Ultrasound promoted synthesis of some novel fused pyrans

Article abstract of DOI:10.1016/j.ultsonch.2011.10.008

Novel fused pyrans were synthesized from the reaction of the tetrahydropyran-4-one with arylidine malononitriles. Different fused pyran derivatives were obtained from the mentioned reaction depending on type of catalyst used and type of energy used. Reactions were carried out under silent and ultrasonic conditions. In general, it was found that sometimes ultrasound irradiations change the reaction path in comparing with silent condition. In addition to improvement in reaction times, the products were obtained in high yields and their structures were determined by elemental analyses, spectral data.

Full text of DOI:10.1016/j.ultsonch.2011.10.008

Ultrasonics Sonochemistry 19 (2012) 491–497
Contents lists available at SciVerse ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Ultrasound promoted synthesis of some novel fused pyrans
a
a
c
Tamer S. Saleh a,b, , Naglaa M. Abd El-Rahman , Ahmed A. Elkateb , Nehal O. Shaker ,
⇑
Naema A. Mahmoud c, Shimaa A. Gabal a
a Green Chemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt
b Chemistry Department, Faculty of Science, King AbdulAziz University, Jeddah 21589, Saudi Arabia
c Chemistry Department, Faculty of Science (Girls’ Branch), Al-Azhar University, Nasr City, Cairo 11754, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2011
Received in revised form 29 September 2011
Accepted 14 October 2011
Available online 3 November 2011
Novel fused pyrans were synthesized from the reaction of the tetrahydropyran-4-one with arylidine
malononitriles. Different fused pyran derivatives were obtained from the mentioned reaction depending
on type of catalyst used and type of energy used. Reactions were carried out under silent and ultrasonic
conditions. In general, it was found that sometimes ultrasound irradiations change the reaction path in
comparing with silent condition. In addition to improvement in reaction times, the products were
obtained in high yields and their structures were determined by elemental analyses, spectral data.
Ó 2011 Elsevier B.V. All rights reserved.
Keywords:
Tetrahydropyran-4-one
Isochromene
Tetrahydropyrano[4,3-b]pyran
Pyrano[4,3-b]pyridine
Ultrasound irradiation
1. Introduction
In the last few years, the application of ultrasound in synthetic
organic chemistry became more and more interesting. ‘‘Sonochem-
The pyran ring system and fused pyrans are widely present in
the animal and plant kingdom, they possess diverse pharmacolog-
ical activities [1–5], like cromakalim (Fig. 1), which is pyran deriv-
ative used to treat hypertension as it will relax vascular smooth
muscle to lower blood pressure [6,7].
istry’’ is a new trend in organic chemistry, offering a versatile and
facile pathway for a large variety of syntheses. Thus, a large
number of organic reactions can be carried out under ultrasonic
irradiation in high yields, short reaction times and mild conditions
[17–21].
Pyrano pyran presents in many natural marine products such as
brevetoxin B (Fig. 2) [8,9], which contains repeating units of the
pyrano[3,2-b]pyran ring system (shown in red,1 Fig. 2).
In addition, the presence of pyranopyridine scaffold in the
frame work of several biologically active naturally occurring alka-
loids of plant origin [10–12] has enthused researchers to synthe-
size and study their potential biological activities. They are
known to possess antiallergic, anti-inflammatory, and estrogenic
properties [13,14].
Motivated by the afore-mentioned findings, and in a continua-
tion of our interest in synthesis of a wide range of heterocyclic
systems, for biological screening programme in our laboratory
[22–27], and as a part of our growing interest in sonochemistry
[28–31]. We describe here a facile sonochemical synthesis of some
novel fused pyrans.
2. Results and discussion
The structural complexity of natural products, such as intricate
ring systems and numerous chiral centers, may lead to limited
supplies and hamper mechanism of action studies and clinical
development [15]. For this reason, structural simplification of nat-
ural products is a powerful and highly productive tool for lead
development and analog design [16].
The reaction of tetrahydropyran-4-one (1) with arylidine
malononitrile derivatives (2a–c) in ethanol in presence of catalytic
amount of piperidine under ultrasonic irradiation at room temper-
ature afforded a product in each time identified as isochromene
derivatives in good yields and shorter reaction time in comparing
with conventional condition (silent reactions), the products
formed may be formulated as (6a–c) or its isomer (7a–c)
(Scheme 1).
⇑
Corresponding author at: Green Chemistry Department, National Research
Centre, Dokki, Cairo 12622, Egypt. Tel.: +20 101978724; fax: +20 235727556.
Each steroisomers 6 or 7 present as pair of enantiomers as in
Fig. 3, a pair of enantiomers 6a–c was formed [(8R, 8aS) and (8S,
8aR)]. The obtained spectra do not show any hints for diastereomeric
E-mail address: tamsaid@yahoo.com (T.S. Saleh).
For interpretation of color in Fig. 2, the reader is referred to the web version of
1
this article.
1350-4177/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2011.10.008

492
T.S. Saleh et al. / Ultrasonics Sonochemistry 19 (2012) 491–497
absorption band, two absorption bands at 3350, 3249 cmꢀ1 due to
O
N
amino group, one absorption band at 2213 cmꢀ1 due to cyano
group. Its 1H NMR revealed the presence of two triplet signals
due to two adjacent methylene group at 2.71, 3.04 and two singlet
signals at d 4.00 and 4.15 due to CH2, CH, respectively, a D2O
exchangeable proton due to NH2 group in addition to multiplet
due to aromatic protons. Formation of the products 8a–c may pro-
ceed via cyclization of intermediate A (Scheme 3).
HO
O
N
Fig. 1. Structure of cromakalim.
