Asymmetric hetero-Diels-Alder reactions of alkenyldihydrooxazoles. Synthesis of oxazolo[3,2-c]pyrimidines and related compounds

Article abstract of DOI:10.1039/a905700e

Alkenyldihydrooxazoles undergo a highly diastereoselective formal aza-Diels-Alder reaction with aryl and arenesulfonyl isocyanates to give oxazolo[3,2-c]pyrimidines. Depending on the substitution pattern of the alkenyldihydrooxazole, these compounds may then undergo addition of a second equivalent of the isocyanate to give either tetrahydrooxazoIo[3,2-c]pyrimidine-8-carboxamides or octahydroazeto[2,3-<7]oxazolo[3,2c]pyrimidines. The second addition is sensitive to steric and electronic factors, and can be prevented in some cases. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a905700e

View Article Online / Journal Homepage / Table of Contents for this issue
Asymmetric hetero-Diels–Alder reactions of alkenyldihydro-
oxazoles. Synthesis of oxazolo[3,2-c]pyrimidines and related
compounds
Mark C. Elliott* and Elbertus Kruiswijk
Department of Chemistry, Cardiff University, PO Box 912, Cardiff, UK CF10 3TB.
E-mail: elliottmc@cardiff.ac.uk
Received (in Cambridge, UK) 14th July 1999, Accepted 2nd September 1999
Alkenyldihydrooxazoles undergo a highly diastereoselective formal aza-Diels–Alder reaction with aryl and
arenesulfonyl isocyanates to give oxazolo[3,2-c]pyrimidines. Depending on the substitution pattern of the
alkenyldihydrooxazole, these compounds may then undergo addition of a second equivalent of the isocyanate
to give either tetrahydrooxazolo[3,2-c]pyrimidine-8-carboxamides or octahydroazeto[2,3-d ]oxazolo[3,2-
c]pyrimidines. The second addition is sensitive to steric and electronic factors, and can be prevented in
some cases.
Introduction
while Sakamoto had reported the use of alkenylthiazolines as
azadienes in reactions with diphenylketene (Scheme 3). In
9
The Diels–Alder reaction has proven its synthetic utility
numerous times since its discovery over 70 years ago. Much
1
recent work has focussed on asymmetric variations of this reac-
tion, whether diastereoselective as a result of chiral starting
2
3
materials or enantioselective through catalysis. In contrast to
this, aza-Diels–Alder reactions, and particularly asymmetric
4
aza-Diels–Alder reactions, have received much less attention.
In fact, prior to our own work in this area, the only example
5
Scheme 3
of a chiral 1-azadiene in a Diels–Alder reaction was the use of
unsaturated SAMP-hydrazones reported by Ghosez and co-
workers, while Waldner has reported an asymmetric aza-Diels–
related work, Richter and Ulrich reported reactions of N,N-
dimethyl-NЈ-(∆ -thiazolin-2-yl)formamidine with phenyl iso-
cyanate. Cross-conjugated azatrienes were used by Saito
et al. with isocyanates in a tandem process.
All these reactions share the common factor of a hetero-
cumulene reacting as the dienophilic component, and since
isocyanates are more readily accessible than ketenes, we decided
to use the study of Hellmann as a basis for our own work. We
were initially hindered by the lack of experimental detail in the
report of Hellmann, and unable to reconcile the single piece of
spectroscopic data reported, an infrared stretching frequency
6
2
Alder reaction of a 1-azadiene with a homochiral thiazolinone
10
7
dienophile.
11
We felt that alkenyldihydrooxazoles 1 had much to offer as
azadienes, given their ready preparation from amino acid
derivatives, and that these reactions would allow the generation
of up to three stereogenic centres in a single step (Scheme 1),
Ϫ1
of 1760 cm , with the proposed structure 4.
Results and discussion
The many methods for the preparation of dihydrooxazoles
12
have been reviewed by Meyers and Gant. We were mindful of
the potential problem of conjugate addition of excess amino
alcohol to the desired alkenyldihydrooxazoles, and so chose to
pursue a two step route involving formation and cyclisation of
the corresponding amides (Scheme 4). Starting with the readily
available (2R)-2-aminobutan-1-ol 5 of 64.4% ee the amides
6–10 were obtained in 62–91% yield from the appropriate acid
chloride under Schotten–Baumann conditions according to the
Scheme 1
with the opportunity to introduce further functionality by
modification of potentially versatile products 2.
We were somewhat surprised to find only a single example of
the use of alkenyldihydrooxazoles as azadienes in the literature8,
this being the work of Hellmann and co-workers (Scheme 2),
13
procedure of Langlois et al. These were used without further
purification with the exception of 10 which was recrystallised
from diethyl ether. A number of methods can be used for the
14
cyclisation to the dihydrooxazole, but we have found the use
of methanesulfonyl chloride and triethylamine in dichloro-
methane to be most convenient. Dihydrooxazole 13 surprisingly
decomposed on attempted distillation or prolonged contact
with silica gel. Rapid chromatography gave only a minor
Scheme 2
J. Chem. Soc., Perkin Trans. 1, 1999, 3157–3166
This journal is © The Royal Society of Chemistry 1999
3157

View Article Online
Table 1 Reactions of 14 with selected isocyanates
1
Reagents and conditions: i, 2 equivalents R NCO, see below.
Compound
(yield %)
1
Entry
R
R
t/h
T/ЊC
1
2
3
4
Et
Et
Et
Et
Ph
4-BrC H
4-MeOC H
4-NO C H
65
18
25
—
150
150
150
—
16a (81)
16b (42)
16c (see text)
(0)
6
4
6
4
2
6
4
Scheme 4 Reagents and conditions: i, Na CO , CH Cl , H O; ii,
2
3
2
2
2
MeSO Cl, Et N, CH Cl .
2
3
2
2
Fig. 1
improvement, but fortunately the crude product was pure
we do feel that the data we have is not conclusive and have been
unable to assign the stereochemistry of the major isomer.
Compounds 16a–c were formed from 14 (Table 1, entries 1–
3), in each case as an approximately 1.7:1 mixture of diastereo-
isomers. Reaction of 14 with 4-nitrophenyl isocyanate led to no
isolable products, presumably due to the ease of hydrolysis of
the β-lactam (entry 4).
In each case we were unable to separate the diastereoisomers
by either crystallisation or chromatography. Not surprisingly
these compounds decomposed extensively upon chromato-
graphy over silica gel. Chromatography over neutral alumina
gave essentially pure compounds, although traces of the N,NЈ-
diarylurea, a hydrolysis product of the isocyanate, could not
completely be removed. In the case of 16a, the compound was
obtained essentially pure simply by extracting the reaction mix-
ture with chloroform and filtering and evaporating. Very little
improvement was observed upon chromatography. In the case
of 16c, the reaction was extremely capricious. On one occasion
we were able to obtain a 70% yield of reasonably pure material
by dissolving the crude reaction mixture in chloroform. On a
number of other occasions only a small amount of product was
observed, along with extensive decomposition.
15
enough to use directly. Dihydrooxazoles 11, 12 and 14
were purified by short path distillation. Compound 15 was
formed essentially quantitatively, and no purification was
required.
Dihydrooxazole 3, used earlier by Hellmann and prepared in
a similar manner to that shown in Scheme 4, was used initially.
Reaction with phenyl isocyanate under a wide range of condi-
tions gave either recovered dihydrooxazole or complex mixtures
from which we were unable to isolate products. In no instance
Ϫ1
did we observe the 1760 cm band in the infrared spectrum
even of the crude reaction mixture. Since this dihydrooxazole is
quite volatile, we moved next to 14, although due to the substi-
tution pattern this was not expected to lead to the generation of
a new stereogenic centre. In the event, this proved to be a
fortuitous choice, since the products obtained when 14 was
heated to 150 ЊC with phenyl isocyanate appeared to be a
mixture of diastereoisomers in which two equivalents of the iso-
cyanate had been incorporated. The NMR data for these com-
pounds was not particularly conclusive, and we were unable to
separate the diastereoisomers. However, based on the tentative
assumption that the initial reaction would be a formal hetero-
Diels–Alder, we reasoned that the second equivalent of the
isocyanate might add to the electron-rich double bond in the
initial adduct to give compounds 16 containing the previously
unknown azeto[2,3-d ][1,3]oxazolo[3,2-c]pyrimidine ring system
These compounds exhibit some unusual spectroscopic
features. For example, the infrared stretch of the β-lactam
Ϫ1
carbonyl is lower than might be expected (typically 1730 cm ).
Also, the quaternary carbon bearing the three heteroatoms is
13
(
Scheme 5). These structures appear to fit the available data,
significantly deshielded in the C NMR spectrum (around 150
ppm). Both these features can be rationalised by the contribu-
tion of a zwitterionic resonance form 17 (Fig. 1). The existence
of compounds 16 as full zwitterionic species seems unlikely on
the grounds of polarity.
and have been supported by later results (vide infra), although
Due to our difficulty in satisfactorily characterising com-
pounds 16, we reasoned that moving the methyl group in 14 to
the terminus of the double bond would lead to the formation of
a new stereogenic centre in the addition of the first equivalent
of the isocyanate, and if a β-lactam were formed during the
second addition, it would be expected to fragment as shown in
Scheme 6.
Scheme 5 Reagents and conditions: i, 2 equivalents PhNCO, 150 ЊC,
5 h.
6
3
158
J. Chem. Soc., Perkin Trans. 1, 1999, 3157–3166

View Article Online
Table 2 Reactions of 2-alkenyldihydrooxazoles 11–13 with selected
isocyanates
1
Reagents and conditions: i, 2 equivalents R NCO, see below.
Compound
(yield %)
1
R
R
t/h
48
24
21
T/ЊC
Scheme 6
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Ph
Ph
Ph
Ph
Ph
Ph
4-BrC H
4-O
4-MeOC H
4
4-MeC H SO
Ph
4-BrC H
4-O NC H
4-MeOC H
4-MeC H SO
Ph
4-BrC H
4-O NC H
4-MeOC H
4-MeC H SO
25
25
25
25
25
18a (58)
18b (61)
18c (82)
18d (65)
Gratifyingly this proved to be the case, so that when 11 was
heated with two equivalents of phenyl isocyanate at 150 ЊC
sealed tube) for 1 hour, the 2:1 adduct 18a formed as only a
single diastereoisomer within the detection limits of 400 MHz
H NMR spectroscopy (Scheme 7). Subsequent experiment-
6
4
NC
H
6
2
4
120
(
6
a
0.5
46
1.25
18e (66)
6
4
2
2
2
25
19a (53)
19b (69)
19c (71)
(0)
1
150
150
—
6
4
1
2
6
4
—
6
4
0.5
1
1
1
1
25
19e (90)
20a (76)
20b (59)
20c (74)
6
4
150
150
150
150
25
6
4
2
6
4
b
20d (10)
6
4
0.5
20e (94)
6
4
a
b
Reaction carried out in toluene solution. Not fully purified.
Scheme 7 Reagents and conditions: i, 2 equivalents PhNCO, 150 ЊC,
1
h.
ation showed that the reaction also proceeds, albeit slowly, at
room temperature. At either temperature, only the same single
diastereoisomer was observed. Results from a range of iso-
cyanates are summarised in Table 2. The stereochemistry of
1
8c, 18e and 20e were confirmed by single crystal X-ray
16
analysis. The other compounds are assumed, on the basis of
similar spectroscopic data, to have the same stereochemistry.
Based on these results, we feel that the β-lactam structures 16
are correct.
