Evidence for the intermediacy of arylbenzylnitrenium ions in the thermal rearrangement of isoxazolidines derived from C,N-diarylnitrones and 2-morpholin-4-yl-acrylonitrile

Article abstract of DOI:10.1002/chem.200390102

In contrast to the diaryl, dialkyl, alkylaryl, and parent series, nothing is known about the generation and chemical behavior of arylbenzylnitrenium ions. Herein, we report that these species can be generated by a process involving an unprecedented therma

Full text of DOI:10.1002/chem.200390102

FULL PAPER
Evidence for the Intermediacy of Arylbenzylnitrenium Ions in the Thermal
Rearrangement of Isoxazolidines Derived from C,N-Diarylnitrones and
2-Morpholin-4-yl-acrylonitrile
Annie Liard,[a] Thi-Huu Nguyen,[a] Abdel Illah Djelloul Smir,[b] Michel Vaultier,[c]
AÔcha Derdour,[b] and Jacques Mortier*[a]
Abstract: In contrast to the diaryl, dialkyl, alkylaryl, and parent series, nothing is
known about the generation and chemical behavior of arylbenzylnitrenium ions.
Herein, we report that these species can be generated by a process involving an
unprecedented thermal rearrangement of isoxazolidines derived from C,N-diary-
lnitrones and 2-morpholin-4-yl-acrylonitrile. The products from these reactions are
dramatically dependent upon the nature of the nitrone. Most of the observed
chemistry originates from the singlet state.
Keywords: alkenes
alkenes ¥ electrophilic reactions ¥
nitrenium ions ¥ rearrangement
¥
captodative
bond.[1] It has also been shown that these esters generate
nitrenium ions in an aqueous environment.[2]
Introduction
Nitrenium ions are nitrogen-containing organic compounds in
which the nitrogen atom has an incomplete (sextet) electron
shell and a formal positive charge. Nitrenium ions can exist in
two electronic states, the singlet state, in which the electrons
are paired, and the triplet state, in which both nonbonding
orbitals are singly occupied
Generally speaking, nitrenium ions are formed by hetero-
À
lytic cleavage of an N X bond. The Bamberger rearrange-
ment (Scheme 2), which takes place on treatment of N-
phenylhydroxylamine with aqueous mineral acid to result in
(Scheme 1). As a rule, these
N
N
N X
N
species are extremely electro-
philic and their lifetimes in
solution are in the picosec-
ond-to-microsecond range.
It has been known for some
time that the mutagenicity and
triplet
singlet
Scheme 1. Singlet and triplet
states of nitrenium ions.
Cl
H
N O
Cl
Cl
N O P
H
Cl
Stieglitz rearrangement
Bamberger rearrangement
carcinogenicity of aromatic amines are attributable to their
arylhydroxylamine ester metabolites which generate aromat-
N
À
ic-substituted nitrenium ions upon heterolysis of the N O
N O SO2Ar
Hoffman
N O
CN
[a] Prof. Dr. J. Mortier, Dr. A. Liard, T.-H. Nguyen
this work
¬
Universite du Maine
Scheme 2. Bamberger and Stieglitz rearrangements as methods to form
nitrenium ions.
¬
¬
¬
Unite de chimie organique moleculaire et macromoleculaire
¬
UMR CNRS 6011, Faculte des sciences et techniques
avenue Olivier Messiaen
72085 Le Mans Cedex 9 (France)
Fax : (‡33)243-83-39-02
the formation of 4-aminophenol,[3, 4] the Stieglitz rearrange-
ment, which involves the reaction of a N-monoalkylhydroxyl-
amine with phosphorus pentachloride,[3b] and the solvolysis of
N-arylsulfonyloxyamines,[5] are only a few of the many types
of reactions in which the divalent electron-deficient nitrogen
serves as the crucial intermediate.
E-mail: jacques.mortier@univ-lemans.fr
[b] A. I. Djelloul Smir, Prof. A. Derdour
¬
¡
Universite d×Oran-Es-Senia, Laboratoire de synthese organique
Oran (Algeria)
[c] Dr. M. Vaultier
¬
¡
¬
¡
Universite Rennes-I, Synthese et electrosynthese organiques
UMR CNRS 6510, Campus de Beaulieu
35042 Rennes Cedex (France)
Nitrenium ions are generally produced in the singlet state
and consequently they must undergo an intersystem crossing
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1000 1007
(ISC) to the low-lying triplet state. Gassman and Cryberg
have reported ISC on 4,7,7-trimethyl-2-chloroazabicy-
clo[2.2.1]heptane with heavy atom solvents as catalysts.[6]
However, subsequent studies by other researchers who used
different leaving groups produced negative results. In addi-
tion, more recent experimental studies[7] have indicated the
possibility of stabilization of the singlet as a result of
electrostatic interactions with the solvents.
generation and chemical behavior of arylbenzylnitrenium
ions. Herein, we report that these species can be generated by
a process involving an unprecedented thermal rearrangement
of isoxazolidines derived from C,N-diarylnitrones and 2-mor-
pholin-4-yl-acrylonitrile. The products from these reactions
are dramatically dependent upon the nature of the nitrone.
‡
It is well-established that the parent nitrenium NH2 has a
singlet triplet splitting of 30 kcalmolÀ1 (a positive sign
Results and Discussion
corresponds to the triplet state being lower in energy).[8]
A
combination of experimental results and well-converged
quantum-mechanical studies indicates that alkyl and aromatic
substituents preferentially stabilize the singlet state in each
system; the stabilizations are roughly 20 and 50 kcalmolÀ1 for
a methyl and phenyl substituent, respectively;[9] however,
bulky substituents on the nitrogen atom or electron-deficient
p systems favor the triplet state.[10]
Theoretical calculations also agree that p-donor substitu-
ents on the phenyl ring attached to the nitrogen atom of
arylnitrenium ions further stabilize the singlet relative to the
triplet state. Likewise, p acceptors stabilize the triplet relative
to the singlet state.[10] Stabilization of the cationic charge in
nitrenium by p conjugation is so important that phenyl-
nitrenium ions have been found to exhibit substantial
quinoidal, that is, iminocyclohexadienyl cation-like, charac-
ter.[4c] The presence of a charge and a free orbital govern not
only the reactivity but also the strictly controlled interaction
pathway of these species. The reaction characteristics also
govern the nature of the resulting intermediate complexes and
reaction products.[4b]
We have examined the reactions of various C,N-diarylni-
trones 1a i with the captodative alkene 2[15] (Scheme 3).
Reactions were conducted on a 1 3mm scale of the reactants
(1:1 ratio), under the conditions given in Table 1. The solvent
was removed under reduced pressure and the residue was
purified by column chromatography on silica gel by elution
with heptane/ethyl acetate. Products 3 7 were obtained in
variable amounts depending on the conditions used.
