Intramolecular functionalisation by a methylene radical of a 1,2-diol and a vicinal amino alcohol: Models for coenzyme B12-dependent diol dehydratase and ethanolamine ammonia lyase

Article abstract of DOI:10.1039/b004917o

Coenzyme B₁₂-dependent diol dehydratase converts 1,2-diols (e.g. propane-1,2-diol) into the corresponding aldehyde and water. The similar enzyme ethanolamine ammonia lyase transforms vicinal aminoalcohols (e.g. 2-aminoethanol) into the corresponding aldehyde and ammonia. Model systems have been developed that replicate key features of the putative enzymatic mechanism, i.e. removal of a hydrogen atom from the CH₂OH group of a 1,2-diol or vicinal aminoalcohol by a methylene radical derived from an alkylcobalt compound, and conversion of a 1,2-diol or vicinal aminoalcohol into a carbonyl compound and water or ammonia triggered by such a methylene radical. The models are based on alkyl(pyridine)bis(dimethylglyoximato)cobalt complexes [alkyl(pyridine)cobaloximes, Cbx], which were synthesised from appropriate organic precursors using standard methodology. The complexes contain a 1,2-diol [as in 4,5-dihydroxy-2,2-dimethylpentyl(pyridine)cobaloxime] or vicinal aminoalcohol [as in 6-amino-5-hydroxy-2,2-dimethylhexyl(pyridine)cobaloxime] tethered to the cobalt by a carbon chain. Photolysis or thermolysis of 4,5-dihydroxy-2,2-dimethylpentyl(pyridine)cobaloxime at pH 3 or 9 gave 4,4-dimethylpentanal. It is proposed that homolysis of the Co-C bond of 4,5-dihydroxy-2,2-dimethylpentyl(pyridine)cobaloxime induced by photolysis or thermolysis affords the 1,2-dihydroxy-4,4-dimethyl-1-pentyl radical via a 1,5-H shift, which is converted into the 4,4-dimethyl-1-oxo-2-pentyl radical, and hence 4,4-dimethylpentanal. The pathway for formation of the aldehyde was diagnosed using the specifically deuteriated analogue [5,5-²H₂]-4,5-dihydroxy-2,2-dimethylpentyl(pyridine)cobalo xime, which gave [1,5-²H₂]-4,4-dimethylpentanal accompanied by 3,3-dimethylbutanal on thermolysis or photolysis at pH 3. The protected model compound 2a was hydrolysed to 6-amino-5-hydroxy-2,2-dimethylhexyl(pyridine)cobaloxime, which was heated at pH 3 or 9 to give 5,5-dimethylhexan-2-one and ammonia.

Full text of DOI:10.1039/b004917o

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Intramolecular functionalisation by a methylene radical of a
1,2-diol and a vicinal amino alcohol: models for coenzyme B12-
dependent diol dehydratase and ethanolamine ammonia lyase
1
Rosaleen J. Anderson,*a,b Susan Ashwell,b Ian Garnettb and Bernard T. Golding*b
a Institute of Pharmacy and Chemistry, Fleming Building, University of Sunderland,
Sunderland, UK SR1 3SD
b Department of Chemistry, Bedson Building, University of Newcastle upon Tyne,
Newcastle upon Tyne, UK NE1 7RU
Received (in Cambridge, UK) 20th June 2000, Accepted 19th October 2000
First published as an Advance Article on the web 28th November 2000
Coenzyme B12-dependent diol dehydratase converts 1,2-diols (e.g. propane-1,2-diol) into the corresponding aldehyde
and water. The similar enzyme ethanolamine ammonia lyase transforms vicinal aminoalcohols (e.g. 2-aminoethanol)
into the corresponding aldehyde and ammonia. Model systems have been developed that replicate key features
of the putative enzymatic mechanism, i.e. removal of a hydrogen atom from the CH2OH group of a 1,2-diol or
vicinal aminoalcohol by a methylene radical derived from an alkylcobalt compound, and conversion of a 1,2-diol
or vicinal aminoalcohol into a carbonyl compound and water or ammonia triggered by such a methylene radical. The
models are based on alkyl(pyridine)bis(dimethylglyoximato)cobalt complexes [alkyl(pyridine)cobaloximes, Cbx],
which were synthesised from appropriate organic precursors using standard methodology. The complexes contain
a 1,2-diol [as in 4,5-dihydroxy-2,2-dimethylpentyl(pyridine)cobaloxime] or vicinal aminoalcohol [as in 6-amino-
5-hydroxy-2,2-dimethylhexyl(pyridine)cobaloxime] tethered to the cobalt by a carbon chain. Photolysis or thermolysis
of 4,5-dihydroxy-2,2-dimethylpentyl(pyridine)cobaloxime at pH 3 or 9 gave 4,4-dimethylpentanal. It is proposed that
homolysis of the Co–C bond of 4,5-dihydroxy-2,2-dimethylpentyl(pyridine)cobaloxime induced by photolysis or
thermolysis affords the 1,2-dihydroxy-4,4-dimethyl-1-pentyl radical via a 1,5-H shift, which is converted into the
4,4-dimethyl-1-oxo-2-pentyl radical, and hence 4,4-dimethylpentanal. The pathway for formation of the aldehyde
was diagnosed using the specifically deuteriated analogue [5,5-2H2]-4,5-dihydroxy-2,2-dimethylpentyl(pyridine)-
cobaloxime, which gave [1,5-2H2]-4,4-dimethylpentanal accompanied by 3,3-dimethylbutanal on thermolysis or
photolysis at pH 3. The protected model compound 2a was hydrolysed to 6-amino-5-hydroxy-2,2-dimethyl-
hexyl(pyridine)cobaloxime, which was heated at pH 3 or 9 to give 5,5-dimethylhexan-2-one and ammonia.
class of coenzyme B12-dependent reactions5,6 in which a sub-
Introduction
strate molecule (SH) is converted into an intermediate
The coenzyme B12-dependent enzymes propanediol dehydratase
(EC 4.2.1.28 from Klebsiella pneumoniae),1 glycerol dehydratase
(EC 4.2.1.30, also from K. pneumoniae)1d,2 and ethanolamine
ammonia lyase (EC 4.3.1.7 from Clostridia)3 perform similar
reactions. The diol dehydratases catalyse the conversion of a
1,2-diol into the corresponding aldehyde and water [eqn. (1)],1,2
ؒ
substrate-derived radical S . A group X (OH, NH2 or substi-
tuted carbon) is thereby activated, and migrates (1,2-shift) to
ؒ
ؒ
the radical centre. This leads to an isomeric radical (I or P , see
Scheme 1) and hence to an intermediate (IH) or product (PH).
(1)
Scheme 1 General mechanistic scheme for coenzyme B12-dependent
enzymatic reactions [AdoCH2-Cbl = coenzyme B12 (adenosylcobal-
amin), SH = substrate, IH = intermediate, PH = product; S , I and P
are the corresponding protein-bound radicals].
while ethanolamine ammonia lyase catalyses the conversion
of a vicinal aminoalcohol into the corresponding aldehyde
and ammonia [eqn. (2)].3,4 These enzymes have been termed
ؒ
ؒ
ؒ
(2)
With the diol dehydratases and ethanolamine ammonia lyase,
IH loses water or ammonia to give the end-product aldehyde.
The sequence described (Scheme 1) is initiated by homolytic
fission of the cobalt–carbon σ-bond of the B12 coenzyme
(adenosylcobalamin, AdoCbl), leading to the 5Ј-deoxyadenosyl
ؒ
radical, which abstracts a hydrogen atom from SH to give S
eliminases because the overall catalytic reaction is an elimin-
ation of either water (diol dehydratases) or ammonia (ethanol-
amine ammonia lyase) from a substrate molecule.5 The diol
dehydratases and ethanolamine ammonia lyase belong to a
and 5Ј-deoxyadenosine. The latter gives up a hydrogen atom to
ؒ
ؒ
I or P forming IH or PH and regenerating the 5Ј-deoxyadeno-
syl radical. According to the ‘bound radical’ hypothesis7,8 all of
the radicals described are ‘anchored’ to the protein throughout.
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This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b004917o

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Experimental support for the pathway described has come
from spectroscopic studies (electron paramagnetic resonance,
EPR) of the working enzymes, which detected intermediate
radicals.3b,9,10 Model studies pertaining to the diol dehydratases
have shown the possibility of activation of a 1,2-diol by hydro-
gen atom abstraction from C-1, induced by a primary organic
radical and leading, via a 1,2-dihydroxyalkyl radical, to a prod-
uct aldehyde or ketone.11,12 A critical issue in the context of the
diol dehydratases is the mechanism of the conversion of the
intermediate 1,2-dihydroxyalkyl radical into a 1,1-dihydroxy-2-
alkyl radical. Insights into possible mechanisms13 have been
provided by ab initio molecular orbital calculations, which have
indicated that the enzyme mediates a 1,2-hydroxy shift by
‘partial protonation’ of the migrating hydroxy group.14
A
recently determined crystal structure of diol dehydratase15
supports this mechanism by showing that the substrate diol
binds at a distance of ca. 10 Å from the cobalt of the cofactor,
where it interacts with several amino acid residues and a
potassium ion. The latter observation explains why diol de-
hydratase requires a monovalent cation for activity (preferably
ϩ
NH4 or Kϩ).16 Hence, the migration of the hydroxy group
may be assisted either through its interaction with the Lewis
acid Kϩ or through partial protonation by NH4ϩ. The enzyme
also contains an active site carboxylate (Gluα170), which inter-
acts with the non-migrating hydroxy group and assists the
rearrangement in a ‘push–pull’ manner.14,15
It was long ago suggested that the ethanolamine ammonia
lyase reaction proceeds via intermediate radicals.17 This con-
clusion was supported by EPR studies10 and by the finding that
the chiral methyl group in the ethanal derived from incub-
ating either enantiomer of [2-2H,2-3H]-2-aminoethanol with
ethanolamine ammonia lyase was racemic in each case.18 We
have sought to develop a model system that replicates two key
features of the putative enzymatic mechanism: (i) regiospecific
removal of a hydrogen atom from CHOH of a vicinal amino-
alcohol by a methylene radical derived from an alkylcobalt
compound, and (ii) conversion of a vicinal aminoalcohol into
a carbonyl compound and ammonia triggered by such a
methylene radical.
Scheme 2 Synthesis of model compounds (1a/b) for diol dehydratases.
