Synthetic studies using unsaturated and active phosphonium salts. A convenient preparation of furano- and pyrano[2,3-c]pyridazines and substituted quinolines

Article abstract of DOI:10.1002/hc.20065

By applying vinyl- (3) and allyltriphenyl-phosphonium bromides (9) to 4-cyano-5,6-difur-2′yl-2H-pyridazin-3-one (1) the corresponding fused 5,8-oxazolo- 6, 12 (～37%) and pyrano- 8, 13, 14 (～20%) derivatives are isolated whereas with alkylphosphonium bromides 15a,b fused furans 17a,b (22%) and isopyrroles 18a,b (～45%) are obtained. On the other hand, the reaction of 2-[(benzylidene)amino]-benzonitrile (2) with 3 and 9 yielded benzoazepines 20 and 21 (～56%). With 15a,b, quinolines 23a,b (～46%) and quinazoline 25 (～24%) are obtained.

Full text of DOI:10.1002/hc.20065

Heteroatom Chemistry
Volume 16, Number 1, 2005
S
ynthetic Studies Using Unsaturated and
Active Phosphonium Salts. A Convenient
Preparation of Furano- and
Pyrano[2,3-c]pyridazines and Substituted
Quinolines
1
1
2
Wafaa M. Abdou, Neven A. Ganoub, Amin F. Fahmy,
1
and Abeer M. Shaddy
1
Department of Pesticide Chemistry, National Research Centre, Dokki, D-12622, Cairo, Egypt
2
Department of Chemistry, Faculty of Science, Ain-Shams University, Cairo, Egypt
Received 3 March 2004; revised 15 September 2004
nitrogen multiple bonds, we reported that the reac-
tion of 4-cyano-5,6-difur-2 yl-2H-pyridazin-3-one (1)
with resonance-stabilized ylides resulted in the for-
mation of a series of fused pyrano and furano [2,3-
c]pyridazine derivatives [2] (Scheme 1).
ABSTRACT: By applying vinyl- (3) and allyltriphenyl-
ꢀ
ꢀ
phosphonium bromides (9) to 4-cyano-5,6-difur-2 yl-
2H-pyridazin-3-one (1) the corresponding fused 5,8-
oxazolo- 6, 12 (∼37%) and pyrano- 8, 13, 14 (∼20%)
derivatives are isolated whereas with alkylphos-
phonium bromides 15a,b fused furans 17a,b (22%)
and isopyrroles 18a,b (∼45%) are obtained. On the
other hand, the reaction of 2-[(benzylidene)amino]-
benzonitrile (2) with 3 and 9 yielded benzoazepines
On contrary, application of such reagents to 2-
[(benzylidene)amino]benzonitrile (2) afforded, in all
cases, quinoline derivatives in reasonable yields as
the major products [2] (Scheme 2).
It has been pointed out [2] that the reaction of 1
with such ylides proceeded only when the latter were
generated in situ from the corresponding phospho-
nium salts in the presence of ∼4 excess LiOH or LiH.
The findings highlighted the inertness of molecule 1,
which was attributed to the low reactivity of the ni-
trile function and the amidic carbonyl group toward
nucleophilic attack. The thermal condition, coupled
with the presence of an excess of a strong base, used
for the generation of ylide, however, deprotonates ei-
ther the ylide or the pyridazinone promoting thus a
further reaction. Such interesting results encouraged
us to examine the reaction of unsaturated- 3, 9, and
active phosphonium bromides 15a,b with these two
nitriles 1 and 2. The program aimed at synthesizing
heterocycle patterns condensed with pyridazine or
phenyl moieties required for a biological chemistry
program.
2
0 and 21 (∼56%). With 15a,b, quinolines 23a,b
(
∼46%) and quinazoline 25 (∼24%) are obtained.
ꢁ
C
2005 Wiley Periodicals, Inc. Heteroatom Chem 16:
6–64, 2005; Published online in Wiley InterScience (www.
5
interscience.wiley.com). DOI 10.1002/hc.20065
INTRODUCTION
In one of our previous studies [1] on the synthe-
sis of new biologically active heterocycles based on
known drug skeletons from alkylidenephosphoranes
as starting synthons and substrates that bear carbon–
Correspondence to: Wafaa M. Abdou; e-mail: wabdou@
intouch.com.
ꢁ
c 2005 Wiley Periodicals, Inc.
5
6

Synthetic Studies Using Unsaturated and Active Phosphonium Salts 57
SCHEME 1
RESULTS AND DISCUSSION
in the range δ 6.18–6.23. Further evidence was ob-
tained from the C NMR spectrum, which displayed
1
3
Treatment of 1 with an equimolar amount of vinyl-
the methylene carbon resonance at δ 68.7 and 6-C
C
triphenylphosphonium bromide (3) in a mixture
at 133.2 ppm.
ꢀ
of LiOH/H
2
O/EtOH yielded 2,3-difur-2 yl-4-cyano-
Obviously, the product 6 is produced via the
corresponding intermediate 4, suggested by Yavari
et al. [3] for the synthesis of 1H-pyrrolizines by treat-
ing pyrrole-2-carbaldehyde with vinylphosphonium
salts. Then, extrusion of hydrogen bromide from 4
and prototropic rearrangement, phosphonium ylide
5 occurs. This is followed by an attack of the enolate
oxygen on ꢀ-carbon [4] with the simultaneous expul-
sion of triphenylphosphine yielding 6 (Scheme 3).
