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Volume 62 
Part 6 
Pages o2318-o2320  
June 2006  

Received 26 April 2006
Accepted 9 May 2006
Online 12 May 2006

Key indicators
Single-crystal X-ray study
T = 293 K
Mean [sigma](C-C) = 0.004 Å
R = 0.042
wR = 0.126
Data-to-parameter ratio = 12.7
Details

The dipolar cycloaddition of methyl acrylate to 5,6-diethyl-1-methyl-3-oxidopyrazinium

aThe School of Chemistry, The University of Manchester, Manchester M13 9PL, England
Correspondence e-mail: john.joule@manchester.ac.uk

5,6-Diethylpyrazin-2-one reacts with iodomethane to give a quaternary salt, deprotonation of which, in situ, liberates a 3-oxidopyrazinium which undergoes a 1,3-dipolar cycloaddition with methyl acrylate to form methyl (Z)-5-ethyl-4-ethylidene-8-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octane-6-endo-6-carboxylate. The crystal structure revealed (i) the existence of the imine product as its enamine tautomer, (ii) the Z geometry of the exocyclic double bond, and (iii) the endo orientation of the ester group. Pairwise hydrogen bonding between the NH H atom and the amide carbonyl group links the molecules into centrosymmetric dimers.

Comment

In our investigations of the 1,3-dipolar cycloaddition chemistry of 3-oxidopyraziniums (Kiss et al., 1987[Kiss, M., Russell-Maynard, J. & Joule, J. A. (1987). Tetrahedron Lett. 28, 2187-2190.]; Allway et al., 1990[Allway, P. A., Sutherland, J. K. & Joule, J. A. (1990). Tetrahedron Lett. 31, 4781-4783.]; Yates et al., 1995[Yates, N. D., Peters, D. A., Allway, P. A., Beddoes, R. L., Scopes, D. I. C. & Joule, J. A. (1995). Heterocycles, 40, 331-347.]; Helliwell et al., 2006[Helliwell, M., You, Y. & Joule, J. A. (2006). Acta Cryst. E62, o1293-o1294.]), we have demonstrated that these reactions efficiently produce bridged bicyclic systems - 3,8-diazabicyclo[3.2.1]octanes - which comprise key structural components of such biologically active natural products as anticancer quinocarcin (Takahashi & Tomita, 1983[Takahashi, K. & Tomita, F. (1983). J. Antibiot. 36, 468-470.]; Tomita et al., 1983[Tomita, F., Takahashi, K. & Shimizu, K. (1983). J. Antibiot. 36, 463-467.]; Hirayama & Shirahata, 1983[Hirayama, N. & Shirahata, K. (1983). J. Chem. Soc. Perkin Trans. 2, pp. 1705-1708.]) and antibiotic lemonomycin (He et al., 2000[He, H., Shen, B. & Carter, G. T. (2000). Tetrahedron Lett. 41, 2067-2071.]).

[Scheme 1]

In a series of benchmark papers by Katritzky and co-workers (for reviews, see Dennis et al., 1976[Dennis, N., Katritzky, A. R. & Takeuchi, Y. (1976). Angew. Chem. Int. Ed. Engl. 15, 1-9.]; Katritzky & Dennis, 1989[Katritzky, A. & Dennis, N. (1989). Chem. Rev. 89, 827-861.]) on the cycloadditions of 3-oxidopyridiniums, there were no examples of adduct formation using dipoles in which either one or two substituents were located on the 1,3-dipole at the future ring-junction positions. We have shown that one methyl group, so located, is not deleterious to the cycloaddition process using 1,5,6-trimethyl-3-oxidopyrazinium (Helliwell et al., 2006[Helliwell, M., You, Y. & Joule, J. A. (2006). Acta Cryst. E62, o1293-o1294.]). This report describes our investigation of the reactivity of 5,6-diethyl-1-methyl-3-oxidopyrazinium, (3), in which a larger ethyl group is located at one of the future ring-junction positions and, in addition, this group is adjacent to another relatively bulky ethyl group.

5,6-Diethylpyrazin-2-one, (1), was prepared by the condensation of hexane-3,4-dione with glycinamide following the established method (Jones, 1949[Jones, R. G. (1949). J. Am. Chem. Soc. 71, 78-81.]; Karmas & Spoerri, 1952[Karmas, G. & Spoerri, P. E. (1952). J. Am. Chem. Soc. 74, 1580-1584.]; Yates et al., 1995[Yates, N. D., Peters, D. A., Allway, P. A., Beddoes, R. L., Scopes, D. I. C. & Joule, J. A. (1995). Heterocycles, 40, 331-347.]). Reaction of (1) with iodomethane produced the methiodide (2), treatment of which with triethylamine allowed the generation of the zwitterion (3), in situ, and in the presence of methyl acrylate. As in all previous cases, the immediate products of such cycloadditions [(4) in this case] are not isolated but tautomerize to the more stable enamide structures, (5) in this case. Thus, the presence of even an ethyl group at a future ring-junction position does not prevent cycloaddition. It is noteworthy that, with increasing bulk, a greater proportion of endo isomer is formed, actually the only stereoisomer isolated in this case. The Z stereochemistry of the exocyclic double bond was established by the crystal structure study. Suitable crystals of the adduct were examined crystallographically, confirming the structure and stereochemistry (Fig. 1[link]). Intermolecular hydrogen bonding between the NH H atom and the amide carbonyl group leads to the formation of centrosymmetric dimers (Table 1[link]).