On the other hand, the products formed under ultrasonic condi-
tion from the same reaction identified as 4-amino-3,3-dicyano-2,5-
diaryl-2,3,5,6,8,9-hexahydropyrano[300,400:50,60]pyrano[2,3-b]pyri-
dine 10a–c. The 1H NMR of the products 10a–c revealed three
singlet signals due to methylene group of pyran, CH (pyran) and
CH (pyridine), respectively, and that two triplet signals due to
two adjacent methylene group, a D2O exchangeable proton due
to NH2 group in addition to multiplet due to aromatic protons
(cf. Section 4). The latter spectroscopic data of the reaction prod-
ucts formed under ultrasonic irradiation and their satisfactory ele-
mental analyses supported the structure 10a–c as postulated in
Scheme 3 which suggest the reaction proceed via formation of
1:2 adduct. Although the latter spectral data fits better structure
10, an independent chemical proof seemed mandatory. Thus, com-
pound 8a on reaction with further one molecule of 2a in ethanol
and catalytic amount of piperidine under ultrasonic irradiation,
gave the 1:2 adduct product 10a in 52% yield. A plausible mecha-
nism for the formation of compound 10a–c is outlined in Scheme
3. Compound 10a–c are formed via initial Michael adduct 9a–c
followed by intramolecular cyclization. It is obvious that in this
reaction, ultrasonic change path of reaction in comparing with con-
ventional condition.
Also, we extended the study to find out the reactivity tetrahy-
dropyran-4-one (1) with arylidine malononitrile derivatives 2a–c
in ethanol in presence of ammonium acetate under both ultrasonic
irradiation at room temperature or conventional condition (reflux)
only one product obtained in each time (as evidenced by TLC) iden-
tified as 2-amino-4-aryl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-
carbonitrile 14a–c in excellent yields and shorter reaction time un-
der ultrasonic irradiation in comparing with conventional condi-
tion (silent reactions) Scheme 4.
The isolated products 14a–c gave satisfactory elemental analy-
ses and spectroscopic data (IR, 1H NMR, MS) consistent with their
assigned structures for example its IR spectra of the 14a revealed
no absorption bands due to carbonyl group and two absorption
bands at 3219, 3158 due to amino group and a band at 2214 due
to cyano group. Their 1H NMR of the same compound revealed
the presence of two triplet signals due to two adjacent methylene
group at 2.71, 3.04 and two singlet signals at d 3.65, 5.57 due to
methylene group and a D2O exchangeable proton due to NH2 group
respectively in addition to multiplet due to aromatic protons.
The formation of pyrano[4,3-b]pyridine derivatives 14a–c from
the reaction of tetrahydropyran-4-one (1) with arylidine malono-
nitrile derivatives 2a–c seems to follow the sequence outlined in
Scheme 4, which shows that the reaction starts with initial Michael
addition to form Michael adduct 11 followed by intramolecular
cyclization and spontaneous autooxidation (intermediates 12 and
13) to give pyrano[4,3-b]pyridine derivatives 14a–c as end
products.
pair of enantiomers 7a–c (8R) and (8S). The 1H NMR of the formed
product show that the hydrogen atoms on C-8 and C-8a are trans
and have both axial position (J = 12.3 Hz). Thus the structure 7a–c
was easily ruled out on basis of spectral data.
All efforts to separate the mixture of two enantiomers 6A and 6B
by chromatographic methods failed due to their equal Rf values.
Moreover, structure 6 seems more likely based on its similarity
to the well established behavior of cyclic ketones towards aryli-
dine-malononitrile derivatives as reported previously [32,33].
The structures of compounds 6a–c were established on the ba-
sis of their elemental analyses and spectral data. The IR spectrum
revealed the absence of any band due to carbonyl function, in addi-
tion to appearance of absorption bands of amino group in the re-
gion 3380–3249 cmꢀ1 and absorption band of cyano groups in
the region 2224–2215 cmꢀ1. Taken compound 6b as representative
example, its mass spectrum revealed a molecular ion peak at m/z
327. The nature of these compounds makes the proton NMR study
particularly interesting due to the non-equivalence of the methy-
lene protons. Ha and Hb appear as two doublets of doublets with
different chemical shifts. The shift at down field can be assigned
to the proton Ha. The proton Hc appears as doublet of triplets,
due to its coupling with the protons Ha, Hb, and Hd was located up-
field. The proton Hd is coupled with Hc to form a doublet at lower
field to Hc [34]. Time of reaction and yields are shown in Table 1.
Table 1 shows that ultrasound technique reduced the time of
reactions from several hours to minutes and improved the yields
from 52–56% (under conventional conditions) to 82–87%.
The formation of the products 6a–c is assumed to take place via
first condensation of tetrahydropyran-4-one with malononitrile,
produced as result of hydrolysis of 2 to yield 3 (This observation
is further evidenced for the existence of 1 in its solutions in equi-
librium with its constituents as has been suggested earlier [35]),
which on reaction with further molecule of 2 gives products 6a–
c via an initial Michael adduct 4 followed by an intermolecular
cyclization (intermediate 5) and subsequent tautomerism to be
the final product (Scheme 1).
A further evidence for the formation of the products 6a–c with
above mechanism stems from the synthesis of the same products
6a–c by condensing 1 with malononitrile to afford 3 [36] which
reacted with 2a–c to afford products identical in all respects
(m.p., mixed m.p. and IR) with those corresponding 6 (Scheme 2).
In contrast to the above mentioned behavior, when we doing
the reaction of tetrahydropyran-4-one (1) with arylidine malono-
nitrile derivatives 2a–c in ethanol in presence of 2–3 drops of 5%
sodium hydroxide solution as catalyst instead of piperdine under
both ultrasonic irradiation at room temperature or conventional
condition (reflux) as shown in Scheme 3. There is only one isolable
product formed in each case (as examined by TLC) but it was found
that the product formed under conventional condition differing
from that formed under ultrasonic irradiation.
