6126
J. Org. Chem. 1999, 64, 6126-6134
Configurational Assignment of 5-Substituted Pyrazolidin-3-ones Using Circular Dichroism Spectroscopy Jadwiga Frelek,*,† Irma Panfil, Zofia Urban´czyk-Lipkowska, and Marek Chmielewski* Institute of Organic Chemistry of the Polish Academy of Sciences, Kasprzaka 44, 01-224 Warsaw, Poland Received February 20, 1998
The chiroptical properties of the title compounds bearing various substituents at the N(1) and N(2) nitrogen atoms are discussed. It was found that the sign of the n-π* Cotton effect centered at about the 230-250 nm region can be correlated with the absolute configuration of the stereogenic center at C(5). It was also found that the sign of this Cotton effect is predictable by Weigang’s lactam sector rule. MMX calculations, supported by X-ray measurements, showed that substituents at the nitrogen atoms significantly affect the conformation of the five-membered ring. It was additionally concluded that the conformation of the five-membered ring in 5-substituted pyrazolidin3-ones is the sign-determining factor for an n-π* transition. Introduction Pyrazolidin-3-ones represent an interesting class of heterocyclic compounds.1-3 Due to the strong reducing properties 1-phenylpyrazolidin-3-onesalso called phenidonesand its derivatives belong to the most widely used compounds by leading photographic companies such as Agfa, Kodak, Fuji, Konica, etc.4 Some pyrazolidinones can serve as β-lactam antibiotic substitutes due to their significant antibacterial and antirheumatic activity.5 On the other hand, pyrazolidin-3-ones can easily be transformed into β-lactams by a photochemically mediated ring contraction.6,7 5-Substituted pyrazolidinones having a polyol side chain can readily be synthesized via addition-rearrangement reaction of hydrazines to sugar δ- and γ-enelactones.8,9 However, the assignment of the regio- and stereochemistry of the products obtained by the addition of hydrazines to these enelactones is not straightforward because a direct proof of their structure and configuration by 1H or 13C NMR spectra is ambiguous. A clear elucidation of the structure should be achieved using a circular dichroism (CD) method. Therefore, it seems worthwhile †
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[email protected]. (1) Claramunt, R. M.; Elguero, J. Org. Prep. Proc. Int. 1991, 23, 273320. (2) Marchand-Brynaert; Ghosez, L. In Recent Progress in the Chemical Synthesis of Antibiotics; Lucas, G., Ohno, M., Eds.; SpringerVerlag: New York, 1990; pp 765-770. (3) Ternansky, R. J.; Draheim, S. E. In Recent Advances in the Chemistry of β-Lactam Antibiotics; Chemical Society Special Publication; Bentley, P. H., Southgate, R., Eds.; 1989; pp 139-156. (4) (a) Reeman, J. J. Photogr. Sci. 1973, 21, 227-232. (b) Washizu, S.; Yamaguchi, J.; Shinozaki, F.; Shimomura, A.; Usami, T.; Endo, T.; Saeki, K. Ger. Offen. 3,835,062, 1989; Chem. Abstr. 1989, 111, 222120. (5) (a) Rutjes, F. P. J. T.; Udding, J. H.; Hiemstra, H.; Speckamp, W. N. Heterocycles 1992, 33, 81-85. (b) Jungheim, L. N. Tetrahedron Lett. 1989, 30, 1889-1892. (c) Ternansky, R. J.; Draheim, S. E. Tetrahedron Lett. 1980, 32, 2805-2808. (6) Ege, S. N. J. Chem. Soc., Chem. Commun. 1968, 759-764. (7) (a) White, J. D.; Toske, S. G. BioMed. Chem. Lett. 1993, 3, 23832388. (b) White, J. D.; Toske, S. G. Tetrahedron Lett. 1993, 34, 207210. (c) Perri, S. T.; Slater, S. C.; Toske, S. G.; White, J. D. J. Org. Chem. 1990, 55, 6037-6047. (8) (a) Panfil, I.; Chmielewski, M. Heterocycles 1993, 34, 2267-2272. (b) Panfil, I.; Krajewski, J.; Gluzin´ski, P.; Stefaniak, L.; Chmielewski, M. Tetrahedron 1994, 50, 7219-7230. (9) (a) Borisch, J.; Pa¨tzel, M.; Liebscher, J.; Janes, P. G. Tetrahedron Lett. 1993, 34, 2449-2752. (b) Liebscher, J.; Pa¨tzel, M. Synlett 1994, 471-478.