Reagents and conditions: i LiAlD4, Et2O, rt, 62%. ii Isobutyryl chloride,
pyridine, 0 ЊC, 99%. iii Lithium isopropylcyclohexylamide, n-butyl-
lithium, THF, then TMSCl, MeOH, Ϫ70 ЊC-reflux, 41%. iv LiAlH4,
Et2O, rt, 80%. v p-Cymene, p-TsOH, reflux, 60%. vi NaBH4, EtOH,
NaOH, rt, 72%. viiCBr4, PPh3, MeCN, reflux, 91%. viiiMCPBA, CH2, rt,
73%. ix BF3ؒEt2O, (CH3)2CO, Ϫ75 ЊC, 64%. x BrCbx, NaBH4, EtOH,
{→Cbx(I)}, 35%. xi HCl (aq.), rt, 82%.
In a preliminary communication11f we described a model
system for diol dehydratase in which regiospecific removal of
a hydrogen atom from a 1,2-diol was achieved by a methylene
radical derived from an alkylcobaloxime [4,5-dihydroxy-2,2-
dimethylpentyl(pyridine)cobaloxime 1a], with conversion of
the 1,2-diol into an aldehyde. In this paper we provide full
details of these studies and the results of further experiments
with a specifically deuteriated diol substrate (1b), which sup-
ports the reaction pathway proposed.5 We also describe the
first model system for ethanolamine ammonia lyase, which
replicates the two features defined above. This was achieved by
a remarkable remote functionalisation initiated from the oxazo-
lidinone 2a of 6-amino-5-hydroxy-2,2-dimethylhexyl(pyridine)-
cobaloxime 2b. This model compound was used, rather than a
direct analogue of 1a, because of its synthetic accessibility. For
both 1a and 2b, the critical path between the initially formed
radical and the site that undergoes H-atom abstraction is such
that a 1,5-H shift can occur. This has been shown to be favoured
over a 1,4- or 1,6-H shift.11d
dimethyl-1-pentyl radical 29a undergoing rearrangement to
the 1,2-dihydroxy-4,4-dimethyl-1-pentyl radical 30a by a 1,5-
hydrogen shift (for further details see below). To support this
hypothesis we synthesised the specifically deuteriated analogue
1b, by a similar route to that used for 1a, as shown in Scheme 2
(X = D). The main difference in the syntheses of 1a and 1b
concerned the preparation of the intermediate 2,2-dimeth-
ylpent-4-en-1-ol, either unlabelled 5a or dideuteriated at C-5,
5b. In the unlabelled series this was obtained by acid-catalysed
condensation of isobutyraldehyde with allyl alcohol, followed
by an in situ Claisen rearrangement to afford 4, which was
reduced to 5a. For the synthesis of the corresponding di-
deuteriated compound 5b, reduction of acryloyl chloride with
lithium aluminium deuteride gave [1,1-2H2]prop-2-en-1-ol 3b,19
which was converted into the corresponding ester 10b by
treatment with isobutyryl chloride. The ester was subjected
to an Ireland-type Claisen rearrangement,20 which afforded
[5,5-2H2]-2,2-dimethylpent-4-enoic acid 11b. Reduction of the
1
acid gave the alcohol 5b. The H NMR spectral data for each
Results and discussion
Synthesis of model compounds for diol dehydratases
deuteriated intermediate (3b, 5b–11b, cf. Scheme 2) and for
1b was compared with that for the corresponding unlabelled
compound (3a, 5a–11a and 1a, respectively) and confirmed
the integrity of the deuterium atoms throughout the
synthesis.
The synthetic route to the unlabelled model compound, 4,5-
dihydroxy-2,2-dimethylpentyl(pyridine)cobaloxime 1a starting
from allyl alcohol 3a and isobutyraldehyde, via the inter-
mediates 4 and 5a–9a, is shown in Scheme 2 (X = H). Photolysis
or thermolysis of this compound at pH 3 or 9 gave 4,4-
dimethylpentanal 25a with yields in the range 15–45%, Scheme
3. Formation of the aldehyde is initiated by homolysis of the
Co–C σ-bond of 1a, with the resulting 4,5-dihydroxy-2,2-
Synthesis of a model compound for ethanolamine ammonia lyase
The protected model compound 2a was synthesised from the
same starting materials as used for 1a, via intermediates 12–19
(see Scheme 4). Thus, 2,2-dimethylpent-4-en-1-ol 5a was pro-
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Scheme 3 Thermal and photochemical decomposition of the diol dehydratase model. Reagents and conditions: i 2,4-Dinitrophenylhydrazine,
H2SO4 (aq.), rt.
Scheme 4 Synthesis of a model compound (2a/b) for ethanolamine ammonia lyase. Reagents and conditions: i p-Cymene, p-TsOH, reflux, 60%.
t
ii NaBH4, EtOH, rt, 72%. iii BuMe2SiCl, DMF, imidazole, rt, 100%. iv (i) 2-Methylbut-2-ene, BH3ؒTHF, THF, 0 ЊC; (ii) NaOH–H2O2, rt, 82%.
v (COCl)2, DMSO, CH2Cl2, Ϫ78 ЊC, 53%. vi CH3NO2, NaOH, EtOH, 0 ЊC, 77%. vii Pd/C, H2, EtOH, rt, 65%. viii (i) MeOCOCl, Et3N, CH2Cl2, 0 ЊC;
(ii) NaH, THF, rt, 75%. ix TBAF, THF, rt, 62%. x (CF3SO2)2O, Et3N, CH2Cl2, Ϫ75 ЊC, 100%. xi Cbx(), EtOH, rt, 75%. xii LiOH, in situ, rt, 100%.
tected as its tert-butyldimethylsilyl ether 12, which was con-
verted into the aldehyde 14, by hydroboration to alcohol 13,
followed by Swern oxidation. Base-promoted reaction of 14
with nitromethane (Henry reaction) gave 15, which was reduced
to 16. The amino and hydroxy groups in 16 were protected by
formation of oxazolidinone 17. Removal of the silyl group from
17 gave 18, which was activated by conversion into triflate 19.
Reaction of 19 with (pyridine)cob()aloxime gave cobaloxime
2a, which was fully characterised spectroscopically. In partic-
1
ular, the H and 13C NMR data, including a COSY spectrum,
were in complete accord with structure 2a. Numerous attempts
to isolate analytically pure 6-amino-5-hydroxy-2,2-dimethyl-
hexyl(pyridine)cobaloxime 2b from hydrolysis of 2a were
unsuccessful. For thermal degradation experiments it was
found best to generate a solution of 2b in situ by hydrolysis of
2a, carefully monitored by TLC.
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Thermolysis and/or photolysis of model compounds 1a/b and 2b
analysis). Photolytic degradation of 1a gave 43–45% 4,4-
dimethylpentanal at pH 3 and 20–25% aldehyde at pH 9 (DNP
and GC analysis). The reaction mixtures were also analysed for
the presence of 4,4-dimethylpentane-1,2-diol 28 (authentic
sample obtained as shown in Scheme 5), because pentane-1,2-
diol was a significant by-product in the photolysis of 4,5-
dihydroxypentyl(pyridine)cobaloxime.11d,e However, no 28 was
found, indicating the improved efficiency of the model resulting
from gem-dimethyl substitution. Heating or photolysing 1b at
pH 3 using the procedures described for 1a gave a mixture of
two DNPs, which were identified as 26b and 33 by comparison
of the 1H NMR of the mixture with data for authentic samples
(i.e. non-deuteriated 26a in the case of 26b). For photolysis a
ratio of ca. 1:1 was obtained for 26b:33, whereas thermolysis
gave predominantly 33. The spectrum corresponding to 26b
showed a singlet at δ 0.93 (6H) for the gem-dimethyl group and
a broad resonance at δ 0.92 (2H) assigned to the CH2D group.
The resonance observed at δ 7.57 corresponded to ca. 0.5H
and was assigned to the hydrazone CH of 33, there being no
resonance from the deuterated hydrazone of 26a.
The oxazolidinone group of the protected cobaloxime 2a was
hydrolysed using 1 M lithium hydroxide in water (7 days at
room temperature, in darkness). This procedure had been
previously developed for the hydrolysis of 17 to 16. Monitoring
the hydrolysis of 2a using lithium hydroxide in D2O by 1H
NMR showed the disappearance of the resonances at δ 3.35, 3.7
and 4.6 from the oxazolidinone ring and the appearance of new
signals at δ 3.2 (assigned to CHOH of 2b) and 3.35 and 3.7
(assigned to CH2NH2 of 2b). After adjusting the pH of the
alkaline solution of 2b to 3 or 9 by addition of acetic acid and
degassing with argon, it was heated at 100 ЊC until decom-
position was complete, as shown by TLC monitoring. Thus,
heating 2b at pH 3 for 5 h caused complete decomposition of
the alkylcobaloxime and gave 37% (average of two experiments)
of 5,5-dimethylhexan-2-one 35. The identity of the ketone was
established by GC analysis of an ethereal extract of an aliquot
of the reaction mixture, using an authentic sample of 5,5-
dimethylhexan-2-one as a reference standard. Further confirm-
ation of the identity of the ketone and its yield were obtained
by conversion into its DNP derivative, which was also com-
pared with an authentic sample. The DNP was obtained
by adding the reaction mixture from a thermolysis of 2b to
aqueous acidic DNP reagent and extracting with ether. The
thermal decomposition of 2b at pH 9, 100 ЊC, gave 50%
(average of two experiments) of 5,5-dimethylhexan-2-one
(DNP 36 and GC analysis).
Thermolysis and photolysis of alkylcobaloximes cause
homolysis of the Co–C bond and the release of the alkyl group
as a radical.21 The rates of these processes and the fates of both
the alkyl radical and cob()aloxime moiety are pH-dependent.
Early models for diol dehydratases used photolytic cleavage
of the Co–C bond as this process occurs readily in aqueous
media in contrast to the relatively harsh thermal conditions
required.11a–e,12 However, the initial homolysis proceeds from an
excited state of the alkylcobaloxime and may be regarded as an
imperfect model for the enzymatic reactions, which are non-
photolytic. The gem-dimethyl group in compounds 1a, 1b
and 2b significantly lowers the temperature required to achieve
thermal homolysis of the Co–C bond and also blocks a
side-reaction observed with simpler model compounds [e.g.
4,5-dihydroxypentyl(pyridine)cobaloxime], whereby
a
β-
elimination involving the 4,5-dihydroxypentyl radical diverts
this radical from a 1,5-hydrogen shift towards the by-product
4,5-dihydroxypent-1-ene.11d,e This strategy was based on the
observation of Grate and Schrauzer and others that the
thermal stability of neopentylcobalamin is much lower than
that of alkylcobalamins with primary alkyl groups.22
Following thermal or photochemical degradation of 1a, 1b
and 2b, aldehyde and/or ketone products were isolated, charac-
terised (1H NMR and MS analyses) and quantified (UV-VIS
spectroscopy) as their 2,4-dinitrophenylhydrazones (DNPs).
