Synthesis of [1-13C]-para-xylene and [2-13C]-para-xylene

Article abstract of DOI:10.1002/jlcr.584

An efficient synthesis of [1-¹³C]-para-xylene (1a) and [2-¹³C]-para-xylene (1b) is described. The incorporation of the label has been achieved by cyclocondensation of suitable 1,5-bis(bromomagnesio)alkanes with either ethyl [1-¹

Full text of DOI:10.1002/jlcr.584

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2002; 45: 601–610.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.584
Research Article
Synthesis of [1-13C]-para-xylene and [2-13C]-
para-xylene
Michael Mormann and Dietmar Kuck*
. . .
.
Fakultat fur Chemie, Universitat Bielefeld, Universitatsstrasse 25,
D-33615 Bielefeld, Germany
Summary
An efficient synthesis of [1-13C]-para-xylene (1a) and [2-13C]-para-xylene (1b) is
described. The incorporation of the label has been achieved by cyclocondensa-
tion of suitable 1,5-bis(bromomagnesio)alkanes with either ethyl [1-13C]acetate
or ethyl [13C]formate which gave [ring-13C]-labelled dimethylcyclohexanols.
Dehydration of these alcohols followed by dehydrogenation of the inter-
mediate dimethylcyclohexenes furnished the title compounds in 32 and 40%
overall yield, respectively. Copyright # 2002 John Wiley & Sons, Ltd.
Key Words: carbon-13 labelled arenes; [1-13C]-para-xylene; [2-13C]-para-
xylene; arenium ions, gaseous; carbon scrambling
Introduction
Arenium ions (protonated arenes) represent the key intermediates in
electrophilic aromatic substitution, one of the most-studied and best-
understood reactions in organic chemistry.1 The structure and reactivity
of these species and their derivatives in solution,2–4 in the solid state5–7
and in the gas phase8–12 have been extensively studied. The investigation
of the chemistry of gaseous ions has mostly been carried out by mass
.
*Correspondence to: Dr. D. Kuck, Fakultat fur Chemie, Universitat Bielefeld, Universitatsstraße
25, D-33615 Bielefeld, Germany. E-mail: dietmar.kuck@uni-bielefeld.de
.
.
.
.
Contract/grant sponsor: Graduiertenforderung des Landes Nordrhein-Westfalen
Contract/grant sponsor: Fond der Chemischen Industrie
Copyright # 2002 John Wiley & Sons, Ltd.
Received 5 February 2002
Revised 1 March 2002
Accepted 6 March 2002

602
M. MORMANN AND D. KUCK
spectrometric techniques and provides deep insights into the intrinsic
properties of isolated ions, i.e. cations and anions in the absence of
solvent molecules and counterions.12
In the course of our studies on the gas-phase ion chemistry of lower
protonated alkylbenzenes and their olefinic isomers, we have focused on
the isomerization processes occurring prior to the fragmentation of these
ions.13–16 Long-lived xylenium ions [1+H]+ (i.e. protonated xylenes)
fragment mainly by loss of dihydrogen and methane. However, careful
examination of the mass spectra of [1+H]+ reveals also the loss of ethene
from these ions, indicating complex skeletal rearrangement processes,
such as (reversible) ring expansion to protonated methylcycloheptatrienes
[2+H]+ and (irreversible) ring contraction of the latter isomers to
ethylbenzenium ions [3+H]+ prior to the loss of C2H4 (Scheme 1).17,18
To investigate the complex rearrangement reactions described above
with respect to carbon scrambling19 in more detail, we have synthesized
the [ring-13C]-para-xylenes 1a and 1b bearing the label in positions C-1
and C-2, respectively. Several approaches have been reported on the
incorporation of carbon isotopes into aromatic rings or into their less
unsaturated, six-membered ring precursors. These have involved Diels–
Alder reactions,20,21 cyclotrimerization and co-cyclotrimerization of
alkynes,22,23 condensation reactions of C–H acidic compounds with
suitable carbonyl compounds or Michael acceptors,24–26 cyclization of
hexatrienes27–29 and cyclocondensation of bis-organometallic species
with esters.30–34 In the present contribution, we demonstrate that the
latter approach can be favourably used to synthesize [ring-13C]-labelled
para-xylenes.
