Molecular iodine catalysed domino cyclization in aqueous medium: a simple and efficient synthetic route to 1,4-dihydropyridazines

Article abstract of DOI:10.1039/c5ra05370f

A facile, efficient and environmentally friendly approach has been developed for the diverse synthesis of 1,4-dihydropyridazines from (E)-2-benzylidene-1-phenylhydrazine and α,β-unsaturated aldehyde under aqueous condition using molecular iodine as a green and recoverable catalyst. This procedure features low cost and easily available starting materials, an inexpensive and recoverable catalyst, short reaction time, reliable scalability, excellent yield and mild reaction conditions, as well as use of aqueous medium. The scope of this method was thoroughly explored under three different reaction conditions resulting in the generation of a library of title compounds. In view of the various advantages of the present investigation, this methodology gives a convenient and straightforward pathway to construct 1,4-dihydropyridazines in an eco-friendly fashion.

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PAPER
Molecular iodine catalysed domino cyclization in aqueous medium: A
simple and efficient synthetic route to 1,4-dihydropyridazines
I.R.Siddiqui,* Rahila, Pragati Rai, Hozeyfa Sagir and Malik A Waseem
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A facile, efficient and environmentally friendly approach has been developed for the diverse synthesis of
1,4ꢀdihydropyridazines from (E)ꢀ2ꢀbenzylideneꢀ1ꢀphenylhydrazine and α,βꢀunsaturated aldehyde under
aqueous condition using molecular iodine as green and recoverable catalyst. This procedure features lowꢀ
cost, and easily available starting materials, inexpensive, and recoverable catalyst, short reaction time,
10 reliable scalability, excellent yield and mild reaction conditions, as well as use of aqueous medium. The
scope of this method was thoroughly explored under three different reaction conditions resulting in the
generation of a library of title compounds. In view of various advantages of the present investigation, this
methodology gives a convenient and straightforward pathway to construct 1,4ꢀdihydropyridazines in an
ecoꢀfriendly fashion.
15 1. Introduction
Me
O
Me
O
In view of today’s environmental and economic concerns, the
development of ecoꢀfriendly and green protocols employing
environmentally acceptable chemicals, solvents, catalysts, atom
efficient procedures is highly favored1. This tight legislation to
20 maintain greenness in synthetic pathway led us to develop a
method which has low environmental impact. In this context, the
use of water as reaction medium offers several advantages such
as it is abundantly available, inexpensive, redoxꢀstable, nonꢀtoxic,
nonflammable, and environmentally sustainable and, sometimes
25 it allows simple separation and reuse of the catalyst2. In addition
to this, water facilitates novel solvation and molecular assembly
processes leading to remarkable modes of reactivity and
selectivity unattainable in organic solvents3.
NH
NH
N
N
N
MeO
NC
N
N
H
N
H
CN
Levosimendan
Pimobendan
OH
Me
Et
O
OEt
N
N
O
H
EtO
N
N
N
N
N
H
N
Me
O
Emorfazone
Cadralazine
In recent years, there has been an increase in molecular iodine
30 catalyzed transformations because of its low toxicity, easy
handling, readily availability, and economic consideration. As a
mild oxidizer it displays tolerance to wide range of functional
groups and possesses excellent polarizability, which is
presumably of crucial importance for its amazing catalytic
35 potential4. Undoubtedly, iodine could substitute for transition
metals as catalysts. Successful experiments have confirmed that
iodine catalysis is a powerful tool for formation of carbon–carbon
and carbon–heteroatom bonds. Thus, iodineꢀpromoted domino
reactions continue to be an area of active research in synthetic
40 chemistry owing to numerous advantages associated with this
ecoꢀfriendly element5.
Figure 1 1,4ꢀdihydropyridazine ring containing biologically
50 active compounds
cardiotonic vasodilator pimobendan, the antihypertensive agent
cadralazine, and the antiꢀinflammatory agent emorfazone (Fig 1).
