Regioselective condensation of alkylidenephosphoranes with bifunctionalized compounds: New approach to the synthesis of fused O- and N-heterocycles

Article abstract of DOI:10.1080/104265090921092

A series of fused pyran- (～40% yield) and furan- (～20% yield) derivatives were regioselectively prepared from the reactions of 5,6-difur-2′yl-3-oxo-2,3-dihydropyridazin-4-carbonitrile with ester- and keto phosphorus ylides, whereas new ylides were obtained, in addition to fused furans, in almost equal yields (33%) from the reaction of the same substrate with cyanomethylene(triphenyl)phosphorane. However, application of such Wittig reagents on 2-[(benzylidene)amino]-benzonitrile afforded, in all cases, 4-hydroxyquinolines in a ～42% yield as major products. Moreover, 2-[(triphenylphosphoranylidene)amino] benzonitrile, with the corresponding alkene, was also isolated a side products. Copyright Taylor & Francis Inc.

Full text of DOI:10.1080/104265090921092

Phosphorus, Sulfur, and Silicon, 180:2373–2390, 2004
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090921092
Regioselective Condensation of Alkylidenephosphoranes
with Bifunctionalized Compounds: New Approach to the
Synthesis of Fused O- and N-Heterocycles
Wafaa M. Abdou
Neven A. F. Ganoub
Department of Pesticide Chemistry, National Research Centre, Dokki,
Cairo, Egypt
Amin F. M. Fahmy
Department of Chemistry, Ain Shams University, Cairo, Egypt
Abeer A. M. Shaddy
Department of Pesticide Chemistry, National Research Centre, Dokki,
Cairo, Egypt
A
series of fused pyran- (∼40% yield) and furan- (∼20% yield) deriva-
tives were regioselectively prepared from the reactions of 5,6-difur-2ꢀyl-3-oxo-
2,3-dihydropyridazin-4-carbonitrile with ester- and keto phosphorus ylides,
whereas new ylides were obtained, in addition to fused furans, in almost
equal yields (33%) from the reaction of the same substrate with cyanomethy-
lene(triphenyl)phosphorane. However, application of such Wittig reagents on 2-
[(benzylidene)amino]-benzonitrile afforded, in all cases, 4-hydroxyquinolines in a
∼42% yield as major products. Moreover, 2-[(triphenylphosphoranylidene)amino]
benzonitrile, with the corresponding alkene, was also isolated a side products.
Keywords Alkylidenephosphoranes; N-Heterocycles; nitriles; Shiff’s base
Many pyridazine derivatives1 are reported as insecticides, miticides,
nematocides,1a acaricides, fungicides,1b and cardiotonics.1c In addition,
many substituted benzofurans show marked pharmacological activity,
e.g., 2-(4-hydroxybenzoyl)benzofuran exhibits a relaxant effect on his-
tamine and an acetylcholine spasm.2 This has been the main impetus
behind growth of research in new derivatives of these substrates during
the last four decades.
Received June 17, 2004; accepted October 22, 2004.
Address correspondence to Wafaa M. Abdou, National Research Centre, Department
of Pesticide Chemistry, Dokki, Cairo, Egypt. E-mail: wabdou@intouch.com
2373

2374
W. M. Abdou et al.
Over the past decade, we have investigated the synthetic util-
ity of phosphorus ylides. We also have illustrated the usefulness
of such reagents for the synthesis of heterocycles with numerous
examples.3 Consequently, in the present work, we describe the use
of alkylidenephosphoranes 3 for building fused heterocyclic systems
that are condensed with pyridazine and phenyl species. Target com-
pounds were achieved from the reactions of 3a, 3b, 3c, 3d, and 3e
with 5,6-difur-2ꢀyl-3-oxo-1,3-dihydropyridazin-4-carbonitrile (1) and 2-
[(benzylidene)amino]benzonitile (2) (Scheme 2).
The investigation also highlighted the influence of replacing the car-
bonyl group with a Schiff’s base (anil) moiety at the ortho-position
with respect to the nitrile group in the behavior toward phosphorus
ylides. The reactions studied and the products obtained are depicted in
Schemes 2, 4, 5, and 7.
SCHEME 1
RESULTS AND DISCUSSION
The required carbonitrile 1 was prepared according to the literature4
by ternary condensation of 2-furaldehyde, ethylcyanoacetate, and hy-
drazine hydrate in an alcoholic sodium ethoxide solution. No reaction
was observed when equimolar amounts of 1 and ester-3a and 3b, keto
ylides 3c and 3d, or cyanomethylene(triphenyl)phosphorane (3e) were
refluxed in dry toluene (or dry ethyl acetate), even after 3 days. How-
ever, treatment of 1 with ylide 3a or 3b, generated in situ from the
corresponding phosphonium bromide 4a or 4b by addition of aqueous
lithium hydroxide in chloroform, yielded 5-amino-3,4-difur-2ꢀyl-7H-7-
oxopyran[2,3-c]pyridazine (8) (∼39% yield) and alkyl 5-amino-3,4-difur-
2ꢀylfuro[2,3-c]pyridazine-6-carboxylates (10a and 10b) (∼26% yield)
(Scheme 2).

