First Total Synthesis and Structural Confirmation of C13-Butylrubber Oligomers

Article abstract of DOI:10.1002/ejoc.201800496

The first total synthesis of an important C13 butyl rubber oligomer is reported. The structure of the oligomer, which is an important and potentially toxic extractable and leachable component of elastomeric closures, is confirmed by synthesis for the firs

Full text of DOI:10.1002/ejoc.201800496

A Journal of
Accepted Article
Title: First Total Synthesis and Structural Confirmation of C13-
Butylrubber Oligomers
Authors: Fabrizio Minicone, Robin Attrill, Michael Hodgson, Katherine
Wheelhouse, and Adrian P. Dobbs
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800496
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10.1002/ejoc.201800496
European Journal of Organic Chemistry
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First Total Synthesis and Structural Confirmation of C13-
Butylrubber Oligomers
Fabrizio Minicone,[a] Robin Attrill,[b] Michael Hodgson,[b] Katherine Wheelhouse[b] and Adrian Dobbs*[a]
Abstract: The first total synthesis of an important C13 butyl rubber
oligomer is reported. The structure of the oligomer, which is an
important and potentially toxic extractable and leachable component
of elastomeric closures, is confirmed by synthesis for the first time.
The method described is scalable, making large quantities of the
oligomer available for the first time for AMES toxicity studies. The
challenging synthesis commences with isophorone and the key steps
of the synthesis involve the development of highly novel dithoacetal
chemistry, cuprate addition and Tebbe olefination.
oligomers as C13H24 and its halogenated derivatives C13H23Br or
C13H23Br, and C21H40. Furthermore, the structures of the
oligomers have been proposed to be (1-3) on the basis of
extensive NMR studies.1, 2
Dedicated with deep fondness and respect to Professor Istvan E.
Markó (1956-2017), who liked a challenging total synthesis!
Figure 1. Proposed structures of butyl rubber oligomers.
Introduction
It is proposed that these oligomers are formed during the
polymerization process by an intramolecular cyclisation process,
combining one isoprene and two isobutylene units (Scheme 2).
Elastomeric or rubber closures (‘seals’) have found widespread
application, particularly in the pharmaceutical industry, frequently
as components for injection systems, such as in stoppers and
caps Elastomeric closures are particularly attractive and widely
used owing to a number of beneficial features, including their
ability to reseal. However, the composition of such rubbers is
highly complex and may comprise many components, including
the elastomer (basic unit) as well as anti-oxidants, fillers, curing
agents, activators and accelerators. While the production of the
rubbers has improved greatly over the last 30 years, there still
remains the problems of impurities within the rubbers, and the
potential for leaching of materials from the rubbers into the vial
contents.
A series of C13 and C21 oligomers, together with their
halogenated derivatives, have long been postulated as the key
Scheme 1. Proposed mechanism of formation of the C13H24 oligomer.
extractable components.1
Through a large-scale rubber-
extraction/isolation/purification technique, sufficient material has
been isolated to determine the molecular formulae of these
Compounds (1) and (3) have recently become commercially
available and are obtained via extraction and purification from a
large number of rubber seals!2 It is reported that they can be
present in quantities between 0.05 – 0.6 g per kg material.
Extractable and leachable studies have shown that in certain
instances, these may leach out of the rubber and into the drug
[a]
[b]
F. Minicone, A.P. Dobbs*
Department of Pharmaceutical, Chemical & Environmental Sciences
University of Greenwich
Grenville Building, Chatham Maritime, Kent ME4 4TB, UK.
A.Dobbs@gre.ac.uk
http://www.gre.ac.uk/engsci/study/pharchemenv/staff/adrian-dobbs
M. D. Hodgson, R. Attrill, K. Wheelhouse
Medicines Research Centre
product.
Crucially, there is no toxicity data about these
compounds, mainly owing to being only ever isolated in these
minute quantities. A completed syntheses of these compounds is
therefore urgent, both for verification of the structural assignments
and to provide sufficient material for further toxicological
evaluation via AMES tests. Herein, we report the first total
synthesis of the C13 oligomer, (1) by a robust and scalable route.