Among pyridazine derivatives, dihydropyridazines are a class of
compounds that is receiving much attention for their potential use
55 as antihypertensive, vasodilating agents and coronary therapeutic
agents, or as spasmolytic agents, specially when the substituent at
C4 is aromatic7. In 1994, Chiou reported that fused 1,4ꢀ
dihydropyridazines showed ocular antiꢀinflammatory activity as
an interleukinꢀ1 blocker8. Considering the fact that not many
60 efficient syntheses9 are present in literature for the 1,4ꢀdihydro
derivative, and also as part of the continuing efforts in our
laboratory towards the development of environmentally benign
protocols for the syntheses of heterocyclic frameworks10, we
As a privileged fragment, pyridazineꢀderived molecules are an
important class of structural motif, as they possess potent
biological activities including antifungal, antimicrobial, antiꢀ
45 inflammatory, antihypertensive activities6, and are present in
market as the calciumꢀsensitizing ionotropic agent levosimendan,
planned an efficient synthesis of
65 (Scheme 1).
1,4ꢀdihydropyridazines
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R
N
30
Having established iodine as the catalyst of choice for the
reaction, we next sought out to survey variety of solvents. For
this, similar reactions were carried out in different solvent system
viz. dichloromethane, benzene, acetonitrile, water, chloroform,
and tetrahydrofuran respectively. It was noted that best yield was
I2
H
N
O
N
(10mol%)
N
R
H2O, r.t., 3-4 h
R'
H
Ph
Ph
R'
3
15 examples
79ꢀ92% yield
1
2
35 obtained in water (entry 12). Other solvents such as
dichloromethane, benzene and chloroform gave moderate yield of
the product (entries 9, 10, 13). Acetonitrile and tetrahydrofuran
afforded the product in low yield (entries 11, 14). It was also
noted that no improvement in product yield was obtained when
40 the reaction was carried out at a high temperature (entry 15) or at
reflux condition (entry 16). We also evaluated the amount of
iodine required for this reaction. The results from Table 2 show
that 10 mol % of iodine is optimum choice for the reaction as
higher loading of the catalyst (table 2, entries 3 and 4) had no
45 influence on the reaction yield. On the basis of the above results,
the optimized reaction conditions were to use 10 mol% of iodine
as the catalyst and water as the solvent at room temperature.
Scheme 1 Synthesis of 1,4ꢀDihydropyridazine derivatives
2. Result and Discussion
Herein, we report a successful realization of molecular iodine
catalyzed synthesis of 1,4ꢀdihydropyridazines from (E)ꢀ2ꢀ
benzylideneꢀ1ꢀphenylhydrazine and α,βꢀunsaturated aldehyde
(Scheme 1).
To test the feasibility of our hypothesis, (E)ꢀ2ꢀbenzylideneꢀ1ꢀ
phenylhydrazine 1a, which was obtained in turn by condensation
5
10 of
the
commercially
available
benzaldehyde
with
phenylhydrazine and cinnamaldehyde 2a was selected as a
prototypical case (Scheme 1). Several experimental conditions
including catalyst, solvent and temperature were explored (Table
1). The initially revealed treatment of 1a and 2a with 10 mol%
15 InCl3 in toluene at room temperature for 10 h afforded 3a in 51%
yield (entry 1). Lower product yield was obtained when the
reaction was repeated with TfOH in toluene (entry 2).
Subsequently our studies showed that the product yield could be
increased upto 80% employing pꢀTsOH, however prolonged
20 reaction time was required (entry 3). Similarly, a survey of other
catalyst was found to afford 3a in low to moderate yields of 35ꢀ
59% (entries 4ꢀ6). To our delight, molecular iodine catalyzed
reaction between 1a and 2a gave product 3a in 84% yield within
3 h, showing a further increase of 4% in product yield compared
25 with pꢀTsOH catalysis (entry 7). CAN catalyzed reaction
furnished the product in low yield. A control experiment showed
that no desired product was formed in the absence of iodine
(entry 8).
