ν-Triazolines. Part 42. Study on the reactivity of 4,5-dihydro-1-(6-methyl-2-oxo-2H-pyran-4-yl)-5-morpholino-ν-triazoles. Synthetic approach to pyrano[4,3-b]pyrrol-4(1H)-ones

Article abstract of DOI:10.1039/b008531f

Pyrolysis of 4-aryl-5-morpholino-4,5-dihydrotriazoles 3 affords two products: pyrano[4,3-b]pyrrol-4(1H)-ones 4 and arylacetamidines 5. The reaction mechanism of this transformation is discussed and reaction conditions optimized to enhance the formation of

Full text of DOI:10.1039/b008531f

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ꢀ-Triazolines. Part 42.1 Study on the reactivity of 4,5-dihydro-1-
(6-methyl-2-oxo-2H-pyran-4-yl)-5-morpholino-ꢀ-triazoles.
Synthetic approach to pyrano[4,3-b]pyrrol-4(1H)-ones
1
Emanuela Erba, Donato Pocar and Pasqualina Trimarco*
Istituto di Chimica Organica, Facoltà di Farmacia e Centro Interuniversitario di Ricerca
sulle Reazioni Pericicliche e Sintesi di Sistemi Etero e Carbociclici, Università di Milano,
Via Venezian 21, I-20133 Milano, Italy. E-mail: trimarco@mailserver.unimi.it
Received (in Cambridge, UK) 23rd October 2000, Accepted 29th May 2001
First published as an Advance Article on the web 28th June 2001
Pyrolysis of 4-aryl-5-morpholino-4,5-dihydrotriazoles 3 affords two products: pyrano[4,3-b]pyrrol-4(1H)-ones 4 and
arylacetamidines 5. The reaction mechanism of this transformation is discussed and reaction conditions optimized
to enhance the formation of pyrrole-fused pyran-2-one derivatives 4. 2-Aminoaziridines are considered to be key
intermediates in this transformation.
2H-Pyran-2-ones are of interest as synthons for organic syn-
thesis, particularly since many derivatives, isolated from natural
sources, exhibit remarkable biological properties.2 Renewed
interest comes from the discovery of a new type of non-peptidic
HIV-protease inhibitor containing this nucleus.3
In 2H-pyranones the C-3 position is nucleophilic, presenting
the characteristic reactivity of enols, and electrophiles react at
C-3 with conservation of the pyrone ring.4
Our research group has been studying transformations and
uses of 5-amino-4,5-dihydro-ν-triazoles, mainly as precursors
of substituted amidines, synthons from which N-heterocycles
can be derived.5 It is well known that 5-amino-4,5-dihydro-ν-
triazoles readily aromatize to triazoles6a by heat or under the
action of acid or base by elimination of a molecule of amine.
The 5-amino-4,5-dihydro-ν-triazoles give rise to amidines when
the R group on N-1 is highly electron withdrawing and the 5-
amino group is tertiary.6b In a previous paper7 we pointed out
that thermolysis can induce 4,5-dihydro-ν-triazole ring cleavage
(Scheme 1). The zwitterionic intermediate, produced by ring–
chain tautomerism of the triazoline ring, undergoes two dif-
ferent reactions: direct formation of the amidine by N2 loss and
simultaneous hydride transfer, or alternatively ring contraction
into the 2-aminoaziridine, associated with N2 loss. We also
observed the formation of labile diaminoethylenic derivatives,
whose formation has been rationalized by invoking the presence
of an aziridine intermediate. Cleavage of the aziridine bond
between N and the C atom bearing the amino residue, through
its iminium form, explained the ethylenic intermediates.
These results prompted us to synthesize 5-amino-4,5-di-
hydro-ν-triazoles bearing a 2H-pyran-2-one group at N-1,
and to explore the possibility of linking both the reactivity of
2-aminoaziridines and the nucleophilic features of C-3 in the
2H-pyran-2-one nucleus.
Scheme 1
Results and discussion
4,5-Dihydro-ν-triazoles 3a–d,f,g were easily obtained from
cycloaddition of azide 1 and appropriate enamines 2a–d,f,g
in benzene while 3e was prepared by one-pot procedure10 from
Suitable conditions were sought to achieve transformation of
the intermediate aminoaziridine pyrrole-fused pyran-2-one
derivatives. Little chemistry of this ring system has been
investigated8 although some substituted derivatives have been
prepared from pyrrol-2-ylacetic acid derivatives9 by a multi-
step sequence. A synthetic pathway involving 5-amino-4,5-
dihydro-ν-triazoles has never been described.
propionaldehyde, 4-azido-6-methyl-2H-pyran-2-one 1 and
morpholine without isolation of the intermediate enamine 2e
(Scheme 2). Satisfactory yields were obtained and the structures
of products, including their trans configuration,11 were
established from 1H NMR data (see Experimental section).