This method was validated for both 1a and 2b by independent
analysis of the product aldehyde or ketone by GC. Authentic
samples of 4,4-dimethylpentanal 25a and its DNP derivative
26a were independently synthesised (Scheme 5). All thermal
After extraction of 5,5-dimethylhexan-2-one DNP, the solu-
tion was basified and distilled to give an aqueous solution of
ammonia, which was analysed using Nessler’s reagent. This
gave ammonia yields of 47% (pH 3 thermolysis of 2b) and 67%
(pH 9 thermolysis of 2b). A control experiment was performed
in which compound 16 was subjected to a sequence of
thermolysis at pH 3, addition to DNP reagent, basification and
distillation. The resulting distillate contained no ammonia.
Scheme 5 Synthesis of authentic samples of the standards, 4,4-
dimethylpentanal 25a and its DNP 26a, and 4,4-dimethylpentane-1,2-
diol 28. Reagents and conditions: i (i) BH3ؒTHF, 2-methylbut-2-ene, 0 ЊC.
(ii) NaOH, H2O2, 5 ЊC, 62%. ii Pyridinium dichromate, CH2Cl2, rt, 75%.
iii 2,4-Dinitrophenylhydrazine, H2SO4 (aq.), rt, 63%. iv (CH2OH)2, 2,6-
tert-butyl-4-methyl-pyridinium tetrafluoroborate, benzene, reflux, 75%.
v Ph3SnH, AlBN, benzene, 45 ЊC, 67%. vi THF (aq.), DOWEX 50W, rt.
vii Bu3SnH, benzene, reflux, 81%. viii CH3OH, MeCOCl, reflux, 90%.
Mechanism of thermal decomposition of 1a, 1b and 2b and
photochemical decomposition of 1a and 1b
The decompositions of 1a and 1b under both thermal and
photochemical conditions can be rationalised as in Scheme 3.
The critical step following homolysis of the Co–C bond of 1a
to give 29a is a 1,5-H shift, which affords the 1,2-dihydroxy-4,4-
dimethyl-1-pentyl radical 30a. This species is converted into
the 4,4-dimethyl-1-oxo-2-pentyl radical 31a, and hence 4,4-
dimethylpentanal 25a. The detailed mechanism of the pathway
from 30a to 25a cannot be defined without further experimental
information. In the light of recent ab initio molecular orbital
calculations on the diol dehydratase reaction and the deter-
mination of the crystal structure of the enzyme (see Intro-
duction), future model studies need to focus on the proton
and photochemical experiments were performed, at least in
duplicate, with a deoxygenated solution (argon or nitrogen) of
the alkylcobaloxime. It was shown for 1a that admission of
oxygen to reactions reduced the yield of aldehyde to zero.
Heating 1a in pH 3 aqueous acetic acid for 7 h at 100 ЊC
caused complete decomposition of the alkylcobaloxime and
gave 20–22% 4,4-dimethylpentanal 25a according to both DNP
and GC analysis. Thermal decomposition of 1a at pH 9,
100 ЊC, gave 15–21% 4,4-dimethylpentanal (DNP and GC
J. Chem. Soc., Perkin Trans. 1, 2000, 4488–4498
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Scheme 6 Thermal or photochemical decomposition of the ethanolamine ammonia lyase model compound.
transfer steps that may activate the migrating/eliminated
2,2-dimethylpent-4-enal (53.6 g, 48%), with a further 15 g
hydroxy group in enzymatic and model reactions.
contaminated with p-cymene (total yield 60%).
Following homolysis of the Co–C bond of 1b to give 29b, the
type of 1,5-H shift proposed for 29a is impeded by a primary
kinetic isotope effect.11d Although an analogous 1,5-D shift
occurs with 29b to give 30b and hence 25b via 31b, a competing
1,5-H shift occurs from the 2-hydroxy group leading to 3,3-
dimethylbutanal 32. Thus, it is proposed that 29b gives 34,
which fragments to 3,3-dimethylbutanal 32 and the hydroxy-
methyl radical.
2,2-Dimethylpent-4-en-1-ol 5a24
2,2-Dimethylpent-4-enal 4 (11.2 g, 0.1 mol) in aq. ethanol was
reduced with sodium borohydride (1.4 g, 0.037 mol) in 0.2 M
aq. NaOH. Fractional distillation of the crude product gave 2,2-
dimethylpent-4-en-1-ol 5a (8.2 g, 72%), bp 54 ЊC (22 mmHg) or
154 ЊC (760 mmHg).25
Thermolysis of 2b proceeds in a similar manner to the
thermolysis of 1a. However, the 1,5-H shift in the initially
formed radical 37 now leads via 38–40 to the ketone product 35
and ammonia (see Scheme 6).
5-Bromo-4,4-dimethylpent-1-ene 6a25,26
2,2-Dimethylpent-4-en-1-ol 5 (6.6 g, 58.0 mmol), was treated
with carbon tetrabromide (20.0 g, 60.5 mmol) and triphen-
ylphosphine (15.9 g, 60.5 mmol) in acetonitrile (150 cm3) using
the procedure of Hooz and Gilani.26 The crude product was
purified by column chromatography (light petrol) to give
Conclusions
1
The model experiments described in this paper support the
proposed reaction pathways for propanediol dehydratase,
glycerol dehydratase and ethanolamine ammonia lyase by
showing that 1,2-diols and vicinal aminoalcohols can be
converted into a carbonyl compound and water or ammonia,
respectively, by reaction pathways in which radicals are likely
intermediates. The model systems described replicate an
important feature of the enzymatic reactions, i.e. the regio-
selective activation of a substrate molecule by a hydrogen atom
abstraction induced by a primary organic radical. However,
the detailed mechanisms of rearrangement of the radicals can
only be determined by further investigations.
5-bromo-4,4-dimethylpent-1-ene 6a (11.6 g, 91% by H NMR
analysis) contaminated with bromoform.
2-(3-Bromo-2,2-dimethylpropyl)oxirane 7a
5-Bromo-4,4-dimethylpent-1-ene 6a (9.3 g, 52.6 mmol) was
oxidised with m-chloroperoxybenzoic acid (11.8 g, 58 mmol) in
DCM (150 cm3) over 15 h at room temp. The excess of peracid
was destroyed with sodium sulfite. The crude product was
purified by column chromatography (light petrol:ether, 8:1) to
give a colourless syrup. This was flash distilled (bp 42 ЊC at 0.3
mmHg) to yield 2-(3-bromo-2,2-dimethylpropyl)oxirane 7a (5.4
g, 73%) as a viscous, colourless oil (Found: C, 43.71; H, 6.86;
C7H13BrO requires C, 43.54; H, 6.79%); νmax (film)/cmϪ1 3050,
1261 and 666 (s); δH (200 MHz; CDCl3), 3.78 (1H, d, CH2Br,
J 10.1), 3.70 (1H, d, CH2Br, J 10.1), 3.28–3.34 (1H, dddd,
CHOC, J 4.0, 4.6, 7.2 and 5.1), 3.09–3.15 (1H, dd, CH2O, J 4.0
and 2.7), 2.76–2.84 (1H, dd, CH2O, J 2.7 and 5.1), 2.02–2.09
(1H, dd, CH2, J 4.6 and 14.3), 1.75–1.85 (1H, dd, CH2, J 7.2
and 14.3), 1.50 (6H, s, Me2); δC (50 MHz; CDCl3), 48.8 (t,
CH2Br), 46.4 (t, CH2O), 46.2 (t, CH2), 42.6 (d, CH), 34.8 (s,
CMe2), 26.1 (q, Me2); m/z (EI) 177 (10%, Mϩ Ϫ Me), 135 (60),
113 (10), 55 (100), 41 (95).
Experimental
Materials and methods
Unless otherwise stated gas chromatography (GC) was per-
formed on a Pye 104 machine fitted with an 8Љ ov17 column of
4 mm inner diameter with a nitrogen flow rate of 55 cm3 minϪ1
,
and a temperature gradient of 12 ЊC minϪ1 from 100 ЊC. Water
for analytical purposes was obtained from a Purite still plus HP.
Light petrol refers to the fraction boiling between 40 and 60 ЊC.
Petrol refers to the fraction boiling between 60 and 80 ЊC. For
other purification procedures and details of instruments etc. see
ref. 23. All alkylcobaloximes were protected from light. J values
are given in Hz.
4-(3-Bromo-2,2-dimethylpropyl)-2,2-dimethyl-1,3-dioxolane 8a
A solution of 2-(3-bromo-2,2-dimethylpropyl)oxirane (2.01 g,
10.4 mmol) in acetone (8 cm3) was flushed with dry nitrogen for
15 min and cooled to Ϫ75 ЊC. Boron trifluoride–diethyl ether
(300 µl) was added and the resulting solution was stirred at
Ϫ75 ЊC for 5 h. A solution of 0.1 M NaOH (15 cm3) was added
and, after vigorous agitation, the acetone was removed under
2,2-Dimethylpent-4-enal 424
The aldehyde 4 was prepared as described by Brannock.24
Fractional distillation of the reaction mixture yielded
4492
J. Chem. Soc., Perkin Trans. 1, 2000, 4488–4498

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reduced pressure. Ether (15 cm3) was added and the organic
layer was separated, washed with 0.1 M NaOH solution, water
and brine, dried (K2CO3) and the solvent removed. The product
was purified by column chromatography (light petrol:ether,
8:1) to give 4-(3-bromo-2,2-dimethylpropyl)-2,2-dimethyl-1,3-
dioxolane 8a (1.66 g, 64%) as a colourless oil (Found: C, 47.75;
H, 7.29; C10H19BrO2 requires C, 47.82; H, 7.62%); νmax (film)/
cmϪ1 1380, 1155 and 656; δH (200 MHz; CDCl3) 4.09–4.19 (1H,
m, CH, J 5.8, 7.6, 7.8 and 4.0), 4.05 (1H, dd, CH2O, J 5.8 and
7.6), 3.46 (1H, t, CH2O, J 7.6), 3.40 (1H, d, CH2Br, J 10.0), 3.35
(1H, d, CH2Br, J 10.0), 1.64 (1H, dd, CH2, J 14.4 and 7.8), 1.60
(1H, dd, CH2, J 14.4 and 4.0), 1.39 (3H, s, Me), 1.34 (3H, s,
Me), 1.09 (3H, s, Me), 1.07 (3H, s, Me); δC (50 MHz; CDCl3)
108.9 (s, O2CMe2), 73.1 (d, CH), 70.4 (d, CH2O), 46.8 (t,
CH2Br), 43.2 (t, CH2), 34.4 (s, CMe2), 27.0 (q, Me), 26.8 (q,
Me), 26.1 (q, Me), 26.0 (q, Me); m/z (EI) 251 (10%, MHϩ), 235
(80), 175 (20), 135 (20), 95 (100).