Table 2 Optimization of mol% of iodinea
Ph
H
N
O
N
I2 (mol%)
H2O, rt
N
N
Ph
Ph
H
Ph
Ph
Ph
3a
Yieldb (%)
1a
2a
Entry
Iodine (mol%)
t (h)
1
2
3
4
5
5
3
3
3
65
88
88
88
10
15
20
aReaction conditions: 1mmol (E)ꢀ2ꢀbenzylideneꢀ1ꢀphenylhydrazine
hydrazine and 1mmol cinnamaldehyde stirred at rt in water. bIsolated
yield
50
After estabilishing a reliable practical procedure for the
synthesis of 1,4ꢀdihydropyridazines, we next explored the scope
of the present procedure to a variety of substrates. The results are
summarized in Table 3. In general, the experiments showed the
standard reaction conditions to be broad, providing a variety of
Table 1 Optimization of the reaction conditionsa
Ph
H
N
55 substituted 1,4ꢀdihydropyridazines in good to excellent yields.
Initially, we investigated the electronic effect of the aromatic
substituent on the benzene ring of (E)ꢀ2ꢀbenzylideneꢀ1ꢀ
phenylhydrazine. It was found that the presence of phenyl or
electronꢀdonating substituent on the aromatic ring was more
60 advantageous (table 3, entries 1 and 3) than the presence of
electron withdrawing substituent (table 3, entry 2). Moreover,
biphenyl system also underwent smooth conversion to the desired
product in 60% yield (table 3, entry 4). Next, various substituent
on the aromatic ring of cinnamaldehyde were also examined.
65 Electronꢀdonating groups such as ꢀMe and ꢀOMe on the
cinnamaldehyde underwent a smooth reaction in the presence of
catalytic iodine to yield the desired products in 73% and 62%
yields respectively (table 3, entries 7 and 8). Good yields were
obtained with the substrates having weakly electronwithdrawing
70 groups (table 3, entries 9, 10, and 11). A better result was
obtained when the substituents on the aromatic ring of
cinnamaldehyde was ꢀ2ꢀF or ꢀ3ꢀNO2 affording the product in
90% and 92% yields respectively (table 3, entries 14 and 15).
O
N
Catalyst (10mol%)
solvent, temp
N
N
Ph
Ph
H
Ph
Ph
Ph
3a
t (h)
1a
2a
Entry
Catalyst (10
Solvent
T (°C)
Yield
(%)
51
24
80
35
42
84
mol%)
InCl3
TfOH
pꢀTsOH
FeCl3
ZnCl2
I2
CAN
ꢀ
1
2
3
4
5
6
7
8
9
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
rt
rt
rt
rt
rt
rt
rt
rt
rt
10
10
12
10
10
3
10
15
3
59
NDc
53
I2
10
11
12
13
14
15
16
I2
I2
I2
I2
I2
I2
I2
Benzene
MeCN
H2O
CHCl3
THF
rt
rt
rt
rt
rt
60°C
reflux
3
3
3
3
3
3
3
64
49
88
50
36
88
88
H2O
H2O
aReaction conditions: 1mmol (E)ꢀ2ꢀbenzylideneꢀ1ꢀphenylhydrazine
hydrazine and 1mmol cinnamaldehyde. bIsolated yield. cNot detected.
2
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Table 3 Scope of the iodine catalyzed synthesis of 1,4ꢀ
10 On the basis of above results and together with the literature
survey the formation of compound 3 could be explained by the
reaction sequence given in scheme 2. The reaction was initiated
by the activation of the carbonyl group of the cinnamaldehyde by
iodine as it behaves as a mild Lewis acid thus forming aldehydeꢀ
15 iodine complex which increases the electrophilic character of the
carbonyl carbon of the cinnamaldehyde facilitating dehydration
which leads to the formation of the intermediate 4. Compound 4
undergoes iodine promoted intramolecular cyclization to give
intermediate 5. Intermediate 5, by the loss of one hydrogen
20 affords the desired product 3. Along these lines, it is noteworthy
to mention that this method facilitates the use of ecoꢀfriendly
solvent and catalyst.
dihydropyridazinesa
R
N
H
O
N
I2 (10mol%)
H2O, rt
N
N
R
R'
H
Ph
Ph
R'
3(aꢀo)
1(aꢀe)
2(aꢀk)
Entry
R
R'
Product
t (h)
Yieldb,c
(%)
88
68
84
3
1
2
3
4
5
Ph
4ꢀClC6H4
4ꢀMeOC6H4
1ꢀnaphthyl
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3
4
3
4
4
60
56
4ꢀ
3. Conclusions
bromonaphthyl
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
3f
3g
3h
3i
3j
3k
3l
3.5
3.5
4
3
3
3
3
3
82
73
62
84
86
86
84
82
In summary, we have devised a simple, and rapid approach for
25 the synthesis of 1,4ꢀdihydropyridazines under aqueous conditions
using the inexpensive and recoverable catalyst at room
temperature. In addition, environmentally friendly reaction
conditions, operational simplicity, avoidance of toxic reagents
and volatile solvents, and the compatibility with various
30 functional groups are the advantages of the present procedure.