The reaction of nitrone 1a (X ˆ OEt, Yˆ H) in toluene at
608C gave enaminone 3a as a main product along with 4a and
6a (Table 1, entry 1). In 4a, the EtO-substituted aryl ring
migrated to the nitrogen atom. At 808C (Table 1, entry 2), a
new product, 7a, was identified. Yield of 7a increased
dramatically with the temperature (runs at 908C and 1108C;
Table 1, entries 3 and 4 respectively). The formation of7a was
reduced or suppressed by addition of benzoquinone
(5 mol%), hydroquinone (5 mol%) and triphenylmethane
(1 equiv) in refluxing toluene (Table 1, entries 5 7). In the
presence of triphenylmethane and hydroquinone, the yield of
6a increased to 30% and 40%, respectively.
Within the past ten years, methods have been developed for
the direct study of arylnitrenium ions by laser flash photolysis
(LFP). The first reports from Falvey and co-workers involved
the photochemical ring-opening in acetonitrile of an anthra-
nilium salt.[11, 12] The LFP method made it possible to measure
the UV spectra of such short-lived (80 200 ns) species for the
first time.[13, 14]
Scheme 4 and Scheme 5 outline the probable reaction
pathways for the chemistry discussed so far. Since both
electron-rich and moderately electron-poor alkenes are
known to add unidirectionally to nitrones to yield 5-donor-
substituted (or 5-acceptor-substituted) isoxazolidines in a
concerted mechanism,[16] it is conceivable that 5-morpholino-
isoxazolidine-5-carbonitrile (8) is formed as an intermediate
in this process; however, it is unstable under the reaction
conditions and undergoes further transformation.[17]
In contrast to the (di)aryl, (di)alkyl, alkylaryl, and parent
series, to our knowledge, nothing is known about the
X
COMorph
X
COMorph
COMorph
N
N
N
CN
+
+
Y
OMe
X
Y
Y
Y
CN
3
4
5
N
O
+
Morph
COMorph
NH
CN
N
COMorph
X
1a-i
2
X
+
+
a X = OEt, Y = H
b X = H, Y = H
c X = Cl, Y = H
d X = NMe2, Y = H
e X = NO2, Y = H
Morph =
N
O
X
Y
Y
6
7
f
X = H, Y = CN
g X = H, Y = OMe
h X = OEt, Y = OMe
i
X = OEt, Y = CN
Scheme 3. Reactions of nitrones 1a i with captodative 2-morpholin-4-yl-acrylonitrile (2).
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1001

J. Mortier et al.
FULL PAPER
[a]
Table 1. Product distributions.
Entry
Nitrone
X
Y
Solvent
Co-reactant/
co-solvent
T
[8C]
t
3
4
5
6
7
2[b]
6/A[%][c]
[h]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1c
1d
1e
1f
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CN
CN
OMe
OMe
CN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
60
80
90
110
110
110
110
110
reflux
40
50
61
61
77
60
70
80
70
75
90
110
reflux
80
61
61
110
90
90
26
4
4
4
4
4
4
4
4
36
36
4
4
4
36
36
3
25
4
4
3
2
4
4
21
4
4
4
4
4
4
4
40
38
23
11
36
35
22
37
13
72
78
45
49
0
38
37
33
0
0
0
0
0
0
0
0
0
54
0
0
18
31
33
15
48
24
38
23
61
0
15
33
37
74
0
26
8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
94
0
0
0
0
0
0
0
0
14
14
12
7
15
40
30
14
25
0
0
6
27
65
2
28
10
5
1
0
0
0
0
1
28
7
16
1
19
17
18
21
15
40
33
19
25
0
0
7
13
26
0
17
13
100
100
100
100
6
100
100
100
100
26
benzoquinone[d]
hydroquinone[d]
triphenylmethane[e]
water 95:5 v/v
0
10
26
0
0
0
0
0
0
0
water 50:50 v/v
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
CHCl3
CHCl3
CHCl3
CCl4
0
6
triphenylmethane[e]
13
26
0
13
6
0
benzene
benzene
benzene
toluene
toluene
toluene
toluene
toluene
benzene
CHCl3
62
24
35
48
41
19
24
0
40
43
0
19
27
0
0
17
3
49
51
62
34
6
51
47
47
18
19
62
95
47
8
19
42
0
MeOH 50:50 v/v
9
10
53
62
0
0
0
CHCl3
0
0
0
0
0
0
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
NMe2
NO2
H
H
H
100
100
100
110
reflux
reflux
90
0
53
1f
MeOH 50:50 v/v
MeOH 50:50 v/v
0
0
1g
1h
1i
OEt
OEt
19
73
19
16
0
0
18
0
0
0
43
10
32
0
110
4
[a] Entries 3, 20, 25 28, 30, 32, and 33: yields of isolated product after purification by column chromatography on silica gel (see Experimental Section). In
other cases, the product distribution was determined by 1H NMR spectroscopy. [b] Unreacted alkene 2. [c] A ˆ 3 ‡ 4 ‡ 5 ‡ 6. [d] 5mol%. [e] One
equivalent.
An attractive rationale for the formation of 3, 4, and 6
would involve initial heterolytic cleavage of the N O bond of
8 (path A, Scheme 4) leading to a nitrenium ion 11 (or more
expected to resemble a nitrogen cation radical in its chemical
reactivity. In the presence of a hydrogen source, such as H2O
in toluene or on glassware, 11 should convert into a cation
3
‡
correctly: ion pair of nitrenium ion 11 CNÀ). Spin conserva-
radical, which could in turn react with a second hydrogen
radical to give the ammonium 12 and then 6 by loss of HCN.
The formation of 6 would be the result of a net two-electron
reduction of the triplet-state nitrenium ion.
Compound 7 is probably formed by the mechanism
presented in Scheme 5 (path B). 4-Isoxazoline (14) most
reasonably arises from loss of hydrogen cyanide by the
unstable isoxazolidine 8 above 908C. Because the formation
of 7 is suppressed by addition of radical inhibitors, the
reaction presumably proceeds by homolytic cleavage of the
tion requires that the first-formed ion is a singlet. Singlet
nitrenium ions having both a nonbonding pair of electrons
and an empty orbital, behave as Lewis acids or Lewis bases
and generally rapidly react with nucleophiles.[4] In this study,
1
the strongly electrophilic singlet nitrenium 11 presumably
reacts with the EtO-substituted aryl ring to give either the
strained aziridine 9 by intramolecular cyclization (SE) or the
iminium salt 10 by migration of the EtO-substituted aryl ring
to the nitrenium center. The stable enone 3 could arise from
the deprotonation of 9 by cyanide ions, followed by ring
opening and rearomatization. Hydrocyanation of 3 would
then lead to 4. Alternatively, reaction of the iminium 10 with
cyanide could afford 4 directly and then 3 by loss of hydrogen
cyanide.[18]
À
N O bond affording a biradical 15 that would cyclize at the
carbon atom to yield aziridine 16.[20, 21] N-Arylaziridines, 16,
are thermally unstable and afford azomethine ylide 17.[22]
Product 7 would then result from the addition of hydrogen
cyanide to 17. These mechanisms were confirmed by addi-
tional experiments (vide infra).
