6(S)-Methyl-3(S)-(1-methyl­ethyl)­piperazin-2-one

The identity of the title piperazinone, C₈H₁₆N₂O, obtained by an unusual deoxy­genation reaction, has been confirmed by its crystal structure. We describe the conform­ation of this template used to mimic conformationally flexible peptides and lipids and compare it to related piperazinones.

Key indicators

• Single-crystal X-ray study
• T = 200 K
• Mean [sigma](C-C) = 0.002 Å
• R factor = 0.032
• wR factor = 0.073
• Data-to-parameter ratio = 12.3

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry


 Alert Level B:



THETM_01  Alert B The value of sine(theta_max)/wavelength is less than 0.575
          Calculated sin(theta_max)/wavelength =    0.5614

Author response: The presented X-ray data of the title compound were determined in 1996 with the intention to publish them in Acta Crystallographica Section C. However, the demands to publish in this journal increased during the time so that the sine (theta max.)/wavelength of less then 0.575 now is no longer sufficient for Acta Cryst. C. Unfortunately, no crystals of the title compound do exist any longer. Therefore, we decided to submit our article to Acta Crystallographica Section E. We hope that the presented data are suitable for publication in this journal.

 Alert Level C:



PLAT_420  Alert C D-H Without Acceptor       N(4)   -   H(4)              ?

General Notes



REFLT_03
         From the CIF: _diffrn_reflns_theta_max           59.95
         From the CIF: _reflns_number_total               1315
         Count of symmetry unique reflns          789
         Completeness (_total/calc)            166.67%
         TEST3: Check Friedels for noncentro structure
         Estimate of Friedel pairs measured       526
         Fraction of Friedel pairs measured     0.667
         Are heavy atom types Z>Si present           no
          Please check that the estimate of the number of Friedel pairs is
          correct. If it is not, please give the correct count in the
          _publ_section_exptl_refinement section of the submitted CIF.


 0 Alert Level A = Potentially serious problem

 1 Alert Level B = Potential problem

 1 Alert Level C = Please check

---

S1. Comment

The title chiral 3,6-disubstituted piperazin-2-one, (I), was obtained during the synthesis of a potential head group mimic of the natural occurring bioactive lipid ceramide. The piperazinone skeleton has been used before as a conformationally restricted analog in the synthesis of peptidomimetics (Kolter et al., 1995; Suarez-Gea et al., 1996; Schanen et al., 1996; Uchida et al., 1996). More recently, 4-N-alkylated piperazin-2-ones have been synthesized on a different route as conformationally rigid analogs of another bioactive lipid, viz. diacylglycerol (Endo et al., 1997). Compound (I) has been prepared from the protected configurationally stable dipeptide aldehyde (III) (Kolter et al., 1992) by hydrogenolysis. During this reaction, a reproducible deoxygenation of the 6-hydroxymethyl residue to a methyl group occurs as an unexpected side reaction in about 20% yield. Similar results have been obtained with starting material, where the isopropyl group is replaced by a benzyl residue (not shown). The mechanism of this reaction is not clear, but the identity of the deoxygenated compound (I) was confirmed by this crystallization experiment. Furthermore, the crystal structure gives information on the three-dimensional structure of the piperazinone scaffold and the influence of ring substituents on the ring conformation (Michel et al., 1987).