Regioselective Condensation of Alkylidenephosphoranes
2375
SCHEME 2
The mechanism of condensation of the nitrile 1 with ylides 3a and
3b probably involved the initial formation of an intermediate of type
5 with a subsequent ring closure to afford dihydroazaphosphete 6.5,6
Under thermal conditions, and in the presence of a base (LiOH), the

2376
W. M. Abdou et al.
SCHEME 3
SCHEME 4

Regioselective Condensation of Alkylidenephosphoranes
2377
SCHEME 5
zwitterion 5 presumably was formed. The iminophosphorane 7 then re-
sulted from the opening of the four membered ring, lactonization, and
extrusion of the appropriate alcohol moiety. Further hydrolysis of 7
yielded the final product 8 and triphenylphosphine oxide (Scheme 2(i)).
On the other hand, rearrangement6,7 of 5 to the imino intermediate 9,
followed by the attack of anionic oxygen on the ylidic carbon, led to the
furopyridazines 10a or 10b via elimination of triphenylphosphine and
prototropic rearrangement (Scheme 2(ii)). An analogous mechanism
has been reported previously by Barnhardt6a and recently by Vicente5a
for the reactions of phosphonium salts with nitriles.
SCHEME 6

2378
W. M. Abdou et al.
SCHEME 7
In contrast to these findings that were obtained from the reaction
of pyridizanone 1 with 3a and 3b, Wittig olefination occurred when
3a and 3b were allowed to react with ethyl 2-phenyl-5-methyl-3-oxo-
2, 3-dihydropyridazine-6-carboxylate (A) in dry toluene to give the

Regioselective Condensation of Alkylidenephosphoranes
2379
corresponding olefin Ba and Bb8 (‘Scheme 3’). Considering the latter re-
action of pyridazine A with 3a and 3b, the ylide’s attack of the carbonyl-
carbon in A and not of the nitrile moiety as it took place in the reactions
of pyridazinone 1 with 3a and 3b could be attributed to the lack of a
mobile hydrogen in A. However, it seemed necessary to extend this
investigation to optimize the conditions that control the selectivity of
the nucleophilic attack toward substituted pyridazines of type 1. Vari-
ation of the type of the pyrimidine substituent, the reaction solvent,
the temperature, and the base used, will be addressed in a forthcoming
communication.
When a mixture of an equimolar amount of 1 and 2-oxopropyl
(triphenyl)phosphonium chloride (4c) or (2-oxo-2-phenylethyl)(tri-
phenyl)phosphonium bromide (4d) in dimethylformamide was
treated with LiH or CHCl3/H2O/LiOH (best yields with LiH/DMF), the
substituted furopyridazines 13a and 13b (∼18% yield) and pyranopy-
ridazines 15a and 15b (∼41% yield) were isolated (Scheme 4).
Obviously, the reaction of 1 with 4c and 4d proceeds under more dras-
tic conditions (a higher temperature [DMF] and stronger base [LiH])
than that used for 1 with 4a (or 4b). Scheme 4 shows that 3c and 3d
can affect a replacement9 of the nitrile group, forming the phosphonium
intermediate 11, which loses HCN, giving the phosphorane 12. Hydrol-
ysis of 12, followed by internal hemi-acetalization,10 yielded 13a and
13b (Scheme 4(i)). On the other hand (parallel to 9, Scheme 2), the
expected initially formed zwitterion intermediates 14a and 14b, which
would give rise to the iminopyrans 15a and 15b through intramolecular
cyclization and the elimination of triphenylphosphine oxide (Scheme
4(ii)). The formation of an intermediate of type 1411,12 and its trans-
formation into imines has, however, been reported for the reaction of
alkylidenephosphoranes and nitriles.6a Following this, Schemes 2 and
4 point out a variety of reaction pathways, which can follow an initial
attack of phosphorus ylides 3a, 3b, 3c, and 3d to CN moiety.
On treating pyridizanone
1
with cyanomethylene (triph-
enyl)phosphonium chloride (4e), in CH3/H2OLiOH, (5,6-difur-2ꢀyl-3-
oxo-1,3-dihydropyridazin-4-yl) (triphenyl)phospharylideneacetonitrile
(16, 33% yield) along with the substituted furopyridazine 17 (∼30%
yield) were obtained according to Scheme 5. On heating the complex
ylide 16 under reflux, in ethyl acetate containing a catalytic amount
of triethylamine with benzaldehyde for 10 h, the Wittig-reaction
readily occurred yielding 2-(5,6-difur-2ꢀyl-3-oxo-1,3-dihydropyridazin-
4-yl)-3-phenylacrylonitrile (18, 52% yield). Only one isomer of 18 was
isolated and it was suggested that it may have a syn-configuration
(based on NMR investigation of the CH resonance). Thus, the exocyclic

