Substituent effects on the 4π + 2π cycloadditions of 4H-pyran-4-one derivatives

Article abstract of DOI:10.1039/a900827f

The simple y-pyranones 4,5, and 6 undergo 4π + 2π cycloaddition reactions with Danishefsky's diene 8 and azomethine ylides 12,16, and 25 to give a range of cycloadducts. The position of the electron-withdrawing group is the decisive factor in these reactions, with the 2-substituted derivatives 5 and 6 being less reactive than the 3-substituted γ-pyranone 4. The esters, 4 and 5, react via addition across the 2,3-C=C bond of the pyranone ring, whilst the aldehyde 6 reacts via addition across the C=O of the carbaldehyde group.

Full text of DOI:10.1039/a900827f

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Substituent effects on the 4ð ؉ 2ð cycloadditions of 4H-pyran-4-
one derivatives
Mónika Rudas,a Imre Fejes,a Miklós Nyerges,a Áron Szöllõsy,b László Tõkea* and
Paul W. Groundwaterc
a Research Group of the Hungarian Academy of Sciences, Department of Organic Chemical
Technology, Technical University of Budapest, H-1521 Budapest P.O.B. 91, Hungary
b Institute for General and Analytical Chemistry, Technical University of Budapest,
H-1111 Budapest Gellért tér 4, Hungary
c School of Health Sciences, University of Sunderland, Sunderland, UK SR1 3SD
Received (in Cambridge) 1st February 1999, Accepted 5th March 1999
The simple γ-pyranones 4, 5, and 6 undergo 4π ϩ 2π cycloaddition reactions with Danishefsky’s diene 8 and
azomethine ylides 12, 16, and 25 to give a range of cycloadducts. The position of the electron-withdrawing group
is the decisive factor in these reactions, with the 2-substituted derivatives 5 and 6 being less reactive than the
3-substituted γ-pyranone 4. The esters, 4 and 5, react via addition across the 2,3-C᎐C bond of the pyranone ring,
᎐
whilst the aldehyde 6 reacts via addition across the C᎐O of the carbaldehyde group.
᎐
Ph
In the search for non-cytotoxic antitumour agents, which act via
the inhibition of protein tyrosine kinases, a variety of flavon-
O
O
O
X
O
CO2But
N
oids and their modified or annelated analogues have been
synthesised.1 We have recently prepared a number of pyrano-
acridones (e.g. 1) which exhibited good activity in biological
assays for the inhibition of growth factor mediated cell prolifer-
ation.2 As part of an ongoing investigation in our laboratories
into the synthesis of biologically active compounds, we became
interested in the reactivity of the 4H-pyran-4-ones as 2π com-
ponents in a variety of [4π ϩ 2π] cycloaddition reactions.3
In contrast to the well documented reactivity of 4H-benzo-
pyran-4-ones4 2a (X = O, EWG = CN, COOMe) or benzothio-
pyranones5 2b (X = S, EWG = CN, COOMe) the cycloadditions
of simple γ-pyrones have received rather limited attention.
Before the start of our investigations the only previous example
was a footnote by McCombie et al.,6a who reported that the
pyranone ester 4 reacted readily with diazomethane in a 1,3-
dipolar cycloaddition to give a single pyrazoline cycloadduct 3.
Since then one further report has emerged on a synthetic entry
to the trichothecene skeleton which successfully utilises a simple
4H-pyran-4-one as a Diels–Alder component.6b
EWG
O
N
N
H
Ph
O
O
H
1
2
3
6
O
O
CO2But
Ph
O
Ph
O
CO2Et
Ph
O
O
CHO
CHO
4
5
O
O
i
ii
Ph
O
CO2Et
Ph
O
CH2OH Ph
O
5
7
6
Scheme 1 Reagents and conditions: i, NaBH4, MeOH; ii, MnO2.
ester to the corresponding alcohol 7, which was then readily
oxidised to aldehyde 6 by manganese() oxide at room
temperature.
Results and discussion
We have considered the cycloaddition reactions of three 4H-
pyran-4-ones, including tert-butyl 4-oxo-6-phenyl-4H-pyran-
3-carboxylate 4 previously studied by McCombie et al.6a
During our earlier work we observed the non-reactivity of the
2-substituted ester, ethyl 4-oxo-6-phenyl-4H-pyran-2-carboxyl-
ate 5, towards different dienes and azomethine ylides. We now
describe some cycloadducts using these γ-pyranones as the 2π
component. We have also studied the reactivity of 4-oxo-4H-
pyran-2-carbaldehyde 6 in similar reactions.