Synthesis of the nitrogen bridgehead heterocycles is
of interest because they constitute an important class
of natural and nonnatural products, many of which
exhibit useful biological activity [5]. In contrast, the
fused pyran 8 resulted from an initial addition of the
anion 1B [6] to 3 to form the phosphonium salt 7.
Further attack of the ylide on the carbon–nitrogen
triple bond [7] and hydrolysis leads to the forma-
tion of 8 (Scheme 3). An analogous mechanism has
been previously reported by Schweizer et al. [8] for
the reaction of vinylphosphonium bromide 3 with
anthranilonitrile.
5
,8-oxazolo[2,3-b]-1,2-dihydropyridazine (6, 36%)
ꢀ
and 5-amino-3,4-difur-2 ylpyrano[2,3-c]-1,2-dihy-
dropyridazine (8, 23%).
Structures 6 and 8 were assigned to the isolated
products on the basis of their elemental analyses,
1
13
IR, H, C NMR, and mass spectral data. Thus, the
1
H NMR spectrum of 6 exhibited the characteristic
resonances for the oxazole ring system (δ
H
6.57 and
7.79) along with resonances corresponding to the fu-
1
3
ran rings and NH (δ 5.23). Its C NMR spectrum
displayed the oxazole carbon resonances at δ 118.8
(7-C), 145.4 (6-C), 154.8 (9-C) and the cyano group
at 100.6 (4-C), 117.7 (CN). The MS spectrum of 6,
as expected, confirms its molecular weight. Initial
fragmentation involves loss of C
the rings. On the other hand, the IR spectrum of 8
showed strong broad bands at 3366, 3253 cm due
to free NH and the nearly complete disappearance
of nitrile and carbonyl bands; its H NMR spectrum
showed a singlet at δ 5.78 due to the amino protons.
The methylene protons in 8 are nonequivalent, and
the shift between them is small compared with gem-
inal coupling constant. Thus, the AB system pattern
is quite distorted, and the net result is three peaks
in the range δ 4.25–4.38. The methine proton on
2
H
2
and scission of
−
1
2
1
A similar treatment of 1 with one equivalent of
allyltriphenylphosphonium bromide (9) afforded
ꢀ
2,3-difur-2 yl-4-cyano-7-methyl-5,8-oxazolo[2,3-b]-
ꢀ
pyridazine (12, 39%) along with 3,4-difur-2 yl-7-
methyl-5H-5-iminopyrano[2,3-c]-1,2-dihydropyri-
dazine (13, 13%) and its oxidation form, pyranone
6-C appeared as an ill defined two pairs (J = 1.8 Hz)
SCHEME 2

5
8 Abdou et al.
SCHEME 3
1
4 (19%) (Scheme 4). Iminopyran 13 was iden-
13, most probably, derived from the attack of the
parallely formed oxygen anion 1B on the ꢁ-carbon
atom of 9B to form the phosphorane, which is
converted into 13 via an intramolecular cyclization
[1f, 8], according to Scheme 4. Finally 14 is regarded
as the oxidized form of 13 through the hydrolysis.
A similar transformation is known for the imino
function to the keto-structure [10].
In contrast, when a DMF solution of an equimo-
lar amount of 1 and methylidenetriphenylphospho-
rane, prepared in situ from its bromide salt 15a, in
the presence of lithium hydride, was heated under
reflux, the reaction was not complete, even after 2
days. On repetition of the reaction between 1 and
an excess (up to 2 equiv.) of 15a in refluxing DMF,
tical in all aspects with material previously ob-
tained from the reaction of 1 with 2-(oxopropyl)-
(triphenyl)phosphorane (C-Scheme 2 [2]). Further
treatment of 13 with alkali afforded 14 in 72%
yield. The formation of 12 can be rationalized, as
with the reaction between 1 and 3, through the
attack of the initially formed nitrogen anion 1A
on the ꢁ-carbon atom in 10, to generate the phos-
phorane 11. Further attack of the enolate oxygen
on ꢀ-carbon [4] with concomitant elimination of
triphenylphosphine would produce the final prod-
uct 12. The electrophilic attack of an electrophile
at the central atom of the allyl group in 10 is a
documented process [9]. Meanwhile, iminopyran

Synthetic Studies Using Unsaturated and Active Phosphonium Salts 59
(
br, 1H) due to the two NH in 18Aa. However, the
1
3
structure of 18Ba is confirmed from C NMR data,
which is consistent with the equilibrium 18Aa ꢁꢀ
18Ba and showed signals among others, at 13.7
(
CH ), 112.2 ( CH ). However, the results of the
3
2
spectroscopic interpretation for 18Ba indicate that
both isopyrrolidene form 18A and its isopyrrole tau-
tomer 18B present in equilibrium although struc-
ture 18B should be more stable and in turn more
preferable on steric hindrance reasons. The forma-
tion of the products 17 and 18 may be envisaged as
occurring via the previous workers [2,7b,10,11] sug-
gested structure 16 for the intermediate of the reac-
tion between nitriles and ylides. Further intramolec-
ular attack of the anionic oxygen on the ylidic carbon
in 16B afforded the fused furan 17. On the other
hand, Wittig olefination of 16C with a second ylide
species, followed by intramolecular cyclization and
the loss of Ph
3
P, led to the formation of 18A ꢁꢀ18B.
Olefination of the amidic carbonyl group in 1 with
2
active ylides (Ph P CHR ) is not surprising since it
3
has been reported that N-phenyl substituted pyri-
dazinone derivative undergoes olefination reaction
with resonance-stabilized phosphorus ylides [12].
