Steric control of reactivity: Formation of oximes, benzodiazepinone N-oxides and isoxazoloquinolinones

Article abstract of DOI:10.1039/a707857i

Reaction of the alkenyl carbonyl compounds 1 with hydroxylamine can lead to the formation of the oximes 2, the benzodiazepinone N-oxides 3 or the isoxazoloquinolinones 5. The product(s) of reaction are shown to depend on the electronic nature of the terminal olefinic substituent R³ and the space filling capacity of the substituants R¹, R² and R⁴. When the olefinic centre is electron poor (R³ = CO₂Et) ketocarbonyls convert exclusively to bicyclic nitrones 3 whereas aldehydes are more sensitive to subtle changes in skeletal structure and give rise to oximes 2, tricycles 5 or mixtures of both. For aldehyde and ketone substrates when the olefinic centre carries an aryl substituent (R³ = Ph) the primary product of reaction is the corresponding oxime which on thermal activation converts to the tricyclic isoxazoloquinolinones.

Full text of DOI:10.1039/a707857i

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Steric control of reactivity: formation of oximes, benzodiazepinone
N-oxides and isoxazoloquinolinones
Frances Heaney,* Sharon Bourke, Desmond Cunningham and Patrick McArdle
Department of Chemistry, University College Galway, Ireland
Reaction of the alkenyl carbonyl compounds 1 with hydroxylamine can lead to the formation of the
oximes 2, the benzodiazepinone N-oxides 3 or the isoxazoloquinolinones 5. The product(s) of reaction are
shown to depend on the electronic nature of the terminal olefinic substituent R3 and the space filling
capacity of the substituents R1, R2 and R4. When the olefinic centre is electron poor (R3 ؍ CO2Et)
ketocarbonyls convert exclusively to bicyclic nitrones 3 whereas aldehydes are more sensitive to subtle
changes in skeletal structure and give rise to oximes 2, tricycles 5 or mixtures of both. For aldehyde and
ketone substrates when the olefinic centre carries an aryl substituent (R3 ؍ Ph) the primary product of
reaction is the corresponding oxime which on thermal activation converts to the tricyclic
isoxazoloquinolinones.
R4
R1
Introduction
X
The addition of hydroxylamine to aldehydes and ketones is a
well known reaction, indeed the sharp melting points of the
highly crystalline oxime derivatives have traditionally been used
to characterise the parent carbonyl compounds. With multi-
functional alkenyl carbonyl compounds 1 the reaction can be
NOH
O
R3
N
R5
R2
2
R4
R1
proton transfer
Path B
IOOC
X
R3
O
R4
R1
R4
R1
N
O–
O
N
N+
N
X
X
H
R5
R2
O
••
H
R3
R3
1
N
Aldehydes
R5
R2
R5
R2
2
O
a. R1, R2, R4, R5, X = H; R3 = CO2Et
b. R1, R2, R4, R5 = H; X = Cl; R3 = CO2Et
c. R1, R2, R4, R5, X = H; R3 = Ph
O
4
Path A 1,3-Azaprotio
APT cyclotransfer
Ketones–aryl substituted olefin
cycloaddition
d. R1 = Ph; R2, R4, R5 = H; X = H; R3 = Ph
e. R1 = Ph; R2, R4, R5 = H; X = Cl; R3 = Ph
Ketone–ester substituted olefin
H
R4
R4
f. R1 = Ph; R2, R4, R5, X = H; R3 = CO2Et
g. R1 = Ph; R2, R4, R5 = H; X = Cl; R3 = CO2Et
h. R1 = Ph; R2, R4, R5 = H; X = NO2; R3 = CO2Et
i. R1 = Me; R2, R4, R5, X = H; R3 = CO2Et
R1
O–
O
N
R1
R3
X
X
N+
R3
N
O
N
Tertiary amide aldehydes
j. R1, R4, R5, X = H; R2 = Me; R3 = CO2Et
R5
R2
R5
R2
O
k. R1, R4, R5, X = H; R2 = Me; R3 = Ph
5.6.6-Tricyclic adduct
Isoxazoloquinolinone
6,7-Bicyclic dipole
Benzodiazepinone N-oxide
Ring substituted aldehydes
l. R1, R2, X = H; R4, R5 = Me; R3 = CO2Et
m. R1, R2, R4, X = H; R5 = Me, R3 = CO2Et
n. R1, R2, R5, X = H; R4 = Me; R3 = CO2Et
5
3
Scheme 1
transition state geometry for the cyclisation and cycloaddition
reactions. The promotion of cycloadditions is classically driven
by employing high pressure or high temperature reaction condi-
tions, the use of a catalyst or a specific solvent or in more recent
times by microwave activation.5 At the most rudimentary level
steps taken to increase the rate of encounter of the reacting
moieties can be expected to improve the rate of the reaction;
therein lies perhaps the most important feature of the intra-
molecular reaction, the entropic advantage. A higher stratum
of control over the participating centres invokes the employ-
ment of remote space filling substituents to minimise the spatial
disparity between the reactants. In a recent review Sammes and
Weller6a detail the role of steric factors in promoting or hinder-
ing intramolecular reactions. Especially relevant to the current
work is a paper on intramolecular cycloadditions where the
complicated and the primary product may not be that which is
isolated; in an earlier communication we have shown that these
oximes may react further in one of two ways.1 (i) An intra-
molecular 1,3-azaprotio cyclotransfer (APT) may take place
leading to the formation of a seven-membered cyclic dipole 3
(this is a pseudo 7-exo trig process2),3 Scheme 1, path A. (ii)
Oxime–nitrone tautomerisation may be facilitated by the avail-
ability of an internal unsaturated moiety which can readily trap
the transient dipole in a cycloaddition furnishing the tricyclic
adduct 5,4 this tandem dipole formation–cycloaddition
sequence is also known as an intramolecular oxime olefin cyclo-
addition reaction, IOOC, Scheme 1, path B.
Clearly if reactions of types (i) and (ii) are to take place then
the oxime 2 or the nitrone 4 must be able to adopt the required
J. Chem. Soc., Perkin Trans. 2, 1998
547

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reacting dipole and olefin are attached by short handles to an
aromatic ring.6b Significantly, reactions which do not otherwise
take place are shown to proceed well when steric buttresses are
incorporated into the ortho-position/s of a benzene ring
(positions analogous to R4 and R5). The article does not cite
any examples where bulky substituents, in positions other than
ortho (e.g. R1 and R2), are able to act as predictable steric
buttresses. Neither are there any illustrated examples of the
importance of steric factors in dictating the course of the reac-
tion when the substrate, through its tautomeric form, has the
possibility of undergoing more than one type of ring-forming
reaction (Scheme 1).
and the driving force for the cyclisation reaction is the increased
electrophilicity of the olefinic centre in 8, R3 = COMe, due to
the superior electron withdrawing ability of the ketone sub-
stituent with respect to the ester and aryl substituents of
the amido alcohols 8. Benzoxazepines have previously been
prepared by a K2CO3 promoted cyclisation of amino alcohols
like 8.9
The amido aldehydes 1a–c react with NH2OHؒHCl in an eth-
anolic pyridine solution at room temp. to furnish a single isomer
of the corresponding oximes 10a–c (82–85% yield). Dreiding
R1
In this paper we will show how the electronic nature of R3
and the space filling capacity of the substituents, R1, R2 and R4
influence the course of the reaction of 1 with NH2OH.
a. R1, X = H; R3 = CO2Et
X
NOH
b. R1 = H; X = Cl; R3 = CO2Et
c. R1, X = H; R3 = Ph
R3
d. R1 = Ph; X = H; R3 = Ph
e. R1 = Ph; X = Cl; R3 = Ph
N
O
H
Results and discussion
10
The preparation of the targeted carbonyl substrates 1a–c and
1j–n involves as the key step coupling of the amines 6 with the
appropriate acyl halides 7; oxidation of the resulting o-
amidobenzyl alcohol 8 furnishes the desired aldehydes (Scheme
2). The ketones 1d–i were prepared by direct condensation of
stereomodels of these molecules indicate that the aldoxime
functionality enjoys a considerable degree of conformational
mobility and therefore under the mild reaction conditions there
is no impetus for further reaction (with the pendant olefinic
moiety). Oximation of the ketones 1d,e requires more forcing
conditions (EtOH, 80 ЊC) and results in the formation of a
ketoxime which has a restricted degree of mobility. It is evident
from a study of Dreiding scale models of 10d,e that the planes
in which the two aromatic rings lie are at an angle of ca. 70Њ to
each other. In this conformation the reacting centres, the oxime
moiety or its tautomeric nitrone and the olefinic centre can
approach the transition state required for further reaction
(formation of the benzodiazepinone N-oxides 3 or the isox-
azoloquinolinones 5) (Fig. 1). It is apparent, however, that the
R4
H
R3
X
OH
NHR2
Cl
+
C
O
R5
6
7
a. R3 = CO2Et
b. R3 = Ph
c. R3 = COMe
a. R2, R4, R5, X = H
b. R2, R4, R5 = H; X = Cl
c. R2 = Me; R4, R5, X = H
d. R2, X = H; R4, R5 = Me
e. R2, R4, X = H; R5 = Me
f. R2, R5, X = H; R4 = Me
R1
O–
N+
a. R1, X = H
b. R
1 = H; X = Cl
X
CO2Et
f. R1 = Ph; X = H
g. R1 = Ph; X = Cl
h. R1 = Ph; X = NO2
i. R1 = Me; X = H
N
O
H
3
NaHCO3
CH2Cl2
r.t.
activation energy is too high to allow either an APT or an
IOOC reaction to take place and so the oximes 10d,e are the
sole products of reaction under these conditions.
R4
R1
X
O
COMe
OH
R3
H
H
N
N
O
O
N
N
O
R
H3
Y
H5a
Ph
O
Y
R5
R2
8
C
C
H
X
H
9
H
O
3 = CO2Et, Ph
A
H2a
A
B
B
R
N
N
O
CH2Cl2 PCC
X
H
Me
O
5
5
1a–c and 1j–n
d. X = H; Y = Ph
e. X = Cl; Y = Ph
f. X = H; Y = CO2Et
h. X = NO2; Y = CO2Et
j. Y = CO2Et
k. Y = Ph
NH2
+
7
H
R4
A
O
C
N
H3
CO2Et
H5a
1d–i
Scheme 2
H2a
B
N
H
O
the commercially available o-aminoacetophenone/benzo-
phenone derivative with the acyl halide 7. The substrate 7a was
prepared in three steps from maleic anhydride7 and cinnamoyl
chloride 7b was commercially available. The keto-substituted
derivative 7c was prepared in accordance with the procedure of
Scheffold and Dubs8 and its coupling with the amino alcohol
6a lead directly to the formation of the 1,4-benzoxazepinone 9.
The formation of this product is considered to be by way of a
tandem condensation–intramolecular Michael-type addition
R5
5
l. R4, R5 = Me
m R4 = H; R5 = H
R4 = Me; R5 = H
n
Upon further thermal activation the aldoximes 10a,b (xylene,
140 ЊC) undergo intramolecular cyclisation (APT) giving the
548
J. Chem. Soc., Perkin Trans. 2, 1998

