Pyrimidine annelated heterocycles-synthesis and cycloaddition of the first pyrimido[1,4]diazepine N-oxides

Article abstract of DOI:10.1039/b007163n

5-Formyl- and 5-acetyl-4-(alkenylamino)pyrimidines 5 have been prepared as precursors to novel pyrimido[1,4]-diazepine N-oxides 3. In addition to cyclisation to the targeted dipoles the substrates 5 have also been observed to form imidazopyrimidines 12 and 39 via an intramolecular Michael addition; additionally 5b has been observed to form the pyrimidoazepinone 42. Aldonitrone 3a cycloadded readily to olefinic dipolarophiles; ketodipole 3b did not share this reactivity. Both dipoles reacted with acetylenic dipolarophiles but the ensuing cycloadducts 37 were unstable; facile ring contraction of their isoxazolopyrimidodiazepine skeletons to the pteridine nucleus is noted. The structure of 37c has been determined by X-ray crystallography.

Full text of DOI:10.1039/b007163n

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Pyrimidine annelated heterocycles—synthesis and cycloaddition of
the first pyrimido[1,4]diazepine N-oxides
Frances Heaney,*a Cathriona Burke,b Desmond Cunninghamb and Patrick McArdleb
1
a Department of Chemistry, The National University of Ireland, Maynooth, Ireland
b Department of Chemistry, The National University of Ireland, Galway, Ireland
Received (in Cambridge, UK) 5th September 2000, Accepted 23rd January 2001
First published as an Advance Article on the web 27th February 2001
5-Formyl- and 5-acetyl-4-(alkenylamino)pyrimidines 5 have been prepared as precursors to novel pyrimido[1,4]-
diazepine N-oxides 3. In addition to cyclisation to the targeted dipoles the substrates 5 have also been observed to
form imidazopyrimidines 12 and 39 via an intramolecular Michael addition; additionally 5b has been observed
to form the pyrimidoazepinone 42. Aldonitrone 3a cycloadded readily to olefinic dipolarophiles; ketodipole 3b
did not share this reactivity. Both dipoles reacted with acetylenic dipolarophiles but the ensuing cycloadducts 37
were unstable; facile ring contraction of their isoxazolopyrimidodiazepine skeletons to the pteridine nucleus is noted.
The structure of 37c has been determined by X-ray crystallography.
chloropyrimidine proceeded in high yield only when the amino
Introduction
component did not carry an α-substituent.4
Pyrimidines and their ring fused derivatives have a broad
spectrum of biological activity; best known as the heterocyclic
Results and discussion
core of the nucleic acid bases, these ring systems are often
incorporated into drugs designed for cancer and anti-viral
treatment.1 We have been investigating the preparation and
The general approach to the preparation of γ-aminocrotonates
related to 7 involves nucleophilic displacement of an allylic
halide or nosylate (p-nitrobenzenesulfonate) from the appro-
priate crotonate.5 The amine 7 was prepared from reaction of
methyl 4-bromobut-2-enoate with benzylamine. The identity of
the reaction product is sensitive to the experimental conditions.
With an equimolar ratio of reactants the N,N-bisalkylated
compound 8 is the major product (69%); moderate yields of
the corresponding diesters were obtained by Rahman and co-
workers6 on reaction of primary alkyl amines with the same
bromobutenoate. The optimal yield of 7 (65%) was obtained
following reaction with three equivalents of benzylamine (Et2O,
0 ЊC). With a large excess of benzylamine, 10 equivalents, the
4-aminopyrrolidinone 9 resulted (100%). The lactam likely
arises from 7 in two steps, viz. an initial Michael type addition
of a second molecule of BnNH2, giving 10, followed by a 5-exo-
trig cyclisation. Alternatively 10 may arise from 7 via an initial
shift of the amino group from the external to the internal
position by way of an aziridine intermediate, 11 and ring
opening by amine attack at the less substituted ring carbon7
(Scheme 2).
cycloaddition potential of 1,4-benzodiazepinone N-oxides2
1
and more recently have turned our attention to a hitherto
unknown series of pyrimidine compounds, the isoxazolo-
pyrimidodiazepines 2. 8,9-Dihydro-7H-pyrimido[4,5-e][1,4]-
diazepine N6-oxides, 3, were the target nitrones and their
synthesis from (alkenylamino)pyrimidines 5 was envisaged
(Scheme 1). Similar substrates have been widely investigated by
Noguchi’s group in their comprehensive study of the prepar-
ation of fused azepine rings by intramolecular thermal ene
reactions (carbonyl, imine or hydrazone).3 In a recent com-
munication we reported that the preparation of compounds like
5 from a condensation reaction of a secondary amine with a
The condensation between the allylic amine 7 and the
Scheme 1
622
J. Chem. Soc., Perkin Trans. 1, 2001, 622–632
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b007163n

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Fig. 2
The isoxazolopyridopyrimidine 14 is furnished diastereo-
specifically and has cis ring junction stereochemistry as indi-
cated by both coupling constant [J9b,3a 6.01 Hz], and nuclear
Overhauser enhancement difference spectroscopy results
(NOEDS), summarised in Fig. 1]. Intramolecular cycloaddition
of related azomethine ylides, nitrile oxides and nitrile imines
giving 5,6,6-ring systems, pyrrolo- 15, isoxazolo- 16 and
Fig. 1
pyrazolo-pyridopyrimidines 17 have been reported.10 In a closer
parallel Noguchi has demonstrated, and afforded a mechanistic
proposal for, an IOOC reaction of a pyrido[1,2-a]pyrimidine
system,8e e.g. the oxime 18 upon heating in EtOH afforded the
Scheme 2
chloropyrimidine 6a furnished 5a in high yield (78%) following
stirring in CHCl3 at rt in the presence of triethylamine. We
anticipated a straightforward carbonyl to oxime functionalis-
ation on reaction of 5a with NH2OH, however a number of
products resulted from this reaction. The starting aldehyde 5a
and the proposed oxime 4a both have a high density of func-
tionality and imidazopyrimidines 12a,b can arise from these
tetracycle 19a in 93% yield; when the reaction solvent was
changed to C6H6 diastereomeric adducts 19a,b (76% and 14%
yield respectively) were obtained together with the tricyclic
N-oxide 20 (8%). The product distribution with Noguchi’s sub-
strate differs significantly from ours; the low yield of the dipole
and the absence of any imidazo fused adducts is a consequence
of the electronically neutral pendant double bond in 18. The
corresponding centre in 4a carries a methoxycarbonyl sub-
stituent which facilitates nucleophilic attack by the oxime or
pyrimidine nitrogen atoms furnishing dipole 3a and imidazo-
pyrimidines 12a/b respectively. In keeping with the requirement
for a high degree of electrophilicity at the unsaturated centre it
is perhaps not surprising that the terminally unsubstituted
alkynyl substrate 21 failed to partake in any ring forming reac-
tions. After several hours heating alone or in the presence of
AgBF4 21 was returned unchanged. The nitrone forming power
of the intramolecular oxime–alkyne cyclisation reaction has
been demonstrated thermally for 6-membered dipoles11 and
Ag() catalysed oxime–allene cyclisation leading to 5- and
6-membered nitrones has been reported.12 The cyclisation of 21
substrates by cyclisation of the nucleophilic pyrimidine nitro-
gen atom onto the pendant electrophilic alkene.4 The oxime 4
has two further channels for reactivity, viz. tautomerisation to
the corresponding NH-dipole 13 with subsequent cycloaddition
to 14 [intramolecular oxime olefin cycloaddition, IOOC, Fig.
1],8 or 7-exo-trig cyclisation to the targeted pyrimidodiazepine
N-oxide 3a [azaprotio cyclotransfer reaction, APT,9 Fig. 2]. The
conditions best disposed to nitrone formation employed MeOH
at 0 ЊC, whence 3a was isolated in 65% yield accompanied by
14% of the tricyclic isoxazolopyridopyrimidine 14 [IOOC
product], 5% of the imidazopyrimidine 12a and 5% of the
corresponding oxime 12b.
J. Chem. Soc., Perkin Trans. 1, 2001, 622–632
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Table 1 13C Resonance position for the methylenic carbon atoms in
the adducts 23–26
Adduct (NMR CH2 on isoxazol-
solvent)
idine ring
NCH2Ph C-6
CH2CO2Me
23 (CDCl3)
24 (CDCl3)
25 (CDCl3)
26 (C6D6)
39.23
42.80
42.23
67.85
53.50
54.43
53.81
54.33
52.95 33.44
52.94 36.76
50.46 36.83
50.00 36.87
has both electronic and geometrical disadvantages when com-
pared with substrates like 4 and thus has a prohibitively high
activation energy.
Cycloaddition of nitrone 3a to N-methylmaleimide (THF, rt,
24 h) proceeded with high diastereofacial selectivity; the major
adduct 22 was isolated in 73% yield and a second isomer too
stituent in the 5-position of the isoxazolidine ring and the
major adduct 26 is a “4-substituted” regioisomer. The regio-
chemical assignments are easily made following analysis of the
13C DEPT 135 spectrum. The adducts have four methylene
groups in total; three of these, NCH2Ph, C-6 and CH2CO2Me,
are common to all the adducts and their 13C resonance posi-
tions are similar (Table 1). For any “5-substituted” isoxazolid-
ines the fourth methylene carbon is C-11 and it has two directly
attached carbon atoms. The final methylene carbon atom of
“4-substituted” adducts is C-10. It has neighbouring oxygen
and carbon atoms; consequently it is deshielded with respect to
C-11 in the regioisomeric compounds.
