2(S)-N-tert-Butoxy­carbonyl­amino-N-methoxy-N-methylbutan­amide

In the solid state the title compound, C₁₁H₂₂N₂O₄, is in an antiperiplanar conformation. The conformation of the compound shows no similarity with the synclinal conformation of the chelated intermediate formed during nucleophilic attack.

Key indicators

• Single-crystal X-ray study
• T = 123 K
• Mean [sigma](C-C) = 0.002 Å
• R factor = 0.034
• wR factor = 0.090
• Data-to-parameter ratio = 21.1

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry


 Alert Level C:



STRVAL_01
         From the CIF: _refine_ls_abs_structure_Flack    0.200
         From the CIF: _refine_ls_abs_structure_Flack_su    0.800
           Alert C Flack test results are meaningless.

General Notes



REFLT_03
         From the CIF: _diffrn_reflns_theta_max           28.29
         From the CIF: _reflns_number_total               3362
         Count of symmetry unique reflns         1970
         Completeness (_total/calc)            170.66%
         TEST3: Check Friedels for noncentro structure
         Estimate of Friedel pairs measured      1392
         Fraction of Friedel pairs measured     0.707
         Are heavy atom types Z>Si present           no
          ALERT: MoKa measured Friedel data cannot be used to
                 determine absolute structure in a light-atom
                 study EXCEPT under VERY special conditions.
                 It is preferred that Friedel data is merged in such cases.


 0 Alert Level A = Potentially serious problem

 0 Alert Level B = Potential problem

 1 Alert Level C = Please check

---

S1. Comment

N-methoxy-N-methyl-amides have been extensively used as carbonyl cation equivalents (Sibi, 1993). They are easy to prepare by several methods and show few side-reactions during nucleophilic addition or selective reduction to aldehydes. These advantages led us to the decision to use the title compound, (I), as an intermediate in alkylation reactions to prepare derivatives of a natural occurring lipid, sphingosine. Initially, compound (I) was prepared by Harbeson by a different route (Harbeson et al., 1994). The crystal structure of another N-methoxy-N-methyl-amide is reported by Zheng et al. (2000).

The underlying basis for the usefulness of N-methoxy-N-methyl-amides is the formation of a stable chelated tetrahedral intermediate after nucleophilic attack (Fig. 1), which prevents further additions to undesired side-products (Evans et al., 1991).

The structure of (I) with the atom numbering is shown in Fig. 2. Selected geometrical parameters are listed in Table 1. Within the crystal structure five intermolecular hydrogen bonds (Steiner, 2002) were found (Table 2). The four C—H···O hydrogen bonds are weak, whereas the N6—H6···O41 bond is a normal hydrogen bond. With the exception of the C52—H52C···O41 hydrogen bond in which the deviation from the ideal 180° torsion angle is 30.3°, all intermolecular hydrogen bonds are almost linear. Within the molecule, the torsion angle O2—N3—C4—O41 is −172.47 (10)° (nearly ideal antiperiplanar conformation). The conformation of (I), with a torsion angle of 60°, shows no similarity with the synclinal conformation assumed to occur in the chelated tetrahedral intermediate during nucleophilic attack.

