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Acta Crystallogr Sect E Struct Rep Online. 2009 April 1; 65(Pt 4): o819.
Published online 2009 March 25. doi:  10.1107/S1600536809009246
PMCID: PMC2968827

Di-tert-butyl N-[2,6-bis­(methoxy­meth­oxy)phen­yl]imino­diacetate

Abstract

The title mol­ecule, C20H31NO8, has pseudo-C2 symmetry about the C—N bond, with the bis­(tert-butoxy­carbon­yl)amino group twisted from the benzene ring plane by ca 60° and the bulky tert-butoxy­carbonyl (Boc) groups are orientated away from the substituted aniline group. As part of an anti­bacterial drug discovery programme furnishing analogues of platensimycin, we unexpectedly synthesized the bis-Boc-protected aniline.

Related literature

For the synthesis, see: Nicolaou et al. (2006 [triangle])Khakham (2007 [triangle]). For related structures, see: Marino et al. (2002 [triangle]); Macleod et al. (2003 [triangle]). For the protection of amino groups in synthesis, see: ; Kshirsagar (2008 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-65-0o819-scheme1.jpg

Experimental

Crystal data

  • C20H31NO8
  • M r = 413.46
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-65-0o819-efi1.jpg
  • a = 11.2544 (3) Å
  • b = 19.6759 (6) Å
  • c = 9.8325 (3) Å
  • β = 93.207 (1)°
  • V = 2173.90 (11) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.10 mm−1
  • T = 123 K
  • 0.25 × 0.25 × 0.25 mm

Data collection

  • Bruker X8 APEX CCD diffractometer
  • Absorption correction: multi-scan (SADABS; Sheldrick, 1997 [triangle]) T min = 0.95, T max = 0.97
  • 15504 measured reflections
  • 4207 independent reflections
  • 3714 reflections with I > 2σ(I)
  • R int = 0.026

Refinement

  • R[F 2 > 2σ(F 2)] = 0.037
  • wR(F 2) = 0.095
  • S = 1.05
  • 4207 reflections
  • 264 parameters
  • H-atom parameters constrained
  • Δρmax = 0.25 e Å−3
  • Δρmin = −0.22 e Å−3

Data collection: APEX2 (Bruker, 2005 [triangle]); cell refinement: APEX2 and SAINT (Bruker, 2005 [triangle]); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: X-SEED (Barbour, 2001 [triangle]); software used to prepare material for publication: CIFTAB (Sheldrick, 1997 [triangle]).

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809009246/pv2145sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809009246/pv2145Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

The authors acknowledge support from Monash University and the Australian Research Council.

supplementary crystallographic information

Comment

Protection of amino functionalities utilizing bulky tert-butylcarboxy groups is a common synthetic strategy in drug dicovery research programmes (Kshirsagar, 2008). Typically, mono-substituted derivatives are formed from reactions of anilines and di-tert-butyldicarbonate, with di-substitution generally inhibited by the poorer nucleophilic character of the intermediate secondary carbamate. In the current example, reaction of 2,6-bis(methoxymethoxy)aniline with the di-tert-butyldicarbonate gave 2-[bis(tert-butoxycarbonyl)amino]-1,3-bis(methoxymethoxy)benzene (I) in good yield. Surprisingly NMR spectra showed no evidence of restricted rotation of the tert-butoxycarbonyl groups in solution. The solid state structure showed a pseudo C2 symmetric molecule with the two methoxymethoxy arms of the benzene nucleus forming an S-shaped configuration. The bis(tert-butoxycarbonyl)amino fragment is twisted from the aromatic ring plane with the torsion angles C2—C1—N1—C12 57.7 (2) °; C6—C1—N1—C11 59.7 (2) ° smaller than for an analogous bis Boc aniline di-tert-butyl(2-(2-((4-methylphenyl)thio)-5-oxo-3-(3-oxohexyl) tetrahydrofuran-3-yl)phenyl)imidocarbonate (II) (73.6 °, 93.3 °) Marino et al. 2002), but larger than those observed for mono-protected anilines (e.g. 36.3 (3) ° in 2-(2'-N-tert-butoxycarbonyl)phenyl-1,3-dithiane (Macleod et al. 2003). The bulky tert-butoxycarbonyl groups are orientated away from the aniline group in I and II in contrast to the only other bis(tert-butoxycarbonyl)aniline structure, 2-(2'(N,N'-bis(tert-butoxycarbonyl)amino)phenyl-1,3-dithiane, in which the carbonyl groups point away from the aromatic ring (Macleod et al. 2003). No significant interactions between molecules of the title compound were observed (closest contact O7···H7a(#1) 2.474 Å, #1 x, 1/2 - y, 1/2 + z) and the observed configuration presumably derives from the steric repulsion between the ortho methoxymethoxy substitutents of the analine and the bulky tert-butoxycarbonyl groups.