2380
W. M. Abdou et al.
1
methine proton appeared as a singlet at δ 5.85 ppm in the H NMR
spectrum of 18, which is in accordance with a chemical shift expected
for the Z-configuration and readily eliminates the E isomer. The latter
would predict a singlet at a more downfield resonance in the range δ
6.5–7.6 ppm. Furthermore, it is reported13 that the presence of the two
higher-ranking groups on the same side of the double bond is in favor
of the assigned Z structure.
The results presented in Schemes 2, 4, and 5 make it likely that
resonance-stabilized phosphoranes 3 attack 1 only at the nitrile group,
instead of the amidic carbonyl function, whereby the betaine interme-
diates corresponding to 5 are formed in all the reactions of 3a, 3b, 3c,
3d, and 3e with the nitrile 1. However, perusal of the literature indi-
cated that attempts to add nitriles to resonance-stabilized ylides, i.e.,
those carrying electron-withdrawing groups on the ylide carbon, were
unsuccessful.5b The findings also reflect the inertness of molecule 1.
This is probably due to the low reactivity of the nitrile function and
the carbonyl group of amides toward nucleophilic attack.14 The ther-
mal conditions, coupled with the presence of an excess of a strong base
(LiOH or LiH) used for the generation of a ylide, however, deprotonate
either the ylide or the pyridazinone promoting thus a further reaction.
The attack at the nitrile-carbon, in these cases, could be attributed to
the formation of lithium ion complexes with the nitrile and, thereby, in-
crease the electrophilic reactivity of the carbon atom of the cyano group
in the condensation reactions under consideration. Furthermore, the
adjacent carbonyl group reinforces the electrophilic character of the ni-
trile moiety. The probable mechanism of the condensation step in the
reaction of the ylide, derived from phosphonium salt with arylnitriles,
in the presence of lithium ion, was previously discussed by Barnhardt
and colleagues6a (Scheme 6).
The reactions of alkylidenephosphoranes 3a, 3b, 3c, and 3d with
2-[(benzylidene)amino]benzonitrile (2) were investigated next in an
effort to search for possible dissimilarities that might occur when
another electronegative species (−N C) was introduced, in lieu
of the amidic carbonyl group, at the ortho-position to the nitrile
moiety. The required Schiff-base 2 was prepared in a reasonable
yield (88%) from the condensation of the parent o-aminobenzonitrile
with benzaldehyde.15 Treatment of anil 2 with ester ylide 3a (one
equivalent) in boiling chloroform containing a trace amount of
piperidine for 60 h afforded 4-hydroxyquinoline 22a (42% yield),
2-[(triphenylphosphoranylidene)amino]benzonitrile (23)16 (22%) and
methyl cinnamate (24a) (20% yield). Similarly, 2 reacted with 3b, 3c,
3d, and 3e to give 22b17,18 or 22c, 22d, and 22e (∼40% yield) together

Regioselective Condensation of Alkylidenephosphoranes
2381
with 23 (∼20% yield) and the corresponding olefin 24b, 24c 24d, and
24e (∼20% yield). When 23 was allowed to react with benzaldehyde,
the Wittig reaction readily occurred and yielded the expected product
2, whereas o-aminobenzonitrile was obtained by alkali-hydrolysis of 23
(or by standing at room temperature for few days). Benzylidine deriva-
tives 24 were verified by m.p. and mixed m.p., as well as comparative
spectra with reference samples.
Scheme 7 shows a working hypothesis for the formation of the iso-
lated products 22, 23, and 24. Wittig reagent 3 adds to the imine link-
age of 2, giving the intermediate 19. The further collapse11 of 19, by
the transfer of nitrogen from carbon to phosphorus (Wittig-type reac-
tion), yields the iminophosphorane 23 and the respective alkene 24.
On the other hand, the prototropic rearrangement of 19 results in the
intermediates 20. Next, internal Hofmann elimination of Ph3P and in-
tramolecular cyclization leads to 4-imino-quinolines 21, which affords
4-hydroxyquinolines 22 by hydrolysis. A similar transformation, i.e., an
imino group to a hydroxyl moiety, is known for the imino intermediates
to the corresponding hydroxyl compounds or the keto-structure.5,6,19
1
It also is worthy to note that the IR and H NMR spectra of 22 indi-
cated the presence of 22 only in the enol form, which is the more stable
structure.20 Furthermore, the formed alkenes 24 did not have any fur-
ther reaction with Wittig reagents. This finding is along the line, which
has been previously pointed out, that such reagents do not react with
the isolated alkenes from Wittig reactions.11
Finally, the methods previously described for the preparation of
quinoline 22b are lengthy and indirect.17,18 For example, 22b was syn-
thesized from the condensation of ethyl benzoylmalonates and aniline.
The acrylates, unstable under normal conditions, was cyclized to 22b
(∼27% yield) using acetic anhydride and sulfuric acid. In the present
context, 22a–e (∼ 42% yield) could be available by a one-step synthe-
sis from the reaction of the proper anilide with resonance-stabilized
phosphorus ylides.
CONCLUSION
In summary, the present investigation clearly shows that the phos-
phoranes 3a, 3b, 3c, 3d, and 3e behave toward the nitriles 1 and 2
in different manners. The nature of the α-substituent to the nitrile
group in 1 and 2 plays, however, a decisive role in their reactions with
the Wittig reagents of type 3 . Thus, 3 exclusively attacks the nitrile
group in 1, whereas the imino function 2 is the reactive one. Finally, the
O- and N-heterocycles prepared in the present work might be biologi-
cally active compounds based on known drug skeletons.