Diels–Alder reactions
The reactivity of γ-pyranones 4 and 5 towards Danishefsky’s
diene 8 and 2-trimethylsilyloxybuta-1,4-diene has previously
been studied by us.3 The aldehyde 6 did not react, even after
long reaction times, with monosubstituted dienes (2-trimethyl-
silyloxybuta-1,4-diene or 1-methoxybuta-1,4-diene), but from
the reaction with Danishefsky’s diene 8 we were able to isol-
ate the bis(pyranylketone) 9 (Scheme 2). The stereochemistry
of the Diels–Alder adduct was deduced from the 2D-NOESY
spectrum. Enhancements of the signals for the H-2Ј and H-6Ј
protons confirmed that they are on the same face of the mole-
cule, consistent with an endo-approach of the dienophile to
Danishefsky’s diene 8. The methoxy group was eliminated by
the action of trifluoroacetic anhydride, at room temperature, to
give the 5Ј,6Ј-dihydro-2,6Ј-bipyran 10. The γ-pyranone alde-
hyde 6 acts as a heterodienophile in this cycloaddition, with the
Synthesis of the pyranones
The γ-pyranones 4 and 5 were prepared according to literature
methods.3b,6a,7 The aldehyde 6 has previously been prepared
from phenylacetylene derivatives under basic conditions in low
yield.8 We have developed a new route to aldehyde 6 starting
from the readily available ester 5 (Scheme 1). The direct reduc-
tion of ester 5 to aldehyde 6 using RedAl, or DIBAL-H at low
temperatures was unsuccessful. We have, however, reduced the
J. Chem. Soc., Perkin Trans. 1, 1999, 1167–1172
1167

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removed by the aid of a Dean–Stark trap), and this resulted in
the formation of the corresponding cycloadducts. The more
reactive pyranone 4 gave cycloadduct 17 in a good yield. The
less reactive ester 5 reacted also, to give cycloadduct 18, but the
yield was considerably reduced under the same conditions
(Scheme 5).
O
O
O
O
TMSO
OMe
8
i
O
O
OMe
Ph
CHO
Ph
6
9
CH3NCH2CO2H + (CH2O)n
i
ii
O
O
O
O
O
O
CO2But
O
O
Me
N
Ph
4
5
N
Me
N
Me
Ph
Ph
10
CO2Et
H
17
16
18
Scheme 2 Reagents and conditions: i, PhCH3, 70–80 ЊC, 18 h, 36%;
ii, CH2Cl2, TFAA, room temp., 48 h, 88%.
Scheme 5 Reagents and conditions: i, PhCH3, reflux.
More interestingly, the reactions of 4-oxo-4H-pyran-2-carb-
aldehyde 6 with these non-stabilised azomethine ylides, 12 and
16, led to the oxazolidine cycloadducts 19 and 20. Once again
C᎐O double bond being more reactive than the C᎐C double
᎐
᎐
bond. This is a major difference in comparison with the known
reactions of the analogous 4-oxobenzopyran-3-carbaldehydes
with electron-rich dienes.2a
the C᎐O double bond proved to be more reactive as the
᎐
dipolarophile in the 1,3-dipolar cycloaddition than the C᎐C
᎐
Reactions with non-stabilised azomethine ylides
double bond with an electron-withdrawing group (Scheme 6).
Both 4H-pyran-4-one derivatives 4 and 5 reacted smoothly with
the non-stabilised azomethine ylide 12 [generated by the desil-
ylation method from N-benzyl-N-(methoxymethyl)(trimethyl-
silyl)methylamine 119] at room temperature. The reaction of
γ-pyranone 4, as expected, gave rise to the formation of the
hexahydropyrano[2,3-c]pyrrole cycloadduct 13 in good yield
(Scheme 3).
O
O
O
O
O
O
16
12
O
N
O
N
Ph
Ph
CHO Ph
19
6
20
CH3
Ph
O
Scheme 6
CO2But
Ph
Ph
i
4
Reactions with ester-stabilised azomethine ylides
N
MeO
N
TMS
N
Ph
Ph
O
Azomethine ylides stabilised by the presence of one or more
electron-withdrawing or conjugating (e.g. phenyl) groups are
reported to be less reactive in normal electron demand
cycloadditions than the corresponding relatively electron-rich
unsubstituted analogues. For example, we have previously
reported that the azomethine ylide 21 (generated from the imine
of glycine esters in the presence of LiBr as a catalyst) acted as
a 4π component in a 1,3-dipolar cycloaddition. Ester 5 was
unreactive towards the stabilised azomethine ylide 21 but the
reaction with the pyranone 22 gave the cycloadduct 23 in mod-
erate yield (Scheme 7).3 The aldehyde 6 was also unreactive
under these conditions.
H
11
12
13
Scheme 3 Reagents and conditions: i, TFAA, toluene, room temp.
The γ-pyranone 5, however, reacted slowly, to yield a single
product 15—presumably arising from the reaction of the inter-
mediate cycloadduct 14 with excess of reagent 12—in moderate
yield (Scheme 4).
