2,2,5,5,8,8-Hexa­methyl-2,3,5,6,7,8-hexa­hydro­imidazo­[1,2-a]­pyrazine-3,6-dione, a bicyclic product of α-amino­isobutyric acid condensation

The title compound, C₁₂H₁₉N₃O₂, is an unusual product of silica-catalyzed intermolecular condensation of α-amino­isobutyric acid. The mol­ecule has three types of C—N bonds: a double bond, a cis-amide bond and single bonds, two of which are typical and two having intermediate lengths due to π-electron delocalization between C=N and C=O groups. The cis-amide moieties interact to form dimers via hydrogen bonds which stack in parallel layers.

S1. Comment

The large family of imidazo[1,2-a]pyrazines (Basiuk, 1997) includes a few examples of rather exotic bicyclic amidine-type compounds composed of three α-amino acid residues. \sch

The formation of this bicyclic amidine system was first reported more than three decades ago (Jones et al., 1963, 1965). During subsequent years, several groups worked on different aspects of the bicyclic amidine chemistry (Titlestad, 1972; Ali et al., 1973; Rothe et al., 1979; Ali & Khatun, 1985; Ali, 1990; Yamada et al., 1993; Saviano et al., 1996). As a result, approximately ten compounds of this class have been reported. The prerequisites of their synthesis have been (1) the use of tri- to pentapeptide precursors, in some cases along with rather drastic activating reagents such as phosphorus pentachloride or thionyl chloride (Titlestad, 1972; Ali et al., 1973; Ali & Khatun, 1985; Ali, 1990); and (2) the inclusion of sterically hindered α-amino acids into molecules of the peptide starting material; such acids include α-aminoisobutyric acid (Titlestad, 1972; Ali et al., 1973; Ali & Khatun, 1985; Ali, 1990) and α,α-diisopropylglycine (Yamada et al., 1993; Saviano et al., 1996). X-ray structures of these compounds are apparently only known for the bicyclic amidine with R¹ = R² = R⁵ = ⁱPr and R³ = R⁴ = R⁶ = H (Saviano et al., 1996).

Our recent studies of amino acid pyrolysis products by gas chromatography-Fourier transform infrared spectroscopy-mass spectrometry revealed that a direct formation of the bicyclic amidines is possible when simple amino acids (e.g., α-aminoisobutyric acid, alanine, valine, norvaline and leucine) are pyrolyzed at about 773 K (Basiuk, 1998; Basiuk & Navarro-González, 1998; Basiuk et al., 1998a), or even at 473–573 K but in the presence of silica gel as a dehydration catalyst (Basiuk & Navarro-González, 1997; Basiuk et al., 1998b). In the latter case, bicyclic amidine yields can reach the 1–10% level. Although the amidines form along with many other pyrolysis products, it was possible to separate the α-aminoisobutyric acid derivative (R¹ = R² = R³ = R⁴ = R⁵ = R⁶ = Me), (I), by means of recrystallization. In this paper we report the results of its X-ray diffraction analysis.

A view of the bicyclic amidine is shown in Fig. 1. In many regards, this compound is similar to the triisopropyl analog reported by Saviano et al. (1996). In particular, the double bond lengths are: 1.235 (2) for C2–O7, 1.215 (2) for C14–O17, and 1.271 (2) Å for C5–N12 [versus 1.233 (2), 1.215 (2) and 1.276 (2) Å for the triisopropyl analog]. Of the other C–N bonds existing in the molecule, N1–C2 is typical for cis-amides [1.331 (2) Å]; N1–C6, N4–C3 and N12–C13 are common single C–N bonds [1.461 (2), 1.480 (2) and 1.477 (2) Å, respectively]. The remaining two, N4–C5 and N4–C14, exhibit intermediate values [1.397 (2) and 1.390 (2) Å, respectively], thus pointing to an evident π-electron delocalization between the C5–N12 and C14–O17 double bonds.

The five-membered ring is planar within 0.009 (2) Å (atom C5), the six-membered ring deviates up to 0.097 (2) Å (atom C6) and has a slight boat conformation [puckering parameters: Q = 0.143 (2) Å, θ = 112.6 (8)°, ϕ = 125.5 (8)° (Cremer & Pople, 1975)].