The structure of (I) with the atom numbering is shown in Fig. 1. Selected geometrical parameters are listed in Table 1. The six-membered ring system adopts a distorted half-chair conformation, with atoms N4 and C5 on opposite sides with respect to the C6/N1/C2/C3 plane. In the piperazinone, the substituents in the 3- and 6- positions are in a cisoid configuration. The methyl group shows a pseudo-axial orientation [torsion angle C2—N1—C6—C61 is −100.2 (2)°], whereas the isopropyl substituent is pseudo-equatorial orientated [the torsion angle C31—C3—N4—C5 is −174.9 (2)°]. There is one moderate intermolecular hydrogen bond (Steiner, 2002) within the crystal. This hydrogen bond, between N1—H and O21, shows a nearly linear geometry [deviation from the ideal angle: 40.3 (1)°; Table 2]. The structure of a closely related piperazin-2-one has been published before (Michel et al., 1987), in which the p-hydroxybenzyl substituent in the 3- and the ethyl carboxylate residue in the 6-position are also arranged in a cisoid configuration. We compared bond lengths and angles within the ring of (I) with those in the published structure. The deviations from the bond lengths range from 0.002 to 0.027 Å and for the angles from 0.0 to 3.2°. Therefore, although the authors proposed the contribution of a dipole–dipole interaction between these substituents, the ring conformation is very similar to (I). The structure of an additional piperazin-2-one with a trans-relationship between a 3-isopropyl and a 6-hydroxymethyl substituent has been described before (Kolter et al., 1996). Here, the ring also adopts a half-chair conformation, showing stronger distortion compared to (I) [deviation from the ideal C6/N1/C2/C3 plane dihedral angle is 1.7° greater than that of compound (I)]. Also, the hydrogen bond between the NH group and the intermolecular piperazinone oxo group shows a similar geometry. The absolute configuration of (I) could not been determined reliably [Flack (1983) parameter x = 0.2 (3)]. Therefore, (I) was assigned to agree with the chirality as established by synthesis. In the past, conformationally flexible bioactive molecules, lipids and peptides, have been mimicked by heterocycles of this type. The data on the conformation of 3,6-disubstituted piperazin-2-ones in the solid state should be helpful in the design of further lipid and peptide mimics based on this skeleton.

S2. Experimental

Glassware was flame dried under an argon atmosphere and allowed to cool. Dipeptide aldehyde (III) (Kolter et al., 1992) (321.4 mg, 1 mmol) was dissolved in methanol (10 ml). After addition of a catalytic amount of palladium on charcoal (5%), the mixture was stirred under a hydrogen atmosphere for 18 h. The catalyst was filtered off and washed twice with methanol (10 ml). After evaporation of the solvent, the residue was purified by column chromatography on silicia gel (chloroform/methanol 10:1) as eluant, giving colourless crystals (yield: 32.5 mg, 20.8%) suitable for X-ray analysis. TLC: 20:1 dichloromethane–methanol, R_F: 0.29; α_D: −121.5° (c = 0.38; CHCl₃); m.p.: 385 K; ¹H NMR (400 MHz, d₆-DMSO): δ 0.81 [d, J = 6.8 Hz, 3H; CH(CH₃)₂], 0.92 [d, J = 6.8 Hz, 3H; CH(CH₃)₂], 1.09 (d, J = 6.4 Hz, 3H; CH₃), 2.23 [dqq, J = 3.4 Hz, J = 6.8 Hz, J = 6.8 Hz, 1H; CH(CH₃)₂], 2.62 (ddd, J = 0.8 Hz, J = 3.4 Hz, J = 12.4 Hz, 1H; H-5), 2.82 (dd, J = 4.0 Hz, J = 12.4 Hz, 1H; H-5), 2.98 (d, J = 3.4 Hz, 1H; H-3), 3.30 (m, 1H; H-6), 3.36 (m, br., 1H; NH), 7.62 (m, br, 1H; CONH); EI-HRMS: calculated: M⁺, m/z = 156.1260, found: m/z = 156.1262.

S3. Refinement

Friedel pairs are not merged. The position of the amide H atom and amine H atom was determined from a difference Fourier map and the coordinates were refined freely, with its isotropic displacement parameter constrained to U_iso(H) = 1.2U_eq(N). All remaining H atoms were treated as riding, with C—H = 0.98–1.00 Å, and U_iso(H) = 1.2U_eq(CH, CH₂) and 1.5U_eq(CH₃).

Computing details

Data collection: CAD-4 Software (Enraf-Nonius, 1989); cell refinement: CAD-4 Software; data reduction: XCAD4 (Sheldrick, 1992); program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL-NT (Sheldrick, 2001); software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. The structure of (I), showing the atom-numbering scheme and displacement ellipsoids at the 50% probability level for the non-H atoms. H atoms are shown as small spheres of arbitrary radii.
	Fig. 2. A view of the unit cell, showing the intermolecular hydrogen bonding.