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CH3
CO2Et
H
( a )
( b )
H
R3
O
H
O
O–
R3
N+
O
N
N
H
N:
O
N
H
*
*
11
*
H
*
H
mediary oxime in the generation of 3f–i arises from the observ-
ation that the isoxazoloquinolinones 5f (31%) and 5h (32%),
can be isolated on prolonged heating in ethanolic pyridine of
the benzodiazepinone N-oxides 3f and 3h, respectively. The
formation of the tricyclic adducts from these dipoles implies
that, under these conditions, the bicyclic nitrone exists in equi-
librium with the oxime. Thus the tricyclic adducts 5f,h are
the thermodynamic products and the dipoles 3f,h the kinetic
products of reaction (Scheme 4).
****
Torsion angle ≈ 70 °
Fig. 1 Model representation of 10d in the transition state required for
(a) benzodiazepinone N-oxide formation and (b) isoxazoloquinolinone
formation
benzodiazepinone N-oxides 3a,b, in 78 and 62% yield respect-
ively. The analogous aryl substituted aldoxime 10c fails to cyclise
even at this temperature suggesting that the aryl group on the
trans-disubstituted olefinic bond fails to provide enough elec-
tronic activation for the cyclisation reaction. Heating a xylene
solution of the conformationally restricted ketoximes 10d,e at
reflux temperature effects their conversion, not to the 6,7-
bicyclic dipoles, but rather, to the isoxazoloquinolinones 5d,e in
78 and 63% yield, respectively. These observations suggest that
the activation energy for the formation of the tricycles, 5d,e, is
lower than that required for the alternative intramolecular cycli-
sation reaction (APT, leading to 3d,e), and that for substrates
like 1a–e, even at high reaction temperatures, the olefinic centre
needs to be electron deficient for the cyclisation reaction to
proceed.
Ph
Ph
O–
+
NH2OH•HCl,
EtOH, C5H5N
X
X
N
NOH
O
H
CO2Et
CO2Et
80 °C, 64 h
H
N
H
N
H
O
3f. X = H
h. X = NO2
H
H
O
N
Ph
+
N
Ph
H
CO2Et
O–
X
X
CO2Et
H
The increased electrophilicity of the unsaturated centre in the
ketones 1f–i with respect to 1d,e is expected to influence the
course of their reaction with NH2OH. Therefore it is not sur-
prising that 1f–i react with NH2OHؒHCl, upon heating at reflux
in ethanolic pyridine (24 h), to give the benzodiazepinone N-
oxides 3f–i. As remarked above, the ketoximes 10d,e have
reduced conformational space available to their oxime func-
tionality and the same restricted mobility is expected for the
oximes arising from 1f–i. The easy attainment of the transition
state for the formation of the 6,7-bicyclic dipole combined with
the enhanced electrophilicity of the olefinic moiety in 1f–i
promotes the intramolecular APT reaction. The dipoles 3f–i
were obtained in 49–64% yield. Surprisingly no conversion of
starting material was observed when the reaction was con-
ducted at room temp. The substituent R1 clearly operates as a
steric buttress assisting in the attainment of the transition state
required for benzodiazepinone N-oxide formation whilst the
role of the C-5 aryl ring substituent (1g, X = Cl, 1h, X = NO2)
appears to be restricted to influencing the solubility of the
carbonyl parent. In order to maximise the yield of nitrone the
continuous extraction technique was employed—even with this
precaution 3g,h could only be obtained in 49 and 52% yield,
respectively.
N
N
H
O
H
O
5f. X = H
h. X = NO2
Scheme 4
The aldehyde 1j is a tertiary amide analogue of 1a and it may
be anticipated that the additional substitution on the olefinic
tether (R2 = Me) will influence its reactivity. Reaction with
NH2OHؒHCl (pyridine, EtOH) at room temp. gives the tricyclic
isoxazoloquinolinone 5j in excellent yield. It may be that the
promotion of the IOOC reaction sequence can be ascribed
solely to the restricted mobility of the amide tether ensuring
that the reacting centres can obtain the required alignment for
the cycloaddition step, however in a series of papers on ring
formation at the periphery of heterocyclic systems Noguchi and
co-workers propose that restriction of the dipole/dipolarophile
conformations is only one of two ways in which substitution at
the alkenylamide nitrogen atom may influence reactivity of sub-
O
H
OH
N
N
That dipole formation (1f–i→3f–i) does involve an oxime
intermediate (as in Scheme 1, path A) rather than proceeding
via an alternative sequential intermolecular conjugate type
addition–intramolecular condensation sequence (Scheme 3) is
N
N
R
12
R = Bn, Ph, allyl, SO2Ph
heat
heat
R1
R1
O
X
CO2Et
H
H
OH
O
O
X
CO2Et
O
O
O
N
O
N
N
'NH2OH'
N
HN
H
H
'Conjugate type
addition'
••
N
N
N
N
N
O
H
H
H
H
N
N
R
R
Condensation
3f–i
13
14
O
O–
N+
O
O
N
Scheme 3
N
Me
supported by the failure of 11 to react with NH2OH, suggesting
that attack of the free hydroxylamine at the electron deficient
double bond does not occur. Further support for the inter-
N
N
N
N
R
R
15
16
J. Chem. Soc., Perkin Trans. 2, 1998
549

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( a )
( b )
CO2Et
H
CO2Et
H
O–
O–
H
N+
H
N+
H
O
H
H
H
H
H
O
N
N
C
H
C
H
Hp
H
Hp
H
H
H
E-Dipole 4j, rotamer A
E-Dipole 4j, rotamer B
trans-5j
cis-fused adduct
Fig. 3 Model representation of the transition state leading to the
isoxazoloquinolinone 5j
12 Hz.11 Nuclear Overhauser enhancement difference spectro-
scopy (NOEDS) results for 5j failed to lend support to this
assignment (irradiation of H-3 causes a 3.3% enhancement on
each of H-2a and H-5a) and the relative stereochemistry of this
adduct was unambiguously assigned following a single crystal
X-ray structure determination. The crystal structure confirms
the expected trans relationship between H-5a and H-2a as well
as between H-2a and H-3 [Fig. 2(a)]. It also reveals a dimeric
association of 5j, two molecules make up the unit cell with
H-bonding evident between the NH proton of the isoxazolidine
ring in one molecule and the carbonyl oxygen atom of the ester
side chain at C-3 of a second molecule, the NH ؒ ؒ ؒ O᎐C
᎐
H-bond distance being 3.038 Å [Fig. 2(b)].
The observed diastereospecificity in the formation of 5j,k is
ascribed to the operation of geometric and steric constraints
arising in the transition state leading to the cycloadduct. By
studying Dreiding stereomodels of the dipole leading to 5j it is
evident that the approach leading to the formation of the cis
fused isomer, depicted in Fig. 3(b) involves rotamer B of the
(E)-dipole of 4j and is severely disadvantaged by a steric clash
between the N-methyl group (which is only slightly out of the
plane of the aromatic ring) and the peri-hydrogen Hp. Employ-
ing rotamer A of the (E)-dipole the approach shown in Fig.
3(a) leads to the formation of the trans-fused adduct. Attain-
ment of this stereochemically distinct transition state involves
displacement of the N-methyl group from the plane of the aro-
matic ring by an angle of ca. 50Њ and consequently it encounters
much less steric hindrance than the alternative state, Fig. 3(b).
Therefore rotamer A is the reactive rotamer and the trans-fused
adduct 5j is the only diastereoisomer formed in the reaction.
The effect of space filling substituents on the ortho-positions
of the aromatic ring in 1 was next investigated. The 3,6-
dimethyl derivative 1l reacts with NH2OH (EtOH, 80 ЊC) by the
same reaction sequence as 1j,k yet the tricyclic adduct 5l has
opposite stereochemistry at the BC ring junction. In this case
product stereochemistry is assigned on the basis of NOEDS
results and on the magnitude of the vicinal coupling constant;
J2a,5a = 7 Hz which is a typical value for systems of this type
which have cis fusion of the BC rings of the tricyclic frame-
work.11 Irradiation of H-5a caused a 10.3% enhancement in
H-2a indicating a cis relationship between these two protons.
Due to the conservation of stereochemistry at the olefinic
centre on cycloaddition H-2a and H-3 are expected to be in a
trans arrangement, this is supported by a 1.2% enhancement on
H-2a following irradiation of H-3.
Fig. 2 (a) Single crystal X-ray structure of the isoxazoloqinolinone 5j.
(b) Dimeric association of 5j in the unit cell.
strates analogous to 1j.10 They postulate that the oxime–NH–
nitrone isomerisation cycloaddition sequence in molecules like
12 may be facilitated by either or both the amino nitrogen or the
carbonyl group acting as an intramolecular catalyst in the pro-
ton transfer step. The pyridopyrimidine 12 reacts upon heating
to give the isomeric tetracycles 13 and 14, their dehydro deriv-
ative 16 and the dipole 15. In the event that such catalysis is an
important mechanistic feature then the increased basicity of the
amido nitrogen atom in 1j, with respect to 1a, may explain the
ease of the IOOC reaction sequence leading to the formation
of 5j.
To discover if substitution at the amide N-position alone is
enough to bring about formation of the tricyclic adduct the
amidoaldehyde 1k was prepared. This substrate carries an N-
methyl substituent yet its olefinic centre is electron neutral with
respect to 1j and so whether the transient dipole will have suf-
ficient electronic activation to undergo cycloaddition can be
examined. On attempting oximation of 1k at room temp. the
corresponding oxime 17k was isolated. Increasing the reaction
H
NOH
R3
N
O
Me
17k. R3 = Ph
j. R3 = CO2Et
A plausible explanation for the stereochemical course of this
reaction, involving geometric and steric factors, arises following
inspection of Dreiding scale models of the distinct transition
states which can lead to cycloadduct formation. It appears rea-
sonable that the transient dipole 4l should adopt rotamer B in
its preferred conformation [Fig. 4(a)]; in the alternative con-
formation [Fig. 4(b)] sizeable steric clashes are evident between
the dipole NH hydrogen atom and the adjacent methyl group.
Hence the origin of the diastereospecificity of the reaction, the
dipole shown in Fig. 4(a) is the only low energy conformer
temperature to 80 ЊC failed to promote further reaction, how-
ever heating a solution of the oxime in xylene at reflux (140 ЊC)
leads to quantitative conversion to the tricyclic adduct 5k.
Thermal activation is therefore necessary to overcome the poor
reactivity of the phenyl substituted internal olefin.
The trans stereochemistry at the BC ring junction in 5j,k is
suggested on inspection of the magnitude of the vicinal coup-
ling constant, J2a,5a = 13.5 and 13.2 Hz, respectively; struc-
turally related compounds have trans coupling constants of ca.
550
J. Chem. Soc., Perkin Trans. 2, 1998