4ꢀMeC6H4
4ꢀMeOC6H4
4ꢀFC6H4
4ꢀClC6H4
4ꢀBrC6H4
4ꢀCNC6H4
4ꢀ
MeO2CC6H4
2ꢀFC6H4
3ꢀO2NC6H4
9
10
11
12
13
3m
14
15
Ph
Ph
3n
3o
3
3
90
92
4. Experimental
aReaction conditions: 1mmol (E)ꢀ2ꢀbenzylideneꢀ1ꢀphenylhydrazine
hydrazines and 1mmol cinnamaldehydes stirred at rt in water. bIsolated
yield. cAll compounds gave satisfactory C, H, and N analyses ± 0.22%
and satisfactory spectral (1H NMR, 13C NMR, and EIꢀMS) data.
4.1 Materials and methods
All chemical were reagent grade purchased from Aldrich and
Alfa Aesar and were used without purification. IR spectra were
35 recorded in KBr on a PerkinꢀElmer 993 IR spectrophotometer.
NMR spectra were recorded on a BRUKER AVANCE IIꢀ400FT
Spectrometer (400 MHz for 1HNMR, 100MHz for 13CNMR)
using CDCl3 as solvent and TMS as an internal reference. Mass
I2
R
I2
R
O
N
N
HN
N
Ph
spectra were recorded on
a JEOL SXꢀ102 (FAB) mass
Ph
R'
2
40 spectrometer at 70ev. Elemental analyses were carried out in a
Coleman automatic carbon, hydrogen and nitrogen analyzer. All
the reactions were monitored by TLC using precoated sheets of
silica gel G/UVꢀ254 of 0.25mm thickness (Merck 60F254).
Melting points were determined by open glass capillary method
45 and were uncorrected.
R'
4
1
R
N
N
H
4.2 General procedure for the synthesis of 1,4-
dihydropyridazines
I2
Ph
A mixture of (E)ꢀ2ꢀbenzylideneꢀ1ꢀphenylhydrazine (1.0 mmol)
{bezaldehyde (1.0 mmol) and phenylhydrazine (1.0 mmol) stirred
50 for 10 min at rt} and cinnamaldehyde (1.0 mmol) in 10 mL of
water was taken in a 50 mL flask and 10 mol% of iodine was
added to it. Then the reaction mixture was stirred at room
temperature until the reaction reached completion, as evidenced
by TLC. Iodine was removed from the reaction mixture by
55 quenching it with finely powdered Na2S2O3 and stirring until the
disappearance of iodine. The reaction mixture was extracted with
EtOAc twice and the organic layer was washed successively with
10% NaHCO3 and H2O and dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The residue
60 was purified by silica gel (mesh 60ꢀ120) chromatography
(hexane–EtOAc) to afford the corresponding products.
R'
5
R
N
N
Ph
R'
3
Scheme 2 A Plausible mechanistic pathway for the synthesis of
dihydropyridazines derivatives
5
Thus, these results demonstrated the potential usefulness of
this strategy for the diverse synthesis of 1,4ꢀdihydropyridazines
derivatives. The structures of all the products were elucidated
3a. 1,4-dihydro-1,3,4-triphenylpyridazine
IR(KBr, cmꢀ1): νmax = 3442, 2912, 2843, 1666, 1599, 1493, 1480,
with the help of IR, HNMR, 13CNMR, and elemental analysis.