Fig. 2
reaction at 150 ЊC, or addition of another equivalent of phenyl
isocyanate to the single adduct resulted in the formation of the
double adduct 22 as a single diastereoisomer (Scheme 8), the
Reactions with toluene-4-sulfonyl isocyanate were particu-
larly rapid, while those with 4-methoxyphenyl isocyanate were
much slower (with compound 19d only a trace of the desired
1
product was visible in the H NMR spectrum of the crude reac-
tion mixture). Reactions with tert-butyl isocyanate and benzyl
isocyanate were unsuccessful, reflecting the lower reactivity of
these compounds.
We were intrigued by the possibility of preparing mixed
adducts using two isocyanates in appropriate proportions.
Unfortunately reaction of 11 with 5 equivalents of either
phenyl isocyanate or 4-methoxyphenyl isocyanate and 1 equiv-
alent of toluene-4-sulfonyl isocyanate gave only the adduct
derived from double addition of toluene-4-sulfonyl isocyanate.
Clearly while the second addition is faster than the first, it is still
slow enough to permit selective reaction of a more reactive
isocyanate.
With these results in hand, we felt that if we were to use a
substrate such as 15 it should give complete stereocontrol in the
first step. As a result of this, the β-lactam formation in the
second step would be directed by an adjacent stereocentre
rather than a remote one, and so we might expect better stereo-
control. Although this did prove to be the case, the reactions
were not as simple as expected. Reaction of this dihydrooxazole
with 2 equivalents of phenyl isocyanate at 65 ЊC resulted in the
formation of a single adduct 21 in 62% yield. Conducting the
Scheme 8 Reagents and conditions: i, PhNCO, see Discussion.
relative stereochemistry of which was supported by NOE
experiments (Fig. 2), although these can hardly be considered
13
conclusive. The C NMR spectrum of 22 shows 11 distinct
resonances corresponding to aromatic methines; presumably
these arise due to hindered rotation of one of the phenyl
groups.
The α-hydrogen on the dihydrooxazole CH group is signifi-
2
cantly shielded (δH 3.2), presumably by the phenyl group
attached to the β-lactam nitrogen, although this was not
observed in compounds 16a–16c.
On the basis of the available data, we assume that the stereo-
J. Chem. Soc., Perkin Trans. 1, 1999, 3157–3166
3159

View Article Online
chemistry of 22 is as shown, although this assignment owes
more to predictions based upon the known stereochemistry of
compounds 18–20 and to our difficulty in rationalising any
other stereochemical outcome than to unambiguous evidence.
Reaction between either 14 or 15 with toluene-4-sulfonyl iso-
cyanate gave adducts in which only a single equivalent of the
isocyanate added (Scheme 9). We have considered the possibil-
steric interactions between the isocyanate oxygen and the sub-
stituent at the 4-position of the dihydrooxazole.
In order to test the sensitivity of the reaction to steric effects,
dihydrooxazole 25 was prepared via the corresponding amide.
This compound did not react with aryl and arenesulfonyl
isocyanates, even under forcing conditions. This observation
is consistent with our transition state model (vide infra), where
for ring closure to occur, the isocyanate oxygen would be
particularly close to the gem-dimethyl group.
Scheme 9 Reagents and conditions: i, TsNCO, toluene, 25 ЊC.
The second addition may proceed either by a direct
[
2π ϩ 2π ] thermally allowed cycloaddition followed by the
s a
ity that the second addition may be reversible, although the lack
of reactivity of 24 with phenyl isocyanate does cast doubt on
this. It is possible that the reactivity of the double bond is
attenuated by the electron-withdrawing effect of the toluene-4-
sulfonyl group, and this, in conjunction with steric hindrance
due to the methyl group, prevents the second addition. Com-
pound 23 was produced essentially pure, and decomposed upon
attempted purification; in particular on removal of the last
traces of toluene, the compound rapidly decomposed. Never-
theless, acceptable spectroscopic data have been obtained.
Compound 24 undergoes a retro-Diels–Alder reaction to pro-
duce 15 when kept in solution (CDCl or benzene-d ) for 10–14
cleavage of the β-lactam (Scheme 11, path a) or by a stepwise
3
6
17
days. Presumably this reaction is driven by the hydrolysis
of toluene-4-sulfonyl isocyanate by traces of water in the
solvent.
In the IR spectra of compounds 21, 23 and 24, a signal was
Ϫ1
observed at approximately 1760 cm which could not be read-
ily explained. It seems likely that this is due to an impurity,
possibly the azetidinedione formed by dimerisation of the iso-
18
8
cyanate. This may also explain the observations of Hellmann.
The Diels–Alder reaction has been the subject of numerous
computational studies, with concerted and stepwise (biradical
19
20
and ionic) pathways being considered. Tietze et al. have
studied the Diels–Alder reaction of 1-azabuta-1,3-dienes at
both semiempirical and ab initio levels, their results suggesting
a two-step cycloaddition mechanism. Our own recent compu-
tational study on the reactions of alkenyldihydrooxazoles with
21
isocyanates is in agreement with a similar study by Fabian and
22
Kollenz on the reaction of 1-azadienes with ketene in that
a stepwise reaction as shown in Scheme 10 is supported. The
origin of the asymmetric induction appears to be reduction of
Scheme 11
23
enamine acylation (Scheme 11, path b). We have no evidence
to allow us to distinguish between these mechanisms at the
present time, although computational studies are underway.
In conclusion, alkenyldihydrooxazoles undergo a novel
stereoselective formal hetero-Diels–Alder reaction with iso-
cyanates. These reactions have been used to prepare a number
of novel heterocyclic systems, and we have outlined the scope
and limitations of the reaction.
Experimental
All melting points were determined on a Gallenkamp melting
point apparatus, and are uncorrected. Infrared spectra were
recorded on a Perkin-Elmer 1600 FTIR spectrophotometer.
Mass spectra were recorded on a Fisons VG Platform II
spectrometer. High-resolution mass spectra were recorded at
the EPSRC National Mass Spectrometry Service Centre in
Swansea. Elemental analyses were recorded using a Perkin-
Elmer 240 C elemental analyser. NMR spectra were recorded
Scheme 10
3
160
J. Chem. Soc., Perkin Trans. 1, 1999, 3157–3166

View Article Online
on a Bruker DPX 400 spectrometer operating at 400 MHz for
H and at 100 MHz for C at 25 ЊC. All chemical shifts are
(alkene CH), 122.8 (alkene CH), 65.6 (OCH ), 53.8 (CH), 25.5
2
1
13
(CH ), 24.6 (CH ), 12.8 (CH ) and 11.0 (CH ).
2
2
3
3
reported in ppm downfield from TMS; J values are given in Hz.
Flash chromatography was performed unless otherwise stated
on Matrex silica 60 35–70 micron.
(
E)-N-[(2R)-1-Hydroxybutan-2-yl]-3-phenylprop-2-enamide (8)
E)-Cinnamoyl chloride (9.66 g, 58 mmol) was added to a
(
solution of (2R)-2-aminobutan-1-ol (4.70 g, 52 mmol) in
dichloromethane (50 ml). Saturated aqueous sodium carbonate
solution (30 ml) was added and the resulting mixture stirred
overnight. The aqueous layer was then saturated with sodium
chloride and extracted three times with dichloromethane (50
ml). The combined organic layers were dried over MgSO4,
filtered and the solvent was removed in vacuo to afford the title
compound (7.20 g, 62%) as a white solid, mp 93–96 ЊC, which
2
-(Propen-2-yl)-4,5-dihydro-1,3-oxazole (3)
Triethylamine (9.16 g, 88 mmol) and methacryloyl chloride
8.86 g, 88 mmol) were added to 2-aminoethanol (5.35 g, 88
(
mmol) in dichloromethane (50 ml) and the solution stirred
for 15 h. After cooling to 5 ЊC, triethylamine (9.16 g, 88 mmol)
and methanesulfonyl chloride (10.03 g, 88 mmol) were added
and the resulting suspension was stirred for 24 h. The organic
layer was washed twice with saturated NaHCO (25 ml), dried
over Na SO , filtered and concentrated in vacuo. The product
ϩ
was used without further purification (Found: M , 219.1259.
3
Ϫ1
C H NO requires M, 219.1259); νmax(CHCl )/cm 3020,
2
4
13 17
2
3
was purified by short path distillation to afford the title com-
pound (1.64 g, 17%) as a colourless oil, bp 110 ЊC/1 mmHg;
νmax (neat)/cm 2989, 1655, 1609 and 1141; δH (400 MHz;
1662, 1622; δH (400 MHz; CDCl ) 7.55 (1 H, d, J 15.6, alkene
3
CH), 7.38 (2 H, m, aromatic CH), 7.31–7.29 (3 H, m, aromatic
CH), 6.42 (1 H, d, J 15.6, alkene CH), 6.20 (1 H, broad d, J 7.9,
NH), 3.96–3.91 (1 H, m, CH), 3.68 (1 H, dd, J 11.2 and 3.5, one
of OCH ), 3.57 (1 H, dd, J 11.2 and 5.6, one of OCH ), 3.51
Ϫ1
CDCl ) 5.85 (1 H, s, alkene CH), 5.47 (1 H, s, alkene CH),
3
4
.29 (2 H, t, J 9.5, OCH ), 3.81 (2 H, t, J 9.5, NCH ) and 2.01
2
2
2
2
(
3 H, s, CH ); δ (100 MHz; CDCl ) 165.9 (C), 133.0 (alkene
(1 H, broad s, OH), 1.63–1.53 (1 H, m, one of CH ), 1.51–1.44
3
C
3
2
C), 122.0 (alkene CH ), 67.7 (OCH ), 55.4 (CH ) and 19.7
(1 H, m, one of CH ) and 0.91 (3 H, t, J 7.4, CH ); δ (100
2
2
2
2
3
C
(
CH ).
MHz; CDCl ) 167.3 (C᎐O), 141.8 (alkene CH), 135.1 (aromatic
3
3
C), 130.1, 129.3, 128.2 (all aromatic CH), 121.0 (alkene CH),
65.5 (OCH ), 54.0 (CH), 24.7 (CH ) and 11.1 (CH ); m/z (EI)
2 2 3
ϩ
219 (M , 14%), 188 (100), 131 (100), 103 (100) and 77 (100).
(
E)-N-[(2R)-1-Hydroxybutan-2-yl]but-2-enamide (6)
(
E)-Crotonyl chloride (17.26 g, 0.17 mol) was added to a mix-
ture of (2R)-2-aminobutan-1-ol (13.38 g, 0.15 mol) in dichloro-
methane (200 ml) and saturated aqueous sodium carbonate
solution (120 ml). The mixture was stirred overnight after
which the aqueous layer was saturated with sodium chloride
and extracted three times with dichloromethane (75 ml). The
N-[(2R)-1-Hydroxybutan-2-yl]-2-methylprop-2-enamide (9)
Methacryloyl chloride (20.14 g, 0.19 mol) was added to a mix-
ture of (2R)-2-aminobutan-1-ol (15.61 g, 0.18 mol) in dichloro-
methane (200 ml) and saturated aqueous sodium carbonate
solution (120 ml). The mixture was stirred overnight, after
which the aqueous layer was saturated with sodium chloride
and extracted three times with dichloromethane (50 ml). The
combined organic layers were dried over MgSO , filtered and
4
the solvent was removed in vacuo to afford the title compound
(
19.34 g, 82%) as a yellow solid, mp 73–75 ЊC, which was
ϩ
used without further purification (Found: MH , 158.1181.