O
O
H
12
The 1,3-dipolar cycloadditions of azomethine ylides derived
from isoquinolinium salts 24 by deprotonation has previously
N
Ph
Ph
O
CO2Et
Ph
O
CO2Et
O
5
14
CO2Et
H
H
Ph
N
CO2Et
NH
Ph
Me
N
Ph
O
O
O
Ph
R1
21
O
CO2But
N
Ph
Ph
Ar
O
CO2Et
22
15
Scheme 4
O
O
CO2Et
NH
R3
H
Both 4H-pyran-4-one derivatives 4 and 5 reacted with
another non-stabilised azomethine ylide 16. This dipole was
generated by Tsuge’s protocol10 for the decarboxylative con-
densation of sarcosine with paraformaldehyde. A solution of
the γ-pyranone and an excess of sarcosine and paraformalde-
hyde in toluene was heated under reflux (the water formed was
Ar
Ph
23 R3 = CO2But, Ar = p-MeOC6H4
Scheme 7
1168
J. Chem. Soc., Perkin Trans. 1, 1999, 1167–1172

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Table 1 1H NMR shifts and coupling constants for cycloadducts 26 and 27
Entry
δ(H-2)
δ(H-3)
δ(H-4a)
δ(H-5)
δ(H-12b)
26a syn-endo
26b syn-exo
27 syn-endo
6.16, s
6.22, s
—
—
—
6.28, s
5.71, d (J 11.5 Hz)
5.87, d (J 5 Hz)
—
overlapping
overlapping
4.26, s
5.25, s
5.30, s
4.37, d (J 6 Hz)
been reported by us.11 The reaction of the derived ylide 25 with
γ-pyranone 4 gave rise to the formation of an inseparable mix-
ture of regio- and stereoisomers of cycloadducts 26 and 27 in
good overall yield (Scheme 8). The identifiable signals in the 1H
MeO
H
O
N
CO2Me
O
MeO
H
O
6
+ 25
H
O
CO2But
MeO
MeO
30
Ph
N
CO2Me
Ph
O
Scheme 10
Br
4
24
Et3N
Experimental
MeO
Column chromatography was performed using Merck Kieselgel
60 (70–230 mesh), and TLC on aluminium sheets coated with
Kieselgel 60 F254. Plates were stained with anisaldehyde solution
[glacial acetic acid (100 cm3), sulfuric acid (2 cm3), and anisalde-
hyde (1 cm3)] and heated at ca. 150 ЊC. IR spectra were obtained
on a NICOLET FTIR instrument. Low resolution electron
impact mass spectra were obtained on a Fisons VG Platform II
or Trio 2000 VG and high resolution spectra on a VG ZAB-E
spectrometer (EPSRC Mass Spectrometry Service Centre,
Swansea). NMR spectra were obtained on a Bruker AM 500
N
CO2Me
MeO
25
MeO
11
OMe
MeO
OMe
MeO
11
OMe
10
10
12
12
9
8
9
O
O
O
1
(500 MHz for H and 125 MHz for 13C) and a Bruker AC 250
H
E
H
E
H
1
H
1
Ph
O
2
8
12b
12b
instrument at 30 ЊC. Coupling constants (J) are given in Hz
and all chemical shifts are relative to an internal standard of
tetramethylsilane. Melting points are uncorrected.
2
12c
5
12c
N
N
N
7
7
4a
4a
6
5
6
4
3
3
Ph
O
Ph
H
H
E
4
CO2Me
CO2Me
CO2Me
O
2-Hydroxymethyl-6-phenyl-4H-pyran-4-one 7
26a syn-endo
26b syn-exo
27 syn-endo
E = CO2But
Ethyl 4-oxo-6-phenyl-4H-pyran-2-carboxylate 5 (28.4 g, 0.116
mol) was dissolved in methanol (200 cm3) and sodium boro-
hydride (18 g, 0.48 mol) was added in small portions over 30
min. The reaction mixture was refluxed for 3 h, cooled, and
treated with 5% aq. HCl (30 cm3). The methanol was removed
under vacuum, the residue was dissolved in water (100 cm3) and
the aqueous phase extracted with ether (3 × 50 cm3). The
organic layer was dried over magnesium sulfate and evaporated
under reduced pressure to give the title compound 7 as a white
powder (9.76 g, 42%), mp 147–149 ЊC (Found: C, 71.4; H,
4.9. C12H10O3 requires C, 71.3; H, 5.0%); νmax(KBr)/cmϪ1 3151
(OH), 1650 (C᎐O), 1596 (C᎐C); δ (500 MHz, [2H ]DMSO) 4.43
Scheme 8
NMR spectrum of the mixture are summarised in Table 1. By
comparison of this data with that from our previous work
we could deduce the most likely stereochemistry of these
cycloadducts.
The reaction of ylide 25 with γ-pyranone 5 gave the expected
anti-endo cycloadduct 29 as a single isomer, but in a very low
yield (<5%). The stereochemistry of this adduct has been
deduced by comparison to our previous work. Under these
reaction conditions the first step was the transesterification of
the ethoxycarbonyl function to methoxycarbonyl. Most of the
transesterified γ-pyranone 28 was recovered from the reaction
mixture (Scheme 9). A larger excess of dipole caused problems
᎐
᎐
H
6
(2H, d, J 7, CH2,), 5.79 (1H, t, J 7, OH), 6.29 (1H, d, J 3, H-5),
6.88 (1H, d, J 3, H-3), 7.61–7.48 (3H, m, H-3Ј,4Ј,5Ј), 7.98–7.88
(2H, m, H-2Ј,6Ј); δC ([2H6]DMSO) 60.0 (CH2), 111.1 (CH),
111.9 (CH), 126.4 (2 × CH), 129.5 (2 × CH), 131.3 (quat.),
131.9 (CH), 162.83 (quat.), 169.2 (quat.), 179.3 (C᎐O); m/z 202
8
9
᎐
MeO
(Mϩ, 100%), 174 (43), 157 (74), 129 (24), 115 (34), 105 (74),
102 (88), 77 (65), 69 (52).