2.09 (6H, s, dmgMe2), 2.07 (6H, s, dmgMe2), 1.98 (1H, d,
CoCH2, J 8.9), 1.57 (1H, d, CoCH2, J 8.8), 1.46 (1H, dd, CH2,
J 14.8 and 6.1), 1.18 (1H, dd, CH2, J 14.5 and 4.3), 0.73 (3H, s,
Me), 1.05 (1H, s, OH), 1.01 (1H, s, OH), 0.63 (3H, s, Me); δC (50
MHz; CDCl ) 151.1 (C᎐N), 150.7 (C᎐N), 149.5 (α-pyr), 137.6
᎐
᎐
3
(γ-pyr), 125.2 (β-pyr), 69.9 (CHOH), 68.4 (CH2OH), 45.2
(CH2), 42.0 (CoCH2), 38.7 (CMe2), 29.6 (Me), 29.2 (Me), 12.3
(dmgMe2), 12.2 (dmgMe2); m/z (FAB) 500 (10%, MHϩ), 421,
420, 368, 290 (100), 289 (94).
Prop-2-enyl 2-methylpropionate 10a27
Prop-2-enyl 2-methylpropionate was prepared from allyl
alcohol 3a (3.00 g, 3.51 cm3, 0.05 mol) and isobutyryl chloride
(5.54 g, 5.48 cm3, 0.05 mol) according to the procedure of
Arnold and Kulenovic:27 colourless oil (6.77 g, 99%); νmax (film)/
cmϪ1 2978, 1738 and 1650; δH (200 MHz; CDCl3) 5.78–5.97 (m,
1H, ᎐CH-), 5.14–5.32 (m, 2H, CH ᎐), 4.51–4.55 (2H, m, CH ),
᎐
᎐
2
2
2.53 (1H, quintet, CH, J 7.0), 1.14 (6H, d, Me2, J 7.0); δC (50
4,5-Dihydroxy-2,2-dimethyl-4,5-di-O-isopropylidenepentyl-
(pyridine)bis(dimethylglyoximato(1؊)-N,NЈ)cobalt 9a
MHz; CDCl ) 176.8 (COO), 132.4 (᎐CH), 117.8 (᎐CH ), 64.9
᎐
᎐
3
2
(CH2O), 34.0 (CH), 19.0 (Me2); m/z (EI) 128.085 (Mϩ, C7H12O2
Bromo(pyridine)bis(dimethylglyoximato(1Ϫ)-N,NЈ)cobalt
(0.52 g, 1.2 mmol) was suspended in ethanol (40 cm3) in a
Schlenk tube, degassed and flushed with nitrogen for 1 h.
Sodium borohydride (0.13 g, 3.4 mmol) was added as a suspen-
sion in ethanol (2 cm3) and the mixture was stirred for 1 h until
a homogeneous dark brown–green solution was obtained. To
this solution, 4-(3-bromo-2,2-dimethylpropyl)-2,2-dimethyl-
1,3-dioxolane 8a (0.16 g, 0.6 mmol) was added, and the result-
ant solution was protected from light and stirred at room temp.
for 12 h. Air was bubbled through the clear orange solution for
30 min before water (100 cm3) was added and the product alkyl-
cobaloxime was extracted into ethyl acetate. The combined
organic extracts were dried (K2CO3) and the solvent removed.
The residue was dissolved in a minimum amount of DCM and
purified by column chromatography (96:3:1 DCM–methanol–
pyridine). Product-containing fractions were combined and
the solvent was removed. The residue was subjected to high
vacuum to remove traces of pyridine. Alkylcobaloxime 9a (0.12
g, 35%) was isolated as an orange–yellow crystalline solid
(Found: C, 51.05; H, 6.81; N, 12.78; C23H38CoN5O6 requires C,
51.20; H, 7.10; N, 12.98%); νmax (disc)/cmϪ1 3150 (br) and 1234
(s); δH (200 MHz; CDCl3) 8.47 (2H, d, α-pyr, J 4.9), 7.65 (1H, t,
γ-pyr, J 6.0), 7.25 (2H, t, β-pyr, J 4.2), 3.93–4.05 (2H, m,
CH2O), 3.30 (1H, t, CH, J 9.9), 2.06 (6H, s, dmgMe2), 2.05 (6H,
s, dmgMe2), 1.77 (1H, d, CoCH2, J 9.0), 1.45 (1H, d, CoCH2,
J 9.0), 1.36 (2H, m, CH2), 1.28 (3H, s, Me), 1.25 (3H, s, Me),
0.73 (3H, s, Me), 0.69 (3H, s, Me); δC (50 MHz; CDCl3) 150.2
requires 128.084) 128 (10%, Mϩ), 71 (20), 57 (40).
[1,1-2H2]Prop-2-en-1-ol 3b27
[1,1-2H2]Prop-2-en-1-ol was prepared19 by reduction with
lithium aluminium deuteride (5.0 g, 0.2 mmol) of acryloyl
chloride (16.2 g, 0.2 mmol) to give the deuteriated allyl alcohol
3b (6.7 g, 62%), which was used without further purification;
νmax (film)/cmϪ1 3370, 2964, 2934 and 1035; δH (200 MHz;
CDCl ) 5.8–6.1 (1H, m, ᎐CH), 5.0–5.3 (2H, m, ᎐CH ), 2.0–2.2
᎐
᎐
3
2
(1H, br s, OH); δC (50 MHz; CDCl3) 137.3 (CH), 115.4 (CH2),
63.2 (t, CD2).
[1,1-2H2]Prop-2-enyl 2-methylpropionate 10b
[1,1-2H2]Prop-2-enyl 2-methylpropionate 10b was prepared
from [1,1-2H2]prop-2-en-1-ol 3b in the same manner as 10a. The
title compound 10b was obtained as a colourless oil (6.61 g,
88%); νmax (film)/cmϪ1 2976, 1736 and 1645; δH (200 MHz;
CDCl ) 5.67–5.96 (1H, m, ᎐CH-), 5.15–5.33 (m, 2H, CH ᎐),
᎐
᎐
2
3
2.45–2.70 (1H, quintet, CH, J 7.0), 1.16 (6H, d, Me2, J 7.0), the
methylene multiplet at δ 4.5 was not present; δC (50 MHz;
CDCl ) 176.7 (COO), 132.4 (᎐CH), 118.0 (᎐CH ), 64.9 (CD O),
᎐
᎐
3
2
2
34.0 (CH), 19.0 (Me2); m/z (EI) 130.0963 (Mϩ, C12H102H2O2
requires 130.0962), 130 (15%), 71 (100), 43 (100).
2,2-Dimethylpent-4-enoic acid 11a20,28
Prop-2-enyl 2-methylpropionate 10a (1.28 g, 10 mmol, 1.4 cm3)
was subjected to a Claisen rearrangement according to the
procedure of Ireland et al.,20 to yield the carboxylic acid 11a
(0.53 g, 41%) as a colourless oil; δH (200 MHz; CDCl3), 11.4–
11.6 (1H, br s, COOH), 5.60–5.80 (1H, m, vinylic CH), 4.95–
(C᎐N), 150.1 (C᎐N), 149.4 (α-pyr), 137.5 (γ-pyr), 125.1 (β-pyr),
᎐
᎐
107.7 (O2CMe2), 73.9 (CHO), 70.9 (CH2O), 46.1 (CH2), 42.2
(CoCH2), 38.5 (CMe2), 28.8 (Me), 28.5 (Me), 27.1 (Me), 26.1
(Me), 12.1 (dmgMe4); m/z (FAB) 540 (MHϩ), 539, 461, 290
(100%).
5.06 (2H, m, ᎐CH ), 2.20–2.25 (2H, dt, CH , J 7.4 and 0.9), 1.12
᎐
2
2
(6H, s, Me2).
4,5-Dihydroxy-2,2-dimethylpentyl(pyridine)bis(dimethyl-
glyoximato(1؊)-N,NЈ)cobalt 1a
[5,5-2H2]-2,2-Dimethylpent-4-enoic acid 11b
4,5-Dihydroxy-2,2-dimethyl-4,5-di-O-isopropylidenepentyl-
(pyridine)bis(dimethylglyoximato(1Ϫ)-N,NЈ)cobalt 9a (0.16 g,
0.3 mmol) was dissolved in ethanol (3 cm3) and 2 M HCl (0.45
cm3) was added. The solution was stirred in the dark at room
temp for 5 h. The solvent was removed and the residue was
subjected to column chromatography (90:9:1, DCM–
methanol–pyridine). After removal of the solvent, traces of
pyridine were removed under high vacuum to give the diol-
cobaloxime 1a (0.11 g, 82%) as an orange crystalline solid
(Found: C, 48.61; H, 6.57; N, 13.80; C20H34CoN5O6 requires C,
48.10; H, 6.86; N, 14.02%); νmax (disc)/cmϪ1 3406 br, 2910–2950
and 1560; δH (200 MHz; CDCl3) 8.46 (2H, d, α-pyr), 7.68 (1H, t,
γ-pyr), 7.27 (2H, t, β-pyr), 3.59 (1H, m, CHOH), 3.48 (1H, dd,
CH2OH, J 11.0 and 3.3), 3.30 (1H, dd, CH2OH, J 11.0 and 7.9),
[5,5-2H2]-2,2-Dimethylpent-4-enoic acid 11b was prepared from
[1,1-2H2]prop-2-enyl 2-methylpropionate 10b in the same
manner as 11a yielding the title compound (2.63 g, 40%) as a
pale yellow oil; νmax (film)/cmϪ1 3100, 1703 and 1603; δH (200
MHz; CDCl3) 11.25–11.6 (1H, br s, COOH), 5.6–5.7 (1H, br t,
᎐CH), 2.4–2.6 (2H, m, ᎐CH ), 2.1 (2H, d, -CH , J 7.4), 1.1 (6H,
᎐
᎐
2
2
s, Me ); δ (50 MHz; CDCl ) 184.6 (COOH), 133.7 (CH᎐), 44.3
᎐
2
C
3
(CH2), 33.9 (CMe2), 24.6 (Me2); m/z (EI) 130.0982 (Mϩ,
C7H102H2O2 requires 130.0962), 130.1 (7%), 115 (25), 85 (100),
43 (60).
