Conversion of Hexahydrotriazines to Imidazolines

Abstract: The isolation and characterization of an imidazoline obtained from the reaction of ammonia and an aldehyde is reported. The stereochemistry of the imidazoline is confirmed using x-ray diffraction and is used in support of a mechanism involving the conversion of an intermediate hexahydrotriazine to an imidazoline. The mechanism is also supported by the direct conversion of a hexahydrotriazine to an imidazoline.

The chemistry of hexahydrotriazines has appeared in the literature since the 1800's when it was recognized that ammonia formed trimeric compounds with aldehydes.[1] Most synthetic routes to hexahydrotriazines in the literature employ aqueous solvent systems. Under these conditions hydrates of hexahydrotriazines are normally isolated.[2] Recently we achieved the synthesis of hexahydrotriazines under anhydrous conditions employing acetonitrile as the solvent. These reaction conditions yield crystals of hexahydrotriazines without water present in the lattice. This led to the observation of unique 1H nmr characteristics exhibited by these compounds.[3] When the synthesis of hexahydrotriazine 1 was carried out by this anhydrous route a very small amount of the isomeric hexahydrotriazine 2 was detected by 1H nmr.[4]

In an attempt to isolate 2 the reaction was scaled up and the product crystallized at room temperature instead of at -30oC as done previously. This procedure indeed gave two distinct types of crystals which could be physically separated. The majority of the crystals were in the form of needle-like prisms while the remainder were plate-like crystals. The needle-like crystals were identified as 1 by 1H nmr.[5] The plate-like crystals yielded a 1H nmr spectrum of a molecule that no longer had C3 symmetry. However, it was not the anticipated hexahydrotriazine 2. In fact, the 500 MHz 1H nmr spectrum indicated that there were three different pyridine rings present. Two

Figure 1

An especially interesting aspect of the structure of this compound was the cis relationship of pyridine rings. The question then became: How did it form? Previous experience with hexahydrotriazines led us to recall that with mild heating and in fact even at room temperature (albeit slowly) hexahydrotriazines decompose to give diimines and ammonia. An example of this process is the decomposition of hexahydrotriazine 4 in CDCl3 which is transformed completely to diimine 5 after sitting at room temperature for 7 days.

Since a hexahydrotriazine was isolated from the reaction along with 3, we beleive that it is formed first and that formation of 3 is a product of its decomposition, forming a diimine analogous to 5 as an intermediate. The proposed mechanism is shown in Scheme I.

Scheme I

The first step is the formation of hexahydrotriazine 1, which loses ammonia to give diimine 6. The trans,trans stereochemistry of 6 is expected from the antiperiplanar Grob-like fragmentation of 1. Deprotonation by base (probably ammonia since the solution is saturated with it) followed by an allowed disrotatory electrocyclic ring closure gives anion 8. Anion 8 yields imidazoline 3 upon protonation. This mechanism adequately explains the cis stereochemistry of the pyridine rings in the product. As further proof of this mechanism hexahydrotriazine 1 was dissolved in d6-DMSO and placed in a sealed tube. The sealed tube was then heated to 110oC for 24 hours. Examination of the solution at that time revealed only imidazoline 3 to be present.
A literature structure search on aryl-substituted imidazolines turned up an example of what appears to be an analogous anion electrocyclic ring closure for the 9 to 11 conversion shown below.[7] It thus appears that this type of ring closure for aryl substituted b-diimines may be general.

Acknowledgement: SCB wishes to thank the NSF for funding (CHE-8908065) of the Vanderbilt X-Ray facility. JTI wishes to thank the University of MN for use of their 500 MHz nmr spectrometer.