Scheme 1.
Copyright # 2002 John Wiley & Sons, Ltd.
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SYNTHESIS OF [1-13C]-PARA
603
Results and discussion
The synthesis of [1-13C]-para-xylene was achieved by following the
synthesis route outlined in Scheme 2.
Ethyl [1-13C]acetate was prepared as described previously32 and used
as the carbon-13 containing building block. Application of the method
described by Cannone et al.35–37 involved the cyclocondensation of this
ester with 3-methyl-1,5-bis(bromomagnesio)hexane in THF and pro-
duced a mixture of the diastereomeric 1,4-dimethyl-[1-13C]cyclohex-
anols 4 in 92% yield. Elimination of water from the latter using para-
toluenesulphonic acid furnished 1,4-dimethyl-[1-13C]cyclohexene 5a.38
Alternatively, iodine-assisted dehydration32 of 4 gave similar results
after optimization using unlabelled reagents.
The final step, the dehydrogenation of the cycloalkene, appeared to
be critical within the synthesis of carbon-13 ring-labelled lower
alkylbenzenes. Oxidation reagents such as DDQ or tetrachloro-para-
benzoquinone are not suitable for such conversions due to the low
electron density present in the alkene.34,39,40 Dehydrogenation using an
industrial catalyst (Pt or Pd on asbestos) at 4508C was reported to lead
to partial disproportionation.31,32 Therefore, we decided to use
palladium on charcoal as the catalyst in the presence of maleic acid as
a hydrogen acceptor, analogous to a procedure described by Robertson
and Djerassi.33 However, GC–MS analysis of the product indicated the
Scheme 2.
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M. MORMANN AND D. KUCK
Scheme 3.
formation of minor amounts (ca 6%) of 1,4-dimethylhexanes as
disproportionation products.
The synthesis of the isomeric para-xylene 1b bearing the carbon-13
label in ring position C-2 was achieved in a similarly straightforward
manner (Scheme 3). Cyclocondensation of 1,5-bis(bromomagnesio)-2-
methylhexane and ethyl [13C]formate41,42 as the carbon-13 containing
synthone led to incorporation of the label at the desired position of the
cyclohexanol 6, which was obtained as a mixture of four diastereomeric
species (GC–MS). It is noted that the yield of cyclohexanol 6 was similar
(85%) to that of isomer 4; thus, the secondary/primary 1,5-dibromide
proved to react as efficiently as did the bis(primary) 1,5-dibromide.
Dehydration of the cyclohexanol 6 to cyclohexene 5b and subsequent
dehydrogenation led to xylene 1b in 40% overall yield.
Experimental
General
1H nuclear magnetic resonance (NMR) spectra were measured on a
Bruker DRX 500 (500 MHz) instrument. Electron ionization (EI) mass
spectra were recorded on a double-focusing sector-field instrument with
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SYNTHESIS OF [1-13C]-PARA
605
EBE geometry (VG Autospec, Fisons, Manchester/UK), ionization
energy 70 eV, accelerating voltage 8 kV. Samples were introduced via a
heated septum inlet. GC–MS analysis was performed on a Shimadzu
QP 5050 instrument equipped with a GC17 (version 3), HP-5 MS
column (25 m, ID 0.2 mm, film thickness 0.33 mm, He carrier gas,
optimized temperature programme), ionization mode EI (70 eV),
quadrupole mass filter at full scan from m/z 50–500, cycle time 0.6 s.