1
Unfortunately the H NMR data of the adducts 23–26 are
not good enough to permit discrimination between the possible
diastereomeric structures. For the major adduct, 26, with the
exception of the methoxy and the aryl protons, all the reson-
ance signals in the 1H NMR spectrum recorded at rt appeared
broad. When the spectrum was recorded with a probe temper-
ature of Ϫ19.9 ЊC the signals sharpened to reveal the expected
multiplicities. It is thus apparent that the adduct enjoys a degree
of conformational mobility at rt which is removed on cooling to
~Ϫ20 ЊC. A Dreiding scale model of the tricyclic framework of
26 indicates significant flexibility; the diazepine ring easily flips
between the boat and various half chair conformations and
there is also some opportunity for ring inversion of the isoxazol-
idine nucleus. Molecular modelling and/or NMR analyses have
been performed on skeleta related to 26, e.g. isoxazolo[2,3-d]-
[1,4]benzodiazepinone 27,13a imidazo[1,5-a][1,4]benzodiazepine
Fig. 3 NOEDS results for compound 22.
small in quantity to be isolated was seen in the 1H NMR
spectrum of the crude reaction mixture. The relative stereo-
chemistry of 22, the first example of this ring system, is tent-
atively assigned as shown following NOEDS experiments; the
pertinent results are summarised in Fig. 3. That the 12a- and
12b-protons are cis is evident from their mutual enhancement
upon irradiation of each other (~6%). On its own the small
enhancement (~1%) on 7-H following irradiation of 12b-H is
insufficient to confidently assign these protons as being cis-
orientated; however this proposal is indirectly supported by the
following enhancements: 12b-H to 6-H (~5%) and 6-H to 7-H
(~2%). The tetracyclic skeleton of 22 thus arises from a transi-
tion state involving an endo-addition of the dipolarophile to the
face of the dipole carrying the CH2CO2Me substituent.
Cycloaddition to monosubstituted olefinic dipolarophiles
progressed in much poorer chemical yield and showed varying
degrees of selectivity. On reaction of 3a with methyl vinyl
ketone four adducts, 23–26, were isolated in 23, 12, 18 and 41%
yields respectively (based on 53% conversion of nitrone). The
first three, 23–25, are stereoisomeric adducts with the acyl sub-
28,13b 2,3-dihydro-1H-1,4-benzodiazepine 2913c and 1,4-benzo-
diazepine-2,5-diones 30,13d however no systematic study has
been reported for tricycles like 26 which have a higher degree of
saturation in the B and C rings.
After 3 d stirring at rt in THF with phenyl vinyl sulfone 61%
of nitrone 3a was converted into two diastereoisomeric “4-
substituted” cycloadducts. The regiochemical assignments are
again based on the 13C resonance position of the isoxazolidine
ring methylene group (~66 ppm in both cases). Efforts to assign
the relative stereochemistry of these adducts from NOEDS
data failed. The major adduct 31 (57%) has key resonance
signals (10-H, 10Ј-H, 11-H) coincident in both CDCl3 and
624
J. Chem. Soc., Perkin Trans. 1, 2001, 622–632

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Fig. 5
Fig. 4 NOEDS results for compounds 31 and 32.
Fig. 6
C6D6. Irradiation of the signal representing 7-H (CDCl3)
caused a ~1% enhancement on the signal for 11a-H (recipro-
cated on back irradiation of 11a-H) (Fig. 4). Since the tricycle
has conformational freedom it is difficult to correlate the small
cross ring enhancement with a cis-relationship between these
protons; however this value is very similar to that observed for
the maleimide adduct 22 where the corresponding protons were
indirectly shown to be in close proximity. The minor adduct 32
(34%) has limited stability in CDCl3, consequently spectra were
recorded in C6D6; unfortunately in this solvent 10-H and 7-H
were coincident, prohibiting any chance to ascertain the cross
ring stereochemistry. Irradiation of the signal representing
11-H caused a ~16% enhancement on the signal for 11a-H; this
adduct therefore results from an endo addition of phenyl vinyl
sulfone to one face of the dipole.
NMR spectra were recorded in toluene-d8 at Ϫ60 ЊC. In
addition to resonance signals characteristic of the tricycle the
spectrum showed a small number of signals (of low intensity)
not immediately attributable to cycloadduct or its precursors. It
is plausible that these “additional” signals represent a minor
conformer (“hidden partner”) of the tricyclic framework.13
Reaction of 3a with dimethyl acetylenedicarboxylate in THF
at 0 ЊC (24 h) led to a number of new compounds. Attempts to
separate the crude material by flash chromatography further
increased the complexity of the mixture and only a small
Dimethyl fumarate was expected to be a good candidate for
cycloaddition with 3a,14 accordingly these components were
1
amount (7%) of cycloadduct was isolated. H NMR analysis
of this material shows resonance signals characteristic of the
protons of 37a (Fig. 5). A second product, isolated in 10%
yield, was later identified as the pteridine 43. In common with
most 4-isoxazolines16 37a is rather unstable and it readily
decomposed. Examination of the components of thermal
decomposition showed 37a to be a precursor of 43.
stirred in THF at rt. Reaction progress was monitored by
TLC and appeared to progress toward cycloadduct formation.
However, following chromatographic separation (SiO2, Et2O,
1
petroleum ether), H NMR (CDCl3) analysis of the fractions
The presence of a methyl substituent at the C-position of the
dipole 3 is likely to exert modest steric demands and could be
expected to influence the reactivity, regio- and stereoselectivity
of any cycloaddition reactions. Further, the presence of such a
substituent will influence the conformational properties of the
ensuing cycloadducts. Gilman and co-workers have reported
that the introduction of a But group at the N-1 position of
diazepam effectively inhibits conformational racemisation and
synthesis of each enantiomer becomes possible17 (Fig. 6).
The ketodipole 3b has been prepared by a reaction sequence
parallel to that described for the aldonitrone 3a. The acyl-
considered as pure cycloaddition product indicated the pres-
ence of three compounds: cycloadduct 33 as well as starting
nitrone and dimethyl fumarate. Evidently the adduct is quite
unstable and retrocycloaddition begins almost immediately in
CDCl3 and is complete on standing at rt for 3 d. Varying
degrees of instability are noted in other deuterated solvents
(C6D6, THF-d8, CD3CN, acetone-d6, toluene-d8). Repulsive
steric interactions are likely responsible for the instability of 33
which has a greater degree of substitution than the adducts
previously discussed. High cycloreversion rates for adducts of
cyclic nitrones with dimethyl fumarate/maleate have been noted
previously, e.g. in studues by Gandolfi and co-workers with
dihydroisoquinoline N-oxide 34 equilibrium was established
between the diastereomeric cycloadducts 35 and 36;15 for our
more highly substituted dipole equilibrium is between cyclo-
adduct and reactants. The reaction of 3a with fumarate was
repeated, firstly on an analytical scale at rt in acetone (slowest
retrocycloaddition rate) with an excess of one reactant (fum-
arate, 10 equivalents) and progress was followed by HPLC.
Enhancement of intensity of the signal occurred due to product
stabilised after 27 h stirring. An independent HPLC measure-
ment showed the position of the equilibrium to be sensitive to
temperature, with lower temperatures (4 ЊC) favouring cyclo-
1
adduct. On scale-up a fresh sample of 33 was isolated and H
J. Chem. Soc., Perkin Trans. 1, 2001, 622–632
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Scheme 3
pyrimidine 6b resulted from PCC oxidation of the alcohol 38
ing synthetic intermediates in the preparation of folic acid
(87%), itself prepared from commercially available 6-chloro-
2,4-dimethoxypyrimidine. Condensation of 6b with 7 gave 5b
in 82% yield. Treatment of 5b with NH2OH was expected
to furnish 3b via an oximation–cyclisation sequence. However
imidazopyrimidine formation competed and 12c and 39 were
isolated together with nitrone. A key feature in distinguishing
between the two imidazopyrimidines is the 13C resonance pos-
ition of the C-5 carbon atom; in 12c this is an “oxo” carbon and
resonates at ~155 ppm whilst in 39 this position is an “hydroxy-
imino” carbon and it resonates at ~147 ppm. Further the mass
spectrum of 39 has molecular ion at 387. In the best experiment
both base and hydroxylamine hydrochloride were used in
excess; pyridine was employed as the reaction solvent and a five-
fold excess of NH2OHؒHCl was used (rt, 48 h). These condi-
tions furnished nitrone 3b (49%) as well as imidazopyrimidines
12c (25%) and 39 (24%). Reaction in MeOH with pyridine as
base (rt, 24 h) gave the dipole 3b (12%) and the 5-oxo-
imidazopyrimidine 12c (65%) as the only products whilst a
MeOH, NaHCO3 combination (rt, 72 h) gave nitrone 3b (41%)
and the 5-(hydroxyimino)imidazopyrimidine 39 (52%). In
MeOH pyridine functions as a homogeneous base whilst
NaHCO3 will remain a solid; this difference and their different
pKa values [pyridine 5.25 and NaHCO3 6.35] may influence the
pH of the reaction medium and the availability of free NH2OH
for reaction and so account for the different product distribu-
tion. Thus 12c, the dominant product from reaction using an
(approximately) equimolar quantity of pyridine does not
require NH2OH for its formation whilst the generation of both
3b and 39, the products of reaction employing NaHCO3 as
base, does involve NH2OH. A plausible origin of 12c and 39 is
summarised in Scheme 3. The different products are likely a
consequence of the nature of the attacking species—H2O,
MeOH or NH2OH—on the intermediate zwitterion 40 with 41a
being the precursor to 12c and 41b leading to 39. Finally when
5b was heated alone in MeOH the pyrimidoazepinone 42 (74%)
and the 5-oxoimidazopyrimidine 12c (25%) were formed. Pre-
sumably 42 arises via Michael attack of the enolate of 5b onto
derivatives.18
The keto dipole 3b failed to cycloadd to any of N-methyl-
maleimide, methyl vinyl ketone, dimethyl fumarate/maleate or
phenyl vinyl sulfone, returning unchanged starting materials
after stirring at elevated temperatures. However it did react
with acetylenic substrates, methyl propiolate and dimethyl
acetylenedicarboxylate. The reaction of 3b with dimethyl
acetylenedicarboxylate after 72 h stirring in THF yielded only a
small sample of one cycloadduct (6%); 1H NMR data supports
its assignment as 37b and due to the instability of the cyclo-
adduct no further analytical data could be acquired. The major
product was characterised as the pteridine 43 (47%). If 37b is
heated alone in boiling MeOH quantitative conversion to 43
occurs after 2 h.