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For simple (no ortho-ring substituents and secondary amido-
( a )
H
O–
H
( b )
H
H
CO2Et
H
H
CO2Et
N+
alkenyl nitrogen atom) aldehydes and unactivated ketones
(R3 = Ph) the reaction produces oximes whilst for simple
ketones with R3 = CO2Et bicyclic dipoles result. In those cases
where a sterically bulky group (R4≠ H) is positioned ortho to the
carbonyl functionality tricyclic isoxazolobenzodiazepinones
result, this tricyclic system also arises if the amide nitrogen is
tertiary (R2 ≠ H). In no case is an APT reaction observed when
the olefinic moiety is substituted with a phenyl group, one
explanation considers that this substituent has no significant
influence on the electrophilicity of the pendant olefinic centre
and therefore no ability to promote the internal cyclisation
reaction. However since intramolecular APT reactions have
been observed with terminally unsubstituted olefins12 the steric
bulk of the phenyl group must appreciably increase the acti-
vation energy required for the cyclisation reaction. Whilst the
details of the mechanism of the IOOC reaction are unclear we
have been able to identify certain structural features which
effect its promotion; steric buttresses positioned at one of three
sites, ortho to the oxime group, i.e. at R4, or along the chain
connecting either the oxime or the olefin to the benzene ring i.e.
at R1 or R2. That the substituent R2 may have both a steric and
electronic role in facilitating tricycle formation cannot be dis-
missed.10 The merit of the steric buttressing effect in the
acceleration of intramolecular ring-forming reactions of
‘unsaturated oximes’, reactions which do not otherwise pro-
ceed, has been illustrated. Future studies in this area will be
directed toward the incorporation of removable groups at the
key positions R1, R2 and R4.
O–
H
H
H
H
N+
C
H
C
H
H
H
O
O
N
N
H
H
C
C
H
H
H
H
H
H
E-Dipole 4l, rotamer B
E-Dipole 4l, rotamer A
cis-5l
trans-fused adduct
Fig. 4 Model representation of the transition state leading to the
isoxazoloquinolinone 51
which is able to participate in cycloaddition. Such exquisite dis-
crimination in intramolecular cycloaddition reactions is a well
known and attractive feature of this class of pericyclic reaction.
For both nitrones 4j and 4l when the dipole has Z geometry it
is not possible to place the reacting centres (olefinic substituent
and dipole) in the same plane and hence this dipolar conform-
ation cannot lead to any cycloaddition product. Nogouchi
and co-workers also invoke the E-dipole in the intramolecu-
lar cycloaddition of the structurally related nitrone arising
from 12.10
R4
H
NOH
O
CO2Et
Experimental
N
R5
H
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 EX90 FT NMR and a
JEOL EX270 FT NMR spectrometer at probe temperatures
with tetramethylsilane as internal reference and deuteriochloro-
form as solvent; J values are given in Hertz. IR spectra were
recorded on a Perkin-Elmer 1600 series FTIR spectro-
photometer, samples were prepared as nujol mulls. Flash
column chromatography was carried out on silica gel (200–400
mesh; Kiesslgel 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 procedure and light petroleum
refers to that fraction of light petroleum boiling between
40–60 ЊC.
18l. R4 = R5 = Me
m. R4 = H, R5 = Me
n. R4 = Me, R5 = Me
That the adducts 5j–l arise from a domino oximation–
tautomerisation–cycloaddition reaction sequence (Scheme 1) is
supported by the observation that for each carbonyl parent the
reaction can be stopped at the level of the oxime if lower reac-
tion temperatures are employed, Ϫ25 ЊC in the case of 1j (giv-
ing 17j) and room temp. for 1k (giving 17k) or 1l (giving 18l);
further heating of a solution of the oxime results in formation
of the corresponding adducts 5j–l. Significantly the monomethyl
analogue 1m reacts under standard oximation conditions
(NH2OHؒHCl, EtOH, room temp. or 80 ЊC) to give only the
corresponding oxime (18m) in 74% yield. Further heating of the
isolated oxime (xylene 140 ЊC) failed to induce reaction and no
trace of the expected tricyclic adduct 5m was encountered.
Since the 3,6-dimethyl substrate 1j so readily participates in the
IOOC reaction sequence and the 3-methyl derivative shows no
such reactivity it is apparent that the 6-methyl substituent plays
a critical role as a steric buttress encouraging the attainment of
the necessary transition state for the cycloaddition reaction of
the intermediate nitrone. To investigate if the C-6 substituent is
both necessary and sufficient to promote this reaction path the
behaviour of the aldehyde 1n has been studied. Upon heating in
ethanolic pyridine (80 ЊC) with NH2OHؒHCl the anticipated
tricyclic adduct 5n was formed in 23% yield together with 61%
of the corresponding oxime 18n. That the BC ring junction in
5n should be cis fused is suggested by comparison with Fig. 4
and this conclusion is sustained by the J2a,5a coupling constant
of 8.1 Hz.11
General procedure for the formation of carbonyl substrates 1
Preparation of the aldehydes 1a–c and 1j–n. Preparation of the
benzyl alcohols 8.—The acyl halide 7 (0.057 mol) was added
dropwise to a cooled suspension of the amino alcohol 613
(0.057 mol) and sodium hydrogen carbonate (0.067 mol) in
anhydrous dichloromethane (50 cm3). The mixture was stirred
for 1 h at room temp. The organic layer was washed, dried and
the solvent removed under reduced pressure. The resulting solid
was crystallised from diethyl ether–light petroleum to yield
the pure alcohols 8. The yields of the alcohols ranged from
41–84%, all gave satisfactory micro analytical and spectro-
scopic data, see Table 1(a) and (b).
Oxidation of the alcohols 8.—Freshly prepared pyridinium
chlorochromate14 (0.042 mol) was suspended in anhydrous
dichloromethane (50 cm3). The appropriate alcohol 8 (0.028
mol) in dichloromethane (20 cm3) was added in one portion.
After 1.5 h dry diethyl ether was added and the solution
was passed through 10 cm of silica gel. The solvent was
removed under reduced pressure and the resulting solid was
purified by crystallisation from diethyl ether–light petroleum
Conclusions
The influence of the space filling substituents, R1, R2 and R4
and of the electronic nature of R3 on the course of the reaction
of the carbonyl compounds 1 with NH2OH, is quite striking.
J. Chem. Soc., Perkin Trans. 2, 1998
551

View Article Online
Table 1(a) Analytical data for the alcohols 8
Found (%) [requires (%)]
Entry no. Compound no. R1
R2
H
H
H
R3
R4
H
R5
H
X
H
Cl
H
H
H
H
H
H
Yield (%) mp/ЊC
Molecular formula
115–116 C13H15O4N
128–130 C13H14O4NCl
118–119 C16H15O2N
C
N
H
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
H
H
H
H
H
H
H
H
CO2Et
CO2Et
Ph
53
46
43
49
43
41
42
49
62.63
[62.65]
54.99
[55.03]
75.93
[75.88]
63.93
[63.87]
76.36
[76.40]
65.02
[64.98]
63.82
[63.87]
63.89
[63.87]
6.07
[6.02]
4.85
[4.93]
5.89
[5.93]
6.41
[6.46]
6.39
[6.36]
6.89
[6.86]
6.43
[6.46]
6.50
[6.46]
5.68
[5.62]
4.90
[4.94]
5.49
[5.53]
5.49
[5.32]
5.27
[5.24]
5.01
[5.05]
5.40
[5.32]
5.33
[5.32]
H
H
H
H
Me CO2Et
Me Ph
H
H
70–72
93–95
C14H17O4N
C17H17O2N
H
H
H
H
H
CO2Et
CO2Et
CO2Et
Me
H
Me
Me
H
136–137 C15H19O4N
124–125 C14H17O4N
8g
8h
Me
70–72
C14H17O4N
Table 1(b) Spectroscopic data for the alcohols 8
Entry no. Compound no. δH
δC
ν/cmϪ1
1
8a
9.30 (1H, s, NH), 8.02 (1H, d, ArH, J 8.02), 165.52 (NHCO), 162.19 (CO2Et), 136.94 (C-1), 3264.0 (OH),
7.22 (5H, m, ArH, CH᎐CH), 4.65 (2H, s, 128.79 (C-2), 131.01, 125.15, 122.45 and 123.42 3121.5 (NH),
᎐
CH2OH), 4.24 (2H, q, OCH2, J 7.31), 3.91 (Ar),
136.63
(CH᎐CHCO2Et),
131.48 1716.6 (CO2Et),
᎐
(1H, s, CH2OH), 1.32 (3H, t, CH2CH3, J 7.31)
(CH᎐CHCO2Et), 63.96 (CH2OH), 61.34
1643.1 (NHCO)
᎐
(OCH2), 14.09 (CH2CH3)
2
8b
9.11 (1H, s, NH), 8.14 (1H, d, ArH, J 8.12), 165.12 (CO2Et), 162.31 (NHCO), 135.21 (C-1), 3275.9 (OH),
7.31 (2H, m, ArH), 7.01 (1H, d, CH᎐CH- 129.92 (C-2), 121.94 (C-1), 128.47, 128.95 and 3112.0 (NH),
᎐
CO2Et, J 14.57), 6.91 (1H, d, CH᎐CHCO2Et,
123.52 (Ar), 136.52 (CH᎐CHCO2Et), 131.45
1714.7 (CO2Et),
1643.8 (NHCO)
᎐
᎐
J 14.57), 4.74 (2H, s, CH2OH), 4.29 (2H, q,
OCH2, J 7.30), 2.57 (1H, s, OH), 1.35 (3H, t,
CH2CH3, J 7.30)
(CH᎐CHCO2Et), 64.38 (CH2OH), 61.54
᎐
(OCH2), 14.35 (CH2CH3)
3
4
8c
8d
8.89 (1H, s, NH), 8.14 (1H, d, ArH, J 7.90), 163.01 (NHCO), 140.56 (Ar), 136.34 (C-1),
7.78 (1H, d, CH᎐CHPh, J 15.80), 7.25 (8H, m,
3256.3 (OH),
129.01 (C-2), 132.92 (CH᎐CHPh), 122.75 3103.6 (NH),
᎐
᎐
ArH), 6.48 (1H, d, CH᎐CHPh, J 15.80), 4.70
(s, 2H, CH2OH), 3.42 (1H, br, OH)
(CH᎐CHPh), 128.28, 127.69, 127.49, 126.33,
119.53 and 115.71 (Ar), 66.97 (CH2OH)
1654.3 (NHCO)
᎐
᎐
7.37 (4H, m, ArH), 6.81 (1H, d, CH᎐CH- 165.60 (NCH3CO), 165.43 (CO2Et), 140.03 3258.1 (OH),
᎐
CO2Et, J 15.33), 6.66 (1H, d, CH᎐CHCO2Et,
(C-1), 129.26 (C-2), 133.38, 131.32, 129.10 and 1730.4 (CO2Et),
᎐
J 15.33), 4.57 (2H, s, CH2OH), 4.12 (2H, q,
OCH2, J 7.15), 3.36 (3H, s, NCH3), 3.14 (1H,
s, CH2OH), 1.22 (3H, t, CH2CH3, J 7.15)
128.15 (Ar), 138.21 (CH᎐CHCO2Et), 131.40
1693.4
(NCH3CO)
᎐
(CH᎐CHCO2Et), 61.03 (CH2OH), 60.71
᎐
(OCH2), 37.28 (NCH3), 14.01 (CH2CH3)
5
6
8e
8f
8.21 (1H, d, ArH, J 8.02), 7.93 (1H, d, 166.23 (NCH3CO), 145.41, 142.32, 134.82,
CH᎐CHPh, J 15.60), 7.31 (8H, m, ArH), 6.57
135.89 (CH᎐CHPh), 123.30 (CH᎐CHPh),
᎐
᎐ ᎐
(1H, d, CH᎐CHPh, J 15.60), 4.63 (2H, s,
OCH2)
130.45, 128.43, 127.59, 121.09, 118.29, 115.11,
65.34 (CH2OH), 36.91 (NCH3)
9.60 (1H, br, NH), 7.44 (2H, m, ArH), 7.02
165.79 (NHCO), 162.35 (CO2Et), 135.75,
(1H, d, CH᎐CHCO2Et, J 14.91), 6.89 (1H, d, 134.41 and 129.30 (Ar), 127.31 (C-6), 121.71
᎐
CH᎐CHCO2Et,
J
14.91), 4.65 (2H, s, (C-3),
135.52
(CH᎐CHCO2Et),
130.48
᎐
᎐
CH2OH), 4.21 (2H, q, OCH2, J 7.30), 2.23 (CH᎐CHCO2Et), 67.21 (CH2OH), 61.92
᎐
(3H, s, CH3), 1.98 (3H, s, CH3), 1.21 (3H, t,
CH2CH3, J 7.30)
(OCH2), 20.54 (CH3), 18.72 (CH3), 14.91 (t,
3H, CH2CH3)
7
8
8g
8h
9.32 (1H, br, NH), 7.59 (3H, m, ArH), 7.11
165.20 (NHCO), 162.71 (CO2Et), 136.47 (C-1),
130.77 (C-2), 127.31 (C-6), 135.90, 133.24 and
3266.2 (OH),
3095.8 (NH),
1716 (CO2Et),
1645.2 (NHCO)
(1H, d, CH᎐CHCO2Et, J 15.34), 6.92 (1H, d,
᎐
CH᎐CHCO2Et,
J
15.34), 4.73 (2H, s, 127.79 (Ar), 135.45 (CH᎐CHCO2Et), 131.77
᎐
᎐
CH2OH), 4.37 (2H, q, OCH2, J 7.30), 2.89 (CH᎐CHCO2Et), 65.01 (CH2OH), 61.39
(1H, br s, OH), 1.91 (3H, s, CH3), 1.27 (3H, t,
CH2CH3, J 7.30)
᎐
(OCH2), 18.26 (CH3), 14.21 (CH2CH3)
9.07 (1H, s, NH), 8.01 (1H, d, ArH, J 8.04),
165.50 (CO2Et), 161.86 (NHCO), 137.01 (C-1),
129.49 (C-2), 122.45 (C-3), 129.73, 134.24 and
3258.1 (OH),
3099.0 (NH),
7.48 (2H, m, ArH), 7.01 (1H, d, CH᎐CH-
᎐
CO2Et, J 15.38), 6.84 (1H, d, CH᎐CHCO2Et,
J 15.38), 4.67 (2H, s, CH2OH), 4.26 (2H, q,
122.98 (Ar), 134.81 (CH᎐CHCO2Et), 130.92
1730.4 (CO2Et),
1693.4 (NHCO)
᎐
᎐
(CH᎐CHCO2Et), 64.36 (CH2OH), 61.35
᎐
OCH2, J 7.33), 3.01 (1H, br, OH), 2.33 (3H, s, (OCH2), 20.83 (CH3), 14.01 (CH2CH3)
CH3), 1.34 (3H, t, CH2CH3, J 7.33)
yielding the desired aldehydes. The yields of the new com-
pounds ranged from 68–79%; all gave satisfactory micro
analytical and spectroscopic data, see Table 2(a) and (b), entries
1–3 and 10–14.
Preparation of the ketones 1d–i. The acyl halide 7 (0.057 mol)
was added dropwise to a cooled suspension of the amino
ketone (0.057 mol) and sodium hydrogen carbonate (0.067 mol)
in anhydrous dichloromethane (50 cm3). The mixture was
stirred for 1 h at room temp. The organic layer was washed,
dried and the solvent removed under reduced pressure. The
resulting solid was crystallised from diethyl ether–light petro-
leum to yield the pure ketones 1d–i. The yields of the ketones
ranged from 49–57%; all gave satisfactory micro analytical and
spectroscopic data, see Table 2(a) and (b), entries 4–9.
552
J. Chem. Soc., Perkin Trans. 2, 1998