Unlike the triisopropyl analog, crystals of the present bicyclic amidine do not display any crystallographic disorder. This is likely due to conformational rigidity of the α,α-dimethyl fragments in the α-aminoisobutyric residues, as compared to their isopropyl counterparts.

As might be expected, the present crystal structure includes a pattern of hydrogen bonding (Fig. 2) similar to that described by Saviano et al. (1996). Interaction between cis-amide moieties gives rise to the formation of hydrogen-bonded dimers: N1···O7 2.929 (2) Å, N1–H1···O7 161.5 (11)°. The dimers form parallel layers. There is also possible intramolecular bonding between O17 and methyl groups C9 and C8 due to weak C–H···O interactions. The corresponding length and angles are: C8···O17 3.191 (3) Å and C8–H8C···O17 119.1 (8)°; C9···O17 3.116 (3) Å and C9–H9A···O17 121.2 (7)°.

S2. Experimental

α-Aminoisobutyric acid from Sigma, and silica gel and solvents from Aldrich were used without further purification. Crystalline α-aminoisobutyric acid (4 g) was heated in the presence of silica gel (10 g) as dehydration catalyst in a continuously evacuated round-bottom flask at about 10 ^-1 Torr under 503–513 K. During the heating, the amino acid sublimed, reacted with the silica gel, and the resulting products along with unreacted amino acid condensed in the unheated flask neck. To increase conversion of the starting reagent into condensation products, the flask was opened and the sublimate was returned to the bottom of the flask to again make contact with the silica gel, and the procedure was repeated 2 more times. This triple sublimation took, in total, about 8 h. Crude sublimate was removed from the flask neck and washed with chloroform (3 × 20 ml). The resulting solution was evaporated to produce 0.27 g of an amorphous, rusty brown substance. Four-fold recrystallization from methanol gave the bicyclic condensation product as colorless needles. (yield 23 mg, 0.75%). Calculated for C₁₂H₁₉N₃O₂ (%): C 60.74, H 8.07, N 17.71. Found (%): C 60.79, H 8.13, N 17.68. IR (KBr): ν = 1736 (C=O stretch, imidazole ring), 1670 (C=O stretch, pyrazine ring), 1646 cm^-1 (C=N stretch). ¹H NMR (200 MHz, CDCl₃): δ = 1.32 [s, 6H, CH₃ (2-Me)], 1.65 [s, 6H, CH₃ (5-Me)], 1.75 [s, 6H, CH₃ (8-Me)].

S3. Refinement

Atom H1, on N1, was constrained to lie on the external bisector of the C2–N1–C6 angle, with the N–H distance free to refine and U_iso(H1) = 1.2 times U_eq(N1). The CH₃ groups were allowed to rotate but not tip, and the C–H distances were allowed to refine (the same shifts were applied along all 3 C–H bonds in each group). U_iso(methyl H) was set to 1.5 times U_eq(methyl C).

Computing details

Data collection: XSCANS (Siemens, 1994); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXTL (Sheldrick, 1997); program(s) used to refine structure: SHELXTL; molecular graphics: PLATON99 (Spek, 1999); software used to prepare material for publication: PLATON99.

Figures

	Fig. 1. Molecular structure drawn with 50% probability displacement elipsoids.
	Fig. 2. Packing diagram.

2,2,5,5,8,8-hexamethyl-4,5,7,8-tetrahydroimidazo[1,2-a]pyrazine- -3,6-dione

Crystal data

C12H19N3O2	Z = 2
Mr = 237.30	F(000) = 256
Triclinic, P1	Dx = 1.233 Mg m^−3
a = 5.902 (1) Å	Mo Kα radiation, λ = 0.71073 Å
b = 8.628 (2) Å	Cell parameters from 20 reflections
c = 12.949 (2) Å	θ = 20.0–21.4°
α = 95.02 (1)°	µ = 0.09 mm^−1
β = 93.34 (1)°	T = 289 K
γ = 102.45 (1)°	Needle, colorless
V = 639.4 (2) Å^3	0.40 × 0.30 × 0.20 mm