S2. Experimental

Glassware was flame dried under an argon atmosphere and allowed to cool. (S)-2-Aminobutyric acid (5 g, 48.5 mmol) was dissolved in a cold (273 K) solution of dioxane (50 ml) and 1M aqueous NaOH (100 ml). To the flask di-tert-butyl-dicarbonate (12.8 g, 59.0 mmol) was added in portions under stirring. After stirring for two days, the solvent was removed by evaporation under reduced pressure. The clear solution was acidified with 1M KHSO₄ to a pH of 2–3 (white precipitate occurs) and then cold saturated NaHCO₃ was added carefully to neutralize the mixture, which was then extracted with ethyl acetate several times. The collected organic phases were dried over Na₂SO₄, filtered and concentrated in vacuo to yield a colourless oil, which was used without further purification. The oil was dissolved in anhyd. dichloromethane (200 ml) and cooled to 250 K. N,O-Dimethylhydroxylamine hydrochloride (4.86 g, 49.8 mmol) and N-methyl morpholine (5.5 ml, 49.8 mmol) were added in one portion. After stirring for 10 min, N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide hydrochloride (9.55 g, 49.8 mmol) was dissolved in the clear solution and stirring continued for 1 h; during which time a white solid precipitated. The aqueous phase was extracted with dichloromethane and the collected organic phases washed with saturated NaHCO₃ and then dried over Na₂SO₄, filtered and evaporated under reduced pressure to yield a colourless solid. The product was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 2:1) to give colourless crystals (yield: 7.01 g, 58.8%) which were suitable for X-ray analysis.

S3. Refinement

The absolute configuration of the title compound could not be determined from the X-ray data but was fixed by the absolute stereochemistry of the starting material, (S)-2-aminobutyric acid. The position of the amide H atom was determined from a difference Fourier map and its coordinates refined freely, with the isotropic displacement parameter constrained to U(H) = 1.5 U_eq (N). All remaining H atoms were treated as riding, with C—H = 0.98–1.00 Å, and U_iso(H) = 1.2 U_eq (CH, CH₂) and 1.5 U_eq (CH₃).

Computing details

Data collection: COLLECT (Nonius, 1997–2000); cell refinement: HKL SCALEPACK (Otwinowski & Minor 1997); data reduction: HKL DENZO (Otwinowski & Minor 1997) and SCALEPACK; program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL-Plus (Sheldrick, 1991); software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. The structure of the tetrahedral intermediate.
	Fig. 2. The structure of (I), showing the atom-numbering scheme and displacement ellipsoids at the 50% probability level. H atoms are shown as small spheres of arbitrary radii.

2(S)—N-tert-Butoxycarbonylamino-N-methoxy-N-methyl-butanamide

Crystal data

C11H22N2O4	Dx = 1.194 Mg m^−3
Mr = 246.31	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121	Cell parameters from 19365 reflections
a = 6.6315 (1) Å	θ = 1–28°
b = 9.8478 (2) Å	µ = 0.09 mm^−1
c = 20.9769 (5) Å	T = 123 K
V = 1369.91 (5) Å^3	Prisms, colourless
Z = 4	0.40 × 0.20 × 0.10 mm
F(000) = 536

Data collection

Nonius Kappa-CCD diffractometer	3020 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.032
Graphite monochromator	θmax = 28.3°, θmin = 2.8°
ϕ and ω scans	h = −8→8
19820 measured reflections	k = −13→13
3362 independent reflections	l = −27→27

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)] = 0.034	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.090	w = 1/[σ^2(Fo^2) + (0.0542P)^2 + 0.0843P] where P = (Fo^2 + 2Fc^2)/3
S = 1.07	(Δ/σ)max = 0.001
3362 reflections	Δρmax = 0.20 e Å^−3
159 parameters	Δρmin = −0.29 e Å^−3
1 restraint	Absolute structure: Flack H D (1983), Acta Cryst. A39, 876-881
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.2 (8)

Special details

Experimental. dx = 39.740 (6) mm; mos.= 0.446 (1) 2 x 60 s; 1 °.; 579 frams

TLC: 2:1 cyclohexane-ethyl acetate, R_f: 0.36; α_D: +4.1 ° (c = 0.66; CHCl₃); m.p.: 334 K; ¹H-NMR (400 MHz, CDCl₃): δ 0.87 (t, J = 7.0 Hz, 3H; CH₃), 1.36 (s, 9H; C(CH₃)₃), 1.50 (m, 1H; CH₂), 1.69 (m, 1H; CH₂), 3.13 (s, 3H; CH₃), 3.70 (s, 3H; CH₃), 4.55 (m, 1H; CHN), 5.33 (d, J = 8.9 Hz, 1H; NH); ¹³C-NMR (100 MHz, CDCl₃): δ 9.66 (CH₃), 25.74 (CH₂), 28.33 (C(CH₃)₃), 31.76 (NCH₃), 51.35 (OCH₃), 61.33 (CHN), 78.99 (C(CH₃)₃), 155.41 (NCO), 172.91 (CON); elemental analyses (%): C₁₁H₂₂N₂O₄ (246.31): calc.: C 53.64, H 9.00, N 11.37; found: C 53.76, H 9.22, N 11.26; FAB-MS (3-Nitrobenzoic acid): 269.1 (M+Na)⁺, 247.2 (M+H)⁺.