The conversion of isoxazolidine 8 into the amine 6 could
follow either of two routes. One path would involve a hydride
abstraction from the solvent by the singlet state 111 to yield 6
directly.[19] Alternatively, if this singlet has a sufficient lifetime
and if spin inversion would decrease the energy of the system,
In the first four entries of Table 1, the ratio 6/A (A ˆ 3 ‡ 4
‡ 5 ‡ 6) does not greatly vary in the temperature range of
60 1108C (17 ! 21%) or when benzoquinone is added
(Table 1, entry 5). This ratio notably increases on addition of
hydroquinone or triphenylmethane (40% and 33%, respec-
1
3
singlet 11 should convert to triplet 11. The triplet would be
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Arylbenzylnitrenium Ions
1000 1007
Scheme 4. Thermal rearrangement of isoxazolidines derived from C,N-diarylnitrones (1a i) and 2-morpholin-4-yl-acrylonitrile (2).
tively) whereas the formation of 7 is inhibited. These
observations are consistent with a radical mechanism for the
formation of 7 (Scheme 5). Because the yield of 6 is not
reduced by addition of hydroquinone or triphenylmethane
but increased instead, it is assumed that 6 is not formed via the
3
triplet nitrenium 11 but more likely by hydride abstraction
from the solvent by the singlet
state 11.[23]
1
Morph
Morph
Morph
The product distribution is
only slightly modified by addi-
tion of a small amount of water
(5% v/v) (Table 1, entry 8). It is
worthy of note that the forma-
CN
Homolytic
cleavage
O
O
O
Path B
–HCN
N
N
N
X
X
X
Y
Y
Y
tion of 7a is suppressed when
the reaction is carried out in a
14
8
15
refluxing biphasic mixture of
toluene/water (50:50, Table 1,
entry 9). If nitrenium ions are
involved in these reactions, they
have sufficient lifetimes in
aqueous solution to be viable
intermediates.
X
CN
4e
N
COMorph
COMorph
N
COMorph
HCN
N
X
X
Y
Y
Y
At 408C in chloroform, the
reaction of 1a with the capto-
dative alkene 2 gave 3a exclu-
17
7
16
À
Scheme 5. Thermally induced homolytic cleavage of the N O bond of 4-isoxazolines.
Chem. Eur. J. 2003, 9, No. 4
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1003

J. Mortier et al.
FULL PAPER
sively (Table 1, entry 10). Upon warming to 508C, 3a and
4a–resulting from the intramolecular reaction of the singlet
nitrenium 11a–were produced (Table 1, entry 11); at 618C,
products 3i and 4i resulting from the rearrangement of the
singlet nitrenium, whereas 6i and 7i were not formed
1
À
(Table 1, entry 33). In the intermediate 14i, the N O bond
a small amount of 6a (6%) was also formed (Table 1,
entry 12). The yield of 6a increased by addition of 1 equiv
of triphenylmethane at 618C (Table 1, entry 13). Because
chloroform is not a good hydrogen donor and the concen-
tration of residual water is lower in chloroform than in
toluene, 6a is not produced in higher amounts under these
conditions. Compound 7a is not formed when the reaction is
carried out in refluxing chloroform, probably because the
temperature is not high enough to undergo HCN elimination.
In carbon tetrachloride, 4a and 6a are formed exclusively
(Table 1, entry 14). Although the conversion is slow in
benzene, the product distribution is similar to that observed
in toluene (Table 1, entries 15 17).
is strengthened when an electron-withdrawing substituent Y is
connected to the phenyl group.
In conclusion, it can be stated that all the experimental
information on the arylbenzylnitrenium ion 11 can be
explained by assuming that it has a singlet ground state and
that all of its presently known chemical reactions occur from
that state. These results corroborate the theoretical literature
which predicts singlet ground states for arylnitrenium ions.
Our failure to detect triplet nitrenium ions could be the result
of this structural feature. Arylnitrenium ions and arylbenzyl-
nitrenium ions display a similar chemical behavior. The main
difference observed is the capacity of the latter to undergo
aryl migration.
With the nitrone 1b (X ˆ Yˆ H) at 708C, 6b was formed
almost exclusively (Table 1, entry 18). Higher amounts of 6b
were obtained at 908C (Table 1, entry 20). Above 908C, the
formation of 7b became predominant: as previously ob-
served, the higher the temperature, the higher the yield of 7b
(Table 1, entries 18 21). Clearly, migration of the X-substi-
tuted aryl ring to the nitrenium center leading to 3 and 4 is not
observed because the donating effect of X (H) is not
sufficient. Similar product distributions were observed when
the reaction was carried out in refluxing benzene or chloro-
form (Table 1, entries 23 and 24). An increase of the reaction
time improved only the yield of 7b (Table 1, entry 25).
Theoretical calculations agree that p-donor substituents on
the phenyl ring directly attached to the nitrenium (i.e. Y)
further stabilize the singlet with respect to the triplet.[8, 24]
Recent experimental evidence suggests that one phenylnitre-
nium ion substituted with strong p-acceptor groups has a
triplet ground state.[25] In the case of nitrone 1b (X ˆ Yˆ H),
when methanol was added to toluene (50% v/v), 13b was
Experimental Section
All operations were performed in an atmosphere of dry nitrogen.
Commercially available reagents and solvents were purified and dried,
when necessary, by standard methods just prior to use. All melting points
are uncorrected. 1H and 13C NMR spectra were recorded in CDCl3.
Chemical shifts are reported downfield from TMS, which was used as the
internal reference. Ratios in mixtures were calculated from 1H NMR
scpectroscopy. Elemental analyses were obtained from the Service de
microanalyse, CNRS ICSN, Gif-sur-Yvette (France). High-resolution mass
¬
measurements were performed at the Centre regional de mesures
physiques de l×Ouest, Rennes (France).
Preparation of diarylnitrones 1a i: The (Z)-a-aryl-N-phenyl nitrones
were prepared by the reaction of suitably substituted benzaldehyde with
phenylhydroxylamine in ethanol; their physical constants have already
been reported.[27] The (Z)-a-phenyl-N-aryl nitrones were prepared by
condensation of suitably substituted phenylhydroxylamine with benzalde-
hyde. The purity of all compounds was checked by melting point
determinations and H NMR.[28]
1
[26]
formed almost quantitatively (Table 1, entry 22). It seems
General procedure: A solution of N-arylhydroxylamine (50 mmol) and
aldehyde (50 mmol) in ethanol (50 mL) was stirred overnight at 208C. The
mixture was then cooled to 08C, collected by filtration, and recrystallized.
reasonable to assume that product 13b is derived from the
addition of methanol to the para position of the ring of the
singlet nitrenium 11b followed by a net 1,5-hydrogen shift
(Scheme 4). The isomer resulting from the addition of the
ortho position of the ring was not detected.
1
a-(4-Ethoxyphenyl)-N-phenylnitrone (1a): Yield: 97%; white solid; m.p.
138 1398C (ethyl acetate); 1H NMR (400 MHz): d ˆ 1.45 (t, J(H,H) ˆ
7.0 Hz, 3H; OCH2CH3), 4.11 (q, J(H,H) ˆ 7.0 Hz, 2H; OCH2CH3), 6.98 (d,
J(H,H) ˆ 9 Hz, 2H; Ar), 7.45 7.50 (m, 3H; Ar), 7.76 7.78 (m, 2H; Ar),
Consistent with our previous observations, nitrone 1c (X ˆ
Cl, Yˆ H) when reacted in toluene at 1108C (Table 1,
entry 26) afforded 6c and 7c exclusively, whereas the nitrone
1d (X ˆ NMe2, Yˆ H) gave 3d and 6d. The nitrone 1e (X ˆ
NO2, Yˆ H) when treated with alkene 2 in toluene at 908C,
yielded 6e as a unique product (Table 1, entry 28).
