Synthesis and reactivity of a novel group of hydroxylamine-containing 2π- and 4π-components

Article abstract of DOI:10.1039/a708380g

The synthesis of hydroxylamine-based reagents, alkene 2, alkyne 3 and a butadienyl variant pyrone 4 are described. While the relative instability of alkyne 3 has limited further evaluation, alkene 2 and pyrone 4 successfully participate in 1,3-dipolar and Diels-Alder cycloaddition reactions respectively. Reaction of 4 with DMAD gives O-arylated hydroxylamine 13, the structure of which is confirmed by crystallographic analysis.

Full text of DOI:10.1039/a708380g

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Synthesis and reactivity of a novel group of hydroxylamine-
containing 2ð- and 4ð-components
Alan J. Pearce,a Daryl S. Walter,b Christopher S. Framptonb and
Timothy Gallagher*,a
a School of Chemistry, University of Bristol, Bristol, UK BS8 1TS
b Roche Discovery Welwyn, Welwyn Garden City, UK AL7 3AY
The synthesis of hydroxylamine-based reagents, alkene 2, alkyne 3 and a butadienyl variant pyrone 4 are
described. While the relative instability of alkyne 3 has limited further evaluation, alkene 2 and pyrone
4 successfully participate in 1,3-dipolar and Diels–Alder cycloaddition reactions respectively. Reaction of
4 with DMAD gives O-arylated hydroxylamine 13, the structure of which is confirmed by crystallographic
analysis.
Hydroxylamines (RNHORЈ) represent an important structural
motif that is often associated with molecules exhibiting useful
biological and medicinal profiles, including antiviral, antifungal
and anxiolytic profiles.1 The synthesis of variously O-substi-
tuted hydroxylamines 1 relies most usually on exploiting the
nucleophilicity of either oxygen or nitrogen towards an
appropriate electrophilic component and preparation may be
carried our via either O᎐C or N᎐O bond formation, as illus-
trated in general terms in Scheme 1.2–5
O
O
N
O
N O
O
O
2
3
O
N
O
O
O
O
N
O
O
O
S
S
N
OH
HO
4
R′—X
O
O
O
2, are attractive as a synthetically flexible class of electron-rich
dieneophiles or dipolarophiles and two successful pathways to
the O-ethenyl derivative 2 have been identified. Certain limit-
ations also became apparent with the chemistry involved and
these aspects of the study are also described.†
R′—X
ref. 3
ref. 2
H2N—O—R′
1
EWG
R′—OH
ref. 5
The first synthesis of 2 is illustrated in Scheme 2. N-Hydroxy-
ref. 4
OH
O
O
H2N—OSO3Ar
N
(O)n
SPh
i
N
OH
N O
Scheme 1
Me
O
O
We have sought to develop an alternative method for the
synthesis of O-substituted hydroxylamines, substrates which
can then be used to prepare N,O-disubstituted variants.6 Our
approach to the synthesis of O-substituted hydroxylamines is
based on identifying synthetically flexible units that already
contain a preformed N᎐O᎐C array, and in this paper we
describe the preparation of a series of building blocks 2, 3 and
4 based on this concept. A variety of routes have been evalu-
ated for the synthesis of the 2π-containing components—the
O-alkenyl and O-alkynyl derivatives 2 and 3 respectively—and
a 4π dienyl variant, pyrone 4, is also described. In addition, we
present some preliminary studies relating to the reactivity of
these molecules as participants in 1,3-dipolar and Diels–Alder
cycloaddition processes.
5
6 n = 0
7 n = 1
ii
iii
O
N
O
O
2
Scheme 2 Reagents and conditions: i, PhSCH(Me)Cl, Et3N (66%);
ii, MCPBA (84%); iii, xylene, CaCO3, reflux (44%)
† Attempts to prepare O-alkenyl derivatives (cf. 2) via methylenation of
a range of O-formyl derivatives i using titanium-based reagents16 was
unsuccessful.
Results and discussion
Synthesis of N-protected O-alkenyl hydroxylamines
O
The synthesis of O-alkenyl hydroxylamines has, to date, relied
on the addition of a suitable N-substituted hydroxylamine to an
electron-deficient alkyne.7 Simple O-alkenyl derivatives, such as
R2N
O
H
i
J. Chem. Soc., Perkin Trans. 1, 1998
847

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phthalimide (NHP) 5 underwent O-alkylation using 1-chloro-
ethyl phenyl sulfide8 to give adduct 6. Oxidation of 6 gave a
diastereomeric mixture of sulfoxides 7 (together with a small
quantity of the corresponding sulfone), and thermolysis of
sulfoxides 7 produced the crystalline O-ethenyl hydroxylamine
2 in 24% overall yield from 5.
O
O
i
N
O
N
O
Br
Br
O
O
2
10
Two variants on this alkylation–elimination strategy have
been examined, but without success. We were unable to alkylate
NHP with phenyl vinyl sulfoxide under a variety of both base-
and acid-mediated reaction conditions. Alternative N-protect-
ing groups were also of interest and N-benzyl-N-benzyl-
oxycarbonylhydroxylamine 8 did undergo alkylation with 2-
bromoethyl phenyl selenide to give adduct 9 in 50% yield.