Table 2 shows that ultrasound technique reduced the time of
reactions from several hours to minutes and improved the yields
from 79–83% (under conventional conditions) to 90–95%.
The product formed under conventional condition identified as
2-amino-4-aryl-4,5,7,8-tetrahydropyrano[4,3-b]pyran-3-carboni-
trile 8a–c. The structure of compounds 8a–c was established on
the basis of their elemental analyses and spectral data. For example
its mass spectrum of compound 8a revealed a molecular ion peak
at m/z 254, IR spectrum of the compound 8a revealed no carbonyl
Generally, ultrasound showed beneficial effect on synthesis of
some novel fused pyrans in which decreases time of the above
reaction from several hours in conventional procedure to few min-
utes with high yield under ultrasound irradiation. The improve-
ment induced by ultrasound can be attributed to the well
established theory of ultrasonic irradiation in which it differs from

T.S. Saleh et al. / Ultrasonics Sonochemistry 19 (2012) 491–497
493
CHO
HO
Me
H
O
H
O
H
H
O
Me
H
Me
H
H
H
O
H
O
H
H
Me
H
H
H
O
O
H
O
O
Me
H
O
O
O
Me
Fig. 2. Structure of brevetoxin B.
Table 1
O
Synthesis of isochromene derivative 6a–c under both ultrasonic irradiation and
CN
CN
conventional method.
NC
NC
)))
or reflux
+
O
Compound
Ar
Ultrasonic irradiation
Conventional
EtOH, Pip.
Ar
Time (min.)
Yield (%)
Time (h)
Yield (%)
O
6a
6b
6c
C6H5
C6H4CN-p
C6H4F-p
45
30
30
82
87
85
9
6
7
52
56
56
1
2a-c
3
2a-c
traditional energy sources (such as heat) in duration, pressure, and
energy per molecule. Because of the immense temperatures and
pressures and the extraordinary heating rate generated by cavita-
tion bubble collapse, ultrasound provides an unusual mechanism
[37,38] so reaction time decreases clearly and high yield obtained.
In addition, according to sonochemical reactions classification
of Luche [39–41], we have both types false and true sonochemistry,
in which some of the above mentioned reactions are considered
false sonochemistry type in which cavitation effect provides the
mechanical energy for all subsequent chemical reactions, including
bond scission induced by viscous frictional forces and same prod-
ucts produced under both silent and ultrasonic conditions, and
the other mentioned reactions considered true sonochemistry type
which occur due to the effects derived directly from the ‘‘hotspots’’
of cavitational collapse energy, which cause in our case what is
called ‘‘sonochemical switching’’ means the products obtained
under conventional conditions are different from those obtained
under the influence of ultrasound [41].
N
C
NH
CN
NC
CN
CN
Ar
NC
H
HC
CN
Ar
H
H
O
O
5
4
NH2
NH2
CN
CN
NC
NC
CN
CN
Ar
Ar
O
O
2,6 Ar
3. Conclusion
7a-c
6a-c
a C6H5
b C6H4CN-p
Tetrahydropyran-4-one was found to be a good precursor for
synthesis of novel fused pyrans in reaction with arylidine malono-
nitriles which afforded of isochromene, tetrahydropyrano
[4,3-b]pyran, hexahydro-pyrano[300,400:50,60]pyrano[2,3-b]pyridine
and pyrano[4,3-b]pyridine derivatives respectively depending on
type of catalyst used and type of energy used for this reaction.
Moreover, the present work evidences that sometimes ultrasound
irradiations change the reaction path in comparing with silent con-
dition. In general, improvements in rates and yield of reactions are
observed when reactions were carried out under sonication com-
pared with classical condition.
c
C6H4F-p
Scheme 1.
corded in potassium bromide disks on a pye Unicam SP 3300 and
Shimadzu FT IR 8101 PC infrared spectrophotometers. The NMR
spectra were recorded on a Varian Mercury VXR-300 NMR spec-
trometer. 1H spectra were run at 300 MHz and 13C spectra were
run at 75.46 MHz in deuterated chloroform (CDCl3) or dimethyl
sulphoxide (DMSO-d6). Chemical shifts were related to that of
the solvent. Mass spectra were recorded on a Shimadzu GCMS-
QP 1000 EX mass spectrometer at 70 eV. Elemental analyses were
carried out on Elmentar instrument C, H, N, S analyzer Vario EL III.
Sonication was performed by Fischer sonicator (with a frequency
of 25 kHz and a nominal power 150 W).
4. Experimental
4.1. General
All melting points were measured on a Gallenkamp melting
point apparatus and are uncorrected. The infrared spectra were re-
Arylidine malononitriles were prepared according to literature
procedure [42].

494
T.S. Saleh et al. / Ultrasonics Sonochemistry 19 (2012) 491–497
NH2
NH2
NH2
NH2
CN
CN
Hd
Ar
CN
CN
CN
6
NC
NC
NC
NC
7
CN
CN
CN
H
Ar
5
H
Ar
H
Ar
8
8a
1
4
3
Hc
Hb
Ha
(8R, 8aS)
H
O
O
O
O
2
(8S, 8aR)
(8R, 8aR)
(8S, 8aS)
6A,B a-c
7a-c
Fig. 3. Enantiomers of stereoisomer 6 and 7.
4.2. Typical procedure for the reactions
appropriate arylidine malononitrile 2a–c (10 mmol), catalytic
amount of piperidine (3–4 drops) were added in 50 mL Erlenmeyer
flask. The mixture was subjected to ultrasound irradiation for
15 min (until the starting materials were no longer detectable by
TLC). All The reactions were kept at room temperature 25–30 °C
which attained by addition or removal of water in ultrasonic bath
(the temperature inside reaction vessel was 28–30 °C). The precip-
itate was filtered off, washed with ethanol and recrystallized from
ethanol to afford the corresponding (6A,Ba–c).