Compound 6 f was obtained almost quantitatively (95%,
Table 1, entry 29) when nitrone 1 f (X ˆ H, Yˆ CN) was
reacted in toluene at 1108C. The addition of methanol
(Table 1, entry 30) reduced the yield of 6 f; however, it did
not modify the product distribution. The reaction of 1g (X ˆ
H, Yˆ OMe) only led to degradation products (Table 1,
entry 31).
Nitrone 1h contains electron-donating substituents on both
aromatic rings (X ˆ OEt, Yˆ OMe). At 908C in toluene,
products 3h, 4h, and 6h were formed in similar yields, while
5h and 7h were not detected (Table 1, entry 32). At 1108C in
toluene, nitrone 1i (X ˆ OEt, Yˆ CN) led exclusively to
7.85 (s, 1H; C HN), 8.93 ppm (d, 2H; J(H,H) ˆ 9.0 Hz, Ar); 13C NMR
ˆ
(100 MHz): d ˆ 14.7, 63.6, 114.7, 121.6, 123.6, 129.1, 129.6, 131.2, 134.2,
148.9, 160.9 ppm.
a-Phenyl-N-phenylnitrone (1b): Yield: 85%; white solid; m.p. 110
110.58C (ethanol); 1H NMR (400 MHz): d ˆ 7.46 7.51 (m, 6H; Ar),
ˆ
7.76 7.79 (m, 2H; Ar), 7.93 (s, 1H; CH N), 8.03 8.42 ppm (m, 2H; Ar);
13C NMR (100 MHz): d ˆ 120.9, 127.8, 128.1, 129.1, 130.1, 133.8, 148.3 ppm.
a-(4-Chlorophenyl)-N-phenylnitrone (1c): Yield: 94%; white solid; m.p.
1
154.5 1558C (ethanol); H NMR (400 MHz): d ˆ 7.43 7.52 (m, 5H; Ar),
ˆ
7.74 7.78 (m, 2H; Ar), 7.91 (s, 1H; CH N), 8.36 ppm (d, J(H,H) ˆ 8.7 Hz,
2H; Ar); 13C NMR (100 MHz): d ˆ 121.7, 128.9, 129.2, 130.1, 133.3, 136.3,
148.7 ppm.
a-(4-Dimethylaminophenyl)-N-phenylnitrone (1d): Yield: 97%; white
solid; m.p. 131 1328C (ethyl acetate); 1H NMR (80 MHz): d ˆ 3.05 (s,
6H; N(CH3)2), 6.76 6.85 (m, 2H), 7.48 7.53 (m, 3H; Ar), 7.89 7.98 (m,
ˆ
2H), 8.18 ppm (s, 1H; CH N).
a-(4-Nitrophenyl)-N-phenylnitrone (1e): Yield: 97%; white solid; m.p.
191 1928C (ethanol); 1H NMR (80 MHz): d ˆ 7.50 7.54 (m, 3H; Ar),
ˆ
7.76 7.81 (m, 2H; Ar), 8.08 (s, 1H; CH N), 8.29 8.33 (m, 2H; Ar), 8.52
8.58 ppm (m, 3H; Ar).
1004
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2003, 9, No. 4

Arylbenzylnitrenium Ions
1000 1007
a-Phenyl-N-(4-cyanophenyl)nitrone (1 f): Yield: 86%; yellow solid; m.p.
155.5 1568C (ethanol) (lit. [27] 161 1628C); 1H NMR (400 MHz): d ˆ
7.49 (m, 3H; Ar), 7.78 (d, J(H,H) ˆ 8.9 Hz, 2H; Ar), 7.92 (d, J(H,H) ˆ
Ar); 13C NMR (100 MHz): d ˆ 42.2, 45.5, 52.3, 57.7, 66.4, 116.6, 119.4, 122.9,
129.2, 129.4, 131.4, 135.3, 146.7, 166.9 ppm; elemental analysis calcd. for
C22H25N3O3 (M ˆ 379.45 gmolÀ1): C 69.64, H 6.64, N 11.07; found: C 69.37,
H 6.49, N 11.00.
8.9 Hz, 2H; Ar), 8.05 (s, 1H; CH CN), 8.4 ppm (m, 2H; Ar); 13C NMR
ˆ
(100 MHz): d ˆ 113.5, 117.2 123.4, 128.0, 128.2, 129.8, 132.1, 133.9, 135.8,
1-Morpholin-4-yl-3-phenyl-3-phenylaminopropan-1-one (6b) and [(2-mor-
pholin-4-yl-2-oxo-ethyl)phenylamino]phenyl-acetonitrile (7b): Nitrone 1b
(197 mg, 1 mmol) and alkene 2 (138 mg, 1 mmol) were heated in toluene
(1 mL) at 908C for 4 h. Evaporation of the solvent followed by column
chromatography (cyclohexane/ethyl acetate: 65:35 ! 50:50) afforded 6b
(192 mg, 62%) and 7b (64 mg, 19%).
152.9 ppm.
a-Phenyl-N-(4-methoxyphenyl)nitrone (1g): Yield: 65%; brown solid;
m.p. 116 116.58C (ethanol); 1H NMR (400 MHz): d ˆ 3.87 (s, 3H; OCH3),
6.95 (d, J(H,H) ˆ 9.4 Hz, 2H; Ar), 7.48 (m, 3H; Ar), 7.78 (d, J(H,H) ˆ
ˆ
9.4 Hz, 2H; Ar), 7.90 (s, 1H; C NH), 8.41 ppm (m, 2H; Ar).
a-(4-Ethoxyphenyl)-N-(4-methoxyphenyl)nitrone (1h): Yield: 71%;
brown solid; m.p. 105 105.58C (ethanol); 1H NMR (400 MHz): d ˆ 1.45
(t, J(H,H) ˆ 7 Hz, 3H; OCH2CH3), 3.74 (s, 3H; OCH3), 4.12 (q, J(H,H) ˆ
7 Hz, 2H; OCH2CH3), 6.98 (m, 4H; Ar), 7.78 (m, 2H; Ar), 7.91 (m, 1H;
Ar), 8.25 ppm (m, 2H; Ar).