Although use of a milder selenoxide fragmentation offered an
opportunity to retain a more sensitive array of nitrogen protect-
ing groups in the O-alkenyl product, we were not successful in
oxidising adduct 9 (using either NaIO4 or MCPBA) to promote
a selenoxide-mediated elimination (Scheme 3).
ii
O
N
O
O
3
Scheme 5 Reagents and conditions: i, Br2, CH2Cl2 (91%); ii, LiHMDS,
THF, Ϫ78 ЊC (17%)
hydroxylamine derivatives.§ With this objective in mind, the
pyrone derivative 4 became an attractive target: pyrones are
known to be highly effective dienes and, following initial cyclo-
addition, decarboxylation then restores a butadienyl or aryl
moiety, depending on the nature of the dienophile used.13 The
synthesis of the pyrone derivative 4 is outlined in Scheme 6.
O
O
S(O)Ph
N
OH
N O
O
O
S(O)Ph
5
O
Cl
O
i
N
O
O
i
Bn(Cbz)N OH
Bn(Cbz)N
O
Bn(Cbz)N O
O
O
O
8
9
11
4
SePh
Scheme 3 Reagents and conditions: i, PhSeCH2CH2Br, NaH (50%)
Scheme 6 Reagents and conditions: i, N-hydroxyphthalimide 5, Et3N,
DMF (84%)
The second and more direct route to alkene 2, which is shown
in Scheme 4, was carried out using a transvinylation based on
4-Chloro-2H-pyran-2-one 1114 underwent smooth (net) substi-
tution using NHP 5 under mildly basic conditions to give 4 in
84% yield.
O
O
i
N
OH
N O
Preliminary cycloaddition studies
Both the O-alkenyl derivative 2 and butadien-2-yl variant 4
offer synthetic utility and, while this is not necessarily restricted
O
O
5
2 (82%)
Scheme 4 Reagents and conditions: i, AcOCH᎐CH2, Hg(OCOCF3)2
᎐
‡ The purity of the vinyl acetate used is important to the success of the
transformation shown in Scheme 4 and must be freshly distilled other-
wise O-acetylation of 5 predominates (A. J. Liepa, private communi-
cation). Using the other hydroxylamine derivatives mentioned, complex
mixtures were obtained under the mercury-catalysed transvinylation
conditions. With 8, the major component has been tentatively assigned
as the corresponding O-acylated adduct.9b
§ Attempts to prepare a simpler butadien-2-yl derivative iv failed. While
adduct ii was obtained by alkylation of 4-bromo-4,5-dihydrothiophene
dioxide,17 we were unable to isomerise this product to give the desired
2,5-dihydrothiophene dioxide iii
(7 mol%) cat. H2SO4, reflux
an exchange involving vinyl acetate.9 This transformation was
promoted by mercury() trifluoroacetate and 2 was isolated in
82% yield. This process involves a single step and isolation
of the product from the reaction mixture is straightforward.
It is, however, important to appreciate that this process did not
accommodate other N-protected hydroxylamines, such as 8,
Bn2NOH10 and Boc2NOH11 and these substrates did not yield
the corresponding O-ethenyl adducts under similar conditions.‡
O
O
Synthesis of O-alkynyl hydroxylamine 3
The synthesis of the corresponding O-ethynyl hydroxylamine 3,
also based on NHP, is shown in Scheme 5. Addition of bromine
to alkene 2 provided the crystalline dibromide 10 which under-
went a double elimination under basic conditions to give the
O-ethynyl derivative 3 in 15% overall yield, a compound that
proved difficult to fully characterise. Alkyne 3 proved to be
relatively unstable—as with related alkoxyalkynes,12 3 was
prone to polymerisation—and although accessible, the chem-
istry of this 2π-component has not been further explored.
N
O
N O
O
O
O
O
S
S
O
O
ii
iii
O
N
O
Synthesis of an O-butadienyl hydroxylamine 4
Electron-rich 4π components also offer significant synthetic
potential, particularly in the construction of substituted O-aryl
O
iv
848
J. Chem. Soc., Perkin Trans. 1, 1998

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O
O
i
N
O
N O
O
N
O
O
2
12
Ph
O
ii
R2N
O
O
O
4
CO2Me
CO2Me
Fig. 1 ORTEP diagram of O-arylated hydroxylamine 13. Thermal
ellipsoids are at the 50% probability level.
N
O
CO2Me
O
CO2Me
iv
detected) under the reaction conditions used to achieve
cycloaddition (toluene, sealed-tube, 190 ЊC). The yield of the
hydroxylamine derivative 14 has not been optimised, but quite
clearly the limits on compatibility of the N᎐O bond to thermal
reaction conditions must be recognised. A further aspect of
the chemistry of pyrone 4 was uncovered following a reaction
involving an alkene-based dienophile. Thermolysis of 4 in the
presence of N-phenylmaleimide gave phenol 17 in 84% yield.
This product is presumed to arise via aromatisation of adduct
16 in a process that again involves a facile N᎐O (likely hetero-
lytic) cleavage.
13
O
iii
and HO
SO2Tol
N
O
4
4
O
SO2Tol
14
15
O
O
In summary, N-hydroxyphthalimide is readily incorporated
into the synthetically useful O-ethenyl and O-butadienyl deriv-
atives 2 and 4 respectively. Problems were encountered with the
stability of the simple O-alkynyl variant 3, but this may not be
an issue with more substituted analogues. Preliminary cyclo-
addition studies have already defined certain reactivity patterns,
but further work will be undertaken to explore other, more
general aspects of the chemistry of the hydroxylamine-based
reagents that have been reported in this paper.