7
O
N
CO2Me
CO2Me
MeO
12b
H
H
O
12
5
5
4-Oxo-6-phenyl-4H-pyran-2-carbaldehyde 6
12c
O
2
3
2-Hydroxymethyl-6-phenyl-4H-pyran-4-one 7 (0.49 g, 2.4
Ph
O
CO2Me
mmol) was dissolved in dichloromethane (20 cm3) and activated
manganese() oxide (1.8 g, 21 mmol) was added. The reaction
mixture was stirred efficiently for 48 h at room temperature then
the black suspension was filtered through a pad of silica, which
was washed with warm ethyl acetate (50 cm3). The resulting
solution was evaporated under reduced pressure to give a pale
yellow solid. The solid was purified by flash chromatography,
eluting with hexane–ethyl acetate (1:4) to give the aldehyde 6 as
a white powder (0.24 g, 49%), mp 115–116 ЊC (lit.8 118–119 ЊC)
(Found: C, 71.9; H, 4.1. C12H8O3 requires C, 72.0; H, 4.0%);
νmax(nujol)/cmϪ1 1658 (C᎐O), 1589 (C᎐C); δ (250 MHz, CDCl )
28
29
Ph
Scheme 9
with by-products (which form in the absence of the reactive
partner).
Finally, the reaction of ylide 25 with the γ-pyranone aldehyde
6 once again resulted in addition across the C᎐O double bond
᎐
to give the oxazolidine 30 as a single isomer in a moderate yield
(Scheme 10). The stereochemistry of this adduct was confirmed
by a 2D-NOESY spectrum.
᎐
᎐
H
3
J. Chem. Soc., Perkin Trans. 1, 1999, 1167–1172
1169

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6.86 (1H, d, J 2.5, H-5), 6.90 (1H, d, J 2.5, H-3), 7.63–7.37 (3H,
m, H-3Ј,4Ј and 5ЈH), 7.93–7.71 (2H, m, H-2Ј and 6ЈH), 9.73
(1H, s, CHO); δC(125 MHz, CDCl3) 113.0 (CH), 121.5 (CH),
126.2 (2 × CH), 129.2 (2 × CH), 130.2 (quat.), 132.2 (CH),
156.6 (quat.), 163.8 (quat.), 179.3 (quat.), 184.3 (CHO); m/z 200
(Mϩ, 100%), 172 (95), 157 (20), 115 (25), 105 (15), 102 (33), 77
(41), 69 (40), 51 (18).
J 7 and 5, H-3a), 6.09 (1H, s, H-6), 7.28 (5H, m, Ph), 7.43 (2H,
t, J 7.5, Ph-3Ј and 5ЈH), 7.49 (1H, t, J 7.5, Ph-4ЈH), 7.73 (2H, d,
J 7.5 Hz, Ph-2Ј and 6ЈH); δC(125 MHz, CDCl3) 26.8 (3 × CH3),
57.5 (NCH2), 57.8 (NCH2), 58.9 (NCH2), 59.9 (quat.), 81.5
(CH), 81.9 (quat.), 99.1 (CH), 125.5 (2 × CH), 126.1 (CH),
127.3 (2 × CH), 127.5 (2 × CH), 127.7 (2 × CH), 130.7 (CH),
131.8 (quat.), 137.2 (quat.), 166.4 (quat.), 167.2 (C᎐O), 187.1
᎐
(C᎐O).