(6S)-Methyl-3(3)-methylethyl-piperazine-2-one

Crystal data

C8H16N2O	Dx = 1.171 Mg m^−3
Mr = 156.23	Cu Kα radiation, λ = 1.54178 Å
Orthorhombic, P212121	Cell parameters from 25 reflections
a = 8.471 (2) Å	θ = 40–46°
b = 9.282 (1) Å	µ = 0.62 mm^−1
c = 11.271 (1) Å	T = 200 K
V = 886.2 (2) Å^3	Block, colourless
Z = 4	0.30 × 0.23 × 0.20 mm
F(000) = 344

Data collection

Enraf-Nonius CAD-4 diffractometer	Rint = 0.073
Radiation source: fine-focus sealed tube	θmax = 60.0°, θmin = 6.2°
Graphite monochromator	h = −9→9
ω scans	k = −10→1
3164 measured reflections	l = −12→12
1315 independent reflections	Standard reflections: 3 (orientation), 3 (intensity); every 200 (orientation) reflections
1289 reflections with I > 2σ(I)	intensity decay: none

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.032	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.073	w = 1/[σ^2(Fo^2) + (0.0246P)^2 + 0.0864P] where P = (Fo^2 + 2Fc^2)/3
S = 1.12	(Δ/σ)max < 0.001
1315 reflections	Δρmax = 0.15 e Å^−3
107 parameters	Δρmin = −0.15 e Å^−3
2 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.053 (2)

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	0.49978 (14)	0.65770 (11)	0.40547 (12)	0.0294 (3)
H1	0.5366 (18)	0.7065 (16)	0.4689 (14)	0.035*
C2	0.34366 (16)	0.65519 (13)	0.39126 (14)	0.0299 (4)
O21	0.25477 (13)	0.72369 (11)	0.45736 (12)	0.0482 (4)
C3	0.27706 (17)	0.57216 (13)	0.28589 (13)	0.0288 (3)
H3	0.2547	0.6435	0.2215	0.035*
C31	0.12092 (17)	0.49810 (13)	0.31715 (16)	0.0328 (4)
H31	0.0495	0.5723	0.3527	0.039*
C32	0.1431 (2)	0.37890 (17)	0.40836 (18)	0.0458 (4)
H32A	0.0401	0.3378	0.4290	0.069*
H32B	0.1926	0.4187	0.4798	0.069*
H32C	0.2108	0.3034	0.3751	0.069*
C33	0.04232 (19)	0.4417 (2)	0.20484 (17)	0.0483 (5)
H33A	0.0305	0.5206	0.1478	0.072*
H33B	−0.0619	0.4026	0.2245	0.072*
H33C	0.1078	0.3656	0.1700	0.072*
N4	0.39153 (14)	0.46939 (11)	0.23979 (12)	0.0311 (3)
H4	0.3497 (17)	0.4296 (16)	0.1736 (14)	0.037*
C5	0.54484 (17)	0.53625 (15)	0.21980 (14)	0.0347 (4)
H5A	0.5323	0.6242	0.1711	0.042*
H5B	0.6151	0.4688	0.1769	0.042*
C6	0.61544 (16)	0.57408 (13)	0.33786 (14)	0.0315 (4)
H6	0.7101	0.6361	0.3238	0.038*
C61	0.66666 (17)	0.44379 (16)	0.40979 (17)	0.0405 (4)
H61A	0.7493	0.3916	0.3667	0.061*
H61B	0.5759	0.3801	0.4224	0.061*
H61C	0.7078	0.4757	0.4867	0.061*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0307 (6)	0.0245 (5)	0.0329 (8)	−0.0021 (5)	0.0005 (6)	−0.0069 (5)
C2	0.0321 (8)	0.0234 (6)	0.0343 (9)	0.0043 (6)	−0.0009 (7)	−0.0022 (6)
O21	0.0392 (7)	0.0496 (6)	0.0559 (9)	0.0136 (5)	−0.0006 (6)	−0.0261 (6)
C3	0.0323 (7)	0.0265 (6)	0.0275 (8)	0.0032 (5)	−0.0002 (6)	0.0021 (5)
C31	0.0283 (7)	0.0372 (7)	0.0328 (9)	0.0018 (5)	−0.0003 (7)	−0.0037 (6)
C32	0.0453 (9)	0.0490 (8)	0.0430 (11)	−0.0066 (7)	0.0064 (9)	0.0072 (7)
C33	0.0371 (9)	0.0624 (9)	0.0454 (12)	−0.0082 (7)	−0.0045 (8)	−0.0084 (8)
N4	0.0318 (7)	0.0301 (5)	0.0314 (8)	−0.0039 (5)	0.0053 (6)	−0.0090 (5)
C5	0.0350 (8)	0.0349 (6)	0.0342 (10)	−0.0039 (6)	0.0108 (7)	−0.0018 (6)
C6	0.0286 (8)	0.0281 (6)	0.0379 (10)	−0.0041 (5)	0.0080 (7)	−0.0028 (6)
C61	0.0371 (8)	0.0393 (7)	0.0453 (10)	0.0098 (6)	0.0016 (8)	−0.0030 (7)