6b: Beige crystals (dichloromethane/diethyl ether); m.p. 142 1438C;
1H NMR (400 MHz): d ˆ 2.81 (dd, J(H,H) ˆ 14.4 Hz, J(H,H) ˆ 6.4 Hz, 1H;
ˆ
ˆ
CHHC O), 2.90 (dd, J(H,H) ˆ 14.4 Hz, J(H,H) ˆ 6.4 Hz, 1H; CHHC O),
3.08 3.25 (m, 3H; morph), 3.31 3.39 (m, 1H; morph), 3.44 3.63 (m, 4H;
ˆ
morph), 4.79 (t, J(H,H) ˆ 6.4 Hz, 1H; CHCH2C 0), 6.53 (d, J(H,H) ˆ
7.2 Hz, 2H; Ar), 6.64 (t, J(H,H) ˆ 7.2 Hz, 1H; Ar), 7.08 (t, J(H,H) ˆ
7.2 Hz, 2H; Ar), 7.22 7.42 ppm (m, 5H; Ar); 13C NMR (100 MHz): d ˆ
36.5, 42.3, 45.6, 54.5, 66.3, 66.7, 121.2, 129.3, 133.1, 147.0 ppm; elemental
analysis calcd (%) for C19H22N2O2 (M ˆ 310.39 gmolÀ1): C 73.52, H 7.14, N
9.03; found: C 73.22, H 7.15, N 9.08; high-resolution MS: m/z calculated for
C19H22N2O2: 310.16813; found 310.1704 (7 ppm).
a-(4-Ethoxyphenyl)-N-(4-cyanophenyl)nitrone (1i): Yield: 52%; yellow
solid; m.p. 164.5 1658C (ethanol); 1H NMR (400 MHz): d ˆ 1.45 (t,
J(H,H) ˆ 7 Hz, 3H; OCH2CH3), 4.18 (q, J(H,H) ˆ 7Hz, 2H; OCH2CH3),
6.98 (d, J(H,H) ˆ 8.6 Hz, 2H; Ar), 7.79 (d, J(H,H) ˆ 8.6 Hz, 2H; Ar), 7.89
ˆ
(d, J(H,H) ˆ 9.4 Hz, 2H; Ar), 7.91 (s, 1H; CH CN), 8.42 ppm (d, J(H,H) ˆ
9.4 Hz, 2H; Ar).
7b: Beige crystals (dichloromethane/diethyl ether); m.p. 121 1228C;
1H NMR (400 MHz): d ˆ 3.30 3.38 (m, 2H; morph), 3.44 3.65 (m, 6H;
Reactions of nitrones (1a i) with 2-morpholin-4-yl-acrylonitrile (2).
3-[(4-Ethoxyphenyl)phenylamino]-1-morpholin-4-yl-propenone
(3a),
ˆ
morph), 3.94 (d, J(H,H) ˆ 16.0 Hz, 1H; CHHC O), 4.08 (d, J(H,H) ˆ
2[(4-ethoxyphenyl)phenylamino]-4-morpholin-4-yl-4-oxobutyronitrile (4a),
3-(4-ethoxyphenyl)-1-morpholin-4-yl-3-phenylaminopropan-1-one (6a),
and 4-ethoxyphenyl-[(2-morpholin-4-yl-2-oxo-ethyl)phenylamino]acetoni-
trile (7a): Nitrone 1a (482 mg, 2 mmol) and alkene 2 (276 mg, 2 mmol)
were heated in toluene (2 mL) at 908C for 4 h. Evaporation of the solvent
followed by column chromatography (cyclohexane/ethyl acetate: 75:25 !
50:50) afforded 3a (162 mg, 23%), 4a (250 mg, 33%), 6a (85 mg, 12%),
and 7a (205 mg, 27%).
ˆ
16.0 Hz, 1H; CHHC O), 5.79 (s, 1H; CH-CN), 6.97 7.03 (m, 3H; Ar),
7.25 7.31 (m, 2H; Ar), 7.38 7.44 (m, 3H; Ar), 7.56 7.60 ppm (m, 2H; Ar);
13C NMR (100 MHz): d ˆ 42.3, 45.6, 51.7, 58.6, 66.4, 66.9, 116.8, 122.8, 128.1,
129.1, 129.4, 132.7, 147.2, 167.1 ppm; elemental analysis calcd (%) for
C20H21N3O2 (M ˆ 335 gmolÀ1): C 71.62, H 6.31, N 12.53; found: C 71.80, H
6.30,
N 12.50; high-resolution MS: m/z calculated for C20H21N3O2:
335.16338; found 335.1632 (0 ppm).
3a: Yellow oil; 1H NMR (400 MHz): d ˆ 1.42 (t, J(H,H) ˆ 6.8 Hz, 3H;
3-(4-Methoxyphenylamino)-1-morpholin-4-yl-3-phenylpropan-1-one
(13b): Nitrone 1b (591 mg, 3 mmol) and alkene 2 (414 mg, 3 mmol) were
heated in a refluxing mixture of toluene (1.5 mL) and methanol (1.5 mL)
for 4 h. Evaporation of the solvent followed by column chromatography
(cyclohexane/ethyl acetate: 66:33 ! 50:50) afforded 13b (960 mg, 94%).
Brown crystals (dichloromethane/diethyl ether); m.p. 123 1248C;
1H NMR (400 MHz): d ˆ 2.80 (dd, J(H,H) ˆ 14.0 Hz, J(H,H) ˆ 7.2 Hz,
OCH2CH3), 3.36 3.76 (m, 8H; morph), 4.05 (q, J(H,H) ˆ 6.8 Hz, 2H;
ˆ
OCH2CH3), 5.13 (d, J(H,H) ˆ 12.8 Hz, 1H; CH CH), 6.94 (d, J(H,H) ˆ
8.8 Hz, 2H; Ar), 7.01 7.10 (m, 5H; Ar), 7.29 (m, 2H; Ar), 8.23 ppm (d,
J(H,H) ˆ 12.8 Hz, 1H; CH CH); 13C NMR (100 MHz): d ˆ 15.1, 29.9, 63.9,
ˆ
67.1, 92.8, 115.8, 119.5, 121.4, 122.2, 124.3, 127.9, 129.6, 167.6 ppm; elemental
analysis calcd (%) for C21H24N2O3 (M ˆ 352.43 gmolÀ1): C 71.57, H 6.86, N
7.95; found: C 71.40, H 6.75, N 7.91; high-resolution MS: m/z calculated for
C21H24N2O3: 352.17869; found 352.1814.
ˆ
1H; CHHC O), 2.89 (dd, J(H,H) ˆ 14.0 Hz, J(H,H) ˆ 7.2 Hz, 1H;
ˆ
CHHC O), 3.12 3.88 (m, 4H; morph), 3.52 3.68 (m, 4H; morph), 3.69
(s, 3H; OCH3), 4.75 (t, J(H,H) ˆ 5.6 Hz, CHNH), 6.53 (d, J(H,H) ˆ 8.8 Hz,
2H; Ar), 6.69 (d, J(H,H) ˆ 8.8 Hz, 2H; Ar), 7.23 7.29 (m, 1H; Ar), 7.30
7.36 (m, 2H; Ar), 7.38 7.42 ppm (m, 2H; Ar); elemental analysis calcd (%)
for C20H24N2O3 (M ˆ 340.4 gmolÀ1): C 70.57, H 7.11, N 8.23; found: C 70.90,
H 7.08, N 8.24; high-resolution MS: m/z calculated for C20H24N2O3:
340.17869; found 340.1796 (2 ppm).
