Synthetic use of the primary kinetic isotope effect in hydrogen atom transfer 2: Generation of captodatively stabilised radicals

Article abstract of DOI:10.1039/c3ob40275d

Using C-3 di-deuterated morpholin-2-ones bearing N-2-iodobenzyl and N-3-bromobut-3-enyl radical generating groups, only products derived from the more stabilised C-3, rather than the less stabilised C-5 translocated radicals, were formed after intramolecu

Full text of DOI:10.1039/c3ob40275d

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Synthetic use of the primary kinetic isotope effect in
hydrogen atom transfer 2: generation of captodatively
stabilised radicals
Cite this: Org. Biomol. Chem., 2013, 11,
2712
Mark E. Wood,*a Sabine Bissiriou,a Christopher Loweb and Kim M. Windeatta
Received 6th February 2013,
Accepted 4th March 2013
Using C-3 di-deuterated morpholin-2-ones bearing N-2-iodobenzyl and N-3-bromobut-3-enyl radical gen-
erating groups, only products derived from the more stabilised C-3, rather than the less stabilised C-5
translocated radicals, were formed after intramolecular 1,5-hydrogen atom transfer, suggesting that any
kinetic isotope effect present was not sufficient to offset captodative stabilisation.
DOI: 10.1039/c3ob40275d
www.rsc.org/obc
Introduction
Radical-based hydrogen atom abstraction, particularly when
carried out in an intramolecular sense, offers potentially the
most straightforward and direct method for the functionalisa-
tion of otherwise “unreactive” carbon–hydrogen bonds.1
A
combination of kinetic and thermodynamic factors contribute
towards determining the regioselectivity of such a process and
for abstraction by highly reactive carbon-centred radicals such
as vinyl and aryl, the process is generally most efficient for the
Scheme 1 1,5-Hydrogen vs. 1,5-deuterium transfer in the generation of pyrro-
lidin-2-yl radicals.3,4
formation of a thermodynamically stable (e.g. tertiary alkyl2) radicals derived from the proteinogenic amino acids6 has been
product radical, presumably via a low energy transition state, a topic of discussion for some considerable time and steric,
appearing at a late stage in the reaction coordinate. For the conformational and polar effects must all be considered in
successful use of radical-based remote functionalisation in assessing such radical stability.7,8 Despite some examples
synthetic procedures, regiochemical control is vital and in an which suggest evidence to the contrary,9 it is still generally
attempt to address this key issue, we have recently reported accepted that overall, they can be subject to so-called “capto-
preliminary studies into the extent to which the primary dative” stabilisation.10 Depending on the other nitrogen sub-
kinetic isotope effect exerted by deuterium can be used to stituents, this can be regarded as either a synergistic or
block such hydrogen atom transfer in a synthetic context.3,4 additive stabilising effect, resulting from the electron donating
Despite the additional stability conferred by the adjacent nitro- and withdrawing abilities of the adjacent nitrogen atom and
gen atom5 (which might be expected to reduce selectivity), a carbonyl groups respectively (Fig. 1).
significant kinetic isotope effect was still observed for the
abstraction of hydrogen vs. deuterium in the formation of erated morpholin-2-ones 1 and 2 (Fig. 2), which combine the
pyrrolidin-2-yl radicals (Scheme 1).4
structural features of both a simple tertiary amine and an
The ideal substrates for our proposed studies were di-deut-
As the next logical step in exploring this methodology, we α-amino acid (glycine). When subjected to standard tin
chose to investigate the extent to which the kinetic isotope hydride-based radical dehalogenation conditions, the resulting
effect can compete with product radical stability when the radi- aryl or vinyl radical intermediates would be optimally posi-
cals produced by hydrogen atom abstraction or, more correctly, tioned to abstract either hydrogen, to generate a straight-
the transition states leading to them, could potentially be forward α-aminoalkyl radical (3 or 5) at C-5 or deuterium to
more highly stabilised. The stability of α-carbon-centred
aBiosciences, College of Life and Environmental Sciences, University of Exeter,
Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK.
E-mail: m.e.wood@exeter.ac.uk; Tel: +44 (0)1392 723450
bUCB Celltech, 208 Bath Road, Slough SL1 3WE, UK
Fig. 1 Captodative stabilisation of amino acid α-radicals.
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Fig. 2 Deuterated morpholin-2-one substrates for hydrogen atom abstraction
Scheme 3 Morpholin-2-one preparation by nucleophilic addition/pinacol
rearrangement. Reagents and conditions: glyoxal (40% w/w in H2O, 0.9 equiv.),
4-toluenesulfonic acid (0.5 equiv.), C6H6, 80 °C (–H2O), 72 h, (59%).
experiments.
Scheme 4 Attempted introduction of deuterium via hydrogen/deuterium
exchange. Reagents and conditions: NaOCD3 (up to 5 equiv.), CD3OD (excess), rt.
mixture of the C-3 deuterated morpholin-2-one 1 along with
varying quantities (depending on the reaction duration) of the
ring-opened, deuterated transesterification product
(Scheme 4).14
9
Although 9 could be re-cyclised to 1 by heating in the pres-
ence of 4-toluenesulfonic acid, we were never able to achieve a
level of α-deuteration greater than 50%, even when using up to
5 equiv. of sodium methoxide-d3 with extended reaction times,
in the exchange step. This approach to deuterium incorpor-
ation was therefore, abandoned.
A minor modification to the general procedure reported by
Kashima and Harada,15 combining 2-(2-iodobenzylamino)-
ethanol 7 and methyl bromoacetate-2,2-d2 10 (99.5 atom% D)‡
in the presence of Hünig’s base was successful however, giving
deuterated morpholin-2-one 1 in 64% yield (based on 7,
Scheme 5).
Scheme 2 Competition between radical stability and primary kinetic isotope
effect.
Radical precursor 2 was also prepared using a similar metho-
dology. Firstly, ethanolamine was N-monoalkylated using 3-bro-
mobut-3-enyl methanesulfonate 114,17 and the morpholin-2-one
moiety was constructed as before, from secondary amine 12,
using methyl bromoacetate-2,2-d2 10 (99.5 atom% D)‡
(Scheme 6). The non-deuterated analogue of the morpholin-
2-one 13 was also prepared from 12 using an identical
methodology.
Radical reactions were firstly attempted with the non-deut-
erated morpholin-2-one 8 in order to assess the effectiveness
and regioselectivity of 1,5-hydrogen atom transfer in this
system. Reduction of a 42 mM solution of 8 in benzene at
reflux, with 1.5 equiv. of tributyltin hydride, was carried out
using AIBN as the initiator. Only one morpholin-2-one
produce a potentially captodatively stabilised amino acid
α-radical (4 or 6) at C-3 (Scheme 2). Substrate 2 also contains
an intramolecular alkene trap for possible 5-exo trig cyclisation
of either intermediate translocated radical (5 or 6).
Our initial approach to the preparation of the required deut-
erated substrates 1 and 2 was based around the use of hydro-
gen/deuterium exchange11 for introduction of the isotope labels.
2-(2-Iodobenzylamino)ethanol 712 was treated with glyoxal in the
presence of 4-toluenesulfonic acid (under dehydrating con-
ditions) to give the required unlabelled morpholin-2-one 8 via
nucleophilic addition/pinacol rearrangement (Scheme 3).13
Exposure of 8 to a large excess of methanol-d4 in the pres-
ence of varying quantities of sodium methoxide-d3† gave a
†Prepared by the careful addition of the appropriate quantity of sodium to the
‡Prepared from acetic acid-d4 (99.5 atom% D) via Hell–Volhard–Zelinsky reac-
tion followed by esterification.16
cooled (0 °C) methanol-d4 solvent (99.8 atom% D).
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Scheme 5 Morpholin-2-one 1 preparation using methyl bromoacetate-2,2-d2
Scheme 8 1,5-Hydrogen atom transfer to give the more stable intermediate
radical 16.
i
10. Reagents and conditions: 10 (1.2 equiv.), Pr2EtN (3.9 equiv.), CH3CN, 0 °C to
reflux, 14 h (64%).
Fig. 3 Possible products from reduction of 8 with Bu3SnH (17) or Bu3SnD
(18, 19, 20).
Scheme 6 Preparation of morpholin-2-ones bearing an N-3-bromobut-3-enyl
i
substituent. Reagents and conditions: (a) ethanolamine (2.8 equiv.), Pr2EtN (3.0
equiv.), CH3CN, 18 h (56%); either, for 2: methyl bromoacetate-2,2-d2 10 (0.85
i
equiv.), Pr2EtN (3.3 equiv.), CH3CN, reflux, 12 h (82%) or for 13: methyl bromo-
acetate (1.7 equiv.), Hünig’s base (3.3 equiv.), CH3CN, reflux, 12 h (77%).
and slow addition of the reducing agents had no discernible
effect on the outcome of this process. 1H and 13C NMR spectra
suggested that the dimer 14 was formed exclusively as a single
diastereoisomer in all of these reactions but unfortunately, we
were not able to determine the relative stereochemistry.