H
H
v
N
O
O
NPh
O
16
O
HO
NPh
Experimental
O
17
General
ϩ
Ϫ
᎐
Scheme 7 Reagents and conditions: i, PhC᎐N ᎐O (25%); ii, MeO2-
CC᎐CCO2Me, toluene, 150 ЊC (26%); iii, TolO2SC᎐CH, toluene, 190 ЊC
᎐
All solvents and commercially available reagents were purified
and dried as required, according to standard literature pro-
cedures. Light petroleum refers to the fraction boiling in the
range 40–60 ЊC. Ether refers to diethyl ether. IR spectra were
obtained on a Perkin-Elmer 1600 FTIR spectrophotometer.
Mass spectra were obtained on a Fisons VG Analytical
Autospec spectrometer using EI (70 eV), CI (CH4 as reagent
gas) or FAB modes. NMR spectra were recorded on a JEOL
JNM-GX270, JEOL JNM-LA300 or JEOL JNM-GX400
spectrometer and J values are reported in Hz. Melting points
were determined on a Kofler hot-stage and are uncorrected.
Elemental analyses were determined on a Perkin-Elmer 240C
elemental analyser. TLC was performed using aluminium plates
coated with Merck silica gel 60F254 and flash chromatography
was carried out using silica gel (Merck 60). Preparative reversed-
phase (RP) HPLC was performed using a Dynamax column
(20 mm ID × 5 cm L, 5 µm, C18, 300 Å) and Gilson pump
eluting at 20 cm3 minϪ1 with detection (UV, 254 nm). Solvent A
consisted of 0.1% TFA in water and solvent B of 0.1% TFA
in acetonitrile. Reactions using a sealed-tube refer to a sealed
reaction vessel with an internal volume of 7 cm3.
᎐
᎐
᎐
᎐
(14: 7%; 15: 43%); iv, toluene, 190 ЊC (quantitative by TLC); v,
N-phenylmaleimide, toluene, 205 ЊC (84%)
to their use in Diels–Alder and related reactions, our initial
studies have focused on these cycloaddition processes. Pre-
liminary results pertaining to the reactivity associated with this
aspect of the study are all shown in Scheme 7.
For a number of reasons, we were drawn towards verifying
the use of the O-alkenyl derivative 2 as a 1,3-dipolarophile.
Exposure of 2 to benzonitrile oxide gave the corresponding
cycloadduct 12 (25%; 41% yield based on recovered 2) with only
one regioisomer being observed, which is consistent with the
reactivity associated with simple vinyl ethers.15
As stated earlier, the instability of the O-alkynyl derivative 3
proved to be a problem, but the reactivity encountered with the
pyrone-based 4π component 4 was more readily harnessed.
Exposure of 4 to DMAD gave the expected O-arylated
hydroxylamine 13 in 26% isolated yield, the structure of which
was confirmed by single crystal X-ray analysis (Fig. 1). Pyrone
4 also underwent cycloaddition to p-tolylsulfonylacetylene, but
in this case two products were obtained. The minor component
was the desired O-arylated adduct 14 (isolated in 7% yield) and
the major product was phenol 15 (43% yield). A simple control
experiment showed that the adduct 14 fragmented, via N᎐O
bond homolysis, to give phenol 15 (with phthalimide being
N-(1-Phenylsulfonylethoxy)phthalimide and N-(1-Phenylsulfinyl-
ethoxy)phthalimide 7
N-(1-Phenylthioethoxy)phthalimide8 6 (4.46 g, 14.9 mmol) was
dissolved in dichloromethane (10 cm3), cooled to 0 ЊC and
vigorously stirred. m-Chloroperbenzoic acid (86% pure, 3.64 g,
J. Chem. Soc., Perkin Trans. 1, 1998
849

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21.1 mmol) was added portionwise over 20 min after which
time TLC (ether) indicated no starting material. The reaction
mixture was immediately poured into a separating funnel
containing ether (50 cm3) and washed with aq. sodium sulfite
(50 cm3, 1 mol dmϪ3) and then saturated aq. sodium hydrogen
carbonate (2 × 50 cm3), The organic layer was dried (MgSO4),
filtered and the solvent removed in vacuo. Purification by flash
chromatography (ether–pentane, 2:3) afforded N-(1-phenyl-
sulfonylethoxy)phthalimide (0.21 g, 4%), as a colourless crystal-
line solid, mp 158–160 ЊC (ethyl acetate–light petroleum)
(Found: C, 58.1; H, 3.9; N, 4.1. C16H13NO5S requires C, 58.0; H,
3.95; N, 4.2%); νmax(KBr)/cmϪ1 1789 (C᎐O), 1737 (C᎐O), 1310
N-Benzyl-N-benzyloxycarbonylhydroxylamine 8
N-Benzylhydroxylamine hydrochloride (752 mg, 4.7 mmol) was
added to a solution of sodium hydrogen carbonate (792 mg,
9.4 mmol) in water (15.0 cm3) and stirred at 0 ЊC for 0.5 h.
Dichloromethane (10 cm3) and benzyl chloroformate (0.67 cm3,
4.7 mmol) were added dropwise, and the reaction mixture
stirred for 0.5 h at 0 ЊC. After a further 0.5 h at room temper-
ature, the organic layer was separated and the aqueous layer
was extracted with dichloromethane (5 cm3). The combined
extracts were washed with brine, dried (MgSO4), filtered
and concentrated in vacuo to afford N-benzyl-N-benzyloxy-
carbonylhydroxylamine 8 (957 mg, 79%), as a colourless crystal-
line solid, mp 93–95 ЊC (dichloromethane–light petroleum)
(Found: C, 69.8; H, 5.9; N, 5.2. C15H15NO3 requires C, 70.0;
H, 5.9; N, 5.45%); νmax(KBr)/cmϪ1 1697 (C᎐O); δ (270 MHz,
᎐
᎐
(SO2), 1135 (SO2); δH(270 MHz, CDCl3) 8.29 (2 H, m, Ph),
7.89–7.60 (7 H, m, Ar), 5.32 (1 H, q, J 6.4, CH), 1.64 (3 H, d,
J 6.4, CH3); m/z (FABϩ) 332 (M ϩ Hϩ, 46%), 190 [(M ϩ H Ϫ
PhSO2H)ϩ, 100].