In summary, the findings from the reactions of
pyridazinone carbonitrile 1 with unsaturated- and
nonstabilized ylides, which have been reported in
the present investigation, or with stable ylides that
are reported in the earlier work [2], highlight the
initial attack by alkylidenephosphoranes would vary
with the electronic characteristics of the phospho-
rus reagent. Considering the previous report [2], the
common feature of the reactions of ester and keto
ylides with 1 seemed to be proceeding via the initial
attack on the nitrile group (Scheme 1). Conversely,
the involvement of pyridazine portion (Schemes 3, 4)
and the amidic carbonyl group (Scheme 5) in the re-
actions of 1 with unsaturated and active ylides have
also been observed.
SCHEME 4
containing LiH, for 30 h afforded 5-amino-3,4-difur-
ꢀ
2
ylfurano[2,3-c]-1,2-dihydropyridazine (17a, 22%)
ꢀ
and
5-methyl-3,4-difur-2 yl-6H-isopyrrolo[2,3-c]-
1,2-dihydropyridazine (18a, 43%) (Scheme 5).
The reaction products of 1 with ethyltriph-
enylphosphonium bromide (15b) under the same
conditions were assigned analogous structures 17b
(
22%) and 18b (47%) on the basis of comparable
spectroscopic arguments. The chemical structures of
7 and 18 were delineated from their spectroscopic
1
Next, the behavior of 2-[(benzylidene)amino]-
benzonitrile (2) toward the same unsaturated- and
nonstabilized ylides was investigated (Schemes 6–8).
When 2 was caused to react with one equivalent of
the phosphonium bromide 3 in a mixture of LiOH/
properties. Thus, the IR spectrum of 17a showed the
characteristic band due to the amino group at 3054
and 2853 cm and the disappearance of the bands
at ∼2230 and ∼1650 cm corresponding to CN and
C O groups in 1 [6]. On the other hand, the spec-
troscopic data indicated that 18B is tautomeric with
−
1
−1
H O/EtOH yielded 5-amino-2-phenylbenzoazepine
2
(20), advantageously, in 55% yield (see Scheme 6).
1
8A, since its IR spectrum revealed two strong broad
Compound 20 may be regarded as a product of
an intramolecular Wittig-type reaction [7]. Such an
addition-cyclization product apparently results from
the initial addition of 3 to the azomethine portion of
2, giving the ylide 19. Further attack of the ylidic car-
bon on the nitrile group and hydrolysis would lead
to the formation of 20 [7], as it is discussed for the
formation of 8 from the reaction of 1 with 3.
−1
bands at 2922 and 2854 cm due to 1- and 6-NH
groups in 18Aa. A sharp and strong band also ap-
peared at 1619 cm due to the exocyclic double bond
in 18Aa. The H NMR spectrum showed two signals
at 1.95 (s, 3H) and 4.87 (s, 2H) ppm due to the methyl
in 18Ba and the methylidene protons in 18Aa. Two
broad signals appeared at 4.57 (br, 1H) and at 5.25
−1
1

6
0 Abdou et al.
SCHEME 5
Similar to 20, this synthesis was extended to
-amino-3-methyl-2-phenylbenzoazepine (21, 58%),
which was readily obtained by allowing anil 2 to
react with 9 in ethanol containing LiOH solution
Finally, the heating of 2 with one equivalent
alkyltriphenylphosphonium bromides 15a,b in DMF
under reflux with a catalytic amount of LiH gave
the known substituted quinolines 23a [13] or 23b
[14](∼43%) along with 4-amino-3-(2-benzonitrile)-
5
(
0.5 M) according to Scheme 7.
SCHEME 6

Synthetic Studies Using Unsaturated and Active Phosphonium Salts 61
to the structure of the phosphoranes. It is worth
mentioning here that the methods previously de-
scribed for the preparation of substituted quinolines
23a [13] and 23b [14] are lengthy and indirect. For
example compound 23b, which is patented as new
type calcium channel antagonist for the treatment of
pain, was synthesized by the condensation of isatin
and propiophenone in ethanol containing KOH pel-
lets to give 3-methyl-2-phenyl-4-quinolinecarboxylic
acid. The latter could be converted to the correspond-
ing amine 23b after multistep synthesis [14]. In the
present context, 23b (45%) could be available by a
one step synthesis from the reaction of the proper
anilide with 15b.
SCHEME 7
2
-phenyl-1-hydroquinazoline (25) (∼24%). A rea-
sonable mechanistic explanation of these trans-
formations involves the expected initially formed
zwitterion 22, which leads to 23a,b, in the usual
pathway, and 2-[(triphenylphosphorylidene)amino]-
benzonitrile, which resulted from partial collapse
of 22 [2]. In contrast to the reaction between
CONCLUSION
The previously noted observations show that the ear-
lier [2] studied reactions of 1 and 2 with resonance-
stabilized ylides can be considerably extended.
Moreover, application of alkylidene-phosphoranes to
the substrates 1 and 2 provide an easy route, not
only for the expected fused O-and N-heterocycles,
but also for N-bridgehead nitrogen heterocycles, for
example, 6 and 12 and quinazoline 25. Data on the
pharmaceutical potency of the new compounds will
be published elsewhere.
2
and resonance-stabilized ylides (Scheme 2), the
iminophosphorane 24 could not be isolated. Instead,
it underwent an addition-cyclization reaction with
the Shiff’s base 2 to give the final adduct 25 as shown
in Scheme 8.