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
C1	0.3483 (2)	0.80113 (13)	0.56443 (7)	0.0360 (3)
H1A	0.4701	0.8553	0.5718	0.054*
H1B	0.2301	0.8512	0.5797	0.054*
H1C	0.3339	0.7832	0.5187	0.054*
O2	0.36423 (13)	0.67448 (9)	0.59820 (4)	0.02711 (19)
N3	0.53544 (16)	0.60343 (11)	0.57723 (5)	0.0252 (2)
C31	0.7155 (2)	0.62789 (14)	0.61501 (6)	0.0300 (3)
H31A	0.6873	0.6077	0.6599	0.045*
H31B	0.7557	0.7232	0.6108	0.045*
H31C	0.8248	0.5693	0.5999	0.045*
C4	0.50610 (17)	0.48948 (12)	0.54203 (5)	0.0202 (2)
O41	0.64865 (13)	0.41643 (8)	0.52818 (4)	0.02516 (19)
C5	0.28824 (19)	0.45748 (12)	0.52326 (5)	0.0226 (2)
H5	0.2158	0.5448	0.5150	0.027*
C51	0.18403 (18)	0.38390 (14)	0.57853 (6)	0.0286 (3)
H51A	0.1723	0.4474	0.6149	0.034*
H51B	0.0457	0.3590	0.5651	0.034*
C52	0.2923 (2)	0.25629 (15)	0.60096 (6)	0.0343 (3)
H52A	0.2172	0.2154	0.6363	0.051*
H52B	0.4285	0.2800	0.6153	0.051*
H52C	0.3011	0.1913	0.5657	0.051*
N6	0.28131 (16)	0.37545 (10)	0.46600 (4)	0.0223 (2)
H6	0.239 (2)	0.2936 (14)	0.4662 (7)	0.034*
C7	0.31868 (17)	0.43294 (11)	0.40907 (5)	0.0214 (2)
O71	0.37025 (16)	0.55113 (9)	0.40194 (4)	0.0331 (2)
O8	0.29209 (14)	0.34248 (8)	0.36164 (4)	0.02320 (18)
C9	0.28089 (19)	0.38672 (13)	0.29463 (5)	0.0270 (3)
C91	0.1209 (3)	0.49283 (17)	0.28593 (7)	0.0466 (4)
H91A	−0.0083	0.4579	0.3015	0.070*
H91B	0.1091	0.5155	0.2406	0.070*
H91C	0.1576	0.5745	0.3100	0.070*
C92	0.4827 (3)	0.4343 (3)	0.27165 (8)	0.0734 (7)
H92A	0.5826	0.3622	0.2781	0.110*
H92B	0.5231	0.5152	0.2956	0.110*
H92C	0.4745	0.4564	0.2262	0.110*
C93	0.2141 (5)	0.25698 (17)	0.26163 (7)	0.0682 (7)
H93A	0.0814	0.2299	0.2777	0.102*
H93B	0.3119	0.1847	0.2703	0.102*
H93C	0.2059	0.2726	0.2156	0.102*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0425 (8)	0.0290 (6)	0.0365 (7)	0.0108 (6)	−0.0025 (6)	−0.0019 (5)
O2	0.0285 (4)	0.0272 (4)	0.0256 (4)	0.0052 (4)	0.0014 (4)	−0.0070 (3)
N3	0.0222 (5)	0.0257 (5)	0.0277 (5)	0.0028 (4)	−0.0044 (4)	−0.0080 (4)
C31	0.0296 (6)	0.0299 (6)	0.0305 (6)	−0.0030 (5)	−0.0082 (5)	−0.0026 (5)
C4	0.0212 (6)	0.0205 (5)	0.0188 (5)	0.0000 (4)	0.0004 (4)	0.0004 (4)
O41	0.0224 (4)	0.0235 (4)	0.0296 (4)	0.0024 (3)	0.0017 (3)	−0.0025 (3)
C5	0.0225 (5)	0.0247 (5)	0.0205 (5)	0.0031 (5)	−0.0036 (4)	−0.0055 (4)
C51	0.0190 (6)	0.0425 (7)	0.0244 (6)	−0.0042 (5)	0.0018 (4)	−0.0056 (5)
C52	0.0296 (6)	0.0480 (8)	0.0251 (6)	−0.0103 (6)	−0.0013 (5)	0.0092 (6)
N6	0.0276 (5)	0.0195 (4)	0.0199 (5)	−0.0030 (4)	−0.0032 (4)	−0.0022 (4)
C7	0.0204 (5)	0.0203 (5)	0.0236 (5)	0.0001 (4)	−0.0043 (4)	−0.0004 (4)
O71	0.0438 (5)	0.0228 (4)	0.0326 (5)	−0.0084 (4)	−0.0089 (4)	0.0033 (4)
O8	0.0312 (4)	0.0213 (4)	0.0172 (4)	−0.0007 (3)	−0.0007 (3)	0.0004 (3)
C9	0.0311 (6)	0.0316 (6)	0.0183 (5)	−0.0004 (5)	−0.0016 (5)	0.0038 (5)
C91	0.0512 (9)	0.0561 (9)	0.0324 (7)	0.0188 (8)	−0.0135 (7)	0.0041 (7)
C92	0.0359 (9)	0.153 (2)	0.0309 (8)	−0.0110 (12)	0.0002 (7)	0.0390 (11)
C93	0.143 (2)	0.0413 (8)	0.0207 (7)	0.0037 (11)	−0.0102 (10)	−0.0066 (6)