REFERENCES AND NOTES

1. (a) M.A. Laurent, Ann. 1837, 21, 130. (b) Lenart, G. H. Liebigs Ann. Chem. 1915, 410, 100. (c) Young, J. A.; Schmidt, J. J.; Krimmel, J. A. J. Org. Chem. 1971, 36, 347. (d) Nielsen, A.t.; Atkins, R.L.; DiPol, J; Moore, D. W. J. Org. Chem. 1974, 39, 1349.
2. See for example: Lund, E. W. Acta. Chem. Scand. 1958, 12, 1768.
3. Most notably the N-H proton resonances were sharp under non-exchanging conditions. A paper describing these unique features is in preparation.
4. Anhydrous ammonia was bubbled through a solution of 4-pyridinecarboxaldehyde (443 mg) in acetonitrile (9 mL). The resulting solution was placed in the freezer for 2-8 hours, after which the crystals formed were isolated by decanting off the solvent and washing with cold acetonitrile.
5. A thorough literature search resulted in a reference in which compound 1 was mentioned: Gu, C.; Gu, W. New Front. Organomet. Inorg. Chem., Proc. China-Jpn.-U.S.A. 2nd Trilateral Semin., 1982, 3-15. Edited by: B-K, Teo. Sci. Press: Beijing, Peop. Rep. China 1984. This reference does not include any spectral data or preparation procedures. Therefore, the following spectral data is presented. Compound 1: 360 MHz 1H NMR (CDCl3) d 8.65 (6 H, d, J = 5.8 Hz), 7.58 (6 H, d, J = 5.8 Hz), 5.29 (3 H, t, J = 9.8 Hz), 1.62 (3 H, t, J = 9.8 Hz, N-H). 90 MHz 13C NMR (CDCl3) d 150.19 (CH), 149.12 (tert. C), 121.18 (CH), 71.60 (CH).
6. A colorless rectangular crystal of C18H15N5 having approximate dimensions of 0.48 x 0.30 x 0.25 mm was mounted on a glass fiber. All measurements were made on a Rigaku AFC6S diffractometer with graphite monochromated Cu Ka radiation. The unit cell constants were a = 10.235 (1)�, b = 8.846 (2)�, c = 17.485 (1)�, a = 90.00, ß = 106.14 (6)�, g = 90.00, V = 1520.7 (6)�, Z = 4, and the calculated density is 1.316 g/cm (F.W. = 301.35) with a space group (#14) monoclinic P21/c. There were 1626 reflections collected and 269 variables to give R = 0.043, Rw = 0.053, and GOF = 2.111.
7. Hunter, D. H.; Sim, S. K.; J. Am. Chem.Soc., 1969, 91, 6202.

I wish to submit the following manuscript to Tet let This paper describes
Suitable reviewers would be Jerry Berson, Allan Marchand Alan Katritxsky

ENDNOTES********************************

[1]. a. M.A. Laurent, Ann. 1837, 21, 130. (b) Lenart, G. H. Liebigs Ann. Chem. 1915, 410, 100. (c) Young, J. A.; Schmidt, J. J.; Krimmel, J. A. J. Org. Chem. 1971, 36, 347. (d) Nielsen, A.t.; atkins, R.L.; DiPol, J; Moore, D. W. J. Org. Chem. 1974, 39, 1349.

[2]. See for example: Lund, E. W. Acta. Chem. Scand. 1958, 12, 1768.

[3].Most notably the N-H proton resonances were sharp under non-exchanging conditions. A paper describing these unique features is in progress.

[4]. Anhydrous ammonia was bubbled through a solution of 4-pyridinecarboxaldehyde (50 mg) in acetonitrile (10 mL). The resulting solution was placed in the freezer for 2-4 hours, afterwhich the crystals formed were isolated by decanting off the solvent and washing with cold acetonitrile.

[5]. A thorough literature search resulted in a reference in which compound 1 was mentioned: Gu, C.; Gu, W. New Front. Organomet. Inorg. Chem., Proc. China-Jpn.-U.S.A. 2nd Trilateral Semin., 1982, 3-15. Edited by: B-K, Teo. Sci. Press: Beijing, Peop. Rep. China 1984. This reference does not include any spectral data or preparation procedures. Therefore, the following spectral data is presented. Compound 1: 360 MHz 1H NMR (CDCl3) d 8.65 (6 H, d, J = 5.8 Hz), 7.58 (6 H, d, J = 5.8 Hz), 5.29 (3 H, t, J = 9.8 Hz), 1.62 (3 H, t, J = 9.8 Hz, N-H). 90 MHz 13C NMR (CDCl3) d 150.19 (CH), 149.12 (tert. C), 121.18 (CH), 71.60 (CH).

[6]. A colorless rectangular crystal of C18H15N5 having approximate dimensions of 0.48 X 0.30 X 0.25 mm was mounted on a glass fiber. All measurements were made on a Rigaku AFC6S diffractometer with graphite monochromated Cu Ka radiation. The unit cell constants were a = 10.235 (1)�, b = 8.846 (2)�, c = 17.485 (1)�, a = 90.00, b = 106.14 (6)�, g = 90.00, V = 1520.7 (6)�, Z = 4, and the calculated density is 1.316 g/cm (F.W. = 301.35) with a space group (#14) monoclinic P21/c. There were 1626 reflections collected and 269 variables to give R = 0.043, Rw = 0.053, and GOF = 2.111.

[7]. Hunter