Synthesis and crystal structure of 1-(4-bromobenzyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane

Article abstract of DOI:10.1023/A:1009531514664

1-(4-Bromobenzyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane, C₁₃H₁₅BrO₃, has been synthesized from 4-bromophenylacetic acid chloride via the oxetan ester (3-methyl-3-oxetanyl)-methyl-2-(4-bromophenyl)acetate. The crystal s

Full text of DOI:10.1023/A:1009531514664

Journal of Chemical Crystallography, Vol. 29, No. 4, 1999
Note
Synthesis and crystal structure of
1-(4-bromobenzyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane
Marianne Sveaas Løiten,(1)* Christian Gløga˚rd,(1) Jo Klaveness,(1) and Berit Fjærtoft(1)
Received April 3, 1998
1-(4-Bromobenzyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane, C13H15BrO3, has been synthe-
sized from 4-bromophenylacetic acid chloride via the oxetan ester (3-methyl-3-oxetanyl)-
methyl-2-(4-bromophenyl)acetate. The crystal structure of the title compound has been
determined at low temperature (120 K), by X-ray diffraction methods. This compound
crystallizes in the monoclinic space group P21/n (No. 14), Z ϭ 4, with lattice parameters
˚
a ϭ 6.019(5), b ϭ 20.990(5), c ϭ 9.915(2) A, and ͱ ϭ 101.29(1)Њ.
KEY WORDS: Contrast agents; crystal structure; ortho ester.
Introduction
Contrast agents for medical X-ray examinations
are aromatic, hydrophilic, and water soluble com-
pounds containing at least three iodine atoms. The
most frequently used agents today are nonionic com-
pounds, such as iohexol and iodixanol, due to the
relative low osmolality and reduced toxicity of such
compounds compared to ionic agents.1 Various metal
chelates have been evaluated as potential X-ray con-
trast agents, however, none of these compounds are
commercially available due to the superior toxicity
profile of iodine agents.2
Scheme 1
As an intermediate for the synthesis of triphenyl-
bismuth compounds with ester or amide groups, we
present the crystal structure of the bicyclic ortho ester
1- (4 - bromobenzyl) - 4 - methyl-2, 6, 7- trioxabicyclo
[2.2.2]octane II in this paper.
Recently, there has been an increasing focus on
bismuth compounds in medicine. Bismuth com-
pounds are potential X-ray contrast agents for medi-
cal imaging due to the high X-ray absorption efficacy
and are also of interest in ulcer therapy.3 As part
of our ongoing program in medicinal chemistry on
organobismuth compounds, we have been concerned
with functionalized bromobenzene intermediates
(Scheme 1), part of which follows.
Experimental
General
The 1H NMR spectra were recorded at 300 MHz
with Bruker Avance DPX 300. The 13C NMR spectra
were recorded at 75 MHz. Chemical shifts (ͳ) are
reported in ppm using CDCl3 (77.00 ppm) as refer-
ence in 13C spectra and residual CHCl3 (7.24 ppm)
1
as reference in H spectra. The mass spectra under
electron impact conditions (EI) were recorded at 70
eV ionizing potential; the spectra are presented as
m/z (% relative intensity). The elementary analysis
are performed at Ilse Beetz Laboratory, Germany.
(1) School of Pharmacy, University of Oslo, P.O. Box 1155, Blind-
ern, N-0316 Oslo, Norway.
* To whom correspondence should be addressed.
493
1074-1542/99/0400-0493$16.00/0  1999 Plenum Publishing Corporation