Compounds 3a–g were thermolyzed by heating them in
boiling toluene until complete consumption of the starting
DOI: 10.1039/b008531f
J. Chem. Soc., Perkin Trans. 1, 2001, 1723–1728
This journal is © The Royal Society of Chemistry 2001
1723

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δC ≈ 103), quaternary carbons being assigned from the results
of a COLOC experiment. For all compounds 4 proton/carbon
resonances are reported in the Experimental section.
Conclusive structural assignment of compounds 4a–d,f,g was
obtained by NOESY experiments (DMSO-d6) on 4a, which
displayed clear correlations between H-7 and the CH3 linked to
C-6. A positive Overhauser effect confirmed also the spatial
proximity of the NH group to H-7 as well as to the ortho hydro-
gens of the C-2 phenyl group.
The formation of amidines 5 is expected6b according to the
general rearrangement path of 5-amino-4,5-dihydrotriazoles as
indicated in Scheme 1. The production of fused heterocycles
4 can be rationalized as occurring via aminoaziridine C
(Scheme 4). The previously observed7 bond cleavage between
Scheme 2 a 2e not isolated, but obtained in situ: see Experimental
section, preparation of compound 3e.
compound (about 1–2 hours). Starting from 3a–d,f,g a mixture
of pyrrole-fused pyran-2-ones 4a–d,f,g and amidines 5a–d,f,g,
respectively, was formed. Dihydro-ν-triazole 3e gave only
amidine 5e (Scheme 3).
Scheme 3 a 4e was obtained in toluene but only in the presence of
BF3ؒEt2O (Tables 1 and 2).
Scheme 4
Spectroscopic data established the structure of tertiary
amidines 5a–g and of 2-aryl-6-methylpyrano[4,3-b]pyrrol-
4(1H)-ones 4a–d,f,g. Assignment of protons and carbons in 1H
and 13C spectra of amidines 5a–g was made on the basis of
HETCOR and COLOC experiments, and data related to the
pyran-2-one nucleus were in agreement with the literature.12 All
amidines 5 (in CDCl3) show a typical pattern for the signal of
the C-3 proton in the range δ 5.15–5.29 and for the C-5 proton
in the range δ 5.58–5.66. A NOESY experiment, performed for
amidine 5a, demonstrated correlation between the singlet at
δ 3.8 (CH2Ph) and the singlet at δ 5.29 (pyran-2-one 3-H),
supporting the assigned (E) configuration of the amidine
double bond.
All pyrano[4,3-b]pyrrol-4-ones 4a–d,f,g show typical proton
signals (in DMSO-d6) due to the C-7 and C-3 protons at δ ≈ 6.5
and δ 6.87–7.07, respectively. The complete assignment of the
peaks in the 13C NMR spectrum was facilitated by 2D NMR
spectroscopy performed on the pyrano[4,3-b]pyrrol-4(1H)-one
4a: HETCOR experiments allowed attribution of the CH-7
signals (δ 6.48 and δC 96) as well as the CH-3 signal (δ 7.01 and
the N atom and the C atom linked to the morpholine residue
forms D, where nucleophilic attack of C-3 of the pyran-2-one
on the iminium carbon occurs to give a dihydropyrano[4,3-b]-
pyrrol-4-one intermediate, which, by amine loss, turns into the
corresponding pyrano[4,3-b]pyrrol-4(1H)-one 4.
The reaction was studied in more detail, both to confirm that
bicycles 4 do not arise from the amidines 5, and to determine
those factors that would enhance the yield of the pyrrole-fused
pyran-2-ones 4. In a first experiment amidine 5a was refluxed
in toluene for 60 min, under the same conditions adopted for
1
the decomposition of 4,5-dihydro-ν-triazole 3a. The H NMR
spectrum of the crude mixture showed only the signals of
amidine 5a, thus confirming the independence of paths leading
to 4 and 5, respectively.
In order to increase the yield of compounds 4, 4,5-dihydro-ν-
triazoles 3a–g were treated under two different conditions: i)
refluxing in propan-1-ol until disappearance of starting
material was complete; ii) boiling in dry toluene with an
equimolar amount of BF3ؒEt2O for the same time. Propan-1-ol
was selected on account of its suitable boiling point. It was
1724
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Table 1 Ratios of 4 and 5 estimated by 1H NMR spectroscopy
d, f, g, dissolved in benzene (20 ml), was added under stirring
at room temperature. Enamine 2c solution in benzene was
added dropwise to the stirred azide solution at 0–5 ЊC. As soon
as the starting azide had disappeared (TLC, cyclohexane–ethyl
acetate 3 : 7), the solvent was removed under reduced pressure
and the crude product was crystallized from an appropriate
solvent.