Geometric parameters (Å, º)

N1—C2	1.3324 (17)	C33—H33A	0.9800
N1—C6	1.4639 (18)	C33—H33B	0.9800
N1—H1	0.902 (14)	C33—H33C	0.9800
C2—O21	1.2354 (18)	N4—C5	1.4568 (18)
C2—C3	1.5241 (19)	N4—H4	0.905 (14)
C3—N4	1.4561 (17)	C5—C6	1.501 (2)
C3—C31	1.532 (2)	C5—H5A	0.9900
C3—H3	1.0000	C5—H5B	0.9900
C31—C32	1.522 (2)	C6—C61	1.519 (2)
C31—C33	1.523 (2)	C6—H6	1.0000
C31—H31	1.0000	C61—H61A	0.9800
C32—H32A	0.9800	C61—H61B	0.9800
C32—H32B	0.9800	C61—H61C	0.9800
C32—H32C	0.9800
C2—N1—C6	126.34 (12)	H33A—C33—H33B	109.5
C2—N1—H1	116.5 (10)	C31—C33—H33C	109.5
C6—N1—H1	116.6 (10)	H33A—C33—H33C	109.5
O21—C2—N1	121.57 (14)	H33B—C33—H33C	109.5
O21—C2—C3	120.30 (12)	C3—N4—C5	111.70 (10)
N1—C2—C3	118.03 (12)	C3—N4—H4	107.5 (10)
N4—C3—C2	111.27 (11)	C5—N4—H4	113.3 (10)
N4—C3—C31	111.30 (10)	N4—C5—C6	108.53 (12)
C2—C3—C31	111.55 (12)	N4—C5—H5A	110.0
N4—C3—H3	107.5	C6—C5—H5A	110.0
C2—C3—H3	107.5	N4—C5—H5B	110.0
C31—C3—H3	107.5	C6—C5—H5B	110.0
C32—C31—C33	111.44 (13)	H5A—C5—H5B	108.4
C32—C31—C3	112.02 (12)	N1—C6—C5	108.60 (12)
C33—C31—C3	109.91 (13)	N1—C6—C61	109.60 (13)
C32—C31—H31	107.8	C5—C6—C61	113.63 (11)
C33—C31—H31	107.8	N1—C6—H6	108.3
C3—C31—H31	107.8	C5—C6—H6	108.3
C31—C32—H32A	109.5	C61—C6—H6	108.3
C31—C32—H32B	109.5	C6—C61—H61A	109.5
H32A—C32—H32B	109.5	C6—C61—H61B	109.5
C31—C32—H32C	109.5	H61A—C61—H61B	109.5
H32A—C32—H32C	109.5	C6—C61—H61C	109.5
H32B—C32—H32C	109.5	H61A—C61—H61C	109.5
C31—C33—H33A	109.5	H61B—C61—H61C	109.5
C31—C33—H33B	109.5
C6—N1—C2—O21	175.79 (13)	C2—C3—C31—C33	168.92 (12)
C6—N1—C2—C3	−7.8 (2)	C2—C3—N4—C5	−49.78 (16)
O21—C2—C3—N4	−164.47 (13)	C31—C3—N4—C5	−174.87 (13)
N1—C2—C3—N4	19.12 (16)	C3—N4—C5—C6	68.57 (15)
O21—C2—C3—C31	−39.53 (17)	C2—N1—C6—C5	24.42 (18)
N1—C2—C3—C31	144.06 (13)	C2—N1—C6—C61	−100.24 (17)
N4—C3—C31—C32	58.32 (17)	N4—C5—C6—N1	−52.05 (13)
C2—C3—C31—C32	−66.61 (15)	N4—C5—C6—C61	70.19 (15)
N4—C3—C31—C33	−66.15 (16)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O21^i	0.90 (1)	2.13 (2)	2.876 (2)	140 (1)

Symmetry code: (i) x+1/2, −y+3/2, −z+1.