Reaction of 3-formylchromone-N-benzoylhydrazone with ketenes. Synthesis and structural studies of chromone 1,3,4-oxadiazolines

Article abstract of DOI:10.1002/jhet.5570440223

(Chemical Equation Presented) The reaction of 3-formylchromone-N- benzoylhydrazone with ketenes, prepared in situ from the corresponding acid chlorides 2a-d and the mixed anhydride 2e was studied. In all cases 2-(4′-oxo-4′H-3′-chromyl)-5-phenyl-2,3-dihydro-1,3, 4-oxadiazoles (3) were isolated in yields varying from 40 to 80%. A full structure assignment of all products has been made on the basis of 1D and 2-D (COSY H-H, COSY C-H, COLOC C-H) NMR spectra. A plausible reaction mechanism is also proposed based on theoretical approaches and experimental results.

Full text of DOI:10.1002/jhet.5570440223

Mar-Apr 2007
425
Reaction of 3-Formylchromone-N-benzoylhydrazone with Ketenes.
Synthesis and Structural Studies of Chromone 1,3,4-Oxadiazolines
George C. Kaspentakis, Constantinos A. Tsoleridis* and Julia Stephanidou-Stephanatou
Department of Chemistry, Laboratory of Organic Chemistry, University of Thessaloniki, Thessaloniki 54124,
Macedonia, Greece; e-mail: tsolerid@chem.auth.gr
Received July 12, 2006
Revised October 3, 2006
O
O
O
O
COCHR1R2
R1R2C=C=O
COPh
H
N
N
N
N
O
H
3
Ph
1
The reaction of 3-formylchromone-N-benzoylhydrazone with ketenes, prepared in situ from the
corresponding acid chlorides 2a-d and the mixed anhydride 2e was studied. In all cases 2-(4'-oxo-4'H-3'-
chromyl)-5-phenyl-2,3-dihydro-1,3,4-oxadiazoles (3) were isolated in yields varying from 40 to 80%. A
full structure assignment of all products has been made on the basis of 1D and 2-D (COSY H-H, COSY C-
H, COLOC C-H) NMR spectra. A plausible reaction mechanism is also proposed based on theoretical
approaches and experimental results.
J. Heterocyclic Chem., 44, 425 (2007).
Scheme 1
INTRODUCTION
R1
R2
Flavones and chromones are unique molecules because
of the availability of their structural framework in a
variety of natural products and biologically active
molecules [1]. Although 3-formylchromone has emerged
as the most valuable synthon for the incorporation of the
chromone moiety leading to the synthesis of a variety of
heterocycles [2], its synthetic utility is limited due to
facile opening of the chromone ring [2–4], hence
strategies are being developed to circumvent it [5].
Concerning 3-formylchromone hydrazones, a perusal of
the literature revealed that although their antimicrobial
activity and bleaching effect [6] as well as their
mutagenicity and antimutagenicity were studied [7], their
chemistry has not yet been reported. With this in mind,
we chose to study the reaction of 3-formylchromone-N-
benzoylhydrazone with ketenes, since ketenes exhibit a
very rich cycloaddition chemistry due to their structural
and electronic peculiarities [8], and also because from the
few studied reactions between ketenes and 3-
formylchromone or 3-formylchromone Schiff bases [4+2]
cycloaddition products were mainly isolated [2a]. Another
very important feature of chromone chemistry, which lead
us to this study, was the fact that chromones substituted
by a heterocyclic ring at the 3 position [9a] are known to
exhibit a wide range of biological activity such as
antialergic, antimicrobial, antifungal, anticholesteric,
hypolipidemic and antiblaster action as well stimulate the
central nervous system [9b]. On the other hand, the
isolated products contain also the 1,3,4-oxadiazoline ring,
which is shown to have important biological activities
[10], and in addition, constitutes a versatile precursor of
reactive intermediates [11].