[5,5-2H2]-2,2-Dimethylpent-4-en-1-ol 5b
[5,5-2H2]-2,2-Dimethylpent-4-enoic acid 11b (2.65 g, 20.3
J. Chem. Soc., Perkin Trans. 1, 2000, 4488–4498
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mmol) in ether (20 cm3) was reduced with lithium aluminium
hydride (2.40 g, 63 mmol) in ether (80 cm3) to yield the alcohol
5b (1.9 g, 80%) as a colourless oil; νmax (film)/cmϪ1 3400 and
δ (120 MHz; CDCl ) 150.1 (C᎐N), 149.3 (α-pyr), 137.5 (γ-pyr),
᎐
C 3
125.1 (β-pyr), 69.6 (CHOH), 44.6 (CH2), 42.0 (br, CoCH2), 38.5
(CMe2), 29.9 (Me), 29.8 (Me), 12.2 (dmgMe2), 12.1 (dmgMe2)
[NB the expected resonance for CD2OH was not identified]; m/z
(FAB) 502 (MHϩ), 423, 422, 368, 290 (100%), 289.
1050; δH (200 MHz; CDCl ) 5.73–5.83 (1H, br t, ᎐CH), 3.27
᎐
3
(2H, s, CH2O), 1.96 (2H, d, CH2), 1.88 (1H, br s, OH), 0.84 (6H,
s, Me2); m/z (EI) 117.1241 (MHϩ, C7H132H2O requires
117.1248), 117 (15%), 116 (5), 73 (100), 43 (95).
1-[tert-Butyl(dimethyl)silyloxy]-2,2-dimethylpent-4-ene 12
2,2-Dimethylpent-4-en-1-ol 5a (13.7 g, 0.1 mol), tert-
butyldimethylsilyl chloride (25.0 g, 0.2 mol) and imidazole (11.3
g, 0.2 mol) in dimethylformamide (100 cm3) were stirred under
a nitrogen atmosphere overnight (18 h). Work-up was carried
out in the usual manner.29 The crude product was purified by
flash column chromatography (light petrol) and the solvent was
removed to yield the title compound 12 (27.4 g, 100%) as a
colourless liquid; νmax (film)/cmϪ1 2957, 1641 and 1257; δH (200
[1,1-2H2]-5-Bromo-4,4-dimethylpent-1-ene 6b
This compound was synthesised from [5,5-2H2]-2,2-
dimethylpent-4-en-1-ol 5b in the manner of 6a (1.9 g, 50% by
NMR analysis); νmax (film)/cmϪ1 2924 and 1653; δH (200 MHz;
CDCl ) 5.69–5.78 (1H, br t, ᎐CH), 3.25 (2H, s, CH Br), 2.07
᎐
3
2
(2H, d, CH2, J 7.5), 0.99 (6H, s, Me2); m/z (EI) 178 (5%, Mϩ),
135 (60), 99 (64), 55 (100).
MHz; CDCl ) 5.68–5.89 (1H, m, RCH᎐), 4.92–4.97 (2H, m,
᎐
3
[3,3-2H2]-2-(3-Bromo-2,2-dimethylpropyl)oxirane 7b
᎐CH ), 3.20 (2H, s, CH O), 1.96 (2H, dt, CH , J 4.3 and 1.10),
᎐
2
2
2
t
0.87 (9H, s, Bu), 0.80 (6H, s, Me2), 0.07 (6H, s, SiMe2); δC (50
MHz; CDCl ) 135.8 (RC᎐), 116.7 (᎐CH ), 71.3 (CH O), 43.2
[3,3-2H2]-2-(3-Bromo-2,2-dimethylpropyl)oxirane 7b was syn-
thesised from [1,1-2H2]-5-bromo-4,4-dimethylpent-1-ene 6b in
the manner of 7a. Distillation under reduced pressure (bp 42 ЊC
at 0.3 mmHg) yielded the deuteriated bromo epoxide 7b (1.1 g,
52%) as a colourless oil; νmax (film)/cmϪ1 3046, 1267 and 663;
δH (200 MHz; CDCl3) 3.37 (1H, d, CHBr, J 10.1), 3.32 (1H, d,
CH’Br, J 10.1), 2.93 (1H, dd, CHO, J 4.7 and 7.2), 1.6–1.75
(1H, dd, CH, J 4.7 and 14.3), 1.45 (1H, dd, CHЈ, J 7.2 and
14.3), 1.1 (6H, s, Me2); δC (50 MHz; CDCl3) 48.2 (CH2Br), 46.4
(CH2), 42.7 (CH), 34.6 (CMe2), 26.2 (Me2).
᎐
᎐
3
2
2
(CH2), 35.6 (CMe2), 26.0 (SiCMe3), 24.0 (Me2), 18.3 (SiCMe3),
Ϫ5.5 (SiMe2); m/z (EI) 228 (10%, Mϩ), 97 (45).
1-[tert-Butyl(dimethyl)silyloxy]-2,2-dimethylpentan-5-ol 1330,31
Hydroboration of 1-[tert-butyl(dimethyl)silyloxy]-2,2-dimethyl-
pent-4-ene 12 (2.05 g, 9.0 mmol) in tetrahydrofuran (10 cm3) was
achieved with disiamylborane (1,2-dimethylpropylborane).30
Work-up and oxidation was carried out using the procedure of
Brown et al.31 The crude product was purified by flash column
chromatography (CH2Cl2) to yield the alcohol 13 (1.7 g, 82%)
as a colourless oil; δH (200 MHz; CDCl3) 3.59 (2H, t, CH2OH,
J 6.7), 3.22 (2H, s, CH2OSi), 1.67 (1H, br s, OH), 1.50–1.61
[5,5-2H2]-4-(3-Bromo-2,2-dimethylpropyl)-2,2-dimethyl-1,3-
dioxolane 8b
This was synthesised from [3,3-2H2]-2-(3-bromo-2,2-
dimethylpropyl)oxirane 7b in the manner of 8a to yield the
deuteriated bromo acetal 8b (0.84 g, 53%) as a colourless oil; δH
(200 MHz; CDCl3) 4.1 (1H, dd, CHO), 3.3 (2H, s, CH2Br), 1.6–
1.8 (1H, dd, CH2, J 14.2 and 7.8), 1.4–1.6 (1H, dd, CH2, J 14.2
and 4.0), 1.35 (3H, s, Me), 1.30 (3H, s, Me), 1.1 (3H, s, Me),
1.06 (3H, s, Me); δC (50 MHz; CDCl3) 108.9 (O2CMe2), 73.1
(CH), 46.8 (CH2Br), 43.2 (CH2), 34.4 (CMe2), 27.0 (Me), 26.8
(Me), 26.1 (Me), 26.0 (Me).
t
(2H, m, CH2), 1.11–1.48 (2H, m, CH2), 0.87 (9H, s, Bu), 0.81
(6H, s, Me2), 0.00 (6H, s, SiMe2); δC (50 MHz; CDCl3) 71.4
(CH2OH), 63.9 (CH2OSi), 35.0 (CMe2), 34.5 (CH2), 27.4 (CH2),
25.9 (Me2), 24.1 (tBu), 18.3 (SiCMe3), Ϫ5.5 (SiMe2).
5-[tert-Butyl(dimethyl)silyloxy]-4,4-dimethylpentanal 14
Swern oxidation of 1-[tert-butyl(dimethyl)silyloxy]-2,2-
dimethylpentan-5-ol 13 (3.78 g, 15.4 mmol) in DCM (10 cm3)
with oxalyl chloride (2.2 g, 1.5 cm3, 17 mmol) and dimethyl
sulfoxide (2.6 g, 2.4 cm3, 34 mmol) in DCM (45 cm3) at
Ϫ78 ЊC,32 followed by flash column chromatography (CH2Cl2)
of the crude product, yielded the aldehyde 14 (2.0 g, 53%) as a
colourless oil; νmax (film)/cmϪ1 2930 and 1713; δH (200 MHz;
CDCl3) 9.73 (1H, br t, CHO), 3.22 (2H, s, CH2O, 2.33–2.40
(2H, m, CH2CH2CHO), 1.5–1.7 (2H, t, CH2CH2CHO, J 8.2),
0.86 (9H, s, tBu), 0.82 (6H, s, Me2), Ϫ0.01 (6H, s, SiMe2).
[5,5-2H2]-4,5-Dihydroxy-2,2-dimethyl-4,5-di-O-isopropylidene-
pentyl(pyridine)bis(dimethylglyoximato(1؊)-N,NЈ)cobalt 9b
This was synthesised from [5,5-2H2]-4-(3-bromo-2,2-dimeth-
ylpropyl)-2,2-dimethyl-1,3-dioxolane 8b in the manner of 9a to
yield the deuteriated alkyl-cobaloxime 9b (0.12 g, 35%) as
orange plates; νmax (disc)/cmϪ1 2955 and 1240; δH (200 MHz;
CDCl3) 8.5 (2H, m, α-pyr), 7.65 (1H, t, γ-pyr), 7.25 (2H, t,
β-pyr), 3.31 (1H, s, CHO), 2.07 (6H, s, dmgMe2), 2.06 (6H, s,
dmgMe2), 1.92 (1H, d, CoCH2, J 8.8), 1.55 (1H, d, CoCH2,
J 8.8), 1.4 (2H, m, CH2), 1.34 (3H, s, Me), 1.30 (3H, s, Me), 0.77
(3H, s, Me), 0.73 (3H, s, Me); δC (50 MHz; MeOH) 150.7
1-[tert-Butyl(dimethyl)silyloxy]-5-hydroxy-2,2-dimethyl-6-
nitrohexane 1533
5-[tert-Butyl(dimethyl)silyloxy]-4,4-dimethylpentanal 14 (2.01
g, 8.2 mmol) and nitromethane (0.50 g, 8.2 mmol) in ethanol
(4 cm3) were cooled in an ice bath and sodium hydroxide
solution (0.9 cm3, 10 M, 9 mmol) was added dropwise over 30
min. The reaction mixture was stirred for 3 h on an ice bath
then acetic acid solution (10 cm3, 1 M) was added. The ethanol
was removed under reduced pressure and the aq. residue was
extracted with ethyl acetate. The combined organic extracts
were washed with sodium hydroxide solution (0.1 M), brine,
and dried. Removal of the solvent and purification of the
residue by flash column chromatography (CH2Cl2) gave the
nitro alcohol 15 (1.8 g, 77%) as a colourless oil; νmax (film)/cmϪ1
3435, 2955, 1556, 1363 and 1099; δH (200 MHz; CDCl3) 4.3–4.5
(2H, m, CH2NO2), 4.1–4.3 (1H, m, CHOH), 3.2 (2H, s,
CH2OSi), 2.4 (1H, br s, OH), 1.2–1.6 (4H, m, CH2CH2), 0.89
(9H, s, tBu), 0.88 (6H, s, Me2), 0.02 (6H, s, SiMe2); δC (50 MHz;
CDCl3) 80.6 (CH2NO2), 71.1 (CH2OH), 69.5 (CH2OSi), 35.0
(CMe2), 33.9 (CHOHCH2), 28.5 (CHOHCH2CH2), 25.9 (OSi-
(C᎐N), 149.1 (α-pyr), 139.8 (γ-pyr), 126.9 (β-pyr), 110.4
᎐
(O2CMe2), 75.6 (CHO), 45.2 (CH2), 35.5 (CMe2), 27.7 (Me),
27.4 (Me), 26.7 (Me), 26.6 (Me), 12.7 (dmgMe4) [NB the
expected resonance for CD2OH was not identified]; m/z (FAB)
542 (MHϩ), 541, 463, 290.