[Figure 1]
Figure 1
The molecular structure of (5), with displacement ellipsoids drawn at the 50% probability level.

Experimental

To hexane-3,4-dione (4.80 g, 0.04 mol) in water (5 ml) was added sodium metabisulfite (7.60 g, 0.04 mol) and the mixture stirred for 1 h at room temperature. An addition compound was precipitated as a gummy solid on addition of methanol (18 ml) and ethanol (6 ml) and separated by filtration. The solid was dissolved in water (5 ml) and glycinamide hydrochloride (2.27 g, 0.02 mol) was added. The pH was then adjusted to 8 with 10 M KOH and the mixture maintained at 333-353 K for 2 h. The pH was adjusted to 10 and the mixture kept at 323-333 K for 30 min. The mixture was cooled and adjusted to pH 6 with concentrated HCl, then cooled to 273 K. 5,6-Diethylpyrazin-3-one was precipitated as square white crystals (1.34 g, 44%; m.p. 443-445 K), [delta]H (300 MHz, CDCl3) 1.26 (3H, t, J = 7.5 Hz, CH2CH3), 1.34 (3H, t, J = 7.5 Hz, CH2CH3), 2.63 (2H, q, J = 7.5 Hz, CH2CH3), 2.66 (2H, q, J = 7.5 Hz, CH2CH3), 8.07 (1H, s, H-2), 13.32 (1H, s, NH); analysis found: C 62.64, H 7.95, N 16.25%; C8H12N2O requires C, 63.13; H, 7.95; N, 18.41%.

5,6-Diethylpyrazin-2-one (500 mg, 3.3 mmol) and iodomethane (1.2 ml, 16.5 mmol) were heated under reflux in acetonitrile (25 ml) under N2 for 24 h. The solvent was removed under vacuum. The residue was extracted with CH2Cl2 and the solid was filtered off to give the methiodide as a greenish crystalline solid (548 mg, 57%) which was used in the next step without further purification: Analysis: [delta]H (300 MHz, D2O) 1.20 (3H, t, J = 7.6 Hz, CH2CH3), 1.25 (3H, t, J = 7.6 Hz, CH2CH3), 2.80 (2H, q, J = 7.6 Hz, CH2CH3), 2.90 (2H, q, J = 7.6 Hz, CH2CH3), 4.20 (3H, s, NCH3), 8.15 (1H, s, H-2).

A solution of 1-methyl-5,6-diethylpyrazin-3-onium iodide (100 mg, 0.725 mmol) with triethylamine (0.22 ml, 1.45 mmol) and methyl acrylate (0.33 ml, 3.63 mmol) in dry acetonitrile (5 ml) was heated at reflux for 1.5 h to give an orange solution. The solvent and excess methyl acrylate were evaporated under vacuum. From the residue a pure sample of methyl 5-ethyl-8-methyl-(Z)-4-ethylidene-2-oxo-3,8-diazabicyclo[3.2.1]octane-6-endo-6-carboxylate was obtained by flash chromatography (silica, n-hexane-EtOAc 7:3) as colourless plates (15 mg, 9%). Analysis: [delta]H (300 MHz, CDCl3) 1.01 (3H, t, J = 7 Hz, CH2CH3), 1.56 (3H, d, J = 7 Hz, CHCH3), 1.02 1.66 (1H, m, one of CH2CH3), 2.13 1.03 (1H, m, one of CH2CH3), 2.25 (3H, s, NCH3), 1.04 2.33 (1H, m, H-7), 2.48 (1H, dd, J = 5, 13 Hz, H-7), 1.05 3.21 (1H, dd, J = 5, 11 Hz, H-6), 3.58 (1H, d, J = 8 Hz, H-1), 1.06 3.64 (3H, s, OCH3), 4.53 (1H, q, J = 7 Hz, CHCH3), 1.07 6.95 (1H, s, NH).

Crystal data
  • C13H20N2O3

  • Mr = 252.31

  • Monoclinic, P 21 /c

  • a = 10.00 (2) Å

  • b = 8.842 (10) Å

  • c = 14.693 (10) Å

  • [beta] = 90.36 (8)°

  • V = 1300 (3) Å3

  • Z = 4

  • Dx = 1.290 Mg m-3

  • Mo K[alpha] radiation

  • [mu] = 0.09 mm-1

  • T = 293 (2) K

  • Plate, colourless

  • 0.4 × 0.3 × 0.2 mm

Data collection
  • Rigaku R-AXIS diffractometer

  • [varphi] scans

  • Absorption correction: none

  • 10171 measured reflections

  • 2173 independent reflections

  • 1840 reflections with I > 2[sigma](I)