᎐
Diels–Alder reactions
Ethyl
2-benzyl-1,2,3,3a,7,7a-hexahydro-7a-[(N-methyl-N-
2-(2Ј,3Ј,5Ј,6Ј-Tetrahydro-6Ј-methoxy-4Ј-oxo-4ЈH-pyran-2Ј-
yl)-6-phenyl-4H-pyran-4-one 9. 4-Oxo-6-phenyl-4H-pyran-2-
carbaldehyde 6 (0.15 g, 0.75 mmol) and Danishefsky’s diene
8 (0.16 g, 0.93 mmol) were dissolved in dry toluene (8 cm3)
and the reaction mixture was stirred at 70–80 ЊC for 18 h. The
reaction mixture was then evaporated under reduced pressure
and the residue recrystallised from ether–hexane–ethanol to
give the title compound 9 as a light brown powder (80 mg,
36%), mp 122 ЊC (Found: Mϩ, 300.100. Calc. for C17H16O5: M,
300.100); νmax(KBr)/cmϪ1 1712 (C᎐O), 1655 (C᎐O), 1614 (C᎐C);
benzylamino)methyl]-7-oxo-5-phenylpyrano[2,3-c]pyrrole-3a-
carboxylate 15. From ethyl 4-oxo-6-phenyl-4H-pyran-2-carb-
oxylate 5, as a pale yellow oil (0.06 g, 29%) (Found: C, 75.5; H,
6.7; N, 5.4. Calcd. for C32H34N2O4: C, 75.3; H, 6.7; N, 5.5%);
νmax(liquid film)/cmϪ1 1726 (ester C᎐O), 1646 (C᎐O), 1611
᎐
᎐
(C᎐C); δ (500 MHz, CDCl ) 1.33 (3H, t, J 7.2, CH CH ), 2.00
᎐
H
3
3
2
(3H, s, NCH3), 2.88 (1H, d, J 13.5, NCH2), 3.02 (1H, d, J 8.5,
NCH2), 3.05 (1H, d, J 13.5, NCH2), 3.32 (1H, d, J 13.5, NCH2),
3.35 (1H, d, J 11.5, NCH2), 3.41 (1H, d, J 11.5, NCH2), 3.53
(1H, d, J 8.5, NCH2), 3.56 (1H, d, J 13.5, NCH2), 3.67 (1H,
d, J 13.5, NCH2), 3.77 (1H, d, J 13.5, NCH2), 4.20 (2H, m,
CH2CH3), 6.21 (1H, s, H-6), 7.15–7.28 (10H, m, Ph), 7.45 (2H,
t, J 7.8, H-3Ј,5Ј), 7.49 (1H, t, J 7.8, H-4Ј), 7.79 (2H, d, J 7.8,
H-2Ј,6Ј); δC(125 MHz, CDCl3) 14.5 (CH3CH2), 43.1 (NCH3),
59.1 (CH2), 59.3 (quat.), 59.7 (CH2), 61.7 (CH2), 63.1 (CH2),
64.1 (CH2), 64.4 (CH2), 90.2 (quat.), 101.7 (CH), 126.6
(2 × CH), 126.8 (CH), 127.0 (CH), 127.9 (2 × CH), 128.3
(2 × CH), 128.4 (2 × CH), 128.9 (2 × CH), 129.1 (2 × CH),
131.6 (CH), 132.8 (quat.), 138.4 (quat.), 138.9 (quat.), 165.4
᎐
᎐
᎐
δH(500 MHz, CDCl3) 2.65 (1H, dd, J 15.6 and 7.5, CH2-5), 2.82
(3H, m, CH2), 3.56 (3H, s, OMe), 4.73 (1H, dd, J 10.9 and 4.0,
H-2Ј), 4.88 (1H, dd, J 7.5 and 2.8, H-6Ј), 6.57 (1H, d, J 2, H-3),
6.75 (1H, d, J 2, H-5), 7.41 (3H, m, Ph), 7.51 (2H, m, Ph);
δC(125 MHz, CDCl3) 43.8 (CH2), 47.1 (CH2), 56.7 (OCH3), 69.7
(CH), 101.1 (CH), 111.5 (CH), 112.9 (CH), 125.8 (2 × CH),
129.2 (2 × CH), 130.8 (quat.), 131.7 (quat.), 163.5 (quat.), 164.7
(quat.), 179.7 (C᎐O), 202.5 (C᎐O); m/z 300 (Mϩ, 10%), 199 (60),
᎐
᎐
186 (28), 170 (100), 105 (11), 102 (21), 58 (19).
(quat.), 170.7 (C᎐O), 194.5 (C᎐O).
᎐
᎐
2-(2Ј,3Ј-Dihydro-4Ј-oxo-4ЈH-pyran-2Ј-yl)-6-phenyl-4H-
pyran-4-one 10. 2-(2Ј,3Ј,5Ј,6Ј-Tetrahydro-6Ј-methoxy-4Ј-oxo-
4ЈH-pyran-2Ј-yl)-6-phenyl-4H-pyran-4-one 9 (14 mg, 47 µmol)
was dissolved in dichloromethane (2 cm3) and trifluoroacetic
anhydride (2 drops) was added. The reaction mixture was
stirred for 48 hours at room temperature, then saturated
aqueous sodium hydrogen carbonate solution (3 cm3) was
added. The organic layer was separated, dried over magnesium
sulfate, and evaporated under reduced pressure to give 10 as a
light yellow solid (11 mg, 88%), mp 131–132 ЊC (Found: Mϩ,
268.0725. Calc. for C16H12O4: M, 268.074); δH(500 MHz,
CDCl3) 2.91 (1H, dd, J 16.5 and 4.5, H-3Ј), 2.98 (1H, dd, J 16.5
and 12.5, H-3Ј), 5.37 (1H, dd, J 12.5 and 4.5, H-2Ј), 5.61
(1H, d, J 6.1, H-5Ј), 6.53 (1H, s, H-5), 6.77 (1H, s, H-3), 7.47
(1H, d, J 6.1, H-6Ј), 7.53 (3H, m, Ph), 7.73 (2H, d, J 7.2, Ph);
δC(125 MHz, CDCl3) 39.6 (CH2), 76.5 (CH), 108.4 (CH), 111.9
(CH), 114.0 (CH), 126.0 (2 × CH), 129.4 (2 × CH), 130.8
(quat.), 132.0 (CH), 163.9 (quat.), 162.3 (CH), 161.9 (quat.),
179.5 (C᎐O), 189.6 (C᎐O); m/z 268 (Mϩ, 11%), 239 (22), 212
6-Phenyl-2-(3-benzyl-1,3-oxazolidin-5-yl)-4H-pyran-4-one 20.