O
O
O
O
O
COCH
H
C
R1R2CHCOX
+
+
O
H
N
N
N
N
2
Ph
O
O
H
O
3
Ph
1
4
3
5
2
1
4
CONHNHCOCHR1R2
8
9
5
11 12 13
7
6
5
Reaction Conditions
Product Yield %
2a R1 = H, R2 = Cl, X = Cl
Et3N/C6H5CH3 reflux, 4h 3a
38
40
60
80
50
2b R1 = R2 = Cl,
X = Cl
"
"
"
"
"
"
3b
3c
3d
3e
2c R1 = R2 = CH3, X = Cl
2d R1 = R2 = Ph, X = Cl
2e R1 = H, R2 = OPh, X = OTs Et3N/CH2Cl2
rt, 24h
RESULTS AND DISCUSSION
3-formylchromone-N-benzoylhydrazone
prepared [6] by condensation of 3-formylchromone with
benzohydrazide reacted with ketenes, derived in situ by
dehydrohalogenation of the corresponding acid chlorides
2 in the presence of triethylamine, and afforded the
The
(1)
hitherto unknown 2-chromyl-1,3,4-oxadiazolines
3
(Scheme 1). In the case of chloro- and dichloroketene the
2-chromyl-1,3,4-oxadiazolines 3a and 3b were isolated in
moderate yield (~40%), whereas in the case of dimethyl-
and diphenylketene compounds 3c and 3d were obtained
in good yield (60-80%).
Furthermore, the reaction of 1 with the mixed
anhydride 2e was studied. The anhydride, a synthetic
equivalent of acid chloride, was prepared from
phenoxyacetic acid and p-toluenesulphonyl chloride in the
presence of triethylamine in dichloromethane at room

426
G. C. Kaspentakis, C. A. Tsoleridis and J. Stephanidou-Stephanatou
Vol 44
Table 1
13C, 1H, C-H Correlation and COLOC NMR Data for Compounds 3a and 3b.
Compound 3a
Compound 3b
Position [a]
C
H [b]
C
H [b]
COLOC [c]
2
5
88.9
157.3
124.5
127.3
128.7
132.0
163.1
41.6
6.98 (s)
88.9
157.9
124.4
127.5
128.8
132.3
159.8
63.8
7.00 (1H, d, 0.2)
175.1, 156.2
6
7,11
8,10
9
7.87–7.92 (m)
7.41–7.48 (m) [d]
7.48–7.55 (m) [e]
7.89–7.94 (2H, m)
7.39–7.42 (2H, m)
7.48–7.57 (1H, m) [d]
132.3, 157.9
127.5
12
13
2΄
4.53 (2H, s)
8.13 (s)
6.87 (1H, s)
156.3
156.2
8.11 (1H, d, 0.2)
175.1, 156.3,
117.4, 88.9
3΄
4΄
117.9
175.3
124.0
125.9
117.4
175.1
123.7
125.9
4a΄
5΄
8.18 (ddd,
8.0, 1.7, 0.4)
7.42 (ddd,
8.18 (ddd,
8.0, 1.7, 0.4)
7.42 (ddd,
134.3
125.9
134.3
6΄
7΄
125.9
134.3
8.0, 7.1, 1.1) [f]
7.70 (ddd,
8.0, 7.1, 1.1) [e]
7.70 (ddd,
8.4, 7.1, 1.7)
7.44 (m) [g]
8.4, 7.1, 1.7)
7.42–7.50 (m) [f]
8΄
118.3
156.2
118.3
156.3
125.9, 123.7
8a΄
[a] For carbon numbering see Figure 1. [b] The protons on this column are correlated to carbon atoms on the left
column via 1JC–H. Multiplicities and coupling constants nJ (in Hz) in parentheses. [c] Long range (2JC–H and 3JC–H
)
correlations between the protons on the left and the carbons stated on this column. [d,e,f,g] Overlapped
multiplets, distinguished by homo- and hetero-COSY.
temperature. Under the mild reaction conditions
employed, the corresponding chromyloxadiazoline 3e was
isolated in 50% yield. During the reaction time an amount
of 3-formyl-N-benzoylhydrazone decomposed giving 3-
formyl-chromone 4 and benzohydrazide, which reacted
further with ketenes to afford the corresponding N-
benzohydrazides 5a–5d in yields ranging from 3 to 20%.
Structure Assignments The assigned molecular
structures of all new compounds 3a–e are based on
rigorous spectroscopic analysis including IR, NMR (1H,
13C, COSY H–H, NOESY H–H, HETCOR C–H and
COLOC C–H), MS and elemental analysis data. In Tables
1 and 2 the NMR data [13C, 1H and the C–H correlation
via one bond (HETCOR C–H) and two and/or three bonds
(COLOC C–H)] are presented.