Melting points (uncorrected) were determined using an electrothermal
melting point apparatus. All reactions were carried out under dry argon
in flame-dried glassware. All reactants used were purified by standard
procedures; solvents were dried immediately before use.43
Barium [13C]carbonate was obtained from Deutero GmbH, Kastel-
laun, Germany (carbon-13 contents 92%). 1,5-Dibromo-3-methylpent-
ane was obtained from 1,5-dihydroxy-3-methylpentane (Fluka) by
treatment with concentrated hydrobromic acid.44 1,5-Dibromo-2-
methylhexane was prepared by condensation of ethyl acetoacetate and
methyl methacrylate to give diethyl 2-acetyl-4-methylglutarate, which
was converted into 2-methyl-5-ketohexanoic acid by hydrolysis in
concentrated hydrochloric acid.45,46 The keto acid was reduced to a
mixture of diastereomeric 2-methyl-1,5-hexanediols using lithium
aluminium hydride in THF. The diol was esterified with para-
toluenesulphonyl chloride in pyridine giving the corresponding bis(tos-
ylate) as a crude product,47 followed by conversion into 1,5-dibromo-2-
methylhexane using lithium bromide in acetone.48
Synthesis of [1-13C]-para-xylene 1a
Sodium [1-13C]acetate. This compound was prepared by reacting
[13C]carbon dioxide, which was generated from barium [13C]carbonate
and degassed concentrated sulphuric acid, with methylmagnesium
iodide in diethyl ether, as described previously32 using a modified
apparatus.49
Ethyl [1-13C]acetate. This compound was prepared from sodium
[1-13C]acetate and triethyl phosphate.50
1,4-Dimethyl-[1-13C]cyclohexanol 4. A solution of the bis(Grignard)
reagent prepared from 1,5-dibromo-3-methylpentane (19.9 g,
81.6 mmol) and magnesium turnings (4.66 g, 192 mmol) in 100 ml
THF was stirred at 0 8C, while a solution of ethyl [1-13C]acetate
(2.2 g, 24.7 mmol) in 20 ml of THF was added dropwise. Stirring of the
reaction mixture was continued for 48 h at ambient temperature. After
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M. MORMANN AND D. KUCK
hydrolysis by careful addition of saturated aqueous ammonium chloride
at 0 8C, the mixture was extracted several times with diethyl ether. In
addition, the aqueous layer was extracted with the same solvent for 24 h
by use of a Kutscher–Steudel extractor. The combined organic layers
were washed with saturated sodium chloride solution and dried over
sodium sulphate. The solvents were carefully removed by distillation
through a 30-cm-Vigreux column. The crude residue obtained was
sublimed at 65 8C (25 mbar) yielding cyclohexanol 4 (2.93 g, 92%) as a
mixture of diastereomers (GC–MS) and as a colourless solid; mp.: 648C;
1H-NMR (500 MHz, CDCl3): d=1.60–1.69 (m, 2 H), 1.48–1.51 (m,
2 H), 1.35–1.38 (m, 3 H), 1.22–1.33 (m, 3 H), 1.21 (d, J(1H,13C)=4.1 Hz,
3 H), 0.91 (d, J =5.9 Hz, 3 H); MS (EI, 70 eV): m/z=129 (4, M*+), 114
(17), 112 (4), 111 (3), 100 (2), 96 (18), 85 (7), 72 (100), 71 (38), 59 (23), 44
(33), 41 (28).
1,4-Dimethyl-[1-13C]cyclohexene 5a. A mixture of cyclohexanol 4
(2.8 g, 21.7 mmol) and para-toluenesulphonic acid (200 mg, 1.1 mmol)
was heated to 160 8C in a microdistillation apparatus equipped with a
20-cm electrically heated Vigreux column. The azeotropic alkene/water
mixture (bp.: 81–87 8C) distilling off was collected at a column
temperature of 90 8C. The organic layer was separated and dried
carefully by addition of sodium pieces (200 mg). Subsequent distillation
afforded cyclohexene 5a (1.78 g, 78%) as a colourless liquid; bp.: 1218C;
1H-NMR (500 MHz, CDCl3): d=5.34 (br s, 1 H), 1.91–2.03 (m, 2 H),
1.66–1.70 (m, 2 H), 1.64 (d, J(1H,13C)=5.9 Hz, 3 H), 1.55–1.60 (m, 2 H),
1.18–1.25 (m, 1 H), 0.93 (d, J =6.2 Hz, 3 H); MS (EI, 70 eV): m/z=111
(40, M*+), 96 (77), 82 (19), 78 (10), 69 (91), 68 (1 0 0), 59 (13), 55 (24),
41 (27).