GlaxoSmithKline
Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800496
European Journal of Organic Chemistry
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Results and Discussion
Obtaining the 1,2,4-substitution pattern was considered
challenging from the outset, particularly given the steric bulk
presented by the four methyl groups. A number of commercial
compounds contain the two gem-dimethyl groups in the correct
arrangements and were initially deemed to be suitable starting
materials.
It
is
possible
to
access
starting
3-(2-propenyl)-2,2,6,6-
(4) from
carvone.3
tetramethylcyclohexanone
Regrettably, all attempts to remove the carbonyl group were
unsuccessful. Direct reduction of the ketone via Wolff-Kishner or
Clemmensen reductions only gave unreacted starting material.
Formation of a cyclic dithioacetal using ethane-1,2-dithiol, for
subsequent reduction, was also unsuccessful, again with
quantitative recovery of starting material. Lithium aluminium
hydride reduction did give the corresponding alcohol (5), although
attempts to remove this using radical methods were again
unfruitful, with the alcohol unreactive under all attempted
conditions (Scheme 2).
Scheme 3. Attempted mesylate displacement leading either to bicyclic product
(7) or rearranged product (7a/7b).
With no other suitable 1,2,4-substituted precursors being
commercially available, ketone (8) was seen as a suitable starting
material. Introduction of the formyl group, masked as an acetal,
was facile and high yielding employing triethyl orthoformate and
TiCl4 (9, 72 %). However, all attempts to remove the ketone were
unsuccessful. Wolff-Kishner conditions, either with hydrazine or
TBS-protected hydrazine, gave no reaction. Sodium borohydride
reduction did afford the alcohol (10) in excellent yield, but
regrettably any attempts to remove this either showed no reaction
or gave a product suggestive of polymerization. Only treatment
with dilute sulfuric acid gave any traces of the elimination product
(11), and not in yields to be of any use.
Scheme 2. Unsuccessful methods towards (1) starting from 3-(2-propenyl)-
2,2,6,6-tetramethylcyclohexanone.
It was possible to produce the mesylate (6) derived from (5), but
not the tosylate (Scheme 3). Treatment with sodium borohydride
or lithium aluminium hydride to displace the mesylate gave no
reaction. Reaction of (6) with L-selectride gave a product lacking
in the mesyl moiety and containing a terminal alkene, which was
initially believed to be the desired target (1). GC-MS analysis
showed two close running compounds, both giving identical mass
spectra but with m/z = 178.32, two mass units less than the
proposed compound (1). Extensive NMR studies suggested that
rather than reduction, the hydride had deprotonated the allylic-
CH3 group, which lead to intramolecular displacement of the
mesylate to furnish the bridged cycloalkane (7), with the correct
observed molecular weight. However, from the NMR spectra, it
is impossible to discount the alternative structures (7a or 7b),
formed via direct SN1-type loss of the mesylate followed by
carbocation rearrangement/ring contraction to the more stable
carbocation and elimination, to give the various possible 5-
membered ring products (Scheme 3).
Scheme
tetramethylcyclohexanone.
4.
Attempted
route
to
(1)
starting
from
3,3,5,5-
The problems encountered in all these approaches were
attributed to the two gem dimethyl groups present in the different
starting materials. Therefore a novel approach was required that
would not rely upon late stage removal of a ketone moiety. It was
also envisaged that any successful route would not have the four
problematic methyl groups present throughout the synthesis, but
rather would introduce these at an appropriate stage in the
synthesis.