1
4a: White crystals (ethanol); m.p. 149 1508C; H NMR (400 MHz): d ˆ
1.45 (t, J(H,H) ˆ 6.8 Hz, 3H; OCH2CH3), 2.69 (dd, J(H,H) ˆ 16.0 Hz,
ˆ
J(H,H) ˆ 6.8 Hz, 1H; CHHC O), 2.88 (dd, J(H,H) ˆ 16.0 Hz, J(H,H) ˆ
ˆ
6.8 Hz, 1H; CHHC O), 3.14 3.29 (m, 2H; morph), 3.48 3.67 (m, 6H;
morph), 4.04 (q, J(H,H) ˆ 6.8 Hz, 2H; OCH2CH3), 5.47 (t, J(H,H) ˆ
6.8 Hz, 1H; CHCN), 6.82 7.26 (m, 5H; Ar), 6.93 (d, J(H,H) ˆ 8.8 Hz,
2H; Ar), 7.16 ppm (d, J(H,H) ˆ 8.8 Hz, 2H; Ar); 13C NMR (100 MHz): d ˆ
14.9, 35.5, 42.3, 45.7, 47.9, 63.8, 66.3, 66.7, 115.7, 117.7, 121.1, 129.3, 136.6,
147.4, 157.7, 166.2 ppm; elemental analysis calcd (%) for C22H25N3O3 (M ˆ
379.5 gmolÀ1): C 69.64, H 6.64, N 11.07; found: C 69.35, H 6.59, N 11.08;
high-resolution MS: m/z calculated for C22H25N3O3: 379.18959; found
379.1901.
3-(4-Chlorophenyl)-1-morpholin-4-yl-3-phenylaminopropan-1-one
(6c)
and (4-chlorophenyl)-[(2-morpholin-4-yl-2-oxoethyl)phenylamino]aceto-
nitrile (7c): Nitrone 1c (693 mg, 3 mmol) and alkene 2 (414 mg, 3 mmol)
were heated in toluene (3 mL) at 1108C for 4 h. Evaporation of the solvent
followed by column chromatography (cyclohexane/ethyl acetate: 65:35 !
50:50) afforded 6c (185 mg, 18%) and 7c (688 mg, 62%).
6a: Dark yellow crystals (ethanol); m.p. 156 1578C; 1H NMR (400 MHz):
d ˆ 1.40 (t, 3H; J(H,H) ˆ 6.8 Hz, OCH2CH3), 2.77 (dd, J(H,H) ˆ 14.4 Hz,
6c: Brown crystals (dichloromethane/diethyl ether); m.p. 123 1248C;
1H NMR (400 MHz): d ˆ 2.81 (dd, J(H,H) ˆ 14.4 Hz, J(H,H) ˆ 8.8 Hz, 1H;
ˆ
ˆ
ˆ
CHHC O), 2.87 (dd, J(H,H) ˆ 14.4 Hz, J(H,H) ˆ 7.6 Hz, 1H; CHHC O),
3.15 3.36 (m, 3H; H morph), 3.41 3.60 (m, 5H; morph), 4.77 (t, J(H,H) ˆ
7.6 Hz, 1H; CHNHAr), 6.50 (d, J(H,H) ˆ 7.2 Hz, 2H; Ar), 6.65 (t,
J(H,H) ˆ 7.2 Hz, 1H; Ar), 7.07 (dd, 2H; J(H,H) ˆ 7.2 Hz, J(H,H) ˆ 8 Hz;
Ar), 7.27 (d, J(H,H) ˆ 8 Hz, 2H; Ar), 7.33 ppm (d, J(H,H) ˆ 8 Hz, 2H; Ar);
13C NMR (100 MHz): d ˆ 39.8, 41.8, 46.3, 54.6, 66.3, 66.6, 113.6, 117.7, 127.8,
128.9, 129.2, 141.3, 146.7, 168.8 ppm; elemental analysis calcd (%) for
C19H21ClN2O2 (M ˆ 344.84 gmolÀ1): C 66.18, H 6.14, N 8.12; found: C 66.20,
H 6.15, N 8.18; high-resolution MS: m/z calculated for C19H21ClN2O2:
344.12916; found 344.1289.
J(H,H) ˆ 5.6 Hz, 1H; CHHC O), 2.87 (dd, J(H,H) ˆ 14.4 Hz, J(H,H) ˆ
ˆ
6.4 Hz, 1H; CHHC O), 3.12 3.18 (m, 3H; morph), 3.19 3.28 (m, 1H;
morph), 3.46 3.63 (m, 4H; morph), 3.98 (q, J(H,H) ˆ 6.8 Hz, 2H;
ˆ
OCH2CH3), 4.74 (t, J(H,H) ˆ 6.0 Hz, 1H; CHCH2C O), 6.53 (d,
J(H,H) ˆ 8.0 Hz, 2H; Ar), 6.63 (t, J(H,H) ˆ 7.2 Hz, 1H; Ar), 6.84 (d,
J(H,H) ˆ 8.4 Hz, 2H; Ar), 7.08 (dd, J(H,H) ˆ 7.2 Hz, J(H,H) ˆ 8 Hz, 2H;
Ar), 7.27 ppm (d, J(H,H) ˆ 8.4 Hz, 2H; Ar); 13C NMR (100 MHz): d ˆ 14.9,
40.0, 41.9, 46.4, 54.8, 63.5, 66.3, 66.7, 113.6, 114.8, 117.4, 127.4, 129.1, 147.0,
158.3, 134.4, 169.4 ppm; high-resolution MS: m/z calculated for
C21H26N2O3: 354.19434; found 354.1947 (0 ppm).
7a: Yellow oil (dichloromethane/diethyl ether); 1H NMR (400 MHz): d ˆ
7c: Yellow crystals (dichloromethane/diethyl ether); m.p. 139.5 1408C;
1H NMR (400 MHz): d ˆ 3.39 3.41 (m, 2H; morph), 3;56 3;72 (m, 6H;
1.42 (t, J(H,H) ˆ 6.8 Hz, 3H; OCH2CH3), 3.29 3.35 (m, 2H; morph),
ˆ
ˆ
3.44 3.67 (m, 6H; morph), 3.91 (d, J(H,H) ˆ 16.4 Hz, 1H; CHHC O),
morph), 3.96 (d, J(H,H) ˆ 16.4 Hz, 1H; CHHC O), 4.12 (d, J(H,H) ˆ
ˆ
ˆ
4.06 (d, J(H,H) ˆ 16.4 Hz, 1H; CHHC O), 4.06 (q, 2H; J(H,H) ˆ 6.8 Hz,
16.4 Hz, 1H; CHHC O), 5.77 (s, 1H; CHCN), 6.90 (d, J(H,H) ˆ 7.6 Hz,
OCH2CH3), 5.72 (s, 1H; CHCN), 6.90 (d, J(H,H) ˆ 8.8 Hz, 2H; Ar), 6.97
7.03 (m, 3H; Ar), 7.25 7.37 (m, 2H; Ar), 7.45 ppm (d, J(H,H) ˆ 8.8 Hz, 2H;
2H; Ar), 6.99 (t, J(H,H) ˆ 7.2 Hz, 1H; Ar), 7.25 (dd, J(H,H) ˆ 7.2 Hz,
J(H,H) ˆ 7.6 Hz, 2H; Ar), 7.35 (d, J(H,H) ˆ 8.4 Hz, 2H; Ar), 7.53 ppm (d,
Chem. Eur. J. 2003, 9, No. 4
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0904-1005 $ 20.00+.50/0
1005