Compound
3
Toluene,
BF3ؒEt2O
Toluene
PrnOH
3a
3b
3c
3d
3e
3f
4a : 5a (33 : 67)
4b : 5b (38 : 62)
4c : 5c (37 : 63)
4d : 5d (44 : 56)
4e : 5e (0 : 100)
4f : 5f (48 : 52)
4g : 5g (32 : 68)
4a : 5a (18 : 82)
4b : 5b (34 : 66)
4c : 5c (66 : 34)
4d : 5d (19 : 81)
4e : 5e (0 : 100)
4f : 5f (28 : 72)
4g : 5g (22 : 78)
4a : 5a (70 : 30)
4b : 5b (88 : 12)
4c : 5c (82 : 18)
4d : 5d (94 : 6)
4e : 5e (25 : 75)
4f : 5f (83 : 17)
4g : 5g (63 : 37)
4-(4,5-Dihydro-5-morpholino-4-phenyl-1H-1,2,3-triazol-1-yl)-
6-methyl-2H-pyran-2-one 3a. Reaction time 2 h; yield 6.5 g
(96%); white plates from Pri2O; mp 85 ЊC (decomp.); IR (Nujol)
3g
νmax 1700 (C᎐O) cmϪ1; 1H NMR (200 MHz; CDCl3) δ 2.30 (3H,
᎐
s, Me), 2.39–2.47 (4H, m, CH2NCH2), 3.64–3.72 (4H, m,
CH2OCH2), 4.62 (1H, d, J 3.4, 5-H), 5.61 (1H, d, J 3.4,
4-H), 5.72 (1H, s, 3-H pyranone), 6.78 (1H, s, 5-H pyranone),
6.95–7.42 (5H, m, ArH) (Calc. for C18H20N4O3: C, 63.52;
H, 5.92; N, 16.46. Found: C, 63.69; H, 6.03; N, 16.18%).
expected that this polar and protic solvent might influence the
equilibrium between the conformers A and B previously seen in
Scheme 1. In this reaction setting we were expecting the dipolar
form A to prevail and, from N2 loss, the amount of amidines 5
to increase.
Dry toluene and BF3ؒEt2O were used in attempts to stabilize
the iminium intermediate D in Scheme 4. It is well known that
aziridines with electron-withdrawing groups,13 such as alkyl-
sulfonyl, acyl, alkoxycarbonyl, and in our case the unsaturated
lactone pyran-2-one linked to the N atom, conjugatively
stabilize the negative charge that develops on the nitrogen in the
ring-opening transition state. In this context (see Scheme 4) BF3
could bond to the anionic nitrogen, in iminium form D, or
conjugatively to the enolate oxygen atom and hence promote
the formation of 4. Table 1 collects the results obtained under
three different conditions. The ratio 4 : 5 in the product mixture
was determined by 1H NMR analysis.
The data of Table 1 confirm the correctness of the above
choices and give support to the formulated mechanistic
hypothesis, that the achievement of heterocycles 4 and the
amidines 5 comes from two competitive pathways. An effective
increase in the yield of amidines 5 was seen when the reaction
was performed propan-1-ol, while the addition of the Lewis
acid catalyst brought about an increase of the yield of pyrrole-
fused pyran-2-one derivatives 4, suggesting that the partici-
pation of polar solvents and/or complexing catalyst can act on
the equilibrium between A and B, favouring the hydride transfer
or the formation of the aziridine intermediate.
4-(4,5-Dihydro-5-morpholino-4-p-tolyl-4-1H-1,2,3-triazol-1-
yl)-6-methyl-2H-pyran-2-one 3b. Reaction time 2 h; yield 5.7 g
(81%); white plates from Pri2O; mp 108 ЊC (decomp.); IR
1
(Nujol) νmax 1700 (C᎐O) cmϪ1; H NMR (200 MHz; CDCl3)
᎐
δ 2.29 (3H, s, Me), 2.33 (3H, s, p-tolyl), 2.35–2.44 (4H, m,
CH2NCH2), 3.63–3.69 (4H, m, CH2OCH2), 4.58 (1H, d, J 3.4,
5-H), 5.57 (1H, d, J 3.4, 4-H), 5.71 (1H, s, 3-H pyranone), 6.78
(1H, s, 5-H pyranone), 6.87 and 7.17 (4H, dd, AB system, J 8.0,
ArH (Calc. for C19H22N4O3: C, 64.39; H, 6.26; N, 15.81.
Found: C, 64.6; H, 6.31; N, 15.55%).
4-[4,5-Dihydro-4-(4-Methoxyphenyl)-5-morpholino-1H-1,2,3-
triazol-1-yl]-6-methyl-2H-pyran-2-one 3c. Reaction time 2 h;
yield 4.7 g (64%); white plates from Pri2O; mp 65–66 ЊC
1
(decomp.); IR (Nujol) νmax 1700 (C᎐O) cmϪ1; H NMR (200
᎐
MHz; CDCl3)
δ 2.30 (3H, s, Me), 2.38–2.47 (4H, m,
CH2NCH2), 3.63–3.70 (4H, m, CH2OCH2), 3.80 (3H, s, OMe),
4.58 (1H, d, J 3.4, 5-H), 5.56 (1H, d, J 3.4, 4-H), 5.71 (1H, s,
3-H pyranone), 6.79 (1H, s, 5-H pyranone), 6.88–6.98 (4H,
m, ArH) (Calc. for C19H22N4O4: C, 61.61; H, 5.99; N, 15.13.
Found: C, 61.84; H, 6.12; N, 14.97%).