Figure 1. Investigated compounds 1-21 and γ-lactam model compound 22.
to examine the chiroptical properties of this important class of compounds. To accomplish a stereochemical assignment, we have undertaken a circular dichroic study on a representative group of 5-substituted pyrazolidin-3-ones 1-21 presented in Figure 1. In this paper we report on CD measurements of the title compounds and present the usefulness of this technique in the determination of their absolute configuration, the site of N-substitution, and the conformation of the five-membered ring.
10.1021/jo9803232 CCC: $18.00 © 1999 American Chemical Society Published on Web 08/05/1999
5-Substituted Pyrazolidin-3-ones
J. Org. Chem., Vol. 64, No. 17, 1999 6127 Table 1. Selected Bond Length for 3, 2, and 22 and Differences in Bond Lengths |22 - 3|and |22 - 2| (pm)
Figure 2. δ-Enelactones i-iii used as substrates.
Results and Discussion Synthesis. The synthesis of compounds 1-4, 6-10, 13, 16, 18, and 19 was performed following a conjugate addition-rearrangement of unsubstituted and N-substituted hydrazines to the sugar δ-enelactones i-iii (Figure 2). The addition of unsubstituted hydrazine to lactones i and ii affords exclusively anti products with respect to the terminal substituent of the lactone.8b The same high anti stereoselectivity and low regioselectivity have been reported for the addition-rearrangement of N-methylhydrazine to R,β-unsaturated γ-lactones. The syntheses of compounds 14 and 178a and 5, 11, 12, 20, and 218b have been reported earlier. Structure and Chiroptical Properties. The pyrazolidin-3-ones can be treated as heterocyclic analogues of γ-lactams. Two electronic transitions have been characterized for amides and lactams in condensed-phase spectra between 180 and 250 nm. These are an n-π* transition at λmax ) 210-230 nm and a π-π* transition at λmax ) 180-200 nm. In the case of lactams a relationship between the sign of the n-π* Cotton effect (CE) and the chiral sense of the lactam ring has been reported.10-12 Among the several rules proposed, Weigang’s sector rule,12 which explains the optical activity of lactones and lactams, appears to be the most general one. It takes into consideration all possible conformations of the lactam ring and predictable effects of other rings and substituents. According to this rule, the sign of the n-π* band depends on the conformation of the five-membered lactam ring. This sign correlates with the sign of the sector containing the out-of-plane ring atom of envelope conformers or, in the case of a planar ring conformation, the substituent(s). A comparison of the bond lengths in the pyrazolidinone ring, determined by the X-ray structure analysis of compounds 2 and 3, with the respective bond lengths of the γ-lactam model compound 2213 confirms the suitability of γ-lactams as reference compounds for chiroptical considerations of pyrazolidinones. As shown in Table 1, the bond lengths in a pyrazolidin-3-one system are similar to those found for the γ-lactam model compound 22. The greatest difference in the bond lengths is found for the N(1)-N(2) bond in 2 and 3 and the C(1)-N(2) in 22 {for clarity the carbon atom in 22, which corresponds to the N(1) nitrogen atom in 2 and 3, is numbered as C(1)}. In addition, X-ray data prove that the nitrogen atom N(1) in compound 3 is pyramidal (the sum of the valence angles N(2)-N(1)-C(5), N(2)-N(1)-C(9), and C(5)-N(1)-C(9) for 3 is equal to 325.0°). This fact, (10) Beecham, A. F. Tetrahedron Lett. 1969, 55, 4897-4898. (11) Ogura, H.; Takayanagi, H.; Furauhata, K. J. Chem. Soc., Perkin Trans. 1 1976, 665-668. (12) Ong, E. C.; Cusachs, L. C.; Weigang, O. E., Jr. J. Chem. Phys. 1977, 67, 3289-3297. (13) Stevens, R. V.; Beaulie, N.; Chau, W. H.; Daniewski, A. R.; Takeda, T.; Waldner, A.; Williard, P. G.; Zutter, U. J. Am. Chem. Soc. 1986, 108, 1039-1049.