᎐
H
CDCl3) 7.38–7.28 (10 H, m, Ph), 6.02 (1 H, br s, N-OH), 5.22
(2 H, s, PhCH2), 4.71 (2 H, s, PhCH2); m/z (EI) 239 (Mϩ Ϫ H2O,
1%), 213 (Mϩ Ϫ CO2, 2), 91 (C7H7ϩ, 100), 65 (C5H5ϩ, 7); m/z
(FABϩ) 258 (M ϩ Hϩ, 100).
Further elution (ether) yielded N-(1-phenylsulfinylethoxy)-
phthalimide 7 (3.95 g, 84%), as a ca. 1:1 mixture of diastereo-
mers, as a colourless solid, mp 102 ЊC (decomp.) (ethyl acetate–
light petroleum) (Found: C, 60.7; H, 4.5; N, 4.3. C16H13NO4S
requires C, 60.95; H, 4.2; N, 4.5%); νmax(KBr)/cmϪ1 1792 (C᎐O),
N-Benzyl-N-benzyloxycarbonyl-O-[2-(phenylseleno)ethyl]-
hydroxylamine 9
᎐
1737 (C᎐O), 1045 (S᎐O); δ (270 MHz, CDCl ) 8.03–7.49 (9 H,
᎐
᎐
H
3
m, Ar), 5.21/5.01 (1 H, q, J 6.2, CH), 1.54/1.29 (3 H, d,
J 6.2, CH3); m/z (FABϩ) 316 (M ϩ Hϩ, 71%), 190 {[M ϩ H Ϫ
PhS(O)H]ϩ, 100}.
Sodium hydride (4.4 mg, 0.11 mmol, 60% in mineral oil) was
added to a solution of N-benzyl-N-benzyloxycarbonylhydroxyl-
amine 8 (28 mg, 0.11 mmol) in tetrahydrofuran (0.5 cm3) and
the mixture was stirred under nitrogen at room temperature.
After 15 min, a solution of 2-bromoethyl phenyl selenide18
(31.9 mg, 0.12 mmol) in tetrahydrofuran (0.1 cm3) was added
and the mixture was stirred at room temperature for 20.5 h.
After heating at reflux for a further 4 h, the mixture was cooled
to room temperature, the solvent was removed in vacuo and the
residue was purified by flash chromatography (ethyl acetate–
light petroleum, 5:95) to afford N-benzyl-N-benzyloxycarbonyl-
O-[2-(phenylseleno)ethyl]hydroxylamine 9 (24 mg, 50%), as a
colourless oil (Found: C, 63.0; H, 4.9; N, 3.2. C23H23NO3Se
N-Ethenyloxyphthalimide 2
(i) Via thermolysis of the sulfoxide 7. Calcium carbonate
(3.70 g, 37.0 mmol) was added to a solution of N-(1-phenyl-
sulfinylethoxy)phthalimide 7 (3.89 g, 0.63 mmol) in xylene (20
cm3) and the mixture was heated to reflux. After 15.5 h, reac-
tion was complete, as judged by TLC (ether), and the reaction
mixture was cooled to room temperature, filtered through
Celite and the solvent removed in vacuo. Flash chromatography
(ether–light petroleum, 2:5) afforded N-ethenyloxyphthalimide
2 (1.04 g, 44%), as a colourless crystalline solid. For character-
isation see route (ii).
requires C, 62.7; H, 5.3; N, 3.2%); νmax(film)/cmϪ1 1711 (C᎐O),
᎐
1221 (C᎐O), 1081 (C᎐O); δH(270 MHz, CDCl3) 7.43–7.19 (15
H, m, Ar), 5.19 (2 H, s, PhCH2), 4.64 (2 H, s, PhCH2), 3.97 (2 H,
t, J 7.3, OCH2), 2.93 (2 H, t, J 7.3, SeCH2); m/z (CI) 442
(M ϩ Hϩ, 22%), 185 (Ph80SeCH2CH2ϩ, 82), 91 (C7H7ϩ, 100)
(Found: M ϩ Hϩ, 442.0925. C23H23NO380Se requires M ϩ Hϩ,
442.0921).