Experimental

The title compound (I) was synthesized from 2,6-bis(methoxymethoxy)aniline (Nicolaou et al., 2006) and commercially available di-tert-butyldicarbonate in the presence of a catalytic amount of 4-(dimethylamino)pyridine (DMAP), using tetrahydrofuran as solvent (Khakham, 2007). To a 50 ml round bottom flask was added 2,6-di(methoxymethoxy)aniline (0.820 g, 3.85 mmol) and di-tert-butyldicarbonate (2.51 g, 11.5 mmol) and 4-(dimethylamino)pyridine (0.120 g, 0.982 mmol) and tetrahydrofuran (15 ml). The reaction mixture was heated at reflux with stirring for 24 h, cooled then evaporated to dryness. The resulting residue was purified by flash chromatography (1:4 ethyl acetate/hexane) and the major fractions were combined then evaporated to dryness. The title compound was recrystallized from dichloromethane-hexane as colorless needles (549 mg, 46%) suitable for X-ray diffraction. Mp 366–367 K.

Refinement

All H atoms for the primary molecules were initially located in the difference Fourier map but were placed in geometrically idealized positions and constrained to ride on their parent atoms with phenyl, methyl and methylene C—H distances 0.95, 0.98 and 0.99 Å, respectively and Uiso(H) = 1.5 and 1.2 times Ueq(C) for methyl and non-methyl H-atoms, respectively.

Figures

Fig. 1.
Molecular diagram of the title compound. Displacement ellipsoids are drawn at the 50% probability level.

Crystal data

C20H31NO8F(000) = 888
Mr = 413.46Dx = 1.263 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybcCell parameters from 15504 reflections
a = 11.2544 (3) Åθ = 2.1–26.0°
b = 19.6759 (6) ŵ = 0.10 mm1
c = 9.8325 (3) ÅT = 123 K
β = 93.207 (1)°Prism, colourless
V = 2173.90 (11) Å30.25 × 0.25 × 0.25 mm
Z = 4

Data collection

Bruker X8 APEX CCD diffractometer4207 independent reflections
Radiation source: fine-focus sealed tube3714 reflections with I > 2σ(I)
graphiteRint = 0.026
Thin–slice [var phi] and ω scansθmax = 26.0°, θmin = 2.1°
Absorption correction: multi-scan (SADABS; Sheldrick, 1997)h = −13→11
Tmin = 0.95, Tmax = 0.97k = −24→24
15504 measured reflectionsl = −12→12

Refinement

Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.037Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.095H-atom parameters constrained
S = 1.05w = 1/[σ2(Fo2) + (0.0455P)2 + 0.7413P] where P = (Fo2 + 2Fc2)/3
4207 reflections(Δ/σ)max < 0.001
264 parametersΔρmax = 0.25 e Å3
0 restraintsΔρmin = −0.22 e Å3

Special details

Experimental. 1H NMR (CDCl3) δ 1.45(18H, s, tert-Bu), 3.51 (6H, s, OCH3), 5.21 (4H, s, OCH2O), 6.85 (2H, d, J = 8 Hz, H3 H5), 7.21 (1H, t, J = 8 Hz, H4). 13C NMR (CDCl3) δ 27.9 (CH3), 56.0 (CH3), 82.0 (CH2), 95.0 (CH2), 108.7 (CH), 128.7 (CH), 151.5 (Cq), 162.0 (Cq). ESI MS (20 V) m/z 844 ([2M+NH4]+, 25%), 414 ([M+H]+, 26%), 358 (35%), 302 (100%), 258 (40%), 182 (39%).
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 (Å2)