Given the known reactivity of amino acid α-radicals towards
allylstannanes in intramolecular SH2′-type reactions,18 we also
attempted to intercept intermediate radical 16 with both allyl-
tributyltin and (2-methylallyl)tributyltin, the latter being
known to show high reactivity towards similar, potentially elec-
trophilic radicals.19 With a substrate concentration of 42 mM
in benzene, treatment of 8 with allyltributyltin (1.2 equiv.) and
(2-methylallyl)tributyltin (1.0 equiv.), with thermal radical
initiation using AIBN however, gave none of the possible SH2′
reaction products. Again, the dimeric species 14 proved to be
the only isolable product (in 75% yield in both cases) contain-
ing a morpholin-2-one moiety. Unsurprisingly, exposure of
radical precursor 8 to hexabutyldistannane (1.0 equiv.) under
identical reaction conditions also gave 14 in 92% isolated yield
(Scheme 7).
Reasoning that intramolecular trapping of an α-amino acid-
derived radical such as that in intermediate 16 should be
entropically more favourable and hence, more rapid than inter-
molecular trapping, we also attempted the reduction of N-3-
bromobut-3-enyl morpholinone radical precursor 13 with tri-
butyltin hydride. 92–94 mM solutions of 13 in benzene were
reduced with tributyltin hydride (1.1 equiv.) in the presence of
AIBN, at both 80 °C (thermal initiation) and 25 °C (with photo-
chemical initiation using a medium pressure mercury vapour
lamp) but both reactions gave the dimeric product 21 in low
(30 and 16% respectively) yields as the only morpholin-2-one-
containing product. As for dimer 14, the product appeared to
be a single diastereoisomer but again, we were unable to
Scheme 7 Tributyltin hydride-mediated reduction of morpholin-2-one 8 and
reactivity towards allylstannanes and hexabutyldistannane. Reagents and con-
ditions: either Bu3SnH (1.5 equiv.), AIBN, C6H6, reflux, 14 h (60%) or Bu3SnD (1.5
equiv.), AIBN, C6H6, reflux, 14 h (63%). Allyltributyltin (1.2 equiv.), (2-methylallyl)-
tributyltin (1.0 equiv.) of hexabutyldistannane (1.0 equiv.), AIBN, C6H6, reflux,
14 h (75% with allyltributyltin, 92% with (2-methylallyltributyltin and 92% with
hexabutyldistannane).
containing product, the symmetrical dimer 14, was obtained
(in 60% isolated yield) from this reaction (Scheme 7). An iden-
tical result was also obtained using tributyltin deuteride with,
as expected, no deuterium incorporation into the dimeric
bimorpholine-2,2′-dione product 14. These results suggested
complete regioselectivity in the intramolecular hydrogen atom
transfer with intermediate aryl radical 15, to produce the more
highly stabilised radical intermediate 16, which subsequently
dimerised (Scheme 8).
Interestingly, none of the possible straightforward
reduction products 17–20 (Fig. 3) were found in either of the
reactions carried out§ and substrate 8 concentration changes
§Tlc analysis of the crude radical reaction products with an authentic sample of
17 for comparison, gave no indication of the presence of these monomeric
reduction products.
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Fig. 4 Comparison of non-bonding/steric destabilisation of alanine and
glycine α-radicals.
Scheme 9 Reduction of 4-(3-bromobut-3-enyl)morpholin-2-one 13 with tribu-
tyltin hydride. Reagents and conditions: either Bu3SnH (1.1 equiv.), AIBN, C6H6,
reflux, 6 h (30%) or Bu3SnH (1.1 equiv.), AIBN, C6H6, 25 °C with UV irradiation,
6 h (16%) or Bu3SnCl (0.1 equiv.), NaBH3CN (2.0 equiv.), AIBN, tBuOH, reflux,
18 h (16%).
determine the relative stereochemistry. A similar reaction
using in situ generation of tributyltin hydride from tributyltin
chloride and sodium cyanoborohydride also resulted in a poor
yield of 21 (16%) and the outcome of all of the three reduction
reactions showed no apparent dependence on N-3-bromobut-3-
enyl morpholinone substrate 13 concentration (Scheme 9).
From these experiments, the overwhelming preference for
C-3 radical (e.g. 16) formation via 1,5-hydrogen atom transfer
was clear, with no products being obtained from the corres-
ponding C-5 radical in any of the experiments. Assuming that
the hydrogen atom abstraction is a kinetically controlled
process, this suggests substantial stabilisation of a late tran-
sition state, ultimately consistent with captodative stabilisation
of the resulting C-3 (e.g. 16) radical. The dimerisation of
amino acid α-radicals, including other structurally similar
morpholin-2-one-3-yl radicals is a well-established process.20,21
But although alkylation and allylation is certainly possible,18,21
the lack of formation of any such products from the inter- and
intramolecular trapping reactions described above reinforce
the idea of substantial C-3 radical stabilisation in morpholin-
2-one systems.
Fig. 5 Alanine α-radical precursors.
Scheme 10 Tributyltin deuteride/hydride-mediated reduction of morpholin-2-
one 24. Reagents and conditions: either Bu3SnD (1.6 equiv.), AIBN, C6H6, reflux,
12 h (89%) or Bu3SnH (1.6 equiv.), AIBN, C6H6, 25 °C with UV irradiation, 12 h
(59%).
The same product 26 was also obtained (in 59% yield) from a
similar reduction of 24 with 1.6 equiv. of tributyltin hydride at
25 °C, with photochemical cleavage of the chemical initiator
AIBN (Scheme 10).
In comparison, reduction of the N-3-bromobut-3-enyl mor-
pholinone substrate 25 with 1.1 equiv. of tributyltin hydride,
gave an apparent single diastereoisomer of the now expected
dimer 27 but as the minor component in an inseparable
mixture (1.0 : 1.2 ratio) with the straightforward reduction
product 28 (Scheme 11). There was however, no evidence of
the possible 5-exo-trig cyclisation products (29 and 30, Fig. 6)
which could have been formed from the possible intermediate
C-3 and C-5 radicals, resulting from 1,5-hydrogen atom
For di- and polypeptides containing both glycine and
alanine residues, a preference has been observed for hydrogen
abstraction at the α-position of the glycine, rather than the
alanine residue(s).20,22 This effect has been attributed to non-
bonding/steric interactions imposed by amide bonds, prevent-
ing alanine α-radicals 22 achieving the planarity required for
the most effective captodative stabilisation. This effect is sig-
nificantly lessened however, in the case of the corresponding
glycine α-radicals 23 (Fig. 4).23,24 Assuming that this should be
less of an issue with N-alkylated amino acids rather than
amides, we also examined intramolecular hydrogen atom
transfer in the racemic morpholin-2-one radical precursors 24
and 25, prepared from 7 and 12 (in 50 and 82% yields respect-
ively) using ( )-methyl bromopropionate (Fig. 5).
Reduction of a 40 mM solution of 24 in benzene with 1.6
equiv. of tributyltin deuteride at 80 °C, gave the dimeric bimor-
pholine-2,2-dione 26 as the exclusive morpholin-2-one-contain-
ing product, in 89% yield. (Again, 1H NMR suggested the
product to be a single diastereoisomer of indeterminate stereo-
chemistry.) No deuterium-containing products could be ident-
Scheme 11 Reduction of morpholin-2-one 25 with tributyltin hydride.
Reagents and conditions: Bu3SnH (1.1 equiv.), AIBN, C6H6, reflux, 6 h (27, 29%;
28, 17%).
2
ified in the H NMR spectrum of the crude reaction product.
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Fig. 6 Possible 5-exo-trig cyclisation products (not formed).
Scheme 12 Reduction of 4-(2-iodobenzyl)-3,3-dideuteromorpholin-2-one
1
with tributyltin hydride. Reagents and conditions: either Bu3SnH (1.5 equiv.),
AIBN, C6H6, reflux, 6 h (68%) or Bu3SnH (1.5 equiv.), AIBN, C6H6, 25 °C with UV
irradiation, 6 h (59%) or Bu3SnH (1.5 equiv.), AIBN, C6H5F, −50 °C with UV
irradiation, 5 h (59%).
Fig. 7 Valine substrates used in bromination/chlorination experiments.25
transfer. (Morpholin-2-one 28 was identified by comparison of
the 1H and 13C NMR spectra of the inseparable product
mixture and an authentic sample, prepared from 2-(but-3-enyl-
amino)ethanol and ( )-methyl 2-bromopropionate using the
same procedure as for the preparation of 25.)
With a clear selectivity having been observed for formation
of the more stable morpholin-2-one C-3 radical rather than the
C-5 alternative in intramolecular hydrogen 1,5-hydrogen atom
transfer, we turned our attention to the C-3 di-deuterated sub-
strates 1 and 2. Using N-benzoylvaline derivatives 31–33
(Fig. 7), Easton et al. observed a primary kinetic isotope effect
for radical-based α-bromination of 32 with N-bromosuccini-
mide but no significant isotope effect for bromination at the
β-position in 33. Conversely, the corresponding use of sulfuryl
chloride revealed a significant kinetic isotope effect for
β-chlorination in 33 but no isotope effect for α-chlorination in
32.25 These results led to the conclusion that less stable radi-
cals (the 3° β-radical in the case of valine) are more likely to be
formed by hydrogen atom transfer if electrophilic radicals
such as chlorine atoms are involved in the abstraction process
and there is little development of radical character in the tran-
sition state. Less electrophilic radicals such as bromine atoms
and a later, more stable transition state should give rise to pre-
ferential formation of the most stable radical.