On stirring 3b at rt (24 h) with excess methyl propiolate (as
solvent and reactant) three new products, the “4-substituted”
isoxazoline, 37c (42%), the NH- 43 (17%) and the N-substituted
44 (23%) pteridines, were formed. Full characterisation of the
primary cycloadduct, 37c, by NMR spectroscopy proved
impossible as decomposition took place in CDCl3 during the
time span required for acquisition of 13C data. However, the
adduct was stable in the solid phase and crystals suitable for
X-ray analysis were obtained from petroleum ether–Et2O. The
ORTEX drawing of 37c (Fig. 7), shows the tricyclic skeleton to
adopt the folded rather than the extended conformation.13a The
hydrogen on C(9) and the methyl group on C(10) are on the
same side of the fused ring system. However the molecule
is not flat at the fusion point with the C(20)–C(10)–N(2)–C(9)
dihedral angle being 91Њ. The hydrogen atom on C(9) is 4.158 Å
from the mean of the hydrogens on the methyl group. This
interproton distance is close to the limit for detection of nuclear
Overhauser effects. That the tricycle 37c is the precursor of the
NH-pteridine has been illustrated; thus simply heating 37c
alone in boiling MeOH furnishes 43 in 95% yield. That the
N-substituted pteridine 44 arises from the unsubstituted parent
by a pseudo Michael addition reaction to a molecule of methyl
propiolate was also verified by an independent experiment. The
pteridine nucleus is the product of a thermal ring contraction
of the isoxazolopyrimidodiazepine skeleton and the rearrange-
ment of 37c likely follows the mechanism suggested by Freeman
the internal double bond with the tertiary amine function-
ality behaving as base (either inter- or intramolecularly); its
formation indicates yet another available reaction path for
this densely functionalised substrate. Pyrimido[4,5-b]azepin-5-
ones have previously been considered as potentially interest-
626
J. Chem. Soc., Perkin Trans. 1, 2001, 622–632

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dipoles react with acetylenic substrates but the primary adducts
have a low degree of stability and readily rearrange to the
pteridine nucleus. This ring contraction may be a useful route to
synthesis of unusually substituted pteridines.
Experimental
Melting points were determined on an Electrothermal melting
point apparatus and are uncorrected. Elemental analyses were
performed on a Perkin-Elmer model 240 CHN analyser. NMR
spectra were recorded using a JEOL JNM-LA400FT NMR
instrument operating at 400 MHz for 1H and 100 MHz for 13
C
nuclei with tetramethylsilane as internal reference; J values are
given in Hz. Mass spectroscopy was performed on a Profile
Kratos Analytical Instrument. Flash chromatography was
carried out on silica gel (200–400 mesh; Kieselgel 60, E. Merck)
with air pump pressure. Analytical TLC plates were purchased
from Merck. Samples were located by UV illumination using a
portable Spectroline Hanovia lamp (λ = 254 nm) or by the use
of iodine staining. All solvents used were purified by standard
procedures and petroleum ether refers to fractions of light
petroleum boiling between 40–60 ЊC.
Fig. 7 ORTEX Drawing of 37c. Crystallographic numbering system
shown.
and co-workers for isoxazolobenzodiazepines, involving a
1,2-carbon-to-nitrogen shift followed by cleavage of the N–O
bond of the isoxazoline ring19 as outlined in Scheme 4. An
Methyl (E)-4-(benzylamino)but-2-enoate 7, methyl (E)-4-
{benzyl[(E)-4-methoxy-4-oxobut-2-enyl]amino}but-2-enoate 8
and 1-benzyl-4-(benzylamino)pyrrolidin-2-one 9
A solution of methyl 4-bromocrotonate (1.00 g, 5.6 mmol) in
Et2O (3 cm3) was added slowly to a solution of benzylamine
(10 equivalents, 6.0 g, 56 mmol) in Et2O (20 cm3) at 0 ЊC. The
resulting mixture was stirred at 0 ЊC for 24 h, then concentrated
under reduced pressure. The residue was dissolved in CH2Cl2
(50 cm3), washed with brine (3 × 50 cm3), dried over Na2SO4
and reconcentrated under reduced pressure. Purification by
flash chromatography (Et2O–petroleum ether 1 : 1) afforded
three pure products, which are listed in order of elution. Ter-
tiary amine 8, a white solid (0.16 g, 10%), mp 66–67 ЊC (Et2O,
petroleum ether) (Found C, 67.31; H, 6.61; N, 4.76. C17H21NO4
requires C, 67.25; H, 6.92; N, 4.62%); δH: 7.19 (5H, m, Ar-H),
6.88 (2H, m, 2Ј-H, 3-H), 5.97 (2H, dt, J 15.74 and 1.83, 3Ј-H,
2-H), 3.65 (6H, s, OCH3, OCH3), 3.52 (2H, s, CH2Ph), 3.14 (4H,
dd, J 5.86 and 1.83, 1-H, 1Ј-H, 4-H, 4Ј-H); δC: 166.65 (CO2CH3,
CO2CH3), 145.97 (2Ј-C, 3-C), 138.33 (Ar-C), 128.60, 127.48,
127.33 (Ar-CH), 122.70 (2-C, 3Ј-C), 58.42 (CH2Ph), 54.51
(1Ј-C, 4-C), 51.52 (CO2CH3, CO2CH3); secondary amine 7, a
yellow oil (0.74 g, 65%) (Found C, 69.86; H, 6.89; N, 6.78.
C12H15NO2 requires C, 70.24; H, 7.32; N, 6.83%); δH: 7.36 (5H,
m, Ar-H), 7.02 (1H, m, 3-H), 6.03 (1H, dt, J 15.74 and 1.83,
2-H), 3.80 (2H, s, CH2Ph), 3.74 (3H, s, OCH3), 3.42 (2H, dd,
J 5.13 and 1.83, 4-H, 4Ј-H); δC: 166.76 (CO2CH3), 146.89 (3-C),
139.63 (Ar-C), 128.33, 127.99, 127.02 (Ar-CH), 121.03 (2-C),
53.10 (CH2Ph), 51.40 (CO2CH3), 49.32 (4-C); lactam 9, a brown
oil (0.31 g, 20%) (Found C, 77.46; H, 7.23; N, 9.76. C18H20N2O
requires C, 77.11; H, 7.19; N, 9.99%); δH: 7.28 (10H, m, Ar-H),
4.47 (2H, d, J 2.20, NHCH2Ph), 3.71 (2H, d, J 2.93, NCH2Ph),
3.44 (2H, m, 4-H, 5-H), 3.07 (1H, dd, J 9.52 and 4.03, 5Ј-H),
2.69 (1H, dd, J 16.84 and 7.69, 3-H), 2.32 (1H, dd, J 16.84 and
5.13, 3Ј-H), 1.84 (1H, br s, NH); δC: 172.96 (C-2), 139.33
(Ar-C), 136.10 (Ar-C), 128.59, 128.42, 127.99, 127.48, 127.14
(Ar-CH), 52.93 (C-4), 51.52 (NHCH2Ph), 50.21 (C-3), 43.22
(NCH2Ph), 38.70 (C-4).
Scheme 4
analogous rearrangement explains the formation of 43 from
37a,b.
Pteridines, being widely distributed in nature, are of general
interest due to their potential biological activity. They are most
commonly synthesised starting from a condensation reaction
of a 5,6-diaminopyrimidine (Gabriel–Isay reaction or modifi-
cation of) or much less commonly from a pyrazine nucleus;20
their preparation by transformation of other heterocyclic
rings is much less common. This is the first example of
a pteridine synthesis by ring contraction of an isoxazolo-
pyrimidodiazepine.
Conclusion
Pyrimido[1,4]diazepine N-oxides have been prepared for the
first time and the cycloadditive ability of 3 has been shown to
be dependent on the degree of substitution at the C-atom of the
dipole. The aldonitrone 3a reacts with both olefinic and acetyl-
enic substrates whilst the C-substituted dipole 3b is inactive to
olefinic dipolarophiles. With monosubstituted olefins 3a dis-
plays a preference for formation of 4-substituted isoxazolidine
rings. The diastereoselectivity of the cycloaddition is lowest
with methyl vinyl ketone and highest with N-methylmaleimide.
The dimethyl fumarate cycloaddition product had a short life-
time at rt and underwent retrocycloaddition to exist in equi-
librium with the starting nitrone 3a and dipolarophile. Both
Methyl (E)-4-[benzyl(5-formyl-2,6-dimethoxypyrimidin-4-yl)-
amino]but-2-enoate, 5a
To a stirred solution of 4-chloro-5-formyl-2,6-dimethoxypyr-
imidine21 (1.65 g, 8.13 mmol) in CHCl3 (15 cm3), 7 (2.00 g,
8.13 mmol) and triethylamine (0.82 g, 8.13 mmol) were added at
0 ЊC. The reaction mixture was warmed to rt and stirring con-
tinued for 10 h. The crude mixture was washed with brine
(3 × 50 cm3), dried over anhydrous Na2SO4 and concentrated
J. Chem. Soc., Perkin Trans. 1, 2001, 622–632
627

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under reduced pressure. Crystallisation (petroleum ether, Et2O)
afforded the title product, 5a, a white solid (2.30 g, 78%), mp
79–80 ЊC (Et2O, petroleum ether) (Found C, 61.44; H, 5.53; N,
11.16. C19H21N3O5 requires C, 61.46; H, 5.66; N, 11.32%);
δH: 10.06 (1H, s, CHO), 7.25 (5H, m, Ar-H), 6.74 (1H, dt,
J 16.10 and 5.37, 3Ј-H), 5.87 (1H, d, J 16.10, 2Ј-H), 4.76 (2H, s,
CH2Ph), 4.26 (2H, d, J 5.37, 4-H, 4Ј-H), 4.05 (3H, s, OCH3),
3.92 (3H, s, OCH3), 3.72 (3H, s, CO2CH3); δC: 184.91 (CHO),
175.26 (C-2), 166.31 (CO2CH3), 165.05 (C-6), 164.34 (C-4),
143.61 (C-3Ј), 136.50 (Ar-C), 128.67, 127.58, 122.71 (Ar-CH),
127.71 (C-2Ј), 97.05 (C-5), 54.95 (OCH3), 54.75 (OCH3), 54.70
(CH2Ph), 51.59 (CO2CH3), 50.90 (C-4Ј).