View Article Online
Table 2(a) Analytical data for the carbonyl compounds 1
Found (%) [requires (%)]
Entry no. Compound no. R1
R2
H
H
H
R3
R4
H
H
H
R5
H
H
H
X
Yield (%) Molecular formula mp/ЊC
C
H
N
1
2
3
1a
1b
1c
H
H
H
CO2Et
CO2Et
Ph
H
Cl
H
73
78
68
C13H13NO4
C13H12NO4Cl
C16H13NO2
71–73
74–75
93–95
63.19
[63.16]
55.39
[55.42]
76.43
[76.49]
5.26
[5.26]
4.29
[4.26]
5.17
[5.18]
5.69
[5.67]
4.29
[4.26]
5.57
[5.57]
4
5
1d
1e
Ph
Ph
H
H
Ph
Ph
H
H
H
H
H
57
51
C22H17NO2
52–54
58–60
80.69
[80.73]
72.99
5.17
[5.20]
4.47
4.26
[4.28]
3.89
Cl
C22H16NO2Cl
[73.03]
[4.43]
[3.87]
6
7
8
9
1f
1g
1h
1i
Ph
Ph
Ph
Me
H
H
H
H
CO2Et
CO2Et
CO2Et
CO2Et
H
H
H
H
H
H
H
H
H
49
53
C19H17NO4
C19H16NO4Cl
C19H16N2O6
C14H15NO4
62–64
98–100
112–114
73–74
70.61
[70.59]
63.72
[63.78]
61.98
[61.96]
64.39
[64.37]
5.29
[5.26]
4.51
[4.48]
4.30
[4.35]
5.78
[5.75]
4.36
[4.33]
3.94
[3.91]
7.57
[7.61]
5.33
[5.36]
Cl
NO2 53
H
52
10
11
1j
H
H
Me CO2Et
Me Ph
H
H
H
H
H
H
79
69
C14H15NO4
C17H15NO2
81–83
64.39
[64.37]
76.95
5.76
[5.75]
5.62
5.34
[5.36]
5.29
1k
102–105
[76.98]
[5.66]
[5.28]
12
13
14
1l
H
H
H
H
H
H
CO2Et
CO2Et
CO2Et
Me
H
Me
Me
H
H
H
H
C15H17NO4
C14H15NO4
C14H15NO4
89–90
72–75
84–86
65.45
[65.40]
64.30
[64.37]
64.37
6.18
[6.07]
5.74
[5.75]
5.79
5.09
[5.09]
5.39
[5.36]
5.30
68
65
72
1m
1n
Me
[64.37]
[5.75]
[5.36]
Preparation of 9; 1,2,3,5-tetrahydro-3-(2-oxopropyl)-4,1-benzo-
xazepin-2-one
The solvent was removed and the resulting white solid
crystallised from dichloromethane–light petroleum, yielding
the pure nitrone. The yields of the new nitrones ranged
from 62–78%, both gave satisfactory micro analytical and
spectroscopic data, see Table 4(a) and (b), entries 1 and 2.
4-Oxopent-2-enoic acid chloride 7c (0.057 mol) was added
dropwise to a cooled suspension of the amino alcohol 6a (0.057
mol) and sodium hydrogen carbonate (0.067 mol) in anhydrous
dichloromethane (50 cm3). The mixture was stirred for 1 h at
room temp. The organic layer was washed, dried and the sol-
vent removed under reduced pressure. The resulting solid was
crystallised from diethyl ether–light petroleum to yield the pure
benzoxazepinone 9, yield 84%, mp 98–100 ЊC; δH(270 MHz)
9.32 (1H, s, NH), 7.02–7.75 (4H, m, ArH), 4.72 (1H, d, J 11.3,
5-H), 4.59 (1H, d, J 11.3, 5-H), 4.32 (1H, dd, J 6.0 and 8.1, 3-
H), 3.02 (1H, dd, J 17.6 and 8.7, CH2COMe), 2.62 (1H, dd, J
17.6 and 6.0, CH2COMe), 2.24 (3H, s, COMe); δC(67.5 MHz)
206.33 (COCH3), 170.43 (NHCO), 130.24, 128.31, 127.11,
125.22, 121.77 and 120.34 (Ar), 70.31 (C-5), 60.08 (C-3), 33.21
(CH2COMe), 30.21 (COCH3).
Preparation of the tricycles 5d,e; 3,9b-diphenyl-1,3,3a,4,5,9b-
hexahydroisoxazolo[4,3-c]quinolin-4-ones
Ketoximes 10d,e (7.6 mmol) were heated at reflux (140 ЊC) in
xylene (10 cm3). The solvent was removed and the resulting
white solid crystallised from diethyl ether–light petroleum,
yielding the pure isoxazoloquinolinone. The yields of the new
tricycles ranged from 63–78%, both gave satisfactory micro ana-
lytical and spectroscopic data, see Table 5(a) and (b), entries 1
and 2.
General procedure for the formation of the nitrones 3f–i; 3-
ethoxycarbonylmethyl-1,3-dihyhdro[1,4]benzodiazepin-2-one
N-oxides
General procedure for the formation of the oximes 10a–e
The appropriate carbonyl substrate 1a–e (0.024 mol), hydroxyl-
amine hydrochloride (0.029 mol) and pyridine (0.029 mol) were
stirred at room temp. in anhydrous ethanol (50 cm3) for 24 h.
The ethanol was removed under reduced pressure and the
resulting residue was dissolved in dichloromethane and washed
with water (4 × 25 cm3). The organic layer was dried and con-
centrated to yield the oxime, which was purified by crystal-
lisation from diethyl ether–light petroleum. The yields of the
new oximes ranged from 59–85%, all gave satisfactory micro
analytical and spectroscopic data, see Table 3(a) and (b),
entries 1–5.
The appropriate carbonyl substrate 1f–i (0.024 mol), hydroxyl-
amine hydrochloride (0.029 mol) and pyridine (0.029 mol) were
heated at reflux (80 ЊC) in anhydrous ethanol (50 cm3) for 16 h.
The ethanol was removed under reduced pressure. The resulting
residue was dissolved in dichloromethane and washed with
water (4 × 25 cm3). The organic layer was then dried and the
dichloromethane removed. Purification was carried out using
flash chromatography (SiO2, diethyl ether) to yield the pure
nitrone. The yields of all new nitrones ranged from 49–64%, all
gave satisfactory micro analytical and spectroscopic data, see
Table 4(a) and (b), entries 3–6.
Preparation of the nitrones 3a,b; 3-ethoxycarbonylmethyl-2,3-
dihydro-1H-1,4-benzodiazepin-2-one N-oxides
Preparation of the tricycles 5f,h: 3-ethoxycarbonyl-9a-phenyl-
1,3,3a,4,5,9b-hexahydroisoxazolo[4,3-c]quinolin-2-ones
Prolonged heating (72 h) of the above reaction mixture
resulted in a decrease in the amount of nitrone present and the
Aldoximes 10a,b (7.6 mmol) were heated at reflux (110 ЊC)
in toluene (10 cm3) in the presence of pyridine (8 mmol).
J. Chem. Soc., Perkin Trans. 2, 1998
553