Scheme 13 Reduction of 4-(3-bromobut-3-enyl)-3,3-dideuteromorpholin-2-
one 2 with tributyltin hydride. Reagents and conditions: either Bu3SnH (1.1
equiv.), AIBN, C6H6, reflux, 6 h (59%) or Bu3SnH (1.1 equiv.), AIBN, 25 °C with
UV irradiation, 6 h (6%) or Bu3SnH (1.1 equiv.) added over 1 h, AIBN, C6H6,
25 °C with UV irradiation, 6 h total (20%) or Bu3SnCl (0.1 equiv.), NaBH3CN
(2.0 equiv.), AIBN, tBuOH, 80 °C, 18 h (29%).
as the solvent at both 80 and 25 °C and fluorobenzene at
−50 °C. All three reactions gave the symmetrical di-deuterated
dimer 34 as the sole product containing a morpholin-2-one
moiety, in yields of 68–59% (Scheme 12).
Likewise, the corresponding C-3 linked bimorpholine-2,2′-
dione 35 was obtained (in 59% yield) as the exclusive, detect-
able morpholin-2-one derived product from a tributyltin
hydride-mediated reduction of radical precursor 2, carried out
at 80 °C, even at a lower substrate 2 concentration than used
in previous experiments (9.5 mM). Lowering of the reaction
temperature to 25 °C only resulted in a substantial lowering of
the yield of 35 to 6% and both slow addition of tributyltin
hydride at 25 °C and in situ generation of the reducing agent
(at 80 °C) gave similar results with again, no evidence for for-
mation of either of the possible 5-exo-trig radical cyclisation
products under any of these conditions (Scheme 13).
Hammett ρ+ values obtained for homolytic aromatic substi-
tution reactions, suggest that sp2 aryl radicals are nucleophilic
in character26 and the selectivity for C-3 rather than C-5 radical
formation during hydrogen transfer in morpholin-2-ones
observed in the reactions described above suggested a late,
product radical-like transition state for C-3 hydrogen removal
in the morpholin-2-ones. A combination of these factors
would therefore, be expected to offset any primary kinetic
isotope effect in intramolecular hydrogen atom transfer reac-
tions involving substrates 1 and 2 and this is indeed what we
observed.
The C-3 di-deuterated N-2-iodobenzyl morpholin-2-one 1
was reduced with 1.5 equiv. of tributyltin hydride at a substrate
1 concentration of 42 mM. As before, AIBN was used as the
radical initiator, with thermal decomposition at 80 °C and
photochemical initiation at 25 and −50 °C. Benzene was used
Conclusions
Our previously reported studies showed that in cases where
the resulting carbon-centred radical (or the transition state
leading to it) is not highly stabilised, deuterium can effectively
block intramolecular hydrogen atom transfer to an extent that
could potentially be usable in synthetic applications.4 In the
studies presented here, we have shown using competition
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experiments, that when the translocated radical thus formed 2-(2-iodobenzylamino)ethanol 7 (600 mg, 2.2 mmol) and N,N-
can be captodatively stabilised, any kinetic isotope effect that diisopropylethylamine (1.50 cm3, 8.6 mmol) in acetonitrile
may be present is offset by radical stabilisation. These results (14 cm3) at 0 °C. The resulting solution was then stirred and
echo those obtained in similar radical-based reactions which heated under reflux for 14 h, before evaporation of the solvent
involve intermolecular hydrogen atom transfer.25
in vacuo and the addition of diethyl ether (5 cm3). After stirring
Our results serve to emphasise the care that must be taken the mixture for 5 min, the precipitated amine salt was
in interpreting mechanistic studies that use kinetic isotope removed by filtration and the filter cake was washed a further
effect data, particularly in cases where such an effect is appa- three times with diethyl ether (3 × 5 cm3). The combined
rently not observed. Recently, there has been renewed interest organic extracts were dried (magnesium sulfate) then filtered
in attempts to improve the pharmacokinetic properties of and the solvent was evaporated in vacuo, the resulting residue
certain drugs via deuteration.27 If the design and use of such being purified by flash chromatography on silica gel (80% pet-
labelled pharmaceuticals is to be effective, it will be vital to roleum ether–20% ethyl acetate) to give the title compound
have a full mechanistic understanding of the fundamental (450 mg, 64%) as a white solid (Found MH+ (ES+) 320.0112,
chemical processes involved in their metabolism and these C11H10D2INO2 requires 320.0111); mp 63–65 °C; νmax(thin
studies highlight some of the considerations that need to be film)/cm−1 2950–2800 (w) (C–H), 1736 (s) (CvO), 1500 (w) and
made regarding straightforward radical processes in this 613 (m); δH (300 MHz; CDCl3) 2.78 (2H, t, J = 6, NCH2CH2),
context.
3.63 (2H, s, arylCH2), 4.42 (2H, t, J = 6, CH2O), 7.01 (1H, m,
Overall therefore, it is clear that deuterium is unlikely to be arylCH), 7.35 (2H, m, 2 × arylCH) and 7.88 (1H, d, J = 6,
generally effective as a “protecting group” to prevent unwanted arylCH); δD (61.4 MHz; CHCl3) 3.35 (s, NCD2C(O)); m/z
hydrogen atom removal if a highly stabilised radical results 320 (5%), 319 (M+, 12), 217 (23), 148 (100), 134 (22), 127 (13),
from this process.
93 (2), 92 (10), 91 (18), 90 (24), 89 (30), 63 (12) and 44 (39); m/z
(CI) 321 (10%), 320 (MH+, 100), 224 (8), 195 (12), 194 (92),
193 (10), 134 (12) and 106 (14).
4-(3-Bromobut-3-enylamino)ethanol
(12). Ethanolamine
Experimental
General experimental
(740 μl, 12.3 mmol) and N,N-diisopropylethylamine (2.32 cm3,
13.3 mmol) were added sequentially to a stirred solution of
3-bromobut-3-enyl methanesulfonate 114 (1.00 g, 4.4 mmol) in
For full general experimental details, see ref. 4.
4-(2-Iodobenzyl)morpholin-2-one (8). Glyoxal (40% w/w acetonitrile (22 cm3). The stirred mixture was heated at reflux
solution in water, 870 μl, 7.6 mmol) was added to a solution of for 18 h and the solvent was removed in vacuo. Diethyl ether
2-(2-iodobenzylamino)ethanol
7
(2.30 g, 8.3 mmol) and (8 cm3) was added to the resulting residue and after stirring
4-toluenesulfonic acid monohydrate (790 mg, 4.2 mmol) in the solution/suspension for 5 min, the precipitated amine salt
benzene (50 cm3), which was stirred and heated under reflux, was removed by filtration and the filter cake was washed a
using a Dean-Stark apparatus for 72 h. The solvent was evapor- further three times with diethyl ether (3 × 8 cm3). The com-
ated in vacuo and the resulting residue was partitioned bined organic extracts were evaporated to dryness in vacuo and
between ethyl acetate (60 cm3) and saturated aqueous sodium the resulting residue was purified by flash chromatography on
bicarbonate solution (20 cm3). The separated organic phase silica gel (80% diethyl ether–20% methanol) to give the title
was washed with water (3 × 20 cm3) and saturated aqueous compound (479 mg, 56%) as a colourless syrup (Found MH+
sodium chloride solution (20 cm3), then dried (magnesium (CI) 194.0173, C6H1379BrNO requires 194.0181); νmax(thin
sulfate), filtered and the solvent evaporated in vacuo. The film)/cm−1 3400 (br s) (OH, NH), 3018–2619 (m) (C–H), 1632
residue was purified by flash chromatography on silica gel (m), 1538 (w), 1462 (w), 1372 (w), 1310 (w), 1198 (w), 1146 (w),
(80% petroleum ether–20% ethyl acetate) to give the title com- 1119 (w) and 895 (w); δH (300 MHz; CDCl3) 2.03 (2H, br s, OH
pound (1.42 g, 59%) as a cream-coloured solid (Found MH+ and NH), 2.60 (2H, t, J = 6, C(Br)CH2), 2.77 (2H, t, J = 5,
(ES+) 317.9984, mp 64–65 °C; C11H13INO2 requires 317.9985); NCH2CH2OH), 2.84 (2H, t, J = 6, C(Br)CH2CH2N), 3.64 (2H, t,
mp 64–65 °C; νmax(thin film)/cm−1 2950–2800 (w) (C–H), J = 5, CH2OH), 5.48 (1H, d, J = 2, CH2vC) and 5.65 (1H, d,
1736 (s) (CvO), 1500 (w) and 613 (m); δH (300 MHz; CDCl3) CH2vC); δC (75 MHz; CDCl3) 41.3 (C(Br)CH2), 46.8 (C(Br)-
2.77 (2H, t, J = 5, NCH2CH2), 3.41 (2H, s, NCH2C(O)), 3.62 (2H, CH2CH2N), 50.8 (NCH2CH2OH), 60.5 (CH2OH), 118.5 (CH2vC)
s, ArCH2), 4.41 (2H, t, J = 5, CH2O), 6.99 (1H, m, arylCH), 7.34 and 131.5 (CH2vC); m/z (CI) 196 (MH+ (81Br), 10%), 194 (MH+
(2H, dd, J = 3 and 6, 2 × arylCH) and 7.87 (1H, d, J = 6, arylCH); (79Br), 15), 178 (9), 176 (10), 164 (5), 162 (6), 114 (11), 102 (6),
δC (75 MHz; CDCl3) 49.0 (NCH2CH2), 55.9 (arylCH2), 65.6 74 (100) and 56 (7).