2382
W. M. Abdou et al.
EXPERIMENTAL
Melting points (m.p.) are uncorrected. Infrared spectra were measured
with a Perkin-Elmer IR-spectrometer model 597 using KBr discs. The
1H and 13C NMR spectra were recorded by a Bruker Model WH-300
MHz spectrometer using TMS as an internal reference. Chemical shifts
are given in the δ-scale (ppm), coupling constants J in Hz. The 31P NMR
spectra were run on a Varian CFT-20 relative to external H3PO4. Mass
spectra were run at 70 eV on a Schimatzu GCS-QPEX spectrometer
provided with a data system. The appropriate precautions in handling
moisture-sensitive compounds were observed. Light petroleum refers
to the fraction 40–60◦C. Methyl trans-cinnamate (24a) and the ethyl
analog (24b) are available from Aldrich Company.
Reactions of 5,6-di-2-furyl-3-oxo-2,3-dihydropyridazin-4-
carbonitrile (1) with Ester Ylides 3a and 3b
Preparation of Compounds 8 and 10a and 10b
General Method. A solution of 4.5 mmol alkoxycarbonylmethylene
(triphenyl)phosphonium bromide 4a or 4b and 1 g (3.95 mmol) pyri-
dazine 14 in 30 mL CHCl3 was stirred at room temperature up to the
dissolution of the starting materials (∼1 h). Freshly prepared 15 mL
aqueous LiOH (0.5 M) was added in one portion to the mixture, and the
two-phase system was stirred at the reflux temperature up to the con-
sumption of the starting pyridazinone (∼40 h, TLC). After concentration
of the solvent, 20 mL distilled water was added and the solution was
acidified with concentrated HCl. The resulting solution was extracted
with (3 × 50 mL) chloroform. The combined organic layers were dried
over MgSO4 and the solvent was removed under reduced pressure. The
residue was chromatographed on silica gel by using n-hexane/CHCl3
as the eluents whereupon compounds 10a and 8 or 10b and 8 were
isolated, respectively.
With 4a
Methyl
5-amino-3,4-difur-2ꢀ-ylfuro[2,3-c]pyridazine-6-carboxylate
(10a) was obtained (8:2, v/v) as pale yellow crystals (300 mg, 24% yield),
m.p. 158–160◦C (EtOH). Anal. calcd. for C16H11N3O5 (325.29): C, 59.08;
H, 3.41; N, 12.92. Found: C, 59.14; H, 3.33; N, 12.86%. IR: 3458, 3355
1
(NH2), 1695 (C O, ester). H NMR (d6-DMSO): δ 3.39 (s, 3H,H CO,
3
ꢀ
ꢀ
ester), 5.91 (s, 2H,H N), 6.73, 7.16 (2d, JHH = 4.7, 4H, 2 × H3 , H4 ,
2
ꢀ
furans), 7.31, 7.57 (2d, JHH = 4, 2H, 2 × H5 , furans); 13C NMR
(d6-DMSO): δ 55.3 (OCH3, ester), 106.2, 106.8, 110.2, 110.9 (2 × (3ꢀ-C

Regioselective Condensation of Alkylidenephosphoranes
2383
& 4ꢀ-C), furans), 127.6 (9-C), 140.8, 141.3, 144.5, 144.7, 147.4 (2 ×
5ꢀ-C-furans, 5-C, 4-C, 3-C), 151.3, 151.9 (2ꢀ-C-furans), 153.3 (6-C),
155.1 (8-C), 161.4 (C O, ester); MS: m/z (EI) (%): 325 (100) [M+], 310
(7), 294 (11), 266 (22), 258 (18), 191 (46), 199 (27), 132 (64), 67 (30).
5-amino-3,4-difur-2ꢀ-yl-7H-7-oxopyran[2,3-c]pyridazine (8) was ob-
tained (2:8, v/v) as greenish-yellow crystals (430 mg, 37% yield), m.p.
305–307◦C (EtOH). Anal. calcd. for C15H9N3O4 (295.26): C, 61.02; H,
3.07; N, 14.23. Found: C, 61.08; H, 3.01; N, 14.15%. IR: 3435, 3268 (NH2),
1685 (C O, lactone), 1610 (C C, furans). δH NMR (d6-DMSO): δ 5.93 (s,
ꢀ
2H, H N), 6.42 (s, 1H, 6-CH), 6.71, 7.27 (2d, JHH = 4.7, 4H, 2 × H3
&
2
ꢀ
ꢀ
H4 , furans), 7.63, 7.88 (2d, JHH = 4, 2H, 2 × H5 -furyl rings); 13C NMR
(d6-DMSO): δ 106.2, 106.7, 110.2, 110.6 (2 × (3ꢀC & 4ꢀC), furans), 118.5
(6-C), 127.6 (10-C), 140.7, 141.4, 143.6 (5-C, 4-C, 3-C), 147.1, 148.1 (2
× 5ꢀ-C, furans), 151.6, 152.5 (2ꢀ-C, furans), 155.4 (9-C), 174.6 (C =O,
lactone); MS: m/z (EI) (%): 295 (100) [M+], 279 (14), 267 (18), 251 (35),
229 (41), 185 (52), 163 (70), 67 (26).
With 4b
Ethyl
5-amino-3,4-difur-2ꢀ-ylfuro[2,3-c]pyridazine-6-carboxylate
(10b) was obtained (8:2, v/v) as pale-yellow crystals (375 mg,
28% yield), m.p. 132–134◦C (CH2Cl2). Anal. calcd. for C17H13N3O5
(339.32): C, 60.18; H, 3.86; N, 12.38. Found: C, 60.25; H, 3.78; N,
12.26%. IR: 3463, 3364 (NH2), 1695 (C O, ester). 1H NMR (d6-DMSO):
δ 0.92 (t, JHH =7, 3H, OCH2CH ), 3.70 (q, JHH = 7.2, 2H, OCH ),
3
2
ꢀ
ꢀ
5.92 (s, 2H, H N), 6.77, 7.16 (2d, JHH = 4.8, 4H, 2 × H3 -, H4 -furans),
2
ꢀ
7.27, 7.58 (2d, JHH = 4, 2H, 2 × H5 , furans); 13C NMR (d6-DMSO):
δ 15.6 (O.C.CH3, ester), 61.8 (OCH2), 106.6, 106.8, 110.1, 111.2 (2 ×
(3ꢀ-C, 4ꢀ-C), furans), 129.3 (9-C), 140.7, 142.1, 144.5, 144.4, 147.8 (2 ×
5ꢀ-C-furans & 5-C, 4-C, 3-C), 150.6, 151.4 (2ꢀ-C-furans), 153.3 (6-C),
155.1 (8-C), 162.2 (C O, ester); MS: m/z (EI) (%): 339 (100) [M+], 323
(10), 310 (16), 272 (26), 266 (27), 206 (38), 199 (36), 132 (58), 67 (31).
Compound 8 also was obtained (2:8, v/v) in 41% yield (m.p., mixed
m.p., and IR as previously described, see supra).
No reaction was observed when equimolar amounts of 1 and 3a (or
3b) were refluxed in dry toluene (or dry ethyl acetate), even after 3 days.
Reaction of 1 with Keto Ylides 3c and 3d
Preparation of Compounds 13a, 13b, 15a and 15b
General Method. A solution of 1.77 g (2-oxopropyl)(triphenyl)phos-
phonium chloride (4c) (5 mmol) or 2.3 g (2-oxo-2-phenylethyl)-
(triphenyl)phosphonium bromide (4d) (5 mmol) in 25 mL DMF was
added dropwise to 200 mg slurry of LiH dispersion (60% in paraffin