Data collection

Siemens P4 diffractometer	Rint = 0.028
Radiation source: fine-focus sealed tube	θmax = 25.0°, θmin = 1.6°
Graphite monochromator	h = −7→1
ω scans	k = −10→10
2941 measured reflections	l = −15→15
2234 independent reflections	3 standard reflections every 97 reflections
1621 reflections with I > 2σ(I)	intensity decay: 0.019%

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)] = 0.042	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.116	H atoms treated by a mixture of independent and constrained refinement
S = 1.01	w = 1/[σ^2(Fo^2) + (0.0495P)^2 + 0.1584P] where P = (Fo^2 + 2Fc^2)/3
2234 reflections	(Δ/σ)max < 0.001
167 parameters	Δρmax = 0.17 e Å^−3
0 restraints	Δρmin = −0.22 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
N1	0.3780 (3)	0.03424 (19)	0.12592 (13)	0.0502 (5)
H1	0.4396 (18)	−0.0326 (19)	0.0888 (11)	0.060*
C2	0.4238 (4)	0.1828 (2)	0.09934 (14)	0.0406 (5)
C3	0.3580 (3)	0.3171 (2)	0.16797 (13)	0.0337 (4)
N4	0.2551 (3)	0.25582 (16)	0.26197 (11)	0.0340 (4)
C5	0.2061 (3)	0.0976 (2)	0.28546 (13)	0.0324 (4)
C6	0.2402 (3)	−0.0339 (2)	0.20779 (14)	0.0380 (5)
O7	0.5232 (3)	0.21692 (16)	0.02039 (11)	0.0590 (5)
C8	0.1808 (4)	0.3850 (3)	0.10606 (15)	0.0500 (6)
H8A	0.038 (2)	0.3018 (12)	0.0880 (10)	0.075*
H8B	0.2463 (13)	0.4217 (17)	0.0420 (10)	0.075*
H8C	0.144 (2)	0.4754 (16)	0.1483 (7)	0.075*
C9	0.5799 (4)	0.4454 (2)	0.20031 (16)	0.0468 (5)
H9A	0.5407 (7)	0.5357 (14)	0.2471 (10)	0.070*
H9B	0.6493 (16)	0.4892 (13)	0.1357 (8)	0.070*
H9C	0.6975 (17)	0.3967 (7)	0.2396 (10)	0.070*
C10	0.3710 (5)	−0.1434 (3)	0.26047 (18)	0.0652 (8)
H10A	0.400 (3)	−0.2246 (18)	0.2085 (8)	0.098*
H10B	0.2774 (19)	−0.1953 (18)	0.3129 (12)	0.098*
H10C	0.519 (3)	−0.0807 (10)	0.2939 (13)	0.098*
C11	0.0044 (5)	−0.1261 (3)	0.1603 (2)	0.0797 (9)
H11A	−0.0763 (19)	−0.0533 (13)	0.1243 (14)	0.120*
H11B	−0.091 (2)	−0.172 (2)	0.2161 (9)	0.120*