[1-13C]para-xylene 1a. A mixture of cyclohexene 5a (250 mg,
2.3 mmol) and Pd/C catalyst (100 mg, 10% Pd) was shaken for
15 min. The alkene was then separated from the catalyst by centrifuga-
tion and added to an intimately mixed, dried and powdered mixture of
maleic acid (800 mg, 6.9 mmol) and Pd/C catalyst (280 mg, 10% Pd).
This mixture was heated to reflux (130 8C) for 48 h. The product was
collected by condensing it into a cooling trap (liquid nitrogen) to give
para-xylene 1a (105 mg, 44%). GC–MS analysis of the product
indicated contamination with the corresponding cyclohexanes
1
(ca 6%). H-NMR of 1a (500 MHz, CDCl3): d=7.06 (br s, 4 H), 2.31
(d, J(1H,13C)=5.5 Hz, 3 H), 2.31 (s, 3 H); MS (EI, 70 eV): m/z=107 (59,
M*+), 106 (36), 92 (100), 91 (16), 79 (7), 78 (12), 77 (5), 66 (5), 65 (4), 52
(7), 51 (9).
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SYNTHESIS OF [1-13C]-PARA
607
Synthesis of [2-13C]-para-xylene 1b
Potassium [13C]formate. This compound was prepared as described
previously41,42 starting from [13C]carbon dioxide, which was produced
from barium [13C]carbonate (10 g, 50 mmol) by treatment with degassed
concentrated sulphuric acid. [13C]Carbon dioxide was absorbed in a
solution of potassium hydroxide (3.36 g, 60 mmol) in decarbonated
water (80 ml) at 0 8C during a period of 48 h. To the resulting solution of
potassium hydrogen [13C]carbonate was added Pd/C catalyst (10% Pd)
(7.0 g) and the mixture was reacted in an autoclave under hydrogen at
88 8C (initial pressure before heating: 140 bar) for 24 h. Workup of the
reaction mixture by careful removal of the catalyst by filtration and
removal of the water in vacuo gave crude potassium [13C]formate
(4.38 g, >100%), which was directly used in the following conversion.
Ethyl [13C]formate. This compound was prepared from potassium
[13C]formate by reaction with triethylphosphate, as described above for
the synthesis of ethyl [1-13C]acetate; yield 3.48 g (93% based on barium
[13C]carbonate).
2,5-Dimethyl-[1-13C]cyclohexanol 6. A solution of the bis(Grignard)
reagent prepared from 1,5-dibromo-2-methylhexane (37.1 g, 144 mmol)
and magnesium turnings (7.69 g, 317 mmol) in 350 ml of THF was
stirred at 0 8C, while a solution of ethyl [1-13C]formiate (3.0 g,
40.0 mmol) in 60 ml of THF was added dropwise. Stirring of the
reaction mixture was continued for 48 h at ambient temperature. After
hydrolysis by careful addition of saturated aqueous ammonium
chloride, the mixture was extracted five times with diethyl ether. In
addition, the aqueous layer was extracted with the same solvent for 20 h
in a Kutscher–Steudel extractor. The combined organic layers were
washed with saturated sodium chloride solution and dried over
anhydrous sodium sulphate. The solvents were carefully removed by
distillation through a 30-cm-Vigreux column and the residue was
distilled under reduced pressure to give cyclohexanol 6 as a mixture of
1
four diastereomers (GC–MS) (4.38 g, 85%), bp: 77 8C/17 mbar; H-
NMR (500 MHz, CDCl3): d=3.68 (mc, J(1H,13C)=147.0 Hz, 41 H, C1H),
J(1H,13C)=139.9 Hz,
H,
C1H),
3.47
(mc,
1
4
3.61
(mc,
J(1H,13C)=141.4 Hz, H, C1H), 3.07 (mc, J(1H,13C) =138.7 Hz, H,
1
1
4
4
C1H), 1.85–1.92 (m, 1 H), 1.60–1.66 (m, 1 H), 1.52–1.57 (m, 1 H),
1.39–1.48 (m, 2 H), 0.92–0.97 (m, 2 H), 0.81–0.89 (m, 6 H); MS (EI,
70 eV): m/z=129 (3, M*+), 111 (38), 96 (65), 82 (48), 72 (100), 69 (65),
68 (47), 56 (54), 55 (53), 43 (50), 41 (60).