J. Mortier et al.
FULL PAPER
J(H,H) ˆ 8.4 Hz, 2H; Ar); 13C NMR (100 MHz): d ˆ 41.2, 44.3, 51.2, 56.6,
65.3, 65.7, 118.3, 121.8, 128.0, 128.2 ppm; elemental analysis calcd (%) for
C20H20ClN3O2 (M ˆ 369.85 gmolÀ1): C 64.93, H 5.41, N 11.36; found: C
4h: Brown crystals (dichloromethane/diethyl ether); m.p. 75 75.58C;
1H NMR (400 MHz): d ˆ 1.39 (t, J(H,H) ˆ 6.8 Hz, 3H; OCH2CH3), 2.78
ˆ
(dd, J(H,H) ˆ 16.2 Hz, J(H,H) ˆ 6.7 Hz, 1H; CHHC O), 2.79 (dd,
ˆ
64.93,
H
5.37,
N
11.12; high-resolution MS: m/z calculated for
J(H,H) ˆ 16.2 Hz, J(H,H) ˆ 6.7 Hz, 1H; CHHC O), 3.31 (s, 3H; OCH3),
C20H20ClN3O2: 369.12440; found 369.1236.
3.21 3.69 (m, 8H; morph), 4.05 (q, J(H,H) ˆ 6.8 Hz, 2H; OCH2CH3), 5.42
(t, J(H,H) ˆ 6.7 Hz, 1H; CHCH2CO), 6.31 6.39 (m, 2H; Ar), 6.62 (d,
J(H,H) ˆ 9.2 Hz, 2H; Ar), 6.87 (d, J(H,H) ˆ 9.0 Hz, 2H; Ar), 7.11 (d,
J(H,H) ˆ 9.0 Hz, 2H; Ar), 7.29 ppm (d, J(H,H) ˆ 9.2 Hz, 2H; Ar); high-
resolution MS: m/e calculated for C23H27N3O4: 409.20016, found 409.1972.
3-[(4-Dimethylaminophenyl)phenylamino]-1-morpholin-4-yl-propenone
(3d) and 3-(4-dimethylaminophenyl)-1-morpholin-4-yl-3-phenylaminopro-
pan-1-one (6d): Nitrone 1d (271 mg, 1 mmol) and alkene 2 (138 mg,
1 mmol) were heated in toluene (1.5 mL) at 908C for 4 h. Evaporation of
the solvent followed by column chromatography (cyclohexane/ethyl
acetate: 65:35 ! 50:50) afforded 3d (190 mg, 54%) and 6d (67 mg, 19%).
6h: Brown crystals (dichloromethane/diethyl ether); m.p. 81 81.58C;
1H NMR (400 MHz): d ˆ 1.45 (t, J(H,H) ˆ 6.8 Hz, 3H; OCH2CH3), 2.75
ˆ
(dd, J(H,H) ˆ 14.4 Hz, J(H,H) ˆ 6.72 Hz, 1H; CHHC O), 2.86 (dd,
3d: Brown crystals (dichloromethane/diethyl ether); m.p. 62 658C;
ˆ
J(H,H) ˆ 14.4 Hz, J(H,H) ˆ 6.72 Hz, 1H; CHHC O), 3.21 3.67 (m, 8H;
1H NMR (400 MHz): d ˆ 2.12 (s, 6H; N(CH3)2), 3.38 3.65 (m, 8H;
morph), 3.69 (s, 1H; OCH3), 4.02 (q, J(H,H) ˆ 6.8 Hz, 2H; OCH2CH3),
4.67 (t, J(H,H) ˆ 6.72 Hz, 1H; CHCH2CO), 6.51 (d, J(H,H) ˆ 9.2 Hz, 2H;
Ar), 6.72 (m, 2H; Ar), 6.85 (m, 2H; Ar), 7.32 ppm (d, J(H,H) ˆ 9.2 Hz, 2H;
Ar); elemental analysis calcd (%) for C22H28N2O4 (M ˆ 384.5 gmolÀ1): C
69.73, H 7.34, N 7.29; found: C 69.35, H 7.35, N 7.39.
ˆ
morph), 5.13 (d, J(H,H) ˆ 12.8 Hz, 1H; CH CH), 6.78 6.81 (m, 2H; Ar),
7.25 7.32 (m, 2H; Ar), 7.48 7.55 (m, 5H; Ar), 8.24 ppm (d, J(H,H) ˆ
ˆ
12.8 Hz, 1H; CH CH).
6d: Brown crystals (dichloromethane/diethyl ether); m.p. 98 98.58C;
1H NMR (400 MHz): d ˆ 2.12 (s, 6H; N(CH3)2), 2.75 (dd, J(H,H) ˆ
3-[(4-Ethoxyphenyl)-(4-cyanophenyl)-amino]-1-morpholin-4-yl-prope-
none (3i) and 2[(4-ethoxyphenyl)-(4-cyanophenyl)-amino]-4-morpholin-4-
yl-4-oxo-butyronitrile (4i): Nitrone 1i (266 mg, 1 mmol) and alkene 2
(138 mg, 1 mmol) were heated in toluene (1.5 mL) at 1108C for 4 h.
Evaporation of the solvent followed by column chromatography (cyclo-
hexane/ethyl acetate: 70:30 ! 50:50) afforded 3i (276 mg, 73%) and 4i
(65 mg, 16%).
ˆ
14.4 Hz, J(H,H) ˆ 6.4 Hz, 1H; CHHC O), 2.87 (dd, J(H,H) ˆ 14.4 Hz,
ˆ
J(H,H) ˆ 6.4 Hz, 1H; CHHC O), 3.12 3.65 (m, 8H; morph), 4.73 (t,
J(H,H) ˆ 6.4 Hz, 1H; CHCH2CO), 6.53 (d, 2H; Ar), 6.64 6.84 (m, 5H;
Ar), 7.12 7.27 ppm (m, 2H; Ar).
3-(4-Nitrophenyl)-1-morpholin-4-yl-3-phenylaminopropan-1-one (6e): Ni-
trone 1e (727 mg, 3 mmol) and alkene 2 (414 mg, 3 mmol) were heated in
toluene (3 mL) at 908C for 4 h. Evaporation of the solvent followed by
column chromatography (cyclohexane/ethyl acetate 75:25) afforded 6e
(661 mg, 62%). White crystals (ethanol); m.p. 151 1528C; 1H NMR
(200 MHz): d ˆ 2.84 (dd, J(H,H) ˆ 15.2 Hz, J(H,H) ˆ 6.0 Hz, 1H;
3i: Yellow crystals (dichloromethane/diethyl ether); m.p. 174 174.58C;
1H NMR (400 MHz): d ˆ 1.48 (t, J(H,H) ˆ 7.0 Hz, 3H; OCH2CH3), 3.25
3.65 (m, 8H; morph), 4.08 (q, J(H,H) ˆ 7.0 Hz, 2H; OCH2CH3), 5.11 (d,
ˆ
J(H,H) ˆ 12.6 Hz, 1H; CH CH), 6.89 (d, J(H,H) ˆ 9.1 Hz, 2H; Ar), 6.98
ˆ
ˆ
CHHC O), 2.92 (dd, J(H,H) ˆ 15.2 Hz, J(H,H) ˆ 5.9 Hz, 1H; CHHC O),
3.24 3.38 (m, 2H; morph), 3.40 3.69 (m, 6H; morph), 4.75 (s, 1H; NH),
4.91 (t, J(H,H) ˆ 6 Hz, 1H; CHNHAr), 6.45 8.25 ppm (m, 9H); 13C NMR
(100 MHz): d ˆ 39.6, 41.9, 46.2, 54.7, 66.3, 66.7, 113.8, 118.3, 124.1, 127.5,
7.02 (m, 4H; Ar), 7.48 (d, J(H,H) ˆ 9.1 Hz, 2H; Ar), 8.28 ppm (d, J(H,H) ˆ
ˆ
12.6 Hz, 1H; CH CH); elemental analysis calcd (%) for C22H23N3O3 (M ˆ
377.4 gmolÀ1): C 70.01, H 6.14, N 11.13; found: C 70.30, H 6.14, N 11.05;
high-resolution MS: m/z calculated for C22H23N3O3: 377.17394; found
377.1761.