4.2.1. Synthesis of isochromene derivative 6a–c
4.2.1.1. Method A: silent reactions. A mixture of tetrahydropyran-4-
one (10 mmol) (1) and arylidine malononitrile 2a–c (10 mmol)
was heated under reflux in 25 mL ethanol in the presence of cata-
lytic amount of piperidine for a suitable time (untill disappearance
of starting materials as examined by TLC). The crude product, so-
formed, was collected by filtration and recrystallized from ethanol
to afford the corresponding 6-amino-8-aryl-1H-isochromene-
5,7,7(3H,8H,8aH)-tricarbonitrile (6A,Ba–c).
The synthesized compounds (6A,Ba–c) with their physical data
are listed below:
6-Amino-8-phenyl-1H-isochromene-5,7,7(3H,8H,8aH)-tri-carbo-
nitrile (6A,Ba)
4.2.1.2. Method B:sonicated reactions. To a solution of tetrahydropy-
ran-4-one (10 mmol) (1) in ethanol (20 mL), and the appropriate
arylidine malononitrile 2a–c (10 mmol), catalytic amount of piper-
idine (3–4 drops) were added in 50 mL Erlenmeyer flask. The mix-
ture was subjected to ultrasound irradiation for suitable time (cf.
Table 1) until the starting materials were no longer detectable by
TLC. All The reactions were kept at room temperature 25–30 °C
which attained by addition or removal of water in ultrasonic bath
(the temperature inside reaction vessel was 28–30 °C). The precip-
itate was filtered off, washed with ethanol and recrystallized from
ethanol to afford the corresponding 6-amino-8-aryl-1H-isochrom-
ene-5,7,7(3H,8H,8aH)-tricarbonitrile (6A,Ba–c).
IR (KBr): 3359, 3229 (NH2), 2254 (C„N), 2213 (C„N) cmꢀ1; 1H
NMR (300 MHz, CDCl3) d: 2.88 (dt, JHcHa = 10.5 Hz, JHcHb = 4.2 Hz,
JHcHd = 12.3 Hz, Hc), 3.03 (dd, JHbHa = 8.8 Hz, JHbHc = 4.2 Hz, Hb),
3.11 (dd, JHaHb = 8.8 Hz, JHaHc = 10.5 Hz, Ha), 3.34 (m, 2H,CH2),
4.03 (d, JHdHc = 12.3 Hz, Hd), 5.55 (dd, J = 4.3 Hz, J = 3.8 Hz, @CH),
6.55 (s, 2H, NH2, D2O exchangeable), 7.32–7.62 (m, 5H, ArH’s);
13C NMR (75.46 MHz, CDCl3) d: 26.21, 31.58, 36.47, 65.89, 69.98,
88.65, 108.97, 114.52, 118.45, 118.49, 125.06, 127.11, 127.13,
136.95, 147.45, 166.01; MS (m/z): 302 M+. (Found: C, 71.73; H,
4.58; N, 18.40. C18H14N4O requires C, 71.51; H, 4.67; N, 18.53.)
6-Amino-8-(4-cyanophenyl)-1H-isochromene-5,7,7(3H,8H,8aH)-
tri-carbonitrile (6A,Bb)
4.2.1.3. Method C. A mixture of 2-(2H-pyran-4(3H,5H,6H)-yli-
dene)malononitrile (3) (10 mmol) and the appropriate arylidine
malononitrile 2a–c (10 mmol) in presence of catalytic amount of
piperidine (3–4 drops) in ethanol (20 mL) was heated under reflux
condition for 3 h. After completion of the reaction as indicated by
TLC, the solvent was evaporated under reduced pressure and the
formed solid was collected, washed with ethanol and recrystallized
from the mixture of ethanol to give the corresponding 6A,Ba–c.
IR (KBr): 3319, 3222 (NH2), 2249 (C„N), 2213 (C„N), 2192
(C„N) cmꢀ1 1H NMR (300 MHz, CDCl3) d: 2.74 (dt, JHcHa = 10 Hz,
;
JHcHb = 3.9 Hz, JHcHd = 12.3 Hz, Hc), 3.22(dd, JHbHa = 9.2 Hz,
JHbHc = 3.9 Hz, Hb), 3.31 (dd, JHaHb = 9.2 Hz, JHaHc = 10 Hz, Ha), 3.54
(m, 2H,CH2), 4.22 (d, JHdHc = 12.3 Hz, Hd), 5.16 (dd, J = 4.3 Hz,
J = 3.9 Hz, @CH), 6.24 (s, 2H, NH2, D2O exchangeable), 7.45–7.89
(m, 4H, ArH’s); 13C NMR (75.46 MHz, CDCl3) d: 26.87, 32.05,
35.17, 65.87, 68.99, 88.58, 106.54, 109.08, 114.11, 114.52, 118.15,
125.88, 125.95, 132.11, 132.23, 139.87, 146.05, 168.01; MS (m/z):
327 M+. (Found: C, 69.82; H, 3.91; N, 21.27. C19H13N5O requires
C, 69.71; H, 4.00; N, 21.93.)
4.2.1.4. Method D. To a solution of 2-(2H-pyran-4(3H,5H,6H)-yli-
dene)malononitrile (3) (10 mmol) in ethanol (20 mL), and the
NH2
CN
NC
CN
NC
2a-c
refluxor
CN
CN
)))
reflux
+
1
EtOH, Pip.
Ar
CN
O
3
O
2,6 Ar
6a-c
a
C6H5
b C6H4CN-p
c C6H4F-p
Scheme 2.

T.S. Saleh et al. / Ultrasonics Sonochemistry 19 (2012) 491–497
495
N
C
NH
C
CN
CN
Ar
O
NH2
CN
OH
O
OH
O
H
reflux
O
Ar
H
Ar
8a-c
A
)))
EtOH,
1
+
2a-c
2a
2-3 drops
5%NaOH.