[5,5-2H2]-4,5-Dihydroxy-2,2-dimethylpentyl(pyridine)bis-
(dimethylglyoximato(1؊)-N,NЈ)cobalt 1b
This compound was prepared from 9b in the manner of 1a to
give the deuteriated diol-cobaloxime 1b (75 mg, 57%) as orange
plates; νmax (disc)/cmϪ1 3410 br, 2928, 1562, 1446 and 1237;
δH (500 MHz; CDCl3) 8.5–8.55 (2H, d, α-pyr), 7.75 (1H, t,
γ-pyr), 7.25 (2H, t, β-pyr), 3.5 (1H, br t, CHOH, J 5.1), 2.22
(6H, s, dmgMe2), 2.15 (6H, s, dmgMe2), 2.07–2.10 (1H, d, CH-
Co, J 11.0), 1.45–1.55 (1H, d, CHЈ-Co, J 11.0), 1.4 (1H, m,
CH2), 1.2 (1H, m, CHЈ2), 0.8 (3H, s, CH3), 0.65 (3H, s, CH3);
4494
J. Chem. Soc., Perkin Trans. 1, 2000, 4488–4498

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CMe3), 24.2 (CMe2) , 24.0 (CMe2), 18.3 (SiCMe3), Ϫ5.5
(SiMe2); m/z (EI) 306.211 (MHϩ, C14H32NO4Si requires
306.210), 306 (20%).
18.3 (SiCMe3), Ϫ5.5 (SiMe2); m/z (EI) 302.2161 (MHϩ,
C15H32NO3Si requires 302.2154) 302 (10%, MHϩ), 286 (10),
244 (80).
5-(4-Hydroxy-3,3-dimethylbutyl)-1,3-oxazolidin-2-one 18
6-Amino-1-[tert-butyl(dimethyl)silyloxy]-5-hydroxy-2,2-
dimethylhexane 16
To 5-{4-[tert-butyl(dimethyl)silyloxy]-3,3-dimethylbutyl}-1,3-
oxazolidin-2-one 17 (2.64 g, 8.8 mmol) in tetrahydrofuran (50
cm3) was added tetrabutylammonium fluoride29 as a solution in
tetrahydrofuran (1.1 M, 15 cm3, 16.5 mmol) and the reaction
mixture was stirred for 24 h, after which time TLC showed the
absence of starting material. Water (5 cm3) was added and the
tetrahydrofuran was removed. The aqueous component was
extracted into DCM and the organic extracts were washed with
water, brine and dried (MgSO4). The crude product was puri-
fied by flash column chromatography (ethyl acetate) to yield the
alcohol 18 (1.01 g, 62%) as a colourless solid, mp 72 ЊC; νmax
(disc)/cmϪ1 3317, 2957, 2872 and 1745; δH (200 MHz; CDCl3)
6.5 (1H, br s, NH), 4.5–4.7 (1H, m, CHO, J 7.9), 3.65 (1H, t,
CHNH, J 8.4), 3.3 (2H, s, CH2OH), 3.25 (1H, t, CHЈNH, J 7.9),
2.9 (1H, br s, OH), 1.5–1.9 (2H, m, CHOCH2CH2), 1.1–1.5
(2H, m, CHOCH2CH2), 0.95 (6H, s, Me2); δC (50 MHz; CDCl3),
To a solution of 1-[tert-butyl(dimethyl)silyloxy]-5-hydroxy-2,2-
dimethyl-6-nitrohexane 15 (6.31 g, 21.8 mmol) in ethanol (125
cm3) was added a slurry of palladium supported on charcoal
(10%, 3.0 g, 14 mol%) in ethanol (80 cm3). The reaction mixture
was degassed by stirring under water pump vacuum, then the
vacuum was replaced by a hydrogen atmosphere at atmospheric
pressure. The reaction mixture was stirred for 24 h, after which
time the hydrogen atmosphere was removed. Filtration of the
crude reaction mixture through Celite, removal of the solvent
and flash column chromatography (DCM–methanol–aq.
ammonia, 8:1:0.1) of the crude product yielded the amino
alcohol 16 (3.5 g, 65%) as a viscous oil; νmax (film)/cmϪ1 3354,
2955, 2930, 1591, 1473 and 1099; δH (200 MHz; CDCl3), 3.5 (1H,
br s, OH), 3.3 (2H, br s, NH2), 3.2 (2H, s, CH2OSi), 2.9 (1H, br
s, CH-NH2), 2.6 (1H, br s, CH-NH2), 1.1–1.5 (4H, m, CH2CH2),
0.9 (9H, s, tBu), 0.8 (6H, s, Me2), 0.0 (6H, s, SiMe2); δC (50 MHz;
CDCl3) 72.1 (CHOH), 71.1 (CH2OSi), 46.9 (CH2NH2), 35.0
(CMe2), 34.5 (CHOHCH2CH2), 29.3 (CHOHCH2CH2), 25.9
(SiCMe3), 24.3 (Me), 23.9 (Me), 18.3 (SiCMe3), Ϫ5.4 (SiMe2);
m/z (EI) 276.2361 (MHϩ, C14H34NO2Si requires 276.2354), 276
(25%), 245 (40), 218 (60).
160.6 (C᎐O), 77.9 (CHO), 71.1 (CH OH), 46.0 (CH NH), 34.7
᎐
2
2
(CMe2), 32.9 (CHOCH2CH2), 29.5 (CHOCH2CH2), 24.0 (Me),
23.8 (Me); m/z (EI) 188.1279 (MHϩ, C9 H18 NO3 requires
188.1286) 188 (50%), 156 (40), 95 (90), 56 (100).
5-[3,3-Dimethyl-4-(trifluoromethylsulfonyloxy)butyl]-1,3-
oxazolidin-2-one 19
A solution of 5-(4-hydroxy-3,3-dimethylbutyl)-1,3-oxazolidin-
2-one 18 (52.0 mg, 0.28 mmol) and triethylamine (30.9 mg, 52
µl, 0.31 mmol) in DCM (5 cm3) was cooled to Ϫ75 ЊC. To this
solution was added trifluoromethanesulfonic anhydride (86.3
mg, 51 µl, 0.31 mmol). The reaction was allowed to stir at this
temperature for 15 min, then allowed to warm to room tem-
perature. The reaction mixture was washed quickly with 0.1 M
hydrochloric acid solution and dried (MgSO4) to yield the
triflate 19 (89 mg, 100%) which was used without further purific-
ation; δH (200 MHz; CDCl3) 6.2–6.4 (1H, br s, NH), 4.5–4.7 (1H,
br m, CHO), 4.2 (2H, s, CH2OTf), 3.6–3.8 (1H, br t, CHNH),
3.1–3.3 (1H, br t, CHЈNH), 1.5–1.8 (2H, br m, CHOCH2CH2),
1.2–1.5 (2H, br m, CHOCH2CH2), 1.0 (6H, s, Me2).
5-{4-[tert-Butyl(dimethyl)silyloxy]-3,3-dimethylbutyl}-1,3-
oxazolidin-2-one 17
A
solution of 6-amino-1-[tert-butyl(dimethyl)silyloxy]-5-
hydroxy-2,2-dimethylhexane 16 (1.27 g, 4.6 mmol) and triethyl-
amine (3.7 g, 5.13 cm3, 37 mmol, 8 mol equiv.) in DCM (12 cm3)
was cooled in an ice bath. To this a solution of methyl chloro-
formate (2.16 g, 2.13 cm3, 27.6 mmol, 6 mol equiv.) was added
dropwise over a period of 30 min, then the mixture was stirred
at room temperature overnight. The reaction mixture was
poured into dilute hydrochloric acid (1 M, 50 cm3), the organic
layer was separated and the aqueous layer was extracted with
DCM. The combined organic layers were washed with 1 M
hydrochloric acid, sodium bicarbonate solution, water, brine,
and dried. Removal of the solvent yielded the intermediate
1-[tert-butyl(dimethyl)silyloxy]-5-hydroxy-2,2-dimethyl-6-
(methoxycarbonylamino)hexane (1.2 g, 75%). A small portion
of the crude product was purified by flash column chrom-
atography (petrol–ethyl acetate, 3:1) to give a colourless oil
2,2-Dimethyl-4-(2-oxo-1,3-oxazolidin-5-yl)butyl(pyridine)bis-
(dimethylglyoximato(1؊)-N,NЈ)cobalt 2a
The title compound 2a was synthesised from bromo(pyridine)-
bis(dimethylglyoximato(1Ϫ)-N,NЈ)cobalt (0.25 g, 0.56 mmol),
dimethylglyoxime (100 mg), sodium borohydride (63 mg, 1.7
mmol) and 5-[3,3-dimethyl-4-(trifluoromethylsulfonyloxy)-
butyl]-1,3-oxazolidin-2-one 19 (89 mg, 0.23 mmol) in ethanol
(20 cm3) in the same manner as 9a. The product was extracted
into DCM and the extracts were washed with water, brine,
and dried (K2CO3). Removal of the solvent and flash column
chromatography (DCM–methanol–pyridine, 95:2.5:0.1) of the
residue, followed by exposure to high vacuum (0.5 mmHg) to
remove traces of pyridine, gave the alkylcobaloxime 2a as a red
solid (110 mg, 75%); νmax (disc)/cmϪ1 3306, 2924 and 1751; δH
(500 MHz; CDCl3) 18.3 (2H, br s, H bonded dmgOH), 8.55
(2H, dd, α-pyridine, J 1.2 and 6.35), 7.72 (1H, tt, γ-pyridine,
J 1.5 and 7.6), 7.32 (2H, m, β-pyridine, J 1.2 and 7.5), 5.34 (1H,
br s, NH), 4.65–4.60 (1H, m, CHO, J 6.8 and 7.3), 3.68 (1H, t,
CHNH, J 8.3), 3.33 (1H, t, CHЈNH, J 7.9), 2.143 (6H, s,
dmgMe2), 2.136 (6H, s, dmgMe2), 1.79 (2H, s, CoCH2), 1.61–
1.68 (1H, m, COCH2CH2), 1.48–1.55 (1H, m, COCHЈ2CH2),
1.28 (1H, m, COCH2CH2), 1.16 (1H, dt, COCH2CHЈ2, J 4.4
1
which was characterised by H NMR; δH (200 MHz; CDCl3),
5.1 (1H, br s, NH), 3.6 (3H, s, OMe), 3.2–3.6 (2H, m, CH2N),
3.2 (2H, s, CH2OSi), 2.9–3.1 (1H, m, CH2OH), 1.1–1.5 (4H, m,
CH2CH2), 0.9 (9H, s, tBu), 0.8 (6H, s, Me2), 0.0 (6H, s, SiMe2).