H11C	0.0248 (6)	−0.214 (2)	0.1091 (14)	0.120*
N12	0.1222 (3)	0.07327 (17)	0.37233 (12)	0.0403 (4)
C13	0.0975 (3)	0.2296 (2)	0.42087 (13)	0.0346 (4)
C14	0.1876 (3)	0.3467 (2)	0.34367 (14)	0.0358 (4)
C15	−0.1580 (4)	0.2249 (3)	0.43498 (17)	0.0488 (5)
H15A	−0.2490 (13)	0.1998 (17)	0.3657 (9)	0.073*
H15B	−0.1744 (5)	0.3310 (14)	0.4674 (11)	0.073*
H15C	−0.2185 (11)	0.1407 (15)	0.4811 (11)	0.073*
C16	0.2412 (4)	0.2735 (3)	0.52520 (15)	0.0511 (6)
H16A	0.1831 (18)	0.1941 (14)	0.5734 (7)	0.077*
H16B	0.227 (2)	0.3803 (16)	0.5548 (7)	0.077*
H16C	0.406 (2)	0.2748 (17)	0.5150 (3)	0.077*
O17	0.1979 (3)	0.48949 (15)	0.34949 (11)	0.0527 (4)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0784 (14)	0.0347 (9)	0.0454 (10)	0.0227 (9)	0.0340 (9)	0.0034 (7)
C2	0.0517 (13)	0.0387 (11)	0.0340 (10)	0.0119 (9)	0.0166 (9)	0.0038 (8)
C3	0.0447 (11)	0.0309 (9)	0.0276 (9)	0.0101 (8)	0.0124 (8)	0.0051 (7)
N4	0.0483 (10)	0.0266 (8)	0.0284 (8)	0.0090 (7)	0.0141 (7)	0.0013 (6)
C5	0.0385 (10)	0.0288 (9)	0.0315 (9)	0.0091 (8)	0.0091 (8)	0.0041 (7)
C6	0.0511 (12)	0.0300 (9)	0.0335 (10)	0.0084 (8)	0.0165 (9)	−0.0006 (7)
O7	0.0912 (12)	0.0460 (9)	0.0458 (8)	0.0180 (8)	0.0414 (9)	0.0073 (7)
C8	0.0631 (14)	0.0555 (13)	0.0377 (11)	0.0244 (11)	0.0082 (10)	0.0080 (9)
C9	0.0513 (13)	0.0414 (11)	0.0464 (12)	0.0040 (9)	0.0149 (10)	0.0051 (9)
C10	0.109 (2)	0.0441 (13)	0.0581 (14)	0.0423 (13)	0.0303 (14)	0.0105 (11)
C11	0.0658 (18)	0.0862 (19)	0.0690 (17)	−0.0074 (14)	0.0143 (14)	−0.0370 (14)
N12	0.0579 (11)	0.0321 (8)	0.0349 (8)	0.0142 (7)	0.0188 (8)	0.0050 (6)
C13	0.0476 (12)	0.0297 (9)	0.0290 (9)	0.0130 (8)	0.0133 (8)	0.0000 (7)
C14	0.0469 (12)	0.0294 (10)	0.0321 (9)	0.0104 (8)	0.0102 (8)	−0.0010 (7)
C15	0.0518 (14)	0.0485 (12)	0.0486 (12)	0.0135 (10)	0.0158 (10)	0.0042 (9)
C16	0.0591 (14)	0.0583 (13)	0.0359 (11)	0.0129 (11)	0.0065 (10)	0.0026 (9)
O17	0.0838 (12)	0.0297 (8)	0.0481 (8)	0.0158 (7)	0.0254 (8)	0.0021 (6)