(NCH2C(O)), 68.2 (CH2O), 101.0 (arylCI), 128.6, 129.9, 130.8,
4-(3-Bromobut-3-enyl)-3,3-dideuteromorpholin-2-one (2). A
140.3 (arylCH), 139.0 (aryl ipsoC) and 167.8 (CvO); m/z (EI) solution of methyl bromoacetate-2,2-d2 10 (427 mg,
317 (M+, 10%), 217 (25), 146 (85), 89 (55) and 42 (100); m/z (CI) 2.79 mmol) in acetonitrile (3 cm3) was added dropwise to a
318 (MH+, 80%), 192 (100), 146 (15), 106 (15) and 91 (12).
stirred solution of 2-(3-bromobut-3-enylamino)ethanol 12
4-(2-Iodobenzyl)-3,3-dideuteromorpholin-2-one (1). A solu- (443 mg, 3.28 mmol) and N,N-diisopropylethylamine
tion of methyl bromoacetate-2,2-d2 10 (400 mg, 2.6 mmol) in (1.61 cm3, 9.24 mmol) in acetonitrile (8 cm3) at 0 °C. The
acetonitrile (6 cm3) was added dropwise to a stirred solution of resulting solution was then stirred and heated under reflux for
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Organic & Biomolecular Chemistry
12 h, before evaporation of the solvent in vacuo and the added and the reaction was allowed to proceed at reflux for
addition of diethyl ether (3.4 cm3). After stirring the mixture 14 h, with three further aliquots of 2,2′-azobisisobutyronitrile
for 5 min, the precipitated amine salt was removed by filtration (50 mg, 0.31 mmol) being added after 1, 4 and 12.5 h. The
and the filter cake was washed a further three times with solvent was removed in vacuo and the resulting residue was
diethyl ether (3 × 4 cm3). The combined organic extracts were purified by flash chromatography on silica gel containing pot-
dried (magnesium sulfate) then filtered and the solvent was assium fluoride (10% w/w) (gradient from 100% petroleum
evaporated in vacuo, the resulting residue being purified by ether to 50% petroleum ether–50% ethyl acetate) to give the
flash chromatography on silica gel (100% dichloromethane to title compound (72 mg, 60%) as a white solid (Found MH+ (ES+)
80% dichloromethane–20% ethyl acetate) to give the title com- 381.1809, C22H25N2O4 requires 381.1809); mp 136–138 °C;
pound (439 mg, 82%) as a colourless syrup (Found MH+ (CI) νmax(thin film)/cm−1 3000–2800 (m) (C–H), 1732 (s) (CvO) and
236.0252, C8H11D279BrNO2 requires 236.0255); νmax(thin film)/ 1495 (m); δH (400 MHz; CDCl3) 2.48 (2H, dt, J = 3 and 13,
cm−1 3088–2721 (w) (C–H), 1741 (s) (CvO), 1631 (m) (CvC), NCHHCH2), 2.86 (2H, m, NCHHCH2), 3.42, 4.81 (2 × 2H, AB,
1463 (w), 1410 (m), 1357 (w), 1299 (m), 1225 (m), 1173 (s), J = 14, PhCH2), 4.16 (2H, s, NCH), 4.23 (2H, m, OCHH), 4.47
1079 (m), 1057 (w), 960 (w), 929 (w), 894 (w) and 736 (m); δH (2H, dt, J = 2 and 11, OCHH) and 7.26–7.36 (10H, complex,
(400 MHz; CDCl3) 2.54–2.68 (4H, complex, C(Br)CH2CH2), 2.71 phenylCH); δC (100 MHz; CDCl3) 47.7 (NCH2CH2O), 60.3
(2H, t, J = 6, NCH2CH2O), 4.37 (2H, t, J = 6, CH2O), 5.45 (1H, d, (PhCH2), 67.5 (OCH2), 68.8 (NCH), 127.6, 128.4, 128.8 (phe-
J = 2, CHHvC(Br)) and 5.63 (1H, d, J = 3, CHHvC(Br)); δC nylCH), 136.9 (phenyl ipsoC) and 198.9 (CvO); m/z (EI) 190
(100 MHz; CDCl3) 38.6 (C(Br)CH2CH2), 48.9 (C(Br)CH2CH2), ((M/2)+, 8%), 146 (5), 91 (100), 65 (10) and 42 (9); m/z (CI) 381
54.8 (CD2), 55.1 (NCH2CH2O), 68.6 (CH2O)), 118.3 (MH+, 20%), 209 (8), 193 (12), 192 (100), 190 (10), 150 (8), 134
(CH2vC(Br)), 131.1 (CH2vC(Br)) and 167.2 (CvO); m/z (CI) (22), 119 (15), 108 (17), 106 (32), 91 (7), 52 (40) and 44 (14); m/z
238 (MH+ (81Br), 100%), 234 (MH+ (79Br), 100), 158 (5), 156 (7), (ES+) 380.310 (M+, 68%), 189.519 ((M/2)+, 100) and 90.555 (50).
116 (100), 98 (5) and 74 (12).
4-(3-Bromobut-3-enyl)morpholin-2-one (13). A solution of ide (98 atom% D, 260 μl, 0.96 mmol) was added to a degassed
methyl bromoacetate (480 μl, 5.1 mmol) in acetonitrile (5 cm3) solution of 4-(2-iodobenzyl)morpholin-2-one
(200 mg,
Reduction of 8 with tributyltin deuteride. Tributyltin deuter-
8
was added dropwise to a stirred solution of 2-(3-bromobut-3- 0.63 mmol) in benzene (15 cm3) under a nitrogen atmosphere.
enylamino)ethanol 12 (590 mg, 3.0 mmol) and N,N-diisopropyl- After heating to reflux, 2,2′-azobisisobutyronitrile (50 mg,
ethylamine (1.71 cm3, 9.8 mmol) in acetonitrile (13 cm3) at 0.31 mmol) was added and the reaction was allowed to
0 °C. The resulting solution was then stirred and heated under proceed at reflux for 14 h, with three further aliquots of 2,2′-
reflux for 12 h, before evaporation of the solvent in vacuo and azobisisobutyronitrile (50 mg, 0.31 mmol) being added after 1,
the addition of diethyl ether (6 cm3). After stirring the mixture 4 and 12.5 h. The solvent was removed in vacuo and the result-
for 5 min, the precipitated amine salt was removed by filtration ing residue was purified by flash chromatography on silica gel
and the filter cake was washed a further three times with containing potassium fluoride (10% w/w) (gradient from 100%
diethyl ether (3 × 6 cm3). The combined organic extracts were petroleum ether to 50% petroleum ether–50% ethyl acetate) to
dried (magnesium sulfate) then filtered and the solvent was give the title compound (76 mg, 63%) as a white solid. Data as
evaporated in vacuo, the resulting residue being purified by reported above.
flash chromatography on silica gel (100% dichloromethane to
Reaction of 8 with allyltributyltin. Allyltributyltin (240 μl,
80% dichloromethane–20% ethyl acetate) to give the title com- 0.77 mmol) was added to a degassed solution of 4-(2-iodoben-
pound (540 mg, 77%) as a colourless syrup (Found MH+ (ES+) zyl)morpholin-2-one 8 (200 mg, 0.63 mmol) in benzene
234.0122, C8H1379BrNO2 requires 234.0124); νmax(thin film)/ (15 cm3) under a nitrogen atmosphere. After heating to reflux,
cm−1 3070–2728 (m) (C–H), 1742 (s) (CvO), 1630 (m) (CvC), 2,2′-azobisisobutyronitrile (10 mg, 0.06 mmol) was added and
1460 (m), 1435 (m), 1411 (m), 1367 (w), 1342 (w), 1203 (s), 1170 the reaction was allowed to proceed at reflux for 14 h, with
(s), 1068 (m) and 890 (m); δH (300 MHz; CDCl3) 2.56–2.65 three further aliquots of 2,2′-azobisisobutyronitrile (10 mg,
(4H, complex, C(Br)CH2CH2), 2.69 (2H, t, J = 6, NCH2CH2O), 0.06 mmol) being added after 1, 3.5 and 12 h. The solvent was
3.36 (2H, s, NCH2C(O)), 4.40 (2H, t, J = 6, CH2O), 5.48 (1H, d, removed in vacuo and the resulting residue was purified by
J = 3, CHHvC(Br)) and 5.64 (1H, d, J = 3, CHHvC(Br)); flash chromatography on silica gel containing potassium fluor-
δC (75 MHz; CDCl3) 38.6 (C(Br)CH2CH2), 49.0 (C(Br)CH2CH2), ide (10% w/w) (gradient from 100% petroleum ether to 60%
55.2 (NCH2CH2O), 55.5 (NCH2C(O)), 68.6 (CH2O)), 118.3 petroleum ether–40% ethyl acetate) to give the title compound
(CH2vC(Br)), 131.1 (CH2vC(Br)) and 167.2 (CvO); m/z (CI) (90 mg, 75%) as a white solid. Data as reported above.