Regarding the structure of compounds 3 the assignment
of 3b is described. From the molecular ion at m/z
402/404/406 (9:6:1) the conclusion could be drawn that
3b was produced from the reaction of one molecule of 1
with one molecule of dichloroketene, a fact that was also
confirmed from the 13C NMR spectrum, where 17
different signals were observed (Table 1). In addition, the
presence of the characteristic chromone carbonyl carbon
absorption at 175.1 ppm (175.8 in the chromone
hydrazone 1) and of the protonated C(2') carbon
absorption at 156.2 ppm, associated with the one proton
singlet at δ 8.11, indicated that the chromone moiety
remained unaffected. Moreover, the lack of the C=N
carbon absorption of the starting material 1 at 140.8 ppm
suggested a reaction of the dichloroketene with the
hydrazone C=N bond. From the C–H correlated spectrum
in the saturated region, the presence of a methine carbon
at 63.8 ppm (bearing most probably the dichloroketene
chlorine atoms) and the presence of a second methine
carbon at 88.9 ppm were established. In addition, this
methine proton singlet (δ 7.00) gave COLOC correlations
(Figure 1) with the chromone carbonyl carbon at 175.1
ppm and with the C(2') carbon at 156.2 ppm indicating
thus that this methine carbon corresponded to the C=N
carbon of the starting hydrazone 1. The downfield shift of
this methine carbon (88.9 ppm) was due to the
neighboring C=C group, of a nitrogen atom and of a
second heteroatom. The lack of a benzoyl carbonyl in
combination with the COLOC correlation of the o-
aromatic protons with the carbon at 156.2 ppm (the
former benzoyl carbon of 1 being transformed to a C=N

Mar-Apr 2007
Reaction of 3-Formylchromone-N-benzoylhydrazone with Ketenes
427
carbon) supported the hypothesis that the second
heteroatom was the former benzoyl oxygen [12].
Scheme 2
Reaction Mechanism The reaction is most probably
initiated by a nucleophilic attack of the imino hydrazone
nitrogen to the carbonyl carbon of the ketene leading to a
zwitterionic intermediate 6. A proton transfer in the
zwitterion from the neighboring NH group inactivates the
ketene anion and the charge moves to the benzoyl oxygen
with subsequent cyclization of the resulting dipolar
intermediate 7 leading to the formation of oxadiazolines
3. An analogous mechanism was previously proposed by
us for the reaction of ketenes with N-aroyldihydrocyclo-
penta-pyrazolidinol [13]. However, from the reaction of
N,N-dialkylhydrazones with ketenes 2-azetidinone
O
O
O
O
O
O
O
O
O
C
C
O
O
C
C
3
R1
C
R1
O
N
N
N
N
HC
R2
R2
N
C
N
R2 R1
H
H
C
C
Ph
Ph
Ph
1
6
7
After the initial proximity of the two reactants in TS1
derivatives were isolated via
a Staudinger [2+2]
and the formation of N(3)-C(12) bond, the C(13) anion
approaches and abstracts the H(17) (TS2). Next, the
benzoyl oxygen gradually approaches the carbon C(2)
(TS3) and finally gives the product 3b. In Table 3 the
variation in bond lengths or atomic distances from the
reactants (compounds 1 and 2b) to the product, calculated
by AM1, can be observed. The H(17) moves to C(13), the
bond N(4)-C(5) decreases and the carbonyl bond C(5)-
O(1) increases from reactants through TS1–TS2–TS3 to
the product. Moreover, the net charge values (qnet)
indicate a change in electron density during the reaction
process. The electrons from C(2) = N(3) move to the
ketene moiety and after the abstraction of the H-C(7) the
charge moves to N(4)-C(5)-O(1) until the final
cyclization.
cycloaddition reaction, most probably because of the lack
of the N-H moiety [14]. To the contrary, in the present
work, the presence of N-H group is responsible for the
diversification of the reaction mechanism, as depicted in
Scheme 2, leading always to Δ2-1,3,4-oxadiazoline
derivatives 3.
Following the above approach, the transition structures
for the two-step reaction of compound 1 with ketene 2b,
calculated by AM1 method, are depicted in Figure 2.
R2
1'
O
12
COCH
8'
15
H
7'
6'
2'
13
R1
14
N3
2
3'
N
5
6
4'
H5'
H
O
7
O
8
3b R1 = R2 = Cl
3c R1 = R2 = CH3
3e R1 = H, R2 = OPh
For each located TS after complete optimization only
one negative eigenvalue was calculated corresponding to
one imaginary frequency assigned to the bonds (shown by
the arrows) affected by the moving atom, as depicted in
Figure 2. The computed activation energies (ΔH#) are
H11
9
10
Figure 1. Numbering of skeleton and diagnostic COLOC correlations in
compounds 3b, 3c and 3e.