It was proposed to employ an -oxoketene dithioacetal,4-6 derived
from carbon disulfide, as the solution for introducing the required
side chain, and then to introduce one of the problematic gem-
dimethyl groups at a later stage in the synthesis, once all
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10.1002/ejoc.201800496
European Journal of Organic Chemistry
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necessary functional group interconversions were complete
(Scheme 4). Starting from isophorone (11), reaction with
potassium tert-butoxide and carbon disulfide installed the
dithioacetal moiety (12), and HgCl2-mediated hydrolysis6 gave the
thioester (13) in 58% yield over the two steps. Treatment with
sodium methoxide furnished the methyl ester (14) in 80% yield.7
It was at this stage that methyl cuprate addition to the ,-
unsaturated system installed the fourth methyl group (15),
obtained as a mixture of keto-enol tautomers (approximate 1.5:1
gave the ketone (18). This was finally converted to the alkene
using the Tebbe reagent, to give the postulated C13 oligomer (1)
in 10 steps and 3.4% overall yield. The new terminal alkene
peaks were clearly visible at  = 4.64 and 4.82 ppm, which were
completely in agreement with the literature values.1
Comparison of the NMR and mass spectra of (1) with a genuine
sample of (1) and previously reported values1 confirmed that, for
the first time, the C13 oligomer had been prepared synthetically
away from the polymerisation approach. The two mass spectra
were identical, both in the molecular ion and fragmentation pattern
obtained. Therefore the proposed structure of (1) has finally been
unambiguously confirmed by synthesis.
ratio).
Reduction of the ketone with sodium borohydride
proceeded smoothly as before, and this was protected as the
mesylate, (16). Unlike before, elimination of the mesylate
proceeded smoothly, presumably owing to the ,-unsaturated
product (17) that was formed. Reduction of the alkene was
achieved by hydrogenation in ethanol over 5% w/w palladium on
charcoal. Reaction of the ester with trimethyl aluminium/TMEDA
It was possible to prepare the chloro-derivative (2a) using the
procedure of Brindisi et al, employing cerium trichloride and
NaOCl.8
Scheme 5. Total synthesis of the C13 oligomer, 1.
compound. The synthesis is robust and scalable, and provides
material for extensive toxicity studies, in order to evaluate the
potential dangers of this extractable and leachable compound in
medical applications.
Conclusions
In conclusion, we have reported the first de novo total synthesis
of the C13 extractable/leachable oligomer, 1. In completing the
synthesis, we have also confirmed the proposed structure for this
Experimental Section
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2-(Bis(methylthio)methylene)-3,5,5-trimethylcyclohex-3-en-1-one
(12)
Methyl 2,2,4,4-tetramethyl-6-oxocyclohexane-1-carboxylate (15)
A suspension of CuI (9.65 g, 60.69 mmol, 1.1 equiv) in dry Et2O (100 ml)
was cooled to −50 °C. Methyl lithium solution (1.6 M in Et2O, 75.86 ml,
121.4 mmol, 2.2 equiv) was added and the reaction was left stirring at
−50 °C for 30 minutes. A solution of methyl 2,4,4-trimethyl-6-oxocyclohex-
1-ene-1-carboxylate 14 (9.04 g, 46.08 mmol, 1.0 equiv) in dry Et2O (40 ml)
was added dropwise and the reaction was stirred at −50 °C until the
starting material was consumed. A saturated solution of NH4Cl (20 ml)
was added and the reaction was allowed to warm up to room temperature,
before filtering through a silica pad. The organic layer was separated,
dried with MgSO4, filtered and the solvent was removed at reduced
pressure. The crude oil was purified by flash column chromatography
(SiO2, 1% Et2O in Petrol, Rf = 0.5) to give the title compound as a
colourless oil (8.118 g, 83%); major tautomer: IR (cm−1) 1755, 1733, 1710,
1633, 1599, 1459, 1436, 1391, 1371, 1344, 1316, 1276, 1229, 1197, 1154,
1098, 1037; 1H NMR (500 MHz, CDCl3)  3.64 (s, 3H), 3.15 (s, 1H), 2.57
(d, J = 13.0 Hz, 2H), 2.32 (d, J = 13.0 Hz, 2H), 1.85 (d, J = 14 Hz, 2H),
1.45 (d, J = 14.0 Hz, 2H), 1.07 (s, 3H), 1.04 (s, 3H), 1.00 (s, 3H), 0.95 (s,
3H); 13C NMR (125 MHz, CDCl3)  206.9, 169.3, 66.4, 52.4, 51.8, 50.4,
39.2, 35.9, 31.7, 31.6, 31.0, 27.3; HRMS-ASAP (m/z) [M + H]+ calcd for
C12H21O3 requires 213.1485; found, 213.1483.