2384
W. M. Abdou et al.
oil) in 15 mL DMF. The reaction mixture was stirred at room temper-
ature, until all hydrogen evolution had ceased, and 1 g pyridazinone
1 (3.95 mmol) was introduced together. The reaction mixture was al-
lowed to remain at room temperature for another 2 h, and was then
heated under reflux for ∼3 days (TLC). The product mixture was con-
centrated to 10 mL, diluted with 30 mL distilled. H2O, acidified with
conc. HCl, and then extracted with two portions (100 mL) of ethyl ac-
etate. The AcOEt extracts were combined, back-washed with 100 mL
H2O, and dried, and the solvents were evaporated to dryness. The
residue was chromatographed on silica gel with n-hexane/CHCl3 as
the eluent whereupon compounds 13a and 15a or 13b and 15b were
isolated.
3,4-Difur-2ꢀ-yl-6-methylfuro[2,3-c]pyridazine (13a) was obtained
(1:1, v/v) as yellow leaflets (158 mg, 15% yield), m.p. 123–125◦C (MeCN).
Anal. calcd. for C15H10N2O3 (266.26): C, 67.66; H, 3.78; N, 10.52. Found:
1
C, 67.77; H, 3.72; N, 10.45%. IR: 1598, 1610 (C C, furans). H NMR
ꢀ
(CDCl3): δ 2.21 (s, 3H, -CH ), 6.42–6.73 (m, 5H, 5-CH & 2 × (H3 ,
3
ꢀ
H4 ) furans), 7.36, 7.82 (2d, JHH = 4, 2H, 2 × H5, furans); 13C NMR
(CDCl3/d6-DMSO): δ 22.6 (6-C.CH3), 104.4 (5-C), 106.77, 106.8, 110.1,
111.2 (2 × (3ꢀ-C, 4ꢀ-C), furans), 129.3 (9-C), 140.7, 142.1, 144.5, 147.8
(2 × 5ꢀ-C, furans & 4-C, 3-C), 150.6, 151.4 (2ꢀ-C, furans), 152.3 (6-C),
155.1 (8-C); MS: m/z (EI) (%): 266 (55) [M+], 251 (14), 200 (23), 185 (37),
134 (18), 119 (100), 66 (22).
3,4-Difur-2ꢀ-yl-7-methyl-5H-pyrano[2,3-c]pyridazine-5-imine (15a)
was obtained (CHCl3) as orange crystals (485 mg, 42% yield), m.p.
166–168◦C (benzene). Anal. calcd. for C16H11N3O3 (293.29): C, 65.52;
H, 3.78; N, 14.33. Found: C, 65.61; H, 3.74; N, 14.26%. IR: 3330
(NH, weak), 1622 (C NH). 1H NMR (CDCl3/d6-DMSO): 2.24 (s, 3H
ꢀ
-CH ), 6.08 (s, 1H, 6-CH-pyran), 6.42–6.73 (2d (m), 2 × 4H, (H3 ,
3
ꢀ
ꢀ
H4 ), furans), 7.28, 7.89 (2d, JHH = 4, 2H 2 × H5 , furans), 8.99 (s br,
1H, =NH); 13C NMR (CDCl3/d6-DMSO): δ 13.8 (CH3), 106.3, 106.8,
108.2, 110.3, 110.7 (6-C & 2 × (3ꢀ-C, 4ꢀ-C),furans), 128.1 (10-C), 141.2,
141.6, 144.4, 146.1 (2 × 5ꢀ-C-furans & 4-C, and 3-C), 151.5, 152.3,
152.8 (7-C and 2 × 2ꢀ-C-furans), 154.3 (9-C), 158.8 (5-C); MS: m/z (EI)
(%): 293 (21) [M+], 292 (32), 278 (17), 263 (44), 197 (11), 131 (100),
67 (26).
3,4-Difur-2ꢀ-yl-6-phenylfuro[2,3-c]pyridazine (13b) was obtained
(3:7, v/v) as yellow crystals (270 mg, 21% yield), m.p. 148–150◦C
(acetone). Anal. calcd. for C20H12N2O3 (328.33): C, 73.16; H, 3.68;
N, 8.53. Found: C, 73.23; H, 3.61; N, 8.42%. IR: 1595, 1610 (C C,
ꢀ
furans). H NMR (d6-DMSO): δ 6.42–6.78 (m, 5H, 5-CH & 2 × (H3 ,
1
ꢀ
ꢀ
H4 ), furans), 7.28–8.24 (m, 7H, 2 × H5 , furans & H-phenyl); 13C
NMR (CDCl3/d6-DMSO): δ 106.4 (5-C), 106.77, 106.8, 110.5, 110.9 (2 ×