C H NO requires M , 158.1181); ν
combined organic layers were dried over MgSO , filtered and
4
ϩ
Ϫ1
(CHCl )/cm 3392,
the solvent was removed in vacuo to afford the title compound
(25.02 g, 91%) as a pale yellow oil, mp 7–9 ЊC, which was used
8
16
2
max
3
1
674, 1631, 1545; δH (400 MHz; CDCl ) 6.78 (1 H, dq, J 15.2
3
Ϫ1
and 6.8, alkene CH), 5.75 (1 H, apparent dd, J 15.2 and 1.6,
alkene CH), 5.61 (1 H, s, NH), 3.93–3.88 (1 H, m, CH), 3.68
without further purification; νmax (neat)/cm 3349, 1667, 1624,
1533; δ (400 MHz; CDCl ) 6.23 (1 H, broad s, NH), 5.64 (1 H,
H
3
(
1 H, dd, J 11.0 and 3.1, one of OCH ), 3.55 (1 H, dd, J 11.0
s, alkene CH), 5.26 (1 H, s, alkene CH), 3.84 (1 H, m, CH), 3.63
(1 H, broad s, OH), 3.61 (2 H, m, OCH ), 1.89 (3 H, s, CH ),
2
and 5.5, one of OCH ), 2.93 (1 H, broad s, OH), 1.78 (3 H,
2
2
3
dd, J 6.8 and 1.6, CH ), 1.62–1.50 (2 H, m, CH ) and 0.89
1.63–1.41 (2 H, m, CH ) and 0.88 (3 H, t, J 7.5, CH ); δ (100
3
2
2
3
C
(
3 H, t, J 7.5, CH ); δ (100 MHz; CDCl ) 167.3 (C᎐O), 140.9
MHz; CDCl ) 171.3 (C᎐O), 142.0 (alkene C), 121.9 (alkene
3
C
3
3
(
(
alkene CH), 125.3 (alkene CH), 65.8 (OCH ), 53.8 (CH), 24.6
CH ), 67.0 (OCH ), 55.3 (CH), 27.4 (CH ), 20.3 (CH ) and 12.7
2
2
2
2
3
ϩ
ϩ
CH ), 18.1 (CH ) and 11.0 (CH ); m/z (EI) 158 (MH , 89%),
(CH ); m/z (EI) 158 (MH , 100%), 140 (100) and 69 (50).
2
3
3
3
8
6 (17) and 58 (100).
(
E)-N-[(2R)-1-Hydroxybutan-2-yl]-2-methyl-3-phenylprop-2-
(
E)-N-[(2R)-1-Hydroxybutan-2-yl]pent-2-enamide (7)
enamide (10)
A solution of (E)-pentenoic acid (1.97 g, 20 mmol) in thionyl
chloride (25 ml) was heated under reflux overnight. The thionyl
chloride was removed in vacuo, to afford the corresponding acid
chloride, which was added to a solution of (2R)-2-aminobutan-
A solution of (E)-2-methyl-3-phenylpropenoic acid (3.98 g,
24.5 mmol) in thionyl chloride (25 ml) was heated under reflux
for 15 h. After cooling, the excess thionyl chloride was removed
in vacuo to afford (E)-2-methyl-3-phenylpropenoyl chloride
(4.38 g, >99%) as a brown liquid, which was used without
further purification. Saturated sodium carbonate solution (30
ml) was added to a solution of (2R)-2-aminobutan-1-ol (2.31 g,
25.9 mmol) in dichloromethane (50 ml). The (E)-2-methyl-3-
phenylpropenoyl chloride was added and the mixture stirred
overnight. The aqueous layer was saturated with sodium
chloride and extracted twice with dichloromethane (50 ml). The
1
-ol (1.60 g, 18 mmol) in dichloromethane (50 ml). Saturated
aqueous sodium carbonate solution (30 ml) was added and
the resulting mixture stirred overnight. The aqueous layer was
saturated with sodium chloride and extracted three times
with dichloromethane (50 ml). The combined organic layers
were dried over MgSO , filtered and the solvent was removed
4
in vacuo to afford the title compound (2.48 g, 75%) as a light
brown solid, which was used without further purification; ν
combined organic layers were dried over MgSO , filtered and
max
4
Ϫ1
(
CHCl )/cm 3288, 1666, 1628, 1542; δH (400 MHz; CDCl3)
the solvent removed in vacuo to afford a yellow solid which
was then washed with diethyl ether to give the title compound
3
6
.82 (1 H, dt, J 15.2 and 6.4, alkene CH), 5.91 (1 H, broad d,
Ϫ1
J 7.7, NH), 5.74 (1 H, d, J 15.2, alkene CH), 3.84 (1 H, m,
(4.57 g, 76%) as a white solid, mp 88–91 ЊC; νmax(neat)/cm
HCEt), 3.62 (1 H, dd, J 11.0 and 3.4, one of OCH ), 3.52 (1 H,
3344, 3054, 1713 (C᎐O) and 1652; δH (400 MHz; CDCl ) (OH
2
3
dd, J 11.0 and 5.6, one of OCH ), 3.41 (1 H, broad s, OH),
not observed) 7.38–7.29 (6 H, m, aromatic and alkene CH),
4.02–3.97 (1 H, m, HCEt), 3.79 (1 H, dd, J 11.0 and 3.4, one of
OCH ), 3.70–3.66 (1 H, dd, J 11.0 and 5.8, one of OCH ), 2.12
2
2
.16–2.12 (2 H, m, CH ), 1.60–1.53 (1 H, m, one of CH ), 1.48–
2
2
1
.41 (1 H, m, one of CH ), 0.99 (3 H, t, J 7.4, CH ) and 0.89
2
3
2
2
(
3 H, t, J 7.4, CH ); δ (100 MHz; CDCl ) 167.5 (C᎐O), 147.1
(3 H, s, CH ), 1.73–1.59 (2 H, m, CH ) and 1.02 (3 H, t, J 7.4,
3
C
3
3
2
J. Chem. Soc., Perkin Trans. 1, 1999, 3157–3166
3161

View Article Online
CH ); δ (100 MHz; CDCl ) 170.9 (C᎐O), 136.5 (aromatic C),
(4R)-4-Ethyl-2-propen-2-yl-4,5-dihydro-1,3-oxazole (14)
N-[(2R)-1-Hydroxybutan-2-yl]-2-methylprop-2-enamide
3
C
3
1
34.5 (alkene CH), 132.3 (alkene C), 129.7, 128.7, 128.4 (all
(9)
7.46 g, 47 mmol) in dichloromethane (75 ml) was cooled to
aromatic CH), 65.2 (OCH ), 53.9 (CH), 24.7 (CH ), 14.7 (CH )
2
2
3
(
ϩ
and 11.1 (CH ); m/z (EI) 234 (MH , 30%), 202 (41), 145 (86),
3
5
ЊC. Triethylamine (9.60 g, 95 mmol) and methanesulfonyl
1
17 (90) and 115 (100).
chloride (5.44 g, 47 mmol) were added and the solution stirred
overnight. The solution was then washed twice with saturated
NaHCO (50 ml), dried over Na SO , filtered and concentrated
(
4R)-4-Ethyl-2-propenyl-4,5-dihydro-1,3-oxazole (11)
3
2
4
in vacuo. The product was purified by short path distillation to
(
E)-N-[(2R)-1-Hydroxybutan-2-yl]but-2-enamide (6) (4.21 g, 27
afford the title compound (4.33 g, 66%) as a colourless oil, bp
mmol) in dichloromethane (75 ml) was cooled to 5 ЊC. Triethyl-
amine (5.42 g, 54 mmol) and methanesulfonyl chloride (3.07 g,
ϩ
1
20 ЊC/water pump (Found M , 139.0997. C H NO requires
8
13
Ϫ1
M, 139. 0997); νmax (neat)/cm 1652 and 1616; δH (400 MHz;
CDCl ) 5.72 (1 H, s, alkene CH), 5.34 (1 H, s, alkene CH), 4.22
2
7 mmol) were added and the solution was stirred overnight.
The solution was then washed twice with saturated NaHCO3
50 ml), dried over Na SO , filtered and concentrated in vacuo.
3
(
1 H, dd, J 9.4 and 8.2, one of OCH ), 4.03 (1 H, m, HCEt),
(
2
2
4
3
1
.85 (1 H, apparent t, J 7.8, one of OCH ), 1.95 (3 H, s, CH ),
2 3
The product was purified by Kugelrohr distillation to afford the
title compound (2.41 g, 65%) as a colourless oil, bp 120 ЊC/water
pump; νmax (neat)/cm 1674 and 1616; δH (400 MHz; CDCl3)
.66–1.60 (1 H, m, one of CH ), 1.52–1.43 (1 H, m, one of CH )
2
2
Ϫ1
and 0.87 (3 H, t, J 7.5, CH ); δ (100 MHz; CDCl ) 164.7 (C),
3
C
3
1
2
1
33.1 (alkene C), 121.9 (alkene CH ), 702.2 (OCH ), 68.4 (CH),
2 2
ϩ
6
.53 (1 H, dq, J 15.8 and 6.9, alkene CH), 5.95 (1 H, dq, J 15.8
8.8 (CH ), 19.8 (CH ) and 10.3 (CH ); m/z (EI) 139 (M , 25%),
and 1.7, alkene CH), 4.23 (1 H, dd, J 9.2 and 8.2, one of
OCH ), 4.02 (1 H, m, HCEt), 3.85 (1 H, apparent t, J 8.0, one
2
3
3
10 (74), 94 (24) and 55 (100).
2
of OCH ), 1.78 (3 H, dd, J 6.9 and 1.6, CH ), 1.62–1.41 (2 H, m,
2
3
(
(
4R,E)-4-Ethyl-2-(1-phenylpropen-2-yl)-4,5-dihydro-1,3-oxazole
15)
CH ) and 0.90 (3 H, t, J 7.4, CH ); δ (100 MHz; CDCl ) 163.0
2
3
C
3
(
(
(
C), 139.1 (alkene CH), 119.5 (alkene CH), 71.9 (OCH ), 67.9
2
CH), 28.9 (CH ), 18.6 (CH ) and 10.3 (CH ); m/z (EI) 140
(E)-N-[(2R)-1-Hydroxybutan-2-yl]-2-methyl-3-phenylprop-2-
enamide (10) (4.90 g, 21.0 mmol) was dissolved in dichloro-
methane (50 ml). After cooling with an ice–water bath, triethyl-
amine (4.25 g, 42.0 mmol) and methanesulfonyl chloride (2.41
g, 21.0 mmol) were added and the solution was stirred
overnight. The organic layer was washed twice with saturated
aqueous sodium hydrogen carbonate (50 ml) and quickly dried
over Na SO , filtered and concentrated in vacuo, to afford the
title compound (4.80 g, quant.) as a yellowish oil which was used
without further purification (Found: M , 214.1238. C H NO
requires M, 214.1232); νmax (neat)/cm 3056, 1644 and 1614;
δ (400 MHz; CDCl ) 7.26 (1 H, s, alkene CH), 7.22–7.18 (5 H,
m, aromatic CH), 4.21 (1 H, dd, J 9.4 and 8.1, one of OCH ),
2
3
3
ϩ
MH , 39%), 126 (25) and 83 (100).