236 (MH+ (81Br), 100%), 234 (MH+ (79Br), 100), 156 (10) and
114 (5).
Reaction of 8 with (2-methylallyltributyltin). (2-Methylallyl)tri-
butyltin (220 mg, 0.64 mmol) was added to a degassed
4,4′-Dibenzyl-3,3′-bimorpholine-2,2′-dione (14)
solution of 4-(2-iodobenzyl)morpholin-2-one 8 (200 mg,
0.63 mmol) in benzene (15 cm3) under a nitrogen atmosphere.
After heating to reflux, 2,2′-azobisisobutyronitrile (10 mg,
0.06 mmol) was added and the reaction was allowed to
proceed at reflux for 14 h, with three further aliquots of 2,2′-
azobisisobutyronitrile (10 mg, 0.06 mmol) being added after 1,
Reduction of 8 with tributyltin hydride. Tributyltin hydride
(250 μl, 0.93 mmol) was added to a degassed solution of
4-(2-iodobenzyl)morpholin-2-one 8 (200 mg, 0.63 mmol) in
benzene (15 cm3) under a nitrogen atmosphere. After heating
to reflux, 2,2′-azobisisobutyronitrile (50 mg, 0.31 mmol) was
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3.5 and 12 h. The solvent was removed in vacuo and the result- (2 mg, 0.012 mmol) being added after 2 and 4 h. The solvent
ing residue was purified by flash chromatography on silica gel was removed in vacuo and the residue was purified by flash
containing potassium fluoride (10% w/w) (gradient from 100% chromatography on silica gel (gradient from 100% petroleum
petroleum ether to 60% petroleum ether–40% ethyl acetate) to ether to 90% petroleum ether–10% ethyl acetate) to give the
give the title compound (90 mg, 75%) as a white solid. Data as title compound (30 mg, 16%) as a colourless syrup. Data as
reported above.
reported above.
Reaction of 8 with hexabutyldistannane. Hexabutyldistannane
(320 μl, 0.63 mmol) was added to a degassed solution of
4-(2-iodobenzyl)morpholin-2-one 8 (200 mg, 0.63 mmol) in
benzene (15 cm3) under a nitrogen atmosphere. After heating
to reflux, 2,2′-azobisisobutyronitrile (50 mg, 0.3 mmol) was
added and the reaction was allowed to proceed at reflux for
14 h, with three further aliquots of 2,2′-azobisisobutyronitrile
(50 mg, 0.03 mmol) being added after 1, 3.5 and 12 h. The
solvent was removed in vacuo and the resulting residue was
purified by flash chromatography on silica gel containing pot-
assium fluoride (10% w/w) (gradient from 100% petroleum
ether to 50% petroleum ether–50% ethyl acetate) to give the
title compound (110 mg, 92%) as a white solid. Data as reported
above.
Reaction at 80 °C with in situ generation of tributyltin hydride.
Tributyltin chloride (56.4 μl, 0.21 mmol) was added to a
degassed solution of 4-(3-bromobut-3-enyl)morpholin-2-one 13
(483 mg, 2.06 mmol), sodium cyanoborohydride (257 mg,
4.09 mmol) and 2,2′-azobisisobutyronitrile (30 mg, 0.18 mmol)
in tert-butanol (37 cm3) under a nitrogen atmosphere. The
reaction was heated at reflux for 18 h, with three further ali-
quots of 2,2′-azobisisobutyronitrile (30 mg, 0.18 mmol) being
added after 2, 4 and 6 h. The cooled reaction mixture was par-
titioned between diethyl ether (60 cm3) and water (30 cm3) and
the separated aqueous phase was further extracted with diethyl
ether (3 × 30 cm3). The combined organic extracts were washed
with aqueous ammonia solution (2 M, 3 × 30 cm3), water (3 ×
30 cm3) and brine (3 × 30 cm3), dried (magnesium sulfate) and
the solvent was removed in vacuo. The resulting residue was
purified by flash chromatography on silica gel (gradient from
100% petroleum ether to 90% petroleum ether–10% ethyl
acetate) to give the title compound (50 mg, 16%) as a colourless
syrup. Data as reported above.
( )-4-(2-Iodobenzyl)-3-methylmorpholin-2-one (24). A solu-
tion of ( )-methyl 2-bromopropionate (330 μl, 3.0 mmol) in
acetonitrile (5 cm3) was added dropwise to a stirred solution of
2-(2-iodobenzylamino)ethanol 7 (1.00 g, 3.6 mmol) and N,N-
diisopropylethylamine (2.10 cm3, 12.0 mmol) in acetonitrile
(15 cm3) at 0 °C. The resulting solution was then stirred and
heated under reflux for 12 h, before evaporation of the solvent
in vacuo and the addition of diethyl ether (5 cm3). After stirring
the mixture for 5 min, the precipitated amine salt was
removed by filtration and the filter cake was washed a further
three times with diethyl ether (3 × 5 cm3). The combined
organic extracts were dried (magnesium sulfate) then filtered
and the solvent was evaporated in vacuo, the resulting residue
being purified by flash chromatography on silica gel (80%
petroleum ether–20% ethyl acetate) to give the title compound
(500 mg, 50%) as a colourless syrup (Found MH+ (ES+)
332.0142, C12H15INO2 requires 332.0142); νmax(thin film)/cm−1
3000–2750 (w) (C–H), 1740 (s) (CvO), 1500 (w) and 610 (m); δH
(300 MHz; CDCl3) 1.56 (3H, d, J = 7.5, CH3), 2.57–2.65 (1H,
complex, NCHHCH2), 2.89 (1H, dt, J = 3 and 12, NCHHCH2),
3.50, 3.89 (2 × 1H, AB, JAB = 15, arylCH2), 3.51 (1H, q, J = 7.5,
NCH(CH3)), 4.35 (2H, m, CH2O), 7.33 (1H, dt, J = 1 and 6,
arylCH), 7.35 (1H, dt, J = 1 and 6, arylCH), 7.42 (1H, dt, J = 1
4,4′-Di(but-3-enyl)-3,3′-bimorpholine-2,2′-dione (21)
Reaction at 80 °C. Tributyltin hydride (552 μl, 2.05 mmol)
was added to a degassed solution of 4-(3-bromobut-3-enyl)
morpholin-2-one 13 (437 mg, 1.87 mmol) in benzene (20 cm3)
under a nitrogen atmosphere. After heating to reflux, 2,2′-azo-
bisisobutyronitrile (30 mg, 0.18 mmol) was added and the
reaction was allowed to proceed at reflux for 6 h, with two
further aliquots of 2,2′-azobisisobutyronitrile (30 mg,
0.18 mmol) being added after 2 and 4 h. The solvent was
removed in vacuo and the resulting residue was purified by
flash chromatography on silica gel (gradient from 100% pet-
roleum ether to 90% petroleum ether–10% ethyl acetate) to
give the title compound (87 mg, 30%) as a colourless syrup
(Found MH+ (CI) 309.1811, C16H25N2O4 requires 309.1809);
νmax(thin film)/cm−1 3141–2714 (w) (C–H), 1726 (s) (CvO),
1640 (w) (CvC), 1463 (w), 1411 (m), 1377 (w), 1349 (w),
1336 (w), 1298 (m), 1220 (m), 1181 (m), 1136 (m), 1121 (w),
1077 (m), 1065 (m), 1008 (w), 998 (w), 988 (w), 949 (w), 925 (w),
908 (w), 893 (w), 792 (w), 676 (w), 656 (w) and 631 (w); δH
(400 MHz; CDCl3) 2.27 (4H, m, CH2vCHCH2), 2.51 (2H, m,
CHCH2CHHN), 2.54 (2H, m, NCHHCH2O), 3.08 (2H, m,
NCHHCH2O), 3.24 (2H, m, CHCH2CHHN), 3.85 (2H, s, NCH),
4.29 (2H, m, CHHO), 4.50 (2H, dt, J = 2 and 11, CHHO), 5.02
(2H, dd, J = 2 and 10, CHHvCH cis), 5.06 (2H, dd, J = 2 and
18, CHHvCH trans) and 5.77 (2H, m, CH2vCH); δC (100 MHz;
CDCl3) 31.1 (CH2CHvCH2), 47.4 (NCH2CH2O), 55.2
(CH2CH2CHvCH2), 67.1 (OCH2), 68.9 (NCH), 116.5
(CH2vCH), 135.6 (CH2vCH) and 169.1 (CvO); m/z (CI) 309
(MH+, 36%), 156 (100), 100 (25), 53 (28) and 44 (10).