View Article Online
Table 2(b) Spectroscopic data for the carbonyl compounds 1
Entry no. Compound no. δH
δC
ν/cmϪ1
1
1a
11.54 (1H, s, NH), 9.95 (1H, s, CHO), 8.82 195.68 (CHO), 165.13 (NHCO), 162.59 3125.6 (NH),
(1H, d, ArH, J 8.79), 7.65 (2H, m, ArH), 7.30 (CO2Et), 140.27 (C-2), 136.23 (C-1), 136.78, 1720.6 (CO2Et),
(1H, t, ArH, J 8.79), 7.11 (1H, d, CH᎐CH-
123.80 and 120.16 (Ar), 135.28 (CH᎐CH 1688.6 (CHO),
᎐
᎐
CO2Et, J 15.39), 6.93 (1H, d, CH᎐CHCO2Et,
CO2Et), 131.79 (CH᎐CHCO2Et), 61.28
1654.1 (NHCO)
᎐
᎐
J 15.39), 4.29 (2H, q, OCH2, J 7.33), 1.36 (3H, (OCH2), 14.09 (CH2CH3)
t, CH2CH3, J 7.33)
2
3
4
5
6
1b
1c
1d
1e
1f
11.41 (1H, s, NH), 9.90 (1H, s, CHO), 8.82 194.47 (CHO), 164.73 (NHCO), 162.19
(1H, d, ArH, J 8.58), 7.63 (2H, m, ArH), 7.09
(1H, d, CH᎐CHCO2Et, J 15.37), 6.93 (1H, d,
(CO2Et), 138.85 (C-2), 136.06 (C-1), 129.05
(C-4), 122.97, 136.45 and 121.96 (Ar), 135.18
᎐
CH᎐CHCO2Et, J 15.37), 4.31 (2H, q, OCH2, J (CH᎐CHCO2Et), 132.21 (CH᎐CHCO2Et),
᎐
᎐
᎐
7.32), 1.35 (3H, t, CH2CH3, J 7.32)
61.47 (OCH2), 14.20 (CH2CH3)
11.41 (1H, s, NH), 9.96 (1H, s, CHO), 8.89 195.68 (CHO), 162.18 (NHCO), 142.88 (Ar),
3110.5 (NH),
1689.1 (CHO),
(1H, d, ArH, J 8.42), 7.68 (1H, d, CH᎐CHPh,
141.30 (C-2), 136.31 (C-1), 134.57, 128.95,
᎐
J 15.41), 7.46 (8H, m, ArH), 6.63 (1H, d, 128.24, 121.75, 121.51 and 120.16 (Ar), 131.22 1643.7 (NHCO)
CH᎐CHPh, J 15.41)
(CH᎐CHPh), 123.01 (CH᎐CHPh)
᎐ ᎐
᎐
10.43 (1H, s, NH), 7.63 (15H, m, ArH, 192.98 (CO), 162.45 (NHCO), 142.38 (Ar), 3121.0 (NH),
CH᎐CHPh), 6.75 (1H, d, CH᎐CHPh, J 15.81) 140.81 (C-2), 136.73 (C-1), 134.28, 133.92, 1692.3 (CO),
᎐
᎐
133.06, 132.51, 130.88, 130.10, 129.6, 128.93, 1637.0 (NHCO)
128.21, 127.63, 125.90, 125.19 and 121.47 (Ar,
CH᎐CH)
᎐
10.94 (1H, s, NH), 7.42 (14H, m, ArH, 193.31 (CO), 163.60 (NHCO), 142.89 (Ar), 3098.9 (NH),
CH᎐CHPh), 6.69 (1H, d, CH᎐CHPh, J 15.61) 140.89 (C2, Ar), 136.51 (C-1), 134.93, 134.41,
1695.3 (CO),
132.86, 132.70, 131.28, 129.7, 128.81, 128.25, 1642.1 (NHCO)
127.76, 125.39 and 121.05 (Ar, CH᎐CH)
᎐
᎐
᎐
11.37 (1H, s, NH), 8.76 (1H, d, ArH, J 8.7), 199.91 (CO), 165.24 (NHCO), 162.43 (CO2Et),
3112.0 (NH),
7.48 (7H, m, ArH), 7.15 (1H, m, ArH), 7.11
(1H, d, CH᎐CHCO2Et, J 15.41), 6.93 (1H, d,
140.12 (C-2), 139.21 (Ar), 137.21 (C-1), 134.36, 1720.1 (CO2Et),
133.85, 132.65, 129.93, 128.41, 123.42, 122.97, 1689.2 (CO),
᎐
CH᎐CHCO2Et, J 15.41), 4.27 (2H, q, OCH2, J 121.71 and 101.02 (Ar), 134.48 (CH᎐CH-
1648.0 (NHCO)
᎐
᎐
7.32), 1.35 (3H, t, CH2CH3, J 7.32)
CO2Et), 131.45 (CH᎐CHCO2Et), 61.28
᎐
(OCH2), 14.21 (CH2CH3)
7
8
9
1g
1h
1i
10.60 (1H, s, NH), 7.62 (8H, m, ArH), 7.05
193.02 (CO), 166.62 (NHCO), 163.20 (CO2Et),
3115.2 (NH),
(1H, d, CH᎐CHCO2Et, J 15.60), 6.56 (1H, d,
140.23 (Ar), 138.35 (C-2), 136.15 (C-1), 132.86, 1721.2 (CO2Et),
᎐
CH᎐CHCO2Et, J 15.60), 4.25 (2H, q, OCH2, J 131.25, 129.60, 129.40, 128.94, 125.35, 128.12 1687.2 (CO),
᎐
7.04), 1.31 (3H, t, CH2CH3, J 7.04)
and 125.75 (Ar), 135.06 (CH᎐CHCO2Et),
1633.3 (NHCO)
᎐
130.59 (CH᎐CHCO2Et), 60.82 (OCH2), 13.93
᎐
(CH2CH3)
11.12 (1H, s, NH), 8.44 (1H, m, ArH), 7.83
192.43 (CO), 164.46 (CO2Et), 161.85 (NHCO),
3120.5 (NH),
(7H, m, ArH), 7.13 (1H, d, CH᎐CHCO2Et, J
143.23 (C-2), 140.96 (Ar), 136.28 (C-1), 133.35, 1719.5 (CO2Et),
᎐
15.61), 6.64 (1H, d, CH᎐CHCO2Et, J 15.61),
130.95, 129.77, 128.48, 126.74, 125.09 and
1690.5 (CO),
1642.9 (NHCO)
᎐
4.27 (2H, q, OCH2, J 7.30), 1.32 (3H, t,
CH2CH3, J 7.30)
124.07 (Ar), 135.95 (CH᎐CHCO2Et), 130.72
᎐
(CH᎐CHCO2Et), 60.92 (OCH2), 13.93
᎐
(CH2CH3)
12.20 (1H, s, NH), 8.83 (1H, d, ArH, J 8.30), 203.10 (CO), 165.17 (NHCO), 162.45 (CO2Et),
7.94 (1H, d, ArH, J 7.81), 7.59 (1H, t, ArH, J 140.37 (C-2), 137.34 (C-1), 131.13, 123.16,
3098.6 (NH),
1718.1 (CO2Et),
1682 (CO),
7.32), 7.19 (1H, t, ArH, J 7.81), 7.09 (1H, d, 121.83 and 120.82 (Ar), 135.12 (CH᎐CH-
᎐
CH᎐CHCO2Et,
J
15.63), 6.91 (1H, d,
CO2Et), 131.71 (CH᎐CHCO2Et), 61.16
1651.3 (NHCO)
᎐
᎐
CH᎐CHCO2Et, J 15.63), 4.29 (2H, q, OCH2, J (OCH2), 28.44 (CH3), 14.08 (CH2CH3)
᎐
7.33), 2.69 (3H, s, CH3), 1.35 (3H, t, CH2CH3,
J 7.33)
10
11
12
1j
10.05 (1H, s, CHO), 7.99 (1H, d, ArH, J 7.33), 187.87 (CHO), 165.0 (NCH3CO), 163.94
1724 (CO2Et),
7.74 (1H, m, ArH), 7.61 (1H, m, ArH), 7.33
(1H, d, ArH, J 7.30), 6.86 (1H, d, CH᎐CH-
(CO2Et), 143.59 (C-2), 132.91 (C-1), 129.27, 1693.5 (CHO),
132.35 and 131.16 (Ar), 135.60 (CH᎐CH- 1664.3
᎐
᎐
CO2Et, J 15.39), 6.65 (1H, d, CH᎐CHCO2Et,
CO2Et), 131.87 (CH᎐CHCO2Et), 60.87
(NCH3CO)
᎐
᎐
J 15.39), 4.13 (2H, q, OCH2, J 7.33), 3.40 (3H, (OCH2), 38.23 (NCH3), 14.09 (CH2CH3)
s, NCH3), 1.36 (3H, t, CH2CH3, J 7.33)
1k
1l
9.98 (1H, s, CHO), 8.73 (1H, d, ArH, J 8.02),
198.72 (CHO), 165.02 (NMeCO), 143.29 (Ar),
1693.3 (CHO),
1648.0
7.82 (1H, d, CH᎐CHPh, J 15.41), 7.51 (8H, m,
142.33 (C-2), 137.64 (C-1), 135.87, 129.92,
᎐
ArH), 6.92 (1H, d, CH᎐CHPh, J 15.41), 3.42
127.34, 121.68, 121.01 and 120.23 (Ar), 132.98 (NMeCO)
᎐
(3H, s, NCH3)
(CH᎐CHPh), 122.91 (CH᎐CHPh), 37.78
᎐
᎐
(NCH3)
11.49 (1H, br, NH), 9.93 (1H, s, CHO), 7.99
195.20 (CHO), 166.31 (CO2Et), 162.67
(1H, d, ArH, J 8.06), 7.74 (1H, d, ArH, J
(NHCO), 146.96 (C-2), 124.23 and 134.29 (Ar),
8.06), 7.34 (1H, d, CH᎐CHCO2Et, J 15.39), 122.07 (C-5), 118.65 (C-4), 135.75 (CH᎐CH-
᎐
᎐
6.92 (1H, d, CH᎐CHCO2Et, J 15.39), 4.27
CO2Et), 128.19 (CH᎐CHCO2Et), 61.05
᎐
᎐
(2H, q, OCH2, J 7.33), 2.17 (3H, s, CH3), 1.94
(3H, s, CH3), 1.28 (3H, t, CH2CH3, J 7.33)
10.98 (1H, br, NH), 9.93 (1H, s, CHO), 7.48
(OCH2), 22.45 (s, 3H, CH3), 19.21 (s, 3H, CH3),
14.09 (CH2CH3)
13
14
1m
1n
193.76 (CHO), 165.74 (CO2Et), 162.18
(NHCO), 127.75 and 126.49 (Ar), 143.21 (C-2),
(3H, m, ArH), 7.01 (1H, d, CH᎐CHCO2Et, J
᎐
15.34), 6.90 (1H, d, CH᎐CHCO2Et, J 15.34),
137.41 (C-1), 136.06 (CH᎐CHCO2Et), 132.19
᎐
᎐
4.26 (2H, q, OCH2, J 7.32), 2.16 (3H, s, CH3),
1.26 (3H, t, CH2CH3, J 7.32)
(C-6), 131.79 (CH᎐CHCO2Et), 61.43 (OCH2),
᎐
18.45 (s, 3H, CH3), 14.26 (CH2CH3)
11.39 (1H, br, NH), 9.87 (1H, s, CHO), 8.60
195.66 (CHO), 165.19 (NHCO), 162.42 3214.0 (NH),
(1H, d, ArH, J 8.06), 7.44 (2H, m, ArH, J (CO2Et), 137.89 (C-2), 133.61 (C-1), 129.26 1727.1 (CO2Et),
8.06), 7.06 (1H, d, CH᎐CHCO2Et, J 15.32), (C-3), 121.82 and 120.16 (Ar), 136.30 (CH᎐
1694.2 (CHO),
1644.3 (NHCO)
᎐
᎐
6.92 (1H, d, CH᎐CHCO2Et, J 15.32), 4.31
CHCO2Et), 131.47 (CH᎐CHCO2Et), 61.27
᎐
᎐
(2H, q, OCH2, J 7.33), 2.38 (3H, s, CH3), 1.33
(3H, t, CH2CH3, J 7.33)
(OCH2), 20.51 (s, 3H, CH3), 14.10 (CH2CH3)
554
J. Chem. Soc., Perkin Trans. 2, 1998