From 4-oxo-6-phenyl-4H-pyran-2-carbaldehyde 6, as a white
powder (69 mg, 49%), mp 144–145 ЊC (Found: Mϩ, 333.135.
C21H19NO3 requires: M, 333.1365); νmax(KBr)/cmϪ1 1659
(C᎐O), 1615 (C᎐C); δ (500 MHz, CDCl ) 3.18 (1H, dd, J 11
᎐
᎐
H
3
and 7, H-4Ј), 3.49 (1H, dd, J 11 and 7, H-4Ј), 3.85 (2H, s,
NCH2), 4.60 (2H, s, H-2Ј), 4.84 (1H, t, J 7, H-5Ј), 6.51 (1H, d,
J 1.5, H-5), 6.73 (1H, d, J 1.5 Hz, H-3), 7.25–7.35 (6H, m, Ph),
7.48 (2H, m, Ph), 7.72 (2H, m, Ph); δC(125 MHz, CDCl3) 57.1
(NCH2), 58.4 (NCH2), 72.4 (CH), 88.0 (CH2), 111.5 (CH),
112.2 (CH), 125.8 (2 × CH), 127.6 (CH), 128.6 (2 × CH), 128.7
(2 × CH), 129.1 (2 × CH), 131.1 (quat.), 131.5 (CH), 138.1
(quat.), 163.5 (quat.), 167.6 (quat.), 179.9 (C᎐O); m/z 333 (Mϩ,
᎐
5%), 42 (62), 65 (12), 77 (12), 91 (100), 102 (13), 132 (20), 133
(50).
Decarboxylation method—general procedure
᎐
᎐
The corresponding 4H-pyran-4-one (0.59 mmol), sarcosine
(0.20 g, 2.3 mmol) and paraformaldehyde (0.18 g, 5.8 mmol)
were suspended in toluene (10 cm3) and the mixture was
refluxed for 3 h. The water formed was removed by the aid of a
Dean–Stark trap. After completion of the reaction the solvent
was evaporated under reduced pressure and the residue was
purified by flash chromatography.
(13), 170 (100), 115 (13), 102 (33), 77 (18), 69 (18), 55 (11).
1,3-Dipolar cycloadditions of azomethine ylides
Desilylation method—general procedure. The corresponding
4H-pyran-4-one (0.37 mmol) and N-benzyl-N-(methoxy-
methyl)(trimethylsilyl)methylamine 11 (0.12 g, 0.55 mmol) were
dissolved in dry toluene (5 cm3) and trifluoroacetic acid (1 drop)
was added. After stirring for 48 h at room temperature the
reaction mixture was evaporated under reduced pressure and
the residue was purified by column chromatography.
tert-Butyl 2-methyl-1,2,3,3a,7,7a-hexahydro-7-oxo-5-phenyl-
pyrano[2,3-c]pyrrole-7a-carboxylate 17. From tert-butyl 4-oxo-
6-phenyl-4H-pyran-3-carboxylate 4 as a white semi-solid (0.14
g, 72%) (Found: C, 69.9; H, 7.2; N, 4.2. Calcd. for C19H23NO4:
tert-Butyl 2-benzyl-1,2,3,3a,7,7a-hexahydro-7-oxo-5-phenyl-
pyrano[2,3-c]pyrrole-7a-carboxylate 13. From tert-butyl 4-oxo-
6-phenyl-4H-pyran-3-carboxylate 4, as a pale yellow oil (0.14 g,
91%) (Found: C, 74.2; H, 6.8; N, 3.4. Calcd. for C25H27NO4:
C, 74.05; H, 6.7; N, 3.45%); νmax(liquid film)/cmϪ1 1728 (ester
C, 69.3; H, 7.0; N, 4.3%); νmax(KBr)/cmϪ1 1729 (ester C᎐O),
᎐
1648 (C᎐O), 1609 (C᎐C); δ (250 MHz, CDCl ) 1.44 (9H, s,
᎐
᎐
H
3
But), 2.37 (3H, s, NCH3), 3.04 (1H, dd, J 10.5 and 5, H-3), 3.10
(1H, dd, J 10.5 and 6.5, H-3), 3.23 (1H, d, J 10.5, H-1), 3.28
(1H, d, J 10.5, H-1), 5.42 (1H, dd, J 6.5 and 5, H-3a), 6.09 (1H,
s, H-6), 7.46 (3H, m, H-3Ј,4Ј,5Ј), 7.75 (2H, d, J 7, H-2Ј,6Ј);
δC(125 MHz, CDCl3) 27.8 (3 × CH3), 42.3 (NCH3), 58.5 (quat.),
61.2 (CH2), 61.4 (CH2), 82.6 (CH), 83.2 (quat.), 100.0 (CH),
126.5 (2 × CH), 128.7 (2 × CH), 131.8 (CH), 132.8 (quat.),
C᎐O), 1646 (C᎐O), 1608 (C᎐C); δ (500 MHz, CDCl ) 1.44 (9H,
᎐
᎐
᎐
H
3
s, But), 3.00 (1H, dd, J 10.5 and 5, H-3), 3.17 (1H, dd, J 10.5
and 7, H-3), 3.28 (1H, d, J 10, H-1), 3.34 (1H, d, J 10, H-1), 3.63
(1H, d, J 13, CH2Ph), 3.72 (1H, d, J 13, CH2Ph), 5.44 (1H, dd,
1170
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View Article Online
167.6 (quat.), 168.2 (C᎐O), 188.0 (C᎐O); m/z 330 (Mϩ, 17%),
Methyl 4-oxo-6-phenyl-4H-pyran-2-carboxylate 28
᎐
᎐
274 (21), 230 (100).
