Surprising orientation in ring synthesis of 3,5-di­methyl­pyrazin-2(1H)-one

The reaction of pyruvaldehyde with alaninamide gave the title compound, C₆H₈N₂O, and not the anti­cipated 3,6-dimethyl­pyrazin-2-one.

Comment

One of the standard methods to prepare pyrazin-2-ones is by the condensation of a 1,2-dicarbonyl compound with an α-amino acid amide (Garg et al., 2002; Jones, 1949; Karmas & Spoerri, 1952). For example, pyruvaldehyde (1) (see scheme) reacts with glycinamide (2a) to give 6-methyl­pyrazin-2-one (3a) (Yates et al., 1995). The orientation in this ring synthesis represents the combination of the amide N atom with the ketone carbonyl and of the amine group with the aldehyde carbonyl group. In the course of our studies on the dipolar cyclo­addition reactions of 3-oxidopyraziniums (Kiss et al., 1987; Allway et al., 1990; Yates et al., 1995), we required 3,6-dimethyl­pyrazin-2-one (3b) and assumed that, by analogy, it would result from a reaction of pyruvaldehyde with alaninamide (2b).

Reaction of pyruvaldehyde with alaninamide produced a pyrazinone, as anti­cipated, but standard spectroscopic analysis could not unambiguously confirm the structure of the product. For example, ¹H NMR spectroscopy revealed two three-hydrogen singlet signals corresponding to the two methyl groups at δ 2.22 and 2.41 and a one-hydrogen singlet signal for the ring C-hydrogen at δ 6.88, but these data are consistent both with the anti­cipated structure (3b) and also with its isomer, 3,5-dimethyl­pyrazin-2-one (3c).

Suitable crystals were grown from ethyl acetate and an X-ray analysis carried out. This showed the product to be 3,5-dimethyl­pyrazin-2(1H)-one (3c) (Fig. 1). Currently, we have no explanation for this unexpected regioselectivity; however, the moral from this result is that, for each pyrazinone synthesized by this method, unambiguous proof of structure must be sought.

Figure 1 The molecular structure of (3c), with displacement ellipsoids drawn at the 50% probability level.

Experimental

A solution of L-alaninamide hydro­chloride (95%, 0.26 g, 2 mmol) in methanol (1.0 ml) was cooled to 243 K and to it was added a solution of pyruvaldehyde (40%, 0.36 g, 2 mmol) in methanol (0.5 ml) also precooled to 243 K. Next, with stirring, aqueous sodium hydroxide solution (12.5 M, 0.50 ml, 2.5 mmol) was added dropwise while the temperature was maintained below 263 K. The mixture was allowed to stand at 268 K for 2 h, then at r.t. for 3 h. To the mixture was added hydro­chloric acid (12 M, 0.5 ml) followed by solid NaHCO₃ (0.25 g) to neutralize excess acid, and the whole was evaporated to dryness in a vacuum at 363 K. The residue was extracted with three portions (2 ml) of boiling chloro­form. Evaporation of the extract left a yellow solid (205 mg, 83%). This was recrystallized from ethyl acetate (2 ml) to give colourless crystals (58 mg, 24%; m.p. 417–419 K).

Crystal data

• C₆H₈N₂O

• M_r = 124.14

• Monoclinic, P 2₁ /n

• a = 4.009 (10) Å

• b = 14.59 (3) Å

• c = 11.59 (3) Å

• β = 105.25 (10)°

• V = 654 (3) ų

• Z = 4

• D_x = 1.261 Mg m⁻³

• Mo Kα radiation

• Cell parameters from 12419 reflections

• θ = 2.3–24.9°

• μ = 0.09 mm⁻¹

• T = 293 (2) K

• Needle, colourless

• 0.6 × 0.1 × 0.1 mm

Data collection

• Rigaku R-AXIS diffractometer

• φ scans

• Absorption correction: none

• 12419 measured reflections

• 839 independent reflections

• 724 reflections with I > 2σ(I)

