organic compounds
The dipolar cycloaddition of methyl acrylate to 1,5,6-trimethyl-3-oxidopyrazinium
aThe School of Chemistry, The University of Manchester, Manchester M13 9PL, England
*Correspondence e-mail: john.joule@manchester.ac.uk
5,6-Dimethylpyrazin-2-one reacts with iodomethane to give a quaternary salt, deprotonation of which liberates a 3-oxidopyrazinium which undergoes a 1,3-dipolar cycloaddition with methyl acrylate to form methyl 5,8-dimethyl-4-methylene-2-oxo-3,8-diazabicyclo[3.2.1]octane-6-exo-carboxylate, C11H16N2O3, as the major product.
Comment
We have been investigating the 1,3-dipolar cycloaddition chemistry of 3-oxidopyraziniums (Kiss et al., 1987; Allway et al., 1990; Yates et al., 1995). These reactions efficiently produce bridged bicyclic systems, viz. 3,8-diazabicyclo[3.2.1]octanes, which comprise key structural components of such biologically active natural products as anticancer quinocarcin (Takahashi & Tomita 1983; Tomita et al., 1983; Hirayama & Shirahata, 1983) and antibiotic lemonomycin (He et al., 2000). Our studies were initially inspired by the series of benchmark papers by Katritzky and co-workers [for reviews, see Dennis et al. (1976) and Katritzky & Dennis (1989)] on the cycloadditions of 3-oxidopyridiniums. In neither Katritzky's extensive studies nor our own on 3-oxidopyraziniums had the possible influence of a substituent on the 1,3-dipole at one (or both) of the future ring-junction positions been assessed. This report describes our first study to remedy this omission, in which the reactivity of 1,5,6-trimethyl-3-oxidopyrazinium, (3) (see scheme; synthesis of 1,5,6-trimethyl-3-oxidopyrazinium and its reaction with methyl acrylate), was assessed.
5,6-Dimethylpyrazin-2-one, (1) (Jones, 1949; Karmas & Spoerri, 1952), was reacted with iodomethane to produce the methiodide (2), treatment of which with triethylamine allowed the generation of the zwitterion (3), in situ and in the presence of methyl acrylate. The reactivity and regioselectivity of such 3-oxidodiaziniums is easily understood in terms of a resonance contributor [(3a) in this case]. The immediate products of the cycloadditions [(4) in this case] are not isolated, but tautomerize to the enamide structure [(5) in this case], (5a) showing better the bicyclic nature of the product. A mixture of two isomeric products was formed from which the major isomer was isolated, crystalline, allowing an X-ray analysis to show that it was the exo-ester (4) (Fig. 1). Thus, the additional oxidopyrazinium-6-methyl, appearing at the ring junction (C-5) in the cycloadduct, did not affect the efficiency or stereoselectivity of the cycloaddition, compared with the comparable reaction of 1,5-dimethyl-3-oxidopyrazinium which also gave a 6-exo-ester as the major product (Yates et al., 1995).
Experimental
5,6-Dimethylpyrazin-2-one (Jones, 1949; Karmas & Spoerri, 1952) (800 mg, 6.5 mmol) and iodomethane (2 ml, 32.5 mmol, 5 equivalents) were heated under reflux in MeCN (150 ml) under nitrogen for 24 h. The solvent was evaporated under vacuum and the residue extracted with CH2Cl2. Insoluble material was removed by filtration and the solution evaporated, leaving 3,4-dihydro-1,5,6-trimethyl-3-oxopyrazinium iodide as a dark-brown crystalline solid (1.12 g, 66%; m.p. >523 K); 1H NMR (D2O, 300 MHz, δ, p.p.m.)): 8.20 (1H, s, C2—H), 4.15 (3H, s, NMe), 2.50 and 2.45 (2 × s, 2 × 3H, 2 × CMe). Analysis found: C 32.31, H 4.02, N 10.39%; C7H11N2O requires: C 31.60, H 4.17, N 10.53%
A solution of 3,4-dihydro-1,5,6-trimethyl-3-oxopyrazinium iodide (1.5 g, 5.6 mmol), Et3N (1.6 ml, 11.2 mmol, 2 equivalents), and methyl acrylate (1.52 ml, 16.8 mmol, 3 equivalents) in dry MeCN (100 ml) was heated under reflux for 2 h. Solvents were removed from the resulting orange solution under vacuum, H2O (30 ml) was added and the product extracted into CH2Cl2 (3 × 30 ml). The combined dried extract was evaporated leaving a brown oil (0.88 g, 70%) from which, by careful over silica, eluting with n-hexane–EtOAc (1:1), the major (thin-layer chromatography) adduct was obtained as colourless plates (330 mg, 26%; m.p. 383–388 K).