Summarizing, although the initial step in all
of the present (Schemes 6–8) and previous work
(
Scheme 2 in [2]) is nucleophilic attack by the car-
EXPERIMENTAL SECTION
banions at the azomethine portion in 2, the conse-
quences of the initial step vary markedly according
The melting points are uncorrected. The IR spectra
were recorded on a Perkin Elmer spectrophotome-
1
ter model 297 (Grating) using KBr disks. The H and
1
3
C NMR spectra were run in CDCl
3
or d -DMSO as
6
solvents on a Jeol-270 MHz instrument, using SiMe
4
3
1
as an internal reference. The P NMR spectra were
recorded relative to external H PO (85%) with a Var-
3
4
ian CFT-20 instrument. The mass spectra were per-
formed at 70 eV on a Shimadzu GCS-QP 1000 EX
spectrometer provided with a data system. The ap-
propriate precautions in handling moisture-sensitive
compounds were observed. Solvents were dried by
standard techniques. Light petroleum refers to the
◦
fraction 40–60 C.
ꢀ
Reaction of 4-Cyano-5,6-difur-2 yl-2H-pyridazin-
3
-one (1) with Vinyltriphenylphosphonium
Bromide (3): Preparation of Compounds 6 and 8
To a stirred solution of 1 g (3.95 mmol) 1 [6] and
1
2
.6 g (4.4 mmol) 3 in 30 mL EtOH, freshly prepared
0 mL LiOH solution (0.5 M) was added in one por-
tion. The reaction mixture was stirred at r.t. for 2 h
and then heated under reflux for 36 h (TLC). After
removing the solvent, 20 mL of dist. H
2
O was added
SCHEME 8
and then extracted with CHCl . After evaporation
3

6
2 Abdou et al.
of the dried CHCl
matographed on silica gel using n-hexane/CHCl
the eluents whereupon compounds 6 and 8 were
3
solution, the residue was chro-
as
CH
3
), 5.47 (s, 1H, NH), 6.75, 7.18 (2d, JHH 4.8 Hz,
ꢀ
ꢀ
4
3
3
4H, 2 × H , H -furans), 7.25, 7.58 (2d, JHH 4.4 Hz,
ꢀ
5
2H, 2 × H , furans), 7.83 (s, 1H, 6-CH); δ
c
(CDCl
3
);
isolated.
13.8 (CH
3
), 98.6 (4-C), 106.4, 106.7, 110.2, 111.4
ꢀ
ꢀ
ꢀ
2
,3-Difur-2 yl-4-cyano-5,8-oxazolo[2,3-b]pyrida-
(2 × (3 -C, 4 -C), furans), 118.2 (CN), 131.2 (7-C),
142.4, 144.1, 145.8 (3-C, 2-C,6-C), 147.1, 147.8 (2 ×
zine (6) was obtained (1:1, v/v) as yellow crystals
◦
ꢀ
ꢀ
(395 mg, 36%), mp 144–146 C (from MeCN) (found:
5 -C, furans), 154.3, 154.9 (2 × 2 -C, furans), 156.7
+
C, 64.44; H, 3.17; N, 14.96. C15
quires: C, 64.51; H, 3.25; N, 15.05%); νmax (KBr)/cm
224 (NH), 2225 (CN), 1610 (C C, furans); δ (d
H
9
N
3
O
3
(279.26) re-
(9-C); MS: m/z (EI) (%): 293 (47) [M ], 292 (33), 277
−
1
(20), 251 (24), 249 (36), 184 (15), 117 (28), 67 (31).
ꢀ
3
w
H
6
-
3,4-Difur-2 yl-7-methyl-5H-5-iminopyrano[2,3-
DMSO); 5.23 (s, 1H, NH), 6.57 (d, JHH 4.6 Hz, 1H,
c]-1,2-dihydropyridazine (13) was obtained (2:8,
ꢀ
3
7
-CH), 6.77, 7.15 (2d, JHH 4.3 Hz, 4H, 2 × (H ,
v/v) as orange crystals (150 mg, 13%), mp 166–
ꢀ
4
◦
◦
H ), furans), 7.27, 7.58 (2d, JHH 4.2 Hz, 2H, 2 ×
168 C (from benzene) [lit. [2], mp 166–168 C (from
benzene)].
ꢀ
5
H , furans), 7.79 (d, JHH 3.6 Hz, 1H, 6-CH); δ
c
ꢀ
(
(
1
2
d
6
-DMSO); 100.6 (4-C), 106.6, 106.8, 110.1, 111.2
3,4-Difur-2 yl-7-methyl-5H-5-oxopyrano[2,3-c]-
ꢀ
ꢀ
2 × (3 -C, 4 -C), furans), 117.7 (CN), 118.8 (7-C),
1,2-dihydropyridazine (14) was obtained (CHCl ,
3
ꢀ
40.7, 142.1, 144.4, 144.6 (2 × 5 -C, furans and 3-C,
v/v) as pale yellow needles (220 mg, 19%), mp
ꢀ
◦
-C), 145.4 (6-C), 151.8, 152.7 (2 -C, furans), 154.8
186–188 C (from CH
2
Cl
2
) (found: C, 65.37; H, 3.46;
+
(
9-C); MS: m/z (EI) (%): 279 (18) [M ], 278 (13), 253
N, 9.55. C16
3.42; N, 9.52%); νmax (KBr)/cm 1728 (C O), 1610,
1598 (C C, furyl); δ (CDCl ) 2.22 (s, 3H, CH ),
6.21 (s, 1H, 6-CH), 6.53, 6.85 (2d, JHH 3.6 Hz, 4H,
H
10
N
2
O
4
(294.27) requires: C, 65.31; H,
−
1
(
100), 227 (42), 160 (24), 83 (56), 67 (28).