4-[4-(4-Chlorophenyl)-4,5-dihydro-5-morpholino-1H-1,2,3-
triazol-1-yl]-6-methyl-2H-pyran-2-one 3d. Reaction time 24 h;
In conclusion, variations in the reaction medium controlled
the transformation of 4,5-dihydro-ν-triazoles 3 and facilitated
our aim of linking the reactivity of 2-aminoaziridines and the
nucleophilic reactivity of C-3 in the 2H-pyranone nucleus.
yield 5.5 g (73%); white plates from benzene; mp 107 ЊC
1
(decomp.); IR (Nujol) νmax 1700 (C᎐O) cmϪ1; H NMR (200
᎐
MHz; CDCl3)
δ 2.30 (3H, s, Me), 2.38–2.48 (4H, m,
CH2NCH2), 3.64–3.75 (4H, m, CH2OCH2), 4.58 (1H, d, J 3.5,
5-H), 5.58 (1H, d, J 3.5, 4-H), 5.71 (1H, s, 3-H pyranone),
6.75 (1H, s, 5-H pyranone), 6.94 and 7.36 (4H, dd, AB system,
J 8.5, ArH) (Calc. for C18H19ClN4O3: C, 57.68; H, 5.11; N,
14.95. Found: C, 57.89; H, 5.18; N, 14.68%).
Experimental
Mps were determined using a Büchi 510 (capillary) or an
Electrothermal 9100 apparatus and are uncorrected. IR spectra
were measured using a JASCO IR Report 100 instrument. H
1
and 13C NMR spectra (tetramethylsilane as internal standard)
were recorded with EM Varian Gemini 200, Bruker AC 200
and Bruker Avance 300 Spectrometers. J-Values are given in Hz
for solutions in CDCl3 or DMSO-d6. Mass spectral data were
obtained on a Varian MAT 1H COS 50 instrument using
electron-impact ionization techniques at 70 eV. Column
chromatography was performed on Kieselgel 60 (Merck),
0.063–0.200 mm, and elution with cyclohexane–ethyl acetate
(ratios indicated in Experimental section).
4-[4-(4-Bromophenyl)-4,5-dihydro-5-morpholino-1H-1,2,3-
triazol-1-yl]-6-methyl-2H-pyran-2-one 3f. Reaction time 2 h;
yield 5.4 g (64%); cream plates from ethanol; mp 115 ЊC
1
(decomp.); IR (Nujol) νmax 1700 (C᎐O) cmϪ1; H NMR (200
᎐
MHz; CDCl3)
δ 2.32 (3H, s, Me), 2.36–2.47 (4H, m,
CH2NCH2), 3.64–3.75 (4H, m, CH2OCH2), 4.60 (1H, d, J 3.6,
5-H), 5.58 (1H, d, J 3.6, 4-H), 5.73 (1H, s, 3-H pyranone),
6.79 (1H, s, 5-H pyranone), 6.89 and 7.53 (4H, dd, AB system,
J 8.4, ArH) (Calc. for C18H19BrN4O3: C, 51.56; H, 4.57; N,
13.36. Found: C, 51.63; H, 4.81; N, 13.07%).
Materials
4-[4-(4-Fluorophenyl)-4,5-dihydro-5-morpholino-1H-1,2,3-
triazol-1-yl]-6-methyl-2H-pyran-2-one 3g. Reaction time 3 h;
Azide 114 and enamines 2a–c,15 2f,15 2d,16 2g17 have already been
described.
yield 4.1 g (57%); cream plates from ethanol; mp 118 ЊC
1
(decomp.); IR (Nujol) νmax 1690 (C᎐O) cmϪ1; H NMR (200
᎐
4,5-Dihydro-1-(6-methyl-2-oxo-2H-pyran-4-yl)-5-morpholino-
1,2,3-triazoles 3a–d,f,g
MHz; CDCl3)
δ 2.33 (3H, s, Me), 2.40–2.47 (4H, m,
CH2NCH2), 3.68–3.75 (4H, m, CH2OCH2), 4.60 (1H, d, J 3.6,
5-H), 5.60 (1H, d, J 3.6, 4-H), 5.74 (1H, s, 3-H pyranone), 6.80
(1H, s, 5-H pyranone), 6.90–7.16 (4H, m, ArH) (Calc. for
Typical procedure. Azide 1 (3.0 g, 20 mmol) was dissolved in
benzene (20 ml) and an equimolar amount of an enamine 2a, b,
J. Chem. Soc., Perkin Trans. 1, 2001, 1723–1728
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Table 2 Preparation of pyranol[4,3-b]pyrrol-4(1H)-ones 4 or amidines 5 from 5-amino-4,5-dihydro-ν-triazoles 3
Reaction
time (t/min)
Yield of isolated
products (%)
Entry
R
Methoda
T/ЊC
3a
3a
3a
3b
3b
3b
3c
3c
3c
3d
3d
3d
3e
3e
3e
3f
Ph
Ph
Ph
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
60
120
60
90
90
90
90
120
90
100
80
120
120
120
120
120
120
120
120
120
120
111
97
111
111
97
111
111
97
111
111
97
111
111
97
111
111
97
111
111
97
4a (21) 5a (55)
4a (13) 5a (70)
4a (58) 5a (18)
4b (24) 5b (46)
4b (22) 5b (56)
4b (77) 5b (7)
4c (25) 5c (48)
4c (53) 5c (20)
4c (70) 5c (13)
4d (36) 5d (47)
4d (11) 5d (68)
4d (88) 5d (2)
5e (86)
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Me
Me
Me
5e (88)
4e (16) 5e (58)
4f (36) 5f (43)
4f (15) 5f (60)
4f (65) 5f (10)
4g (22) 5g (56)
4g (13) 5g (64)
4g (45) 5g (30)
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-FC6H4
4-FC6H4
4-FC6H4
3f
3f
3g
3g
3g
111
a Solvents: A, toluene; B, propan-1-ol; C, toluene, BF3ؒEt2O.