‡
129.3, 146.3, 150.0, 168.3 ppm; MS (IE) m/z: 355 [M] .
1
4-(3-Morpholin-4-yl-3-oxo-1-phenyl-propylamino)benzonitrile (6 f): Ni-
trone 1 f (666 mg, 3 mmol) and alkene 2 (414 mg, 3 mmol) were heated in
toluene (2.5 mL) at 1108C for 4 h. Evaporation of the solvent followed by
column chromatography (cyclohexane/ethyl acetate: 60:30 ! 50:50) af-
forded 6 f (474 mg, 47%) as a yellow oil. 1H NMR (400 MHz): d ˆ 2.79 (dd,
4i: Yellow oil (dichloromethane/diethyl ether); H NMR (400 MHz): d ˆ
1.45 (t, J(H,H) ˆ 7.0 Hz, 3H; OCH2CH3), 2.68 (dd, J(H,H) ˆ 16.2 Hz,
ˆ
J(H,H) ˆ 6.8 Hz, 1H; CHHC O), 2.79 (dd, J(H,H) ˆ 16.2 Hz, J(H,H) ˆ
ˆ
6.8 Hz, 1H; CHHC O), 3.14 3.67 (m, 8H; morph), 4.05 (q, J(H,H) ˆ
7.0 Hz, 2H; OCH2CH3), 5.12 (t, J(H,H) ˆ 6.8 Hz, 1H; CHCH2CO), 6.78 (d,
J(H,H) ˆ 9.0 Hz, 2H; Ar), 6.98 (d, J(H,H) ˆ 9.1 Hz, 2H; Ar), 7.18 (d,
J(H,H) ˆ 9.1 Hz, 2H; Ar), 7.49 ppm (d, J(H,H) ˆ 9.0 Hz, 2H; Ar); high-
resolution MS: m/z calculated for C23H24N4O3: 404.18484; found 404.1836.
ˆ
J(H,H) ˆ 14 Hz, J(H,H) ˆ 4.8 Hz, 1H; CHHC O), 2.87 (dd, J(H,H) ˆ
ˆ
14 Hz, J(H,H) ˆ 4.8 Hz, 1H; CHHC O), 3.01 3.04 (m, 1H; morph),
ˆ
3.15 3.64 (m, 7H; morph), 4.82 (t, J(H,H) ˆ 4.8 Hz, 1H; CH-CH2C O),
6.48 (d, J(H,H) ˆ 8.8 Hz, 2H; Ar), 6.56 (d, J(H,H) ˆ 8.8 Hz, 2H; Ar), 7.20
7.34 ppm (m, 5H; Ar); elemental analysis calcd (%) for C20H21N3O2 (M ˆ
335.40 gmolÀ1): C 71.62, H 6.31, N 12.53; found: C 71.55, H 6.35, N 12.40.
4[2-(Morpholin-4-carbonyl)-3-phenylaziridin-1-yl]-benzonitrile (16 f): Ni-
trone 1 f (222 mg, 1 mmol), alkene 2 (138 mg, 1 mmol) and triethylamine
(1 mL, 726 mg, 7.2 mmol) were heated in toluene (1 mL) at 1108C for 2 h.
Evaporation of the solvent followed by column chromatography (cyclo-
hexane/ethyl acetate 50:50) afforded 16 f (79 mg, 24%) as a yellow oil.
1H NMR (400 MHz): d ˆ 3.42 (d, J(H,H) ˆ 3.2 Hz, 1H), 3.51 3.85 (m, 8H;
morph), 3.94 (d, J(H,H) ˆ 3.2 Hz, 1H), 6.87 (d, J(H,H) ˆ 8.8 Hz, 2H; Ar),
7.30 7.39 (m, 5H; Ar), 7.48 ppm (d, J(H,H) ˆ 8.8 Hz, 2H; Ar); 13C NMR
(100 MHz): d ˆ 43.5, 45.3, 65.9, 66.0, 119.5, 125.7, 127.5, 127.9, 132.2; high-
resolution MS: m/z calculated for C20H19N3O2: 333.14773; found 333.1480.
Acknowledgements
¬
This work was supported by the CNRS, Universite du Maine, and Institut
universitaire de France. We thank Professor Daniel E. Falvey (University
of Maryland) for stimulating comments.
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none (3h), 2[(4-ethoxyphenyl)-(4-methoxyphenyl)-amino]-4-morpholin-4-
yl-4-oxobutyronitrile (4h), and 3-(4-ethoxyphenyl)-1-morpholin-4-yl-3-(4-
methoxyphenyl)aminopropan-1-one (6h): Nitrone 1h (271 mg, 1 mmol)
and alkene 2 (138 mg, 1 mmol) were heated in toluene (1.5 mL) at 908C for
4 h. Evaporation of the solvent followed by column chromatography
(cyclohexane/ethyl acetate: 70:30 ! 50:50) afforded 3h (73 mg, 19%), 4h
(78 mg, 19%), and 6h (69 mg, 18%).
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3h: Brown crystals (dichloromethane/diethyl ether); m.p. 64.5 658C;
1H NMR (400 MHz): d ˆ 1.41 (t, J(H,H) ˆ 6.8 Hz, 3H; OCH2CH3), 3.22
(m, 2H; morph), 3.36 (m, 2H; morph), 3.57 (m, 4H; morph), 3.68 (s, 3H;
OCH3), 3.98 (q, J(H,H) ˆ 6.8 Hz, 2H; OCH2CH3), 4.85 (s, 1H; CHCHCO),
5.91 (s, 1H; CHCHCO), 6.49 (m, 1H; Ar), 6.81 6.93 (m, 5H; Ar),
7.28 ppm (m, 2H; Ar); elemental analysis calcd (%) for C22H26N2O4 (M ˆ
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CN
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Ph
Ph
Ph3C
H
¬
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À
[20] Homolytic cleavage of the N O bond of 4-isoxazolines is well
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Received: May 16, 2002
Revised: October 25, 2002 [F4099]
Chem. Eur. J. 2003, 9, No. 4
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0947-6539/03/0904-1007 $ 20.00+.50/0
1007