bond
3
|22 - 3|
2
|22 - 2|
22
N(C)1-N2 N(C)1-C5 C3-C4 C3-O3 N2-C3 C4-C5
141.3(7) 150.3(8) 150.0(1) 123.0(8) 133.8(8) 151.0(1)
3.2 2.7 1.0 1.2 0.3 0.3
140(1) 151(1) 149(2) 123(1) 131(1) 150(1)
4.5 2.0 0.4 2.0 2.5 1.3
144.5 153.0 151.0 121.8 133.5 151.3
together with the similarity of bond lengths, gives a good indication that the chromophoric system in pyrazolidin3-ones could be located in the lactam moiety. Therefore, it seems reasonable to examine the applicability of Weigang’s lactam sector rule to configurational and conformational analysis of pyrazolidin-3-ones. All UV and CD data are provided in Tables 2 and 3. In contrast to compounds from Table 2, which possess a lactam chromophore in the five-membered ring, the N(2)acetyl derivatives of the pyrazolidin-3-ones from Table 3 contain an imide chromophore. For that reason these compounds, i.e., pyrazolidinone imides 13-21, will be discussed separately. A. Pyrazolidinone Amides. As can be seen from Table 2, the pyrazolidin-3-ones 1-12 exhibit up to three Cotton effects in the range of λ ) 250-185 nm. In the case of the unsubstituted compounds 1 and 6, the longwavelength CE is observed at ca. 230 nm whereas the short-wavelength one is observed at ca. 200 nm. The third CE, visible only for compounds 5 and 12 measured in isooctane, appears approximately at λ ) 188 nm. Substitution of one of the nitrogen atoms by a methyl group does not significantly influence the position of the CD bands. However, substitution of the N(1) atom by an acetyl group causes a shift of about ∆λ ) 10 nm to the red for both CD bands. In general, the substitution causes an additional increase in the magnitude of particular CEs going from the unsubstituted compounds (1 and 6) to these substituted by a methyl group (2, 3, 7, and 8) and to the N(1) acetamide derivatives (4, 5, and 9-12). Due to the instability of some compounds from this series in polar solvents, e.g., acetonitrile or methanol, and the insolubility of others in nonpolar solvents, it is not possible to systematically study the solvent dependence on the CD spectra. However, the data obtained for compounds 4, 5, 9, and 12 (Table 2) demonstrate a red shift of the long-wavelength band appearing at ca. λmax ) 230-240 nm in going from acetonitrile to isooctane. The observed red shift of this band suggests its origin to be an n-π* lactam transition. In the UV spectra of pyrazolidinone amides 1-12 (Table 2) the n-π* absorption band appears as a shoulder in the range of 248222 nm. For N(1)-acetamides 4, 9, and 10 an additional absorption maximum connected with the presence of an acetamide group is found at λmax ) 215 nm.14 On the other hand, a strong absorption band occurring at λmax ) 207 nm in compounds 5, 11, and 12 can be connected with the presence of a phenyl group. The short-wavelength absorption band at ca. 200 nm, probably of a π-π* origin, is well separated only in the spectra of compounds 1, 2, 4 (in isooctane), and 7. For the remaining compounds it is buried under other, very close lying absorption maxima. In the case of N(1)acetamides 4, 9, and 10 this band overlaps with the band originating from the absorption of the acetate group. In the case of 5, 11, and 12, however, it is buried beneath the 207 nm absorption band as well as the 215 nm band.
6128 J. Org. Chem., Vol. 64, No. 17, 1999
Frelek et al.
Table 2. UV and CD Data of Compounds 1-12 in Isooctane (O) or/and Acetonitrile (A) compd
solvent
UV: (λ (nm))
1
O
2
O
3
A
4
A O
299sh (233) 985 (200) 1420sh (231) 3410 (203) 4370sh (228) a (