Title compound 3. A white gum, (Rf 0.1, Et2O–MeOH 9 : 1)
(68 mg, 65%) (Found C, 58.69; H, 5.39; N, 14.87. C19H22N4O5
requires C, 59.07; H, 5.70; N, 14.51%); δH (C6D6): 8.21 (1H, s,
CHN), 7.10 (5H, m, Ar-H), 4.91 (1H, d, J 14.65, CH2Ph), 4.40
(2H, m, 7-H, CH2Ph), 3.56 (3H, s, OCH3), 3.27 (3H, s, OCH3),
3.39 (1H, dd, J 15.01 and 5.49, 8-H), 3.27 (3H, s, OCH3), 3.12
(1H, dd, J 16.48 and 5.13, CH2CO2CH3), 3.03 (1H, d, J 15.01,
8Ј-H), 2.33 (1H, dd, J 16.48 and 9.15, CH2CO2CH3); δC: 170.43
(C-2), 169.21 (C-4), 163.09 (CO2CH3), 161.09 (C-9a), 136.53
(Ar-C), 131.27 (C-5), 128.60, 127.65, 127.58 (Ar-CH), 86.87
(C-4a), 69.17 (C-7), 54.75 (OCH3), 54.66 (C-8), 54.00 (OCH3),
51.96 (CO2CH3), 49.79 (CH2Ph), 33.53 (CH2CO2CH3).
2,4-Dimethoxy-6-(prop-2-ynylamino)pyrimidine-5-carbaldehyde
oxime 21
9-Benzyl-2,4-dimethoxy-7-(2-methoxy-2-oxoethyl)-8,9-dihydro-
7H-pyrimido[4,5-e][1,4]diazepin-6-ium-6-olate 3a
To a stirred solution of 6-chloro-5-formyl-2,4-dimethoxy-
pyrimidine (110 mg, 0.54 mmol) in CHCl3 (5 cm3), proparg-
ylamine‡ (37.2 µl, 30 mg, 0.54 mmol) and triethylamine (75.5
µl, 55 mg, 0.54 mmol) were added at 0 ЊC. The reaction mixture
was stirred for 20 h at rt and following solvent evaporation and
purification by flash chromatography (petroleum ether–Et2O,
8 : 2) two new products resulted. 2,4-Dimethoxy-6-(prop-2-
ynylamino)pyrimidine-5-carbaldehyde, a white solid (58 mg,
48%), mp 110–111 ЊC (from petroleum ether, Et2O) (Found C,
53.81; H, 5.18; N, 18.66. C10H11N3O3 requires C, 54.30; H, 4.98;
N, 19.0%); δH: 10.06 (1H, s, CHO), 9.36 (1H, br s, NH), 4.34
A solution of 5a (100 mg, 0.27 mmol), NH2OHؒHCl (22.5 mg,
0.32 mmol) and pyridine (25.6 mg, 0.03 cm3, 0.32 mmol) in
MeOH was stirred at 0 ЊC for 36 h. The solvent was removed
under reduced pressure. 1H-NMR spectral analysis of the reac-
tion mixture revealed a number of products; purification by
flash chromatography (Et2O–petroleum ether 1 : 1, through to
Et2O–MeOH 9 : 1) yielded four products, which are listed in
order of elution.
Methyl
5-benzyl-7,9-dimethoxy-1,3,3a,4,5,9b-hexahydro-
isoxazolo[3Ј,4Ј : 4,5]pyrido[2,3-d]pyrimidine-3-carboxylate, 14.
A white solid (13.5 mg, 14%), mp 122–123 ЊC (Et2O, hexane)
(Found C, 59.29; H, 5.55; N, 14.46. C19H22N4O5 requires C,
59.07; H, 5.70; N, 14.51%); δH: 7.24 (5H, m, Ar-H), 4.81 (2H, s,
CH2Ph), 4.49 (1H, d, J 6.01, 9b-H), 4.20 (1H, d, J 2.69, 3-H),
3.90 (3H, s, OCH3), 3.84 (3H, s, OCH3), 3.70 (3H, s, OCH3),
3.31 (1H, dd, J 12.69 and 4.88, 4-H), 3.08 (1H, m, 4Ј-H), 2.80
(1H, m, 3a-H), 1.50 (1H, br s, NH). δC: 173.31 (C-7), 171.43
(C-9), 164.08 (C-5a), 161.72 (CO2CH3), 137.42 (Ar-C), 128.67,
127.48, 127.51 (Ar-CH), 86.17 (C-9a), 80.64 (C-9b), 54.42
(OCH3), 54.05 (OCH3), 53.60 (CO2CH3), 52.50 (C-3), 51.43
(CH2Ph), 45.67 (C-4), 43.88 (C-3a). NOEDS results indicate
cis-geometry at the CB ring junction. Irradiation of 9a-H
caused a 9.34% enhancement on the cross ring 3a-H.
(2H, dd, J 5.49 and 2.20, NCH2), 4.03 (3H, s, OCH3), 4.01 (3H,
᎐
s, OCH ), 2.25 (1H, s, C᎐CH); δ : 187.48 (CHO), 173.55 (C-2),
᎐
3
C
᎐
166.50 (C-4), 163.36 (C-6), 94.54 (C-5), 79.29 (C᎐CH), 71.40
(C᎐CH), 55.05 (OCH ), 54.33 (OCH ), 30.17 (NCH ); and
᎐
᎐
᎐
3
3
2
2,6-dimethoxy-N-(prop-2-ynyl)-5-[(prop-2-ynylimino)methyl]-
pyrimidin-4-amine, a white solid (38 mg, 27%), mp 118–119 ЊC
(from petroleum ether, Et2O) (Found C, 60.07; H, 5.21; N,
21.52. C13H14N4O2 requires C, 60.47; H, 5.43; N, 21.71%);
δ : 10.12 (1H, s, NH), 8.83 (1H, d, J 1.83, HC᎐N), 4.34
᎐
H
(2H, dd, J 5.49 and 2.56, NCH2), 4.13 (2H, dd, J 2.56 and
1.83, C᎐NCH ), 4.01 (6H, s, 2 × OCH ), 2.48 (1H, t, J 2.56,
᎐
2
3
᎐
᎐
C᎐NCH C᎐CH), 2.23 (1H, t, J 2.56, C᎐CH); δ : 170.54 (C-2),
᎐
᎐
᎐
2
C
164.72 (C-4), 162.72 (C-6), 157.97 (HC᎐N), 90.42 (C-5), 80.52
᎐
᎐
᎐
᎐
and 79.59 (2 × C᎐CH), 74.66 (C᎐NCH C᎐CH), 70.59 (C᎐CH),
᎐
᎐
᎐
᎐
2
54.58 (OCH ), 53.99 (OCH ), 47.02 (C᎐NCH ), 30.13 (NCH ).
᎐
3
3
2
2
Methyl 2-(1-benzyl-8-formyl-7-methoxy-5-oxo-1,2,3,5-tetra-
hydroimidazo[1,2-c]pyrimidin-3-yl)acetate, 12a. A white solid
(4.8 mg, 5%), mp 151–153 ЊC (Et2O, MeOH) (Found C, 60.45;
H, 5.52; N, 11.57. C19H22N4O5 requires C, 60.05; H, 5.32; N,
11.76%); δH: 9.94 (1H, s, CHO), 7.30 (5H, m, Ar-H), 5.26 (1H,
d, J 15.12, CH2Ph), 5.04 (1H, d, J 15.13, CH2Ph), 4.80 (1H, m,
3-H), 4.04 (3H, s, OCH3), 3.97 (1H, m, 2-H), 3.65 (3H, s,
OCH3), 3.46 (1H, dd, J 11.22 and 4.88, 2Ј-H), 3.29 (1H,
dd, J 17.08 and 2.93, CH2CO2CH3), 2.65 (1H, dd, J 17.08 and
9.27, CH2CO2CH3); δC: 184.71 (CHO), 173.92 (C-7), 170.43
(CO2CH3), 156.64 (C-5), 153.35 (C-8a), 134.92 (Ar-C), 129.00,
128.34, 128.11 (Ar-CH), 90.26 (C-8), 55.21 (C-3), 54.84
(CH2CO2CH3), 53.96 (CH2Ph), 51.99 (OCH3), 51.40 (OCH3),
36.19 (C-2).
