Synthesis of a new heterocyclic amide-imine.



Abstract. -- Methyl glutarate and ethylenediamine react at 162[degrees]C to form 1,7-diaza-2-oxobicyclo[4.3.0]non-6-ene. This unexpected product may be the result of a transannular amide-amide reaction with loss of water from the first-formed nine-membered ring ethylene glutaramide. This bicyclic amide-imine has been reduced with lithium aluminum hydride to 1,7-diazabicyclo[4.3.0]nonane.

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The difficulty of making nine-membered ring compounds from noncyclic precursors has been demonstrated. Examples can be found in discussions of the unusual properties of medium-sized rings (Prelog 1950; Huisgen 1957; Sicher 1962; Eliel et al. 1965; Dale 1971). The difficulty is caused by overlap of van der Waals radii and repulsion before the two ends of a chain may become joined and, in the ring, by repulsions between transannular hydrogens and by unfavorable dihedral angles. The steric reasoning was first proposed over 60 years ago (Stoll & Stoll-Comte 1930). However, a discussion of torsional constraints (planar groups such as amide and benzo) predicted that ring formation should be easier if these groups were present (Alder & White 1988).

An interesting example of a medium ring with torsional constraint groups was presented by the observation that the nine-membered ring, cyclic ethylene glutaramide, could be made by reaction of ethylenediamine and a diester of glutaric acid in a heated solution of an oxygen-containing solvent (Lippert & Reid 1939). Experimental details for this particular synthesis were not presented in the patent examples, but related examples, reactions of ethylenediamine and other diesters, involved refluxing methanol solvent (b.p. 65[degrees]C) and times of 40 to 50 hours. Over three decades later cyclic ethylene glutaramide was again prepared (Grinberg et al. 1975). These authors tried to dehydrate cyclic ethylene glutaramide by azeotropic distillation, but they were unsuccessful.

This study of the reaction between methyl glutarate and ethylenediamine involved refluxing diglyme solvent (b.p. 162[degrees]C) for 96 hours. The major product was 1,7-diaza-2-oxobicyclo[4.3.0]non-6-ene (Compound 1), a new compound. Reaction at 162[degrees]C appears to provide an example of a transannular reaction between two amide groups of cyclic ethylene glutaramide.

Transannular reactions between one amide group and one other group have already been observed (Witkop et al. 1951; Cohen & Witkop 1955; Shemyakin et al. 1965). Moreover, transannular amide-amide reactions have been observed to give monocyclic products (Glover & Rapaport 1964; Glover et al. 1965). Also noteworthy are reactions in which medium-sized ring dipeptides gave bicyclic products by azeotropic distillation of water (Shemyakin et al. 1965).

When Compound 1 was reduced with lithium aluminum hydride, the product was 1,7-diazabicyclo[4.3.0]nonane (Compound 2).

The structure of Compound 1 was proved by nuclear magnetic resonance (NMR) and by high resolution mass spectrometry (HRMS). The [.sup.13]C chemical shifts are consistent with chemical shifts in similar bicyclic acylamidines (Huang & Wamhoff 1984). Compound 2 has been reported (Alder et al. 1982), but physical properties and analytical information about Compound 2 were not mentioned in the article; therefore, the data are included below.

SYNTHESIS AND ANALYSIS OF EACH COMPOUND

Preparation of compound 1. -- 1,7-Diaza-2-oxobicyclo[4.3.0]non-6-ene (Figure 1). To a flask previously flushed with argon, which was equipped with a magnetic stirrer and a reflux condenser, were added 300 mL of diglyme, 16.0 g (0.1 mol.) of methyl glutarate, and 6.0 g (0.1 mol.) of ethylenediamine. The reaction mixture was stirred and refluxed for 96 hours. During the first 48 hours the solution was transparent, but a precipitate began forming after 48 hours. At room temperature the solid was removed by gravity filtration. It was dried in a vacuum desiccator over phosphoric anhydride. The pale yellow powder weighed 1.72 g and melted with decomposition at 260-270[degrees]C--reported for cyclic ethylene glutaramide, 287-289[degrees]C (Grinberg et al. 1975). Diglyme was removed from the filtrate by distillation. The residue was distilled. Compound 1 distilled at 90-92[degrees]C (0.2 torr). The colorless distillate was a super-cooled liquid which slowly solidified; the solid melted at 45[degrees]C. This colorless distillate weighed 7.7 g (56% yield). The structure was determined by HRMS (molecular ion 139.087349, [C.sub.7][H.sub.11][N.sub.2][O.sup.+]) and two dimensional NMR (COSY, NOSY, HMQC, HMBC): C2, [delta] 157.6; C3, [delta] 24.5; C4, [delta] 18.1; C5, [delta] 31.4; C6, [delta] 167.8; C8, [delta] 40.2; C9, [delta] 52.3; H3, [delta] 2.08; H4, [delta] 1.10; H5, [delta] 1.95; H8, [delta] 3.35; H9, [delta] 3.46. All NMR spectra were taken in [C.sub.6][D.sub.6]. The infrared spectrum of Compound 1 exhibited strong absorption bands at 1692 [cm.sup.-1] and 1652 [cm.sup.-1], but not any absorption at a higher frequency than 3000 [cm.sup.-1].