To a solution of 1-[tert-butyl(dimethyl)silyloxy]-5-hydroxy-
2,2-dimethyl-6-(methoxycarbonylamino)hexane (1.2 g, 3.5
mmol) in tetrahydrofuran (10 cm3) was added sodium hydride
(0.2 g, 7.0 mmol). The reaction mixture was stirred under a
nitrogen atmosphere for 4 h. Saturated ammonium chloride
solution (20 cm3) was added cautiously, then the organic layer
was separated, dried (MgSO4) and the solvent was removed.
The crude product was purified by flash column chroma-
tography (petrol–ethyl acetate, 2:1) to yield the oxazolidinone
17 (0.8 g, 75%) as a colourless solid, mp 85 ЊC; νmax (disc)/cmϪ1
3242, 3159, 2959, 1740 and 1097; δH (200 MHz; CDCl3), 6.25
(1H, br s, NH), 4.4–4.5 (1H, m, CHO, J 7.9), 3.64 (1H, t,
CHNH, J 8.4), 3.20 (1H, t, CHЈNH, J 7.9), 3.20 (2H, s,
CH2OSi), 1.5–1.9 (2H, m, CHOCH2CH2), 1.1–1.5 (2H, m,
t
CHOCH2CH2), 0.9 (9H, s, Bu), 0.8 (6H, s, Me2), 0.0 (6H, s,
and 13.0), 0.74 (6H, s, Me ); δ (125 MHz; CDCl ) 159.8 (C᎐O),
᎐
2 C 3
SiMe2); δC (50 MHz; CDCl ), 160.4 (C᎐O), 77.9 (CHO), 71.2
(CH2OSi), 46.0 (CH2NH), 34.9 (CMe2), 33.1 (CHOCH2CH2),
29.6 (CHOCH2CH2), 25.9 (SiCMe3), 24.2 (Me), 24.0 (Me),
149.3 (α-pyr), 137.4 (γ-pyr), 125.2 (β-pyr), 78.3 (CHO), 45.7
(CH2NH), 41.7 (CoCH2), 36.6 (CHOCH2CH2), 28.2 (Me2),
12.1 (dmgMe4), 9.7 (CHOCH2CH2).
᎐
3
J. Chem. Soc., Perkin Trans. 1, 2000, 4488–4498
4495

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Thermolysis and photolysis of cobaloximes 1a and 1b
manner of 13.30,31 The crude product was purified by column
chromatography (petrol–ethyl acetate, 10:1 to 5:1) to give the
bromo alcohol 20 (0.52 g, 62%) as a colourless oil (Found: C,
43.41; H, 7.94; C7H15OBr requires C, 43.09; H, 7.75%); νmax
(film)/cmϪ1 3550–3200, 2975, 1475, 1390, 1370, 1250 and 1060;
δH (300 MHz; CDCl3) 3.63 (2H, t, CH2OH, J 6.4), 3.87 (2H, s,
CH2Br), 1.88 (1H, br s, OH), 1.44–1.54 (2H, m, CH2), 1.33–1.41
(2H, m, CH2), 0.99 (6H, s, CMe 2); δC (74.5 MHz; CDCl3) 63.4
(CH2OH), 46.5 (CH2Br), 36.02 (CH2), 34.4 (CH2), 27.5 (CMe2),
25.8 (Me2); m/z (EI) 195/197 (MHϩ), 177/179, 115, 97 (100).
Reactions at pH 3 were carried out in 0.1 M aq. acetic acid,
whilst reactions at pH 9 were performed in 0.01 M aq. sodium
tetraborate. Samples for photolysis and thermolysis were pre-
pared by dissolving the cobaloxime (50 mg) in the appropriate
solvent (50 cm3) and deoxygenated by bubbling nitrogen
through the solution for 30 min.
Photolysis. The reaction flask was transferred to a water bath
(15 ЊC) and photolysed at a distance of 2 cm from the light
source (Hanovia medium pressure mercury lamp). Completion
of photolysis at pH 3 was indicated by the absence of any
yellow colour in the solution (about 20 min). Photodecomp-
osition at pH 9 took considerably longer (about 4¹ h) and was
5-Bromo-4,4-dimethylpentanal 21
5-Bromo-4,4-dimethylpentan-1-ol 20 (0.4 g, 2.0 mmol) was
subjected to a pyridinium dichromate oxidation using the
standard procedure.34 Filtration of the residue through a bed of
MgSO4–silica (1:1) and removal of the solvent yielded the
bromo aldehyde 21 (0.3 g, 75%) as a colourless oil; νmax (film)/
cmϪ1 2970, 2740, 1730, 1390, 1370, 1255 and 655; δH (60 MHz;
CCl4) 9.90 (1H, t, CHO), 3.05 (2H, s, CH2Br), 2.30–2.00 (2H,
m, CH2), 1.10–1.60 (2H, m, CH2), 1.00 (6H, s, CMe2); m/z (EI)
193 (35%, MHϩ), 177 (10), 135 (50), 97 (50), 55 (100), 41 (100).
The aldehyde was characterised more fully as the 2,4-
dinitrophenylhydrazone.
¯
²
monitored to completion by TLC.
Thermolysis. The solution was heated at 100 ЊC for 7 h, when
TLC analysis indicated the absence of starting material.
Analysis. Following photolysis or thermolysis the solution
was cooled. For some experiments starting from 1a the solution
was extracted with ether and analysed by GC (comparison with
authentic 4,4-dimethylpentanal 25a). In other experiments
(starting from 1a or 1b) the reaction mixture was poured into
acidic 0.4% 2,4-dinitrophenylhydrazine solution34 (50 cm3) and
stirred for 30 min. The DNP-derivative(s) was extracted into
DCM (3 × 50 cm3). The combined extracts were dried and
evaporated to dryness to give a residue that was purified by
column chromatography on silica (20 g, elution with 2:1
petrol–CH2Cl2). The yellow band of aldehyde-DNP 26a was
collected and the solvent was removed. The residue was taken
up in spectroscopic grade ethanol and the absorbance of the
5-Bromo-4,4-dimethylpentanal 2,4-dinitrophenylhydrazone 22
An acidic solution of 2,4-dinitrophenylhydrazine (0.4 M, 50
cm3) was added to 5-bromo-4,4-dimethylpentanal 21 (20 mg,
0.1 mmol). After stirring at room temperature for 5 h the
derivative was extracted into ethyl acetate (2 × 20 cm3). The
solvent was removed and the DNP derivative purified by
column chromatography (petrol–ethyl acetate, 2:1) to give the
hydrazone 22 as an orange crystalline solid (24 mg, 63%); νmax
(disc)/cmϪ1 3600–3400, 3300, 2850, 1640, 1600, 1540, 1360,
1320, 1260 and 1140; δH (200 MHz; CDCl3) 11.03 (1H, br s,
NH), 9.10 (1H, d, Ph-H, J 2.6), 8.30 (1H, dd, Ph-H, J 2.6 and
9.6), 7.92 (1H, d, Ph-H, J 9.6), 7.56 (1H, t, CH, J 5.2), 3.32 (2H,
s, CH2), 1.09 (6H, s, CMe2); δC (50 MHz; CDCl3) 152.1, 145.2,
138.1, 130.1, 129.1 and 123.6 (Ph), 116.7 (CH), 45.7 (CH2Br),
36.1 (CH2), 34.6 (CH2), 27.8 (CMe2), 25.9 (CMe2).
solution was measured at 359.1 nm (ε 16 000 dm3 molϪ1 cmϪ1
)
to give the yield of the DNP. Starting from 1a, the DNP was
identified as 4,4-dimethylpentanal 2,4-dinitrophenylhydrazone
26a by comparison (1H NMR and TLC) with an authentic
sample. Starting from 1b, the DNP was identified as a mixture
of [1,5-2H2]-4,4-dimethylpentanal 2,4-dinitrophenylhydrazone
26b and 3,3-dimethylbutanal 2,4-dinitrophenylhydrazone 33
by comparison (1H NMR and TLC) with authentic samples
of 33 and the unlabelled compound 26a.
2-(4-Bromo-3,3-dimethylbutyl)-1,3-dioxolane 23
Hydrolysis of the oxazolidinone-cobaloxime 2a and thermolysis
of 2b
5-Bromo-4,4-dimethylpentanal 21 (0.9 g, 4.7 mmol), ethane-
1,2-diol (1.2 cm3, 18.6 mmol) and 2,6-di-tert-butyl-4-methyl-
pyridinium tetrafluoroborate (2 mol%) were heated in refluxing
benzene (12 cm3) under a Dean–Stark trap for 24 h.
Oxazolidinone-cobaloxime 2a (50 mg, 0.09 mmol) was taken up
in aq. lithium hydroxide (1 M, 10 cm3) and stirred in the dark
for 7 days, after which time TLC showed the absence of 2a. The
pH of the solution was adjusted to either 3 or 9 with acetic acid
(1 M), measured with a standardised pH meter, and the volume
was made up to 50 cm3 with water. The solution was degassed
by bubbling with argon for 1 h and processed further in the
manner described for 1a and 1b. The yield of ketone hydrazone
36 was calculated from the weight of the 2,4-dinitrophenyl-
hydrazone produced after removal of solvent in vacuo (0.1
mmHg). The DNP was identified as 5,5-dimethylhexan-2-one
2,4-dinitrophenylhydrazone 36 by comparison (NMR and
TLC) with an authentic sample.