C18H19FN4O3: C, 60.33; H, 5.34; N, 15.63. Found: C, 60.46;
H, 5.41; N, 15.35%).
plates from Pri2O; mp 223 ЊC; IR (Nujol) νmax 3250 (NH), 1675
᎐
1
(C᎐O) cmϪ1; H NMR (300 MHz; DMSO-d6) δ 2.26 (3H, s,
Me), 6.48 (1H, s, 7-H), 7.01 (1H, s, 3-H), 7.19–7.82 (5H, m,
ArH), 12.2 (1H, br s, NH exchangeable); 13C NMR (75 MHz;
DMSO-d6) δ 20.2 (Me), 96.0 (C-7), 103.2 (C-3), 108.3 (C-3a),
125.3, 128.1, 129.7 (ArCH), 131.9 (ArC), 135.98 (C-2), 141.4
Preparation of 4-(4,5-dihydro-4-methyl-5-morpholino-1H-1,2,3-
triazol-1-yl)-6-methyl-2H-pyran-2-one 3e
A benzene solution (30 ml) of morpholine (2.61 g, 30 mmol)
was added dropwise to a stirred solution of azide 1 (4.5 g,
30 mmol) and propanal (1.74 g, 30 mmol) in benzene (30 ml)
at rt until the starting azide had disappeared (ca. 20 h) (TLC
cyclohexane–EtOAc, 1 : 9). The solution was dried with
Na2SO4, filtered, and the filtrate was evaporated under reduced
pressure. The residue was crystallized from Pri2O to afford pure
(C-7a), 156.5 (C-6), 160.4 (C᎐O); MS m/z 225 (Mϩ, 100%), 197
᎐
(35) (Calc. for C14H11NO2: C, 74.65; H, 4.92; N, 6.22. Found:
C, 74.39; H, 5.01; N, 6.12%).
6-Methyl-4-(1-morpholino-2-phenylethylideneamino)-2H-
pyran-2-one 5a. White plates from Pri2O; mp 135 ЊC; IR (Nujol)
νmax 1705 (C᎐O) cmϪ1; 1H NMR (300 MHz; CDCl3) δ 2.15 (3H,
᎐
s, Me), 3.45–3.47 (8H, 2m, morpholino), 3.80 (2H, s, CH2), 5.29
(1H, d, J 1.7, 3-H), 5.66 (1H, d, J 1.7, 5-H), 7.10–7.38 (5H, m,
ArH); 13C NMR (75 MHz; CDCl3) δ 20.3 (Me), 34.7 (CH2),
45.8 (CH2NCH2), 66.8 (CH2OCH2), 96.4 (C-3), 105.0 (C-5),
3e. (5.6 g, 67%), as white needles; mp 113 ЊC (decomp.); IR
1
(Nujol) νmax 1700 (C᎐O) cmϪ1; H NMR (200 MHz; CDCl3) δ
᎐
1.28 (3H, d, J 7.2, 4-Me triazoline), 2.28 (3H, s, Me), 2.30–2.38
(4H, m, CH2NCH2), 3.61–3.68 (4H, m, CH2OCH2), 4.31 (1H,
d, J 3.1, 5-H), 4.58 (1H, dq, J 3.1 and 7.2, 4-H), 5.70 (1H, s, 3-H
pyranone), 6.72 (1H, s, 5-H pyranone) (Calc. for C13H18N4O3:
C, 56.10; H, 6.52; N, 20.13. Found: C, 56.22; H, 6.64; N,
20.01%).
127.6, 128.0, 129.6 (ArCH), 135.3 (ArC), 156.8 (N-C᎐N), 161.8
᎐
(C-6), 165.1 (C-4), 165.4 (C᎐O) (Calc. for C H N O : C, 69.21;
᎐
18 20
2
3
H, 6.45; N, 8.97. Found: C, 69.33; H, 6.53; N, 8.88%).