xyzUiso*/Ueq
O10.01820 (8)0.15220 (4)0.49516 (9)0.0208 (2)
O2−0.17789 (8)0.19162 (5)0.45496 (10)0.0239 (2)
O30.20418 (8)0.02812 (4)0.84955 (9)0.0222 (2)
O40.22082 (9)−0.08991 (5)0.87902 (10)0.0275 (2)
O50.32175 (8)0.04924 (4)0.57699 (9)0.0226 (2)
O60.40454 (8)0.13528 (5)0.70366 (9)0.0215 (2)
O70.10556 (8)0.22153 (4)0.75269 (9)0.0209 (2)
O80.26357 (8)0.23752 (4)0.62311 (9)0.0189 (2)
N10.20550 (9)0.13091 (5)0.66923 (10)0.0170 (2)
C10.10389 (11)0.08748 (6)0.67245 (12)0.0169 (3)
C20.00578 (11)0.09870 (6)0.58212 (12)0.0183 (3)
C3−0.09338 (12)0.05666 (6)0.58451 (14)0.0224 (3)
H3−0.16120.06460.52470.027*
C4−0.09125 (12)0.00289 (7)0.67605 (14)0.0245 (3)
H4−0.1581−0.02660.67660.029*
C50.00498 (12)−0.00910 (6)0.76637 (14)0.0228 (3)
H50.0042−0.04610.82830.027*
C60.10309 (11)0.03395 (6)0.76507 (12)0.0188 (3)
C7−0.07663 (12)0.16675 (7)0.39715 (13)0.0223 (3)
H7A−0.04890.20060.33150.027*
H7B−0.09760.12470.34590.027*
C8−0.15998 (14)0.25694 (7)0.51580 (17)0.0344 (4)
H8A−0.10330.25310.59480.052*
H8B−0.23600.27440.54520.052*
H8C−0.12840.28820.44920.052*
C90.21192 (14)−0.02718 (7)0.94256 (13)0.0283 (3)
H9A0.2824−0.02061.00610.034*
H9B0.1405−0.02710.99690.034*
C100.32667 (13)−0.09618 (8)0.80655 (16)0.0331 (3)
H10A0.3254−0.06260.73280.050*
H10B0.3310−0.14200.76810.050*
H10C0.3962−0.08820.86900.050*
C110.31523 (11)0.10078 (6)0.64174 (12)0.0174 (3)
C120.18617 (11)0.20088 (6)0.68888 (11)0.0159 (2)
C130.52977 (12)0.11794 (7)0.67929 (14)0.0246 (3)
C140.55807 (14)0.04678 (8)0.73059 (17)0.0376 (4)
H14A0.51290.01360.67410.056*
H14B0.53620.04270.82530.056*
H14C0.64340.03800.72550.056*
C150.59817 (13)0.17074 (9)0.76495 (17)0.0393 (4)
H15A0.58300.16400.86120.059*
H15B0.57210.21630.73650.059*
H15C0.68350.16590.75240.059*
C160.55154 (13)0.12683 (9)0.53009 (15)0.0351 (4)
H16A0.50670.09230.47670.053*
H16B0.63670.12170.51650.053*
H16C0.52530.17220.50030.053*
C170.26643 (12)0.31241 (6)0.63900 (13)0.0200 (3)
C180.15042 (12)0.34337 (7)0.58381 (13)0.0238 (3)
H18A0.13600.33040.48810.036*
H18B0.15510.39300.59100.036*
H18C0.08510.32670.63660.036*
C190.36707 (13)0.33176 (7)0.54976 (16)0.0295 (3)
H19A0.34530.31970.45490.044*