(ii) Via transetherification. Mercury() trifluoroacetate (425
mg, 1.0 mmol) was dissolved in freshly distilled‡ vinyl acetate
(42.0 g, 0.49 mol) and the solution was stirred at room temper-
ature under nitrogen in the dark. After 15 min, N-hydroxy-
phthalimide 5 (15.2 g, 93.2 mmol) and then concentrated
sulfuric acid (0.02 cm3 in 1.0 cm3 EtOAc) were added and the
mixture was heated to reflux. Further mercury() trifluoro-
acetate (2.40 g, 5.63 mmol) was added portionwise over 24 h
and after a further 24 h at reflux, TLC (ethyl acetate–light
petroleum, 1:2) indicated consumption of 5. The reaction mix-
ture was cooled to room temperature and the solvent was
removed in vacuo. The residue was initially purified by filtration
through a silica plug (ethyl acetate–light petroleum, 6:1). The
crude solid was then dissolved in ethyl acetate (100 cm3) and
washed with saturated aq. sodium hydrogen carbonate (50
cm3). The aqueous layer was extracted with ethyl acetate
(2 × 100 cm3) and the combined organic extracts were washed
with brine (25 cm3), dried (Na2SO4), filtered and the solvent was
removed in vacuo. Recrystallisation gave N-ethenyloxyphthal-
imide 2 (12.2 g, 70%) and purification of the mother liquors by
flash chromatography (ethyl acetate–light petroleum, 1:3) gave
an additional quantity of 2 (2.12 g, total yield of 82%), as a
colourless crystalline solid, mp 105–107 ЊC (decomp.) (ethyl
acetate–light petroleum) (Found: C, 63.4; H, 3.6; N, 7.3.
C10H7NO3 requires C, 63.5; H, 3.7; N, 7.4%); νmax(KBr)/cmϪ1
1,2-Dibromo-1-(phthalimidooxy)ethane 10
Bromine (366 mg, 2.3 mmol) was added dropwise over 5 min
to a suspension of N-ethenyloxyphthalimide 2 (332 mg, 1.76
mmol) in dichloromethane (5 cm3) at 0 ЊC. After stirring for 10
min at 0 ЊC and 1.5 h at room temperature, the reaction mixture
was washed with 10% aq. sodium thiosulfate (10 cm3). The
aqueous layer was then extracted with dichloromethane (2 × 10
cm3) and combined organic extracts were dried (MgSO4), fil-
tered and the solvent removed in vacuo to afford 1,2-dibromo-1-
(phthalimidooxy)ethane 10 (558 mg, 91%), as a colourless crys-
talline solid, mp 120–122 ЊC (ether–light petroleum) (Found: C,
34.4; H, 1.9; N, 4.0. C10H7Br2NO3 requires C, 34.4; H, 2.0; N,
4.0%); νmax(KBr)/cmϪ1 1790 (C᎐O), 1734 (C᎐O); δ (400 MHz,
᎐
᎐
H
CDCl3) 7.92–7.76 (4 H, m, Ar), 6.55 (1 H, dd, J 8.4, J 3.3,
OCHBr), 4.12 (1 H, dd, J2,2Ј 11.8, J 8.4, 2-H), 3.99 (1 H, dd, J2,2Ј
11.8, J 3.3, 2Ј-H); δ (75.45 MHz, CDCl ) 162.4 (C᎐O), 135.0
᎐
C
3
(CH, Ar), 128.6 (Cipso), 124.1 (CH, Ar), 88.0 (CH, 1-C), 31.2
(CH2, 2-C); m/z (CI) 352 {[M(81Br81Br) ϩ H]ϩ, 0.3%}, 350
{[M(81Br79Br) ϩ H]ϩ, 0.6}, 348 {[M(79Br79Br) ϩ H]ϩ, 0.3}.
1728 (C᎐O), 1641 (C᎐C); δ (270 MHz, CDCl ) 7.85 (4 H, m,
᎐
᎐
H
3
Ar), 6.71 (1 H, dd, J 13.6, J 6.2, OCH), 4.67 (1 H, dd, J 13.6,
J 4.0, Htrans), 4.47 (1 H, dd, J 6.2, J 4.0, Hcis); δC(67.8 MHz,
CDCl ) 162.4 (C᎐O), 151.1 (OCH), 134.8, 123.9 (2 × CH, Ar),
N-Ethynyloxyphthalimide 3
A solution of lithium hexamethyldisilazide (1.10 cm3, 1.10
mmol, 1 mol dmϪ3 in THF) was added dropwise to a solution
of 1,2-dibromo-1-(phthalimidooxy)ethane 10 (151 mg, 0.43
mmol) in THF (2 cm3) at Ϫ78 ЊC under nitrogen. After stirring
at Ϫ78 ЊC for 1 h and then room temperature for 1 h, the reac-
tion mixture was washed with saturated aq. NH4Cl (3 cm3) and
᎐
3
128.9 (Cipso), 90.7 (CH2); m/z (FABϩ) 190 (M ϩ Hϩ, 100%); m/z
(CI) 190 (M ϩ Hϩ, 5%), 148 [(M ϩ H Ϫ C2H2O)ϩ, 100]
(Found: M ϩ Hϩ, 190.0504. C10H7NO3 requires M ϩ Hϩ,
190.0497).
850
J. Chem. Soc., Perkin Trans. 1, 1998

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the aqueous layer was extracted with ethyl acetate (2 × 3 cm3).
The combined organic extracts were washed with HCl (1 cm3, 2
mol dmϪ3), water (1 cm3), saturated aq. sodium hydrogen carb-
onate (1 cm3), dried (Na2SO4), filtered and the solvent removed
in vacuo. The residue was purified by flash chromatography
(ethyl acetate–light petroleum, 2:5) to afford N-ethynyloxy-
phthalimide 3 (14 mg, 17%), as a colourless solid; νmax(KBr)/
cmϪ1 3203 (C᎐H alkyne), 2949, 1775 (C᎐O), 1732 (C᎐O); δ (270
Continued elution gave dimethyl 4-(phthalimidooxy)phthalate
13 (16 mg, 26%; tr 10.6 min) as a colourless crystalline solid, mp
58–60 ЊC (ether–light petroleum) (Found: M ϩ Hϩ, 356.0766.