To a solution of potassium tert-butoxide (24.69 g, 220 mmol, 2.2 equiv) in
dry DMSO (200.0 ml), isophorone 11 (13.82 g, 100.0 mmol, 1.0 equiv)
was added portionwise and the dark red solution was stirred at room
temperature for 30 minutes. Carbon disulfide (8 g, 105.0 mmol,
1.05 equiv) was added in one portion (careful: very exothermic) and the
dark brown solution was stirred for 30 minutes. Iodomethane (31.22 g,
220 mmol, 2.2 equiv) was added (careful: very exothermic) and the dark
brown reaction was stirred at room temperature for 1 h. Water (20 ml) and
Et2O (40 ml) were added to the reaction and the organic layer was
separated and washed with saturated brine solution (20 ml). The aqueous
layers were combined and extracted with Et2O (10 x 20 ml). The organic
layers were combined, dried with MgSO4 filtered and the solvent was
removed at reduced pressure. The crude oil was purified by flash column
chromatography (SiO2, 10% Et2O in Petrol, Rf = 0.3) to give the mixture of
the two tautomers (endo:exo 92:8) of the title compound as a red thick oil
(17.45 g, 72%); major tautomer: IR (cm−1) 1650, 1428, 1382,1362, 1339,
1300, 1253, 1197, 1137, 1115, 1045, 1005; 1H NMR (500 MHz, CDCl3)
 5.60 (d, J = 1.7 Hz, 1H), 2.41 (s, 3H), 2.31 (s, 2H), 2.24 (s, 3H), 2.08 (d,
J = 1.7 Hz, 3H), 1.06 (s, 6H); 13C NMR (125 MHz, CDCl3)  197.3, 151.9,
139.2, 133.0, 132.0, 51.7, 33.2, 28.5, 20.3, 19.9, 18.9; HRMS-ASAP (m/z)
[M + H]+ calcd for C12H19OS2 requires 243.0872; found, 243.0868.
Methyl 6-hydroxy-2,2,4,4-tetramethylcyclohexane-1-carboxylate
S-Methyl 2,4,4-trimethyl-6-oxocyclohex-1-ene-1-carbothioate (13)
To
a
solution of methyl 2,2,4,4-tetramethyl-6-oxocyclohexane-1-
carboxylate 15 (8.12 g, 38.24 mmol, 1.0 equiv) in dry MeOH (50 ml) at
0 °C, was added NaBH4 (1.74 g, 45.89 mmol, 1.2 equiv) and the reaction
stirred until the starting material was consumed. A saturated solution of
NH4Cl (20 ml) was added and the solvent removed at reduced pressure.
The aqueous layer was extracted with Et2O (3 x 30 ml), dried with MgSO4
filtered and the solvent was removed at reduced pressure. The crude oil
was purified by flash column chromatography (SiO2, 10% EtOAc in Petrol,
Rf = 0.3) to give the mixture of the two diastereomers of the title compound
as a white solid (6.97 g, 85%). This was used immediately in the next step.
To
a
dark red solution of 2-(bis(methylthio)methylene)-3,5,5-
trimethylcyclohex-3-en-1-one 12 (17.45 g, 72 mmol, 1.0 equiv) in water
(20 ml) and acetonitrile (120 ml), HgCl2 was added (21.50 g, 79.2 mmol,
1.1 equiv) and the reaction was stirred at 55 °C until the starting material
was completely consumed. The dark green/brown suspension was
allowed to cool down to room temperature, filtered through a silica plug
and the acetonitrile was removed at reduced pressure. The aqueous layer
was extracted with dichloromethane (2 x 50 ml), dried with MgSO4 filtered
and the solvent was removed at reduced pressure. The crude oil was
purified by flash column chromatography (SiO2, 10% EtOAc in Petrol,
Rf = 0.1) to give the title compound as a crystalline yellow solid (12.23 g,
80%); m.p.: 98-102 °C; IR (cm−1) 1659, 1621, 1422, 1377, 1359, 1308,
1150, 1113, 1023; 1H NMR (500 MHz, CDCl3)  2.37 (s, 3H), 2.25 (s, 2H),
2.24 (s, 2H), 1.93 (s, 3H), 1.00 (s, 6H); 13C NMR (125 MHz, CDCl3)  195.4,
194.2, 158.4, 137.1, 50.8, 46.2, 32.9, 28.2, 22.2, 12.2; HRMS-ASAP (m/z)
[M + H]+ calcd for C11H17O2S requires 213.0944; found, 213.0943.