Crystal data
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Data collection
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Refinement
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H atoms were found by difference Fourier methods and refined isotropically, with refined C—H distances in the range 0.932 (15)–1.041 (19) Å and an N—H distance of 0.913 (18) Å.
Data collection: MSC Diffractometer Control Software (Molecular Structure Corporation, 1992); cell DENZO (Otwinowski & Minor, 1987); data reduction: DENZO; program(s) used to solve structure: SAPI91 (Fan, 1991); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Bruker, 2001); software used to prepare material for publication: TEXSAN (Molecular Structure Corporation, 1995).
Supporting information
https://doi.org/10.1107/S1600536806007501/jh2006sup1.cif
contains datablocks global, 4. DOI:Structure factors: contains datablock 4. DOI: https://doi.org/10.1107/S1600536806007501/jh20064sup2.hkl
Data collection: MSC R-AXIS 11 Control (Molecular Structure Corporation, 1992); cell
DENZO (Otwinowski, 1988); data reduction: DENZO (Otwinowski, 1988); program(s) used to solve structure: SAPI91 (Fan, 1991); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Bruker, 2001); software used to prepare material for publication: TEXSAN (Molecular Structure Corporation, 1995).C11H16N2O3 | F(000) = 480 |
Mr = 224.26 | Dx = 1.330 Mg m−3 |
Monoclinic, P21/c | Mo Kα radiation, λ = 0.71069 Å |
a = 9.818 (10) Å | Cell parameters from 17414 reflections |
b = 7.89 (2) Å | θ = 2.1–25.0° |
c = 14.80 (3) Å | µ = 0.10 mm−1 |
β = 102.23 (8)° | T = 293 K |
V = 1120 (4) Å3 | Plate, colourless |
Z = 4 | 0.3 × 0.2 × 0.1 mm |
Rigaku R-AXIS diffractometer | 1516 reflections with I > 2σ(I) |
Radiation source: Rigaku rotating anode | Rint = 0.037 |
Graphite monochromator | θmax = 25.0°, θmin = 2.1° |
116 × 3° φ scans | h = 0→11 |
17414 measured reflections | k = 0→9 |
1767 independent reflections | l = −17→16 |
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.031 | All H-atom parameters refined |
wR(F2) = 0.089 | w = 1/[σ2(Fo2) + (0.0555P)2 + 0.1608P] where P = (Fo2 + 2Fc2)/3 |
S = 1.03 | (Δ/σ)max = 0.003 |
1767 reflections | Δρmax = 0.16 e Å−3 |
210 parameters | Δρmin = −0.13 e Å−3 |
0 restraints | Extinction correction: SHELXL, Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
Primary atom site location: structure-invariant direct methods | Extinction coefficient: 0.037 (6) |