View Article Online
Table 3(a) Analytical data for the oximes 10, 17 and 18
Found (%) [requires (%)]
Entry no.
Compound no.
Substrate no.
Yield (%)
mp/ЊC
Molecular formula
C13H14N2O4
C13H13N2O4Cl
C16H14N2O2
C22H18N2O2
C22H17N2O2Cl
C17H16N2O2
C14H16N2O4
C15H18N2O4
C14H16N2O4
C14H16N2O4
C
H
N
1
2
10a
10b
10c
10d
10e
17k
17j
1a
1b
1c
1d
1e
1k
1j
82
83
85
67
59
76
75
69
76
74
186–187
121–123
121–122
139–141
151–153
102–105
79–80
59.58
[59.54]
52.58
[52.61]
72.17
[72.18]
77.17
[77.19]
70.19
[70.12]
72.79
[72.86]
60.91
[60.87]
61.98
[62.07]
60.88
5.38
[5.34]
4.34
[4.38]
5.30
[5.26]
5.30
[5.26]
4.50
[4.52]
5.69
[5.71]
5.83
[5.80]
6.19
[6.21]
5.78
10.72
[10.69]
9.38
[9.44]
10.54
[10.53]
8.14
[8.18]
7.41
[7.44]
9.95
[10.00]
10.11
[10.14]
9.69
[9.66]
10.09
[10.14]
10.17
[10.14]
3
4
5
6
7
8
18l
1l
123–125
79–80
9
18m
18n
1m
1n
[60.87]
60.89
[60.87]
[5.80]
5.83
[5.80]
10
146–147
Table 3(b) Spectroscopic data for the oximes 10, 17 and 18
Entry no. Compound no. δH
δC
ν/cmϪ1
1
10a
10.30 (1H, s, NH), 8.47 (1H, d, ArH, J 8.63), 165.05 (NHCO), 162.01 (CO2Et), 151.03 3249.6 (OH),
7.99 (1H, s, CH᎐N), 7.49 (2H, m, ArH), 7.29 (CH᎐N), 139.32 (C-2), 134.36 (C-1), 124.99, 1719 (CO2Et),
121.77 and 133.03 (Ar), 135.37 (CH᎐CH- 1667.1 (NHCO),
᎐
᎐
(1H, m, ArH), 7.14 (1H, d, CH᎐CHCO2Et, J
᎐
᎐
15.31), 6.94 (1H, d, CH᎐CHCO2Et, J 15.31),
CO2Et),
132.59
(CH᎐CHCO2Et),
61.5 1591.5 (C᎐N)
᎐
᎐
᎐
4.3 (2H, q, OCH2, J 7.20), 1.35 (3H, t,
CH2CH3, J 7.20)
(OCH2), 14.21 (CH2CH3)
2
10b
9.24 (1H, s, NH), 8.71 (1H, d, ArH, J 8.32),
165.49 (NHCO), 161.89 (CO2Et), 151.70 3200.2 (OH),
1715.8 (CO2Et),
121.77 and 120.56 (Ar), 137.77 (CH᎐CH- 1644.9 (NHCO),
8.17 (1H, s, CH᎐N), 7.18 (2H, m, ArH), 7.03 (CH᎐N), 139.79 (C-2), 135.28 (C-1), 130.75,
᎐
᎐
(1H, d, CH᎐CHCO2Et, J 15.31), 6.88 (1H, d,
᎐
᎐
CH᎐CHCO2Et, J 15.31), 4.26 (2H, q, OCH2, J CO2Et), 131.34 (CH᎐CHCO2Et), 61.48
1578.5 (C᎐N)
᎐
᎐
᎐
7.30), 1.33 (3H, t, CH2CH3, J 7.30)
(OCH2), 14.21 (CH2CH3)
3
4
5
10c
10d
10e
9.57 (1H, s, NH), 8.78 (1H, d, ArH, J 8.43),
165.52 (NHCO), 152.93 (CH᎐N), 142.32 (Ar),
137.89 (C-1), 134.41 (C-2), 132.03, 130.69,
129.98, 128.71, 127.99, 123.57, 121.75, 120.45
3221.0 (NH),
1665 (NHCO)
᎐
8.25 (1H, s, CH᎐N), 7.65 (1H, d, CH᎐CHPh, J
᎐
᎐
15.57), 7.34 (3H, m, ArH), 7.16 (5H, m, ArH),
6.47 (1H, d, CH᎐CHPh, J 15.57)
and 118.97 (Ar, CH᎐CH)
᎐
᎐
9.57 (1H, s, NH), 8.27 (15H, m, ArH,
164.32 (NHCO), 149.29 (CH᎐N), 142.32,
133.45, 132.89, 132.55, 132.48, 128.75, 127.43,
124.72, 121.63, 120.15 and 119.12 (Ar,
᎐
CH᎐CHPh), 6.57 (1H, d, CH᎐CHPh, J 15.57)
᎐
᎐
CH᎐CH)
᎐
9.49 (1H, s, NH), 7.92 (14H, m, ArH,
CH᎐CHPh), 6.55 (1H, d, CH᎐CHPh, J 15.57)
164.32 (NHCO), 149.29 (CH᎐N), 142.32,
134.25, 132.89, 132.78, 131.32, 126.92, 125.24,
124.99, 121.22, 119.99 and 118.22 (Ar-C,
᎐
᎐
᎐
CH᎐CH)
᎐
6
7
17k
17j
8.31 (1H, s, CH᎐N), 7.86 (1H, d, ArH, J 8.05), 171.31 (NMeCO), 151.26 (CH᎐N), 142.31
1643.3
᎐
᎐
7.65 (1H, d, CH᎐CHPh, J 15.53), 7.31 (8H, m,
(Ar), 136.27 (C-2), 135.26 (C-1), 130.21,
(NMeCO)
᎐
ArH), 6.18 (1H, d, CH᎐CHPh, J 5.53), 3.45 (s, 129.92, 127.07, 123.78, 121.99 and 117.83 (Ar,
᎐
3H, NCH3)
8.32 (1H, d, ArH, J 8.28), 8.12 (1H, s, CH᎐N),
CH᎐CH), 36.92 (NCH3)
᎐
165.32 (NMeCO), 163.07 (CO2Et), 150.19 3325.7 (OH),
(CH᎐N), 140.26 (C-1), 133.91 (C-2), 132.63, 1719.1 (CO2Et),
131.90, 129.16 and 128.17 (Ar), 137.57 1652.8 (NMeCO),
J 15.31), 4.21 (2H, q, OCH2, J 7.30), 3.43 (3H, (CH᎐CHCO2Et), 131.24 (CH᎐CHCO2Et), 1586.1 (C᎐N)
᎐
7.46 (3H, m, ArH), 6.92 (1H, d, CH᎐CH-
CO2Et, J 15.31), 6.73 (1H, d, CH᎐CHCO2Et,
᎐
᎐
᎐
᎐
᎐
᎐
s, NCH3), 1.33 (3H, t, CH2CH3, J 7.30)
61.36 (OCH2), 37.32 (NCH3), 14.28 (CH2CH3)
8
18l
11.02 (1H, s, NH), 8.92 (1H, s, CH᎐N), 7.42 165.29 (NHCO), 162.71 (CO2Et), 150.73 3267.2 (OH),
᎐
(1H, d, ArH, J 8.02), 7.28 (1H, d, ArH, J
(CH᎐N), 140.27 (C-2), 136.31 (C-1), 132.03,
1726.3 (CO2Et),
᎐
8.02), 7.02 (1H, d, CH᎐CHCO2Et, J 15.81), 127.13, 126.19 and 123.72 (Ar), 136.01 1649 (NHCO),
᎐
6.82 (1H, d, CH᎐CHCO2Et, J 15.81), 4.26
(CH᎐CHCO2Et), 129.61 (CH᎐CHCO2Et),
1595.3 (C᎐N)
᎐
᎐
᎐
᎐
(2H, q, OCH2, J 7.33), 2.36 (3H, s, CH3), 1.91
(3H, s, CH3), 1.33 (3H, t, CH2CH3, J 7.33)
61.37 (OCH2), 20.26 (CH3), 19.21 (CH3), 14.97
(CH2CH3)
9
18m
18n
8.99 (1H, s, NH), 8.25 (1H, s, CH᎐N), 7.25 166.03 (NHCO), 161.98 (CO2Et), 152.99
3353.4 (OH),
1715.6 (CO2Et),
᎐
(3H, m, ArH), 7.13 (1H, d, CH᎐CHCO2Et, J
(CH᎐N), 137.64 (C-2), 133.51 (C-1), 131.97
᎐
᎐
15.13), 6.96 (1H, d, CH᎐CHCO2Et, J 15.13),
(C-6), 131.01, 122.90 and 118.65 (Ar), 134.74 1638.8 (NHCO),
᎐
4.28 (2H, q, OCH2, J 7.32), 1.74 (3H, s, CH3),
1.34 (3H, t, CH2CH3, J 7.32)
(CH᎐CHCO2Et), 131.71 (CH᎐CHCO2Et),
1594.3 (C᎐N)
᎐
᎐
᎐
61.61 (OCH2), 18.61 (CH3), 14.13 (CH2CH3)
10
11.04 (1H, s, NH), 8.58 (1H, d, ArH, J 8.81), 165.90 (NHCO), 162.18 (CO2Et), 152.84
3244.0 (OH),
8.18 (1H, s, CH᎐N), 7.17 (1H, d, ArH, J 8.81),
(CH᎐N), 137.88 (C-2), 133.77 (C-1), 132.34
1714.7 (CO2Et),
1645.7 (NHCO),
᎐
᎐
7.04 (2H, m, ArH, CH᎐CHCO2Et), 6.87 (1H,
(C-3), 130.45, 120.47 and 118.97 (Ar), 134.80
᎐
d, CH᎐CHCO2Et, J 15.38), 4.23 (2H, q,
(CH᎐CHCO2Et), 131.32 (CH᎐CHCO2Et),
1593.4 (C᎐N)
᎐
᎐
᎐
᎐
OCH2, J 7.33), 2.32 (3H, s, CH3), 1.28 (3H, t, 61.43 (OCH2), 20.59 (CH3), 14.02 (CH2CH3)
CH2CH3, J 7.32)
J. Chem. Soc., Perkin Trans. 2, 1998
555