Methyl
2,2,4,4-tetramethyl-6-((methylsulfonyl)oxy)cyclohexane-1-
carboxylate (16)
To a solution of the two diastereomers of methyl 6-hydroxy-2,2,4,4-
tetramethylcyclohexane-1-carboxylate (6.97 g, 32.50 mmol, 1.0 equiv) in
dichloromethane (50 ml) at 0 °C, triethylamine (4.77 g, 47.13 mmol,
1.45 equiv) and methanesulfonyl chloride (5.58 g, 48.75 mmol, 1.5 equiv)
were added and the reaction was left stirring for 3 h. The reaction was
allowed to warm up to room temperature, then a saturated solution of
NH4Cl (20 ml) was added and the organic layer was separated. The
aqueous layer was extracted with dichloromethane (3 x 30 ml), the organic
layers were combined, dried with MgSO4 filtered and the solvent was
removed at reduced pressure. The crude oil was purified by flash column
chromatography (SiO2, 10% EtOAc in Petrol, Rf = 0.3) to give the mixture
of the two diastereomers of the title compound as a white solid (9.27 g,
97%). This was used immediately in the next step.
Methyl 2,4,4-trimethyl-6-oxocyclohex-1-ene-1-carboxylate (14)
A solution of NaH (1.14 g, 60 mmol, 1.04 equiv) in dry MeOH (50 ml) at
0 °C was transferred to
a solution of S-methyl 2,4,4-trimethyl-6-
oxocyclohex-1-ene-1-carbothioate 13 (12.23 g, 57.6 mmol, 1.0 equiv) in
dry MeOH (50 ml) and stirred at 40 °C until the starting material was
consumed. The reaction was allowed to cool down to room temperature,
then a saturated solution of NH4Cl (20 ml) was added and the solvent was
removed at reduced pressure. The aqueous layer was extracted with
dichloromethane (2 x 50 ml), dried with MgSO4 filtered and the solvent was
removed at reduced pressure. The crude oil was purified by flash column
chromatography (SiO2, 10% EtOAc in Petrol, Rf = 0.05) to give the title
compound as a colourless oil (9.04 g, 80%); IR (cm−1) 1732, 1667, 1634,
1435, 1378, 1369, 1320, 1279, 1239, 1196, 1143, 1068, 1023; 1H NMR
(500 MHz, CDCl3)  3.79 (s, 3H), 2.25 (s, 2H), 2.25 (s, 2H), 1.94 (s, 3H),
1.02 (s, 6H); 13C NMR (125 MHz, CDCl3)  195.4, 167.3, 158.6, 131.9,
52.2, 50.6, 45.9, 33.0, 28.2, 22.5; HRMS-ASAP (m/z) [M + H]+ calcd for
C11H17O3 requires 197.1172; found, 197.1170.
Methyl 4,4,6,6-tetramethylcyclohex-1-ene-1-carboxylate (17)
A solution of NaH (983 mg, 40.1 mmol, 1.3 equiv) in dry MeOH (50 ml) at
0 °C was transferred to a solution of methyl 2,2,4,4-tetramethyl-6-
((methylsulfonyl)oxy)cyclohexane-1-carboxylate 16 (9.27 g, 31.52 mmol,
1.0 equiv) in dry MeOH (50 ml) and stirred at 40 °C until the starting
material was consumed. The reaction was allowed to cool down to room
temperature, then a saturated solution of NH4Cl (20 ml) was added and
the solvent was removed at reduced pressure. The aqueous layer was
extracted with dichloromethane (2 x 50 ml), dried with MgSO4 filtered and
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10.1002/ejoc.201800496
European Journal of Organic Chemistry
FULL PAPER
the solvent was removed at reduced pressure. The crude oil was purified
by flash column chromatography (SiO2, 1% Et2O in Petrol, Rf = 0.5) to give
the title compound as a colourless oil (5.07 g, 82%); IR (cm−1) 1707, 1459,
1436, 1366, 1249, 1190, 1062; 1H NMR (500 MHz, CDCl3)  6.88 (dd,
J = 4.3 Hz, 1H); 1.94 (d, J = 4.3 Hz, 2H), 1.40 (s, 2H), 1.24 (s, 6H), 0.95 (s,
6H); 13C NMR (125 MHz, CDCl3)  167.6, 138.6, 136.7, 53.5, 51.2, 40.4,
33.7, 29.9, 29.8, 29.6; HRMS-ASAP (m/z) [M + H]+ calcd for C12H21O2
requires 197.1536; found, 197.1535.