6-Methyl-2-p-tolylpyrano[4,3-b]pyrrol-4(1H)-one 4b. White
plates from Pri2O; mp 268 ЊC; IR (Nujol) νmax 3150 (NH), 1680
1
(C᎐O) cmϪ1; H NMR (200 MHz; DMSO-d6) δ 2.27 (3H, s,
᎐
Thermal behaviour of dihydrotriazoles 3a–g. Method A
Me), 2.32 (3H, s, p-tolyl), 6.48 (1H, s, 7-H), 6.93 (1H, s, 3-H),
7.24 and 7.66 (4H, dd, AB system, J 8.4, ArH), 12.10 (1H, br s,
NH exchangeable); 13C NMR (50 MHz; DMSO-d6) δ 19.6
(Me), 20.9 (Me), 95.4 (C-7), 101.8 (C-3), 107.7 (C-3a), 124.6,
129.7 (ArCH), 128.6 (ArC), 135.5 (C-2), 136.9 (ArC), 140.6
Typical procedure for the synthesis of compounds 4a–d,f,g and
5a–g. Dihydrotriazoles 3a–g (15 mmol) dissolved in toluene
(70 ml) were heated under reflux for times indicated in Table 2,
progress of the reaction being followed by TLC. After dis-
appearance of the starting material the solvent was removed
in vacuo and a small amount of the residue was dissolved in
DMSO-d6 and the ratio of 4 to 5 was determined by 1H NMR
analysis (see Table 1). The crude residue was taken up with
CH2Cl2 and slowly and partially deposited a compound 4a–
d,f,g as a crystalline product, which was filtered off and
recrystallized as indicated below. The left over mixture was
chromatographed (cyclohexane–ethyl acetate 3 : 7) to give a
first fraction containing a pyrano[4,3-b]pyrrol-4-one 4a–d,f,g
and a second fraction containing an amidine 5a–d,f,g. Dihy-
drotriazole 3e afforded only amidine 5e, isolated by crystalliza-
tion from Pri2O. Pyrrole-fused pyran-2-one 4e was isolated only
from reaction with BF3ؒEt2O (see below). Reaction times of
dihydrotriazoles 3 and yields of isolated products 4 and 5 are
collected in Table 2.
(C-7a), 155.6 (C-6), 159.8 (C᎐O) (Calc. for C H NO : C,
᎐
15 13
2
75.30; H, 5.48; N, 5.85. Found: C, 75.06; H, 5.57; N, 5.63%).
6-Methyl-4-(1-morpholino-2-p-tolylethylideneamino)-2H-
pyran-2-one 5b. White plates from Pri2O; mp 191 ЊC; IR (Nujol)
νmax 1700 (C᎐O) cmϪ1; 1H NMR (200 MHz; CDCl3) δ 2.15 (3H,
᎐
s, Me), 2.32 (3H, s, p-tolyl), 3.44–3.57 (8H, m, morpholine),
3.74 (2H, s, CH2), 5.28 (1H, s, 3-H), 5.65 (1H, s, 5-H), 6.99 and
7.12 (4H, dd, AB system, J 8.4, ArH); 13C (50 MHz; CDCl3)
δ 19.9 (Me), 21.0 (Me), 33.9 (CH2), 45.4 (CH2NCH2), 66.5
(CH2OCH2), 96.2 (C-3), 104.7 (C-5), 127.5, 129.9 (ArCH),
131.8 (ArC), 136.8 (ArC), 156.6 (N-C᎐N), 161.4 (C-6), 164.8
᎐
(C-4), 165.0 (C᎐O) (Calc. for C H N O : C, 69.92; H, 6.79;
᎐
19 22
2
3
N, 8.58. Found: C, 70.20; H, 6.72; N, 8.45%).
2-(4-Methoxyphenyl)-6-methylpyrano[4,3-b]pyrrol-4(1H)-
one 4c. Cream plates from CH2Cl2; mp 242 ЊC; IR (Nujol) νmax
6-Methyl-2-phenylpyrano[4,3-b]pyrrol-4(1H)-one 4a. White
3230 (NH), 1670 (C᎐O) cmϪ1; 1H NMR (200 MHz; DMSO-d6)
᎐
1726
J. Chem. Soc., Perkin Trans. 1, 2001, 1723–1728

View Article Online
δ 2.28 (3H, s, Me), 3.80 (3H, s, OMe), 6.48 (1H, s, 7-H), 6.87
(1H, s, 3-H), 7.02 and 7.71 (4H, dd, AB system, J 8.7, ArH),
12.05 (1H, br s, NH exchangeable); 13C NMR (50 MHz;
DMSO-d6) δ 19.6 (Me), 55.4 (OMe), 95.4 (C-7), 101.1 (C-3),
107.7 (C-3a), 114.6, 126.1 (ArCH), 124.2 (ArC), 135.5 (C-2),
(ArC), 134.11 (C-2), 140.46 (C-7a), 155.62 (C-6), 158.9 and
159.46 (CF, J 245.0), 159.46 (C᎐O) (Calc. for C H FNO :
᎐
14 10
2
C, 69.12; H, 4.15; N, 5.76. Found: C, 68.97; H, 4.05; N, 5.64%).