Geometric parameters (Å, º)

N1—C2	1.331 (2)	C9—H9C	1.0195
N1—C6	1.461 (2)	C10—H10A	0.9782
N1—H1	0.8705	C10—H10B	0.9782
C2—O7	1.235 (2)	C10—H10C	0.9782
C2—C3	1.529 (2)	C11—H11A	0.9965
C3—N4	1.480 (2)	C11—H11B	0.9965
C3—C8	1.526 (3)	C11—H11C	0.9965
C3—C9	1.531 (3)	N12—C13	1.477 (2)
N4—C14	1.390 (2)	C13—C14	1.520 (2)
N4—C5	1.397 (2)	C13—C15	1.522 (3)
C5—N12	1.271 (2)	C13—C16	1.525 (3)
C5—C6	1.504 (2)	C14—O17	1.215 (2)
C6—C11	1.512 (3)	C15—H15A	0.9998
C6—C10	1.524 (3)	C15—H15B	0.9998
C8—H8A	0.9834	C15—H15C	0.9998
C8—H8B	0.9834	C16—H16A	0.9877
C8—H8C	0.9834	C16—H16B	0.9877
C9—H9A	1.0195	C16—H16C	0.9877
C9—H9B	1.0195
C2—N1—C6	129.94 (16)	H9B—C9—H9C	109.5
C2—N1—H1	115.0	C6—C10—H10A	109.5
C6—N1—H1	115.0	C6—C10—H10B	109.5
O7—C2—N1	121.56 (17)	H10A—C10—H10B	109.5
O7—C2—C3	118.11 (16)	C6—C10—H10C	109.5
N1—C2—C3	120.32 (16)	H10A—C10—H10C	109.5
N4—C3—C8	109.29 (15)	H10B—C10—H10C	109.5
N4—C3—C2	110.39 (14)	C6—C11—H11A	109.5
C8—C3—C2	108.88 (15)	C6—C11—H11B	109.5
N4—C3—C9	109.43 (14)	H11A—C11—H11B	109.5
C8—C3—C9	110.81 (16)	C6—C11—H11C	109.5
C2—C3—C9	108.04 (15)	H11A—C11—H11C	109.5
C14—N4—C5	107.13 (14)	H11B—C11—H11C	109.5
C14—N4—C3	125.79 (14)	C5—N12—C13	106.70 (14)
C5—N4—C3	127.08 (14)	N12—C13—C14	104.69 (13)
N12—C5—N4	116.08 (15)	N12—C13—C15	109.61 (16)
N12—C5—C6	123.44 (16)	C14—C13—C15	110.36 (16)
N4—C5—C6	120.38 (15)	N12—C13—C16	110.88 (16)
N1—C6—C5	109.77 (15)	C14—C13—C16	110.81 (16)
N1—C6—C11	109.31 (18)	C15—C13—C16	110.37 (16)
C5—C6—C11	108.76 (17)	O17—C14—N4	126.13 (17)
N1—C6—C10	108.07 (17)	O17—C14—C13	128.50 (16)
C5—C6—C10	110.26 (16)	N4—C14—C13	105.37 (14)
C11—C6—C10	110.7 (2)	C13—C15—H15A	109.5
C3—C8—H8A	109.5	C13—C15—H15B	109.5
C3—C8—H8B	109.5	H15A—C15—H15B	109.5
H8A—C8—H8B	109.5	C13—C15—H15C	109.5
C3—C8—H8C	109.5	H15A—C15—H15C	109.5
H8A—C8—H8C	109.5	H15B—C15—H15C	109.5
H8B—C8—H8C	109.5	C13—C16—H16A	109.5
C3—C9—H9A	109.5	C13—C16—H16B	109.5
C3—C9—H9B	109.5	H16A—C16—H16B	109.5
H9A—C9—H9B	109.5	C13—C16—H16C	109.5
C3—C9—H9C	109.5	H16A—C16—H16C	109.5
H9A—C9—H9C	109.5	H16B—C16—H16C	109.5
C6—N1—C2—O7	−172.0 (2)	N12—C5—C6—N1	−169.57 (19)
C6—N1—C2—C3	9.3 (3)	N4—C5—C6—N1	14.1 (2)
O7—C2—C3—N4	−176.31 (18)	N12—C5—C6—C11	70.9 (3)
N1—C2—C3—N4	2.5 (3)	N4—C5—C6—C11	−105.5 (2)
O7—C2—C3—C8	63.7 (2)	N12—C5—C6—C10	−50.6 (3)
N1—C2—C3—C8	−117.5 (2)	N4—C5—C6—C10	133.01 (19)
O7—C2—C3—C9	−56.7 (2)	N4—C5—N12—C13	1.5 (2)
N1—C2—C3—C9	122.1 (2)	C6—C5—N12—C13	−174.97 (17)
C8—C3—N4—C14	−64.0 (2)	C5—N12—C13—C14	−0.6 (2)
C2—C3—N4—C14	176.27 (17)	C5—N12—C13—C15	117.76 (18)
C9—C3—N4—C14	57.5 (2)	C5—N12—C13—C16	−120.15 (18)
C8—C3—N4—C5	115.6 (2)	C5—N4—C14—O17	−178.0 (2)
C2—C3—N4—C5	−4.1 (3)	C3—N4—C14—O17	1.7 (3)
C9—C3—N4—C5	−122.87 (19)	C5—N4—C14—C13	1.3 (2)
C14—N4—C5—N12	−1.9 (2)	C3—N4—C14—C13	−179.03 (17)
C3—N4—C5—N12	178.43 (18)	N12—C13—C14—O17	178.8 (2)
C14—N4—C5—C6	174.74 (17)	C15—C13—C14—O17	60.9 (3)
C3—N4—C5—C6	−4.9 (3)	C16—C13—C14—O17	−61.7 (3)
C2—N1—C6—C5	−17.3 (3)	N12—C13—C14—N4	−0.5 (2)
C2—N1—C6—C11	101.9 (3)	C15—C13—C14—N4	−118.32 (17)
C2—N1—C6—C10	−137.6 (2)	C16—C13—C14—N4	119.13 (17)