• R_int = 0.045

• θ_max = 24.9°

• h = 0 → 4

• k = 0 → 17

• l = −13 → 13

Refinement

• Refinement on F²

• R[F² > 2σ(F²)] = 0.041

• wR(F²) = 0.110

• S = 1.10

• 839 reflections

• 88 parameters

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

• w = 1/[σ²(F_o²) + (0.0505P)² + 0.2114P] where P = (F_o² + 2F_c²)/3

• (Δ/σ)_max < 0.001

• Δρ_max = 0.18 e Å⁻³

• Δρ_min = −0.15 e Å⁻³

H atoms bonded to C were included in calculated positions using the riding model, with C—H distances of 0.93 and 0.96 Å and with U_iso(H) = 1.5U_eq(C) for methyl H atoms and 1.2U_eq(C) for the other H atoms; atom H1, attached to N1, was found by difference Fourier methods and refined isotropically.

Data collection: MSC Diffractometer Control Software (Molecular Structure Corporation, 1992); cell refinement: DENZO (Otwinowski & Minor, 1987); data reduction: DENZO; program(s) used to solve structure: SHELXS86 (Sheldrick, 1985); 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

Computing details

Data collection: MSC RAXIS11 Control software; cell refinement: DENZO (Otwinowski, 1988); data reduction: DENZO; program(s) used to solve structure: SHELXS86 (Sheldrick, 1985); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); software used to prepare material for publication: TEXSAN (Molecular Structure Corporation, 1995).

3,5-dimethylpyrazin-2(1H)-one

Crystal data

C6H8N2O	F(000) = 264
Mr = 124.14	Dx = 1.261 Mg m^−3
Monoclinic, P21/n	Melting point = 144–146 K
Hall symbol: -P 2yn	Mo Kα radiation, λ = 0.71069 Å
a = 4.009 (10) Å	Cell parameters from 12419 reflections
b = 14.59 (3) Å	θ = 2.3–24.9°
c = 11.59 (3) Å	µ = 0.09 mm^−1
β = 105.25 (10)°	T = 293 K
V = 654 (3) Å^3	Needle, colourless
Z = 4	0.6 × 0.1 × 0.1 mm

Data collection

Rigaku R-AXIS diffractometer	724 reflections with I > 2σ(I)
Radiation source: Rigaku rotating anode	Rint = 0.05
Graphite monochromator	θmax = 24.9°, θmin = 2.3°
5 and 6° φ scans	h = 0→4
12419 measured reflections	k = 0→17
839 independent reflections	l = −13→13

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.041	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.110	H atoms treated by a mixture of independent and constrained refinement
S = 1.10	w = 1/[σ^2(Fo^2) + (0.0505P)^2 + 0.2114P] where P = (Fo^2 + 2Fc^2)/3
839 reflections	(Δ/σ)max < 0.001
88 parameters	Δρmax = 0.18 e Å^−3
0 restraints	Δρmin = −0.15 e Å^−3