Regioselective Condensation of Alkylidenephosphoranes
2385
(3ꢀ-C& 4ꢀ-C), furans), 117.8, 120.8, 129.2, 134.6 (C C, Ph), 128.8 (9-C),
140.6, 142.4, 143.4, 144.1, 147.6 (2 × 5ꢀ-C-furans & 4-C, 3-C), 150.7,
151.4 (2ꢀ-C-furans), 153.6 (6-C), 155.1 (8-C); MS: m/z (EI) (%): 328 (55)
[M+], 327 (33), 262 (27), 196 (100), 67 (35).
3,4-Difur-2ꢀ-yl-7-phenyl-5H-pyrano[2,3-c]pyridazine-5-imine (15b)
was obtained (AcOEt) as brown needles (560 mg, 40% yield), m.p.
285–287◦C (CHCl3). Anal. calcd. for C21H13N3O3 (355.36): C, 70.98;
H, 3.69; N, 11.82. Found: C, 71.08; H, 3.63; N, 11.71%. IR: 3325
1
(NH, weak), 1618 (C NH). H NMR (CDCl3/d6-DMSO): δ 6.03 (s, 1H,
ꢀ
ꢀ
6-CH-pyran), 6.42–6.73 (2d(m),2 × 4H, H3 , H4 , furans), 7.24–8.13
ꢀ
(m, 7H, 2 × H5 -furans and H-phenyl), 8.74 (s br, 1H, =NH); 13C
NMR (CDCl3/d6-DMSO): δ 106.3, 106.8, 108.2, 110.3, 110.7 (6-C & 2 ×
(3ꢀ-C, 4ꢀ-C), furans), 118.7, 121.0, 129.3, 135.4 (C C, Ph), 128.1 (10-C),
141.2, 141.6, 144.3, 144.8 (2 × 5ꢀ-C, furans, 4-C, and 3-C), 148.9, 151.5
(2 × 2ꢀ-C-furans), 153.6 (7-C), 155.2 (9-C), 158.8 (5-C); MS: m/z (EI)
(%): 355 (17) [M+], 354 (26), 353 (29), 340 (22), 274 (31), 208 (100), 67
(24).
When the above reactions, between 1 and 4c (or 4d), using the same
amounts, was refluxed in CHCl3/H2O/LiOH solution for 100 h under the
same conditions and working up previously described for the reaction 1
with 4a (and 4b), compounds 13a (100 mg, 10% yield) and 15a (265 mg,
23% yield) or 13b (167 mg, 13% yield) and 15b (265 mg, 23% yield) were
isolated and characterized (m.p., mixed m.p., and comparative spectra).
No reaction was observed when equimolar amounts of 1 and 3a
(or 3b) were refluxed in dry toluene (or dry ethyl acetate), even after
3 days.
Reaction of 1 with Cyanomethylene(triphenyl)phosphorane
(3e)
A solution of 1.52 g phosphonium chloride 4e (4.5 mmol) and 1 g of
pyridazine 1 (3.95 mmol) in 30 mL CHCl3 was treated with 12 mL
LiOH (0.5 M) for 1 h at room temperature, and then refluxed for 24 h.
The mixture was worked up as described for the reactions 4a (or 4b)
and separated by column chromatography using AcOEt and then EtOH
as the eluents.
5-Amino-3,4-difur-2-ylfuro[2,3-c]pyridazine-6-carbonitrile (17) was
obtained (AcOEt) as pale-brown crystals (340 mg, 30% yield), m.p. 198–
200◦C (CHCl3). Anal. calcd. for C15H18N4O3 (292.26): C, 61.64; H, 2.76;
N, 19.17. Found: C, 61.68; H, 2.70, N, 19.07%. IR: 3459, 3342 (NH2),
1
2212 (CN). H NMR (d6-DMSO): δ 5.94, 5.95 (2d, JHH = 6.5, 2 × 1H,
ꢀ
ꢀ
NH ), 6.48, 6.70 (2d, JHH = 3.5, 4H, 2 × (H3 , H4 ), furans), 7.41, 7.95 (2d,
2
ꢀ
JHH = 3.5, 2H, 2 × H5 -furans); 13C NMR (CDCl3/d6-DMSO): δ 106.3,