H19B0.43950.30730.58040.044*
H19C0.38130.38080.55630.044*
C200.29631 (14)0.33007 (7)0.78745 (14)0.0310 (3)
H20A0.37210.30880.81740.047*
H20B0.23320.31330.84340.047*
H20C0.30290.37950.79730.047*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
O10.0161 (5)0.0216 (5)0.0245 (5)−0.0008 (4)−0.0005 (4)0.0046 (4)
O20.0167 (5)0.0224 (5)0.0325 (5)0.0018 (4)0.0003 (4)−0.0031 (4)
O30.0259 (5)0.0183 (5)0.0222 (4)0.0018 (4)−0.0017 (4)0.0016 (3)
O40.0336 (6)0.0189 (5)0.0300 (5)0.0040 (4)0.0022 (4)0.0032 (4)
O50.0207 (5)0.0203 (5)0.0269 (5)0.0022 (4)0.0023 (4)−0.0058 (4)
O60.0128 (5)0.0250 (5)0.0265 (5)0.0006 (4)−0.0003 (4)−0.0060 (4)
O70.0225 (5)0.0181 (4)0.0227 (4)0.0014 (4)0.0074 (4)−0.0008 (3)
O80.0200 (5)0.0143 (4)0.0227 (4)−0.0020 (3)0.0056 (4)−0.0010 (3)
N10.0135 (5)0.0146 (5)0.0230 (5)0.0002 (4)0.0017 (4)−0.0006 (4)
C10.0150 (6)0.0138 (6)0.0222 (6)−0.0001 (5)0.0047 (5)−0.0026 (5)
C20.0176 (7)0.0157 (6)0.0219 (6)0.0022 (5)0.0050 (5)−0.0013 (5)
C30.0150 (7)0.0208 (6)0.0314 (7)0.0007 (5)0.0024 (5)−0.0028 (5)
C40.0177 (7)0.0174 (6)0.0394 (8)−0.0031 (5)0.0102 (6)−0.0032 (5)
C50.0251 (7)0.0142 (6)0.0302 (7)0.0006 (5)0.0114 (6)0.0019 (5)
C60.0203 (7)0.0159 (6)0.0205 (6)0.0038 (5)0.0042 (5)−0.0032 (5)
C70.0195 (7)0.0260 (7)0.0210 (6)0.0024 (5)−0.0016 (5)−0.0002 (5)
C80.0310 (9)0.0256 (7)0.0462 (9)0.0045 (6)−0.0015 (7)−0.0094 (6)
C90.0428 (9)0.0222 (7)0.0197 (6)0.0051 (6)0.0017 (6)0.0033 (5)
C100.0296 (8)0.0281 (8)0.0415 (8)0.0070 (6)0.0001 (6)−0.0030 (6)
C110.0158 (7)0.0188 (6)0.0175 (6)0.0001 (5)0.0020 (5)0.0025 (5)
C120.0170 (6)0.0156 (6)0.0149 (5)−0.0004 (5)−0.0011 (5)−0.0001 (4)
C130.0123 (7)0.0344 (8)0.0269 (7)0.0022 (5)0.0004 (5)−0.0017 (6)
C140.0230 (8)0.0432 (9)0.0461 (9)0.0101 (7)−0.0037 (7)0.0073 (7)
C150.0194 (8)0.0537 (10)0.0445 (9)−0.0062 (7)−0.0029 (7)−0.0104 (8)
C160.0192 (8)0.0569 (10)0.0295 (8)−0.0030 (7)0.0037 (6)0.0026 (7)
C170.0243 (7)0.0125 (6)0.0235 (6)−0.0036 (5)0.0021 (5)−0.0007 (5)
C180.0275 (8)0.0195 (6)0.0249 (6)0.0018 (5)0.0046 (5)0.0037 (5)
C190.0261 (8)0.0219 (7)0.0413 (8)−0.0044 (6)0.0085 (6)0.0039 (6)
C200.0412 (9)0.0235 (7)0.0275 (7)−0.0060 (6)−0.0066 (6)−0.0038 (6)