Ar
CN
CN
H
H
N
O
N
Ar
CN
CN
)))
C
O
O
2,8,10 Ar
O
N
a
b
C6H5
H
Ar
C6H4CN-p
Ar
NH2
c C6H4F-p
10a-c
9a-c
Scheme 3.
Ar
H
Ar
H
CN
CN
O
O
)))
or reflux
EtOH,
1
2a-c
+
C
N
N
NH
NH
Amm. Acetate
H
H
12
11
2,14 Ar
a C6H5
Ar
Ar
H
b
c
CN
CN
C6H4CN-p
C6H4F-p
O
O
N
NH2
N
H
NH2
14a-c
Scheme 4.
13
6.16 (s, 2H, NH2, D2O exchangeable), 7.26–7.78 (m, 4H, ArH’s);
13C NMR (75.46 MHz, CDCl3) d: 27.01, 31.98, 35.02, 66.14, 67.87,
88.13, 109.24, 116.11, 116.14, 131.12, 131.19, 134.23, 144.19,
149.85, 168.00; MS (m/z): 320 M+. (Found: C, 67.64; H, 4.03; N,
17.40. C18H13FN4O requires C, 67.49; H, 4.09; N, 17.49.)
Table 2
Synthesis of pyrano[4,3-b]pyridine derivative 14a–c under both ultrasonic irradiation
and conventional method.
Compound
Ar
Ultrasonic irradiation
Conventional
Time (min.)
Yield (%)
Time (h)
Yield (%)
14a
14b
14c
C6H5
C6H4CN-p
C6H4F-p
30
15
30
90
95
95
9
5
7
79
83
83
4.2.2. Synthesis of 2-amino-4-aryl-4,5,7,8-tetrahydropyrano[4,3-b]
pyran-3-carbonitrile 8a–c
A mixture of tetrahydropyran-4-one (10 mmol) (1) and aryli-
dine malononitrile 2a–c (10 mmol) was heated under reflux in
25 mL ethanol in the presence of catalytic amount of 5% sodium
hydroxide for 10 h (as examined by TLC). The crude product, so-
formed, was collected by filtration and recrystallized from ethanol
to afford the corresponding 2-amino-4-aryl-4,5,7,8-tetrahydropyr-
ano[4,3-b]pyran-3-carbonitrile 8a–c in 70–79% yield.
2-Amino-4-phenyl-4,5,7,8-tetrahydropyrano[4,3-b]pyran-3-car-
bonitrile (8a)
6-Amino-8-(4-florophenyl)-1H-isochromene-5,7,7(3H,8H,8aH)-
tri-carbonitrile (6A,Bc)
IR (KBr): 3374, 3215 (NH2), 2249 (C„N), 2217 (C„N) cmꢀ1; 1H
NMR (300 MHz, CDCl3) d: 2.65 (dt, JHcHa = 10.8 Hz, JHcHb = 4.2 Hz,
JHcHd = 12.6 Hz, Hc), 3.15 (dd, JHbHa = 9.2 Hz, JHbHc = 4.2 Hz, Hb),
3.28 (dd, JHaHb = 9.2 Hz, JHaHc = 10.8 Hz, Ha), 3.47 (m, 2H, CH2),
4.36 (d, JHdHc = 12.6 Hz, Hd), 5.27 (dd, J = 4.2 Hz, J = 3.9 Hz, @CH),

496
T.S. Saleh et al. / Ultrasonics Sonochemistry 19 (2012) 491–497
Yield 70%, m.p. 254 °C; IR (KBr): 3315, 3229 (NH2), 2219 (C„N)
MS (m/z): 408 M+. (Found: C, 73.77; H, 4.83; N, 13.57.
cmꢀ1; 1H NMR (300 MHz, CDCl3) d: 2.67 (m, 2H, CH2), 3.65 (m, 2H,
CH2), 3.87 (s, 2H, CH2), 4.12 (s, 1H,CH), 5.55 (s, 2H, NH2, D2O
exchangeable), 6.89–7.33 (m, 5H, ArH’s); 13C NMR (75.46 MHz,
CDCl3) d: 26.44, 38.21, 55.32, 63.44, 65.89, 104.87, 116.25,
121.08, 124.58, 124.89, 126.55, 126.97, 138.95, 140.25, 155.29;
MS (m/z): 254 M+. (Found: C, 70.62; H, 5.42; N, 10.90.
C25H20N4O2 requires C, 73.51; H, 4.94; N, 13.72.)
4-Amino-3,3-dicyano-2,5-di(4-cyanophenyl)-2,3,5,6,8,9-hexahy-
dropyrano[300,400:50,60]pyrano[2,3-b]pyridine (10b)
Yield 55%; IR (KBr): 3298, 3162 (NH2), 2198 (C„N), 2113(C„N)
cmꢀ1; 1H NMR (300 MHz, DMSO-d6) d: 2.52 (t, J = 4.5 Hz, 2H, CH2),
3.88 (t, J = 4.5 Hz, 2H, CH2), 4.08 (s, 2H, CH2), 4.65 (s,1H,CH), 4.92
(s,1H,CH), 5.89 (s, 2H, NH2, D2O exchangeable), 7.12–7.91 (m, 8H,
ArH’s); 13C NMR (75.46 MHz, DMSO-d6) d: 24.09, 27.47, 40.89,
51.85, 63.84, 66.00, 103.12, 106.01, 114.49, 119.00, 121.11,
122.01, 126.56, 126.98, 129.17, 129.23, 131.47, 131.99, 142.58,
145.78, 154.23, 162.00, 167.85; MS (m/z): 458 M+. (Found: C,
71.01; H, 3.83; N, 18.18. C27H18N6O2 requires C, 70.73; H, 3.96;
N, 18.33.)
C
15H14N2O2 requires C, 70.85; H, 5.55; N, 11.02.)