C18H13NO7 requires M ϩ Hϩ, 356.0770); νmax(KBr)/cmϪ1 1741
(C᎐O), 1288; δ (400 MHz, CDCl ) 7.89–7.78 (4 H, m), 7.75
᎐
H
3
(1 H, d, J5,6 8.6, 6-H), 7.31 (1 H, d, J3,5 2.6, 3-H), 7.23 (1 H, dd,
J5,6 8.6, J3,5 2.6, 5-H), 3.82 (6 H, br s, OCH3); m/z (FABϩ) 356
(M ϩ Hϩ, 40%), 324 (M ϩ Hϩ Ϫ CH3OH, 100).
᎐
᎐
H
MHz, C6D6) 7.39 (2 H, m, Ar), 6.85 (2 H, m, Ar), 0.34 (1 H, s,
ϩ
ϩ
᎐
C᎐C᎐H); m/z (EI) 187 (M , 7%), 162 [(M Ϫ C H) , 4], 147
N-[4-(p-Tolylsulfonyl)phenoxy]phthalimide 14 and 4-(p-tolyl-
sulfonyl)phenol 15
᎐
2
(Phthϩ, 100). Attempts to recrystallise 3 without extensive
decomposition failed, and we were unable to obtain satisfactory
microanalytical data or high resolution mass data for this
compound.
A mixture of pyrone 4 (40 mg, 0.16 mmol) and p-tolyl-
sulfonylacetylene (34 mg, 0.19 mmol) in toluene (1 cm3) was
heated in a sealed-tube at 150 ЊC for 24 h and then 35 h at
190 ЊC. The solvent was removed in vacuo and flash chrom-
atography (ether–light petroleum, 3:1) afforded a mixture
of N-[4-(p-tolylsulfonyl)phenoxy]phthalimide 14 and 4-(p-tolyl-
sulfonyl)phenol 15.
Preparative RPHPLC (0–20 min, linear gradient of 5 to 95%
of solvent B in solvent A) afforded 4-(p-tolylsulfonyl)phenol 15
(17 mg, 43%, tr 8.4 min), as a colourless solid, mp 140–142 ЊC
(lit.,21 mp 143–144 ЊC); νmax(KBr)/cmϪ1 3361, 1587, 1286;
δH(400 MHz, CDCl3) 7.74 (4 H, m), 7.21 (2 H, d, J 8.1), 6.82
(2 H, d, J 8.8), 5.61 (1 H, br s, OH), 2.32 (3 H, s, CH3); m/z
(FABϩ) 249 (M ϩ Hϩ, 100%).
4-(Phthalimidooxy)-2H-pyran-2-one 4
Triethylamine (1.28 cm3, 9.19 mmol) was added dropwise over
5 min to a solution of N-hydroxyphthalimide 5 (1.50 g, 9.20
mmol) and 4-chloro-2H-pyran-2-one14 11 (1.09 g, 8.35 mmol)
in dry DMF (10 cm3) at room temperature under nitrogen.
After stirring for 2 h, ice–water (20 cm3) was added and the
precipitate was filtered and washed with water (10 cm3), satur-
ated aq. sodium hydrogen carbonate (10 cm3), water (10 cm3)
and ice-cold ether–pentane (1:1, 15 cm3). Drying in vacuo
afforded 4-(phthalimidooxy)-2H-pyran-2-one 4 (1.81 g, 84%), as
a cream solid, mp >230 ЊC (decomp., ethyl acetate–light
petroleum) (Found: C, 60.9; H, 2.6; N, 5.6. C13H7NO5 requires
Continued elution gave N-[4-(p-tolylsulfonyl)phenoxy]-
phthalimide 14 (4 mg, 7%, tr 12.6 min), as a colourless solid,
mp 185 ЊC (decomp.) (Found: M ϩ Hϩ, 394.0745. C21H15NO5S
C, 60.7; H, 2.7; N, 5.45%); νmax(KBr)/cmϪ1 1798 (C᎐Oimide),
᎐
1735 (C᎐O
), 1717 (C᎐O
), 1644 (C᎐C), 1574 (C᎐C),
requires M ϩ Hϩ, 394.0749); νmax(KBr)/cmϪ1 1795 (C᎐Oimide),
᎐
᎐
᎐
᎐
᎐
imide
pyrone
1192 (C᎐O); δH(300 MHz, CDCl3) 7.98–7.87 (4 H, m, Ar), 7.53
(1 H, dd, J5,6 6.0, J3,6 0.6, 6-H), 6.34 (1 H, dd, J5,6 6.0, J3,5 3.0,
5-H), 5.77 (1 H, dd, J3,5 3.0, J3.6 0.6, 3-H); δC(100.61 MHz,
[2H ]DMSO) 169.3, 162.5, 162.1 (3 × C, 2-C, 4-C, C᎐O), 154.5
1742 (C᎐Oimide), 1586, 1151, 1106; δH(400 MHz, CDCl3) 7.88–
᎐
7.85 (4 H, m), 7.78 (2 H, m), 7.72 (2 H, d, J 8.3), 7.23 (2 H, d,
J 8.1), 7.15 (2 H, m, J 8.9), 2.32 (3 H, s, CH3); m/z (FABϩ) 394
(M ϩ Hϩ, 15%), 149 (100).
᎐
6
(CH, 6-C), 135.2 (CH, Ar), 129.1 (Cipso), 123.8 (CH, Ar), 99.2,
Thermolysis of a solution of 14 in toluene (sealed-tube,
190 ЊC, 20 h) showed complete conversion to 15, as judged by
TLC.