Table 2
1H, 13C, C-H Correlation and COLOC NMR Data for Compounds 3c–e.
Posi-
tion [a]
Compound 3c
H [b]
Compound 3d
H [b]
Compound 3e
H [b]
C
COLOC [c]
C
C
COLOC [c]
2
88.3
7.02 (s)
175.4, 156.2,
155.8
88.2
7.09 (s)
89.0
6.98 (s)
175.3, 157.2,
156.4, 118.0
5
6
7,11
156.2
124.7
127.1
156.2
124.5
127.2
157.2
124.5
127.3
7.86–7.93 (m)
7.38–7.44 (m)
[d]
156.2
130.9
7.82–7.90 (m)
7.35–7.45 (m) [d]
7.25–7.45 (m)
7.89–7.95 (m)
157.2, 131.9
8,10
128.6
128.5
128.7
7.38–7.59 (m) [d]
7.41–7.58 (m) [d]
9
12
13
131.5
174.6
31.9
7.48–7.55 (m)
131.6
169.0
54.2
131.9
165.2
65.5
3.39,
(sept, 7.0)
1.20
6.00, (s)
5.42, (d, 16.0)
14
18.2
138.7 [f],
139.2 [f]
129.0 [g], 7.20–7.50 (m)
129.1 [g]
128.5 [h], 7.20–7.50 (m)
128.5 [h]
127.1 [i], 7.20–7.50 (m)
127.1 [i]
158.2f
114.8g
129.5h
121.5i
(d, 7.0)
6.89–7.05 (m)
7.22–7.30 (m)
6.89–7.03 (m)
121.5
158.2
114.8
15
18.9
1.23
(d, 7.0)

428
G. C. Kaspentakis, C. A. Tsoleridis and J. Stephanidou-Stephanatou
Vol 44
Table 2 (continued)
Posi-
tion [a]
Compound 3c
H [b]
Compound 3d
H [b]
Compound 3e
H [b]
C
COLOC [c]
C
C
COLOC [c]
2΄
155.8
8.03 (s)
175.4, 156.3,
118.8, 88.3
155.8
7.90 (s)
156.4
8.11 (s)
175.3, 156.3
118.0, 89.0
3΄
4΄
4a΄
5΄
118.8
175.4
124.6
125.9
118.5
175.3
124.5
125.9
118.0
175.3
124.2
125.9
8.19 (dd,
8.18 (dd,
8.19 (dd,
134.2
8.0, 1.4)
8.0, 1.6)
8.0, 1.6)
6΄
125.7
134.1
118.2
156.3
7.39–7.45 (m) [e]
125.7
134.1
118.2
156.2
7.35–7.45 (m) [e]
125.8
134.2
118.2
156.3
7.41 (ddd,
8.0, 7.0, 1.3) [e]
7.68 (ddd,
8.6, 7.0, 1.6)
7.46 (dd,
7΄
7.67 (ddd,
8.6, 7.0, 1.6)
7.41–7.48 (m) [e]
7.64 (ddd,
8.5, 7.1, 1.7)
7.35–7.45 (m) [e]
125.9
8΄
124.2, 125.8
8.0, 1.6) [e]
8a΄
[a] For carbon numbering see Figure 1. [b] The protons on this column are correlated to carbon atoms on the left column via 1JC–H. Multiplicities
n
3
and coupling constants J (in Hz) in parentheses. [c] Long range (2JC–H and JC–H) correlations between the protons on the left and the carbons
stated on this column. [d,e] Overlapped multiplets, distinguished by homo- and hetero-COSY. [f] For C-ipso of Ph at C-13. [g] For C-ortho of
Ph at C-13. [h] For C-meta of Ph at C-13. [i] For C-para of Ph at C-13.
higher than the experimental ones or those which would
have been calculated by DFT computations and are only
reliable for relative comparisons of similar reactions
[14d,15].
16
13
Imaginary Freq.
12
−333.1
H
17
Imaginary Freq.
H
4
-1385.3
3
3´
2
5
1
TS1 ΔH# = 22.10 kcal/mol
TS2 ΔH# = 44.16 kcal/mol
H
Imaginary Freq. -337.0
TS3 ΔH# = 25.37 kcal/mol
3b ΔHf = -8.86 kcal/mol
Figure 2. Transition structures calculated by AM1 for the reaction of hydrazone 1 with ketene 2b. The small arrows show the bonds
contributed to the imaginary frequency.