2-Amino-4-(4-cyanophenyl)-4,5,7,8-tetrahydropyrano[4,3-b]pyr-
an-3-carbonitrile (8b)
Yield 79%, m.p. 280–282 °C; IR (KBr): 3342, 3216 (NH2), 2226
(C„N) cmꢀ1 1H NMR (300 MHz, CDCl3) d: 2.57 (m, 2H, CH2),
;
3.45 (m, 2H, CH2), 3.77 (s, 2H, CH2), 4.39 (s, 1H,CH), 5.94 (s, 2H,
NH2, D2O exchangeable), 7.22–7.79 (m, 4H, ArH’s); 13C NMR
(75.46 MHz, CDCl3) d: 25.98, 37.59, 54.28, 63.23, 65.87, 103.52,
108.27, 116.54, 120.00, 125.47, 126.48, 126.55, 132.01, 140.57,
143.12, 157.89; MS (m/z): 279 M+. (Found: C, 68.56; H, 4.59; N,
14.90. C16H13N3O2 requires C, 68.81; H, 4.69; N, 15.05.)
2-Amino-4-(4-florophenyl)-4,5,7,8-tetrahydropyrano[4,3-b]pyran-
3-carbonitrile (8c)
Yield 76%, m.p. 272 °C; IR (KBr): 3342, 3218 (NH2), 2212 (C„N)
cmꢀ1; 1H NMR (300 MHz, CDCl3) d: 2.56 (m, 2H, CH2), 3.54 (m, 2H,
CH2), 3.91 (s, 2H, CH2), 4.59 (s, 1H,CH), 6.01 (s, 2H, NH2, D2O
exchangeable), 6.92–7.48 (m, 4H, ArH’s); 13C NMR (75.46 MHz,
CDCl3) d: 25.97, 36.78, 52.19, 63.44, 65.49, 105.11, 115.14,
120.08, 129.54, 129.84, 138.00, 142.14, 154.23, 155.10; MS (m/z):
272 M+. (Found: C, 66.42; H, 4.66; N, 10.19. C15H13FN2O2 requires
C, 66.17; H, 4.81; N, 10.29.)
4-Amino-3,3-dicyano-2,5-di(4-flurophenyl)-2,3,5,6,8,9-hexahy-
dropyrano [300,400:50,60] pyrano[2,3-b]pyridine (16a)
Yield 52%; IR (KBr): 3313, 3189 (NH2), 2208 (C„N) cmꢀ1 1H
;
NMR (300 MHz, DMSO-d6) d: 2.79 (t, J = 5.1 Hz, 2H, CH2), 3.59 (t,
J = 5.1 Hz, 2H, CH2), 4.02 (s, 2H, CH2), 4.89 (s,1H,CH), 5.14
(s,1H,CH), 6.24 (s, 2H, NH2, D2O exchangeable), 7.19–8.06 (m, 8H,
ArH’s); 13C NMR (75.46 MHz, DMSO-d6) d: 24.54, 29.04, 41.98,
49.28, 63.54, 66.00, 103.44, 105.01, 116.45, 116.89, 119.25,
119.48, 120.01, 127.15, 127.59, 131.45, 131.56, 139.02, 141.08,
155.12, 159.49, 166.74, 167.89; MS (m/z): 444 M+. (Found: C,
67.85; H, 3.95; N, 12.46. C25H18FN4O2 requires C, 67.56; H, 4.08;
N, 12.61.)
4.2.4. Synthesis of 2-amino-4-aryl-7,8-dihydro-5H-pyrano[4,3-
b]pyridine-3-carbonitrile 14a–c
4.2.4.1. Method A: silent reactions. A mixture of tetrahydropyran-4-
one (10 mmol) (1) and arylidine malononitrile 2a–c (10 mmol) in
30 mL absolute ethanol containing excess amount of ammonium
acetate was heated under reflux for suitable time (as examined
by TLC) (cf. Table 2). The crude product, so-formed, was collected
by filtration and recrystallized from ethanol/DMF to afford the
corresponding 2-amino-4-aryl-7,8-dihydro-5H-pyrano[4,3-b]pyri-
dine-3-carbonitrile (14a–c).
4.2.3. Synthesis of 4-amino-3,3-dicyano-2,5-diaryl-2,3,5,6,8,9-hexa-
hydropyrano [300,400:50,60] pyrano[2,3-b]pyridine 10a–c
4.2.3.1. Method A: sonicated reactions. To a solution of tetrahydro-
pyran-4-one (10 mmol) (1) in ethanol (20 mL), and the appropriate
arylidine malononitrile 2a–c (10 mmol), catalytic amount of 5% so-
dium hydroxide (0.25 mL) were added in 50 mL Erlenmeyer flask.
The mixture was subjected to ultrasound irradiation for 30 min un-
til the starting materials were no longer detectable by TLC. All the
reactions were kept at room temperature 25–30 °C which attained
by addition or removal of water in ultrasonic bath (the tempera-
ture inside reaction vessel was 28–30 °C). The precipitate was fil-
tered off, washed with ethanol and recrystallized from ethanol/
DMF (3:1) to afford the corresponding 4-amino-3,3-dicyano-2,5-
diaryl-2,3,5,6,8,9-hexahydro-pyrano[300,400:50,60]pyrano [2,3-b]pyri-
dine 10a–c in 45–52% yield.
4.2.4.2. Method B:sonicated reactions. To a solution of tetrahydropy-
ran-4-one (10 mmol) (1) in absolute ethanol (30 mL), and the
appropriate arylidine malononitrile 2a–c (10 mmol), excess
amount of ammonium acetate (25 mmol) was added in 50 mL
Erlenmeyer flask. The mixture was subjected to ultrasound irradi-
ation for suitable time (cf. Table 2) at room temperature (the tem-
perature inside reaction vessel was 28–30 °C), until the starting
materials were no longer detectable by TLC. All the reactions were
kept at room temperature 25–30 °C which attained by addition or
removal of water in ultrasonic bath. The precipitate formed was
filtered off, washed with ethanol and recrystallized from ethanol/
DMF to afford the corresponding 2-amino-4-aryl-7,8-dihydro-5H-
pyrano[4,3-b]pyridine-3-carbonitrile (14a–c).