Geometric parameters (Å, °)

O1—C21.3683 (15)C8—H8C0.9800
O1—C71.4264 (15)C9—H9A0.9900
O2—C71.3907 (16)C9—H9B0.9900
O2—C81.4272 (16)C10—H10A0.9800
O3—C61.3754 (16)C10—H10B0.9800
O3—C91.4210 (15)C10—H10C0.9800
O4—C91.3894 (16)C13—C161.5109 (19)
O4—C101.4272 (18)C13—C141.516 (2)
O5—C111.2017 (15)C13—C151.519 (2)
O6—C111.3317 (15)C14—H14A0.9800
O6—C131.4825 (16)C14—H14B0.9800
O7—C121.2023 (15)C14—H14C0.9800
O8—C121.3266 (15)C15—H15A0.9800
O8—C171.4820 (14)C15—H15B0.9800
N1—C121.4088 (15)C15—H15C0.9800
N1—C111.4096 (16)C16—H16A0.9800
N1—C11.4292 (16)C16—H16B0.9800
C1—C61.3928 (17)C16—H16C0.9800
C1—C21.3954 (18)C17—C181.5136 (19)
C2—C31.3903 (18)C17—C191.5195 (18)
C3—C41.3884 (19)C17—C201.5196 (18)
C3—H30.9500C18—H18A0.9800
C4—C51.382 (2)C18—H18B0.9800
C4—H40.9500C18—H18C0.9800
C5—C61.3923 (18)C19—H19A0.9800
C5—H50.9500C19—H19B0.9800
C7—H7A0.9900C19—H19C0.9800
C7—H7B0.9900C20—H20A0.9800
C8—H8A0.9800C20—H20B0.9800
C8—H8B0.9800C20—H20C0.9800
C2—O1—C7118.55 (10)O6—C11—N1110.18 (10)
C7—O2—C8112.86 (11)O7—C12—O8127.29 (11)
C6—O3—C9118.13 (10)O7—C12—N1121.92 (11)
C9—O4—C10112.61 (11)O8—C12—N1110.71 (10)
C11—O6—C13120.59 (10)O6—C13—C16109.73 (11)
C12—O8—C17120.00 (9)O6—C13—C14110.04 (11)
C12—N1—C11125.51 (10)C16—C13—C14112.79 (13)
C12—N1—C1116.83 (10)O6—C13—C15102.12 (11)
C11—N1—C1117.61 (10)C16—C13—C15110.76 (13)
C6—C1—C2120.13 (11)C14—C13—C15110.89 (13)
C6—C1—N1120.07 (11)C13—C14—H14A109.5
C2—C1—N1119.80 (11)C13—C14—H14B109.5
O1—C2—C3125.34 (12)H14A—C14—H14B109.5
O1—C2—C1114.49 (11)C13—C14—H14C109.5
C3—C2—C1120.17 (12)H14A—C14—H14C109.5
C4—C3—C2118.65 (12)H14B—C14—H14C109.5
C4—C3—H3120.7C13—C15—H15A109.5
C2—C3—H3120.7C13—C15—H15B109.5
C5—C4—C3122.09 (12)H15A—C15—H15B109.5
C5—C4—H4119.0C13—C15—H15C109.5
C3—C4—H4119.0H15A—C15—H15C109.5
C4—C5—C6118.93 (12)H15B—C15—H15C109.5
C4—C5—H5120.5C13—C16—H16A109.5
C6—C5—H5120.5C13—C16—H16B109.5
O3—C6—C5124.99 (11)H16A—C16—H16B109.5
O3—C6—C1115.00 (11)C13—C16—H16C109.5
C5—C6—C1120.01 (12)H16A—C16—H16C109.5
O2—C7—O1113.19 (10)H16B—C16—H16C109.5
O2—C7—H7A108.9O8—C17—C18110.43 (10)
O1—C7—H7A108.9O8—C17—C19101.58 (10)
O2—C7—H7B108.9C18—C17—C19110.37 (11)
O1—C7—H7B108.9O8—C17—C20109.33 (10)
H7A—C7—H7B107.8C18—C17—C20113.10 (11)
O2—C8—H8A109.5C19—C17—C20111.43 (12)
O2—C8—H8B109.5C17—C18—H18A109.5
H8A—C8—H8B109.5C17—C18—H18B109.5
O2—C8—H8C109.5H18A—C18—H18B109.5
H8A—C8—H8C109.5C17—C18—H18C109.5
H8B—C8—H8C109.5H18A—C18—H18C109.5
O4—C9—O3113.22 (10)H18B—C18—H18C109.5
O4—C9—H9A108.9C17—C19—H19A109.5
O3—C9—H9A108.9C17—C19—H19B109.5
O4—C9—H9B108.9H19A—C19—H19B109.5
O3—C9—H9B108.9C17—C19—H19C109.5
H9A—C9—H9B107.7H19A—C19—H19C109.5
O4—C10—H10A109.5H19B—C19—H19C109.5
O4—C10—H10B109.5C17—C20—H20A109.5
H10A—C10—H10B109.5C17—C20—H20B109.5
O4—C10—H10C109.5H20A—C20—H20B109.5
H10A—C10—H10C109.5C17—C20—H20C109.5
H10B—C10—H10C109.5H20A—C20—H20C109.5
O5—C11—O6127.26 (12)H20B—C20—H20C109.5
O5—C11—N1122.45 (11)
C2—C1—N1—C1257.65 (15)C6—C1—N1—C1159.68 (15)

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: PV2145).

References

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