494
Løiten, Gløga˚rd, Klaveness, and Fjærtoft
Table 1. Crystal data, and intensity collection, and refinement data for 1-(4-bromobenzyl)-4-
methyl-2,6,7 trioxabicyclo[2.2.2]octane
Formula
C13H15BrO3
CCDC deposit no.
Formula weight
Crystal size/mm
Color/shape
Crystal system
Space group
CCDC-1003/5551
299.2 g molϪ1
0.4 ϫ 0.4 ϫ 0.5
Colorless/block
Monoclinic
P21/n (No. 14)
Unit cell dimensions
˚
a ϭ 6.019(5) A
˚
b ϭ 20.990(5) A
ͱ ϭ 101.29(1)Њ
˚
c ϭ 9.915(2) A
Volume
3
˚
1228.3(3) A
Z
4
Density (calculated)
Diffractometer
1.64 g cmϪ3
Nicolet P3
˚
Radiation, graphite monochromator
Temperature
Mo KͰ (␭ ϭ 0.71069 A)
120 K
2␪ range
4–50Њ
Index ranges
0 Յ h Յ 9, 0 Յ k Յ 33, -16 Յ l Յ 15
No. of reflections measured
No. of observed reflections (I Ͼ 2.5 ␴(I))n
Absorption correction
No. of parameters p
R ϭ ͚͉⌬F͉/͉F0͉
5951
4030
DIFABS
214
0.038a
0.035b
3.32
Rw ϭ (͚(w(⌬F)2/w(F0)2))1/2
S ϭ (͚(w(⌬F)2/(n Ϫ p)))1/2
Ϫ3
˚
Residual electron density/e A
ϩ0.59, Ϫ0.63
a ⌬F ϭ ͉F0͉ Ϫ ͉Fc͉.
b w ϭ (␴2(F0) ϩ 0.003136(F0)2)Ϫ1
.
Syntheses
temperature. The mixture was stirred under an atmo-
sphere of dry argon for 12 hr. Triethylamine (2.53 g,
25 mmol) and diethylether (50 ml) were added, the
precipitated boron-amine complex was filtered and
the filtrate evaporated in vacuo. The residue was
recrystallized from ethanol/triethylamine (20:1) and
the title compound was isolated as white crystalline
(3-methyl-3-oxetanyl)methyl-2-(4-bromophenyl)
acetate (I). 4-Bromophenylacetic acid chloride (7.00
g, 30 mmol) in dry dichloromethane (30 ml) was
added dropwise to a stirred solution of 3-methyl-3-
hydroxyoxetan (3.06 g, 30 mmol) and pyridine (2.4
ml, 30 mmol) in dry dichloromethane at 0ЊC. The
mixture was stirred for 4 hr, filtered, washed with
water (25 ml), and dried (MgSO4). After evaporation
in vacuo the compound was isolated as a pale yellow
oil. Yield 7.73 g (86%). 1H NMR (300 MHz, CDCl3):
ͳ 7.40–7.44 (m, 2H, ArH), 7.13-7.16 (m, 2H, ArH),
4.45 (d, J ϭ 6.0 Hz, 2H, CH2), 4.33 (d, J ϭ 6.0 Hz,
2H, CH2), 4.15 (s, 2H, CH2), 3.59 (s, 2H, CH2), 1.26
(s, 3H, CH3). 13C NMR (75 MHz, CDCl3): ͳ 170.96
(CuO), 132.69, 131.64, 130.92, 121.19, 79.36, 69.05,
40.58, 39.03, 21.03. MS (EI): 298/300 (28/28, M), 196/
198 (35/35), 169/171 (100/99, ArCO).
1
material. Yield 3.79 g (51%). M. p. 132-133ЊC. H
NMR (300 MHz, CDCl3): ͳ 7.35–7.39 (m, 2H, ArH),
7.14-7.17 (m, 2H, ArH), 3.86 (s, 6H, OCH2), 2.92 (s,
2H, ArCH2), 0.76 (s, 3H, CH3). 13C NMR (75 MHz,
CDCl3): ͳ 134.08 (CCH2, Ar), 132.25 (CH), 130.90
(CH), 120.58(CBr), 108.24 (COCH2), 72.62 (OCH2),
42.21 (ArCH2), 30.45 (CCH3), 14.47 (CH3). MS (EI):
298/300 (15/15, M), 268/270 (17/17, MUOCH2), 242/
244 (11/11), 169/171 (100/96, BrArCH2). Anal. Calcd.
for C13H15BrO3: C, 52.19; H, 5.05. Found: C, 52.11;
H, 5.07. Single crystals for X-ray crystallography were
obtained by dissolving 50 mg of the compound in 1
ml deutered chloroform, which slowly evaporated at
room temperature.
1-(4-Bromobenzyl)-4-methyl-2,6,7-trioxabicyclo
[2.2.2]octane (II). Boron trifluoroacetate (0.89 g, 6.25
mmol) was added to a stirred solution of I (7.48 g,
25 mmol) in dry dichloromethane (35 ml) at room
X-ray data collection. Crystals of 1-(4-bromo-
benzyl)-4-methyl-2,6,7 trioxabicyclo[2.2.2]octane (II)