Geometric parameters (Å, º)

C1—O2	1.4382 (16)	C52—H52B	0.9800
C1—H1A	0.9800	C52—H52C	0.9800
C1—H1B	0.9800	N6—C7	1.3445 (15)
C1—H1C	0.9800	N6—H6	0.854 (13)
O2—N3	1.4043 (13)	C7—O71	1.2223 (14)
N3—C4	1.3572 (15)	C7—O8	1.3471 (13)
N3—C31	1.4532 (16)	O8—C9	1.4735 (13)
C31—H31A	0.9800	C9—C92	1.498 (2)
C31—H31B	0.9800	C9—C91	1.500 (2)
C31—H31C	0.9800	C9—C93	1.519 (2)
C4—O41	1.2229 (14)	C91—H91A	0.9800
C4—C5	1.5302 (17)	C91—H91B	0.9800
C5—N6	1.4483 (14)	C91—H91C	0.9800
C5—C51	1.5319 (17)	C92—H92A	0.9800
C5—H5	1.0000	C92—H92B	0.9800
C51—C52	1.522 (2)	C92—H92C	0.9800
C51—H51A	0.9900	C93—H93A	0.9800
C51—H51B	0.9900	C93—H93B	0.9800
C52—H52A	0.9800	C93—H93C	0.9800
O2—C1—H1A	109.5	C51—C52—H52C	109.5
O2—C1—H1B	109.5	H52A—C52—H52C	109.5
H1A—C1—H1B	109.5	H52B—C52—H52C	109.5
O2—C1—H1C	109.5	C7—N6—C5	119.73 (10)
H1A—C1—H1C	109.5	C7—N6—H6	117.5 (11)
H1B—C1—H1C	109.5	C5—N6—H6	122.2 (11)
N3—O2—C1	109.70 (10)	O71—C7—N6	124.15 (11)
C4—N3—O2	117.80 (9)	O71—C7—O8	125.16 (11)
C4—N3—C31	123.47 (10)	N6—C7—O8	110.69 (9)
O2—N3—C31	114.25 (9)	C7—O8—C9	121.04 (9)
N3—C31—H31A	109.5	O8—C9—C92	110.76 (11)
N3—C31—H31B	109.5	O8—C9—C91	110.95 (11)
H31A—C31—H31B	109.5	C92—C9—C91	112.02 (14)
N3—C31—H31C	109.5	O8—C9—C93	101.58 (10)
H31A—C31—H31C	109.5	C92—C9—C93	112.13 (18)
H31B—C31—H31C	109.5	C91—C9—C93	108.92 (14)
O41—C4—N3	120.31 (11)	C9—C91—H91A	109.5
O41—C4—C5	123.20 (10)	C9—C91—H91B	109.5
N3—C4—C5	116.46 (10)	H91A—C91—H91B	109.5
N6—C5—C4	110.99 (10)	C9—C91—H91C	109.5