  • Rint = 0.042

  • [theta]max = 25.0°

Refinement
  • Refinement on F2

  • R[F2 > 2[sigma](F2)] = 0.042

  • wR(F2) = 0.126

  • S = 1.06

  • 2173 reflections

  • 171 parameters

  • H atoms treated by a mixture of independent and constrained refinement

  • w = 1/[[sigma]2(Fo2) + (0.078P)2 + 0.2408P] where P = (Fo2 + 2Fc2)/3

  • ([Delta]/[sigma])max < 0.001

  • [Delta][rho]max = 0.18 e Å-3

  • [Delta][rho]min = -0.18 e Å-3

Table 1
Hydrogen-bond geometry (Å, °)

D-H...A D-H H...A D...A D-H...A
N1-H1...O3i 0.89 (2) 2.10 (2) 2.975 (3) 170.9 (16)
Symmetry code: (i) -x+1, -y, -z+1.

H atoms bonded to carbon were included in calculated positions using the riding model, with C-H distances of 0.93-0.98 Å and with Uiso(H) = 1.5Ueq(C) for methyl H atoms and 1.2Ueq(C) for the other H atoms; H1 was found by difference Fourier methods and refined isotropically.

Data collection: MSC RAXIS11 Control Software (Molecular Structure Corporation, 1992[Molecular Structure Corporation (1992). MSC RAXIS11 Control Software. MSC, 3200 Research Forest Drive, The Woodlands, TX 77381, USA.]); cell refinement: DENZO (Otwinowski & Minor, 1988[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter & R. M. Sweet, pp. 307-326. London: Academic Press.]); data reduction: DENZO; program(s) used to solve structure: SHELXS86 (Sheldrick, 1985[Sheldrick, G. M. (1985). In Crystallographic Computing 3, edited by G. M. Sheldrick, C. Krüger & R. Goddard, pp. 175-189. Oxford University Press.]) and TEXSAN (Molecular Structure Corporation, 1995[Molecular Structure Corporation (1995). TEXSAN. Version 1.7. MSC, 3200 Research Forest Drive, The Woodlands, TX 77381, USA.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997[Sheldrick, G. M. (1997). SHELXL97. University of Göttingen, Germany.]); molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL (Bruker, 2001[Bruker (2001). SHELXTL. Version 6.12. Bruker AXS Inc., Madison, Wisconsin, USA.]).

Acknowledgements

YY gratefully acknowledges a studentship from The University of Manchester.

References

Allway, P. A., Sutherland, J. K. & Joule, J. A. (1990). Tetrahedron Lett. 31, 4781-4783. [CrossRef] [ChemPort]
Bruker (2001). SHELXTL. Version 6.12. Bruker AXS Inc., Madison, Wisconsin, USA.
Dennis, N., Katritzky, A. R. & Takeuchi, Y. (1976). Angew. Chem. Int. Ed. Engl. 15, 1-9. [CrossRef] [ChemPort] [PubMed]
He, H., Shen, B. & Carter, G. T. (2000). Tetrahedron Lett. 41, 2067-2071. [CrossRef] [ChemPort]
Helliwell, M., You, Y. & Joule, J. A. (2006). Acta Cryst. E62, o1293-o1294. [CrossRef] [details]
Hirayama, N. & Shirahata, K. (1983). J. Chem. Soc. Perkin Trans. 2, pp. 1705-1708.
Jones, R. G. (1949). J. Am. Chem. Soc. 71, 78-81. [CrossRef] [PubMed] [ChemPort]
Karmas, G. & Spoerri, P. E. (1952). J. Am. Chem. Soc. 74, 1580-1584. [CrossRef] [ChemPort]
Katritzky, A. & Dennis, N. (1989). Chem. Rev. 89, 827-861. [CrossRef] [ChemPort]
Kiss, M., Russell-Maynard, J. & Joule, J. A. (1987). Tetrahedron Lett. 28, 2187-2190. [CrossRef] [ChemPort]
Molecular Structure Corporation (1992). MSC RAXIS11 Control Software. MSC, 3200 Research Forest Drive, The Woodlands, TX 77381, USA.
Molecular Structure Corporation (1995). TEXSAN. Version 1.7. MSC, 3200 Research Forest Drive, The Woodlands, TX 77381, USA.
Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter & R. M. Sweet, pp. 307-326. London: Academic Press.
Sheldrick, G. M. (1985). In Crystallographic Computing 3, edited by G. M. Sheldrick, C. Krüger & R. Goddard, pp. 175-189. Oxford University Press.
Sheldrick, G. M. (1997). SHELXL97. University of Göttingen, Germany.
Takahashi, K. & Tomita, F. (1983). J. Antibiot. 36, 468-470. [ChemPort] [PubMed]
Tomita, F., Takahashi, K. & Shimizu, K. (1983). J. Antibiot. 36, 463-467. [ChemPort] [PubMed]
Yates, N. D., Peters, D. A., Allway, P. A., Beddoes, R. L., Scopes, D. I. C. & Joule, J. A. (1995). Heterocycles, 40, 331-347. [ChemPort]


Acta Cryst (2006). E62, o2318-o2320   [ doi:10.1107/S1600536806017107 ]