1,1,5,5-Tetramethyl-2-(prop-1-en-2-yl)cyclohexane (1)
To a solution of 1-(2,2,4,4-tetramethylcyclohexyl)ethan-1-one 19 (148 mg,
0.813 mmol, 1 equiv) in THF (5.0 ml) at 0 °C was added a toluene solution
of the Tebbe reagent (4.87 ml, 2.44 mmol, 3 equiv). The reaction was
allowed to stir at 0 °C for 15 minutes, then to room temperature for 1 h.
The reaction was then cooled to 0 °C, diluted with Et2O (5.0 ml) and
washed with a 0.1 M aqueous solution of NaOH until gas evolution ceased.
The reaction mixture was filtered through a silica pad, the organic layer
extracted and dried over MgSO4. The crude oil was purified by flash
column chromatography (SiO2, 2% Et2O in Petrol, Rf = 0.6) to give the title
compound as a colourless oil (121 mg, 0.67 mmol, 83%); IR (cm−1) 1636,
1455, 1376; 1H NMR (400 MHz, CDCl3)  4.83-4.80 (m, 1H), 4.63-4.60 (m,
1H), 1.77-1.64 (m, 5H), 1.49-1.42 (m, 1H), 1.38-1.32 (m, 1H), 1.27-1.11
(m, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 0.86 (s, 6H); 13C NMR (100 MHz,
CDCl3)  148.0, 112.4, 55.6, 54.9, 40.3, 35.3, 34.7, 34.6, 31.3 27.0, 25.4,
23.8, 23.6; HRMS-EI (Waters GCT Premier Spectrometers) (m/z) [M] calcd
for C13H24 requires 180.1878; found, 180.1877.
Methyl 2,2,4,4-tetramethylcyclohexane-1-carboxylate (18)
Methyl 4,4,6,6-tetramethylcyclohex-1-enecarboxylate 17 (500 mg, 2.55
mmol), Pd/C 5% type 39 (250 mg, 0.5 wt) and ethanol (5.00 mL) were
charged to each of 3 vessels of an HEL High Pressure ChemScan and
hydrogenated at 50 °C, 5 bara for 5 h. Analysis by LCMS indicated
incomplete conversion so the hydrogenation was continued for a further
16 h at 50 °C and 5 bara, after which all reaction were judged complete by
LCMS. The three reaction mixtures were combined and filtered through
Celite, washing through with ethanol (~15 mL). The filtrate was
concentrated to an oil, during which a separate layer was observed. The
material was redissolved in diethyl ether (~30 mL) and dried over Na2SO4
to remove any residual water then filtered and again concentrated,
controlling the vacuum to no more than 200 mbar and the water bath to no
more than 40 °C to minimise loss of product. A small amount of a separate
phase was again observed, for which NMR showed broad signals
corresponding to expected peaks for ethanol. This was removed by pipette
to leave methyl 2,2,4,4-tetramethylcyclohexane-1-carboxylate (0.798 g,
4.03 mmol, 53%) as a colourless oil that was used directly in the next step.