2386
W. M. Abdou et al.
106.8, 110.3, 110.7 (2 × (3ꢀ-C, 4ꢀ-C), furans), 117.4 (CN), 128.1 (9-C),
140.7 (5-C), 141.2, 143.4, 144.1, 144.5 (2 × 5ꢀ-C, furans, 4-C, and 3-C),
150.2, 151.5 (2 × 2ꢀ-C,furans), 153.6 (6-C), 155.2 (8-C); MS: m/z (EI)
(%): 292 (23) [M+], 276 (27), 241 (44), 250 (11), 184 (36), 160 (14), 118
(55), 67 (30).
(5,6-difur-2-yl-3-oxo-2,3-dihydropyridazin-4-yl)(triphenylphospha-
rylidene) acetonitrile (16) was obtained (ethyl alcohol) as brown
powder (680 mg, 33% yield), m.p. 289–291◦C (EtOH). Anal. calcd. for
C32H22N3O3P (527.53): C, 72.86; H, 4.20; N, 7.97; P, 5.87. Found: C,
72.74; H, 4.13; N, 7.88; P, 5.93%. IR: 3360 (NH), 2212 (CN), 1654 (C O,
amide), 1682, 1505 (C ꢀ P). 1H NMR (d6-DMSO): δ 6.46, 6.76 (2d, JHH
=
ꢀ
ꢀ
3.5, 4H (2 × H3 & H4 ), furans), 7.36–7.95 (m, 17H, 2 × H5 -furans &
H-phenyl), 12.98 (br, 1H, NH); 13C NMR (CDCl3/d6-DMSO): δ 88.7 (d,
1 J = 104.6, C=PPH3), 106.3, 107.6, 110.6, 110.5 (2 × (3ꢀ-C & 4ꢀ-C),
CP
furans), 117.4, 118.3, 118.7, 121.0, 122.4, 123.6, 129.3, 133.2, 133.8,
135.4 (CN, C C, Ph & 4-C), 141.4, 144.9 (5-C, and 6-C), 146.9, 150.7
(2 × 5ꢀ-C-furans), 172.4 (3-C =O); 31P NMR (d6-DMSO): δ 14.88 ppm;
MS: m/z (EI) (%): 527 (9) [M+], 501 (14), 265 (38), 239 (100), 199 (26),
133 (42), 67 (27).
No reaction was observed when equimolar amounts of 1 and 3e were
refluxed in dry toluene (or dry ethyl acetate), even after 3 days.
Wittig Reaction of the Produced Ylide 16
To a solution of 0.5g 16 (0.95 mmol) in 15 mL ethyl acetate con-
taining 0.3 mL TEA (1.3 mmol), 160 mg benzaldehyde (1.5 mol) was
added. The reaction mixture was refluxed for 10 h and then the volatile
materials were removed under the reduced pressure. Extraction of
the residual substance with hot petroleum (boiling range, 60–80◦C)
gave on cooling Ph3PO, m.p. 155–156◦C. Crystallization of the residue
from acetone yielded 2-(5,6-difur-2ꢀ-yl-3-oxo-1,3-dihydropyridazin-4-
yl)-3-phenylacrylonitrile (18) (175 mg, 52% yield), m.p. 212–214◦C.
Anal. calcd. for C21H13N3O3 (355.36): C, 70.98; H, 3.69; N, 11.82. Found:
C, 70.92; H, 3.64; N, 11.71%. IR: 3360 (NH), 2219 (CN), 1654 (C O,
amide), 1613 (C C, exocyclic); 1H NMR (d6-DMSO): δ 5.85 (s, 1H,
ꢀ
ꢀ
=CH, exocyclic), 6.35–6.90 (m, 4H, 2 × (H3 -, H4 ), furans), 7.36–8.14
ꢀ
(m, 7H, 2 × H5 -furans and H-phenyl), 12.85 (br, 1H, NH); 13C NMR
(CDCl3/d6-DMSO): δ 98.8 (C-CN), 106.3, 108.6, 110.6, 110.5 (2 × 3ꢀ-
C, 4ꢀC, furans), 117.7 (CN), 118.7, 122.4, 133.7, 135.4 (C C, Ph & 4-
C), 141.4, 142.4, 144.6, 144.9 (2 × 5ꢀ-C, furans, 5-C, and 6-C), 146.9,
148.9, 150.7 (CHPh & 2 × 2ꢀ-C-furans), 174.2 (3-C O); MS: m/z (EI)
(%): 355 (25) [M+], 329 (33), 327 (7), 301 (16), 265 (100), 223 (60),
67 (18).

Regioselective Condensation of Alkylidenephosphoranes
2387
Reactions of 2-[(Benzylidene)amino]benzonitrile (2) with
ylides 3a, 3b, 3c, 3d, and 3e
Preparation of Compounds 22, 23, and 24
A stirred solution of 0.8g 215 (3.88 mmol) and the appropriate ylide
3a, 3b, 3c, 3d, and 3e (4.1 mmol) in 20 mL CHCl3 containing 0.5 mL
piperidine was boiled under reflux for 40–60 h (TLC). The pale-yellow
material that precipitated was collected, crystallized from EtOH, and
identified as 2-[(triphenylphosphoranylidene)amino]benzonitrile (23)
(∼ 20% yield), m.p. 149–151◦C (lit.,16 m.p. 149–151◦C).
The filtrate was evaporated under reduced pressure and the residue
was separated by column chromatography on silica gel. Elution with n-
hexane yielded the corresponding known E-olefin 24a, 24b, 24c, 24d,
and 24e.
Methyl trans-cinnamate (24a) was obtained as colorless liquid, b.p.
260–262◦C (lit.,21a b.p. 260–262◦C).
Ethyl trans-cinnamate (24b) was obtained as colorless liquid, b.p.
126–130◦C/6 m (lit.,21b b.p. 126–131◦C/6 mm).
Benzylidene-acetone (24c) was dissolved in 95% EtOH and
the solution was treated with an aqueous solution of 2,4-
dinitrophenylhydrazinium sulfate. The precipitate was recrystallized,
m.p. 218–220◦C (EtOH) and was identified as benzalacetone-2,4-
dinitrophenylhydrazone [lit.,22 m.p. 218–220◦C, (EtOH)].
Benzylidene-acetophenone (24d) was obtained as pale-yellow crys-
tals, m.p. 55–57◦C (dilute EtOH) [lit.,23a m.p. 55–56◦C (dilute EtOH].
Cinnamonitrile (24e) was obtained as a colorless liquid, TLC, com-
parative IR, and mass spectra with a commercial sample (lit.23 b.p.
137–138◦C/19 mm).
-Elution with n-hexane/CHCl3 (∼2:8 v/v) yielded 4-hydroxy-
quinolines 22a, 22b, 22c, 22d, and 22e.
Methyl 4-hydroxy-2-phenylquinoline-3-carboxylate (22a) was ob-
tained as pale yellow crystals (454 mg, 42% yield), m.p. 276–278◦C
(MeOH). Anal. calcd. for C17H13NO3 (279.30): C, 73.11; H, 4.69; N, 5.01.
Found: C, 73.03; H, 4.62; N, 5.11%. IR(KBr)/cm−1: 3248 (NH), 1712
(C O, ester), 1645 (C O, quinolinone). 1H NMR (CDCl3): δ 3.72 (s, 3H,
OCH ), 7.28–7.74 (m, 5H), 8.34–8.47 (m, 4H), 10.29 (s br, 1H, OH); MS:
3
m/z (EI) (%): 279 (77) [M+], 278 (100), 263 (14), 219 (29), 200 (15), 77
(18).
Ethyl 4-hydroxy-2-phenylquinoline-3-carboxylate (22b) was obtained
as pale-yellow crystals (510 mg, 45% yield), m.p. 260–262◦C from MeOH
(lit.,18 m.p. 260–261◦C).
3-Acetyl-4-hydroxy-2-phenylquinoline (22c) was obtained as yellow
needles (378 mg, 37% yield), m.p. 292–294◦C (EtOH). Anal. calcd. for