4.2.3.2. Method B. To a solution of 2-amino-4-phenyl-4,5,7,8-tetra-
hydropyrano[4,3-b]pyran-3-carbonitrile 8a (10 mmol) in ethanol
(25 mL), and the appropriate benzylidine malononitrile 2a
(10 mmol), catalytic amount of 5% sodium hydroxide (0.25 mL)
were added in 50 mL Erlenmeyer flask. The mixture was subjected
to ultrasound irradiation for 15 min (until the starting materials
were no longer detectable by TLC). All the reactions were kept at
room temperature 25–30 °C bath (the temperature inside reaction
vessel was 28–30 °C). The precipitate was filtered off, washed with
ethanol and recrystallized from ethanol/DMF to afford the corre-
sponding 10a.
2-Amino-4-phenyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-car-
bonitrile (14a)
Yield 90%, m.p. 225 °C; IR (KBr): 3219, 3158 (NH2), 2214 (C„N)
cmꢀ1; 1H NMR (300 MHz, CDCl3) d: 2.78 (t, J = 4.2, 2H, CH2), 3.21 (t,
J = 4.2, 2H, CH2), 3.65 (s, 2H, CH2), 5.57 (s, 2H, NH2, D2O exchange-
able), 7.12–7.58 (m, 5H, ArH’s); 13C NMR (75.46 MHz, CDCl3) d:
26.78, 54.87, 57.47, 79.25, 111.54, 116.00, 125.14, 125.26,
129.25,129.47,131.78, 152.31, 159.45, 163.20; MS (m/z): 251 M+.
(Found: C, 71.96; H, 5.11; N, 16.56. C15H13N3O requires C, 71.70;
H, 5.21; N, 16.72.)
2-Amino-4-(4-cyanophenyl)-7,8-dihydro-5H-pyrano[4,3-b]pyri-
dine-3-carbonitrile (14b)
Yield 95%, m.p. 254 °C; IR (KBr): 3358, 3210 (NH2), 2249 (C„N),
2212 (C„N) cmꢀ1; 1H NMR (300 MHz, CDCl3) d: 2.83 (t, J = 4.8, 2H,
CH2), 3.19 (t, J = 4.8, 2H, CH2), 3.55 (s, 2H, CH2), 5.48 (s, 2H, NH2,
4-Amino-3,3-dicyano-2,5-diphenyl-2,3,5,6,8,9-hexahydropyrano
[300,400:50,60] pyrano[2,3-b]pyridine (10a)
Yield 49%; IR (KBr): 3312, 3190 (NH2), 2195 (C„N) cmꢀ1 1H
;
NMR (300 MHz, DMSO-d6) d: 2.75 (t, J = 5.1 Hz, 2H, CH2), 3.64 (t,
J = 5.1 Hz, 2H, CH2), 3.89 (s, 2H, CH2), 4.59 (s,1H,CH), 4.87
(s,1H,CH), 6.00 (s, 2H, NH2, D2O exchangeable), 7.02–7.91 (m,
10H, ArH’s); 13C NMR (75.46 MHz, DMSO-d6) d: 25.69, 29.54,
42.01, 53.14, 63.85, 65.44, 102.11, 105.53, 118.25, 123.41, 123.65,
126.02, 126.13, 127.11, 140.89, 145.84, 159.41, 165.08, 169.10;

T.S. Saleh et al. / Ultrasonics Sonochemistry 19 (2012) 491–497
497
D2O exchangeable), 7.22–7.33 (m, 4H, ArH’s); 13C NMR
(75.46 MHz, CDCl3) d: 28.36, 58.22, 60.21, 77.25, 111.89, 113.25
116.10, 117.85, 126.87, 130.02, 130.54, 135.09, 150.01, 157.45,
161.12; MS (m/z): 276 M+. (Found: C, 69.78; H, 4.26; N, 20.12.
[15] I.V. Magedov, M. Manpadi, M.A. Ogasawara, A.S. Dhawan, S. Rogelj, S. Van
Slambrouck, W.F.A. Steelant, N.M. Evdokimov, P.Y. Uglinskii, E.M. Elias, E.J.
Knee, P. Tongwa, M.Y. Antipin, A. Kornienko, J. Med. Chem. 51 (2008) 2561.
[16] B. Raghavan, R. Balasubramanian, J.C. Steele, D.L. Sackett, R.A. Fecik, J. Med.
Chem. 51 (2008) 1530.
[17] G. Cravotto, V.V. Fokin, D. Garella, A. Binello, L. Boffa, A. Barge, J. Comb. Chem.
12 (2010) 13.
C16H12N4O requires C, 69.55; H, 4.38; N, 20.28.)
2-Amino-4-(4-flurophenyl)-7,8-dihydro-5H-pyrano[4,3-b]pyri-
dine-3-carbonitrile (14c)
[18] G. Cravotto, P. Cintas, Chem. Soc. Rev. 35 (2006) 180.
[19] L. Pizzuti, P.L.G. Martins, B.A. Ribeiro, F.H. Quina, E. Pinto, A.F.C. Flores, D.
Venzke, C.M.P. Pereira, Ultrason. Sonochem. 17 (2010) 34.
[20] Z. Fu, H. Shao, Ultrason. Sonochem. 18 (2011) 520.
[21] Q. Liu, H. Ai, Z. Li, Ultrason. Sonochem. 18 (2011) 477.
[22] M.R. Shaaban, T.S. Saleh, F.H. Osman, A.M. Farag, J. Heterocycl. Chem. 44 (2007)
177.