1
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1289, 1271, 1223, 1173, 1129, 983, 755, 697. 1H NMR (400 60 127.1 126.4, 125.1, 123.2, 121.5, 36.2. MS (EI) m/z 438 [M+];
MHz, CDCl3) δ (ppm) = 7.79ꢀ7.66 (m, 4H, ArH), 7.44ꢀ7.23 (m,
10H, ArH), 7.15ꢀ7.11 (t, J = 7.3 Hz, 1H, ArH), 6.92 (d, J = 7.8
Hz, 1H, ꢀNꢀCH=Cꢀ), 5.23 (dd, J = 7.8, 5.3 Hz, 1H, ꢀC=CHꢀCꢀ),
4.42 (d, J = 5.3 Hz, 1H, ꢀCꢀCHꢀCꢀ). 13C NMR (100 MHz, CDCl3)
δ (ppm) = 143.6, 142.8, 134.4, 132.9, 131.6, 130.2, 129.3, 128.9,
128.2, 127.4, 124.6, 123.9, 121.6, 119.6, 116.2, 36.6. MS (EI)
m/z 310 [M+]; Analysis Calcd. For C22H18N2: C, 85.13; H, 5.85;
N, 9.03% Found: C, 85.22; H, 5.92; N, 9.11%.
Analysis Calcd. For C26H19BrN2: C, 71.08; H, 4.36; N, 6.38%
Found: C, 71.07; H, 4.30; N, 6.28%.
3f. 1,4-dihydro-4-methyl-1,3-diphenylpyridazine
5
65 IR(KBr, cmꢀ1): νmax = 3061, 2965, 2927, 1655, 1599, 1497, 1363,
1
1274, 1239, 1192, 1123, 1091, 754, 692. H NMR (400 MHz,
CDCl3) δ (ppm) = 7.78ꢀ7.67 (m, 4H, ArH), 7.38ꢀ7.34 (m, 5H,
ArH), 7.18ꢀ7.12 (t, J = 7.3 Hz, 1H, ArH), 6.77 (d, J = 7.4 Hz, 1H,
ꢀNꢀCH=Cꢀ), 5.08 (dd, J = 7.4, 5.6 Hz, 1H, ꢀC=CHꢀCꢀ), 3.24 (dq,
70 J1 = 6.8 Hz, J2 = 5.6 Hz, 1H, ꢀCꢀCHꢀCꢀ); 1.17 (d, J = 6.8 Hz,
3H, Me). 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.7, 134.7,
134.0, 131.9, 130.2, 129.1, 127.7, 125.7, 123.7, 121.5, 116.1,
24.9, 21.5. MS (EI) m/z 248 [M+]; Analysis Calcd. For
C17H16N2: C, 82.22; H, 6.49; N, 11.28% Found: C, 82.34; H,
10
3b. 1-(4-chlorophenyl)-1,4-dihydro-3,4-diphenylpyridazine
IR(KBr, cmꢀ1): νmax = 3456, 2914, 2848, 2290, 1733, 1663, 1613,
1511, 1466, 1374, 1254, 1117, 835, 765, 713. 1H NMR (400
MHz, CDCl3) δ (ppm) = 7.68ꢀ7.53 (m, 4H, ArH), 7.37ꢀ7.33 (m,
15 7H, ArH), 7.28ꢀ7.22 (m, 3H, ArH), 6.87 (d, J = 7.8 Hz, 1H, ꢀNꢀ
CH=Cꢀ), 5.25 (dd, J = 7.8, 5.4 Hz, 1H, ꢀC=CHꢀCꢀ), 4.41 (d, J = 75 6.62; N, 11.21%.
5.4 Hz, 1H, ꢀCꢀCHꢀCꢀ). 13C NMR (100 MHz, CDCl3) δ (ppm) =
3g. 1,4-dihydro-1,3-diphenyl-4-p-tolylpyridazine
142.7, 142.1, 134.5, 133.8, 131.5, 130.7, 129.8, 129.2, 128.9,
128.0, 127.7, 127.1, 124.3, 117.4, 36.5. MS (EI) m/z 344 [M+];
20 Analysis Calcd. For C22H17ClN2: C, 76.63; H, 4.97; N, 8.12%
Found: C, 76.53; H, 5.05; N, 8.05%.