N6—C5—C51	110.47 (10)	H91A—C91—H91C	109.5
C4—C5—C51	109.18 (9)	H91B—C91—H91C	109.5
N6—C5—H5	108.7	C9—C92—H92A	109.5
C4—C5—H5	108.7	C9—C92—H92B	109.5
C51—C5—H5	108.7	H92A—C92—H92B	109.5
C52—C51—C5	114.30 (10)	C9—C92—H92C	109.5
C52—C51—H51A	108.7	H92A—C92—H92C	109.5
C5—C51—H51A	108.7	H92B—C92—H92C	109.5
C52—C51—H51B	108.7	C9—C93—H93A	109.5
C5—C51—H51B	108.7	C9—C93—H93B	109.5
H51A—C51—H51B	107.6	H93A—C93—H93B	109.5
C51—C52—H52A	109.5	C9—C93—H93C	109.5
C51—C52—H52B	109.5	H93A—C93—H93C	109.5
H52A—C52—H52B	109.5	H93B—C93—H93C	109.5
C1—O2—N3—C4	−109.74 (12)	C4—C5—C51—C52	−55.28 (13)
C1—O2—N3—C31	93.12 (12)	C4—C5—N6—C7	−75.00 (13)
O2—N3—C4—O41	−172.47 (10)	C51—C5—N6—C7	163.75 (10)
C31—N3—C4—O41	−17.60 (18)	C5—N6—C7—O71	4.23 (18)
O2—N3—C4—C5	5.74 (15)	C5—N6—C7—O8	−175.98 (10)
C31—N3—C4—C5	160.61 (11)	O71—C7—O8—C9	−13.45 (18)
O41—C4—C5—N6	−26.90 (16)	N6—C7—O8—C9	166.76 (10)
N3—C4—C5—N6	154.95 (10)	C7—O8—C9—C92	70.40 (17)
O41—C4—C5—C51	95.11 (13)	C7—O8—C9—C91	−54.68 (15)
N3—C4—C5—C51	−83.05 (13)	C7—O8—C9—C93	−170.33 (14)
N6—C5—C51—C52	67.04 (13)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N6—H6···O41^i	0.85 (1)	2.16 (1)	3.0085 (13)	176 (2)
C52—H52C···O41^i	0.98	2.45	3.3376 (16)	150
C31—H31B···O71^ii	0.98	2.36	3.3424 (16)	177
C1—H1B···O71^iii	0.98	2.60	3.5589 (18)	166
C93—H93C···O2^iv	0.98	2.56	3.5325 (18)	172

Symmetry codes: (i) x−1/2, −y+1/2, −z+1; (ii) x+1/2, −y+3/2, −z+1; (iii) x−1/2, −y+3/2, −z+1; (iv) −x+1/2, −y+1, z−1/2.