ꢀ
5
-Amino-3,4-difur-2 ylpyrano[2,3-c]-1,2-hydro-
H
3
3
pyridazine (8) was isolated (2:8, v/v) as dark yellow
ꢀ
ꢀ
4
◦
3
crystals (255 mg, 23%), mp 190–192 C (from EtOH)
2 × (H , H )-furans), 7.28, 7.89 (2d, JHH 3.8 Hz,
ꢀ
5
c 3 3
(
(
(
δ
5
found: C, 64.11; H, 3.88; N, 14.86. C15
H
11
N
3
O
3
2H, 2 × H , furans); δ
(CDCl
) 13.8 (CH
), 106.6,
ꢀ
ꢀ
281.27) requires: C, 64.05; H, 3.94; N, 14.94%); νmax
107.1, 110.5, 111.2 (2 × (3 -C, 4 -C), 117.3 (6-C),
−
1
KBr)/cm 3366, 3253 (NH
(d -DMSO); 4.25–4.38 (2d, distorted, 2H, 7-CH
.78 (s
2
), 1610 (C C, furans);
127.5 (10-C), 140.8, 141.6 (4-C, 3-C), 146.8, 147.3
ꢀ
H
6
2
),
(2 × 5 -C, furans), 151.4, 152.6, 152.9 (7-Cand 2 ×
ꢀ
w
, 2H, NH
2
), 6.18–6.23 (two pairs, JHH 1.8
2 -C-furans), 156.3 (9-C), 178.2 (5-C O); MS: m/z
ꢀ
3
+
Hz, 6-CH), 6.71, 7.27 (2d, JHH 4.3 Hz, 4H, 2 × (H
(EI) (%): 294 (100) [M ], 279 (17), 263 (42), 235
ꢀ
4
and H ), furans), 7.63, 7.88 (2d, JHH 4 Hz, 2H, 2 ×
(18), 196 (14), 130 (54), 67 (26).
ꢀ
5
H , furyl rings); δ
c
(d
6
-DMSO); 68.7 (7-CH ), 106.2,
2
ꢀ
ꢀ
1
1
3
06.7, 110.2, 110.6 (2 × (3 -C and 4 -C), furans),
Oxidation of 13. A mixture of 0.3 g (1.02 mmol)
13 and 20 mL NaOH (15% aq.) was heated under re-
flux for 3 h. The mixture was cooled, diluted with 5
28.1 (10-C), 133.2 (6-C), 141.4, 143.6, 145.8 (4-C,
ꢀ
-C, and 5-C), 151.6, 152.5 (2 -C, furans), 156.6
+
(9-C); MS: m/z (EI) (%): 281 (100) [M ], 264 (51),
mL water and extracted with CHCl
tion of the solvent in vacuo, the residual yellow solid
was taken up (72%) with a small amount of CH Cl
3
. After evapora-
248 (11), 236 (22), 197 (18), 130 (28), 67 (32).
2
2
and shown to be identical with 14 (TLC, IR, and mass
spectra).
Reaction of 1 with Allyltriphenylphosphonium
Bromide (9): A Preparation of Compounds 12,
1
3, and 14
A stirred solution of 1 g (3.95 mmol) 1 and 1.66 g
4.34 mmol) of 9 in 30 mL EtOH was treated with
0 mL of aqueous LiOH solution (0.5 M). The reac-
Reaction of 1 with Alkylidenetriphenylphos-
phonium Bromides 15a,b: Preparation of
Compounds 17a,b and 18a,b
(
1
tion mixture was heated under reflux for 2 days, and
then was worked up as described for the reaction of
To a solution of 7.4 mmol of the appropriate salt
15a (or 15b) and 1 g (3.95 mmol) of 1 in 30 mL
dry DMF, a solution of a slurry of 250 mg of LiH
dispersion (57% dispersion in mineral oil) in 10 mL
dry DMF was added in one portion. The system
was stirred at room temperature for 2 h and was
further refluxed for 30 h (TLC). The product mix-
ture was poured into 300 mL distilled water, and ex-
tracted with 2 × 100 mL portion of chloroform. The
combined organic extracts were backwashed with
1
with 3. The residue was chromatographed using n-
hexane/CHCl as the eluents to give compounds 12,
3, and 14, respectively.
3
1
ꢀ
2,3-Difur-2 yl-4-cyano-7-methyl-5,8-oxazolo[2,3-
b]pyridazine (12) was obtained (1:1, v/v) as yellow
◦
crystals (452 mg, 39%), mp 157–159 C (from CH
2
Cl
2
)
(
(
(
found: C, 65.57; H, 3.72; N, 14.24. C16
H
11
N
3
O
3
293.28) requires: C, 65.52; H, 3.78; N, 14.33%); νmax
−
1
KBr)/cm 3205, (NH), 2236 (CN); δ
H
1.97 (s, 3H,
distd. water (50 mL), dried with Na
2
SO and the
4

Synthetic Studies Using Unsaturated and Active Phosphonium Salts 63
solvent was removed under reduced pressure. The
residue was chromatographed on silica gel by using
n-hexane/EtOAc as the eluents whereupon 17a and
5.22; N, 14.42. C17
69.61; H, 5.15; N, 14.32%); νmax (KBr) cm 2922,
2852 (2 × NH), 1627 ( CH , exocyclic); δ (CDCl
0.97–1.32 (m, 2 × 3H, CH , 18Ab and 18Bb), 2.38
q, JHH = 6.8 Hz, 2H, CH CH , 18Bb), 4.18 (q (ill),
1H, = CHCH , 18Ab), 4.56, 4.68 (2s, br, 2 × 1H,
2NH), 6.64–7.78 (m, 6H, H-furans); δ (CDCl ) 14.1,
, 18Ab and 18Bb) 28.8 (CH ,
H
15
N
3
O
2
(293.33) requires: C,
−
1
2
H
3
)
1
8a (or 17b and 18b) were isolated, respectively.