2,4-Dimethoxy-6-(prop-2-ynylamino)pyrimidine-5-carbalde-
hyde (170 mg, 0.77 mmol) was stirred in methanol (10 cm3) with
hydroxylamine hydrochloride (64 mg, 0.93 mmol) at rt for
5 min. Pyridine (75 µL, 74 mg, 0.93 mmol) was added and the
reaction was stirred at rt for 24 h. The solvent was removed
under reduced pressure and the residue dissolved in Et2O,
washed with brine (3 × 25 cm3) and dried over anhydrous
Na2SO4; evaporation of the organics afforded the title product
which was purified by crystallisation. Compound 21, a white
solid (91 mg, 50%), mp 134–135 ЊC (from Et2O) (Found C,
50.92; H, 5.40; N, 22.98. C10H12N4O3 requires C, 50.84; H, 5.12;
N, 23.27%); δH (d6-DMSO): 8.47 (1H, s, CHN), 8.14 (1H, br s,
NH/OH), 6.97 (1H, s, NH/OH), 4.35 (2H, dd, J 5.13 and 2.56,
NCH2), 3.97 (3H, s, OCH3), 3.49 (3H, s, OCH3), 2.24 (1H, s,
᎐
C᎐CH); δ (DMSO): 168.28 (C-2), 163.52 (C-4), 160.51 (C-6),
᎐
C
Methyl 2-(1-benzyl-8-hydroxyiminomethyl-7-methoxy-5-oxo-
1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidin-3-yl)acetate, 12b. A
white solid (4.8 mg, 5%), mp 186–188 ЊC (Et2O, MeOH) (Found
C, 58.17; H, 5.00; N, 14.58. C18H20N4O5 requires C, 58.06; H,
᎐
᎐
143.31 (CHN), 86.59 (C-5), 80.85 (C᎐CH), 73.68 (C᎐CH),
᎐
᎐
54.51 (OCH3), 53.94 (OCH3), 29.95 (NCH2).
Methyl 2-(5-benzyl-1,3-dimethoxy-11-methyl-10,12-dioxo-
6,7,9a,10,11,12,12a,12b-octahydro-5H-pyrimido[5,4-f ]pyrrolo-
[3Ј,4Ј : 4,5]isoxazolo[2,3-d][1,4]diazepin-7-yl)acetate, 22
To a solution of 3a (100 mg, 0.26 mmol) in THF (5 cm3) was
added N-methylmaleimide (34.5 mg, 0.31 mmol). The solution
was stirred at rt for 24 h. The solvent was then removed under
reduced pressure and the crude reaction mixture purified by
flash chromatography (Et2O–petroleum ether, 1 : 1). The title
5.38; N, 15.05%); δ : 8.55 (1H, s, OH), 7.94 (1H, s, CH᎐N), 7.19
᎐
H
(5H, m, Ar-H), 4.78 (1H, d, J 15.63, CH2Ph), 4.71 (1H, m,
3-H), 4.65 (1H, d, J 15.63, CH2Ph), 3.88 (1H, m, 2-H), 3.85
(3H, s, OCH3), 3.57 (3H, s, OCH3), 3.37 (1H, dd, J 10.99 and
4.39, 2Ј-H), 3.26 (1H, dd, J 16.85 and 3.17, CH2CO2CH3), 2.53
(1H, dd, J 16.85 and 9.81, CH2CO2CH3); δC: 171.81 (C-7),
170.75 (CO CH ), 154.28 (C-8a), 154.04 (C-5), 143.15 (CH᎐N),
᎐
2
3
135.08 (Ar-C), 128.93, 128.08, 127.44 (Ar-CH), 79.59 (C-8),
54.95 (OCH3), 54.92 (C-3), 54.79 (C-2), 51.28 (CH2Ph), 51.06
(CO2CH3), 36.03 (CH2CO2CH3).
‡ Propargyl = prop-2-ynyl.
628
J. Chem. Soc., Perkin Trans. 1, 2001, 622–632

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compound 22 was isolated as a white solid (90 mg, 73%),
mp 144–145 ЊC (Et2O) (Found C, 57.84; H, 5.35; N, 14.02.
C24H27N5O7 requires C, 57.95; H, 5.43; N, 14.08%); δH (C6D6):
7.09 (5H, m, Ar-H), 4.72 (1H, br s, 12b-H), 4.64 (1H, d, J 15.61,
CH2Ph), 4.47 (1H, d, J 6.83, 9a-H), 4.21 (1H, d, J 15.61,
CH2Ph), 3.72 (1H, d, J 6.83, 12a-H), 3.57 (4H, s, OCH3, 7-H),
3.50 (3H, s, OCH3), 3.10 (3H, s, CO2CH3), 3.03 (1H, dd, J 13.66
and 9.76, 6-H), 2.81 (1H, d, J 13.66, 6Ј-H), 2.69 (3H, s, NCH3),
2.61 (1H, dd, J 15.61 and 3.90, CH2CO2CH3), 1.94 (1H, dd,
J 15.61 and 8.78, CH2CO2CH3); δC (C6D6): 175.97 (C-10),
173.76 (C-12), 170.11 (C-3), 169.39 (C-1), 165.82 (CO2CH3),
164.00 (C-4a), 137.70 (Ar-C), 128.59, 127.87, 127.27 (Ar-CH),
88.12 (C-12c), 76.96 (C-9a), 62.82 (C-12b), 57.17 (C-7), 53.90
(CH2Ph), 53.69 (OCH3), 53.35 (OCH3), 52.46 (C-12a), 52.08
(C-6), 50.80 (CO2CH3), 36.96 (CH2CO2CH3), 24.31 (N-CH3).
Irradiation of 12b-H caused the following enhancements:
6.04% on 12a-H, 1.38% on 7-H and 5.34% on 6-H. Irradiation
of 6-H caused 16.68% enhancement on 6Ј-H, 13.82% on 12b-H,
1.91% on 7-H, 1.4% on CH2CO2CH3 (1.97 ppm) and 0.91% on
CH2Ph (4.41 ppm).
s, OCH3), 3.45 (3H, s, OCH3), 3.34 (4H, m, 11-H, 7-H, 6-H,
6Ј-H), 2.95 (1H, br d, CH2CO2CH3), 2.44 (1H, dd, J 9.77
and 15.87, CH2CO2CH3), 2.18 (3H, s, CH3), 2.15 (1H, m,
11Ј-H); δC: 213.12 (COCH3), 171.94 (C-3), 169.56 (C-1),
165.57 (CO2CH3), 162.09 (C-4a), 138.35 (Ar-C), 128.47, 127.95,
127.23 (Ar-CH), 93.22 (C-11b), 79.55 (C-10), 63.12 (C-11a),
61.04 (C-7), 54.33 (OCH3), 53.81 (OCH3, CH2Ph), 51.69
(CO2CH3), 50.46 (C-6), 42.23 (C-11), 36.83 (CH2CO2CH3),
25.54 (COCH3).
Adduct 26. A white solid (30 mg, 41%), mp 127–128 ЊC
(Found C, 60.05; H, 6.02; N, 12.11. C23H28N4O6 requires C,
60.50; H, 6.14; N, 12.30%); δH (Ϫ19.9 ЊC): 7.16 (5H, m, Ar-H),
5.45 (1H, d, J 15.13, CH2Ph), 4.58 (1H, d, J 7.33, 11a-H), 4.27
(1H, d, J 15.14, CH2Ph), 3.96 (1H, m, 10-H), 3.79 (3H, s,
OCH3), 3.72 (4H, br s, OCH3, 10Ј-H), 3.61 (3H, s, OCH3), 3.39
(4H, m, 7-H, 11-H, 6-H, 6Ј-H), 2.97 (1H, m, CH2CO2CH3),
2.57 (1H, m, CH2CO2CH3), 2.23 (3H, s, COCH3); δC (C6D6):
205.01 (CO2CH3), 171.76 (C-3), 168.55 (C-1), 165.82
(CO2CH3), 162.18 (C-4a), 137.91 (Ar-C), 128.50, 127.95, 127.27
(Ar-CH), 92.99 (C-11b), 67.85 (C-10), 62.93 (C-11), 62.36
(C-11a), 54.33 (CH2Ph), 54.01 (C-7), 53.55 (OCH3), 51.64
(OCH3, CO2CH3), 50.00 (C-6), 36.87 (CH2CO2CH3), 29.23
(COCH3).
Methyl 2-(10-acetyl-5-benzyl-1,3-dimethoxy-5,6,7,10,11,11a-
hexahydroisoxazolo[2,3-d]pyrimido[5,4-f ][1,4]diazepin-7-yl)-
acetates, 23–25 and methyl 2-(11-acetyl-5-benzyl-1,3-dimethoxy-
5,6,7,10,11,11a-hexahydroisoxazolo[2,3-d]pyrimido[5,4-f ][1,4]-
diazepin-7-yl)acetate, 26
To a solution of 3a (130 mg, 0.34 mmol) in THF (5 cm3) was
added methyl vinyl ketone (28 mg, 0.40 mmol). The resulting
solution was stirred at rt for 3 d. TLC analysis indicated the
presence of four new compounds and unreacted nitrone. Purifi-
cation by flash chromatography (hexane–Et2O, 3 : 2) followed
by crystallisation (hexane, Et2O) afforded samples of each
cycloadduct, the isolated yield of which is based on 53% nitrone
consumption.
Methyl 2-(5-benzyl-11-phenylsulfonyl-1,3-dimethoxy-5,6,7,10,
11,11a-hexahydroisoxazolo[2,3-d]pyrimido[5,4-f ][1,4]diazepin-
7-yl)acetates, 31 and 32
To a solution of 3a (100 mg, 0.26 mmol) in THF (5 cm3) was
added phenyl vinyl sulfone (28 mg, 0.52 mmol). The resulting
mixture was stirred at rt for 3 d after which TLC analysis indi-
cated the presence of two new adducts and some starting
nitrone. Purification by flash chromatography (hexane–Et2O,
3 : 7) followed by crystallisation (hexane, Et2O) gave the separ-
ated products. The isolated yield of each adduct is based on
61% conversion of nitrone.