Reaction at 25 °C. Tributyltin hydride (350 μl, 1.30 mmol) and 6, arylCH) and 7.86 (1H, m, arylCH); δC (75 MHz; CDCl3)
and 2,2′-azobisisobutyronitrile (2 mg, 0.012 mmol) were added 16.6 (CH3), 46.5 (NCH2CH2), 60.7 (NCH(CH3)), 68.7 (CH2O),
to a stirred, degassed solution of 4-(3-bromobut-3-enyl)mor- 100.6 (arylCI), 128.7, 129.7, 130.7, 140.2 (arylCH) and 140.0
pholin-2-one 13 (280 mg, 1.20 mmol) in benzene (13 cm3), (aryl ipsoC) (Note: CvO signal not distinguishable); m/z (EI)
under a nitrogen atmosphere, at 25 °C. The reaction mixture 332 (MH+, 12%), 304 (15), 217 (58), 160 (100), 146 (10), 127
was irradiated with a medium pressure mercury vapour lamp (15), 117 (10), 104 (9), 91 (60), 70 (20), 56 (98) and 42 (22); m/z
for 6 h, with two further aliquots of 2,2′-azobisisobutyronitrile (CI) 332 (MH+, 100%), 204 (10), 160 (20) and 114 (12).
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( )-4-(3-Bromobut-3-enyl)-3-methylmorpholin-2-one (25). A
Organic & Biomolecular Chemistry
Reaction at 25 °C. Tributyltin hydride (260 μl, 0.96 mmol)
solution of ( )-methyl 2-bromopropionate (500 μl, 4.6 mmol) and 2,2′-azobisisobutyronitrile (100 mg, 0.61 mmol) were
in acetonitrile (5 cm3) was added dropwise to a stirred solution added to a stirred, degassed solution of ( )-4-(2-iodobenzyl)-3-
of 2-(3-bromobut-3-enylamino)ethanol 12 (704 mg, 3.6 mmol) methylmorpholin-2-one 24 (200 mg, 0.60 mmol) in benzene
and N,N-diisopropylethylamine (2.06 cm3, 11.8 mmol) in (15 cm3), under a nitrogen atmosphere, at 25 °C. The reaction
acetonitrile (13 cm3) at 0 °C. The resulting solution was then mixture was irradiated with a medium pressure mercury
stirred and heated under reflux for 12 h, before evaporation of vapour lamp for 12 h, with three further aliquots of 2,2′-azo-
the solvent in vacuo and the addition of diethyl ether (6 cm3). bisisobutyronitrile (100 mg, 0.61 mmol) being added after 1, 4
After stirring the mixture for 5 min, the precipitated amine and 10 h. The solvent was removed in vacuo and the residue
salt was removed by filtration and the filter cake was washed a was purified by flash chromatography on silica gel containing
further three times with diethyl ether (3 × 6 cm3). The potassium fluoride (10% w/w) (gradient from 100% petroleum
combined organic extracts were dried (magnesium sulfate) ether to 50% petroleum ether–50% ethyl acetate) to give the
then filtered and the solvent was evaporated in vacuo, the title compound (73 mg, 59%) as a cream-coloured solid. Data as
resulting residue being purified by flash chromatography on reported above.
silica gel (100% dichloromethane to 80% dichloromethane–
4,4′-Di(but-3-enyl)-3,3′-dimethyl-3,3′-bimorpholine-2,2′-dione
20% ethyl acetate) to give the title compound (729 mg, 82%) as (27) and 4-(but-3-enyl)-3-methylmorpholin-2-one (28). Tributyl-
a colourless syrup (Found MH+ (ES+) 248.0281, C9H1579BrNO2 tin hydride (692 μl, 2.57 mmol) was added dropwise to a
requires 248.0281); νmax(thin film)/cm−1 3113–2652 (w) (C–H), degassed solution of ( )-4-(3-bromobut-3-enyl)-3-methylmor-
1737 (s) (CvO), 1630 (m) (CvC), 1467 (m), 1408 (w), 1371 (w), pholin-2-one 25 (578 mg, 2.33 mmol) and 2,2′-azobisisobutyro-
1322 (m), 1211 (m), 1174 (s), 1057 (m), 948 (w), 893 (w) and nitrile (38 mg, 0.24 mmol) in benzene (25 cm3) at reflux, under
736 (m); δH (400 MHz; CDCl3) 1.45 (3H, d, J = 7, CH3), a nitrogen atmosphere. The reaction was allowed to proceed at
2.50–2.68, 2.83–3.08 (4H and 2H, complex, C(Br)CH2CH2 and reflux for 6 h, with two further aliquots of 2,2′-azobisisobutyro-
NCH2CH2O), 3.31 (1H, q, J = 7, CH3CH), 4.33 (2H, m, CH2O), nitrile (38 mg, 0.24 mmol) being added after 2 and 4 h. The
5.44 (1H, d, J = 1.5, CHHvC(Br)) and 5.62 (1H, d, J = solvent was removed in vacuo and the resulting residue was
1.5, CHHvC(Br)); δC (100 MHz; CDCl3) 16.2 (CH3), purified by flash chromatography on silica gel (gradient from
38.9 (C(Br)CH2CH2), 46.7 (C(Br)CH2CH2), 51.9 (NCH2CH2O), 100% petroleum ether to 90% petroleum ether–10% ethyl
59.8 (CH3CH), 68.0 (CH2O), 118.2 (CH2vC(Br)), 131.4 acetate) to give an inseparable mixture of the title compounds
(CH2vC(Br)) and 171.0 (CvO); m/z (CI) 250 (MH+ (81Br), 50%), (27 : 28 1 : 1.2, 180 mg, 29% for dimer 27 and 17% for
248 (MH+ (79Br), 50), 170 (100), 168 (31), 128 (21), 52 (45) monomer 28) as a pale yellow syrup; νmax(thin film)/cm−1
and 44 (16).
3122–2662 (m) (C–H), 1736 (s) (CvO), 1641 (w) (CvC),
1466 (m), 1408 (m), 1391 (w), 1369 (m), 1321 (m), 1294 (s),
1212 (s), 1169 (s), 1117 (m), 1092 (m), 1057 (s), 998 (w),
916 (m), 834 (w), 793 (w), 735 (w), 667 (w) and 652 (w); (Note:
NMR data are presented for the dimer 27 only. 28 was ident-
ified by comparison with spectroscopic data determined for
the authentic sample prepared below.) δH (400 MHz; CDCl3)
1.57 (6H, s, CH3), 2.29 (4H, m, CH2vCHCH2), 2.38 (2H, m,
CHCH2CHHN), 2.71 (2H, m, NCHHCH2O), 2.99 (2H, m,
NCHHCH2O), 3.22 (2H, m, CHCH2CHHN), 4.21–4.43 (4H,
complex, CH2O), 5.00 (2H, dd, J = 2 and 10, CHHvCH), 5.05 (2H,
dd, J = 2 and 16, CHHvCH) and 5.76 (2H, m, CH2vCH); δC
(100 MHz; CDCl3) 16.2 (CH3), 33.3 (CH2CHvCH2), 45.7
(NCH2CH2O), 50.7 (CH2vCHCH2CH2N), 68.1 (OCH2), 71.1
(CCH3), 116.3 (CH2vCH), 135.5 (CH2vCH) and 169.7 (CvO);
m/z (EI) 168 ((M/2)+ for X, 100%), 140 (20), 128 (40), 100 (38), 82
(79) and 55 (96); m/z (CI) 254 (12%), 237 (100), 170 (90), 168 (28),
128 (12), 100 (20), 72 (17), 52 (61) and 44 (14).
4,4′-Dibenzyl-3,3′-dimethyl-3,3′-bimorpholine-2,2′-dione (26)
Reaction at 80 °C. Tributyltin deuteride (98 atom% D,
260 μl, 0.96 mmol) was added to a degassed solution of
( )-4-(2-iodobenzyl)-3-methylmorpholin-2-one 24 (200 mg,
0.60 mmol) in benzene (15 cm3) under a nitrogen atmosphere.
After heating to reflux, 2,2′-azobisisobutyronitrile (100 mg,
0.61 mmol) was added and the reaction was allowed to
proceed at reflux for 12 h, with three further aliquots of 2,2′-
azobisisobutyronitrile (100 mg, 0.61 mmol) being added after
1, 4 and 10 h. The solvent was removed in vacuo and the result-
ing residue was purified by flash chromatography on silica gel
containing potassium fluoride (10% w/w) (gradient from 100%
petroleum ether to 50% petroleum ether–50% ethyl acetate) to
give the title compound (110 mg, 89%) as a cream-coloured
solid (Found (M/2)+ (EI) 204.1018, C12H14NO2 requires
204.1019); mp 99–103 °C; δH (400 MHz; CDCl3) 1.76 (6H, s,
CH3), 2.67 (2H, dt, J = 3 and 11, NCHHCH2), 2.82 (2H, m,
NCHHCH2), 3.39, 4.60 (2 × 2H, AB, J = 14, PhCH2), 4.20 (2H,
dt, J = 3 and 11, OCHH), 4.42 (2H, dt, J = 3 and 11, OCHH),
7.26 (2H, ca dt, J = 2 and 7 phenylCH), 7.34 (4H, t, J = 7.5,
phenylCH) and 7.41 (4H, d, J = 7.5, phenylCH); δC (100 MHz;
CDCl3) 16.6 (CH3), 45.8 (NCH2CH2O), 56.1 (PhCH2), 68.2
(OCH2), 70.8 (NC(CH3)), 127.5, 128.3, 128.7 (phenylCH), 138.2
(phenyl ipsoC) and 169.7 (CvO); m/z (EI) 204 ((M/2)+, 18%), 91
(100), 69 (14) and 41 (23); m/z (CI) 273 (100%), 204 ((M/2)+, 15),
108 (10), 91 (9) and 52 (15).