View Article Online
Table 4(a) Analytical data for the nitrones 3
Found (%) [requires (%)]
Entry no.
Compound no.
Substrate no.
Yield (%)
mp/ЊC
Molecular formula
C13H14N2O4
C
H
N
1
2
3a
3b
10a
10b
78
62
197–199
212–214
59.57
[59.54]
56.64
5.36
[5.34]
4.47
10.72
[10.69]
9.39
C13H13N2O4Cl
[56.62]
[4.42]
[9.44]
3
4
5
6
3f
3g
3h
3i
1f
1g
1h
1i
63
49
52
64
200–204
219–220
219–220
189–190
C19H18N2O4
C19H17N2O4Cl
C19H17N3O6
C14H16N2O4
67.49
[67.45]
61.23
[61.21]
59.49
[59.53]
60.89
[60.86]
5.37
[5.33]
4.62
[4.55]
4.48
[4.44]
5.87
[5.80]
8.28
[8.28]
7.49
[7.50]
19.93
[10.96]
10.14
[10.14]
Table 4(b) Spectroscopic data for the nitrones 3
Entry no. Compound no. δH
δC
ν/cmϪ1
1
3a
9.49 (1H, s, NH), 8.01 (1H, s, CH᎐N), 7.33 169.64 (NHCO), 165.91 (CO2Et), 149.45 3110.4 (NH),
᎐
(4H, m, ArH), 4.64 (1H, d, H-3, J 7.30 and
6.15), 4.13 (2H, q, OCH2, J 7.32), 3.56 (1H,
(CH᎐N), 139.47 (C-9a), 128.55 (C-5a), 127.52,
126.89, 123.25 and 121.51 (Ar), 65.48 (C-3),
1715.2 (CO2Et),
1683.4 (NHCO)
᎐
dd, CHCH2, J 7.30 and 17.81), 3.10 (1H, dd, 60.36 (OCH2), 30.59 (CHCH2), 14.01 (CH3)
CHCH2, J 6.15 and 17.81), 1.23 (3H, t, CH3, J
7.32)
2
3b
9.94 (1H, s, NH), 8.06 (1H, 5, CH᎐N), 7.41 170.32 (NHCO), 166.12 (CO2Et), 151.23 3121.4 (NH),
(3H, m, ArH), 4.68 (1H, dd, H-3, J 7.10 and (CH᎐N), 138.71 (C-9a), 129.01 (C-5a), 126.32,
᎐
1719.3 (CO2Et),
᎐
6.12), 4.17 (2H, q, OCH2, J 7.33), 3.61 (1H,
125.11 and 121.13 (Ar), 65.92 (C-3), 61.03 1691.3 (NHCO)
dd, CHCH2, J 7.10 and 16.94), 3.14 (1H, dd, (OCH2), 30.79 (CHCH2), 14.21 (CH3)
CHCH2, J 6.12 and 16.94), 1.24 (3H, t, CH3, J
7.33)
3
4
3f
10.11 (1H, s, NH), 7.35 (9H, m, ArH), 4.79
(1H, dd, H-3, J 8.57 and 5.50), 4.19 (2H, q, (CH᎐N), 133.47 (C-9a), 125.82 (C-5a), 136.51,
170.80 (NHCO), 166.63 (CO2Et), 143.66 3217.6 (NH),
1736.2 (C᎐N),
131.58, 130.94, 130.75, 129.67, 127.07, 124.81 1702.0 (CO2Et),
᎐
᎐
OCH2CH3, J 7.04), 3.74 (1H, dd, CHCH2, J
8.57 and 17.80), 3.10 (1H, dd, CHCH2, J 5.50
and 17.80), 1.28 (3H, t, CH3, J 7.04)
10.23 (1H, s, NH), 7.55 (2H, m, ArH), 7.31
(4H, m, ArH), 7.16 (1H, d, ArH, J 8.79), 7.07
(1H, s, ArH), 4.75 (1H, dd, H-3, J 8.29 and
and 121.77 (Ar), 66.28 (C-3), 61.03 (CHCH2),
30.66 (OCH2), 14.15 (OCH2CH3)
1654.4 (NHCO)
3g
170.56 (NHCO), 166.21 (CO2Et), 142.85
(CH᎐N), 143.05 (C-7), 132.73 (C-9a), 127.02
᎐
(C-5a), 135.02, 130.81, 130.71, 129.98, 129.13,
5.37), 4.18 (2H, q, OCH2CH3, J 7.33), 3.69 128.17 and 123.20 (Ar), 66.37 (C-3), 61.11
(1H, dd, CHCH2, J 8.29 and 17.56), 3.06 (1H, (CHCH2), 30.53 (OCH2), 14.08 (CH2CH3)
dd, CHCH2, J 5.37 and 17.56), 1.27 (3H, t,
CH3, J 7.33)
10.23 (1H, s, NH), 8.13 (1H, d, ArH, J, 9.27),
7.94 (1H, s, ArH), 7.58 (6H, m, ArH), 4.66
(1H, dd, H-3, J 8.78 and 5.37), 4.13 (2H, q, (C-5a), 140.97, 130.64, 130.58, 128.47, 125.77
OCH2CH3, J 7.32), 3.59 (1H, dd, CHCH2, J
8.78 and 17.56), 3.00 (1H, dd, CHCH2, J 5.37
and 17.56), 1.22 (3H, t, CH3, J 7.32)
10.15 (1H, s, NH), 7.46 (2H, m, ArH), 7.29
(2H, m, ArH), 4.66 (1H, dd, H-3, J 7.02 and (CH᎐N), 134.99 (C-9a), 125.94 (C-5a), 130.50,
5
6
3h
3i
170.30 (NHCO), 165.56 (CO2Et), 143.97 3218.0 (NH),
(CH᎐N), 143.05 (C-7), 132.35 (C-9a), 125.18
1743.2 (C᎐N),
1709.9 (CO2Et),
1548.7 (NHCO)
᎐
᎐
and 122.61 (Ar), 66.67 (C-3), 61.30 (CHCH2),
30.50 (OCH2), 14.11 (OCH2CH3)
170.74 (NHCO), 166.31 (CO2Et), 143.73 3321.6 (NH),
1742.0 (C᎐N),
᎐
᎐
7.02), 4.12 (2H, q, OCH2CH3, J 7.13), 3.58 128.60, 125.25 and 122.02 (Ar), 65.08 (C-3),
(1H, dd, CHCH2, J 7.02 and 17.80), 3.07 (1H, 60.97 (CHCH2), 30.59 (OCH2), 30.40 (CH3),
dd, CHCH2, J 7.02 and 17.80), 2.57 (3H, s, 14.02 (OCH2CH3)
CH3), 1.23 (3H, t, CH3, J 7.13)
1724.9 (CO2Et),
1683.4 (NHCO)
formation of the corresponding isoxazoloquinolinone. The
yields of the new tricycles was in the range 31–32%, both
gave satisfactory micro analytical and spectroscopic data,
see Table 5(a) and (b), entries 3 and 4. Alternatively the
tricyclic adducts 5f,h can be formed on heating the correspond-
ing benzodiazepinone N-oxides 3f,h in ethanolic pyridine
at 80 ЊC.
cm3). The organic layer was dried and the dichloromethane was
removed yielding the crude product, which was purified by crys-
tallisation from diethyl ether–light petroleum. The adduct 5j
was obtained in 53% yield, mp 102–105 ЊC, Table 5(a) and (b),
entry 5.
Preparationoftheoxime17j;ethyl3-{N-[2-(hydroxyiminomethyl)-
phenyl]-N-methylcarbamoyl}acrylate
Formation of the tricyclic adduct 5j; 3-ethoxycarbonyl-5-methyl-
1,3,3a,4,5,9b-hexahydroisoxazolo[4,3-c]quinolin-2-one
The aldehyde 1j (0.024 mol), hydroxylamine hydrochloride
(0.029 mol) and pyridine (0.029 mol) were stirred in anhydrous
ethanol (50 cm3) for 4 h at room temp. The ethanol was
removed under reduced pressure and the resulting solid was
dissolved in dichloromethane and washed with water (4 × 25
The aldehyde 1j (0.024 mol), hydroxylamine hydrochloride
(0.029 mol) and pyridine (0.029 mol) were stirred in anhydrous
ethanol (50 cm3) for 3 h at Ϫ25 ЊC. The ethanol was removed
under reduced pressure and the resulting solid was dissolved in
dichloromethane and washed with water (4 × 25 cm3). The
organic layer was dried and the dichloromethane removed
yielding the crude product, which was purified by crystallis-
556
J. Chem. Soc., Perkin Trans. 2, 1998