Adduct 23. A white solid (17 mg, 23%), mp 111–113 ЊC
(Found C, 60.39; H, 5.67; N, 11.90. C23H28N4O6 requires C,
60.50; H, 6.14; N, 12.30%); δH: 7.22 (5H, m, Ar-H), 4.84 (1H, d,
J 15.61, CH2Ph), 4.67 (1H, d, J 15.61, CH2Ph), 4.46 (1H, m,
11a-H), 4.28 (1H, m, 10-H), 3.85 (3H, s, OCH3), 3.77 (4H, br s,
OCH3, 7-H), 3.54 (3H, s, OCH3), 3.35 (1H, dd, J 14.64 and
3.90, 6-H), 2.91 (3H, m, 6Ј-H, CH2CO2CH3, 11-H), 2.17 (3H, s,
CH3), 2.11 (1H, m, 11Ј-H), 2.06 (1H, dd, J 15.61 and 7.81,
CH2CO2CH3); δC: 203.00 (COCH3), 171.96 (C-3), 169.71 (C-1),
165.12 (CO2CH3), 162.41 (C-4a), 138.27 (Ar-C), 128.46, 127.91,
127.25 (Ar-CH), 91.96 (C-11b), 81.18 (C-10), 58.32 (C-11a),
56.92 (C-7), 54.33 (OCH3), 53.88 (OCH3), 53.50 (CH2Ph), 52.95
(C-6), 51.74 (CO2CH3), 39.23 (C-11), 33.44 (CH2CO2CH3),
25.96 (COCH3).
Adduct 31. A white solid (50 mg, 57%), mp 139–140 ЊC
(Found C, 58.48; H, 5.39; N, 10.54. C27H30N4O7S requires C,
58.48; H, 5.42; N, 10.11%); δH: 7.42 (10H, m, Ar-H), 5.21 (1H,
br s, 11a-H), 4.76 (1H, d, J 15.01, CH2Ph), 4.60 (1H, d, J 15.01,
CH2Ph), 4.43 (3H, m, 10-H, 10Ј-H, 11-H), 3.91 (3H, s, OCH3),
3.83 (3H, s, OCH3), 3.56 (3H, s, OCH3), 3.43 (1H, m, 7-H), 3.26
(1H, br d, 6-H), 2.92 (1H, m, 6Ј-H), 2.69 (1H, dd, J 16.48 and
4.39, CH2CO2CH3), 2.10 (1H, dd, J 16.48 and 8.06, CH2CO2-
CH3); δC: 171.51 (C-3), 169.94 (C-1), 166.72 (CO2CH3), 163.11
(C-4a), 138.23 (Ar-C-S), 138.01 (Ar-C), 133.64, 129.05, 128.67,
128.42, 127.87, 127.61 (Ar-CH), 87.91 (C-11b), 67.36 (C-11),
66.34 (C-10), 60.99 (C-11a), 58.51 (C-7), 54.58 (CH2Ph), 54.41
(OCH3), 54.24 (OCH3), 53.90 (C-6), 51.82 (CO2CH3), 36.88
(CH2CO2CH3). Irradiation of 7-H caused the following
enhancements: 3.77% on CH2CO2CH3 (2.69 ppm), 2.18% on
6-H, 1.07% on 11a-H. Irradiation of 11a-H caused a 3.59%
enhancement on Ar-H, 0.78% on 7-H, 1.19% on 6-H and 0.38%
on CH2CO2CH3 (2.10 ppm).
Adduct 24. An ‘off-white’ solid (9 mg, 12%), mp 114–115 ЊC
(Found C, 60.06; H, 5.64; N, 12.13. C23H28N4O6 requires C,
60.50; H, 6.14; N, 12.30%); δH: 7.22 (5H, m, Ar-H), 4.84 (1H, d,
J 15.13, CH2Ph), 4.66 (2H, m, CH2Ph, 11a-H), 4.49 (1H, dd,
J 9.76 and 4.88, 10-H), 3.86 (3H, s, OCH3), 3.78 (3H, s, OCH3),
3.52 (4H, br s, OCH3, 7-H), 3.19 (1H, d, J 14.15, 6-H), 3.05 (1H,
m, 6Ј-H), 2.76 (1H, dd, J 15.61 and 4.88, CH2CO2CH3), 2.56
(1H, m, 11-H), 2.39 (1H, m, 11Ј-H), 2.20 (3H, s, CH3), 2.12 (1H,
m, CH2CO2CH3); δC: 209.32 (COCH3), 171.74 (C-3), 170.00
(C-1), 165.37 (CO2CH3), 162.87 (C-4a), 138.07 (Ar-C), 128.60,
128.01, 127.37 (Ar-CH), 90.09 (C-11b), 81.52 (C-10), 59.05
(C-11a), 58.33 (C-7), 54.43 (OCH3, CH2Ph), 54.30 (OCH3),
52.94 (C-6), 42.80 (C-11), 51.79 (CO2CH3), 36.76 (CH2CO2-
CH3), 26.49 (COCH3).
Adduct 32. A white solid (30 mg, 34%), mp 158–159 ЊC (Et2O,
hexane) (Found C, 58.59; H, 5.18; N, 9.88. C27H30N4O7S
requires C, 58.48; H, 5.42; N, 10.11%); δH (C6D6): 7.19 (10H,
m, Ar-H), 5.36 (1H, d, J 8.79, 11a-H), 5.15 (1H, d, J 15.38,
CH2Ph), 4.86 (1H, d, J 15.74, CH2Ph), 4.63 (2H, m, 10-H, 7-H),
4.34 (1H m, 11-H), 3.91 (1H, m, 10Ј-H), 3.50 (3H, s, OCH3),
3.37 (3H, s, OCH3), 3.32 (4H, m, OCH3, 6-H), 2.75 (2H, m,
2Ј-H, CH2CO2CH3), 2.04 (1H, dd, J 15.61 and 6.84, CH2CO2-
CH3); δC: 172.10 (C-3), 170.58 (C-1), 165.52 (CO2CH3), 163.50
(C-4a), 140.77 (Ar-C-S), 139.68 (Ar-C), 133.27, 129.18, 128.99,
128.33, 128.00, 127.77 (Ar-CH), 86.54 (C-11b), 70.15 (C-11),
66.30 (C-10), 63.70 (C-11a), 58.40 (C-7), 55.50 (CH2Ph), 54.22
(OCH3, OCH3), 53.56 (C-6), 51.62 (CO2CH3), 38.03 (CH2CO2-
CH3). Irradiation of 10Ј-H caused a 25.47% enhancement on
Adduct 25. A white solid (15 mg, 18%), mp 108–110 ЊC
(Found C, 60.22; H, 6.32; N, 12.63. C23H28N4O6 requires C,
60.50; H, 6.14; N, 12.30%); δH: 7.20 (5H, m, Ar-H), 5.02 (1H,
d, J 15.38, CH2Ph), 4.59 (1H, d, J 15.38, CH2Ph), 4.18 (1H,
m, 10-H), 4.02 (1H, m, 11a-H), 3.73 (3H, s, OCH3), 3.61 (3H,
J. Chem. Soc., Perkin Trans. 1, 2001, 622–632
629

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10-H, and 10.76% on 11-H. Irradiation of 11-H caused a
15.98% enhancement on 11a-H, 4.76% on 10Ј-H and 7.49% on
Ar-H.
OCH ), 2.49 (3H, s, CH ); δ : 197.43 (C᎐O), 168.94 (C-2),
᎐
3 3 C
163.84 (C-6), 157.64 (C-4), 114.89 (C-5), 55.65 (OCH3), 55.14
(OCH3), 31.63 (CH3).
Methyl (E)-4-[(5-acetyl-2,6-dimethoxypyrimidin-4-yl)(benzyl)-
amino]but-2-enoate 5b
Attempted preparation of dimethyl 5-benzyl-1,3-dimethoxy-7-(2-
methoxy-2-oxoethyl)-5,6,7,10,11,11a-hexahydroisoxazolo[2,3-d]-
pyrimido[5,4-f ][1,4]diazepine-10,11-dicarboxylate 33
To a stirred solution of 6b (150 mg, 0.69 mmol) in chloroform
(7 cm3), 7 (142 mg, 0.69 mmol) and NEt3 (0.19 cm3, 139.6 mg,
1.38 mmol) were added at 0 ЊC. The reaction mixture was
stirred for 3 d at rt The crude mixture was washed with brine
(3 × 50 cm3), dried over anhydrous Na2SO4 and the solvent was
removed under reduced pressure. Purification by flash chrom-
atography (petroleum ether–Et2O, 2 : 3) afforded the title com-
pound 5b as a white solid (230 mg, 82%), mp 84–85 ЊC (Et2O,
hexane) (Found C, 62.60; H, 6.32; N, 10.52. C20H23N3O5
requires C, 62.34; H, 5.97; N, 10.91%); δH: 7.18 (5H, m, Ar-H),
6.79 (1H, m, 3Ј-H), 5.86 (1H, d, J 15.63, 2Ј-H), 4.47 (2H, s,
CH2Ph), 4.13 (2H, dd, J 5.32 and 1.71, 4-H, 4Ј-H), 3.88 (3H,
s, OCH3), 3.81 (3H, s, OCH3), 3.64 (3H, s, OCH3), 2.27 (3H, s,
To a solution of 3a (200 mg, 0.52 mmol) in THF (5 cm3) at rt
was added dimethyl fumarate (368 mg, 2.59 mmol). The result-
ing solution was stirred for 24 h. Purification by flash chrom-
atography (hexane–Et2O, 1 : 1) achieved isolation of the
unstable product. A low temperature 1H NMR spectrum
revealed signals characteristic of 33, a white solid; δH (toluene-
d8, Ϫ60 ЊC): 7.96 (5H, m, Ar-H), 5.19 (1H, d, J 15.13, CH2Ph),
4.90 (1H, d, J 7.38, 11a-H), 4.07 (2H, m, CH2Ph, 11-H), 3.91
(1H, d, J 2.93, 10-H), 3.60 (3H, s, OCH3), 3.45 (4H, m, OCH3,
7-H), 3.39 (4H, m, CO2CH3, 6-H), 3.21 (3H, s, CO2CH3), 3.09
(3H, s, CO2CH3), 3.05 (1H, br d, 6Ј-H), 2.78 (1H, dd, J 12.61
and 10.73, CH2CO2CH3), 2.59 (1H, br d, CH2CO2CH3). The
cycloadduct was too unstable to provide 13C NMR or any
further analytical data.