The reaction mixture was cooled and the benzene removed
under reduced pressure. The residue was dissolved in water (50
cm3) and extracted with ether (2 × 25 cm3). The ether layer was
washed with water (25 cm3), dried (MgSO4) and the solvent
removed. The residue was purified by column chromatography
(petrol–ethyl acetate, 10:1) to give the bromo acetal 23 (0.8 g,
75%) as a colourless oil (Found: C, 45.98; H, 7.26; C9H17O2Br
requires C, 45.75; H, 7.25%); νmax (film)/cmϪ1 2965, 2880, 1470,
1410, 1390, 1370, 1230, 1140, 1050 and 1030; δH (300 MHz;
CDCl3) 4.77 (1H, t, CH, J 4.6), 3.90 and 3.79 (4H, 2 m, OCH2-
CH2O), 3.22 (2H, s, CH2Br), 1.52–1.57 (2H, m, CH2), 1.37–1.43
(2H, m, CH2), 0.95 (6H, s, CMe2); δC (75.5 Hz; CDCl3) 104.7
(CH), 64.9 (CH2O), 46.2 (CH2Br), 34.1 (CH2), 33.8 (CH2), 27.8
(CMe2), 25.6 (CMe2); m/z (EI) 235.0342 (M Ϫ Hϩ, C9H16O279Br
requires 235.0334) 235/237, 209/211, 135/137, 73 (100%).
The aqueous layer from preparation of 2,4-dinitrophenyl-
hydrazone was basified to pH 14 and distilled. The distillate
was made up to a known volume of water and aliquots
were analysed for ammonia using the Nessler method,35
by measuring the absorbance at 525 nm.
2-(3,3-Dimethylbutyl)-1,3-dioxolane 24
5-Bromo-4,4-dimethylpentan-1-ol 20
2-(4-Bromo-3,3-dimethylbutyl)-1,3-dioxolane 23 (0.1 g, 0.4
mmol), triphenyltin hydride (0.2 cm3, 0.8 mmol) and a trace of
AIBN were dissolved in d6-benzene (0.3 cm3) and sealed in an
NMR tube under nitrogen. The tube was placed in a water bath
at 45 ЊC and the reaction monitored by the disappearance
The borane-tetrahydrofuran complex was assayed prior to use
by reaction with glycerol in a gas burette.
Hydroboration of 5-bromo-4,4-dimethylpent-1-ene 6a (0.78
g, 4.5 mmol) in tetrahydrofuran (4 cm3) was prepared in the
4496
J. Chem. Soc., Perkin Trans. 1, 2000, 4488–4498

View Article Online
of the CH2Br resonance at 3.20 ppm in the 1H NMR spectrum
(60 MHz).
phenylhydrazone 33 in the manner of 22 for spectroscopic iden-
tification;37 δH (200 MHz; CDCl3) 11.30 (cis) and 11.08 (trans)
(1H, br s, NH), 9.15 (1H, d, Ph-H, J 2.7), 8.32 (1H, dd, Ph-H,
J 2.3 and 9.5), 7.98 (cis) and 7.96 (trans) (1H, d, Ph-H, J 9.5),
7.59 (trans, J 6.29) and 7.09 (cis, J 5.89) (1H, t, CH), 2.34 (trans,
J 6.27) and 2.29 (cis, J 5.98) (2H, d, CH2), 1.12 (cis) and 1.05
(trans) (9H, s, Me3).
After 5¹ h the reaction mixture was poured into water
¯
²
(10 cm3) and the product extracted into petrol (2 × 5 cm3). The
residue was purified by column chromatography (petrol–ethyl
acetate, 10:1) to give the acetal 24 (45 mg, 67%) as a colourless
oil; νmax (film)/cmϪ1 2957, 2868, 1475, 1394, 1365, 1298, 1209,
1047 and 988; δH (300 MHz; CDCl3) 4.74 (1H, t, CH, J 4.8),
3.85–3.93 (2H, m, CH2O), 3.76–3.80 (2H, m, CH2O), 1.53–1.60
(2H, m, CH2), 1.21–1.26 (2H, m, CH2), 0.82 (9H, s, CMe3);
δC (75.5 MHz; CDCl3) 105.5 (CH), 65.0 (CH2O), 38.0 (CH2),
30.1 (CH2), 29.4 (CMe3), 29.3 (CMe3); m/z (EI) 159 (M-Hϩ),
115, 97, 73, 59 (100%).
5,5-Dimethylhexan-2-one 3538
Grignard coupling38,39 of tert-butyl chloride (23.5 g, 0.3 mmol)
to methyl vinyl ketone (7.0 g, 0.1 mol) in ether (40 cm3),
followed by fractional distillation through a short Vigreux
column at 35 mmHg gave the ketone 35 (1.8 g, 14%); bp 69 ЊC
(35 mmHg) (lit.38 71–72 ЊC at 35 mmHg); νmax (film)/cmϪ1 2957,
2868, 1718 and 1365; δH (200 MHz; CDCl3) 2.34 (2H, t,
4,4-Dimethylpentanal 25a
CH2CO, J 8.1), 2.10 (3H, s, Me), 1.42 (2H, t, Me3CH2
J
2-(3,3-Dimethylbutyl)-1,3-dioxolane 24 (0.1 g, 0.6 mmol) was
dissolved in aq. THF (0.4 cm3 THF, 0.6 cm3 H2O) and Dowex
50W ion-exchange resin added. The mixture was stirred at
room temperature for 24 h.
8.1), 0.83 (9H, s, Me3); δC (50 MHz; CDCl ) 209 (C᎐O), 39.5
᎐
3
(CH2CO), 37.4 (Me), 29.9 (Me3CH2), 29.1 (Me3); m/z (EI)
128.1199 (Mϩ, C8H16O requires 128.1201), 128 (18%).
The corresponding hydrazone 3637 was synthesised from 35
in the manner of 22; νmax (disc)/cmϪ1 3323, 3109, 2957, 2866,
2108, 1628, 1506 and 1336; δH (200 MHz; CDCl3) 11.2 (trans)
and 11.0 (cis) (1H, br s, NH), 9.12 (1H, d, Ph-H, J 2.6), 8.27
(1H, dd, Ph-H, J 2.2 and 9.6), 7.95 (1H, d, Ph-H, J 9.6), 7.48
(trans) and 6.91 (cis) (1H, t, CH, J 5.37), 2.31–2.42 (2H, m,
CH2CN), 2.13 (cis) and 2.05 (trans) (3H, s, Me), 1.40–1.45
(2H, m, Me3CH2), 0.99 (cis) and 0.95 (trans) (9H, s, Me3); m/z
(EI) 308.1489 (Mϩ, C14H20N4O4 requires 308.1484), 380 (26%,
Mϩ) 251 (35), 237 (5).
TLC indicated the absence of starting material and the
formation of a DNP positive product. The reaction mixture
was extracted with ether (2 × 1 cm3) and the ether removed
by careful distillation through a Vigreux column, followed by
distillation of the product. GC analysis of the distillate and
residue indicated a clean formation of 4,4-dimethylpentanal.
The aldehyde was further characterised by the preparation of
the 2,4-dinitrophenylhydrazone 26a in the manner of 22;
δH (200 MHz; CDCl3) 11.01 (1H, br s, NH), 9.14 (1H, d, Ph-H,
J 2.6), 8.30 (1H, dd, Ph-H, J 2.6 and 9.6), 7.96 (1H, d, Ph-H,
J 9.6), 7.57 (1H, t, CH, J 5.2), 2.40–2.50 (2H, m, CH2), 1.40–
1.50 (2H, m, CH2), 0.96 (9H, s, CMe3); m/z (EI) 294.1315 (Mϩ,
C13H18N4O4 requires 294.1328), 278, 180 (100%).
Acknowledgements
We thank the EPSRC for support and Mr E. Hart for technical
assistance.
4-(2,2-Dimethylpropyl)-2,2-dimethyl-1,3-dioxolane 27
Under a nitrogen atmosphere, tributyltin hydride (1.2 cm3, 4.5
References
mmol) was added to
a
solution of 4-(3-bromo-2,2-
dimethylpropyl)-2,2-dimethyl-1,3-dioxolane (0.51 g, 2.0 mmol)
in benzene (5 cm3) and the solution was heated at reflux for 20
h. The solvent was removed and the reaction mixture was dis-
tilled under reduced pressure to yield acetal 27 as a colourless
oil (0.28 g, 81%); νmax (film)/cmϪ1 2870–2986 s, 1157 and 1067;
δH (300 MHz; CDCl3) 4.15 (1H, m, CH), 4.04 (1H, dd, CH2O,
J 7.8 and 5.7), 3.42 (1H, t, CH2O, J 7.8 and 7.8), 1.65 (1H, dd,
CH2, J 14.0 and 5.9), 1.40 (1H, dd, CH2, J 14.0 and 8.1), 1.39
(3H, s, Me), 1.36 (3H, s, Me), 0.94 (9H, s, CMe3); δC (50 MHz;
CDCl3) 108.2 (CMe2), 73.9 (CH), 70.9 (CH2O), 47.4 (CH2), 30.1
(CMe2), 30.0 (Me3), 27.1 (Me), 26.1 (Me); m/z (EI) 173 (MHϩ),
158, 157, 142.
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4,4-Dimethylpentane-1,2-diol 2836
4 B. M. Babior, BioFactors, 1988, 1, 21.
A solution of 4-(2,2-dimethylpropyl)-2,2-dimethyl-1,3-dioxo-
lane (0.17 g, 1.0 mol) in methanol (10 cm3) and acetyl chloride
(0.35 cm3) was protected from moisture and heated at reflux for
4 h. The extent of reaction was followed by TLC. Removal
of the solvent yielded sufficiently pure diol 28 (0.12 g, 90%).
A small amount was distilled for analysis using a Kugelrohr
distillation apparatus; bp 90 ЊC at 0.4 mmHg (lit.37 bp 83–86 ЊC
at 0.1 mmHg); νmax (film)/cmϪ1 3360 br, 2870–2950, 1160 and
1089; δH (200 MHz; CDCl3) 3.84 (1H, br m, CHOH), 3.54 (1H,
br m, CH2OH), 3.40 (1H, br m, CHЈ2OH), 1.32 (2H, br m,
CH2), 0.96 (9H, s, Me3); δC (50 MHz; CDCl3) 70.1 (CHOH),
68.1 (CH2OH), 46.9 (CH2), 30.1 (CMe3), 30.1 (Me3); m/z (EI)
265 (M2Hϩ), 133, 115, 101, 57 (100%).
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3,3-Dimethylbutanal 3237
3,3-Dimethylbutan-1-ol was subjected to a pyridinium dichro-
mate oxidation using the standard procedure34 to give the
aldehyde 32 which was converted into its 2,4-dinitro-
J. Chem. Soc., Perkin Trans. 1, 2000, 4488–4498
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