(
4R,E)-4-Ethyl-2-but-1-enyl-4,5-dihydro-1,3-oxazole (12)
(
E)-N-[(2R)-1-Hydroxybutan-2-yl]pent-2-enamide (7) (2.33 g,
2
0 mmol) was dissolved in dichloromethane (75 ml.). After
cooling with an ice–water bath, triethylamine (3.99 g, 39 mmol)
and methanesulfonyl chloride (2.26 g, 20 mmol) were added
and the solution was stirred overnight. The organic layer was
2
4
ϩ
14
17
washed twice with saturated NaHCO (25 ml) and quickly dried
Ϫ1
3
over Na SO , filtered and concentrated in vacuo. The product
2
4
H
3
was purified by Kugelrohr distillation to afford the title com-
2
pound (1.68 g, 51%) as a colourless oil, bp 120 ЊC/1 mmHg
4
.06–3.97 (1 H, m, HCEt), 3.81 (1 H, apparent t, J 7.9, one of
ϩ
(
(
6
Found: M , 153.1154. C H NO requires M, 153.1154); ν
9
15
max
OCH ), 2.08 (3 H, s, CH ), 1.65–1.55 (1 H, m, one of CH ),
1
(
2
3
2
Ϫ1
neat)/cm 2965, 2926, 1674 and 1612; δH (400 MHz; CDCl3)
.56 (1 H, m, alkene CH), 5.94–5.89 (1 H, d, J 12.6, alkene
.47–1.37 (1 H, m, one of CH ) and 0.82 (3 H, t, J 7.4, CH ); δ
2 3 C
100 MHz; CDCl ) 166.0 (C), 136.7 (aromatic C), 135.5 (alkene
3
CH), 4.26 (1 H, apparent t, J 8.2, one of OCH ), 4.00 (1 H, m,
2
CH), 129.7, 128.7, 128.1 (all aromatic CH), 125.8 (alkene C),
2.2 (CH ), 68.2 (CH), 28.9 (CH ), 15.5 (CH ) and 10.3 (CH );
HCEt), 3.81 (1 H, apparent t, J 7.9, one of OCH ), 2.14 (2 H,
2
7
2
2
3
3
m, CH ), 1.62–1.57 (1 H, m, one of CH ), 1.47–1.44 (1 H, m,
ϩ
2
2
m/z (EI) 216 (MH , 54%), 214 (100), 186 (53) and 115 (100).
one of CH ), 0.99 (3 H, t, J 8.0, CH ) and 0.91 (3 H, t, J 7.4,
2
3
CH ); δ (100 MHz; CDCl ) 163.1 (C), 145.7 (alkene CH), 117.2
(3R)-6,9-Diphenyl-3-ethyl-7a-methyl-2,3,5,6,7,7a,8,9-octa-
3
C
3
(
1
(
alkene CH), 72.1 (OCH ), 68.0 (CH), 29.0 (CH ), 26.0 (CH ),
hydroazeto[2,3-d][1,3]oxazolo[3,2-c]pyrimidine-5,8-dione (16a)
A mixture of phenyl isocyanate (504 mg, 2.24 mmol) and (4R)-
2
2
2
ϩ
2.8 (CH ) and 10.5 (CH ); m/z (EI) 153 (M , 44%), 108 (73), 96
3
3
100) and 82 (39).
4
-ethyl-2-propen-2-yl-4,5-dihydro-1,3-oxazole (14) (295 mg,
2
.12 mmol) was heated in a sealed tube at 150 ЊC for 65 hours.
(
4R,E)-4-Ethyl-2-(2-phenylethenyl)-4,5-dihydro-1,3-oxazole (13)
The reaction mixture was dissolved in chloroform, filtered, and
the chloroform was removed in vacuo to afford the essen-
tially pure title compound (649 mg, 81%) as a light yellow
solid (1.7:1 mixture of diastereoisomers), mp 58–60 ЊC (Found:
M , 377.1737. C H N O requires M, 377.1739); ν (CHCl )/
(
(
5
E)-N-[(2R)-1-Hydroxybutan-2-yl]-3-phenylprop-2-enamide
8) (6.35 g, 29 mmol) in dichloromethane (75 ml) was cooled to
ЊC. Triethylamine (5.88 g, 58 mmol) and methanesulfonyl
ϩ
chloride (3.33 g, 29 mmol) were added and the solution stirred
overnight. The solution was then washed twice with saturated
NaHCO (35 ml), dried over Na SO , filtered and concentrated
in vacuo to afford the title compound (5.63 g, 96%) as a brown
oil which was used without further purification, mp 4–7 ЊC
(
(
(
22 23
5
3
max
3
Ϫ1
cm 1729 and 1686; δ (400 MHz; CDCl ) 7.70–6.90 (10 H, m,
H
3
aromatic CH), 4.40–4.20 (1 H, m), 4.14–4.04 (2 H, m), 3.95–
.85 (2 H, m), 1.58–1.46 (5 H, m, CH and CH ), 0.90 (3 H of
3
2
4
3
2
3
major isomer, t, J 7.4, CH ) and 0.85 (3 H of minor isomer, t,
J 7.5, CH ); δC (100 MHz; DMSO-d ) 170.1 (C᎐O), 165.2
3
ϩ
Found: M , 201.1154. C H NO requires M, 201.1153); ν
3
6
13
15
max
Ϫ1
(
(
2 peaks, C᎐O), 152.6 (2 peaks, C-9a), 142.9, 142.7, 137.7, 137.6
all aromatic C), 129.8, 129.7, 129.6, 129.5, 128.7, 127.3, 127.1,
neat)/cm 1654 and 1608; δH (400 MHz; CDCl ) 7.42–7.39
᎐
3
2 H, dd, aromatic CH), 7.31–7.24 (4 H, m, aromatic CH
1
26.3, 126.0 (all aromatic CH), 73.1, 72.9 (both CH ), 67.7
and alkene CH), 6.57 (1 H, d, J 16.3, alkene CH), 4.32 (1 H,
apparent t, J 8.3, one of OCH ), 4.08 (1 H, m, HCEt), 3.88
(
2
(
2 peaks, CH), 53.6, 53.1 (both CH ), 45.1 (2 peaks, C-7a), 29.1,
2
2
2
3
8.6 (both CH ), 18.4, 18.0, 10.6 and 10.2 (all CH ); m/z (EI)
2 3
ϩ
77 (M , 27%), 362 (27), 290 (90) and 124 (100).
1 H, apparent t, J 7.9, one of OCH ), 1.68–1.59 (1 H, m, one of
2
CH ), 1.56–1.47 (1 H, m, one of CH ) and 0.92 (3 H, t, J 7.4,
2
2
CH ); δ (100 MHz; CDCl ) 163.6 (C᎐O), 140.2 (alkene CH),
3
C
3
(
9
(
3R)-6,9-Bis(4-bromophenyl)-3-ethyl-7a-methyl-2,3,5,6,7,7a,8,
-octahydroazeto[2,3-d ][1,3]oxazolo[3,2-c]pyrimidine-5,8-dione
16b)
1
35.6 (aromatic C), 130.1, 129.3, 127.8 (all aromatic CH), 115.7
(
(
alkene CH), 72.3 (OCH ), 68.3 (CH), 29.0 (CH ) and 10.6
2
2
ϩ
CH ); m/z (EI) 201 (M , 39%), 172 (100), 144 (26), 115 (39)
3
and 77 (43).
A mixture of 4-bromophenyl isocyanate (489 mg, 2.47 mmol)
3
162 J. Chem. Soc., Perkin Trans. 1, 1999, 3157–3166

View Article Online
and (4R)-4-ethyl-2-propen-2-yl-4,5-dihydro-1,3-oxazole (14)
172 mg, 1.24 mmol) was heated in a sealed tube at 150 ЊC
for 18 hours. After cooling, the resulting solid was purified by
column chromatography (neutral alumina; eluent 3:1 diethyl
ether–hexane) to afford the title compound (196 mg, 42%) as a
mg, 0.83 mmol) was stirred in a sealed tube for 24 hours. The
(
resulting solid was dissolved in dichloromethane, precipitated
with diethyl ether and filtered to afford the title compound (270
mg, 61%) as a colourless solid, mp 219–221 ЊC (Found: C,
49.49; H, 3.70; N, 7.73. C H Br N O requires C, 49.37; H,
2
2
21
2
3
3
Ϫ1
colourless solid (1.7:1 mixture of diastereoisomers), mp 86–
3.95; N, 7.85%); νmax (CHCl )/cm 3413, 1685, 1650, 1588 and
3
Ϫ1
8
7
8 ЊC; νmax (CHCl )/cm 1733 and 1691; δ (400 MHz; CDCl )
1526; δH (400 MHz; CDCl ) 8.28 (1 H, s, NH), 7.47 (2 H, d,
3
H
3
3
.66–7.53 (4 H, m, aromatic CH), 7.26–7.17 (4 H, m, aromatic
J 8.6, aromatic CH), 7.38 (2 H, d, J 6.8, aromatic CH), 7.34
(2 H, d, J 6.8, aromatic CH), 7.16 (2 H, d, J 8.6, aromatic CH),
4.84 (1 H, q, J 6.2, MeCH), 4.59 (1 H, apparent t, J 8.1, one of
OCH ), 4.48 (1 H, dd, J 8.4 and 1.7, one of OCH ), 4.31 (1 H,
CH), 4.42 (1 H of major diastereoisomer, dd, J 9.4 and 8.5, one
of OCH ), 4.36 (1 H of minor diastereoisomer, dd, J 9.4 and
2
8
1
.2, one of OCH ), 4.18–4.09 (2 H, m), 4.02–3.92 (2 H, m),
2
2
2
.64–1.57 (5 H, m, CH2 and CH ), 1.00–0.88 (3 H of
m, HCEt), 1.99–1.92 (1 H, m, one of CH ), 1.87–1.78 (1 H, m,
3
2
major diastereoisomer, t, J 7.4, CH ) and 0.85 (3 H of minor
one of CH ), 1.20 (3 H, d, J 6.2, CH ) and 0.86 (3 H, t, J 7.4,
3
2
3
diastereoisomer, t, J 7.4, CH ); δ (100 MHz; CDCl ) 169.9,
CH ); δC (100 MHz; CDCl ) 162.4, 152.2 (both C᎐O), 150.1
3
C
3
3
3
1
1
1
1
69.8, 164.8, 164.7 (all C᎐O), 152.2 (2 peaks, C-9a), 141.0,
40.9, 135.6, 135.5 (all aromatic C), 133.1, 132.8, 132.7, 132.6,
30.9, 130.5, 127.2, 126.9 (all aromatic CH), 122.8, 122.8,
(alkene C), 139.3, 138.1 (both aromatic C), 132.7, 132.2, 129.9,
121.7 (all aromatic CH), 121.2, 116.3 (both C-Br), 83.7 (alkene
C), 74.2 (CH ), 57.3, 56.1 (both CH), 23.7 (CH ), 21.2 and 9.0
᎐
2
2
ϩ
81
20.6, 120.6 (all C-Br), 73.4, 73.3 (both CH O), 68.2, 68.1
(both CH ); m/z (EI) 537 (M Ϫ Br , 8%), 535 (16), 533 (8),
2
3
2
(
2
(
both CH), 53.8, 53.4 (both CH N), 45.2, 45.1 (both C-7a),
9.2, 28.8 (both CH ), 18.5, 18.2, 10.4 and 10.2 (all CH ); m/z
2 3
ϩ ϩ
EI) 537 (M , 11%), 535 (M , 16), 533 (12), 521 (100), 518 (84),
522 (19), 520 (53), 518 (25), 365 (28), 363 (27), 199 (28), 197
(32), 171 (47) and 166 (100).
2
4
1
50 (19), 448 (42), 446 (20), 352 (63), 350 (73), 199 (66) and
97 (65).