2388
W. M. Abdou et al.
C17H13NO2 (263.30): C, 77.55; H, 4.98; N, 5.32. Found: C, 77.63; H, 4.88;
1
N, 5.28%. IR: 3437 (OH), 1672 (C O, acetyl); H NMR (CDCl3): δ 2.25
(s, 3H, CH , acetyl), 7.31–7.79 (m, 5H, H-Ph), 8.27–8.44 (m, 4H, H-Ph),
3
10.84 (br, 1H, OH); 13C NMR (CDCl3): δ 26.3 (C(O)CH3), 101.4 (5-C),
119.7, 121.4, 125.2, 126.4, 128.3, 133.4 (7-C, 10-C, 6-C & C C, Ph),
137.3 (3-C), 143.7 (9-C), 151.2 (4-C), 169.6 (2-C), 197.4 (C(O)Me); MS:
m/z (EI) (%): 263 (87) [M+], 262 (100), 235 (23), 220 (31), 143 (48), 77
(25).
3-Benzoyl-4-hydroxy-2-phenylquinoline (22d) was obtained as pale-
yellow crystals (500 mg, 40% yield), m.p. 240–242◦C (benzene). Anal.
calcd. for C22H15NO2 (325.37): C, 81.21; H, 4.65; N, 4.31. Found: C,
81.28; H, 4.57; N, 4.24%. IR: 3462 (OH), 1654 (C O, benzoyl). 1H NMR
(CDCl3): δ 7.25–7.82 (m, 9H, H-Ph), 8.07–8.33 (m, 5H, H-Ph), 9.97 (s br,
1H, OH);13C NMR (CDCl3): δ 26.3 (C(O)CH3), 108.5 (5-C), 119.2, 121.4,
122.8, 123.4, 125.4, 126.7, 129.8, 133.4, 134.4 (6-C, 7-C, 10-C & C C,
Ph), 133.7 (3-C), 144.6 (9-C), 150.3 (4-C), 166.3 (2-C), 178.7 (C(O)Ph);
MS: m/z (EI) (%): 325 (100) [M+], 326 (55), 297 (36), 248 (9), 210 (45),
77 (22).
3-Cyano-4-hydroxy-2-phenylquinoline (22e) was obtained as yellow
crystals (360 mg, 38% yield), m.p. 223–225◦C (CHCl3). Anal. calcd. for
C16H10N2O (246.27): C, 78.03; H, 4.09; N, 11.38. Found: C, 78.09; H,
1
4.01; N, 11.30%. IR: 3450 (OH), 2212 (CN), H NMR (CDCl3): δ 7.25–
8.34 (m, 9H,H-Ar and H-Ph), 11.42 (s br, 1H, OH); 13C NMR (CDCl3):
δ 110.2 (5-C), 112.3 (3-C), 117.9 (CN), 119.6, 121.8, 124.1, 125.6, 128.5,
134.7, (6-C, 7-C, 10-C & C C, Ph), 144.6 (9-C), 153.3 (4-C), 167.6 (2-C);
MS: m/z (EI) (%): 246 (52) [M+], 221 (100).
B-Wittig Reaction of Iminophosphorane 23
To a solution of 0.5 g 23 (1.32 mmol) in 20 mL AcOEt containing
0.3 mL TEA, 160 mg benzaldehyde (1.5 mmol) was added, and the mix-
ture was refluxed for 10 h. After the removal of the volatile materi-
als under reduced pressure, the residual substance was extracted with
hot petroleum ether (b.r. 60–80◦C). Concentration of the extracts and
cooling afforded Ph3PO. Crystallization of the residue from pentane af-
forded yellow crystals of 2-(benzylideneamino)benzonitrile (2) (114 mg,
42% yield), m.p. 109–111◦C (hexane); [lit.,15 m.p. 109–111◦C (hexane)].
C-Alkaline Treatment of 23
A mixture of 0.5 g 23 and 20 mL Na2CO3 (15% aqueous) was heated
under reflux for 1 h. The mixture was cooled, diluted with distilled H2O
(5 mL), and extracted with CHCl3. The residue that was obtained, on
removal of chloroform, was boiled with light petroleum ether to give

Regioselective Condensation of Alkylidenephosphoranes
2389
anthranilonitrile as yellow crystals, m.p. 47–49◦C (light petroleum);
[lit.,24 m.p. 46–48◦C (light petroleum)].
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