1-(4-Bromobenzyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane
495
suitable for X-ray structure determination were ob-
tained by slow evaporation of deutered chloroform
at room temperature.
Data collection was performed at low tempera-
ture on a Nicolet P3 diffractometer. Cell parameters
were determined by a least squares fit of 25 strong
reflections with 2␪ in the range 18–25Њ, and are listed
in Table 1. The intensity data were corrected for
Lorentz and polarization effects, and an absorption
correction was applied using the program DIFABS.4
Further details concerning crystallographic data and
experimental conditions are summarized in Table 1.
Crystal structure determination and refinement.
The structure of (II) was determined with the direct
methods program SIR92,5 and refined using least
squares methods. Positional parameters for all atoms
were refined. All heavy atoms were refined anisotrop-
ically, whereas the hydrogen atoms were refined iso-
tropically. The refinement is summarized in Table 1.
Atomic scattering factors were taken from Interna-
tional Tables for X-ray Crystallography (1974).
Scheme 2
The asymmetric unit of the title compound is
shown in Fig. 1. Final atomic coordinates are listed
in Table 2 and selected geometric parameters are
Table 2. Fractional coordinates with standard deviations and tem-
perature factors for 1-(4-bromobenzyl)-4-methyl-2,6,7 trioxabi-
cyclo[2.2.2]octane
a
Atom
Br(1)
x
y
z
Ueq/Uiso
1.40040(4)
0.8243(2)
0.4506(2)
0.5828(2)
0.8662(3)
0.8042(3)
0.9599(3)
1.1814(3)
1.2499(3)
1.0919(4)
0.6940(4)
0.6380(3)
0.4068(4)
0.4894(3)
0.7886(3)
0.5387(3)
0.4781(4)
0.656(4)
0.917(4)
1.391(4)
1.139(4)
0.747(4)
0.558(5)
0.263(4)
0.445(4)
0.563(4)
0.320(4)
0.826(4)
0.891(4)
0.307(5)
0.507(4)
0.577(4)
0.01061(1) 0.81920(2) 0.028
O1
O2
O3
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
H21
H31
H51
H61
H71
H72
H91
H92
H101
H102
H111
H112
H131
H132
H133
0.2557(1)
0.2375(1)
0.2128(1)
0.1149(1)
0.0631(1)
0.0320(1)
0.0529(1)
0.1040(1)
0.1344(1)
0.1491(1)
0.2156(1)
0.3045(1)
0.2724(1)
0.3167(1)
0.3232(1)
0.3895(1)
0.049(1)
Ϫ0.002(1)
0.116(1)
0.170(1)
0.150(1)
0.123(1)
0.390(1)
0.329(1)
0.283(1)
0.267(1)
0.347(1)
0.320(1)
0.393(1)
0.419(1)
0.400(1)
0.4243(1)
0.3263(1)
0.5537(1)
0.4860(2)
0.5583(2)
0.6569(2)
0.6841(2)
0.6147(2)
0.5146(2)
0.3800(2)
0.4227(2)
0.3478(2)
0.5889(2)
0.4842(2)
0.4889(2)
0.5310(2)
0.535(2)
0.703(2)
0.634(2)
0.470(2)
0.301(2)
0.369(2)
0.343(2)
0.270(2)
0.684(2)
0.582(2)
0.433(2)
0.571(2)
0.537(2)
0.468(2)
0.615(3)
0.023
0.025
0.021
0.020
0.023
0.023
0.021
0.022
0.023
0.022
0.019
0.024
0.022
0.023
0.021
0.029
0.031(6)
0.016(5)
0.025(6)
0.019(5)
0.023(6)
0.035(7)
0.036(7)
0.030(6)
0.026(6)
0.016(5)
0.023(6)
0.022(6)
0.041(7)
0.027(6)
0.039(7)
Results and discussion
The oxetan ester I (Scheme 2) was prepared and
isolated in 86% yield by esterification of the corre-
sponding acid chloride with 3-methyl-3-hydroxy-
methyloxetan in dichloromethane with pyridine as
base. The bicyclic ortho ester II was isolated in 51%
yield after boron trifluoride catalyzed rearrangement
in dichloromethane.6
Fig. 1. ORTEP11-drawing of the asymmetric unit of 1-(4-bromo-
benzyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane. Heavy atoms
are drawn with 50% probability ellipsoids while H-atoms are arbi-
trarily scaled.
a Ueq ϭ Si Sj Uija*a* aiaj .
i
j