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. |
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. |
x | y | z | Uiso*/Ueq | ||
O1 | 0.49890 (11) | 0.24550 (13) | 0.76055 (8) | 0.0498 (3) | |
O2 | 1.10556 (10) | 0.28198 (14) | 0.63198 (8) | 0.0523 (3) | |
O3 | 0.99596 (11) | 0.53179 (13) | 0.62400 (8) | 0.0519 (3) | |
N1 | 0.62845 (13) | 0.06832 (15) | 0.69294 (8) | 0.0394 (3) | |
H1 | 0.5847 (18) | −0.021 (2) | 0.7137 (12) | 0.058 (5)* | |
N2 | 0.67389 (11) | 0.32417 (14) | 0.57739 (7) | 0.0347 (3) | |
C1 | 0.58496 (14) | 0.22418 (17) | 0.71177 (9) | 0.0360 (4) | |
C2 | 0.65104 (15) | 0.36832 (17) | 0.66899 (9) | 0.0367 (4) | |
H2 | 0.5926 (16) | 0.469 (2) | 0.6655 (10) | 0.043 (4)* | |
C3 | 0.79972 (16) | 0.3988 (2) | 0.72487 (11) | 0.0446 (4) | |
H3A | 0.8088 (16) | 0.369 (2) | 0.7904 (13) | 0.053 (4)* | |
H3B | 0.8251 (18) | 0.517 (2) | 0.7213 (12) | 0.056 (5)* | |
C4 | 0.89119 (14) | 0.28417 (18) | 0.67810 (10) | 0.0370 (4) | |
H4 | 0.9360 (14) | 0.2009 (19) | 0.7184 (10) | 0.036 (4)* | |
C5 | 0.78439 (13) | 0.19369 (16) | 0.59858 (9) | 0.0336 (3) | |
C6 | 0.72950 (14) | 0.03561 (16) | 0.63962 (9) | 0.0348 (3) | |
C7 | 0.54837 (17) | 0.2728 (2) | 0.50992 (11) | 0.0467 (4) | |
H7A | 0.4741 (18) | 0.362 (2) | 0.5114 (11) | 0.058 (5)* | |
H7B | 0.5689 (18) | 0.261 (2) | 0.4480 (14) | 0.059 (5)* | |
H7C | 0.5091 (17) | 0.160 (2) | 0.5271 (12) | 0.062 (5)* | |
C8 | 1.00029 (14) | 0.38310 (19) | 0.64213 (9) | 0.0386 (4) | |
C9 | 1.21255 (18) | 0.3595 (3) | 0.59168 (15) | 0.0615 (5) | |
H9A | 1.1729 (19) | 0.391 (2) | 0.5257 (15) | 0.074 (6)* | |
H9B | 1.250 (2) | 0.452 (3) | 0.6286 (16) | 0.079 (6)* | |
H9C | 1.289 (3) | 0.273 (3) | 0.5965 (16) | 0.094 (7)* | |
C10 | 0.83963 (18) | 0.1504 (2) | 0.51235 (11) | 0.0470 (4) | |
H10A | 0.8685 (17) | 0.257 (2) | 0.4818 (12) | 0.054 (4)* | |
H10B | 0.9270 (19) | 0.078 (2) | 0.5311 (12) | 0.065 (5)* | |
H10C | 0.7628 (18) | 0.087 (2) | 0.4651 (13) | 0.062 (5)* | |
C11 | 0.76950 (18) | −0.12241 (19) | 0.63052 (12) | 0.0500 (4) | |
H11A | 0.8372 (17) | −0.147 (2) | 0.5951 (12) | 0.053 (4)* | |
H11B | 0.7307 (19) | −0.215 (2) | 0.6613 (13) | 0.062 (5)* |
U11 | U22 | U33 | U12 | U13 | U23 | |
O1 | 0.0585 (7) | 0.0439 (6) | 0.0569 (7) | 0.0033 (5) | 0.0350 (6) | 0.0006 (5) |
O2 | 0.0375 (6) | 0.0560 (7) | 0.0653 (7) | 0.0066 (5) | 0.0154 (5) | 0.0031 (5) |
