which resulted in slow cleavage of the ester group to the acid 5. We suggest therefore that the
oxime dianion is formed which reacts first with the ester group of 4, followed by ring closure to 3.
Oxime dianions have been already described.4
The thiophene analogue 6 (Scheme 2) reacted similarly with the oxime 1e.
∗
Corresponding author. Fax: +41-616978529; e-mail: alfons.pascual@cp.novartis.com (A. Pascual)
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01076-5
tetl 16389

1
382
Scheme 1.
Table 1
Reaction of bromide 4 with oximes 1a–d
Reaction of 1a with 2.1 equiv. NaH resulted in the formation of an additional compound, to which
5
the fused oxazine ring structure 9 (Scheme 3) could be assigned with a heteronuclear multiple bond
correlation. Interestingly, 3a is not an intermediate in the formation of 9, as shown by treating 3a under the
reaction conditions and with various acids and bases. Related structures like 9a-methoxy-3,9a-dihydro-
4
-oxa-4a-aza-fluoren-9-one have been described by Danishefsky and coworkers.6
The NMR spectra of 3 show exchange broadening for the two CH groups at room temperature. At
2
−
50°C, they both split into an AB system (chemical shift values in CDCl for 3d: H 4.24 and 3.60, H
3 9 5

1
383
Scheme 2.
Scheme 3.
5.54 and 5.32 ppm). This shows that the nine-membered ring assumes a chiral conformation and that ring
inversion is slow on the NMR time scale. The large chemical shift difference between the two protons
H (0.64 ppm) can then be explained by the chiral conformation and the proximity of the carbonyl and
9
the isoxazolyl substituents.
This is borne out by a semiempirical AM1 calculation of the minimised conformation of 3d (Fig. 1). It
shows one of the two protons H to be coplanar with the carbonyl group, an arrangement which introduces
9
7
a strong downfield shift. Thus, the observation of chirality strongly supports the nine-membered ring
structure for 3.
Figure 1. Minimised conformation of 3d.
References
1
2
3
. Presented in part at the 17th International Congress of Heterocyclic Chemistry, Vienna University of Technology, August
–6, 1999.
. Farooq, S.; Trah, S.; Ziegler, H.; Zurflüh, R.; Pascual, A.; Szczepanski, H.; Hall, R. G. (Novartis). World Pat. Appl. WO
7/20809, 1997; Ziegler, H.; Trah, S.; Zurflüh, R.; Farooq, S. (Ciba–Geigy). World Pat. Appl. WO 95/18789, 1995.
. As a typical experiment the synthesis of compound 3d is described: NaH (0.24 g of an approximately 55% oil dispersion,
.52 mmol) are suspended in DMF (5 ml). A solution of the oxime 1d (1.00 g, 2.76 mmol) in DMF (5 ml) is added slowly
at room temperature. After 2 h at room temperature, bromide 4 (0.79 g, 2.76 mmol) in DMF (5 ml) is added dropwise, and
1
9
5

1
384
stirring is continued at room temperature overnight. To the formed red solution, AcOH (1.5 ml) is added and after stirring for
5
min the solvents are evaporated. The residue is diluted with ethyl acetate, washed twice with water and once with saturated
sodium chloride solution. After drying (Na SO ) and evaporating the solvent, the residue is purified by flash chromatography
hexane/ethyl acetate 9:1). 0.50 g (34%) of 3d are obtained. Mp 164–166°C; EI-MS (70 eV): 536 (10), 535 (M , 32), 506
2
4
+
(
(
(
1
17), 505 (46), 504 (12), 474 (10), 304 (36), 116 (100); H NMR (250 MHz, CDCl
part of an AA BB -system, 2H), 7.62 (part of an AA BB -system, 2H), 7.45–7.40 m (3H), 7.25–7.20 m (1H), 7.18 (part of
3
; coupling constants given in Hz): 7.90
0
0
0
0
0
0
0
0
an AA BB -system, 2H), 7.12 (part of an AA BB -system, 2H), 7.05 s (1H), 5.40 s (2H), 3.90 br s (2H), 3.79 s (3H). Physical
data for new compounds 3a–c and 7: For 3a: Mp 125–127°C; H NMR (250 MHz, CDCl
1
0
0
3
): 7.68 (part of an AA BB -system,
0
0
2
2
8
7
H), 7.42–7.39 m (3H), 7.27 m (1H), 7.21 (part of an AA BB -system, 2H), 5.28 s (2H), 4.02 s (3H), 3.88 s (3H), 3.71 s (2H),
.49 s (3H); 13C NMR (250 MHz, CDCl
): see Fig. 2. For 3b: Mp 92–96°C; FD-MS: 376 (M ); H NMR (250 MHz, CDCl
+
1
):
3
3
0
0
0
0
.01 s (1H), 7.89 (part of an AA BB -system, 1H), 7.73 (part of an AA BB -system, 1H), 7.59 m (1H), 7.43–7.37, m (3H),
.26–7.20 m (1H), 5.37 s (2H), 3.80 s (2H), 3.75 s (3H). For 3c: Mp 129–130°C; H NMR (250 MHz, CDCl ): 7.40–7.36 m
3
1
(
3H), 7.21 m (1H), 5.33 s (2H), 4.10 s (3H), 3.87 s (3H), 3.74 br s (2H), 2.51 s (3H). 7: Mp 129–131°C; EI-MS (70 eV): 474
+
1
3
(M , 13), 445 (27), 444 (100), 413 (31), 412 (23), 277 (29), 263 (34), 122 (84); H NMR (250 MHz, CDCl ): 7.54 d (1H, J=6
Hz), 7.52–7.35 m (5H), 7.30–7.25 m (1H), 7.20–7.06 m (2H), 6.85 d (1H, J=6 Hz), 5.36 s (2H), 3.92 s (3H), 3.90 s (2H).
Figure 2. 13C NMR data for 3a and 9.
4
5
. Livingston, M. J.; Chick, M. F.; Shealy, E. O.; Beam, C. F. J. Heterocycl. Chem. 1982, 19, 215.
. Isolation of compound 9: NaH (0.96 g, 22.0 mmol), 1a (2.50 g, 10.5 mmol), and 4 (3.00 g, 10.5 mmol) are reacted as shown
for 3d. After work-up, the residue is filtered on silica gel (ethyl acetate). The first fraction is separated by flash chromatography
(
ethyl acetate:hexane 1:4) to give, in the order of elution, traces of 1a, compound 3a (0.14 g, 3%), 2a (0.19 g, 4%) and
+
1
3
compound 9 (0.11 g, 3%) as resin. Physical data for 9: ESI-MS: 412.19 (M ); H NMR (250 MHz, CDCl ): 7.92 (part of an
0
0
0
0
0
0
AA BB -system, 1H), 7.69 (part of an AA BB -system, 2H), 7.40–7.27 m (4H), 7.03 (part of an AA BB -system, 1H), 6.16
s (D
O exch., 1H), 5.81 s (1H), 5.05 d (1H, J=15 Hz), 4.69 d (1H, J=15 Hz), 4.09 s (3H), 3.66 s (3H), 2.52 s (3H); 13C NMR
250 MHz, CDCl ): see Fig. 2. The second fraction from the filtration contains the acid 5 (2.00 g, 45%).
2
(
3
6
7
. McClure, K. F.; Benbow, J. W.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1991, 113, 8185; Benbow, J. W.;
McClure, K. F.; Danishefsky, S. J. Am. Chem. Soc. 1993, 113, 12 305.
. Jackman, L. M.; Sternhell, S. Application of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry; Pergamon,
Oxford, 2nd ed., 1969, p. 88