IR (cm−1) 1733, 1458, 1434, 1388, 1365, 1325, 1293, 1248, 1213, 1172,
1147, 1034; 1H NMR (500 MHz, CDCl3)  3.62 (s, 3H); 2.07 (dd, J = 12.5,
3.5 Hz, 1H), 1.82 (ddd, J = 27.2, 13.8 and 3.5 Hz, 1H), 1.60-1.54 (m, 1H),
1.47-1.41 (m, 1H), 1.27 (dd, J = 13.8, 2.5 Hz, 1H), 1.14-1.05 (m, 2H), 0.96
(s, 6H), 0.95 (s, 3H), 0.85 (s, 3H); 13C NMR (125 MHz, CDCl3)  175.5,
54.0, 52.9, 51.0, 38.4, 34.5, 33.6, 33.2, 30.9, 27.2, 24.0, 22.6;
HRMS-ASAP (m/z) [M + H]+ calcd for C12H23O2 requires 199.1693; found,
199.1691.
Acknowledgements
We wish to thank GlaxoSmithKline for funding of this project, and
for a postdoctoral fellowship to F.M. The EPSRC National Mass
Spectrometry Service (Swansea) is greatfully acknowledged for
running some mass spectra.
Keywords: C13 butylrubber oligomer • dithioacetal • isophorone
• Tebbe reagent • hydrogenation
1.
I. Kuntz, K. W. Powers, C. S. Hsu and K. D. Rose,
Makromolekulare Chemie-Macromolecular Symposia, 1988,
13-4, 337-362.
1-(2,2,4,4-Tetramethylcyclohexyl)ethan-1-one (19)
2.
3.
4.
5.
6.
7.
https://nelsonlabs.be/services/EandL_Rubber_Oligomers.cfm
(accessed 9.3.2018).
G. A. Molander and J. A. McKie, J. Org. Chem., 1991, 56,
To a solution of N,N'-dimethylethylenediamine (265 mg. 3.00 mmol,
1.1 equiv) in toluene (20.0 ml) at 0 °C, a solution of trimethylaluminum
(4.23 ml, 8.46 mmol, 2.0 M in toluene, 3.1 equiv) was added dropwise.
The reaction mixture was stirred at room temperature for 1 h before adding
a solution of methyl 2,2,4,4-tetramethylcyclohexane-1-carboxylate 18
(541 mg, 2.73 mmol, 1.0 equiv) in toluene (5.0 ml). The resulting mixture
was heated to reflux and was monitored via TLC (5% Et2O in Petrol). The
reaction mixture was cooled to room temperature and quenched with 1 N
aqueous HCl solution. The organic layer was extracted with EtOAc
(3 x 30 ml), dried with MgSO4, filtered and the solvent was removed at
4112-4120.
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reduced pressure.
The crude oil was purified by flash column
chromatography (SiO2, 5% Et2O in Petrol, Rf = 0.2) to give the title
compound as a colourless oil (148 mg, 30%); IR (cm−1) 1707, 1457, 1388,
1358, 1203, 1171; 1H NMR (400 MHz, CDCl3)  2.25 (dd, J = 11.8, 3.0 Hz,
1H), 2.16 (s, 3H), 1.85-1.71 (m, 1H), 1.56-1.39 (m, 2H), 1.34-1.07 (m, 3H),
1.03-0.94 (m, 9H), 0.88 (s, 3H); 13C NMR (100 MHz, CDCl3)  213.0, 60.2,
54.6, 38.7, 34.5, 34.1, 33.4, 32.2, 31.0, 27.4, 23.9, 22.5; HRMS-ASAP
(m/z) [M + H]+ calcd for C12H23O requires 183.1743; found, 183.1741.
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10.1002/ejoc.201800496
European Journal of Organic Chemistry
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The first total synthesis of important
C13 butyl rubber oligomers is
Extractable and leachable oligomers;
C13-butyl rubber oligomers; total
synthesis; structural confirmation;
dithioacetal; Tebbe olefination
reported. The structure of the
oligomer, which is an important
extractable and leachable component
of elastomeric closures, is confirmed
for the first time. The 10-step
synthetic sequence starting from
isophorone is robust and scalable,
making large quantities of the
Fabrizio Minicone, Robin Attrill, Michael
Hodgson, Katherine Wheelhouse,
Adrian Dobbs*
10 steps
3.4%
Page No. – Page No.
oligomer available for the first time.
First Total Synthesis and Structural
Confirmation of C13-Butylrubber
Oligomers
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