[23] M.R. Shaaban, T.S. Saleh, A.M. Farag, Heterocycles 78 (2009) 151.
[24] M.R. Shaaban, T.S. Saleh, A.M. Farag, Heterocycles 78 (2009) 699.
[25] H.A. Abdel-Aziz, T.S. Saleh, H.S.A. El-Zahabi, Arch. Pharm. 343 (2010) 24.
[26] M.R. Shaaban, T.S. Saleh, A.S. Mayhoub, A. Mansour, A.M. Farag, Bioorg. Med.
Chem. 16 (2008) 6344.
Yield 95%, m.p. 229–231 °C; IR (KBr): 3392, 3257 (NH2), 2221
(C„N) cmꢀ1 1H NMR (300 MHz, CDCl3) d: 2.58 (t, J = 4.2, 2H,
;
CH2), 3.02 (t, J = 4.2, 2H, CH2), 3.36 (s, 2H, CH2), 6.01 (s, 2H, NH2,
D2O exchangeable), 7.23–7.39 (m, 4H, ArH’s); 13C NMR
(75.46 MHz, CDCl3) d: 30.25, 58.00, 59.98, 81.28, 112.25, 116.00,
116.09, 117.89, 125.80, 130.55, 130.62, 151.24, 158.00, 161.87,
166.19; MS (m/z): 269 M+. (Found: C, 67.16; H, 4.39; N, 15.44.
C15H12FN3O requires C, 66.90; H, 4.49; N, 15.60.)
[27] M.R. Shaaban, T.S. Saleh, A.S. Mayhoub, A.M. Farag, Eur. J. Med. Chem. 46
(2011) 3690.
[28] N.M. Abd El-Rahman, T.S. Saleh, M.F. Mady, Ultrason. Sonochem. 16 (2009) 70.
[29] T.S. Saleh, N.M. Abd-El-Rahman, Ultrason. Sonochem. 16 (2009) 237.
[30] M. Mokhtar, T.S. Saleh, N.S. Ahmed, S.A. Al-Thabaiti, R.A. Al-Shareef, Ultrason.
Sonochem. 18 (2010) 172.
[31] T.S. Saleh, T.M.A. Eldebss, H.M. Albishri, Ultrason. Sonochem. 19 (2012) 49.
[32] S. Penades, H. Kisch, K. Tortschanoff, P. Margaretha, O.E. Polansky, Monatsh.
Chem. 104 (1973) 447.
[33] I.A. El-Sakka, S.M. El-Kousy, Z.E. Kandeel, J. Prakt. Chem. 333 (1991) 345.
[34] R.M. Silverstein, G.C. Bassler, T.C. Morrill, Spectroscopic Identification of
Organic Compounds, John Wiley and Sons, New York, 1985. p. 205.
[35] A.E. Harb, A.M. Hesien, S.A. Metwally, M.H. Elnagdi, Justus Liebigs Ann. Chem.
(1989) 585.
[36] S.Z. Vatsadze, G. Golikov, A.P. Kriven’ko, N.V. Zyk, Russ. Chem. Rev. 77 (2008)
661.
[37] A. Loupy, J.L. Luche, Sonochemistry in biphasic system, in: J.-L. Luche (Ed.),
Synthetic Organic Sonochemistry, Plenum Press, 1998, pp. 107–165.
[38] K.S. Suslick, Science 247 (1990) 1439.
References
[1] G.P. McGlacken, I.J.S. Fairlamb, Nat. Prod. Rep. 22 (2005) 369.
[2] S.J. Danishefsky, W.H. Pearson, B.E. Segmuller, J. Am. Chem. Soc. 107 (1985)
1280.
[3] S.J. Danishefsky, M.P. DeNinno, Angew. Chem., Int. Ed. Engl. 26 (1987) 15.
[4] S.J. Danishefsky, H.G. Selnick, R.E. Zelle, M.P. DeNinno, J. Am. Chem. Soc. 110
(1988) 4368.
[5] D.R. Williams, R.W. Heidebrecht, J. Am. Chem. Soc. 125 (2003) 1843.
[6] S.W. Weir, A.H. Weston, Br. J. Pharmacol. 88 (1986) 121.
[7] G.M. Herrera, T.C. Resta, J.J. Candelaria, B.R. Walker, J. Cardiovasc. Pharmacol.
31 (1998) 921.
[8] J.A. Dale, H.S. Mosher, J. Am. Chem. Soc. 95 (1973) 512.
[9] G.R. Sullivan, J.A. Dale, H.S. Mosher, J. Org. Chem. 38 (1973) 2143.
[10] S.J. Ahmad, Nat. Prod. 47 (1984) 391.
[11] S. Mitaka, A.–L. Skaltsounis, F. Tillequin, M. Koch, J. Pusset, G. Chauviere, J. Nat.
Prod. 48 (1985) 772.
[12] A. Ulubelen, Phytochemistry 23 (1984) 2123.
[13] J.V. Johnson, S. Rauckman, P.D. Beccanari, B. Roth, J. Med. Chem. 32 (1989)
1942.
[39] J.-L. Luche, Ultrason. Sonochem. 1 (1994) S111.
[40] N. Cabello, P. Cintas, J.-L. Luche, Ultrason. Sonochem. 10 (2003) 25.
[41] J. Berlan, T.J. Mason, Dosimetry for power ultrasound and sonochemistry, in:
T.J. Mason (Ed.), Advances in Sonochemistry, vol. 4, JAI Press, 1996, pp. 54–55.
[42] O. Esteban, T. Martin, Z. Gerarda, M. Rene, D. Franisco, Synth. Commun. 28
(1998) 4649.
[14] N. Yamada, S. Kadowaki, K. Takahashi, K. Umeza, Biochem. Pharmacol. 44
(1992) 1211.