Mar-Apr 2007
Reaction of 3-Formylchromone-N-benzoylhydrazone with Ketenes
429
b)
Atoms
CONCLUSIONS
Reactants
TS1
TS2
TS3
3b
qnet (Electrons × 104, Mulliken)
In conclusion, we have studied the first reaction of
3-formylchromone-N-benzoylhydrazone with ketenes
leading to the hitherto unknown interesting chromyloxa-
diazolines 3. Attention should also be drawn to the fact
that in all reactions the chromone moiety remained
unchanged. All new compounds are promising targets to
study their biological action, because they combine two
known independently bioactive rings. For all new
compounds full assignment of proton and carbon NMR
chemical shifts was achieved. Further investigations of
cycloaddition reactions of 3-formylchromone hydrazones
are being studied.
1
2
3
4
–3591
–1142
–1064
–4153
3908
–3519
577
–4108
703
–4539
2017
–2226
–3384
2511
–2603
1355
–3397
–1299
1339
–1565
–3853
3850
3290
2917
–1348
–4064
3611
4402
2984
5
17
H-C(2)
3297
2694
2624
2815
2444
2467
12
13
16
3126 [b]
–2833 [b]
–1513 [b]
3842
–3632
–3135
3986
–3959
–2740
3521
–1328
–2963
3704
–1366
–3001
ΔHf [c]
–3.08 [d]
19.02
41.08
22.56
–8.86
[a] The numbering refers to TS1 in Figure 2. [b] For ketene 2b.
[c] Enthalpies of formation, in kcal/mol. [d] ΔHf (1) = 11.03; ΔHf
(2b) = –14.11.
EXPERIMENTAL
General Procedure for the Reaction of 3-Formyl-
chromone-N-benzoylhydrazone (1) with ketenes.
A
Melting points were measured on a Kofler hot-stage and
are uncorrected. Column chromatography was carried out
using Merck silica gel. Petroleum ether refers to the fraction
boiling between 60 and 80 °C. NMR spectra were recorded
on a Bruker AM 300 spectrometer at 300 MHz for H and 75
MHz for 13C, respectively, using CDCl3 as solvent. The
solution of the appropriately substituted acetyl chloride 2
(3.0 mmoles) in dry toluene (5 mL) was added dropwise
under reflux over a period of 20 minutes to a stirred solution
of 1 (0.438 g, 1.5 mmoles) in triethylamine (0.45 g, 4.5
mmoles) and dry toluene (40 mL). The reaction mixture was
stirred under reflux for 4 hours and then it was washed with a
10% sodium bicarbonate aqueous solution (50 mL). The
organic layer was separated, dried and evaporated under
reduced pressure. The residue was purified by column
chromatography on silica gel using petroleum ether/ethyl
acetate (7:1) as eluent, slowly increasing the polarity up to
4:1 to give in order of elution: 3-Formylchromone, the
chromyloxadiazoline 3 and the benzohydrazide 5.
1
chemical shifts are expressed in δ values (ppm) relative to
1
TMS as internal standard for H and relative to TMS (0.00
ppm) or to CDCl3 (77.05 ppm) for 13C NMR spectra.
Coupling constants nJ are reported in Hz. IR spectra were
recorded on a Perkin–Elmer 297 spectrometer or on a
Perkin–Elmer 1600 series FTIR spectrometer and are
reported in wave numbers (cm–1). Low-resolution electron
impact mass spectra (EIMS) were obtained on a VG TS-250
instrument and elemental analyses were performed with a
Perkin–Elmer 2400-II CHN analyzer. The minimum energy
conformation of each compound was computed with the
AM1 method [16a] as implemented in the MOPAC package
[16b] and referred to vacuum. All geometry optimizations
were carried out without symmetry constraints and stationary
points were refined by minimization of the gradient norm of
the energy to at least 0.05 kcal/mol, using the LET and
PRECISE keywords.
Reaction of 3-Formylchromone-N-benzoylhydrazone (1)
with Chloroacetyl chloride (2a). The following compounds
were isolated in order of elution:
3-Formylchromone (0.047 g).
3-(2-Chloroacetyl)-2,3-dihydro-5-phenyl-2-(4-oxo-4H-
chromen-3-yl)-1,3,4-oxadiazole (3a). White solid in 38%
yield, mp 195–197 ° (ethanol); ir (nujol) νmax: 1660, 1635, 1620,
1
1560 cm–1; H and 13C nmr are presented in Table 1; EIMS: m/z
(%) 368/370 (25, M+), 319 (15), 292 (55), 262 (35), 248 (20),
235 (17), 216 (94), 205 (22), 188 (27), 173 (94), 159 (20), 146
(45), 131 (20), 121 (50), 108 (95). Anal. Calcd for C19H13ClN2O4
(368.77): C, 61.88; H, 3.55; N, 7.60. Found: C, 62.09; H, 3.40,
N, 7.52.