(3R,7R)-N,6-Bis(4-nitrophenyl)-3-ethyl-7-methyl-5-oxo-2,3,6,7-
tetrahydro-5H-[1,3]oxazolo[3,2-c]pyrimidine-8-carboxamide
(
18c)
A mixture of 4-nitrophenyl isocyanate (401 mg, 2.44 mmol) and
4R)-4-ethyl-2-propenyl-4,5-dihydro-1,3-oxazole (11) (174 mg,
.22 mmol) was stirred in a sealed tube for 21 hours. The
(
8
3R)-6,9-Bis(4-methoxyphenyl)-3-ethyl-7a-methyl-2,3,5,6,7,7a,
,9-octahydroazeto[2,3-d ][1,3]oxazolo[3,2-c]pyrimidine-5,8-
(
1
dione (16c)
resulting solid was triturated with diethyl ether to afford the
title compound (467 mg, 82%) as a yellow solid, mp 203–206 ЊC
A mixture of 4-methoxyphenyl isocyanate (418 mg, 2.80 mmol)
and (4R)-4-ethyl-2-propen-2-yl-4,5-dihydro-1,3-oxazole (14)
(
5
1
Found: C, 56.57; H, 4.18; N, 14.66. C H N O requires C,
22 21 5 7
Ϫ1
(
2
195 mg, 1.40 mmol) was heated in a sealed tube at 150 ЊC for
5 hours. After cooling, the reaction mixture was dissolved in
6.53; H, 4.53; N, 14.98%); νmax (CHCl )/cm 3406, 1682, 1661,
3
612, 1595, 1546, 1523, 1509, 1346, 1332 and 853; δ (400 MHz;
chloroform (5 ml), filtered and concentrated in vacuo to afford
H
CDCl ) 8.67 (1 H, s, NH), 8.31 (2 H, d, J 9.0, aromatic CH),
the title compound (429 mg, 70%) as a colourless waxy solid
3
Ϫ1
8
.23 (2 H, d, J 9.2, aromatic CH), 7.74 (2 H, d, J 9.2, aromatic
CH), 7.60 (2 H, d, J 9.0, aromatic CH), 5.12 (1 H, q, J 6.2,
MeCH), 4.78 (1 H, apparent t, J 8.1, one of OCH ), 4.67 (1 H,
(
ca. 1.7:1 mixture of diastereoisomers); νmax (CHCl )/cm
3
1
733 and 1691. NMR data were broadly in line with com-
pounds 16a and 16b, although the presence of decomposition
products arising from 4-methoxyphenyl isocyanate makes
reporting this data meaningless.
2
dd, J 8.5 and 1.8, one of OCH ), 4.49 (1 H, m, HCEt), 2.12–
2
2
.07 (1 H, m, one of CH ), 2.00–1.89 (1 H, m, one of CH ), 1.35
2
2
(
3 H, d, J 6.3, CH ) and 1.00 (3 H, t, J 7.4, CH ); δ (100 MHz;
3
3
C
DMSO-d ) 162.2, 153.1 (both C᎐O), 149.0 (alkene C), 146.5,
6
(
3R,7R)-N,6-Diphenyl-3-ethyl-7-methyl-5-oxo-2,3,6,7-tetra-
1
45.5, 145.2, 142.1 (all aromatic C), 127.6, 124.9, 124.5, 119.0
hydro-5H-[1,3]oxazolo[3,2-c]pyrimidine-8-carboxamide (18a)
(
(
(
all aromatic CH), 82.5 (alkene C), 74.3 (OCH ), 56.8, 55.0
2
A mixture of phenyl isocyanate (363 mg, 3.05 mmol) and (4R)-
4
both CH), 23.0 (CH ), 21.0 and 8.4 (both CH ); m/z (EI) 303
2
3
-ethyl-2-propenyl-4,5-dihydro-1,3-oxazole (11) (212 mg, 1.52
51%) and 166 (100).
mmol) was stirred in a sealed tube for 48 hours. The resulting
solid was dissolved in dichloromethane and precipitated with
diethyl ether. The precipitate was collected by filtration
to afford the title compound (334 mg, 58%) as a colourless
solid, mp 150–152 ЊC (Found: C, 70.16; H, 6.36; N, 11.44.
C H N O requires C, 70.01; H, 6.14; N, 11.13%); νmax
(
2
3R,7R)-N,6-Bis(4-methoxyphenyl)-3-ethyl-7-methyl-5-oxo-
,3,6,7-tetrahydro-5H-[1,3]oxazolo[3,2-c]pyrimidine-8-carb-
oxamide (18d)
A mixture of 4-methoxyphenyl isocyanate (782 mg, 5.24 mmol)
and (4R)-4-ethyl-2-propenyl-4,5-dihydro-1,3-oxazole (11) (365
mg, 2.62 mmol) was stirred in a sealed tube for 120 hours. The
resulting solid was triturated with diethyl ether to afford the
title compound (752 mg, 65%) as a colourless solid, mp 140–
2
2
23
3
3
Ϫ1
(
CHCl )/cm 3424, 1686, 1649, 1595 and 1535; δH (400 MHz;
3
CDCl ) 8.32 (1 H, s, NH), 7.47 (2 H, d, J 7.8, aromatic CH),
3
7
.35 (2 H, d, J 8.0, aromatic CH), 7.28–7.22 (5 H, m, aromatic
CH), 7.00 (1 H, apparent t, J 7.4, aromatic CH), 4.91 (1 H, q,
1
42 ЊC (Found: C, 65.82; H, 6.41; N, 9.84. C H N O requires
24
27
Ϫ1
3
5
J 6.1, MeCH), 4.60 (1 H, apparent t, J 7.6, one of OCH ), 4.48
2
C, 65.89; H, 6.22; N, 9.60%); νmax (CHCl )/cm 3415, 1686,
1
(
6
CH), 4.80 (1 H, q, J 6.2, MeCH), 4.58 (1 H, apparent t, J 8.2,
one of OCH ), 4.46 (1 H, dd, J 8.4 and 1.6, one of OCH ), 4.29
(
1.92 (1 H, m, one of CH ), 1.87–1.81 (1 H, m, one of CH ), 1.21
(
3
(
1 H, dd, J 8.4 and 1.6, one of OCH ), 4.32 (1 H, m, HCEt),
2
644 and 1536; δH (400 MHz; CDCl ) 8.20 (1 H, s, NH), 7.38
3
1
1
.99–1.93 (1 H, m, one of CH ), 1.88–1.81 (1 H, m, one of CH ),
2 2
2 H, d, J 8.9, aromatic CH), 7.17 (2 H, d, J 8.9, aromatic CH),
.85 (2 H, d, J 8.9, aromatic CH), 6.78 (2 H, d, J 8.9, aromatic
.22 (3 H, d, J 6.2, CH ) and 0.87 (3 H, t, J 7.5, CH ); δ (100
3
3
C
MHz; CDCl ) 162.6, 152.1 (both C᎐O), 150.4 (alkene C), 140.3,
3
1
39.0 (both aromatic C), 129.6, 129.3, 128.3, 127.0, 123.9, 120.2
2
2
(
(
(
all aromatic CH), 83.8 (alkene C), 74.1 (OCH ), 57.3, 56.2
2
1 H, m, HCEt), 3.74 (3 H, s, OCH ), 3.72 (3 H, s, OCH ), 1.97–
3
3
both CH), 23.7 (CH ), 21.2 and 9.0 (both CH ); m/z (EI) 377
2
3
ϩ
2
2
M , 14%), 362 (57), 285 (11), 166 (18), 119 (72) and 55 (100).
3 H, d, J 6.2, CH ) and 0.86 (3 H, t, J 7.5, CH ); δ (100 MHz;
3 3 C
CDCl ) 164.7, 161.0 (both C᎐O), 158.4 (alkene C), 154.1, 152.9,
3
(
2
3R,7R)-N,6-Bis(4-bromophenyl)-3-ethyl-7-methyl-5-oxo-
,3,6,7-tetrahydro-5H-[1,3]oxazolo[3,2-c]pyrimidine-8-carb-
1
35.7, 134.2 (all aromatic C), 131.7, 124.6, 116.9, 116.6 (all
aromatic CH), 85.7 (alkene C), 76.1 (OCH ), 59.3, 58.5 (both
2
oxamide (18b)
CH), 58.0 (two coincident OCH ), 25.9 (CH ), 23.3 and 11.2
3
2
ϩ
A mixture of 4-bromophenyl isocyanate (330 mg, 1.67 mmol)
(both CH ); m/z (EI) 437 (M , 14%), 422 (18), 272 (60), 149
3
and (4R)-4-ethyl-2-propenyl-4,5-dihydro-1,3-oxazole (11) (116
(75), 134 (36) and 108 (100).
J. Chem. Soc., Perkin Trans. 1, 1999, 3157–3166
3163

View Article Online
(
3R,7R)-N,6-Bis((4-methylphenyl)sulfonyl)-3-ethyl-7-methyl-5-
151.6 (both C᎐O), 149.2 (alkene C), 138.1, 136.7 (both aromatic
C), 131.3, 130.7, 128.3, 120.3 (all aromatic CH), 119.6, 114.7
᎐
oxo-2,3,6,7-tetrahydro-5H-[1,3]oxazolo[3,2-c]pyrimidine-8-
carboxamide (18e)
(both C-Br), 78.9 (alkene C), 72.8 (OCH ), 58.9, 55.8 (both
2
CH), 25.3, 22.3 (both CH ), 7.6 and 6.3 (both CH ); m/z (EI)
2
3
A solution of toluene-4-sulfonyl isocyanate (510 mg, 2.59
mmol) and (4R)-4-ethyl-2-propenyl-4,5-dihydro-1,3-oxazole
ϩ
5
49 (M , 1%), 520 (23), 90 (52) and 55 (100).
(
2
11) (180 mg, 1.29 mmol) in dry toluene (20 ml) was stirred for
1 hours. After removing toluene in vacuo, the solid was
(
3R,7R)-N,6-Bis(4-nitrophenyl)-3,7-diethyl-5-oxo-2,3,6,7-tetra-
hydro-5H-[1,3]oxazolo[3,2-c]pyrimidine-8-carboxamide (19c)
recrystallised from ethanol to afford the title compound (453
mg; 66%) as a colourless solid, mp 172–175 ЊC (Found: C,
5
5
1
A mixture of 4-nitrophenyl isocyanate (316 mg, 1.93 mmol) and
(4R,E)-4-ethyl-2-but-1-enyl-4,5-dihydro-1,3-oxazole (12) (161
mg, 0.96 mmol) was stirred in a sealed tube at 150 ЊC for
1 hour. On cooling, the resulting solid was recrystallised from
hot ethanol to afford the title compound (330 mg, 71%) as
a yellow solid, mp 203–206 ЊC (Found: M Ϫ Et, 452.1198.
C H N O requires M, 452.1206); ν
1682, 1546 and 1508; δ (400 MHz; CDCl ) 8.67 (1 H, s, NH),
8.20 (2 H, d, J 9.1, aromatic CH), 8.14 (2 H, d, J 9.1, aromatic
CH), 7.63 (2 H, d, J 9.1, aromatic CH), 7.55 (2 H, d, J 9.1,
aromatic CH), 5.16–5.14 (1 H, m, EtCH), 4.68 (1 H, dd, J 8.4
and 7.1, one of OCH ), 4.58 (1 H, dd, J 8.4 and 1.9, one of
OCH ), 4.38 (1 H, m, HCEt), 2.00–1.90 (1 H, m, one of CH ),
1.85–1.78 (1 H, m, one of CH ), 1.70–1.62 (1 H, m, one of
CH ), 1.55–1.45 (1 H, m, one of CH ), 0.88 (3 H, t, J 7.4, CH )
and 0.82 (3 H, t, J 7.4, CH ); δ (100 MHz; CDCl ) 162.4, 153.5
3.93; H, 5.07; N, 7.85. C H N O S requires C, 54.02; H,
2
4
27
3
7 2
Ϫ1
.10; N, 7.87%); νmax (CHCl )/cm 3361, 1713, 1672, 1598 and
3
042; δH (400 MHz; CDCl ) 9.00 (1 H, s, NH), 7.91 (2 H, d,
3
J 8.3, aromatic CH), 7.79 (2 H, d, J 8.3, aromatic CH), 7.26
2 H, d, J 8.3, aromatic CH), 7.21 (2 H, d, J 8.3, aromatic CH),
.41 (1 H, q, J 6.3, MeCH), 4.62 (1 H, apparent t, J 8.1, one of
OCH ), 4.42 (1 H, dd, J 8.7 and 2.0, one of OCH ), 4.25 (1 H,
ϩ
(
5
Ϫ1
(CHCl )/cm 3405,
21
18
5
7
max
3
2
2
H
3
m, HCEt), 2.35 (3 H, s, CH ), 2.33 (3 H, s, CH ), 1.69–1.66
(
CH ); δ (100 MHz; CDCl ) 162.1, 156.2 (both C᎐O), 149.4
3
3
2 H, m, CH ), 1.18 (3 H, d, J 6.3, CH ) and 0.68 (3 H, t, J 7.3,
2
3
3
C
3
(
1
(
alkene C), 147.6, 147.3, 138.5, 138.4 (all aromatic C), 132.0,
31.8, 131.4, 131.0 (all aromatic CH), 86.1 (alkene C), 77.1
OCH ), 59.4, 53.4 (both CH), 25.4 (CH ), 25.3, 24.2, 24.2 and
2
2
2
2
2
2
1
0.4 (all CH ); m/z (EI) 377 (1%), 165 (49), 191 (99) and 84
3
2
2
3
(
100).