O3 | 0.0581 (7) | 0.0384 (7) | 0.0619 (7) | −0.0046 (5) | 0.0189 (5) | 0.0011 (5) |
N1 | 0.0489 (7) | 0.0294 (7) | 0.0450 (7) | 0.0020 (5) | 0.0215 (6) | 0.0055 (5) |
N2 | 0.0397 (6) | 0.0314 (6) | 0.0348 (6) | 0.0048 (5) | 0.0121 (5) | 0.0027 (5) |
C1 | 0.0410 (8) | 0.0336 (8) | 0.0358 (7) | 0.0041 (6) | 0.0138 (6) | 0.0006 (6) |
C2 | 0.0453 (8) | 0.0285 (8) | 0.0404 (8) | 0.0070 (6) | 0.0182 (6) | 0.0006 (6) |
C3 | 0.0544 (9) | 0.0413 (9) | 0.0417 (9) | −0.0064 (7) | 0.0184 (7) | −0.0105 (7) |
C4 | 0.0402 (8) | 0.0342 (8) | 0.0361 (8) | 0.0023 (6) | 0.0070 (6) | 0.0032 (6) |
C5 | 0.0379 (8) | 0.0292 (7) | 0.0359 (7) | 0.0036 (5) | 0.0127 (6) | −0.0010 (5) |
C6 | 0.0379 (7) | 0.0308 (8) | 0.0362 (7) | 0.0032 (6) | 0.0090 (6) | −0.0012 (5) |
C7 | 0.0453 (9) | 0.0505 (10) | 0.0425 (9) | 0.0030 (7) | 0.0052 (7) | 0.0063 (7) |
C8 | 0.0373 (8) | 0.0407 (9) | 0.0365 (7) | −0.0001 (6) | 0.0049 (6) | −0.0027 (6) |
C9 | 0.0384 (9) | 0.0866 (15) | 0.0620 (12) | −0.0051 (10) | 0.0164 (8) | −0.0053 (11) |
C10 | 0.0529 (10) | 0.0485 (10) | 0.0452 (9) | 0.0005 (8) | 0.0231 (8) | −0.0074 (7) |
C11 | 0.0575 (10) | 0.0318 (9) | 0.0642 (10) | 0.0053 (7) | 0.0212 (8) | −0.0024 (7) |
O1—C1 | 1.234 (2) | C4—C5 | 1.572 (3) |
O2—C8 | 1.339 (2) | C4—H4 | 0.932 (15) |
O2—C9 | 1.448 (3) | C5—C10 | 1.527 (3) |
O3—C8 | 1.202 (3) | C5—C6 | 1.534 (3) |
N1—C1 | 1.349 (3) | C6—C11 | 1.322 (4) |
N1—C6 | 1.416 (2) | C7—H7A | 1.018 (18) |
N1—H1 | 0.913 (18) | C7—H7B | 0.983 (19) |
N2—C2 | 1.462 (3) | C7—H7C | 1.026 (19) |
N2—C7 | 1.469 (3) | C9—H9A | 1.00 (2) |
N2—C5 | 1.480 (3) | C9—H9B | 0.94 (2) |
C1—C2 | 1.513 (3) | C9—H9C | 1.01 (2) |
C2—C3 | 1.537 (3) | C10—H10A | 1.025 (18) |
C2—H2 | 0.972 (16) | C10—H10B | 1.018 (19) |
C3—C4 | 1.538 (3) | C10—H10C | 1.041 (19) |
C3—H3A | 0.982 (18) | C11—H11A | 0.950 (17) |
C3—H3B | 0.973 (18) | C11—H11B | 0.978 (19) |
C4—C8 | 1.510 (3) | ||
C8—O2—C9 | 116.07 (19) | N2—C5—C4 | 100.71 (16) |
C1—N1—C6 | 124.80 (12) | C10—C5—C4 | 115.36 (15) |
C1—N1—H1 | 116.3 (11) | C6—C5—C4 | 107.89 (16) |
C6—N1—H1 | 118.8 (11) | C11—C6—N1 | 119.13 (14) |
C2—N2—C7 | 115.11 (15) | C11—C6—C5 | 126.09 (18) |
C2—N2—C5 | 102.63 (13) | N1—C6—C5 | 114.77 (15) |
C7—N2—C5 | 115.08 (16) | N2—C7—H7A | 107.2 (9) |
O1—C1—N1 | 122.07 (13) | N2—C7—H7B | 110.5 (10) |
O1—C1—C2 | 123.38 (16) | H7A—C7—H7B | 111.9 (14) |
N1—C1—C2 | 114.55 (18) | N2—C7—H7C | 112.1 (10) |
N2—C2—C1 | 111.89 (16) | H7A—C7—H7C | 106.9 (14) |