Table 3
Comparison of: a) Bond Lengths or Atomic Distances (in Å) and b) Net
Atomic Charges (qnet) in Reactants (Compounds 1 and 2b), in various TS
during the Reaction of 1 with 2b and in Product 3b.
N'-(2-Chloroacetyl)benzohydrazide (5a). White solid in a yield
of 20%, mp 163–165 ° (lit [17a] 165 °).
Reaction of 3-Formylchromone-N-benzoylhydrazone (1)
with Dihloroacetyl chloride (2b). The following compounds
were isolated in order of elution:
a)
Bonds [a]
Reactants
TS1
TS2
TS3
3b
1–2
1–5
2–3΄
2–3
3–4
2.874
1.244
1.464
1.309
1.327
1.404
1.003
2.840
1.242
1.458
1.312
1.341
1.410
1.006
2.899
1.811
1.355
1.215
2.828
1.250
1.452
1.323
1.354
1.395
1.260
1.506
1.535
1.491
1.221
2.112
1.297
1.445
1.385
1.372
1.371
2.533
1.121
1.440
1.527
1.236
1.466
1.409
1.498
1.504
1.370
1.327
2.661
1.120
1.421
1.526
1.236
3-Formylchromone (0.044 g).
3-(2,2-Dichloroacetyl)-2,3-dihydro-5-phenyl-2-(4-oxo-4H-
chromen-3-yl)-1,3,4-oxadiazole (3b). White paper like solid in
a yield of 40%, mp 231–233 ° (ethanol); ir (nujol) νmax: 1660,
1635, 1620, 1560 cm–1; 1H, 13C and COLOC nmr data are
presented in Table 1; EIMS: m/z (%) 402/404/406 (8, M+),
367/369 (24), 291 (100), 262 (5), 246 (96), 216 (30), 203 (90),
173 (98), 188 (13), 173 (98), 146 (53), 121 (75), 105 (95). Anal.
Calcd for C19H12Cl2N2O4 (403.22): C, 56.60; H, 3.00; N, 6.95.
Found: C, 56.51; H, 3.10, N, 7.04.
4–5
4–17
13–17
3–12
12–13
12–16
1.323 [b]
1.186 [b]

430
G. C. Kaspentakis, C. A. Tsoleridis and J. Stephanidou-Stephanatou
Vol 44
N'-(2,2-Dichloroacetyl)benzohydrazide (5b). White solid in
1
2; EIMS m/z (%) 426 (30, M+), 333 (6), 321 (40), 319 (55), 305 (20),
291 (45), 290 (53), 280 (10), 262 (35), 248 (12), 230 (25), 216 (95),
205 (28), 188 (25), 173 (90), 172 (95), 146 (70), 131 (90), 121 (80),
120 (72), 108 (89), 107 (90), 106 (97), 105 (92), 103 (100). Anal.
Calcd for C25H18N2O5 (426.42): C, 70.42; H, 4.25; N, 6.57. Found: C,
70.60; H, 4.42; N, 6.70.
20% yield, mp 190–192 ° (lit [17b] 180 °); H nmr: δ 6.40 (s, 1
H, 11-H), 7.41–7.46 (m, 2H, (2,6)-H), 7.51–7.56 (m, 1H, 4-H),
7.92–7.94 (m, 2H, (3,5)-H), 10.52 (s, 1 H, 8-H), 10.83 (s, 1 H, 9-
H); 13C nmr: δ 64.9 (C-11), 127.7 (C-2,6), 128.3 (C-3,5), 131.9
(C-1), 132.0 (C-4), 162.7 (C-10), 165.6 (C-7); EIMS: m/z (%)
246/248 (25, M+), 213 (10), 163 (45), 121 (65).