3
C
3
(
both C᎐O), 150.1 (alkene C), 146.5, 146.2, 144.9, 143.3 (all
᎐
(
[
3R,7R)-N,6-Diphenyl-3,7-diethyl-5-oxo-2,3,6,7-tetrahydro-5H-
1,3]oxazolo[3,2-c]pyrimidine-8-carboxamide (19a)
aromatic C), 128.0, 125.6, 125.0, 119.2 (all aromatic CH), 80.9
(alkene C), 74.7 (OCH ), 60.1, 57.6 (both CH), 27.1, 23.7 (both
CH ), 9.0, 8.1 (both CH ); m/z (EI) 134 (13%), 90 (37), 69 (52),
2
2
3
A mixture of phenyl isocyanate (100 mg, 0.84 mmol) and
4R,E)-4-ethyl-2-but-1-enyl-4,5-dihydro-1,3-oxazole (12) (70
6
3 (57), 55 (93) and 46 (100).
(
mg, 0.42 mmol) was stirred in a sealed tube at 25 ЊC for 46
hours. After cooling, the resulting solid was purified by column
chromatography (eluent 3:1 diethyl ether–hexane) to afford the
title compound (90 mg, 53%) as a yellow solid, mp 64–66 ЊC
(
2
3R,7R)-N,6-Bis((4-methylphenyl)sulfonyl)-3,7-diethyl-5-oxo-
,3,6,7-tetrahydro-5H-[1,3]oxazolo[3,2-c]pyrimidine-8-carb-
oxamide (19e)
(
Found: C, 70.34; H, 6.30; N, 10.76. C H N O requires C,
Toluene-4-sulfonyl isocyanate (312 mg, 1.58 mmol) was added
to (4R,E)-4-ethyl-2-but-1-enyl-4,5-dihydro-1,3-oxazole (12)
(132 mg, 0.79 mmol). The reaction was stirred for 30 min,
during which time the exotherm subsided. The resulting solid
was recrystallised from hot ethanol to afford the title compound
(400 mg, 90%) as a colourless solid, mp 160–163 ЊC (Found:
C, 54.63; H, 5.19; N, 7.84. C H N O S requires C, 54.83; H,
23
25
Ϫ1
3
3
7
1
7
6
(
1
0.57; H, 6.44; N, 10.73%); νmax (CHCl )/cm 3418, 1685, 1649,
3
596, 1535 and 693; δH (400 MHz; CDCl ) 8.38 (1 H, s, NH),
3
.48 (2 H, d, J 7.9, aromatic CH), 7.28 (7 H, m, aromatic CH),
.99 (1 H, t, J 7.4, aromatic CH), 5.04 (1 H, m, EtCH), 4.56
1 H, apparent t, J 8.2, one of OCH ), 4.45 (1 H, dd, J 8.4 and
2
.8, one of OCH ), 4.31 (1 H, m, HCEt), 1.92–1.80 (2 H, m,
2
25 29
Ϫ1
3
7 2
CH ), 1.62–1.59 (2 H, m, CH ), 0.86 (3 H, t, J 7.5, CH ) and
0
(
1
5.34; N, 7.67%); νmax (CHCl )/cm 3361, 1713, 1668, 1598 and
2
2
3
3
.84 (3 H, t, J 7.5, CH ); δ (100 MHz; CDCl ) 162.7, 152.9
1047; δH (400 MHz; CDCl ) 8.89 (1 H, s, NH), 7.98 (2 H, d,
3
C
3
3
both C᎐O), 151.0 (alkene C), 140.4, 139.0 (both aromatic C),
J 8.2, aromatic CH), 7.89 (2 H, d, J 8.3, aromatic CH), 7.37
(2 H, d, J 8.2, aromatic CH), 7.26 (2 H, d, J 8.3, aromatic CH),
5.48 (1 H, t, J 5.0, EtCH), 4.63 (1 H, dd, J 8.7 and 7.6, one of
OCH ), 4.48 (1 H, dd, J 8.7 and 2.6, one of OCH ), 4.28 (1 H,
᎐
29.6, 129.3, 128.1, 127.6, 123.9, 120.1 (all aromatic CH), 80.5
(
alkene C), 74.1 (OCH ), 60.5, 57.2 (both CH), 26.4, 23.8 (both
2
ϩ
CH ), 9.0 and 7.7 (both CH ); m/z (EI) 391 (M , 2%), 362 (63),
2
2
3
2
2
72 (20), 244 (4), 180 (48) and 55 (100).
m, HCEt), 2.47 (3 H, s, CH ), 2.43 (3 H, s, CH ), 1.79–1.62
3
3
(
4 H, m, 2 × CH ), 0.74 (3 H, d, J 7.4, CH ) and 0.66 (3 H, t,
2 3
J 7.4, CH ); δC (100 MHz; CDCl ) 160.3, 154.8 (both C᎐O),
(
3R,7R)-N,6-Bis(4-bromophenyl)-3,7-diethyl-5-oxo-2,3,6,7-
tetrahydro-5H-[1,3]oxazolo[3,2-c]pyrimidine-8-carboxamide
19b)
3
3
1
1
7
2
47.8 (alkene C), 145.5, 145.2, 136.4, 136.1 (all aromatic C),
29.8, 129.7, 129.2, 128.8 (all aromatic CH), 81.5 (alkene C),
5.1 (OCH ), 57.2, 55.7 (both CH), 32.1, 29.6 (both CH ), 23.2,
(
2
3
A mixture of 4-bromophenyl isocyanate (491 mg, 2.48 mmol)
and (4R,E)-4-ethyl-2-but-1-enyl-4,5-dihydro-1,3-oxazole (12)
(
7
chromatography (eluent 1:1 dichloromethane–hexane) to give
the title compound (472 mg, 69%) as a colourless solid, mp
2.0 (both CH ), 8.2 and 8.0 (both CH ); m/z (EI) 106 (52%), 89
2
3
(
80) and 63 (100).
190 mg, 1.24 mmol) was stirred in a sealed tube at 150 ЊC for
5 minutes. The resulting solid was purified by flash column
(
[
3R,7R)-3-Ethyl-5-oxo-N,6,7-triphenyl-2,3,6,7-tetrahydro-5H-
1,3]oxazolo[3,2-c]pyrimidine-8-carboxamide (20a)
6
8–70 ЊC (Found: C, 50.51; H, 4.01; N, 7.43. C H Br N O
A mixture of phenyl isocyanate (163 mg, 1.37 mmol) and
(4R,E)-4-ethyl-2-(2-phenylethenyl)-4,5-dihydro-1,3-oxazole
(13) (138 mg, 0.69 mmol) was heated in a sealed tube at 150 ЊC
for 1.5 hours. The residue was recrystallised from hot ethanol to
afford the title compound (230 mg, 76%) as a colourless solid,
mp 205–208 ЊC (Found: C, 73.70; H, 5.81; N, 9.51. C H N O
23
23
2
3
3
Ϫ1
requires C, 50.29; H, 4.22; N, 7.65%); νmax (CHCl )/cm 3412,
3
1
681, 1653, 1589 and 1526; δ (400 MHz; CDCl ) 8.35 (1 H, s,
H
3
NH), 7.46 (2 H, d, J 6.7, aromatic CH), 7.39 (2 H, d, J 6.7,
aromatic CH), 7.35 (2 H, d, J 6.7, aromatic CH), 7.20–7.18
(
2 H, d, J 6.7, aromatic CH), 4.99 (1 H, m, EtCH), 4.59 (1 H,
27
25
Ϫ1
3
3
dd, J 8.4 and 7.0, one of OCH ), 4.47 (1 H, dd, J 8.4 and 1.9,
requires C, 73.78; H, 5.73; N, 9.56%); νmax (CHCl )/cm 3416,
2
3
one of OCH ), 4.30 (1 H, m, HCEt), 2.00–1.90 (1 H, m, one of
1686, 1650, 1597 and 1541; δ (400 MHz; CDCl ) 8.27 (1 H, s,
2
H
3
CH ), 1.85–1.75 (1 H, m, one of CH ), 1.70–1.60 (1 H, m, one
NH), 7.40 (2 H, d, J 7.6, aromatic CH), 7.22–7.13 (10 H, m,
aromatic CH), 6.99–6.95 (3 H, m, aromatic CH), 5.80 (1 H, s,
2
2
of CH ), 1.54–1.48 (1 H, m, one of CH ), 0.86 (3 H, t, J 7.4,
2
2
CH ) and 0.81 (3 H, t, J 7.4, CH ); δ (100 MHz; CDCl ) 161.1,
PhCH), 4.67 (1 H, apparent t, J 8.2, one of OCH ), 4.53 (1 H,
3
3
C
3
2
3
164
J. Chem. Soc., Perkin Trans. 1, 1999, 3157–3166

View Article Online
ϩ
dd, J 8.5 and 1.9, one of OCH ), 4.44 (1 H, m, HCEt), 2.06–
and 9.0 (CH ); m/z (EI) 499 (M , 1%), 422 (1), 349 (1), 200 (1),
2
3
1
.91 (2 H, m, CH ) and 0.93 (3 H, t, J 7.4, CH ); δ (100 MHz;
149 (100) and 55 (32).
2
3
C
CDCl ) 161.3, 151.3 (both C᎐O), 149.6 (alkene C), 141.4, 139.5,
3
1
1
37.8 (all aromatic C), 128.4, 128.3, 128.1, 127.6, 127.1, 126.7,
26.4, 123.0, 119.3 (all aromatic CH), 82.9 (alkene C), 73.3
(
3R,7R)-N,6-Bis((4-methylphenyl)sulfonyl)-3-ethyl-5-oxo-7-
phenyl-2,3,6,7-tetrahydro-5H-[1,3]oxazolo[3,2-c]pyrimidine-8-
carboxamide (20e)
(
OCH ), 57.8, 56.5 (both CH), 22.9 (CH ) and 8.0 (CH ); m/z
2 2 3
ϩ
(
EI) 439 (M , 14%), 362 (7), 320 (12), 119 (100) and 77 (87).