92.0 (2 × CH, 3-C, 5-C); m/z (CI) 258 (M ϩ Hϩ, 55%).
5-(Phthalimidooxy)-3-phenyl-4,5-dihydroisoxazole 12
Benzohydroxamoyl chloride19 (107 mg, 0.69 mmol) in ether (0.5
cm3) was added to a stirred solution of N-ethenyloxyphthal-
imide 2 (100 mg, 0.53 mmol) in ether (3 cm3) at room temper-
ature under nitrogen. Triethylamine (70 mg, 0.69 mmol) was
added dropwise over 20 min. Three further equivalents each
of benzohydroxamoyl chloride and triethylamine were added
over 24 h, after which TLC (ether–pentane, 2:3) indicated the
presence of starting material (Rf 0.6) and a major product (Rf
0.3), together with some baseline material. Saturated aq. NH4Cl
(5 cm3) was added and the mixture was extracted with ether,
dried (MgSO4) and filtered. Solvent was removed in vacuo and
flash chromatography (ether–pentane, 2:3) afforded 5-(phthal-
imidooxy)-3-phenyl-4,5-dihydroisoxazole 12 (40 mg, 25%, 41%
based on recovered 2), as a colourless crystalline solid, mp
151–152 ЊC (ethyl acetate–light petroleum) (Found: C, 66.6;
H, 3.7; N, 9.0. C17H12N2O4 requires C, 66.2; H, 3.9; N, 9.1%);
νmax(KBr)/cmϪ1 1787, 1732; δH(270 MHz, CDCl3) 7.89–7.42 (9
H, m, Ar), 6.31 (1 H, dd, J4Ј,5 5.5, J4,5 1.8, 5-H), 3.74 (1 H, dd,
J4,4Ј 18.0, J4,5 1.8, 4-H), 3.64 (1 H, dd, J4,4Ј 18.0, J4Ј,5 5.5, 4Ј-H);
m/z (FABϩ) 309 (M ϩ Hϩ, 40%), 146 (100).
5-Hydroxy-2-phenylisoindole-1,3(2H)-dione 17
A mixture of pyrone 4 (27 mg, 0.11 mmol) and N-phenyl-
maleimide (55 mg, 0.32 mmol) in toluene (1 cm3) was heated in
a sealed-tube at 205 ЊC for 24 h. The solvent was then removed
in vacuo and flash chromatography (ether–light petroleum, 3:1)
afforded 5-hydroxy-2-phenylisoindole-1,3(2H)-dione 17 (21 mg,
84%), as a pale yellow crystalline solid, mp 250–252 ЊC
(CH2Cl2–light petroleum) (lit.,22 mp 251 ЊC) (Found: Mϩ,
239.0578. C14H9NO3 requires Mϩ, 239.0582); νmax(KBr)/cmϪ1
3216br, 1776 (C᎐O), 1710 (C᎐O); δ (400 MHz, CDCl ) 7.83
᎐
᎐
H
3
(1 H, d, J6,7 8.2, 7-H), 7.51–7.37 (5 H, m, Ph), 7.35 (1 H, d, J4,6
2.2, 4-H), 7.17 (1 H, dd, J6,7 8.2, J4,6 2.2, 6-H), 5.95 (1 H, br s,
OH); m/z (EI) 239 (Mϩ, 75%), 149 (100).
Crystallographic data for 13
C18H13N1O7, M = 355.29, monoclinic, space group P21/a,
a = 9.471(4), b = 9.776(8), c = 17.477(3) Å, β = 91.93(3)Њ, U =
1617.2(15) Å3 [from 2θ values of 25 reflections measured at
ω (89.10 р 2θ р 102.10Њ Cu-Kα, λ = 1.541 78 Å)], Z = 4,
Dc = 1.459 g cmϪ1, µ = 0.971 mmϪ1, F(000) = 736, T = 123(1) K.
Data collection and processing.23 A colourless plate crystal,
0.26 × 0.20 × 0.10 mm was mounted on a Rigaku AFC7R
four-circle diffractometer equipped with an Oxford Cryo-
systems Cryostream Cooler.24 3115 reflections were collected
at 123(1) K with ω–2θ scans using graphite-monochromated
Cu-Kα radiation, (λ = 1.541 78 Å), scan-width = (1.31 ϩ 0.14
tan θ)Њ, scan speed 32Њ minϪ1 to a θmax of 70.01Њ, (h 0 to 11, k 0
to 11, l Ϫ21 to 21). 2912 reflections unique (Rint = 0.0130) and
2523 observed with I < 2σ(I). Analysis of the intensities of
three standard reflections recorded every 150 reflections showed
an overall decrease in the intensity of 3.17% and the data were
scaled accordingly. The data were corrected for Lorentz
and polarisation effects. No absorption correction was applied
Dimethyl 4-(phthalimidooxy)phthalate 13
A mixture of pyrone 4 (44 mg, 0.17 mmol) and freshly distilled
dimethyl acetylenedicarboxylate (0.5 cm3) was stirred in a
sealed-tube and heated at 150 ЊC for 20 h. The solvent was
then removed in vacuo and flash chromatography (ether–light
petroleum, 3:2) afforded a mixture of trimethyl 5-methoxy-
furan-2,3,4-tricarboxylate (a by-product derived from DMAD)
and dimethyl 4-(phthalimidooxy)phthalate 13.
Preparative RPHPLC (0–20 min, linear gradient of 5 to 95%
solvent B in solvent A) afforded trimethyl 5-methoxyfuran-
2,3,4-tricarboxylate (16 mg; tr 6.3 min), as a colourless solid,
mp 118 ЊC (lit.,20 mp 117–118 ЊC).