3
(
2
3
ꢀ
With 15a. 5-Amino-3,4-difur-2 ylfurano[2,3-c]-
3
1
,2-dihydropyridazine (17a) was obtained (8:2, v/v)
c
3
◦
as orange crystals (232 mg, 22%), mp 137–139 C
15.3, 18.2 (2 × CH
3
2
ꢀ
ꢀ
(
from cyclohexane) (found: C, 62.86; H, 3.35; N,
5.78. C14 (267.24) requires: C, 62.92; H, 3.39;
N, 15.72%); νmax (KBr) cm 3054, 2853 (NH
CDCl ) 5.78 (s br, 2H, NH ), 6.68, 6.89 (2d, JHH 3.5
Hz, 4H, 2 × (H , H ), furans), 7.45, 7.69 (2d, JHH
18Bb) 106.3, 106.8, 110.4, 110.7 (2 × (3 -C and 4 -C),
furans), 127.9, 128.3, 129, 130.6, 140.6, 141.6, 143.2,
145.7, 151.2, 152.6, 154.1, 155.8; MS: m/z (EI) (%):
1
H
9
N
3
O
3
−1
2
); δ
H
+
(
3
2
293 (41) [M ], 292 (100), 278 (10), 263 (19), 248
ꢀ
ꢀ
4
3
(35), 232 (16), 220 (45), 149 (24), 67 (33).
The reaction of equimolar amounts of 1 and 15a
(or 15b) under the same condition, again afforded
17a (or 17b) (∼14%) and 18a (or 18b) (∼28%) along
with 1 (∼20%).
ꢀ
5
3
.5 Hz, 2H, 2 × H , furans), 7.74 (s, 1H, 6-CH); δ
c
ꢀ
ꢀ
(CDCl
3
) 106.3, 106.8, 110.3, 110.7 (2 × (3 -C and 4 -
C), furans), 127.2 (9-C), 141.4, 144.6, 145.5 (4-C, 3-C,
ꢀ
and 5-C), 147.2 (6-C), 150.6, 151.6 (2 × 2 -C), 154.5
+
(
(
8-C); MS: m/z (EI) (%): 267 (37) [M ], 252 (100), 239
66), 224 (17), 157 (28), 67 (33).
Reaction of 2-[(Benzylidene)amino]benzonitrile
ꢀ
3
,4-Difur-2 yl-5-methylisopyrrolo[2,3-c]-1,2-di-
(
2) with Vinyl- (3) and Allyltriphenylphos-
hydropyridazine (18a) was obtained (1:1, v/v) as
phonium Bromide (9): Preparation of
Compounds 20 and 21
◦
pale brown crystals (450 mg, 43%), mp 175–177 C
(
C
1
(
from CHCl
3
) (found: C, 67.86; H, 4.11; N, 15.75.
(265.27) requires: C, 67.92; H, 4.18; N,
15
H
11
N
3
O
2
A solution of the appropriate salt 3 or 9 (4.1 mmol)
and 0.8 g (3.88 mmol) Schiff’s base 2 [15] in 30 mL
EtOH was treated with 15 mL, and the mixture was
heated under reflux for 15 (with 3), or 20 h (with 9).
The reaction mixture was worked up as described for
the reaction of 1 + 3, and separated by column chro-
matography, using n-hexane-EtOAc yielding com-
pound 20 (from 3) or 21 (from 9) and unidentified
products.
−1
5.84%); νmax (KBr) cm 2922, 2854 (2 × NH); 1619
CH , exocyclic); NMR (DMSO): 18Aa δ 4.57, 5.25
); 18Ba δ 1.95
), 6.66–7.89 (m, 7H, 6-CH and H-furans);
) 13.7 (CH ), 112.2 ( CH ), 106.4, 106.8,
2
H
(
(
δ
2s, 2 × 1H, 2NH), 4.87 (s, 2H, CH
s, 3H, CH
(CDCl
2
H
3
c
3
3
2
ꢀ
ꢀ
1
10.5, 110.9 (2 × (3 -C and 4 -C), furans), 118.5
(7-C), 122.5, 130.6 (8-C and 9-C), 141.1, 141.8,
ꢀ
1
44.6, 145.2 (2 × 5 -C, furans, 4-C, 3-C), 151.3, 151.6
ꢀ
+
(
2
2 × 2 -C, furans); MS: m/z (EI) (%): 265 (55) [M ],
5-Amino-2-phenylbenzoazepine (20) was ob-
tained (6:4, v/v) as yellow prisms (500 mg, 55%), mp
64 (100), 250 (18), 249 (26), 235 (31), 207 (9), 198
◦
(17), 121 (28), 67 (31).