N2—C2—C3 | 102.78 (14) | H7B—C7—H7C | 108.2 (14) |
C1—C2—C3 | 109.57 (14) | O3—C8—O2 | 123.22 (16) |
N2—C2—H2 | 110.5 (9) | O3—C8—C4 | 126.06 (14) |
C1—C2—H2 | 109.4 (9) | O2—C8—C4 | 110.72 (19) |
C3—C2—H2 | 112.6 (9) | O2—C9—H9A | 109.9 (11) |
C2—C3—C4 | 104.17 (15) | O2—C9—H9B | 108.4 (13) |
C2—C3—H3A | 111.8 (9) | H9A—C9—H9B | 113.3 (18) |
C4—C3—H3A | 111.4 (10) | O2—C9—H9C | 106.3 (13) |
C2—C3—H3B | 110.2 (10) | H9A—C9—H9C | 111.5 (18) |
C4—C3—H3B | 111.1 (10) | H9B—C9—H9C | 107.1 (18) |
H3A—C3—H3B | 108.2 (14) | C5—C10—H10A | 111.4 (10) |
C8—C4—C3 | 112.36 (19) | C5—C10—H10B | 109.0 (10) |
C8—C4—C5 | 112.40 (16) | H10A—C10—H10B | 106.5 (14) |
C3—C4—C5 | 104.07 (15) | C5—C10—H10C | 109.5 (10) |
C8—C4—H4 | 108.4 (8) | H10A—C10—H10C | 109.1 (14) |
C3—C4—H4 | 111.5 (9) | H10B—C10—H10C | 111.3 (14) |
C5—C4—H4 | 108.0 (9) | C6—C11—H11A | 120.2 (10) |
N2—C5—C10 | 110.64 (14) | C6—C11—H11B | 120.1 (11) |
N2—C5—C6 | 110.23 (16) | H11A—C11—H11B | 119.7 (15) |
C10—C5—C6 | 111.47 (16) | ||
C6—N1—C1—O1 | −178.22 (13) | C8—C4—C5—N2 | −92.40 (16) |
C6—N1—C1—C2 | 1.3 (2) | C3—C4—C5—N2 | 29.43 (13) |
C7—N2—C2—C1 | 57.34 (16) | C8—C4—C5—C10 | 26.72 (18) |
C5—N2—C2—C1 | −68.45 (18) | C3—C4—C5—C10 | 148.56 (14) |
C7—N2—C2—C3 | 174.81 (12) | C8—C4—C5—C6 | 152.07 (12) |
C5—N2—C2—C3 | 49.02 (16) | C3—C4—C5—C6 | −86.09 (18) |
O1—C1—C2—N2 | −144.21 (14) | C1—N1—C6—C11 | 176.04 (14) |
N1—C1—C2—N2 | 36.25 (18) | C1—N1—C6—C5 | −2.9 (2) |
O1—C1—C2—C3 | 102.47 (18) | N2—C5—C6—C11 | 149.07 (16) |
N1—C1—C2—C3 | −77.07 (18) | C10—C5—C6—C11 | 25.8 (2) |
N2—C2—C3—C4 | −28.60 (15) | C4—C5—C6—C11 | −101.83 (19) |
C1—C2—C3—C4 | 90.5 (2) | N2—C5—C6—N1 | −32.04 (17) |
C2—C3—C4—C8 | 120.99 (15) | C10—C5—C6—N1 | −155.31 (13) |
C2—C3—C4—C5 | −0.87 (15) | C4—C5—C6—N1 | 77.05 (17) |
C2—N2—C5—C10 | −171.11 (11) | C9—O2—C8—O3 | −3.8 (2) |
C7—N2—C5—C10 | 63.08 (18) | C9—O2—C8—C4 | 175.82 (13) |
C2—N2—C5—C6 | 65.14 (15) | C3—C4—C8—O3 | −22.0 (2) |
C7—N2—C5—C6 | −60.67 (19) | C5—C4—C8—O3 | 94.99 (18) |
C2—N2—C5—C4 | −48.63 (14) | C3—C4—C8—O2 | 158.37 (13) |
C7—N2—C5—C4 | −174.43 (11) | C5—C4—C8—O2 | −84.64 (16) |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O1i | 0.913 (18) | 2.082 (19) | 2.980 (6) | 167.6 (15) |
Symmetry code: (i) −x+1, y−1/2, −z+3/2. |
Acknowledgements
YY gratefully acknowledges a studentship from the University of Manchester.
References
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