CH ); δ : 200.36 (C᎐O), 170.47 (C-2), 166.44 (C-6), 163.21
᎐
3
C
(CO2CH3), 143.47 (C-3Ј), 143.43 (C-4), 136.38 (Ar-C), 128.73,
127.59, 127.55 (Ar-CH), 122.62 (C-2Ј), 99.23 (C-5), 54.60
(OCH3), 54.30 (OCH3), 54.30 (OCH3), 54.18 (CH2Ph), 51.67
(CO2CH3), 50.44 (C-4Ј), 32.82 (CH3).
Reaction of 3a with dimethyl acetylenedicarboxylate
To a solution of 3a (100 mg, 0.26 mmol) in THF (5 cm3) was
added dimethyl acetylenedicarboxylate (44.3 mg, 47 µl, 0.31
mmol). The solution was stirred at 0 ЊC for 24 h. The solvent
was removed under reduced pressure and the crude product
purified by flash chromatography (Et2O–petroleum ether, 9 : 1);
two products were isolated.
9-Benzyl-2,4-dimethoxy-7-(2-methoxy-2-oxoethyl)-5-methyl-
8,9-dihydro-7H-pyrimido[4,5-e][1,4]diazepin-6-ium-6-olate 3b
A solution of 5b (100 mg, 0.26 mmol) in pyridine (2 cm3, 24.76
mmol) was stirred at 22 ЊC for 5 minutes. Hydroxylamine
hydrochloride (90 mg, 1.3 mmol) was added and stirring con-
tinued for 48 h. The pyridine was removed by evaporation
under reduced pressure. The residue was dissolved in CH2Cl2,
washed with brine (3 × 25 cm3) and dried over anhydrous
Na2SO4. The CH2Cl2 was removed by evaporation under
reduced pressure. Purification by flash chromatography (Et2O–
MeOH, 99 : 1) afforded three new products which are described
in order of elution.
Dimethyl 5-benzyl-1,3-dimethoxy-7-(2-methoxy-2-oxoethyl)-
5,6,7,11a-tetrahydroisoxazolo[2,3-d]pyrimido[5,4-f ][1,4]diaze-
pine-10,11-dicarboxylate, 37a. Yield 10 mg, 7%; δH: 7.27 (5H,
m, Ar-H), 5.17 (1H, d, J 14.89, CH2Ph), 4.67 (1H, s, 11a-H),
4.50 (1H, d, J 14.89, CH2Ph), 4.02 (1H, m, 7-H), 3.96 (3H, s,
OCH3), 3.94 (3H, s, OCH3), 3.92 (3H, s, CO2CH3), 3.64 (3H,
s, CO2CH3), 3.55 (3H, s, CO2CH3), 3.48 (1H, m, 6-H), 3.24
(1H, br d, 6Ј-H), 2.40 (1H, dd, J 16.11 and 6.59, CH2CO2CH3),
2.15 (1H, dd, J 16.11 and 7.32, CH2CO2CH3).
Methyl 2-(8-acetyl-1-benzyl-7-methoxy-5-oxo-1,2,3,5-tetra-
hydroimidazo[1,2-c]pyrimidin-3-yl)acetate, 12c. Yield 24 mg,
25%, mp 134–135 ЊC (Et2O, MeOH) (Found C, 61.92; H, 5.67;
N, 10.59. C19H21O5N3 requires C, 62.30; H, 5.98; N, 10.90%);
δH: 7.36 (3H, m, Ar-H), 7.12 (2H, d, J 6.59, Ar-H), 4.84 (1H, m,
3-H), 4.51 (2H, m, CH2Ph), 4.14 (1H, m, 2-H), 3.96 (3H, s,
OCH3), 3.68 (3H, s, OCH3), 3.61 (1H, dd, J 10.99 and 4.64,
2Ј-H), 3.43 (1H, dd, J 16.85 and 3.17, CH2CO2CH3), 2.68
(1H, dd, J 16.85 and 9.77, CH2CO2CH3), 2.13 (3H, s, CH3);
Methyl 2-(8-benzyl-2,4-dimethoxy-5,6,7,8-tetrahydropteridin-
6-yl)acetate, 43. A white solid (9 mg, 10%), mp 115–116 ЊC
(Et2O, hexane) (Found C, 60.40; H, 6.29; N, 15.70. C18H22N4O4
requires C, 60.32; H, 6.19; N, 15.63%); δH (C6D6): 7.12 (5H, m,
Ar-H), 4.67 (2H, s, CH2Ph), 4.19 (1H, br s, NH), 3.74 (3H,
s, OCH3), 3.73 (3H, s, OCH3), 3.37 (1H, m, 6-H), 3.23 (3H, s,
CO2CH3), 2.85 (1H, dd, J 11.35 and 2.93, 7-H), 2.73 (1H, dd,
J 11.35 and 7.32, 7Ј-H), 2.03 (1H, dd, J 16.84 and 9.15,
CH2CO2CH3), 1.82 (1H, dd, J 16.84 and 3.66, CH2CO2CH3);
δC (C6D6): 171.69 (C-2), 158.19 (CO2CH3), 157.42 (C-4), 152.12
(C-8a), 138.74 (Ar-C), 128.76, 128.25, 127.41 (Ar-CH), 104.44
(C-4a), 53.82 (OCH3), 53.40 (OCH3), 51.15 (CO2CH3), 50.85
(C-7), 50.51 (CH2Ph), 45.33 (C-6), 38.48 (CH2CO2CH3).
δ : 196.39 (C᎐O), 170.88 (C-7), 170.62 (CO CH ), 155.29 (C-5),
᎐
C
2
3
153.26 (C-8a), 134.11 (Ar-C), 128.97, 128.08, 127.31 (Ar-CH),
91.90 (C-8), 56.41 (C-2), 54.79 (CH2Ph), 52.20 (OCH3), 51.95
(C-3), 50.70 (CO2CH3), 36.20 (CH2CO2CH3), 32.08 (CH3).
Methyl 2-(8-acetyl-1-benzyl-7-methoxy-5-hydroxyimino-1,2,
3,5-tetrahydroimidazo[1,2-c]pyrimidin-3-yl)acetate 39. Yield
23 mg, 24%, mp 110–111 ЊC (Et2O) (Found C, 59.21; H, 6.06;
N, 14.22. C19H22O5N4 requires C, 59.07; H, 5.70; N, 14.51%);
δH: 7.42 (1H, s, OH), 7.25 (3H, m, Ar-H), 7.11 (2H, d, J 6.96,
Ar-H), 4.48 (3H, m, CH2Ph, 3-H), 4.01 (1H, t, 2-H), 3.89 (3H, s,
OCH3), 3.59 (3H, s, OCH3), 3.47 (2H, m, 2Ј-H, CH2CO2CH3),
2.51 (1H, dd, J 16.84 and 9.52, CH2CO2CH3), 2.15 (3H, s,
1-(4-Chloro-2,6-dimethoxypyrimidin-5-yl)ethanone 6b
1-(6-Chloro-2,4-dimethoxypyrimidin-5-yl)ethanol22 (0.9 g, 4.12
mmol) was dissolved in CH2Cl2 (10 cm3) and added to a stirred
suspension of freshly prepared pyrimidinium chlorochromate
(4.44 g, 20.6 mmol) in CH2Cl2. The resulting mixture was left to
stir at rt for 6 h. Anhydrous Et2O (20 cm3) was added to the
mixture before filtration through Celite. The insoluble residue
was washed three times with anhydrous Et2O and the washings
were also passed through Celite. The organic portions were
combined and solvent was removed under reduced pressure; the
pure product was crystallised. Title compound 6b was obtained
as a white solid (0.78 mg, 87%), mp 51–52 ЊC (petroleum ether)
(Found C, 44.21; H, 3.75; N, 12.72. C8H9N2ClO3 requires C,
44.3; H, 4.20; N, 12.9%); δH: 4.00 (3H, s, OCH3), 3.99 (3H, s,
CH ); δ : 194.12 (C᎐O), 170.81 (C-7), 167.07 (CO CH ), 157.53
᎐
3
C
2
3
(C-8a), 147.24 (C-5), 134.67 (Ar-C), 128.98, 128.18, 127.80
(Ar-CH), 89.03 (C-8), 56.46 (C-2), 54.47 (OCH3), 53.20
(CH2Ph), 52.01 (C-3), 50.61 (CO2CH3), 35.15 (CH2CO2CH3),
32.35 (CH3); m/z 387 (Mϩ ϩ 1), 357, 314, 287, 271, 91 (CH2Ph),
77 (Ph), 65, 59 (CO2CH3).
Title compound 3b. A yellow oil (Rf 0.15 with Et2O–MeOH
9 : 1) (49 mg, 49%) (Found C, 60.33; H, 5.87; N, 13.61. C20H24-
630
J. Chem. Soc., Perkin Trans. 1, 2001, 622–632

View Article Online
Table 2 Crystal data and structure refinement for 37c
N4O5 requires C, 60.00; H, 6.00; N, 14.00%); δH: 7.28 (5H, m,
Ar-H), 5.06 (1H, d, J 15.38, CH2Ph), 4.80 (1H, m, 7-H), 4.75
(1H, d, J 15.38, CH2Ph), 3.99 (3H, s, OCH3), 3.87 (3H, s,
OCH3), 3.83 (1H, dd, J 12.82 and 9.15, 8-H), 3.62 (3H, s,
OCH3), 3.53 (1H, d, J 12.82, 8Ј-H), 3.17 (1H, dd, J 16.84 and
8.06, CH2CO2CH3), 2.42 (1H, dd, J 16.48 and 5.86, CH2CO2-
CH3); δC: 170.62 (C-2), 169.43 (C-4), 163.70 (CO2CH3), 159.24
(C-9a), 140.82 (Ar-C), 136.61 (C-5), 128.63, 127.99, 127.44
(Ar-CH), 90.46 (C-4a), 62.44 (C-7), 57.04 (C-8), 54.58 (OCH3),
54.28 (OCH3), 53.99 (CH2Ph), 51.95 (CO2CH3), 33.27
(CH2CO2CH3), 19.64 (CH3).