IR(KBr, cmꢀ1): νmax = 2948, 2856, 1663, 1599, 1497, 1270, 1243,
1
1175, 1133, 1072, 809, 754, 690. H NMR (400 MHz, CDCl3) δ
80 (ppm) = 7.82ꢀ7.70 (m, 4H, ArH), 7.43ꢀ7.38 (m, 5H, ArH), 7.16ꢀ
7.10 (m, 5H, ArH), 6.88 (d, J = 8.0 Hz, 1H, ꢀNꢀCH=Cꢀ), 5.21 (dd,
J = 8.0, 5.6 Hz, 1H, ꢀC=CHꢀCꢀ), 4.39 (d, J = 5.6 Hz, 1H, ꢀCꢀCHꢀ
Cꢀ), 2.78 (s, 3H, Me). 13C NMR (100 MHz, CDCl3) δ (ppm) =
143.4, 140.0, 137.2, 134.4, 133.1, 131.6, 130.9, 129.7, 129.2,
3c. 1,4-dihydro-1-(4-methoxyphenyl)-3,4-diphenylpyridazine
IR(KBr, cmꢀ1): νmax = 3443, 2926, 2851, 2296, 1727, 1672, 1606,
25 1509, 1462, 1381, 1247, 1129, 828, 758, 702, 534. 1H NMR (400
MHz, CDCl3) δ (ppm) = 7.77ꢀ7.68 (m, 4H, ArH), 7.38ꢀ7.30 (m, 85 128.1, 127.2, 124.3, 123.8, 121.5, 116.3, 36.3, 21.0. MS (EI) m/z
5H, ArH), 7.29ꢀ7.25 (m, 3H, ArH), 6.92 (d, J = 9.0 Hz, 2H,
ArH), 6.81 (d, J = 7.7 Hz, 1H, ꢀNꢀCH=Cꢀ), 5.18 (dd, J = 7.7, 5.4
Hz, 1H, ꢀC=CHꢀCꢀ), 4.40 (d, J = 5.4 Hz, 1H, ꢀCꢀCHꢀCꢀ), 3.84 (s,
30 3H, OMe). 13C NMR (100 MHz, CDCl3) δ (ppm) = 156.6, 143.2,
137.6, 134.2, 132.2, 131.7, 131.0, 130.1, 128.9, 128.1, 127.8,
127.2, 125.5, 122.4, 120.6, 118.4, 114.5, 55.7, 36.5. MS (EI) m/z
340 [M+]; Analysis Calcd. For C23H20N2O: C, 81.15; H, 5.92; N,
8.23% Found: C, 81.25; H, 5.87; N, 8.27%.
324 [M+]; Analysis Calcd. For C23H20N2: C, 85.15; H, 6.21; N,
8.63%. Found: C, 85.05; H,6.13; N, 8.67%.
3h. 1,4-dihydro-4-(4-methoxyphenyl)-1,3-diphenylpyridazine
90 IR(KBr, cmꢀ1): νmax = 2957, 2838, 1732, 1663, 1599, 1510, 1499,
1
1400, 1367, 1255, 1241, 1177, 1128, 835, 754, 693. H NMR
(400 MHz, CDCl3) δ (ppm) = 7.79ꢀ7.62 (m, 4H, ArH), 7.44ꢀ7.38
(m, 5H, ArH), 7.18ꢀ7.13 (m, 3H, ArH), 6.91 (d, J = 7.6 Hz, 1H, ꢀ
NꢀCH=Cꢀ), 6.88ꢀ6.84 (m, 2H, ArH), 5.21 (dd, J = 7.6, 5.2 Hz,
95 1H, ꢀC=CHꢀCꢀ), 4.36 (d, J = 5.2 Hz, 1H, ꢀCꢀCHꢀCꢀ), 3.96 (s, 3H,
OMe). 13C NMR (100 MHz, CDCl3) δ (ppm) = 159.3, 143.4,
135.1, 134.0, 133.3, 131.3, 130.7, 129.4, 128.5, 127.9, 124.4,
123.8, 121.5, 116.2, 114.5, 55.0, 36.1. MS (EI) m/z 340 [M+];
Analysis Calcd. For C23H20N2O: C, 81.15; H, 5.92; N, 8.23%
35
3d. 1,4-dihydro-1-(naphthalen-1-yl)-3,4-diphenylpyridazine
IR(KBr, cmꢀ1): νmax = 3438, 3061, 2918, 1737, 1653, 1594, 1455,
1379, 1239, 1123, 997, 947, 771, 701. 1H NMR (400 MHz,
CDCl3) δ (ppm) = 7.96ꢀ7.90 (m, 2H, ArH), 7.82ꢀ7.78 (m, 5H,
40 ArH), 7.56ꢀ7.50 (m, 4H, ArH), 7.41ꢀ7.35 (m, 5H, ArH), 7.29ꢀ
7.25 (t, J = 7.2 Hz, 1H, ArH), 6.67 (d, J = 7.6 Hz, 1H, ꢀNꢀCH=Cꢀ 100 Found: C, 81.37; H, 5.76; N, 8.31%.