Special details

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O1	−0.2141 (4)	0.49078 (10)	0.34750 (14)	0.0615 (5)
N1	0.1332 (5)	0.60752 (11)	0.44190 (16)	0.0458 (5)
H1	0.171 (6)	0.5743 (16)	0.518 (2)	0.076 (8)*
N2	0.0425 (4)	0.69612 (11)	0.22727 (14)	0.0439 (5)
C1	−0.0691 (5)	0.56613 (13)	0.34268 (18)	0.0435 (5)
C2	−0.1047 (5)	0.61644 (14)	0.23166 (18)	0.0412 (5)
C3	0.2395 (5)	0.73534 (13)	0.33210 (19)	0.0423 (6)
C4	0.2850 (5)	0.69143 (14)	0.4374 (2)	0.0462 (6)
H4	0.4194	0.7180	0.5072	0.055*
C5	−0.3181 (6)	0.57375 (15)	0.11869 (19)	0.0549 (6)
H5A	−0.3500	0.6171	0.0544	0.082*
H5B	−0.5392	0.5564	0.1292	0.082*
H5C	−0.2018	0.5204	0.1001	0.082*
C6	0.3903 (6)	0.82800 (14)	0.3194 (2)	0.0572 (6)
H6A	0.5251	0.8245	0.2623	0.086*
H6B	0.5352	0.8471	0.3954	0.086*
H6C	0.2067	0.8716	0.2925	0.086*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0870 (12)	0.0459 (10)	0.0492 (10)	−0.0219 (9)	0.0141 (8)	−0.0030 (7)
N1	0.0606 (11)	0.0384 (10)	0.0363 (11)	−0.0041 (8)	0.0093 (9)	−0.0023 (8)
N2	0.0501 (10)	0.0378 (10)	0.0429 (11)	0.0010 (8)	0.0107 (8)	−0.0001 (8)
C1	0.0540 (13)	0.0377 (12)	0.0390 (13)	−0.0027 (10)	0.0126 (10)	−0.0055 (10)
C2	0.0459 (12)	0.0387 (12)	0.0383 (13)	0.0007 (9)	0.0101 (10)	−0.0043 (9)
C3	0.0457 (12)	0.0354 (11)	0.0440 (13)	0.0006 (9)	0.0086 (10)	−0.0038 (10)
C4	0.0508 (13)	0.0390 (12)	0.0449 (13)	−0.0036 (10)	0.0055 (10)	−0.0074 (10)
C5	0.0664 (15)	0.0532 (14)	0.0409 (13)	−0.0086 (11)	0.0066 (11)	−0.0043 (10)
C6	0.0612 (15)	0.0424 (13)	0.0652 (16)	−0.0074 (11)	0.0119 (12)	0.0002 (11)

Geometric parameters (Å, º)

O1—C1	1.251 (3)	C3—C6	1.503 (4)
N1—C1	1.362 (4)	C4—H4	0.9300
N1—C4	1.374 (3)	C5—H5A	0.9600
N1—H1	0.98 (3)	C5—H5B	0.9600
N2—C2	1.310 (3)	C5—H5C	0.9600
N2—C3	1.387 (4)	C6—H6A	0.9600
C1—C2	1.456 (4)	C6—H6B	0.9600
C2—C5	1.498 (4)	C6—H6C	0.9600
C3—C4	1.348 (4)
C1—N1—C4	122.3 (2)	C3—C4—H4	119.9
C1—N1—H1	117.2 (14)	N1—C4—H4	119.9
C4—N1—H1	120.5 (14)	C2—C5—H5A	109.5
C2—N2—C3	119.4 (2)	C2—C5—H5B	109.5
O1—C1—N1	122.1 (2)	H5A—C5—H5B	109.5
O1—C1—C2	122.9 (2)	C2—C5—H5C	109.5
N1—C1—C2	114.9 (2)	H5A—C5—H5C	109.5
N2—C2—C1	122.8 (2)	H5B—C5—H5C	109.5
N2—C2—C5	119.6 (2)	C3—C6—H6A	109.5
C1—C2—C5	117.6 (2)	C3—C6—H6B	109.5
C4—C3—N2	120.5 (2)	H6A—C6—H6B	109.5
C4—C3—C6	123.6 (2)	C3—C6—H6C	109.5
N2—C3—C6	115.9 (2)	H6A—C6—H6C	109.5
C3—C4—N1	120.1 (2)	H6B—C6—H6C	109.5
C4—N1—C1—O1	−178.15 (19)	N1—C1—C2—C5	178.76 (18)
C4—N1—C1—C2	1.5 (3)	C2—N2—C3—C4	1.2 (3)
C3—N2—C2—C1	−0.4 (3)	C2—N2—C3—C6	−178.28 (18)
C3—N2—C2—C5	179.96 (18)	N2—C3—C4—N1	−0.6 (3)
O1—C1—C2—N2	178.72 (19)	C6—C3—C4—N1	178.79 (18)
N1—C1—C2—N2	−0.9 (3)	C1—N1—C4—C3	−0.8 (3)
O1—C1—C2—C5	−1.6 (3)