Formula
Formula weight
C24H28N4O7
484.50
Temperature/K
Crystal system
Space group
293(2)
Triclinic
¯
P1
Unit cell dimensions
a/Å
b/Å
c/Å
α/Њ
β/Њ
10.628(5)
11.108(3)
11.442(5)
71.62(3)
74.82(4)
85.00(3)
1237.1(9)
2
γ/Њ
Volume/Å3
Methyl 2-(9-benzyl-2,4-dimethoxy-5-oxo-6,7,8,9-tetrahydro-5H-
pyrimido[4,5-b]azepin-7-yl)acetate, 42
Z
Absorption coefficient/mmϪ1
Reflections collected
Independent reflections
Reflections observed (>2σ)
Data/restraints/parameters
Final R indices [I > 2σ(I)]
R indices (all data)a
0.097
5872
A solution of 5b (100 mg, 0.26 mmol) was heated to 40 ЊC in
MeOH (10 cm3) for 10 h. Following solvent evaporation, purifi-
cation by flash chromatography (Et2O–MeOH, 99 : 1) afforded
the pure products. Isolated yields were calculated based on 80%
conversion of starting material. Title compound 42, a white
solid (59 mg, 74%), mp 98–99 ЊC (from Et2O, MeOH) (Found
C, 61.92; H, 5.67; N, 10.59. C20H23N3O5 requires C, 62.30; H,
5.98; N, 10.90%); δH: 7.31 (5H, m, Ar-H), 5.23 (1H, d, J 15.13,
CH2Ph), 4.86 (1H, d, J 15.13, CH2Ph), 4.02 (3H, s, OCH3), 3.91
(3H, s, OCH3), 3.66 (3H, s, OCH3), 3.48 (1H, dd, J 14.64 and
4.39, 2-H), 3.18 (1H, dd, J 14.64 and 8.29, 2Ј-H), 2.89 (2H, m,
3-H, 4-H), 2.41 (2H, m, 4Ј-H, CH2CO2CH3), 2.27 (1H, dd,
J 16.11 and 7.81, CH2CO2CH3); δC: 196.05 (C-5), 171.94 (C-8),
169.82 (C-6), 168.75 (CO2CH3), 163.32 (C-9a), 137.46 (Ar-C),
128.71, 127.87, 127.70 (Ar-CH), 97.68 (C-5a), 55.22 (CH2Ph),
54.79 (OCH3, OCH3), 53.78 (C-2), 51.78 (CO2CH3), 47.45
(C-4), 40.06 (C-3), 36.88 (CH2CO2CH3). Imidazopyrimidine
12c (20 mg, 25%) was also isolated, NMR data agree with that
reported above.
5692 [R(int) = 0.0139]
2718
5692/3/641
R1 = 0.0741 wR2 = 0.1800
R1 = 0.1290 wR2 = 0.2121
a R indices: R1 = [Σ||Fo| Ϫ |Fc||]/Σ|Fo| (based on F), wR2 = [[Σw(|Fo2 Ϫ
2
Fc2|)2]/[Σw(Fo )2]]1/2 (based on F2); w = 1/[(σFo)2 ϩ (0.1602*P)2].
2.73 (2H, m, 6Ј-H, CH2CO2CH3), 2.26 (1H, dd, J 16.11 and
8.06, CH2CO2CH3), 1.84 (3H, s, CH3); m/z 484 (Mϩ, 100%),
385, 358, 193, 91 (CH2Ph).
Methyl (E)-3-[8-benzyl-2,4-dimethoxy-6-(2-methoxy-2-oxo-
ethyl)-5,6,7,8-tetrahydropteridin-5-yl]prop-2-enoate, 44. A white
solid (39 mg, 23%), mp 108–109 ЊC (Found C, 59.51; H, 5.49;
N, 12.56. C22H26N4O6 requires C, 59.72; H, 5.92; N, 12.66%);
δ : 7.50 (1H, d, J 13.18, N-CH᎐CH), 7.23 (5H, m, Ar-H), 5.03
᎐
H
(1H, d, J 14.65, CH Ph), 4.76 (1H, d, J 13.18, N-CH᎐CH),
᎐
2
4.51 (1H, d, J 14.65, CH2Ph), 4.12 (1H, m, 6-H), 3.90 (3H, s,
OCH3), 3.86 (3H, s, OCH3), 3.59 (3H, s, CO2CH3), 3.49 (3H,
s, CO2CH3), 3.40 (1H, dd, J 12.45 and 4.03, 7-H), 3.20 (1H, br
d, J 7Ј-H), 2.31 (1H, dd, J 16.11 and 6.96, CH2CO2CH3), 2.14
(1H, dd, J 16.11 and 7.32, CH2CO2CH3); δC: 170.66 (C-2),
169.41 (C-4), 162.79 (C-8a), 160.72 (CO2CH3), 154.04 (CO2-
Dimethyl 5-benzyl-1,3-dimethoxy-7-(2-methoxy-2-oxoethyl)-
11a-methyl-5,6,7,11a-tetrahydroisoxazolo[2,3-d]pyrimido-
[5,4-f ][1,4]diazepine-10,11-dicarboxylate 37b
A solution of 3b (130 mg, 0.325 mmol) and dimethyl acetylene-
dicarboxylate (80 µl, 92 mg, 0.65 mmol) in THF (10 cm3) was
stirred at rt for 72 h. Following solvent evaporation the prod-
ucts were isolated by flash chromatography (petroleum ether–
Et2O, 3 : 2). Title compound 37b (10 mg, 6%); δH (C6D6): 7.17
(5H, m, Ar-H), 4.85 (1H, d, J 15.01, CH2Ph), 4.47 (1H, d,
J 15.01, CH2Ph), 4.05 (1H, m, 7-H), 3.61 (3H, s, OCH3), 3.54
(3H, s, OCH3), 3.48 (1H, dd, J 13.18 and 9.52, 6-H), 3.32 (3H,
s, CO2CH3), 3.24 (3H, s, CO2CH3), 3.17 (3H, s, CO2CH3), 2.83
(2H, m, 6Ј-H, CH2CO2CH3), 2.17 (3H, s, CH3), 2.08 (1H, dd,
J 16.11 and 7.69, CH2CO2CH3). Pteridine 43, a white solid (55
mg, 47%), mp 115–116 ЊC (from Et2O, hexane). Data agree with
that previously recorded.
CH ), 148.85 (N-CH᎐CH-), 137.09 (Ar-C), 128.60, 128.06,
᎐
3
127.65 (Ar-CH), 96.61 (C-4a), 90.59 (N-CH᎐CH-), 54.59
᎐
(OCH3, OCH3), 54.13 (CO2CH3), 51.92 (CO2CH3), 51.07 (C-7),
50.80 (C-6), 47.88 (CH2Ph), 34.78 (CH2CO2CH3); m/z 442 (Mϩ,
100%), 411 (M Ϫ 31 = CH2OH), 369 (M Ϫ 73 = CH2CO2CH3),
278, 193, 149, 104, 91 (CH2Ph).
Methyl 2-(8-benzyl-2,4-dimethoxy-5,6,7,8-tetrahydropteridin-
6-yl)acetate, 43. A white solid (29 mg, 17%), mp 115–116 ЊC
(Et2O, hexane); NMR data agree with that described above.
X-Ray crystal determination of 37c.§ The structure was solved
by direct methods, SHELXS-97,23 and refined by full matrix
least squares using SHELXL-97.24 SHELX operations were
rendered paperless using ORTEX which was also used to obtain
the drawings.25 Data were corrected for Lorentz and polaris-
ation effects but not for absorption. Hydrogen atoms were
included in calculated positions with thermal parameters 30%
larger than the atom to which they were attached. The non-
hydrogen atoms were refined anisotropically. All calculations
were performed on a Pentium PC. Crystal data for 37c are given
in Table 2.
Methyl 5-benzyl-1,3-dimethoxy-7-(2-methoxy-2-oxoethyl)-11a-
methyl-5,6,7,11a-tetrahydroisoxazolo[2,3-d]pyrimido[5,4-f ]-
[1,4]diazepine-11-carboxylate, 37c
Nitrone 3b (200 mg, 0.5 mmol) was stirred with methyl prop-
iolate (1.5 cm3, 1.42 g, 16.9 mmol) at rt for 24 h. TLC analysis
indicated three new products and some unreacted nitrone.
Purification by flash chromatography (hexane–Et2O, 3 : 2) fol-
lowed by crystallisation (hexane, Et2O) gave pure samples of
each product. Adducts are described in order of elution and the
yield of each is based on 69% conversion of nitrone.
Acknowledgements
This work has been supported by an Enterprise Ireland Basic
Science Research Grant (SC/96/402) [F. H. and C. B.] and the
Cycloadduct 37c. A white solid (70 mg, 42%), mp 127–128 ЊC
(Found C, 59.49; H, 5.29; N, 11.27. C24H28N4O7 requires C,
59.50; H, 5.79; N, 11.57%); δH: 7.41 (1H, s, C-10), 7.24 (5H, m,
Ar-H), 4.67 (1H, d, J 14.65, CH2Ph), 4.43 (1H, d, J 14.65,
CH2Ph), 3.94 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.61 (3H, s,
CO2CH3), 3.60 (4H, br s, CO2CH3, 7-H), 3.30 (1H, m, 6-H),
§ CCDC reference number 207/509. See http://www.rsc.org/suppdata/
p1/b0/b007163n/ for crystallographic files in .cif format.
J. Chem. Soc., Perkin Trans. 1, 2001, 622–632
631

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