From ethyl 4-oxo-6-phenyl-4H-pyran-2-carboxylate 5, as a
white solid (0.17 g, 74%), mp 125 ЊC (lit.12 127 ЊC); νmax(KBr)/
cmϪ1 1748 (C᎐O), 1656 (C᎐O), 1618 (C᎐C); δ (250 MHz,
CDCl3) 4.01 (3H, s, OMe), 6.66 (d, 1H, J 2.4, H-5), 7.12 (d, 1H,
J 2.4, H-3), 7.53 (3H, m, H-3Ј,4Ј,5Ј), 7.86 (2H, m, H-2Ј,6Ј);
δC(125 MHz, CDCl3) 53.5 (OCH3) 112.5 (CH), 119.3 (CH),
126.2 (2 × CH), 129.2 (2 × CH), 130.5 (quat.), 132.0 (CH),
152.3 (quat.), 160.6 (quat.), 163.9 (quat.), 179.6 (quat.).
Ethyl 1,2,3,3a,7,7a-hexahydro-2-methyl-7-oxo-5-phenyl-
᎐
᎐
᎐
H
pyrano[2,3-c]pyrrole-3a-carboxylate 18. From ethyl 4-oxo-6-
phenyl-4H-pyran-2-carboxylate 5, as a pale yellow semi-solid
(0.067 g, 38%) (Found: Mϩ, 301.131. C17H19NO4 requires: M,
301.131); νmax(KBr)/cmϪ1 1726 (C᎐O), 1648 (C᎐O), 1603 (C᎐C);
δH(500 MHz, CDCl3) 1.26 (3H, t, J 7.2, CH3CH2), 2.45 (3H, s,
NCH3), 3.03 (1H, t, J 9.5, H-1), 3.23 (1H, t, J 9.5, H-1), 3.25
(1H, d, J 11, H-3), 3.43 (1H, d, J 11, H-3), 3.50 (1H, t, J 9.4,
H-7a), 4.25 (2H, q, J 7.2, OCH2), 5.99 (1H, s, H-6), 7.44 (2H, t,
J 7.5, H-3Ј,5Ј), 7.51 (1H, t, J 7.5, H-4Ј), 7.82 (2H, d, J 7.5,
H-2Ј,6Ј); δC(125 MHz, CDCl3) 14.2 (CH3), 42.3 (NCH3), 51.8
(CH), 59.2 (CH2), 62.7 (CH2), 67.3 (OCH2), 90.2 (quat.), 101.1
(CH), 127.3 (2 × CH), 128.8 (2 × CH), 132.1 (CH), 132.9
(quat.), 169.0 (quat.), 170.3 (C᎐O), 191.0 (C᎐O); m/z 301 (Mϩ,
᎐
᎐
᎐
8,9-Dimethoxy-3-methoxycarbonyl-2-(4-oxo-6-phenyl-4H-
pyran-2-yl)-2,3,6,10b-tetrahydro-5H-[1,3]oxazolo[2,3-a]iso-
quinoline 30
From 4-oxo-6-phenyl-4H-pyran-2-carbaldehyde 6, as a white
solid, recrystallised from ethanol (0.2 g, 44%), mp 133–135 ЊC
(Found: C, 67.4; H, 5.4; N, 3.0. Calcd. for C26H25NO7: C, 67.4;
H, 5.4; N, 3.0%) (Found: MHϩ, 464.170. C26H26NO7 requires:
M, 464.170); νmax(KBr)/cmϪ1 1747 (C᎐O), 1665 (C᎐O); δ (500
᎐
᎐
17%), 255 (30), 202 (28), 154 (12), 150 (31), 105 (56), 82 (79), 77
(30), 69 (15), 57 (100), 42 (22).