), 5.20 (dd, J = 7.6, 5.3 Hz, 1H, ꢀC=CHꢀCꢀ), 4.48 (d, J = 5.3 Hz,
1H, ꢀCꢀCHꢀCꢀ). 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.4,
141.3, 134.7, 134.0, 131.2, 130.3, 129.7, 129.2, 128.9, 128.3,
45 128.0, 127.8, 127.4, 127.1, 126.9, 126.4, 126.0, 125.6, 122.7,
121.1, 36.3. MS (EI) m/z 360 [M+]; Analysis Calcd. For
C26H20N2: C, 86.64; H, 5.59; N, 7.77% Found: C, 86.42; H, 5.65;
N, 7.71%.
3i. 4-(4-fluorophenyl)-1,4-dihydro-1,3-diphenylpyridazine
IR(KBr, cmꢀ1): νmax = 3062, 2922, 2844, 1599, 1509, 1499, 1288,
1224, 1161, 1129, 986, 843, 755, 691. 1H NMR (400 MHz,
105 CDCl3) δ (ppm) = 7.81ꢀ7.66 (m, 4H, ArH), 7.42ꢀ7.39 (m, 5H,
ArH), 7.23ꢀ7.13 (m, 3H, ArH), 7.06ꢀ6.98 (m, 2H, ArH), 6.93 (d, J
= 7.9 Hz, 1H, ꢀNꢀCH=Cꢀ), 5.21 (dd, J = 7.9, 5.3 Hz, 1H, ꢀC=CHꢀ
Cꢀ), 4.41 (d, J = 5.3 Hz, 1H, ꢀCꢀCHꢀCꢀ). 13C NMR (100 MHz,
CDCl3) δ (ppm) = 162.4, 143.6, 138.8, 134.2, 132.6, 131.7,
110 130.9, 129.4, 129.3, 127.3, 124.9, 124.2, 121.6, 116.4, 115.8,
35.8. MS (EI) m/z 328 [M+]; Analysis Calcd. For C22H17FN2: C,
80.47; H, 5.22; N, 8.53%. Found: C, 80.69; H, 5.14; N, 8.48%.
50 3e.