A mixture of toluene-4-sulfonyl isocyanate (310 mg, 1.57
mmol) and (4R,E)-4-ethyl-2-(2-phenylethenyl)-4,5-dihydro-1,3-
oxazole (13) (158 mg, 0.79 mmol) was stirred in a sealed
tube overnight, during which time the product solidified. The
resulting solid was then recrystallised from ethanol to give the
title compound (440 mg, 94%) as a colourless solid, mp 88–92 ЊC
(Found: C, 58.50; H, 5.06; N, 7.07. C H N O S requires C,
(
2
3R,7R)-N,6-Bis(4-bromophenyl)-3-ethyl-5-oxo-7-phenyl-
,3,6,7-tetrahydro-5H-[1,3]oxazolo[3,2-c]pyrimidine-8-
carboxamide (20b)
A mixture of 4-bromophenyl isocyanate (474 mg, 2.39
mmol) and (4R,E)-4-ethyl-2-(2-phenylethenyl)-4,5-dihydro-1,3-
oxazole (13) (241 mg, 1.20 mmol) was stirred in a sealed tube at
29
29
Ϫ1
3
7 2
58.47; H, 4.91; N, 7.05%); νmax (CHCl )/cm 3360, 1712, 1672,
3
1
50 ЊC for 1 hour. The resulting solid was filtered through a pad
1598 and 1043; δH (400 MHz; CDCl ) 8.67 (1 H, s, NH), 7.88
3
of silica (eluent 1:1 dichloromethane–hexane) to give the title
compound (420 mg, 59%) as a colourless solid, mp 215–217 ЊC
(2 H, d, J 8.3, aromatic CH), 7.26 (2 H, d, J 8.2, aromatic CH),
7.19–7.10 (7 H, m, aromatic CH), 6.94 (2 H, d, J 8.3, aromatic
CH), 6.34 (1 H, s, PhCH), 4.58 (1 H, apparent t, J 8.6, one of
OCH ), 4.47 (1 H, dd, J 8.7 and 2.6, one of OCH ), 4.28 (1 H,
ϩ
79
81
(
Found: (FAB) MH ( Br Br), 598.0143. C H Br N O
27 23 2 3 3
Ϫ1
requires MH, 598.0163); νmax (CHCl )/cm 3414, 1685, 1652,
3
2
2
1
7
6
590 and 1529; δ (400 MHz; CDCl ) 8.25 (1 H, s, NH), 7.34–
.27 (5 H, m, aromatic CH), 7.19–7.16 (6 H, m, aromatic CH),
.85 (2 H, d, J 8.6, aromatic CH), 5.72 (1 H, s, PhCH), 4.51
m, HCEt), 2.38 (3 H, s, CH ), 2.25 (3 H, s, CH ), 2.02–1.96
(1 H, m, one of CH ), 1.84–1.77 (1 H, m, one of CH ) and 0.82
2 2
H
3
3
3
(3 H, t, J 7.4, CH ); δ (100 MHz; CDCl ) 160.1, 154.4 (both
3
C
3
(
1 H, apparent t, J 8.1, one of OCH ), 4.39 (1 H, dd, J 8.5 and
C᎐O), 147.4 (alkene C), 145.2, 145.1, 140.9, 136.4, 135.5 (all
2
1
.9, one of OCH ), 4.43 (1 H, m, HCEt), 2.05–1.87 (2 H, m,
aromatic C), 129.9, 129.3, 129.2, 129.1, 129.0, 128.6, 127.7 (all
2
CH ) and 0.92 (3 H, t, J 7.4, CH ); δ (100 MHz; CDCl ) 162.1,
aromatic CH), 83.5 (alkene C), 75.3 (OCH ), 57.7 (CH), 57.4
2
3
C
3
2
1
52.2 (both C᎐O), 150.2 (alkene C), 141.9, 139.5, 137.9 (all
(CH), 23.4 (CH ), 22.0 (CH ), 21.9 (CH ) and 8.5 (CH ); m/z
᎐
2 3 3 3
aromatic C), 132.6, 132.2, 129.7, 129.0, 128.5, 127.3, 121.7 (all
aromatic CH), 121.4, 116.3 (both C-Br), 83.8 (alkene C), 74.3
(EI) 105 (35), 91 (65), 89 (90) and 65 (100).
(
OCH ), 63.4 (PhCH), 57.4 (HCEt), 23.8 (CH ) and 9.0 (CH );
2
2
3
(3R,7R)-6,7-Diphenyl-3-ethyl-8-methyl-5-oxo-2,3,6,7-tetra-
hydro-5H-[1,3]oxazolo[3,2-c]pyrimidine (21)
m/z (EI) 515 (1%), 397 (4), 325 (1), 197 (22) and 63 (100).
A mixture of phenyl isocyanate (511 mg, 4.3 mmol) and
(
3R,7R)-N,6-Bis(4-nitrophenyl)-3-ethyl-5-oxo-7-phenyl-2,3,6,7-
tetrahydro-5H-[1,3]oxazolo[3,2-c]pyrimidine-8-carboxamide
20c)
(
4R,E)-4-ethyl-2-(2-phenylpropen-2-yl)-4,5-dihydro-1,3-oxa-
zole (15) (924 mg, 4.3 mmol) was heated in a sealed tube at
0 ЊC for 30 hours. The residue was purified by column chrom-
(
6
A mixture of 4-nitrophenyl isocyanate (235 mg, 1.43 mmol) and
atography (eluent 2:1 diethyl ether–hexane) to afford the title
(
(
4R,E)-4-ethyl-2-(2-phenylethenyl)-4,5-dihydro-1,3-oxazole
13) (144 mg, 0.72 mmol) was stirred in a sealed tube at 150 ЊC
compound (883 mg, 62%) as a yellow solid, mp 58–60 ЊC; ν
max
Ϫ1
(CHCl )/cm 3066, 1758, 1710 and 1655; δH (400 MHz;
3
for 1 hour. The resulting solid recrystallised from ethanol to
CDCl ) 7.38–7.17 (5 H, m, aromatic CH), 7.11 (3 H, m,
3
afford the title compound (280 mg, 74%) as a yellow solid, mp
aromatic CH), 6.98 (2 H, m, aromatic CH), 5.05 (1 H, s,
HCPh), 4.33 (1 H, poorly resolved dd, J 7.9 and 6.9, one of
2
09–212 ЊC (Found: C, 61.24; H, 4.36; N, 13.53. C H N O
27
23
Ϫ1
5
7
requires C, 61.24; H, 4.38; N, 13.23%); νmax (CHCl )/cm 3406,
OCH ), 4.26 (1 H, m, HCEt), 4.17 (1 H, dd, J 8.2 and 2.1, one
3
2
1
681, 1546 and 1509; δ (400 MHz; CDCl ) 8.56 (1 H, s, NH),
of OCH ), 2.04–1.98 (1 H, m, one of CH ), 1.86–1.77 (1 H, m,
H
3
2
2
8
.12–8.08 (4 H, m, aromatic CH), 7.59 (2 H, dd, J 7.2 and 2.0,
one of CH ), 1.41 (3 H, s, CH ) and 0.93 (3 H, t, J 7.5, CH );
2
3
3
aromatic CH), 7.24–7.19 (7 H, m, aromatic CH), 5.90 (1 H, s,
δC (100 MHz; CDCl ) 152.1 (C᎐O), 143.9 (alkene C), 142.8,
3
PhCH), 4.71 (1 H, apparent t, J 8.3, one of OCH ), 4.71 (1 H,
142.2 (both aromatic C), 130.2, 129.8, 129.6, 129.2, 129.0, 128.2
2
dd, J 8.6 and 2.1, one of OCH ), 4.50 (1 H, m, HCEt), 2.08–
(all aromatic CH), 78.5 (alkene C), 72.5 (OCH ), 70.6, 57.9
2
2
2
0
.03 (1 H, m, one of CH ), 1.99–1.93 (1 H, m, one of CH ) and
(both CH), 25.2 (CH ), 12.5 and 10.4 (both CH ); m/z (APCI)
335 (MH , 100%).
2
2
2
3
ϩ
.96 (3 H, t, J 7.3, CH ); δC (100 MHz; CDCl ) 160.4, 151.1
3
3
(
(
(
both C᎐O), 148.3 (alkene C), 144.7, 144.5, 143.1, 141.6, 139.7
all aromatic C), 127.8, 127.3, 126.2, 125.1, 123.8, 123.2, 117.6
᎐
(
3R,7R,7aR,9aR)-3-Ethyl-7a-methyl-6,7,9-biphenyl-2,3,5,6,7,
all aromatic CH), 82.5 (alkene C), 73.1 (OCH ), 61.1 (PhCH),
2
7a,8,9-octahydroazeto[2,3-d][1,3]oxazolo[3,2-c]pyrimidine-5,8-
dione (22)
5
6.1 (HCEt), 22.2 (CH ) and 7.4 (CH ); m/z (EI) 365 (51%), 102
2
3
(
74) and 55 (100).
A mixture of phenyl isocyanate (414 mg, 3.48 mmol) and
(
4R,E)-4-ethyl-2-(2-phenylpropen-2-yl)-4,5-dihydro-1,3-oxa-
zole (15) (374 mg, 1.74 mmol) was heated in a sealed tube at
50 ЊC for 24 hours. The reaction mixture was allowed to
(
2
3R,7R)-N,6-Bis(4-methoxyphenyl)-3-ethyl-5-oxo-7-phenyl-
,3,6,7-tetrahydro-5H-[1,3]oxazolo[3,2-c]pyrimidine-8-carb-
1
oxamide (20d)
cool, and the resulting solid purified by column chromato-
graphy over neutral alumina (eluent 2:1 diethyl ether–hexane)
to afford the title compound (204 mg, 26%) as a slightly
impure off-white solid, mp 82–84 ЊC (Found MH , 454.2124.
C H N O requires M, 454.2131); ν
A mixture of 4-methoxyphenyl isocyanate (246 mg, 1.65
mmol) and (4R,E)-4-ethyl-2-(2-phenylethenyl)-4,5-dihydro-1,3-
oxazole (13) (166 mg, 0.83 mmol) was stirred in a sealed tube
at 150 ЊC for 1 hour. After cooling, the resulting solid was
recrystallised from ethanol to give the title compound (40 mg,
ϩ
Ϫ1
(CHCl )/cm 3019,
28
28
3
3
max
3
1728 and 1684; δH (400 MHz; CDCl ) 7.58–7.11 (15 H, m,
3
1
0%) as a slightly impure colourless waxy solid; ν (CHCl )/
aromatic CH), 4.80 (1 H, s, CHPh), 4.16 (1 H, dd, J 9.4 and 8.3,
max
3
Ϫ1
cm 3418, 1685, 1646, 1598 and 1511; δ (100 MHz; CDCl )
one of OCH ), 3.95 (1 H, m, HCEt), 3.20 (1 H, apparent t,
C
3
2
1
1
1
6
62.2, 158.8 (both C᎐O), 156.2 (alkene C), 152.0, 151.0, 141.8,
41.7, 133.2 (all aromatic C), 129.4, 128.8, 128.2, 127.5, 122.0,
J 8.6, one of OCH ), 2.08 (3 H, s, CH ), 1.61 (1 H, m, one of
CH ), 1.39–1.32 (1 H, m, one of CH ) and 0.89 (3 H, t, J 7.5,
2 2
᎐
2
3
14.6, 114.4 (all aromatic CH), 83.7 (alkene C), 74.1 (OCH ),
CH ); δC (100 MHz; CDCl ) 169.5, 164.5 (both C᎐O), 152.4
2
3
3
3.9 (PhCH), 57.3 (HCEt), 55.9, 55.8 (both OCH ), 23.9 (CH )
(C-9a), 141.1, 137.0, 135.7 (all aromatic C), 129.8, 129.5, 129.5,
J. Chem. Soc., Perkin Trans. 1, 1999, 3157–3166 3165
3
2

View Article Online
ϩ
1
29.4, 129.1, 129.0, 128.9, 128.8, 128.2, 127.9, 127.5 (all
19.7 (CH ); m/z (EI) 140 (MH , 100%), 124 (93), 109 (60) and
3
aromatic CH), 73.3 (OCH ), 69.9, 67.8 (both CH), 50.8 (C-7a),
68 (75).
2
ϩ
3
1
2.0 (CH ), 24.1 and 10.9 (both CH ); m/z (APCI) 454 (MH ,
2 3
00%).