᎐
᎐
H
MHz, CDCl3) 2.66 (1H, m), 2.97–3.13 (3H, m), 3.89 (9H, s,
3 × OMe), 4.05 (1H, d, J 4.6, H-3), 5.00 (1H, d, J 4.6, H-2), 5.58
(1H, s, H-10b), 6.53 (1H, d, J 1.6, H-5Ј), 6.65 (1H, s, H-7), 6.71
(1H, d, J 1.6, H-3Ј), 6.93 (1H, s, H-10), 7.49 (3H, m, Ph), 7.74
(2H, m, Ph); δC(125 MHz, CDCl3) 29.4 (Ar-CH2), 47.8 (CH2N),
53.0 (OMe), 56.1 (OMe), 56.2 (OMe), 72.6 (CH), 76.7 (CH),
92.6 (CH), 110.7 (CH), 111.4 (CH), 111.7 (CH), 113.0 (CH),
122.3 (quat.), 126.0 (2 × CH), 127.7 (quat.), 129.3 (2 × CH),
131.2 (quat.), 131.7 (CH), 148.0 (quat.), 149.8 (quat.), 163.7
6-Phenyl-2-(3-methyl-1,3-oxazolidin-5-yl)-4H-pyran-4-one
19. From 4-oxo-6-phenyl-4H-pyran-2-carbaldehyde 6, as a pale
yellow oil (71 mg, 47%) (Found: C, 70.2; H, 5.8; N, 5.4. Calcd.
for C15H15NO3: C, 70.0; H, 5.9; N, 5.4%); δH(250 MHz, CDCl3)
2.53 (3H, s, NCH3), 3.15 (1H, dd, J 11.8 and 6.5, H-4Ј), 3.41
(1H, dd, J 11.8 and 6.5, H-4Ј), 4.52 (1H, d, J 8.2, H-2Ј), 4.54
(1H, d, J 8.2, H-2Ј), 4.84 (1H, t, J 6.5, H-5Ј), 6.49 (1H, d, J 2.3,
H-3), 6.72 (1H, d, J 2.3, H-5), 7.51 (3H, m, H-3Ј,4Ј,5Ј), 7.37
(2H, m, H-2Ј,6Ј); δC(125 MHz, CDCl3) 41.9 (NCH3), 59.4
(NCH2), 72.3 (CH), 90.0 (CH2), 111.5 (CH), 112.1 (CH), 125.8
(2 × CH), 129.1 (2 × CH), 131.1 (quat.), 131.5 (CH), 163.5
(quat.), 165.9 (quat.), 171.5 (C᎐O), 179.8 (C᎐O); m/z 465 (24%),
᎐
᎐
464 (MHϩ, 100).
(quat.), 167.6 (quat.), 179.9 (C᎐O); m/z 258 (MHϩ, 100%).
᎐
Acknowledgements
This work was financially supported by the National Fund for
Science and Research (OTKA Project No. F 23684). A grant
from the József Varga Foundation provided to M. R. is grate-
fully appreciated. We thank the EPSRC National Mass
Spectrometry Service Centre, Swansea for high resolution mass
spectra.
Reactions with the dipole generated from 6,7-dimethoxy-2-
(methoxycarbonylmethyl)-3,4-dihydroisoquinolinium bromide—
general procedure
The appropriate 4H-pyran-4-one (1.0 mmol) and 6,7-
dimethoxy-(2-methoxycarbonylmethyl)-3,4-dihydroisoquino-
lin-2-ium bromide 25 (0.29 g, 0.85 mmol) were dissolved in dry
methanol (10 cm3). Triethylamine (0.14 cm3, 0.10 g, 1 mmol)
was added and the reaction mixture was stirred at room tem-
perature for 10–24 h. The solvent was removed under reduced
pressure and the residue was suspended in ether (20 cm3). The
ethereal solution was washed with water (10 cm3) then brine
(5 cm3), dried over MgSO4 and evaporated under reduced pres-
sure. The residue was purified by column chromatography,
eluting with hexane–ethyl acetate (1:1).
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536.228). Ratio of isomers 26a:26b:27 = 29:4:19 (from 1H
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3.27 (2H, m, H-7), 3.37 (1H, d, J 7.3, H-12c), 3.84 (3H, s, OMe),
3.87 (3H, s, OMe), 3.89 (3H, s, OMe), 3.93 (3H, s, OMe), 4.52
(1H, s, H-5), 4.83 (1H, d, J 7.3, H-12b), 6.06 (1H, s, H-2), 6.60
(1H, s, H-12), 7.10 (1H, s, H-9), 7.50 (3H, m, H-3Ј,4Ј,5Ј), 7.75
(2H, d, J 7.6, H-2Ј,6Ј); δC(125 MHz, CDCl3) 23.4 (CH2), 45.3
(CH2), 52.6 (OMe), 53.6 (OMe), 55.9 (OMe), 56.0 (OMe), 57.9
(CH), 63.8 (CH), 71.1 (CH), 90.2 (quat.), 100.9 (CH), 110.4
(CH), 111.0 (CH), 125.8 (quat.), 126.3 (quat.), 127.1 (2 × CH),
128.5 (quat.), 128.7 (2 × CH), 132.1 (CH), 147.7 (quat.), 148.3
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᎐
J. Chem. Soc., Perkin Trans. 1, 1999, 1167–1172
1171

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