J. Chem. Soc., Perkin Trans. 1, 1998
851

View Article Online
6 For recent and representative examples, see: (alkylation) S. D. Young
since preliminary ψ-scans revealed no significant absorption
effects.
and P. P. Tamburini, J. Am. Chem. Soc., 1989, 111, 1933; V. Dupont,
A. Lecoq, J.-P. Mangeot, A. Aubry, G. Boussard and M. Marraud,
J. Am. Chem. Soc., 1993, 115, 8898; D. V. Patel, M. G. Young,
S. P. Robinson, L. Hunihan, B. J. Dean and E. M. Gordon, J. Med.
Chem., 1996, 39, 4197; (reductive amination) F.-C. Huang, T. S.
Shoupe, C. J. Lin, T. D. Y. Lee, W.-K. Chan, J. Tan, M. Schnapper,
J. T. Suh, R. J. Gordon, P. A. Sonnino, C. A. Sutherland, R. G.
Vaninwegen and S. M. Coutts, J. Med. Chem., 1989, 32, 1836;
S. Venkatraman, R. J. Roon, M. K. Schulte, J. F. Koerner and R. L.
Johnson, J. Med. Chem., 1994, 37, 3939; (acylation) R. A. Farr,
P. Bey, P. S. Sunkara and B. J. Lippert, J. Med. Chem., 1989, 32,
1879. See also reference 1.
7 (a) E. J. Breaux, J. Heterocycl. Chem., 1986, 23, 463; (b) S. Bottle,
W. K. Busfield, I. D. Jenkins, B. W. Skelton, A. H. White,
E. Rizzardo and D. H. Solomon, J. Chem. Soc., Perkin Trans. 2,
1991, 1001; (c) S. D. Pastor and E. T. Hessell, J. Org. Chem., 1988,
53, 5776; (d) E. Winterfeldt and W. Krohn, Chem. Ber., 1969, 102,
2336.
Structure solution and refinement.25 The structure was solved
by direct methods. Full-matrix least-squares refinement on F2
2
with weighting scheme wϪ1 = σ2(Fo ) ϩ (0.1000P)2 ϩ 1.5000P,
where P = (Fo2 ϩ 2Fc2)/3, anisotropic displacement parameters,
riding hydrogen atoms and a secondary extinction correction
2
3
Ϫ¹
⁴
x = 0.0043(6), where Fc* = kFc[1 ϩ 0.001xFc λ /sin(2θ)] , con-
verged with a ∆/σmax of 0.001. Final Rw = {Σ[w(Fo2 Ϫ Fc2)2]/
2
2 ¹
²
Σ[w(Fo ) ] } = 0.1610 for all data, conventional R = 0.0503 on
F values of 2523 reflections with I > 2σ(I), S = 1.007 for all data
and 236 parameters. Final difference map between ϩ0.26 and
Ϫ0.25 e ÅϪ3. Full crystallographic details, excluding structure
factor tables, have been deposited at the Cambridge Crystallo-
graphic Data Centre (CCDC). For details of the deposition
scheme, see ‘Instructions for Authors’, J. Chem. Soc., Perkin
Trans. 1, available via the RSC Web pages (http://www.rsc.org/
authors). Any request to the CCDC for this material should
quote the full literature citation and the reference number
207/189.
8 I. Vlattas, L. Della Vecchia and J. J. Fitt, J. Org. Chem., 1973, 38,
3749.
9 (a) W. H. Watanabe and L. E. Conlon, J. Am. Chem. Soc., 1957, 79,
2828; (b) H.-J. Gi, Y. Xiang, R. F. Schinazi and K. Zhao, J. Org.
Chem., 1997, 62, 88; (c) E. Bayer and K. Geckeler, Angew. Chem.,
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10 L. W. Jones and M. C. Sneed, J. Am. Chem. Soc., 1917, 39, 674.
11 L. C. Chan, PhD Thesis, University of Bath, 1992.
12 (a) J. F. Arens, Adv. Org. Chem., 1960, 2, 117; (b) T. L. Jacobs and
W. P. Tuttle, J. Am. Chem. Soc., 1949, 71, 1313; (c) T. L. Jacobs and
W. R. Scott, J. Am. Chem. Soc., 1953, 75, 5497.
13 K. Afarinkia, V. Vinader, T. D. Nelson and G. H. Posner,
Tetrahedron, 1992, 48, 9111.
Acknowledgements
We thank EPSRC and Roche Discovery Welwyn for a CASE
studentship (to A. J. P.), and Dr A. J. Liepa (CSIRO,
Melbourne) for observations relating to the transvinylation
route to 2.
14 V. Kvita and H. Sauter, Helv. Chim. Acta, 1990, 73, 883.
15 (a) A. N. Boa, S. E. Booth, D. A. Dawkins, P. R. Jenkins, J. Fawcett
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16 N. A. Petasis, S.-P. Lu, E. I. Bzowej, D.-K. Fu, J. P. Staszewski,
I. Akritopoulou-Zane, M. A. Patane and Y.-H. Hu, Pure Appl.
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17 W. J. Bailey and E. W. Cummins, J. Am. Chem. Soc., 1954, 76, 1932.
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19 P. Rajagopalan, B. G. Advani and C. N. Talaty, Org. Synth., 1973,
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Paper 7/08380G
Received 20th November 1997
Accepted 12th January 1998
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J. Chem. Soc., Perkin Trans. 1, 1998