4-[2-(4-Fluorophenyl)-1-morpholinoethylideneamino]-6-
methyl-2H-pyran-2-one 5g. White needles from PriOH; mp
140.49 (C-7a), 155.5 (C-6), 158.9 (OMe), 159.9 (C᎐O) (Calc.
126 ЊC; IR (Nujol) νmax 1690 (C᎐O) cmϪ1; 1H NMR (200 MHz;
᎐
᎐
for C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.37;
H, 4.96; N, 5.35%).
CDCl3) δ 2.13 (3H, s, CH3), 3.40–3.58 (8H, m, morpholine),
3.75 (2H, s, CH2), 5.22 (1H, s, 3-H), 5.63 (1H, s, 5-H), 6.95–7.15
(4H, m, ArH) (Calc. for C18H19FN2O3: C, 65.43; H, 5.80;
N, 8.48. Found: C, 65.29; H, 5.87; N, 8.33%).
4-[2-(4-Methoxyphenyl)-1-morpholinoethylideneamino]-6-
methyl-2H-pyran-2-one 5c. Orange plates from Pri2O; mp
106 ЊC; IR (Nujol) νmax 1700 (C᎐O) cmϪ1; 1H NMR (200 MHz;
᎐
Method B
CDCl3) δ 2.16 (3H, s, Me), 3.40–3.50 (4H, m, CH2NCH2), 3.50–
3.60 (4H, m, CH2OCH2), 3.72 (2H, s, CH2), 3.80 (3H, s, OMe),
5.28 (1H, s, 3-H), 5.65 (1H, s, 5-H), 6.85 and 7.03 (4H, dd, AB
system, J 8.7, ArH) (Calc. for C19H22N2O4: C, 66.65; H, 6.48;
N, 8.18. Found: C, 66.88; H, 6.71; N, 6.22%).
A solution of a dihydrotriazole 3a–g (10 mmol) in propan-1-ol
(60 ml) was boiled under reflux, progress of the reaction being
followed by TLC. After disappearance of the starting material
the solvent was removed in vacuo, a small amount of residue
was dissolved in DMSO-d6 and the ratio of 4 and 5 was deter-
mined by 1H NMR analysis (see Table 1). Compounds 4 and 5
were isolated after column chromatography (cyclohexane–ethyl
acetate 3 : 7). The dihydrotriazole 3e yielded only the amidine
5e, which was crystallized. Analytical data were in agreement
with those previously reported. The reaction times and isolated
yields of compounds are collected in Table 2.
2-(4-Chlorophenyl)-6-methylpyrano[4,3-b]pyrrol-4(1H)-one
4d. White plates from. CH2Cl2; mp 291 ЊC; IR (Nujol) νmax
3230 (NH), 1670 (C᎐O) cmϪ1; 1H NMR (200 MHz; DMSO-d6)
᎐
δ 2.28 (3H, s, Me), 6.50 (1H, s, 7-H), 7.07 (1H, s, 3-H), 7.50 and
7.80 (4H, dd, AB system, J 8.5, ArH), 12.22 (1H, br s, NH
exchangeable); 13C NMR (50 MHz; DMSO-d6) δ 19.6 (Me),
95.3 (C-7), 103.3 (C-3), 107.8 (C-3a), 126.3, 129.1 (ArCH),
130.3 and 131.9 (2 × ArC), 134.2 (C-2), 141.0 (C-7a), 156.1
(C-6), 159.7 (C᎐O) (Calc. for C H ClNO : C, 64.75; H, 3.88;
N, 5.39. Found: C, 64.54; H, 3.83; N, 5.31%).
᎐
14 10
2
Method C. Effect of BF3ؒEt2O with respect to pyrolysis of
dihydrotriazoles 3a–e
4-[2-(4-Chlorophenyl)-1-morpholinoethylideneamino]-6-
methyl-2H-pyran-2-one 5d. Pale yellow plates from MeOH; mp
BF3ؒEt2O (1.9 ml, 15 mmol) in dry toluene (30 ml) was added to
a stirred solution of a dihydrotriazole 3a–e (4.2 g, 15 mmol) in
dry toluene (25 ml) at rt. The resulting mixture was refluxed for
the same time used in the toluene thermal decomposition, after
which the reaction was quenched with 10 ml of saturated aq.
NaHCO3 (10 ml). The organic phase was separated, and the
aqueous phase was extracted with ethyl acetate (4 × 50 ml). The
combined organic phases were washed with brine and dried
(Na2SO4), filtered, and evaporated to dryness. Ratio of 4 and 5
158 ЊC; IR (Nujol) νmax 1690 (C᎐O) cmϪ1; 1H NMR (200 MHz;
᎐
CDCl3) δ 2.16 (3H, s, Me), 3.38–3.50 (4H, m, CH2NCH2), 3.50–
3.63 (4H, m, CH2OCH2), 3.76 (2H, s, CH2), 5.24 (1H, s, 3-H),
5.64 (1H, s, 5-H), 7.06 and 7.31 (4H, dd, AB system, J 8.4, ArH)
(Calc. for C18H19ClN2O3: C, 62.34; H, 5.52; N, 8.08. Found:
C, 62.08; H, 5.43; N, 7.95%).