( )-4-(But-3-enyl)-3-methylmorpholin-2-one
(28). Ethanol-
amine (740 μl, 12.2 mmol) and N,N-diisopropylethylamine
(2.32 cm3, 13.3 mmol) were added to a stirred solution of but-
3-enyl methanesulfonate (1.00 g, 6.7 mmol) in acetonitrile
(22 cm3) and the mixture was heated to reflux and stirred for
18 h. After cooling, the solvent was evaporated in vacuo and
diethyl ether (8 cm3) was added to the residue. After stirring
this mixture for 5 min, the precipitated amine salt was
removed by filtration and the filter cake was washed a further
2720 | Org. Biomol. Chem., 2013, 11, 2712–2723
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three times with diethyl ether (3 × 8 cm3). The combined ether fluoride (10% w/w) (gradient from 100% petroleum ether to
solutions were evaporated to dryness in vacuo) and the residue 50% petroleum ether–50% ethyl acetate) to give the title com-
was purified by flash chromatography on silica gel (80% pound (82 mg, 68%) as a white solid (Found MH+ (ES+)
diethyl ether-20% methanol) to give 2-(but-3-enylamino)ethanol 385.2057, C22H21D2N2O4 requires 385.2060); mp 135–136 °C;
(479 mg, 63%) as a colourless oil (Found MH+ (CI) 116.1075, νmax(thin film)/cm−1 3280 (m), 2974 (w), 1732 (s) (CvO),
C6H14NO requires 116.1074); νmax(thin film)/cm−1 3306 (s) (O– 1653 (s) and 1545 (m); δH (400 MHz; CDCl3) 2.49 (2H, dt, J = 3
H), 2924 (s) (n-H), 2273 (w) (C–H) and 1631 (w) (CvC); δH and 13, NCHHCH2), 2.87 (2H, m, NCHHCH2), 3.43, 4.79 (2 ×
(300 MHz; CDCl3) 2.26 (2H, q, J = 6, CH2vCHCH2), 2.71 (2H, t, 2H, AB, J = 14, PhCH2), 4.24 (2H, m, OCHH), 4.47 (2H, dt, J = 2
J = 6, CH2vCHCH2CH2), 2.74 (2H, t, J = 6, CH2CH2OH), 3.64 and 11, OCHH) and 7.27–7.39 (8H, m, phenylCH);
(2H, t, J = 6, CH2OH), 5.11 (2H, complex, CH2vC) and 5.78 δD (61.4 MHz; CHCl3) 4.14 (2D, s, NCD) and 7.37 (2D, s, phe-
(1H, m, CH2vCH); δC (75 MHz; CDCl3) 34.5 (CH2CHvCH2), nylCD); δC (100 MHz; CDCl3) 47.7 (NCH2CH2O), 60.2 (PhCH2),
48.8 (CH2NH), 51.5 (CH2NH), 61.1 (CH2OH), 117.1 (CH2vC) 67.4 (OCH2), 127.7, 128.4, 128.7, 128.8 (phenylCH), 136.7
and 136.4 (CH2vC); m/z (CH) 116 (MH+, 50%), 98 (30) and (phenyl ipsoC) and 168.9 (CvO) (Note: CD2 and phenylCD
74 (100).
solution of ( )-methyl 2-bromopropionate (552 μl, 20%), 92 (100) and 66 (6); m/z (CI) 385 (MH+, 2%), 348 (15),
5.0 mmol) in acetonitrile (5 cm3) was added dropwise to a 326 (25), 285 (10), 273 (20), 245 (20), 224 (20) and 211 (100).
signals not visible owing to dilute sample); m/z (EI) 192 ((M/2)+,
A
stirred solution of 2-(but-3-enylamino)ethanol (460 mg,
4.0 mmol) and N,N-diisopropylethylamine (2.24 cm3,
12.9 mmol) in acetonitrile (15 cm3) at 0 °C. The resulting solu-
tion was then stirred and heated under reflux for 12 h, before
Reaction at 25 °C. Tributyltin hydride (250 μl, 0.93 mmol)
and 2,2′-azobisisobutyronitrile (50 mg, 0.31 mmol) were added
to a stirred, degassed solution of 4-(2-iodobenzyl)-3,3-dideutero-
morpholin-2-one 1 (200 mg, 0.63 mmol) in benzene (15 cm3),
evaporation of the solvent in vacuo and the addition of diethyl under a nitrogen atmosphere, at 25 °C. The reaction mixture
ether (7 cm3). After stirring the mixture for 5 min, the precipi-
was irradiated with a medium pressure mercury vapour lamp
tated amine salt was removed by filtration and the filter cake
for 6 h, with three further aliquots of 2,2′-azobisisobutyroni-
was washed a further three times with diethyl ether (3 × trile (50 mg, 0.31 mmol) being added after 1, 3.5 and 5 h. The
7 cm3). The combined organic extracts were dried (magnesium solvent was removed in vacuo and the residue was purified by
sulfate) then filtered and the solvent was evaporated in vacuo, flash chromatography on silica gel containing potassium fluo-
the resulting residue being purified by flash chromatography ride (10% w/w) (gradient from 100% petroleum ether to 50%
on silica gel (100% dichloromethane to 80% dichloro- petroleum ether–50% ethyl acetate) to give the title compound
methane–20% ethyl acetate) to give the title compound (71 mg, 59%) as a cream-coloured solid. Data as reported
(430 mg, 64%) as a colourless syrup (Found M+ (EI) 169.1122, above.
C9H15NO2 requires 169.1103); νmax(thin film)/cm−1 3109–2705
Reaction at −50 °C. Tributyltin hydride (250 μl, 0.93 mmol)
(w) (C–H), 1739 (s) (CvO), 1641 (m) (CvC), 1467 (m),
1408 (w), 1370 (w), 1321 (m), 1282 (w), 1211 (m), 1153 (s),
1091 (m), 1057 (w) and 915 (w); δH (400 MHz; CDCl3) 1.44 (3H,
d, J = 7, CH3), 2.23 (2H, m, CHCH2CH2), 2.42 (1H, m,
CHCH2CHH), 2.61 (1H, m, NCHHCH2O), 2.71 (1H, m,
and 2,2′-azobisisobutyronitrile (50 mg, 0.31 mmol) were added
to a stirred, degassed solution of 4-(2-iodobenzyl)-3,3-dideutero-
morpholin-2-one 1 (200 mg, 0.63 mmol) in fluorobenzene
(15 cm3), under a nitrogen atmosphere, at −50 °C. The reaction
mixture was irradiated with a medium pressure mercury
CHCH2CHH), 2.99 (1H, m, NCHHCH2O), 3.31 (1H, q, J = 7, vapour lamp for 5 h, with three further aliquots of 2,2′-azobis-
CH3CH), 4.34 (2H, m, CH2O), 5.02 (1H, d, J = 9.5, CHHvCH isobutyronitrile (50 mg, 0.31 mmol) being added after 1, 2 and
cis), 5.07 (1H, d, J = 18, CHHvCH trans) and 5.79 (1H, m, 4 h. The solvent was removed in vacuo and the residue was
CH2vCH); δC (100 MHz; CDCl3) 16.1 (CH3), 31.0 (CHCH2CH2), purified by flash chromatography on silica gel containing
45.5 (NCH2CH2O), 53.3 (CHCH2CH2), 59.8 (CH3CH), 68.0 potassium fluoride (10% w/w) (gradient from 100% petroleum
(CH2O), 116.2 (CH2vCH), 135.7 (CH2vCH) and 171.2 (CvO); ether to 50% petroleum ether–50% ethyl acetate) to give the
m/z (EI) 170 (MH+, 1%), 128 (100), 110 (12), 100 (92), 96 (12), title compound (71 mg, 59%) as a cream-coloured solid. Data as
76 (47) and 56 (42).
reported above.
3,3′-Dideutero-4,4′-bis(2-deuterobenzyl)-3,3′-bimorpholine-
2,2′-dione (34)
3,3′-Dideutero-4,4′-bis(3-deuterobut-3-enyl)-3,3′-bimorpho-
line-2,2′-dione (35)
Reaction at 80 °C. Tributyltin hydride (250 μl, 0.93 mmol)
Reaction at 80 °C. Tributyltin hydride (123 μl, 0.46 mmol)
was added to a degassed solution of 4-(2-iodobenzyl)-3,3- was added to a degassed solution of 4-(3-bromobut-3-enyl)-3,3-
dideuteromorpholin-2-one 1 (200 mg, 0.63 mmol) in benzene dideuteromorpholin-2-one 2 (100 mg, 0.42 mmol) and 2,2′-azo-
(15 cm3) under a nitrogen atmosphere. After heating to reflux, bisisobutyronitrile (13 mg, 0.08 mmol) in benzene (44 cm3) at
2,2′-azobisisobutyronitrile (50 mg, 0.31 mmol) was added and reflux, under a nitrogen atmosphere. The reaction was allowed
the reaction was allowed to proceed at reflux for 6 h, with three to proceed at reflux for 6 h, with two further aliquots of 2,2′-
further aliquots of 2,2′-azobisisobutyronitrile (50 mg, azobisisobutyronitrile (13 mg, 0.08 mmol) being added after 2
0.31 mmol) being added after 1, 3.5 and 5 h. The solvent was and 4 h. The solvent was removed in vacuo and the resulting
removed in vacuo and the resulting residue was purified by residue was purified by flash chromatography on silica gel
flash chromatography on silica gel containing potassium (gradient from 100% petroleum ether to 90% petroleum
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ether–10% ethyl acetate) to give the title compound (39 mg, dried (magnesium sulfate) and the solvent was removed in
59%) as
colourless syrup (Found M+ (EI) 312.1984, vacuo. The resulting residue was purified by flash chromato-
a
C16H20D4N2O4 requires 312.1987); νmax(thin film)/cm−1 1726 graphy on silica gel (gradient from 100% petroleum ether to
(s) and 1640 (w); δH (300 MHz; CDCl3) 2.26 (4H, m, 90% petroleum ether–10% ethyl acetate) to give the title com-
CH2vCDCH2), 2.44–2.71 (4H, complex, CDCH2CHHN and pound (19 mg, 29%) as a colourless syrup. Data as reported
NCHHCH2O), 3.06 (2H, m, NCHHCH2O), 3.24 (2H, m, above.