180–182 C (from acetone) (found: C, 82.11; H, 6.09;
N, 11.9. C16
N, 11.96%); νmax cm 3446–3255 (NH and NH
(CDCl ) 5.49 (s br, 1H, NH), 5.77 (s br, 2H, NH ), 6.23,
6.79 (2d, JHH4.4 Hz, 3-CH and 4-CH), 7.25–8.13 (m,
9H, H-Ph); δ (CDCl ) 111.3 (3-C), 130.78 (4-C), 135.2
H
14
N
2
(234.3) requires: C, 82.02; H, 6.02;
−
1
With 15b. The first fraction (8:2, v/v) af-
forded orange crystals of 5-amino-3,4-difur-2 yl-
2
); δ
H
ꢀ
3
2
6
(
-methylfurano[2,3-c]-1,2-dihydropyridazine (17b)
◦
244 mg, 22%), mp 151–153 C (from MeCN) (found:
C
3
C, 64.11; H, 3.99; N, 14.86. C15
quires: C, 64.05; H, 3.94; N, 14.94%); νmax (KBr) cm
057, 2925 (NH ); δ (CDCl ) 1.32 (s, 3H, CH ) 5.75
s br, 2H, NH
H
11
N
3
O
3
(281.27) re-
(2-C), 121.3, 124.4, 124.9, 126.1, 127.9, 129.6, 131.5
(C C, Ph), 148.2 (5-C); MS: m/z (EI) (%): 234 (18)
[M ], 233 (22), 219 (40), 193 (100), 77 (55).
−
1
+
3
(
(
2
H
3
3
2
), 6.66, 6.87 (2d, JHH = 3.5 Hz, 4H, 2 ×
5-Amino-3-methyl-2-phenylbenzoazepine (21)
ꢀ
ꢀ
4
3
H , H ), furans), 7.46, 7.71 (2d, JHH = 3.5 Hz, 2H,
was obtained (6:4, v/v) as yellow prisms (558 mg,
ꢀ
5
◦
2
1
1
1
(
(
× H -furans); δ
c
(CDCl
3
) 14.2 (CH
3
), 106.4, 106.8,
58%), mp 208–210 C (from EtOH) (found: C, 82.28;
ꢀ
ꢀ
10.2, 110.5 (2 × (3 -C and 4 -C), furans), 127.6 (9-C),
H, 6.42; N, 11.34. C17
82.22; H, 6.49; N, 11.28%); νmax cm 3302, 3061 (NH
and NH ); δ (CDCl ) 1.45 (s, 3H, CH ) 4.41 (s, 1H,
NH), 5.86 (s br, 2H, NH ), 6.67 (s, 1H, 4-CH), 6.94–
7.97 (m, 9H, H-Ph); δ (CDCl ) 14.7 (CH ), 114.6
H
16
N
2
(248.33) requires: C,
−
1
41.6, 143.8, 146.2 (4-C, 3-C, and 5-C), 151.6, 152.2,
ꢀ
54.7, 155.3 (2 × 2 -C, furans, 6-C, 8-C); MS: m/z (EI)
2
H
3
3
+
%): 281 (41) [M ], 266 (41), 253 (33), 252 (100), 224
16), 157 (21), 137 (31), 90 (29), 67 (36).
2
C
3
3
The second fraction (1:1, v/v) yielded orange
crystals of 3,4-difur-2 yl-6H-5-ethyl-7-methyliso-
(4-C), 133.6 (3-C), 136.4 (2-C), 121.6, 122.7, 124.5,
ꢀ
124.9, 126.7, 127.5, 129.8, 131.3 (C C, Ph), 147.2
+
pyrrolo[2,3-c]-1,2-dihydropyridazine (18b) (544 mg,
(5-C); MS: m/z (EI) (%): 248 (14) [M ], 249 (19), 233
◦
4
7%), mp 195–197 C (CHCl
3
) (found: C, 69.66; H,
(52), 218 (27), 193 (100), 77 (62).

6
4 Abdou et al.
Reaction of 2 with Alkyltriphenylphosphonium
Bromides 15a,b: Preparation of Compounds
REFERENCES
[
1] For recent accounts see references a–g: (a) Abdou,
2
3a, 23b, and 25
A DMF solution of the appropriate salt 15a or 15b
4.1 mmol) and the Shiff’s base 2 (0.8 g, 3.88 mmol)
W. M.; Salem, M. A. I.; Sediek, A. A. Monatsh Chem
2
003, 134, 1373–1385; (b) Abdou, W. M. Phospho-
rus Sulfur Silicon 2002, 177, 325–389 (review); (c)
Abdou, W. M.; El-Khoshnieh, Y. O.; Salem, M. A. I.;
Barghash, R. F. Synlett 2002, 1417–1422; (d) Abdou,
W. M.; Fahmy, A. F. M.; Kamel, A. A. Heteroatom
Chem 2002, 13, 357–365; (e) Abdou, W. M.; Fahmy,
A. F. M.; Kamel, A. A. Eur J Org Chem 2002, 1696–
(
was treated with LiH under the experimental con-
ditions described above for the reaction of 1 and
1
5a,b. The reaction mixture was heated under re-
flux for 15 h (with 15a) or 22 h (with 15b), followed
by the usual working up. The product residue was
then separated by column chromatography using n-
1
701; (f) Abdou, W. M.; Salem, M. A. I.; Sediek, A.
A. J Chem Soc (Jpn) 2002, 75, 2481–2485; (g) Abdou,
W. M.; Ganoub, N. A. F.; Shaddy, A. M. Phosphorus
Sulfur Silicon 2000, 165, 171–189.
hexane-CHCl as the eluents.
3
[
[
2] Abdou, W. A.; Ganoub, N. A. F.; Fahmy, A. F. M.;
Shaddy, A. A. M. Phosphorus Sulfur Silicon, 2004,
in press.
The Reaction of 0.8 g (3.88 mmol) 2 with 1.46 g
4.1 mmol) 15a Afforded 23a and 25. 4-Amino-2-
(
3] Yavari, I.; Djahaniani, H.; Taher, M. J. Chem Res (S)
phenylquinoline (23a) was obtained (8:2, v/v) as yel-
1
999, 382–383.