Acknowledgements
We would like to thank Cardiff University for a studentship
(
2
3R)-3-Ethyl-8-methyl-6-((4-methylphenyl)sulfonyl)-5-oxo-
,3,6,7-tetrahydro-5H-[1,3]oxazolo[3,2-c]pyrimidine (23)
(
E. K.) and the EPSRC National Mass Spectrometry Service
Centre, Swansea for high resolution mass spectrometric data.
Toluene-4-sulfonyl isocyanate (728 mg, 3.70 mmol) and (4R)-4-
ethyl-2-propen-2-yl-4,5-dihydro-1,3-oxazole (14) (257 mg, 1.85
mmol) were dissolved in toluene (15 ml) and stirred for 1 h.
After this time the solvent was removed in vacuo, and the result-
ing solid transferred to a sintered glass funnel and washed with
diethyl ether (10 ml) and dried in vacuo to give the title com-
pound (971 mg, 98%) as an impure white solid still containing
References
1
J. H. Blom and W. Koll, Liebigs Ann. Chem., 1925, 443, 242; O. Diels
and K. Alder, Liebigs Ann. Chem., 1928, 460, 98.
2
For leading references see D. Craig, Chem. Soc. Rev., 1987, 16, 187;
M. C. Aversa, A. Barattucci, P. Bonaccorsi and P. Giannetto, Tetra-
hedron: Asymmetry, 1997, 8, 1339; D. J. Ager, I. Prakash and D. R.
Schaad, Aldrichim. Acta, 1997, 30, 3; W. Oppolzer, Angew. Chem.,
Int. Ed. Engl., 1984, 23, 876; D. Enders and O. Meyer, Liebigs Ann.
Chem., 1996, 1023; E. Ciganek, Org. React. (N.Y.), 1984, 32, 1.
For leading references see L. Deloux and M. Srebnik, Chem. Rev.,
Ϫ1
some toluene; νmax (CHCl )/cm 1765 and 1693; δ (400 MHz;
3
H
CDCl ) 7.89 (2 H, d, J 8.2, aromatic CH), 7.30 (2 H, d, J 8.2,
3
aromatic CH), 4.43 (1 H, d, J 13.3, one of CH N), 4.23 (1 H,
2
3
d, J 13.3, one of CH N), 4.17 (1 H, apparent t, J 7.6, one of
2
1
993, 93, 763; C.-J. Li, Chem. Rev., 1993, 93, 2023; L. C. Dias,
OCH ), 4.09 (1 H, m, CHEt), 4.00 (1 H, dd, J 8.1 and 2.6, one
2
J. Braz. Chem. Soc., 1997, 8, 289; H. Brunner, Synthesis, 1988, 645;
H. B. Kagan and O. Riant, Chem. Rev., 1992, 92, 1007;
M. Shibasaki, H. Sasai and T. Arai, Angew. Chem., Int. Ed. Engl.,
1997, 36, 1237.
D. L. Boger and S. N. Weinreb, Hetero-Diels–Alder Methodology in
Organic Synthesis, Academic Press, New York, 1987; T. Kametani
and S. Hibino, Adv. Heterocycl. Chem., 1987, 42, 245; H.
Waldmann, Synthesis, 1994, 535; J. Streith and A. Defoin, Synthesis,
1994, 1107; H. B. Kagan and O. Riant, Chem. Rev., 1992, 92, 1007.
For a preliminary account of this work see: M. C. Elliott and
E. Kruiswijk, Chem. Commun., 1997, 2311.
of OCH ), 2.36 (3 H, s, CH ), 1.75–1.72 (1 H, m, one of CH ),
2
3
2
1
.65 (3 H, s, CH ), 1.57–1.51 (1 H, m, one of CH ) and 0.75
3 2
ϩ
(
3 H, t, J 7.5, CH ); m/z (APCI) 337 (MH , 100%).
3
4
5
(
3R,7R)-3-Ethyl-8-methyl-6-((4-methylphenyl)sulfonyl)-7-
phenyl-5-oxo-2,3,6,7-tetrahydro-5H-[1,3]oxazolo[3,2-c]pyrim-
idine (24)
A
mixture of toluene-4-sulfonyl isocyanate (321 mg,
1
.63 mmol) and (4R,E)-4-ethyl-2-(1-phenylpropen-2-yl)-4,5-
6 R. Beaudegnies and L. Ghosez, Tetrahedron: Asymmetry, 1994, 5,
5
57. For other work by the same group see: B. Serckx-Poncin, A. M.
dihydro-1,3-oxazole (15) (350 mg, 1.63 mmol) was dissolved
in dry toluene (10 ml) and stirred for 1 hour. After removing
the toluene in vacuo, the resulting solid was washed with diethyl
ether and dried in vacuo to afford the title compound (501 mg,
7
Hesbain-Frisque and L. Ghosez, Tetrahedron Lett., 1982, 23, 3261.
A. Waldner, Tetrahedron Lett., 1989, 30, 3061.
W. Seeliger, E. Aufderhaar, W. Diepers, R. Feinauer, R. Nehring,
W. Thier and H. Hellmann, Angew. Chem., Int. Ed. Engl., 1966, 5,
875.
7
8
Ϫ1
5%) as an off-white solid, mp 155–157 ЊC; νmax (CHCl )/cm
3
2
971, 1761 and 1691; δ (400 MHz; CDCl ) 7.34–7.24 (5 H, m,
9 M. Sakamoto, K. Miyazawa, K. Kuwabara and Y. Tomimatsu,
Heterocycles, 1979, 12, 231.
0 R. Richter and H. Ulrich, Chem. Ber., 1970, 103, 3525.
1 T. Saito, H. Kimura, T. Chonan, T. Soda and T. Karakasa, Chem.
Commun., 1997, 1013.
12 T. G. Gant and A. I. Meyers, Tetrahedron, 1994, 50, 2297.
13 C. Kouklovsky, A. Pouilhes and Y. Langlois, J. Am. Chem. Soc.,
1990, 112, 6672.
4 A. Pouilhes, E. Uriate, C. Kouklovsky, N. Langlois, Y. Langlois,
A. Chiaroni and C. Riehe, Tetrahedron Lett., 1989, 30, 1395; A. I.
Meyers, D. L. Temple, R. L. Nolen and E. D. Mihelich, J. Org.
Chem., 1974, 39, 2778.
H
3
aromatic CH), 7.17 (2 H, d, J 8.3, aromatic CH), 7.00 (2 H, d,
J 8.3, aromatic CH), 5.71 (1 H, s, CHPh), 4.25 (1 H, apparent t,
J 7.3, one of OCH ), 4.16–4.11 (2 H, m, CHEt and one of
1
1
2
OCH ), 2.30 (3 H, s, CH ), 2.05–1.99 (1 H, m, one of CH ),
2
3
2
1
.81–1.73 (1 H, m, one of CH ), 1.49 (3 H, s, CH ) and 0.90
2
3
(
3 H, t, J 7.5, CH ); δ (100 MHz; CDCl ) 148.0 (C᎐O), 144.3,
3 C 3
1
1
41.5, 141.4, 136.8 (C-8a and 3 aromatic C), 129.2 (aromatic
CH), 129.0 (broad, 2 aromatic CH), 128.7, 128.1 (both aromatic
CH), 80.9 (alkene C), 71.6 (OCH ), 64.0, 57.0 (both CH), 23.7
2
ϩ
(
CH ), 21.9, 11.5 and 9.3 (all CH ); m/z (APCI) 412 (M , 100%).
2
3
15 More recently we have discovered that this dihydrooxazole can be
more conveniently prepared by direct reaction of the imidate ester
hydrochloride with 2-aminobutan-1-ol. M. C. Elliott and A. E.
Monk, unpublished results.
2
-Propen-2-yl-4,4-dimethyl-4,5-dihydro-1,3-oxazole (25)
2
-Amino-2-methylpropanol (14.03 g, 0.16 mol) in dichloro-
16 M. C. Elliott, D. E. Hibbs, D. S. Hughes, E. Kruiswijk, K. M. A.
Malik and M. B. Hursthouse, J. Chem. Crystallogr., 1998, 28, 663.
methane (100 ml) was added to Na CO ؒ10H O (16 g, 56
2
3
2
1
7 Similar retro-Diels–Alder reactions have been observed in single
adducts derived from alkenyldihydrothiazoles: M. C. Elliott, A. E.
Monk, E. Kruiswijk, D. E. Hibbs, R. L. Jenkins and D. V. Jones,
Synlett, 1999, 1379.
mmol) in water (60 ml). Methacryloyl chloride (18.01 g, 0.17
mol) was added, and the resulting suspension stirred overnight.
The aqueous layer was saturated with sodium chloride,
extracted three times with dichloromethane (50 ml), and the
combined organic layers were dried over MgSO , filtered and
concentrated in vacuo to give N-(2-hydroxy-1,1-dimethylethyl)-
1
8 L. C. Raiford and H. B. Freyermuth, J. Org. Chem., 1943, 8, 230.
19 B. A. Horn, J. L. Herek and A. H. Zewail, J. Am. Chem. Soc., 1996,
118, 8755; V. Mark, J. Org. Chem., 1974, 29, 3179; R. A. Firestone,
Tetrahedron, 1996, 52, 14459; V. Branchadell, J. Font, A. G.
Moglioni, C. Ochoa de Echaguen, A. Oliva, R. M. Ortnuno,
J. Veciana and J. Vidal-Gancedo, J. Am. Chem. Soc., 1997, 119,
4
2
-methylprop-2-enamide (23.23 g, 94%) as a colourless oil. A
portion of this compound (7.34 g, 47 mmol) in dichloro-
methane (100 ml) was cooled to 5 ЊC. Triethylamine (9.45 g, 93
mmol) and methanesulfonyl chloride (5.35 g, 47 mmol) were
added and the solution was stirred overnight. The solution was
washed twice with saturated NaHCO (35 ml) and quickly dried
over Na SO , filtered and concentrated in vacuo. The product
was purified by short path distillation to afford the title com-
pound (3.65 g, 56%) as a colourless oil, bp 125 ЊC, water pump;
νmax (neat)/cm 2969, 2929, 2892, 1657, and 1619; δH (400
MHz; CDCl ) 5.63 (1 H, s, alkene CH), 5.24 (1 H, s, alkene
CH), 3.80 (2 H, s, OCH ), 1.85 (3 H, s, CH ) and 1.17 (6 H, s,
9
992; J. Sauer and R. Sustmann, Angew. Chem., Int. Ed. Engl., 1980,
1
9, 779; V. Kisilev and J. G. Miller, J. Am. Chem. Soc., 1975, 97,
4036; R. Sustmann and W. Sicking, J. Am. Chem. Soc., 1996, 118,
12562; R. Sustmann, P. Daute, R. Sauer and W. Sicking,
Tetrahedron Lett., 1988, 29, 4699.
0 L. F. Tietze, J. Fennen, H. Geissler, G. Schulz and E. Anders,
Liebigs Ann. Chem., 1995, 1681.
1 M. C. Elliott, E. Kruiswijk and D. J. Willock, Tetrahedron Lett.,
1998, 39, 8911.
3
2
4
2
2
Ϫ1
22 W. M. F. Fabian and G. Kollenz, J. Phys. Org. Chem., 1994, 7, 1.
23 J. March, Advanced Organic Chemistry, 4th edn., Wiley Interscience,
New York, 1992, p. 978.
3
2
3
2
1
× CH ); δ (100 MHz; CDCl ) 163.0 (C᎐N), 133.3 (alkene C),
3 C 3
21.6 (alkene CH ), 79.0 (OCH ), 67.7 (C), 28.7 (2 × CH ) and
Paper 9/05700E
2
2
3
3
166
J. Chem. Soc., Perkin Trans. 1, 1999, 3157–3166