CDCH2CHHN), 4.28 (2H, m, CHHO), 4.49 (2H, m, CHHO) and
4.96–5.12 (4H, broad, complex, CH2vCD); δD (61.4 MHz;
CHCl3) 3.78 (2D, s, NCD) and 5.83 (2D, s, CH2vCD); δC
Acknowledgements
(75 MHz; CDCl3) 31.0 (CH2CDvCH2), 46.2 (NCH2CH2O), 55.5
(CH2CH2CDvCH2), 66.4 (OCH2), 66.4 (NCD), 116.5
(CH2vCD), 135.2 (CH2vCD) and 169.1 (CvO); m/z (FI) 313
(MH+, 10%), 157 (10) and 156 (100).
The authors thank EPSRC (Project Studentship to S. B. and
DTA funding to K. M. W.) and UCB Celltech (CASE funding to
K. M. W.) for financial support, Dr Ivan Prokes and Dr Stephen
J. Simpson (Exeter, UK) for NMR work and the EPSRC National
Mass Spectrometry Service Centre (Swansea, UK) and Mr Eric
Underwood (Exeter, UK) for determination of mass spectra.
Reaction at 25 °C. Tributyltin hydride (330 μl, 1.23 mmol)
and 2,2′-azobisisobutyronitrile (18 mg, 0.11 mmol) were added
to a stirred, degassed solution of 4-(3-bromobut-3-enyl)-3,3-
dideuteromorpholin-2-one 2 (269 mg, 1.14 mmol) in benzene
(12 cm3), under a nitrogen atmosphere, at 25 °C. The reaction
mixture was irradiated with a medium pressure mercury
vapour lamp for 6 h, with two further aliquots of 2,2′-azobis-
isobutyronitrile (18 mg, 0.11 mmol) being added after 2 and
4 h. The solvent was removed in vacuo and the residue was
purified by flash chromatography on silica gel (gradient from
100% petroleum ether to 90% petroleum ether–10% ethyl
acetate) to give the title compound (11 mg, 6%) as a colourless
syrup. Data as reported above.
Notes and references
1 J. Robertson, J. Pillai and R. K. Lush, Chem. Soc. Rev., 2001,
30, 94; Ž. Čeković, J. Serb. Chem. Soc., 2005, 70, 287.
2 D. P. Curran and J. Xu, J. Am. Chem. Soc., 1996, 118, 3142.
3 M. E. Wood, S. Bissiriou, C. Lowe and K. M. Windeatt, Org.
Biomol. Chem., 2008, 6, 3048.
Reaction at 25 °C with slow addition of tributyltin hydride. A
solution of tributyltin hydride (320 μl, 1.19 mmol) and 2,2′-
azobisisobutyronitrile (17 mg, 0.10 mmol) in degassed
benzene (2.4 cm3) was added over a period of 1 h (via a syringe
pump) to a stirred, degassed solution of 4-(3-bromobut-3-enyl)-
3,3-dideuteromorpholin-2-one 2 (258 mg, 1.09 mmol) in
benzene (9.3 cm3), under a nitrogen atmosphere, at 25 °C.
During this time, the reaction mixture was irradiated with a
medium pressure mercury vapour lamp and after addition of
the tributyltin hydride/2,2′-azobisisobutyronitrile solution,
irradiation was continued for a further 5 h. The solvent was
4 M. E. Wood, S. Bissiriou, C. Lowe, A. M. Norrish,
K. Sénéchal, K. M. Windeatt, S. J. Coles and M.
B. Hursthouse, Org. Biomol. Chem., 2010, 8, 4653.
5 P. Renaud and L. Giraud, Synthesis, 1996, 913.
6 C. J. Easton, Chem. Rev., 1997, 97, 53.
7 J. Hioe, G. Savasci, H. Brand and H. Zipse, Chem.–Eur. J.,
2011, 17, 3781.
8 C. J. Easton, C. A. Hutton, G. Rositano and E. W. Tan,
J. Org. Chem., 1991, 56, 5614.
9 For example, see: J. J. Brocks, F. M. Welle, H.-D. Beckhaus
and C. Rüchardt, Tetrahedron Lett., 1997, 38, 7721.
removed in vacuo and the residue was purified by flash chrom- 10 H. G. Viehe, Z. Janousek and R. Merényi, Acc. Chem. Res.,
atography on silica gel (gradient from 100% petroleum ether 1985, 18, 148.
to 90% petroleum ether–10% ethyl acetate) to give the title 11 J. Atzrodt, V. Derdau, T. Fey and J. Zimmermann, Angew.
compound (34 mg, 20%) as a colourless syrup. Data as reported
above.
Reaction at 80 °C with in situ generation of tributyltin hydride.
Chem., Int. Ed., 2007, 46, 7744.
12 R. Gosain, A. M. Norrish and M. E. Wood, Tetrahedron,
2001, 57, 1399.
Tributyltin chloride (11.5 μl, 0.04 mmol) was added to a 13 D. Chassonery, F. Chastrette, M. Chastrette, A. Blanc and
degassed solution of 4-(3-bromobut-3-enyl)-3,3-dideuteromor- G. Mattioda, Bull. Soc. Chim. Fr., 1994, 13, 188.
pholin-2-one 2 (100 mg, 0.42 mmol), sodium cyanoborohy- 14 C. Kashima and K. Harada, J. Org. Chem., 1989, 54, 789.
dride (52 mg, 0.83 mmol) and 2,2′-azobisisobutyronitrile 15 C. Kashima and K. Harada, J. Chem. Soc., Perkin Trans. 1,
(61 mg, 0.37 mmol) in tert-butanol (8 cm3) under a nitrogen
1988, 1521.
atmosphere. The reaction was heated at reflux for 18 h, with 16 T. M. Werkhoven, R. van Nispen and J. Lugtenburg,
four further aliquots of 2,2′-azobisisobutyronitrile (61 mg, Eur. J. Org. Chem., 1999, 2909.
0.39 mmol) being added after 2, 4, 6 and 8 h. The cooled reac- 17 A. Padwa and A. G. Waterson, Tetrahedron, 2000, 56, 10159.
tion mixture was partitioned between diethyl ether (60 cm3) 18 For typical examples, see: D. P. G. Hamon, R. A. Massy-
and water (30 cm3) and the separated aqueous phase was
further extracted with diethyl ether (3 × 30 cm3). The combined
organic extracts were washed with aqueous ammonia solution
(2 M, 3 × 30 cm3), water (3 × 30 cm3) and brine (3 × 30 cm3),
Westropp and P. Razzino, Tetrahedron, 1995, 51, 4183;
L. Giraud and P. Renaud, J. Org. Chem., 1998, 63, 9162;
M. I. Chowdhry, P. N. Horton, M. B. Hursthouse and
M. E. Wood, Tetrahedron Lett., 2009, 50, 3400.
2722 | Org. Biomol. Chem., 2013, 11, 2712–2723
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Paper
19 P. Renaud, M. Gerster and M. Ribezzo, Chimia, 1994, 48, 24 V. A. Burgess, C. J. Easton and M. P. Hay, J. Am. Chem. Soc.,
366. 1989, 111, 1047.
20 D. Elad and J. Sperling, J. Chem. Soc., Chem. Commun., 25 C. J. Easton and M. P. Hay, J. Chem. Soc., Chem. Commun.,
1968, 655.
1985, 425; C. J. Easton, M. P. Hay and S. G. Love, J. Chem.
Soc., Perkin Trans. 1, 1988, 265.
26 M. E. Kurz, V. Baru and P.-N. Nguyen, J. Org. Chem., 1984,
49, 1603.
21 O. Benson Jr., S. H. Demirdji, R. C. Haltiwanger and
T. H. Koch, J. Am. Chem. Soc., 1991, 113, 8879.
22 J. Sperling, J. Am. Chem. Soc., 1969, 91, 5389.
23 C. J. Easton and M. P. Hay, J. Chem. Soc., Chem. Commun., 27 S. L. Harbeson and R. D. Tung, Annu. Rep. Med. Chem.,
1896, 55.
2011, 46, 403.
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