496
Løiten, Gløga˚rd, Klaveness, and Fjærtoft
˚
Table 3. Selected bond lengths (A) and torsions (Њ)
trioxabicyclo[2.2.2] ortho ester (OBO) group; re-
fcodes KERZAI8 and WARSUD.9 Bond lengths for
corresponding bonds in the OBO moiety in all three
structures are identical within experimental error.
The three CUO3 bonds are significantly shorter than
the general CUO bond lengths as found by Allen
et al.10
with standard deviations in 1-(4-bromobenzyl)-4-
methyl-2,6,7-trioxabicyclo[2.2.2]octane
Br(1)UC(4)
O(1)UC(8)
O(1)UC(11)
O(2)UC(8)
O(2)UC(9)
O(3)UC(8)
O(3)UC(10)
C(1)UC(16)
C(1)UC(7)
C(2)UC(3)
C(2)UC(1)
C(3)UC(4)
C(5)UC(6)
C(5)UC(4)
C(8)UC(7)
C(12)UC(11)
1.904(2)
1.400(3)
1.445(3)
1.405(3)
1.455(3)
1.404(3)
1.443(3)
1.394(3)
1.506(3)
1.379(3)
1.393(3)
1.379(3)
1.388(3)
1.381(3)
1.515(3)
1.520(3)
1.524(3)
1.518(3)
1.518(3)
Acknowledgment
The authors are indebted to Agnar Aasen, De-
partment of Chemistry, University of Oslo, for assis-
tance during data collection.
References
C(12)UC(10)
C(12)UC(13)
C(12)UC(9)
1. Alme´n, T.; Aspelin, P. In A Global Textbook of Radiology,
Petterson, H. (Ed.) Chap 7. The NICER Institute: Oslo, 1995.
2. Unger, E.; Gutierrez, F. Invest. Radiol. 1986, 21, 802.
3. Sun, H.; Li, H.; Sadler, O. J. Chem. Ber. 1997, 130, 669.
4. Walker, N.; Stuart, D. Acta Crystallogr. 1983, A39, 158.
5. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.; Gia-
covazzo, C.; Guagliardi, A.; Polidori, G. J. Appl. Cryst. 1994,
27, 435.
6. Rakus, K.; Verevkin, S. P.; Peng, W.-H.; Beckhaus, H.-D.;
Ru¨chardt, C. Liebigs Ann. 1995, 2059.
7. Allen, F. H.; Kennard, O. Chem. Design Automation News
1993, 8, 1 31-37.
C(12)UC(11)UO(1)UC(8)
C(12)UC(9)UO(2)UC(8)
C(12)UC(10)UO(3)UC(8)
C(1)UC(7)UC(8)UO(1)
C(1)UC(7)UC(8)UO(2)
C(1)UC(7)UC(8)UO(3)
C(2)UC(1)UC(7)UC(8)
C(6)UC(1)UC(7)UC(8)
Ϫ15.4(2)
Ϫ14.7(2)
Ϫ14.5(2)
69.8(2)
Ϫ170.3(3)
Ϫ51.1(2)
110.1(3)
Ϫ69.6(3)
8. Barrett, A. G. M.; Barta, T. E.; Flygare, J. A.; Sabat, M;
Spilling, C. D. J. Org. Chem. 1990, 55, 2409.
9. Blaskovich, M. A.; Lojoie, G. A. J. Chem. Soc. 1993, 115, 5021.
10. Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Or-
pen, A. G.; Taylor, R. J. Chem. Soc. Perkins Trans II, 1987, S1.
11. Johnson, C. K. Report ORNL-3794Њ, Oak Ridge National
Laboratory: TN, 1965.
given in Table 3. A search in the March 1998 version
of the Cambridge Structural Database7 reveals only
two other compounds containing the 4-methyl-2,6,7-