Reaction of 3-Formylchromone-N-benzoylhydrazone (1)
with Isobutyryl chloride (2c). The following compounds were
isolated in order of elution:
REFERENCES
[1a] Ellis, G. P. In Chromenes, Chromanones and Chromones;
Wiley: New York, 1977; [b] Dewick, P. M. In The Flavonoids,
Advances in Research since 1986; Harborne, J. B., Ed.; Chapmann and
Hall: New York, 1994; p 23; [c] Fujimoto, H.; Inagaki, M.; Satoh, Y.;
Yoshida, E.; Yamazaki, M. Chem. Pharm. Bull. 1996, 44, 1090; [d]
Nakatani, K.; Okamoto, A.; Saito, I. Angew. Chem., Int. Ed. 1999, 38,
3378; [e] Gill, M. In The Chemistry of Natural Products; Thomson, R.
H., Ed.; 2nd ed., Blackie: Surrey, 1993; p 60; [f] Flavonoids in the Living
Systems: Advances in Experimental Medicine and Biology; Manthy, J.
A., Buslig, B. S., Eds.; Plenum: New York, 1998; Vol. 439.
[2a] Ghosh, C. K.; Ghosh, C. Indian J. Chemistry 1997, 36B, 968
and references therein; [b] Sabitha, G. Aldrichim. Acta 1996, 29, 15 and
references therein; [c] Fitton, A. O.; Frost, J. R.; Suschitzky, H.;
Houghton, P. G. Synthesis, 1977, 133.
[3a] Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S.; Foces-
Foces, C.; Llamas-Saiz, A. L.; Jagerovic, N.; Elguero, J. Tetrahedron,
1999, 55, 10187; [b] Sigg, I.; Hass, G.; Winkler, T. Helv. Chim. Acta,
1982, 65, 275; [c] Ghosh, C.; Tewari, N. J. Org. Chem. 1980, 45, 1964.
[d] Fitton, A. O.; Houghton, P. G.; Suschitzky, H. Synthesis 1979, 337.
[4a] Koña, J.; Fabian, W. M. F.; Zahradnik, P. J. Chem. Soc.,
Perkin Trans. 2 2001, 422; [b] Koña, J.; Zahradnik, P.; Fabian, W. M. F.
J. Org. Chem. 2001, 66, 4998.
[5] Borrell, J. I.; Teixidό, J.; Schuler, E.; Michelotti, E.
Tetrahedron Lett. 2001, 42, 5331.
[6] El-Shaaer, H. M.; Foltínová, P.; Lácová, M.; Chovancová, J.;
Stankovičová, H. Il Farmaco 1998, 53, 224.
[7] Foltínová, P.; Lácová, M.; An Loos, D. Il Farmaco 2000, 55, 21.
[8] Tidwell, T. T. In Ketenes; Wiley: New York, 1995; pp 459–571.
[9a] Ghosh, C. K. Heterocycles 2004, 63, 2875; [b] Frasinyuk, M.
S.; Khilya, V. P. Khim. Geterotsikl. Soedin. 1999, 379, 3.
[10a] Hassan, E.; Al-Ashmawi, M. I.; Abdel-Fattah, B. Pharmazie
1983, 38, 833; [b] Khalil, M. A.; El-Sayed, H. A. Arch. Pharm.
(Weinheim) 1993, 326, 489.
3-Formylchromone (0.047 g).
2,3-Dihydro-3-isobutyryl)-2-(4-oxo-4H-chromen-3-yl)-5-
phenyl-1,3,4-oxadiazole (3c). White paper like solid in a yield
of 60%, mp 183–184 ° (ethanol); ir (nujol) νmax: 1660, 1635,
1
1620, 1560 cm–1; H, 13C and COLOC nmr data are presented in
Table 2; EIMS: m/z (%) 362 (15, M+), 292 (35), 291 (100), 188
(10), 173 (33), 147 (20), 133 (18), 121 (35), 105 (84), 77 (55),
71 (47). Anal. Calcd for C21H18N2O4 (362.38): C, 69.60; H, 5.01;
N, 7.73. Found: C, 69.73; H, 4.94; N, 7.62.
N'-Isobutyrylbenzohydrazide (5c). White solid in a yield of
1
16%, mp 185–188 ° (lit [18] 189 °). H nmr: δ 1.19 (d, J = 7.3
Hz, 6 H, 2×CH3), 2.62 (sept, 7.3 Hz, 1 H, 11-H), 7.36–7.41 (m,
2H, (3,5)-H), 7.48–7.52 (m, 1H, 4-H), 7.81–7.84 (m, 2H, (2,6)-
H), 9.58 (1 H, s, 8-H), 9.95 (1 H, s, 9-H). EIMS: m/z (%) 206
(100, M+), 163 (15), 136 (95), 106 (100), 105 (95).