6-Methyl-4-(1-morpholinopropylideneamino)-2H-pyran-2-
one 5e. White plates from Pri2O; mp 85–86 ЊC; IR (Nujol)
1
νmax 1700 (C᎐O) cmϪ1; 1H NMR (200 MHz; CDCl3) δ 1.11 (3H,
determined by H NMR analysis (DMSO-d6) (see Table 1) of
᎐
the residue. The crude mixtures containing 4a–g and 5a–g were
chromatographed (cyclohexane–ethyl acetate 2 : 8) to afford
first the pyrano[4,3-b]pyrrol-4-ones 4 and then the amidines 5.
For analytical data of the products previously obtained see
above. The reaction times and isolated yields of compounds are
collected in Table 2.
t, J 7.6, Me), 2.19 (3H, s, pyranone-Me), 2.36 (2H, dd, J 7.6,
CH2), 3.45–3.51 and 3.70–3.76 (8H, 2m, morpholine), 5.24 (1H,
d, J 1.7, 3-H), 5.62 (1H, d, J 1.7, 5-H); 13C NMR (50 MHz;
DMSO-d6) δ 12.4 (Me linked to CH2), 19.6 (6-Me), 21.7 (CH2),
45.2 (CH2NCH2), 66.2 (CH2OCH2), 95.0 (C-3), 104.5 (C-5),
160.6 (N-C᎐N), 161.5 (C-6), 163.7 (C-4), 165.39 (C᎐O) (Calc.
᎐
᎐
for C13H18N2O3: C, 62.38; H, 7.25; N, 11.19. Found: C, 62.13;
H, 7.46; N, 11.03%).
2,6-Dimethylpyrano[4,3-b]pyrrol-4(1H)-one 4e. White needles
from Pri2O; mp 157 ЊC; IR (Nujol) νmax 3090 (NH), 1670 (C᎐O)
᎐
2-(4-Bromophenyl)-6-methylpyrano[4,3-b]pyrrol-4(1H)-one
4f. White plates from CH2Cl2; mp >300 ЊC (decomp.); IR
1
cmϪ1; H NMR (200 MHz; CDCl3) δ 2.26 (3H, s, 6-Me), 2.34
(Nujol) νmax 3200 (NH), 1660 (C᎐O) cmϪ1; 1H NMR (200 MHz;
(3H, s, 2-Me), 6.27 (1H, s, 7-H), 6.33 (1H, s, 3H), 9.20 (1H, br s,
NH exchangeable); 13C NMR (50 MHz; CDCl3) δ 13.5 (2-Me),
20.2 (6-Me), 96.3 (C-7), 103.4 (C-3), 107.8 (C-3a), 133.1 (C-2),
᎐
DMSO-d6) δ 2.27 (3H, s, Me), 6.5 (1H, s, 7-H), 7.07 (1H, s,
3-H), 7.60–7.80 (4H, m, ArH), 12.25 (1H, br s, NH exchange-
able); 13C NMR (50 MHz; DMSO-d6) δ 19.32 (Me), 95.04 (C-7),
103.00 (C-3), 107.44 (C-3a), 126.23, 131.67 (ArCH), 120.02
and 130.26 (2 × ArC), 133.84 (C-2), 140.72 (C-7a), 155.80
140.64 (C-7a), 155.2 (C-6), 162.4 (C᎐O) (Calc. for C H NO :
᎐
9
9
2
C, 66.25; H, 5.56; N; 8.58. Found: C, 66.06; H, 5.74; N; 8.73%).
(C-6), 159.38 (C᎐O) (Calc. for C H BrNO : C, 55.29; H, 3.31;
N, 4.61. Found: C, 55.03; H, 3.34; N, 4.55%).
Acknowledgements
᎐
14 10
2
We are indebted to Mrs Donatella Nava for recording NOESY,
HETCOR and COLOC NMR experiments and discussing her
experimental data, and to the M.U.R.S.T. (Italian Ministry of
University, Science and Technology) for financial support.
4-[2-(4-Bromophenyl)-1-morpholinoethylideneamino]-6-
methyl-2H-pyran-2-one 5f. Chestnut plates from EtOH; mp
158 ЊC; IR (Nujol) νmax 1695 (C᎐O) cmϪ1; 1H NMR (200 MHz;
᎐
CDCl3) δ 2.08 (3H, s, Me), 3.35–3.55 (8H, m, morpholine), 3.69
(2H, s, CH2), 5.15 (1H, s, 3-H), 5.58 (1H, s, 5-H), 6.94 and 7.37
(4H, dd, AB system, J 8.4, ArH) (Calc. for C18H19BrN2O3:
C, 55.38; H, 4.91; N, 7.18. Found: C, 55.17; H, 4.98; N, 6.93%).
2-(4-Fluorophenyl)-6-methylpyrano[4,3-b]pyrrol-4(1H)-one
4g. White plates from CH2Cl2; mp 248 ЊC; IR (Nujol) νmax 3100
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