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M. MORMANN AND D. KUCK
1,4-Dimethyl-[2-13C]cyclohexene 5b. Reaction of cyclohexanol 6
(3.90 g, 28.0 mmol) with para-toluenesulphonic acid (210 mg,
1.40 mmol) as described above afforded cyclohexene 5b (2.34 g, 76%)
as a colourless oil; bp: 126–1288C; 1H-NMR (500 MHz, CDCl3):
d=5.40 (d, J(1H, 13C)=77.0 Hz, 1 H), 1.88–2.01 (m, 2 H), 1.64–1.67 (m,
2 H), 1.61 (br s, 3 H), 1.52–1.58 (m, 2 H), 1.19–1.26 (m, 1 H), 0.91 (d,
J=6.5 Hz, 3 H); MS (EI, 70 eV): m/z=111 (45, M*+), 110 (7), 96 (87),
95 (13), 92 (13), 82 (42), 81 (10), 69 (100), 68 (85), 67 (21), 56 (34), 55
(32), 54 (16), 42 (19), 41 (32), 40 (17) 39 (21).
[2-13C]para-xylene 1b. Dehydrogenation of cyclohexene 5b (800 mg,
7.20 mmol) was carried out as described for isomer 1a (see above). The
product was collected in a cold trap, yielding 470 mg (61%) as a
colourless liquid. Again, GC–MS analysis revealed the formation of
1
minor amounts of dimethylcyclohexanes (4%); H-NMR (500 MHz,
CDCl3): d=7.04 (s, 3 H), 7.04 (dd, J(1H,13C)=155.8 Hz, J(1H,1H)=
8.2 Hz, 1 H), 2.29 (s, 6 H); MS (EI, 70 eV): m/z=107 (56, M*+), 106
(33), 92 (100), 91 (14), 80 (6), 79 (7), 78 (11), 77 (5), 66 (5), 65 (3), 52 (6),
51 (6), 40 (8) 39 (10).
Conclusion
In the course of our investigations on the skeletal rearrangement
processes of protonated para-xylenes in the gas phase, we have
synthesized [1-13C]-para-xylene 1a and [2-13C]-para-xylene 1b bearing
the carbon-13 label specifically in the ring positions C-1 and C-2,
respectively. The six-membered rings were constructed by cycloconden-
sation of either ethyl [13C]formate or ethyl [1-13C]acetate with the
suitable 1,5-bis(bromomagnesio)alkanes. The dimethylcyclohexanols
obtained were converted to the xylenes by dehydration giving the
ring-labelled dimethylcyclohexenes, followed by catalytic dehydrogena-
tion. The method described for the synthesis of 1a and 1b may also be
applicable to the synthesis of other lower alkylbenzenes by using
[1-13C]esters bearing larger acyl groupings and/or suitably substituted
higher dihaloalkanes precursors for the construction of the labeled six-
membered ring.
The carbon-13 labelled para-xylenes have been studied by chemical
ionization in the ion source of a double-focusing mass spectrometer and
the mechanism of the unimolecular fragmentation of protonated para-
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SYNTHESIS OF [1-13C]-PARA
609
xylene has been elucidated by metastable ion kinetic energy (MIKE)
spectrometry.18
Acknowledgements
.
MM is grateful for financial support from the Graduiertenforderung
des Landes Nordrhein-Westfalen. Financial support from the Fond der
Chemischen Industrie is also gratefully acknowlegded.
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