◦
low crystals (358, 42%), mp 164–166 C (from MeCN)
[4] (a) Moorhoff, C. M. J Chem Res (S) 1997, 130–131;
(M) 879–866.
◦
[
lit. [13c], mp 164 C (from C
6
6
H )].
[
5] (a) Flitsh, W. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R.; Rees, C. W. (Eds.);
Pergamon: London, 1984; Vol. 3, pp. 443–470;
4
-Amino-3-(2-benzonitrile)-2-phenyl-1H-hydro-
quinazoline (25) was obtained (1:1, v/v) as green
◦
crystals (327 mg, 26%), mp 136–138 C (from cyclo-
(b) Tisler, M. Pure Appl Chem 1980, 52, 1611–
hexane) (found: C, 77.71; H, 4.86; N, 17.34. C21
H
16
N
4
1621.
(
324.39) requires: C, 77.76; H, 4.97; N, 17.27%); νmax
[6] Abbady, M. S.; Radwan, Sh. M. Phosphorus Sulfur
Silicon 1994, 86, 203–209.
−
1
cm 3058–3168 (br NH
.87 (s, 2H, NH ), 7.39–7.69 (m, 13H, H-Ph); δ
CDCl ) 112.2 (C-CN), 118.5 (CN), 120.2, 121.3,
24.6, 124.7, 125.6, 126.6, 128.1, 128.5, 131.6, 132.3
2
), 2218 (CN); δ
H
(CDCl
3
)
[
7] (a) Bestmann, H. J.; Zimmerman, R. Org Phosphorus
5
(
1
(
(
(
2
C
Comp 1972, 3, 1–183; (b) Ciganek, E. J Org Chem
3
1
970, 35, 3631–3636.
[8] Schweizer, E. E.; Goff, S. D.; Murray, W. P. J Org Chem
1977, 42, 200–205.
[9] (a) Croce, P. D.; Pocar D. J Chem Soc, Perkin Trans I,
C C, Ph), 148.3 (4-C), 151.6 (9-C); MS: m/z (EI)
+
%): 324 (35) [M ], 310 (21), 284 (22), 233 (9), 221
1
5
976, 619–620; (b) Zbiral, E. Tetrahedron Lett 1970,
107–5110.
27), 181 (100), 103 (40), 77 (56).
[
[
10] Vicente, J.; Chicote, M. T.; Fernandez-Baeza, J.;
Lahoz, F. J Inorg Chem 1991, 30, 3617–3620.
11] (a) Barnhardt, R. G., Jr; McEwen, W. E. J Am Chem
Soc 1967, 89, 1009–1014; (b) Yamakawa, M.; Kubota,
T.; Terui, Y.; Honma, T.; Toda, Y. Bull Chem Soc Jpn
The Reaction of 0.8 g 2 (3.88 mmol) with 1.52 g
5b (4.1 mmol) Afforded 23b and 25. 4-Amino-3-
1
methyl-2-phenylquinoline (23b) was obtained (8:2,
◦
v/v) as yellow crystals (408 mg, 45%), mp 192–194 C
1
978, 51, 3059–3060; (c) Blad e´ -Font, A.; McEwen,
W. E, Wanderwerf, C. A. J Am Chem Soc 1960, 82,
646.
(
from CHCl
3
) (lit. [14], mp or spectral data were not
cited) (found: C, 82.09; H, 5.94; N, 11.88. C16
H
14
N
2
2
(
234.3) requires: C, 82.02; H, 6.02; N, 11.96%); νmax
[
[
12] Nada, A. A.; Erian, A. W.; Mohamed, N. R.; Mahran,
A. M. J Chem Res (S) 1997, 236–237; (M) 1997, 1576–
−
1
cm 2255–3346 (NH
2
); δ
H
(CDCl
3
) 2.24 (s, 3H, CH
3
),
1
594.
5
7
8
1
.77 (s br, 2H, NH
.58–7.74 (m, 3H, H-Ph), 7.77–7.86 (m, 2H, H-Ph),
.08 (d, JHH 8.2 Hz, 1H, H-Ph); δ (CDCl ) 18.2 (CH ),
20.6, 122.4, 124.2, 126.5, 127.1, 129.4, 131.6 (C C,
2
), 7.36–7.56.13 (m, 3H, H-Ph),
13] (a) Sterkowski, L.; Kong, S. B.; Cegla, M. T.; Harden,
D. B. Heterocycles, 1989, 29, 539–546; (b) Casnati,
G.; Quilico, A.; Ricca, A.; Vita-Finzi, P. Gazz Chim
Ital 1966, 96, 1073–1083.
C
3
3
Ph), 133.7 (3-C), 143.7 (9-C), 144.3 (4-C), 148.2 (5-
[14] Ernst, G.; Chapdelaine, M.; Kissel, D.; Hostetler,
G.; McCauley, J. PCT Int. Appl. WO 02 36,568 (Cl.
C07D215/42); CA 2002, 136, 838.
+
C),153.8 (2-C); MS: m/z (EI) (%): 234 (38) [M ], 233
(
42), 219 (22), 218 (100), 193 (65), 77 (55).
[
15] (a) Miyashita, A.; Sasaki, T.; Oishi, E.; Higashino, T.
J Heterocycles 1994, 37, 823–831; (b) Strekowski, L.;
Cegla, S. B. K.; Harden, D. B. J Heterocycl Chem 1989,
26, 923–928.
Compound 25 was obtained (1:1, v/v) as green
crystals (289 mg, 23%), and shown to be identical
with the material, previously described.