Reaction of 3-Formylchromone-N-benzoylhydrazone (1)
with Diphenylacetyl chloride (2d). The following compounds
were isolated in order of elution:
3-Formylchromone (0.005 g).
2,3-Dihydro-3-(2,2-diphenylacetyl)-2-(4-oxo-4H-1-chromen-3-
yl)-5-phenyl-1,3,4-oxadiazole (3d). White paper like solid in
80% yield, mp 178–179 ° (ethanol); ir (nujol) νmax: 1635, 1620
1
cm–1; H and 13C nmr data are presented in Table 2; EIMS: m/z
(%) 486 (10, M+), 396 (20), 381 (22), 293 (70), 291 (50), 264
(10), 235 (15), 195 (55), 194 (90), 172 (63), 171 (41), 168 (79),
164 (72), 163 (85), 152 (81), 139 (72), 121 (100), 120 (88), 115
(78), 106 (89), 105 (77).Anal. Calcd for C31H22N2O4 (486.52): C,
76.53; H, 4.56; N, 5.76. Found: C, 76.68; H, 4.52; N, 5.61.
N'-(2,2-Diphenylacetyl)benzohydrazide (5d). White solid
in 3% yield, mp 200-201 ° (lit [17c] 202–203 °).
[11] Warkentin, J. J. Chem. Soc., Perkin Trans. 1 2000, 2161.
[12] Tsoleridis, C. A.; Stephanidou-Stephanatou, J.; Zika, C.;
Pozarentzi, M.; Alevizopoulos, S. Helv. Chim. Acta 2003, 86, 330.
[13] Tsoleridis, C. A.; Stephanidou-Stephanatou, J.; Gounaridis,
P.; Zika, H.; Pozarentzi, M. Tetrahedron 2003, 59, 4591.
[14a] Fernádez, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.;
Monge, A. Angew. Chem., Int. Ed. 2000, 39, 2893; [b] Fernádez, R.;
Ferrete, A.; Lassaletta, J. M.; Llera, J. M.; Martín-Zamora, E. Angew.
Chem., Int. Ed. 2002, 41, 831; [c] Díez, E.; Fernádez, R.; Marqués-
López, E.; Martín-Zamora, E.; Llera, J. M. Org. Letters 2004, 6, 2749;
[d] Martín-Zamora, E.; Ferrete, A.; Llera, J. M.; Muñoz, J. M.;
Pappalardo, R. R.; Fernádez, R.; Lassaletta, J. M. Chem. Eur. J. 2004,
10, 6111.
Reaction of 3-formylchromone-N-benzoylhydrazone 1 with
the anhydride 2e in the presence of triethylamine. A solution of
0.46 g (3.0 mmoles) of phenoxyacetic acid, 0.57 g (3.0 mmoles)
of toluene-p-sulphonyl chloride, and of 0.61 g (6.0 mmoles) of
triethylamine in dry dichloromethane (15 mL) was stirred at room
temperature for 10 minutes. To this solution 0.292 g (1.0 mmole)
of 3-formylchromone hydrazone 1 was added in dry dichloro-
methane (2 mL) and the final solution was stirred at room
temperature for 24 hours. The reaction mixture was then washed
with 10% aqueous sodium bicarbonate solution (10 mL), with
water (20 mL) and dried. The solvent was evaporated under
reduced pressure and the residue was subjected to column
chromatography on silica gel with petroleum ether/ethyl acetate
(7:1) as eluent with slowly increasing polarity to give the
following compounds in order of elution:
[15] Jursic, B. S.; LeBlanc, B. J. Heterocyclic Chem. 1996, 33,
1389.
[16a] Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J.
P. J. Am. Chem. Soc. 1985, 107, 3902; [b] MOPAC 2000 ver. 1.11,
Fujitsu in Chem3D Ultra 7.0.
3-Formylchromone. 0.050 g.
2,3-Dihydro-2-(4-oxo-4H-chromen-3-yl)-3-(2-phenoxyacetyl)-
5-phenyl-1,3,4-oxadiazole (3e). This compound was obtained as
[17a] Beilstein 9 II, 216; [b] Beilstein 9 IV, 934; [c] Beilstein 9
III, 3306.
yellow solid in a yield of 49%, mp 188–190 ° (ethanol); ir (nujol) νmax
:
[18] Shvaika, O. P.; Makarenko, Yu. I. Zhur. Obshch. Khim.
1963, 33, 1233.
1685, 1625 cm–1; 1H, 13C and COLOC nmr data are presented in Table