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Table 5(a) Analytical data for the isoxazoloquinolinones 5
Found (%) [requires (%)]
Entry no.
Compound no.
Substrate no.
Yield (%)
mp/ЊC
Molecular formula
C22H18N2O2
C
H
N
1
2
5d
5e
10d
10e
78
63
98–100
111–113
77.09
[77.16]
70.22
5.28
[5.30]
4.59
8.21
[8.19]
8.49
C22H17N2O2Cl
[70.19]
[4.56]
[8.51]
3
4
5f
3f
31
32
111–113
102–105
C19H18N2O4
C19H17N3O6
67.41
[67.45]
59.49
5.37
[5.33]
4.48
8.31
[8.28]
19.93
[10.97]
5h
3h
[59.53]
[4.45]
5
6
7
8
5j
1j
17k
1l
53
84
49
23
132–133
123–125
143–145
119–121
C14H16N2O4
C16H16N2O2
C15H18N2O4
C14H16N2O4
60.84
[60.87]
71.68
[71.64]
62.09
[62.07]
60.89
[60.87]
5.80
[5.80]
5.96
[5.97]
6.19
[6.21]
5.84
[5.80]
10.15
[10.14]
10.43
[10.45]
9.65
[9.66]
10.11
[10.14]
5k
5l
5n
1n
Table 5(b) Spectroscopic data for the isoxazoloquinolinones 5
Entry no. Compound no. δH
δC
ν/cmϪ1
1659.2 (NHCO)
1
5d
9.94 (1H, s, NH), 7.31 (9H, m, ArH), 7.04
(5H, m, ArH), 6.51 (1H, d, H-3, J 3.24), 4.52
(1H, d, H-2a, J 3.24)
165.81 (NHCO), 141.11 (Ar), 131.63 (C-9a),
131.01, 130.23, 129.69, 128.22, 125.11, 123.21,
122.22, 119.23 and 114.93 (Ar), 77.63 (C-3),
60.24, 56.36 (C-2a)
2
5e
10.11 (1H, s, NH), 7.63 (5H, m, ArH), 7.31
(4H, m, ArH), 7.11 (4H, m, ArH), 6.43 (1H, d,
H-3, J 3.12), 4.21 (1H, d, H-2a, J 3.12)
168.31 (NHCO), 139.6 (Ar), 131.29, 131.14,
130.66, 129.88, 129.01, 122.94, 123.61, 121.78
and 114.93 (Ar), 77.63 (C-3), 60.24, 56.36 (C-
2a)
3
4
5f
9.77 (1H, s, NH), 7.19 (9H, m, ArH), 6.4 (1H, 170.50 (NHCO), 168.05 (CO2Et), 139.95 (Ar),
d, H-3, J 3.30), 4.97 (1H, d, H-2a, J 3.30), 4.15 135.27 (C-9a), 127.52 (C-5b), 129.73, 128.86, 1719.3 (CO2Et),
(2H, q, OCH2, J 7.33), 1.22 (3H, t, OCH2CH3, 128.31, 126.33, 124.51 and 116.27 (Ar), 83.15 1654.7 (NHCO)
2193.6 (NH),
J 7.33)
(C-3), 71.69 (C-5a), 61.90 (OCH2), 59.69
(C-2a), 13.98 (CH2CH3)
5h
9.65 (1H, s, NH), 7.39 (7H, m, ArH), 6.93
171.03 (NHCO), 168.54 (CO2Et), 139.36 (Ar),
(1H, d, ArH, J 8.06), 6.36 (1H, d, H-3, J 3.13), 135.12 (C-9a), 126.99 (C-5b), 129.54, 128.21,
4.89 (1H, d, H-2a, J 3.13), 4.23 (2H, q, OCH2, 127.93, 124.87, 121.09 and 116.27 (Ar), 82.95
J 7.32), 1.27 (3H, t, CH2CH3, J 7.32)
(C-3), 71.31 (C-5a), 60.74 (OCH2), 59.32
(C-2a), 14.12 (CH2CH3)
5
5j
7.37 (1H, m, ArH), 7.12 (3H, m, ArH), 6.11
(1H, d, H-5, J 13.74), 4.78 (1H, d, H-3, J 8.79),
4.39 (1H, dd, H-5a, J 13.74 and 13.50), 4.20
(2H, q, OCH2, J 7.32), 3.39 (3H, s, NCH3),
3.23 (1H, dd, H-2a, J 8.79 and 13.50), 1.27
(3H, t, CH2CH3, J 7.32)
170.75 (NCH3CO), 166.08 (CO2Et), 140.43 (C-
9a), 123.01 (C-5b), 128.95, 123.65 and 115.89
(Ar), 77.10 (C-5a), 62.54 (C-3), 61.90 (OCH2),
57.70 (C-2a), 29.84 (NCH3), 14.31 (CH2CH3)
6
7
5k
5l
7.57 (1H, d, ArH, J 7.32), 7.29 (6H, m, ArH),
7.11 (1H, d, ArH, J 7.32), 7.07 (1H, d, ArH, J
8.80), 5.56 (1H, d, H-3, J 3.13), 4.64 (1H, d, and 114.93 (Ar), 77.57 (C-3), 60.24 (C-5a),
H-5a, J 13.23), 3.44 (4H, m, NCH3, H-2a)
8.20 (1H, s, NH), 7.21 (2H, m, ArH), 5.42
167.72 (NCH3CO), 140.4, 138.91 (CЈ), 131.24 1654.3
(C-9a), 130.21, 128.70, 128.07, 126.09, 123.48 (CONCH3)
55.96 (C-2a), 29.69 (NCH3)
170.11 (NHCO), 167.10 (CO2Et), 137.74,
3191.6 (NH),
(1H, d, H-3, J 2.93), 4.88 (1H, d, H-5a, J 7.32), 134.41, 131.64 and 125.39 (Ar), 120.79 (C-6),
1714.6 (CO2Et),
4.26 (2H, q, OCH2, J 7.33), 3.20 (1H, dd, H-2a, 113.83 (C-9), 82.72 (C-3), 65.32 (C-6), 58.34 1643.1 (NHCO)
J 7.32 and 2.93), 2.59 (3H, s, CH3), 2.42 (3H, s, (OCH2), 51.20 (C-2a), 18.84 (CH3), 16.78
CH3), 1.33 (3H, t, CH2CH3, J 7.33)
8.35 (1H, s, NH), 7.18 (3H, m, ArH), 5.39 170.34 (NHCO), 168.07 (CO2Et), 120.79 (C-6), 3213.6 (NH),
(1H, d, H-3, J 2.64), 4.89 (1H, d, H-5a, J 8.10),
4.14 (2H, q, OCH2, J 7.32), 3.18 (1H, dd, H-2a,
J 8.10 and 2.64), 2.34 (3H, s, CH3), 1.29 (3H, t,
CH2CH3, J 7.32)
(CH3), 14.25 (CH2CH3)
8
5n
136.24 (C-11a), 125.41 (C-5a), 134.22, 130.45
1724.8 (CO2Et),
and 123.12 (Ar), 80.43 (C-3), 63.92 (C-6), 59.26 1648.2 (NHCO)
(OCH2), 51.38 (C-2a), 19.23 (CH3), 14.18
(CH2CH3)
ation from diethyl ether–light petroleum. The adduct 17j
was obtained in 75% yield, mp 79–80 ЊC, Table 3(a) and (b),
entry 7.
chloride (0.029 mol) and pyridine (0.029 mol) were stirred
at room temp. in anhydrous ethanol (50 cm3) for 24 h. The
ethanol was removed under reduced pressure and the resulting
residue was dissolved in dichloromethane and washed with
water (4 × 25 cm3). The organic layer was dried and concen-
trated to yield the oxime, which was purified by crystallisation
from diethyl ether–light petroleum. The adduct 17k was
Preparation of the oxime 17k; N-[2-(hydroxyiminomethyl)-
phenyl]-N-methyl-2-phenylacrylamide
The carbonyl substrate 1k (0.024 mol), hydroxylamine hydro-
J. Chem. Soc., Perkin Trans. 2, 1998
557

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Table 6 Crystal data and structure refinement for 5j
Preparation of the oximes 18m,n; ethyl 3-[N-(2-hydroxy-
iminomethyl-6-methylphenyl)carbamoyl]acrylate and
ethyl 3-[N-(2-hydroxyiminomethyl-3-methylphenyl)carbamoyl]-
acrylate
Empirical formula
Formula weight
T/K
C14H16N2O4
276.29
293(2)
The methyl substituted aldehydes 1m,n (0.024 mol), hydroxyl-
amine hydrochloride (0.029 mol) and pyridine (0.029 mol) were
stirred at room temp. in anhydrous ethanol (50 cm3) for 16 h.
The ethanol was removed under reduced pressure and the
resulting residue was dissolved in dichloromethane and washed
with water (4 × 25 cm3). The organic layer was dried and the
dichloromethane removed. Purification was carried out by flash
chromatography (SiO2, diethyl ether). The yields of the new
adducts ranged from 74–76%, both gave satisfactory micro ana-
lytical and spectroscopic data, see Table 3(a) and (b), entries 9
and 10.
λ/Å
Crystal system
Space group
Unit cell dimensions
a/Å
b/Å
c/Å
α/Њ
β/Њ
0.71069
Triclinic
P1
¯
8.0540(10)
8.6674(8)
10.8779(7)
90.349(8)
104.700(9)
111.553(7)
678.97(11)
2
γ/Њ
V/Å3
Z
D calc./Mg mϪ3
Absorption coefficent/mmϪ1
F(000)
1.351
0.100
292
Formation of tricycle 5n; 3-ethoxycarbonyl-9-methyl-
1,3,3a,4,5,9b-hexahydroisoxazolo[4,3-c]quinolin-4-one
The methyl substituted aldehyde 1n (0.024 mol), hydroxylamine
hydrochloride (0.029 mol) and pyridine (0.029 mol) were heated
at reflux in anhydrous ethanol (50 cm3) for 12 h. The ethanol
was removed under reduced pressure and the resulting residue
was dissolved in dichloromethane and washed with water
(4 × 25 cm3). The organic layer was dried and the dichloro-
methane removed. Purification was carried out by flash
chromatography (SiO2, diethyl ether). The adduct 5n was
obtained in 23% yield, mp 119–121 ЊC, Table 5(a) and (b), entry
8.
Crystal size/mm
θ range for data collection/Њ
Index ranges
Reflections collected
Independent reflections
Reflections observed (>2σ)
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
0.49 × 0.35 × 0.22
2.54–27.97
0 р h р 9;0 р k р 10;Ϫ14 р l р 13
1520
1460 [R(int) = 0.0132]
1142
Full-matrix least-squares on F2
1460/0/183
1.194
R1 = 0.0443 wR2 = 0.1418
R1 = 0.0557 wR2 = 0.01497
Largest diff. peak and hole/e ÅϪ3 0.298 and Ϫ0.097
R indices; R1 = [Σ |Fo| Ϫ |Fc| ]/Σ|Fo| (based on F)
¹
wR2 = [[Σw(|Fo2 Ϫ Fc2|)2]/[Σw(Fo )2]]² (based on F2)
2
Crystal structure analysis of 5j (see Table 6)
w = 1/[(σFo)2 ϩ (0.1*P)2]
The structure was solved by direct methods, SHELXS-86,15 and
refined by full-matrix least-squares using SHELXL-93.16
SHELX operations were rendered paperless using ORTEX
which was also used to obtain the drawings.17 Data were cor-
rected for Lorentz and polarisation effects but not for adsorp-
tion. The hydrogen atom on N-5 was not included, all other
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 Silicon
Graphics R4000 computer.
¹
Goodness-of-fit = [Σw(Fo2 Ϫ Fc2)2/(Nobs-Nparameters)]²
obtained in 76% yield, mp 102–105 ЊC, Table 3(a) and (b),
entry 6.
Preparation of the tricyclic adduct 5k; 3-phenyl-5-methyl-
1,3,3a,4,5,9b-hexahydroisoxazolo[4,3-c]quinolin-2-one
Aldoxime 17k (7.6 mmol) was heated at reflux (140 ЊC) in
xylene (10 cm3) for 12 h. The solvent was removed and the
resulting white solid crystallised from diethyl ether–light
petroleum, yielding the pure isoxazoloquinolinone. The tri-
cyclic adduct 5k was obtained in 84% yield, mp 123–125 ЊC,
Table 5(a) and (b), entry 6.
Acknowledgements
We acknowledge grant aid for postgraduate research (S. B.)
from Eolas and Mayo Co. Co. and support from the Chemistry
Department, University College, Galway.
Formation of the tricycle 5l; 3-ethoxycarbonyl-6,9-dimethyl-
1,3,3a,4,5,9b-hexahydroisoxazolo[4,3-c]quinolin-4-one
The 3,6-dimethyl substituted aldehyde 1l (0.024 mol), hydroxyl-
amine hydrochloride (0.029 mol) and pyridine (0.029 mol)
were heated at reflux (80 ЊC) in anhydrous ethanol (50 cm3) for
16 h. The ethanol was removed under reduced pressure and
the resulting residue was dissolved in dichloromethane and
washed with water (4 × 25 cm3). The organic layer was dried
and the dichloromethane removed. Purification was carried
out by flash chromatography (SiO2, diethyl ether), yielding the
pure tricyclic product in 49% yield, see Table 5(a) and (b),
entry 7.
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Preparation of the oxime 18l; ethyl 3-[N-(2-hydroxyimino-
methyl-3,6-dimethylphenyl)carbamoyl]acrylate
The 3,6-dimethyl substituted aldehyde 1l (0.024 mol), hydroxyl-
amine hydrochloride (0.029 mol) and pyridine (0.029 mol) were
stirred at room temp. in anhydrous ethanol (50 cm3) for 12 h.
The ethanol was removed under reduced pressure and the result-
ing residue was dissolved in dichloromethane and washed with
water (4 × 25 cm3). The organic layer was dried and the di-
chloromethane removed. Purification was carried out by flash
chromatography (SiO2, diethyl ether). The adduct 18l was
obtained in 69% yield, mp 123–125 ЊC, see Table 3(a) and (b),
entry 8.
558
J. Chem. Soc., Perkin Trans. 2, 1998

View Article Online
15 G. M. Sheldrick, Acta Crystallogr., Sect. A, 1990, 46, 467.
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13 The alcohols 6a–c were obtained by LiAlH4 reduction of
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Paper 7/08758I
Received 31st October 1997
Accepted 6th November 1997
14 G. Piancatelli, A. Scettri and M. D’Auria, Synthesis, 1982, 245.
J. Chem. Soc., Perkin Trans. 2, 1998
559