[FIGURE 1 OMITTED]
 The perchlorate, colorless plates from ethanol, melted at
 120-121[degrees]C.
 Anal.: Calc. for [C.sub.7][H.sub.10][N.sub.2]O*HC1[O.sub.4]: C,
 36.03; H, 4.59; N, 11.59
 Found: C, 35.79; H, 4.54; N, 11.54
 The infrared spectrum of the perchlorate exhibited strong absorption
 bands at 3200, 1710, and 1645 [cm.sup.-1].

 The picrate, yellow needles from ethanol, melted at
 203-204[degrees]C
 Anal.: Calc. for [C.sub.7][H.sub.10][N.sub.2]O*
 [C.sub.6][H.sub.3][N.sub.3][O.sub.7]: C, 42.51; H, 3.57; N, 19.07
 Found: C, 42.73; H, 3.44; N, 18.88


Preparation of compound 2. -- 1,7-Diazabicyclo[4.3.0]nonane (Figure 2). To a flask previously flushed with argon, which was equipped with a magnetic stirrer and a reflux condenser, were added 125 mL of ethyl ether, 3.8 g of lithium aluminum hydride powder, and 2.0 g of Compound 1. The mixture was stirred at room temperature for 14 hours and then was heated to reflux for two hours. The mixture was chilled with an ice-water bath and 10 mL of water was added dropwise. The solid was removed by filtration and the filtrate was concentrated to a yellow/orange residue. The residue was distilled. There was obtained 0.70 g of colorless Compound 2, which distilled at 26[degrees]C (0.2 torr), 38% yield. The structure was studied by HRMS (molecular ion 127.123819, [C.sub.7][H.sub.15][N.sub.2.sup.+]) and two dimensional NMR (COSY, NOSY, HMQC): C2, [delta] 50.3; C3, [delta] 25.1; C4, [delta] 23.4; C5, [delta] 29.9; C6, [delta] 78.6; C8, [delta] 42.8; C9, [delta] 52.2; H2, [delta] 2.97 and [delta] 1.94; H3, [delta] 1.52 and [delta] 1.41; H4, [delta] 1.72 and [delta] 1.20; H5, [delta] 1.77 and [delta] 1.14; H6, [delta] 2.38; H8, [delta] 2.88 and [delta] 2.68; H9, [delta] 2.97 and [delta] 2.00. All NMR spectra were taken in DMSO-[d.sub.6].

[FIGURE 2 OMITTED]

The infrared spectrum of Compound 2 exhibited no absorption in the region between 1500 [cm.sup.-1] and 2700 [cm.sup.-1]. A medium band at 2795 [cm.sup.-1] and a weak band at 3320 [cm.sup.-1] were in Compound 2 spectrum, but not in the Compound 1 spectrum.
 The perchlorate, colorless plates from ethanol, melted at
 135-137[degrees]C (dec.).
 Anal.: Calc. for [C.sub.7][H.sub.14][N.sub.2]*2HCl[O.sub.4]: C,
 26.00; H, 4.93
 Found: C, 25.72; H, 4.90


LITERATURE CITED

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Alder, R. W. & J. M. White. 1988. Nitrogen Heterocycles. Pp. 97-149, in Conformation Analysis of Medium-Sized Heterocycles (R. S. Glass, ed.), VCH Publishers, Inc., New York, 97:xiv + 274 pp.

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Lippert, A. L. & E. E. Reid. 1939. Cyclic Amides and Their Production. United States Patent 2,156,300. May 2, 1939: 4 pp. Chem. Abstr., 1939 33:6064.

Prelog, V. 1950. Newer Developments of the Chemistry of Many-membered Ring Compounds. J. Chem. Soc., 420-428.

Shemyakin, M. M., V. K. Antonov, A. M. Shkrob, V. I. Shchelokov & Z. E. Agadzhanyan. 1965. Activation of the Amide Group by Acylation. Tetrahedron, 21:3537-3572.

Sicher, J. 1962. The Stereochemistry of Many-Membered Rings. Pp. 202-263, in Progress in Stereochemistry, volume 3 (P. B. D. de la Mare and W. Klyne, ed.), Butterworths, Washington, D. C. 202: viii + 368 pp.

Stoll, M. & G. Stoll-Comte. 1930. Zur Kenntnis des Kohlenstoffringes XVI. Uber den Zusammenhang Zwischen Dichte und Molekelanordnung innerhalb einer Reihe homologer normaler aliphatischer und cyclischer Kohlenwasserstoffe. Helv. Chim. Acta, 13:1185-1200.

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Ben A. Shoulders, C. W. Schimelpfenig and Gretchen M. Schimelpfenig*

Department of Chemistry, University of Texas at Austin

Austin, Texas 78712 and

*Department of Chemistry, University of North Texasf

Denton, Texas 76203

BAS at: bens@utxms.cc.utexas.edu

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