1-(1-bromonaphthalen-4-yl)-1,4-dihydro-3,4-
diphenylpyridazine
IR(KBr, cmꢀ1): νmax = 3307, 2919, 1731, 1593, 1459, 1370, 1126,
830, 759, 697. 1H NMR (400 MHz CDCl3) δ (ppm) = 8.26 (dd, J
= 8.0, 4.0 Hz, 1H, ArH), 7.95 (d, J = 8.0 Hz, 1H, ArH), 7.85 (d, J
55 = 8.0 Hz, 1H, ArH), 7.73ꢀ7.59 (m, 6H, ArH), 7.44ꢀ7.30 (m, 7H,
3j. 4-(4-chlorophenyl)-1,4-dihydro-1,3-diphenylpyridazine
ArH), 6.61 (d, J = 7.6 Hz, 1H, ꢀNꢀCH=Cꢀ), 5.24 (dd, J = 7.6, 5.3 115 IR(KBr, cmꢀ1): νmax = 3056, 2927, 2848, 1698, 1662, 1598, 1492,
Hz, 1H, ꢀC=CHꢀCꢀ), 4.48 (d, J = 5.3 Hz, 1H, ꢀCꢀCHꢀCꢀ). 13C
NMR (100 MHz, CDCl3) δ (ppm) = 142.9, 141.2, 134.5, 133.4,
133.2, 132.8, 131.0, 130.4, 129.5, 129.1, 128.5, 127.9, 127.5,
1410, 1271, 1243, 1174, 1130, 983, 836, 756, 692. 1H NMR (400
MHz, CDCl3) δ (ppm) = 7.79ꢀ7.65 (m, 4H, ArH), 7.43ꢀ7.38 (m,
5H, ArH), 7.32ꢀ7.28 (m, 2H, ArH), 7.19ꢀ7.14 (m, 3H, ArH), 6.91
4
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DOI: 10.1039/C5RA05370F
60 3o. 1,4-dihydro-4-(3-nitrophenyl)-1,3-diphenylpyridazine
(d, J = 7.9 Hz, 1H, ꢀNꢀCH=Cꢀ), 5.17 (dd, J = 7.9, 5.2 Hz, 1H, ꢀ
C=CHꢀCꢀ), 4.39 (d, J = 5.2 Hz, 1H, ꢀCꢀCHꢀCꢀ). 13C NMR (100
MHz, CDCl3) δ (ppm) = 143.5, 141.3, 134.0, 133.5, 132.3, 131.9,
131.1, 129.9, 129.3, 128.9, 127.6, 125.1, 124.1, 121.4, 116.3,
35.9. MS (EI) m/z 344 [M+]; Analysis Calcd. For C22H17ClN2: C,
76.63; H, 4.97; N, 8.12%. Found: C, 76.75; H, 5.07; N, 8.26%.
IR(KBr, cmꢀ1): νmax = 3064, 2922, 2848, 1663, 1599, 1493, 1350,
1
1304, 1270, 1244, 1192, 1127, 1009, 755, 689. H NMR (400
MHz, CDCl3) δ (ppm) = 8.15ꢀ8.11 (m, 2H, ArH), 7.79ꢀ7.68 (m,
4H, ArH), 7.59ꢀ7.47 (m, 2H, ArH), 7.44ꢀ7.41 (m, 5H, ArH),
65 7.20ꢀ7.15 (t, J = 7.1 Hz, 1H, ArH), 7.01 (d, J = 7.8 Hz, 1H, ꢀNꢀ
CH=Cꢀ), 5.23 (dd, J = 7.8, 5.3 Hz, 1H, ꢀC=CHꢀCꢀ), 4.56 (d, J =
5.3 Hz, 1H, ꢀCꢀCHꢀCꢀ). 13C NMR (100 MHz, CDCl3) δ (ppm) =
148.7, 144.5, 143.4, 134.4, 133.7, 132.2, 131.3, 130.0, 129.9,
129.3, 127.6, 125.8, 124.4, 122.6, 122.1, 121.3, 116.6, 36.1. MS
5
3k. 4-(4-bromophenyl)-1,4-dihydro-1,3-diphenylpyridazine
IR(KBr, cmꢀ1): νmax = 3054, 2922, 2848, 1597, 1491, 1270, 1243,
10 1176, 1133, 1074, 1012, 987, 833, 754, 691. 1H NMR (400 MHz,
CDCl3) δ (ppm) = 7.77ꢀ7.65 (m, 4H, ArH), 7.47ꢀ7.44 (m, 2H, 70 (EI) m/z 355 [M+]; Analysis Calcd. For C22H17N3O2: C, 74.35;
ArH), 7.40ꢀ7.36 (m, 5H, ArH), 7.18ꢀ7.08 (m, 3H, ArH), 6.92 (d, J
= 7.6 Hz, 1H, ꢀNꢀCH=Cꢀ), 5.19 (dd, J = 7.6, 5.3 Hz, 1H, ꢀC=CHꢀ
Cꢀ), 4.37 (d, J = 5.3 Hz, 1H, ꢀCꢀCHꢀCꢀ). 13C NMR (100 MHz,
15 CDCl3) δ (ppm) = 143.6, 141.7, 134.6, 132.3, 132.1, 131.5,
130.3, 129.3, 129.3, 127.9, 125.1, 124.2, 121.7, 121.4, 116.3,
36.0; MS (EI) m/z 388 [M+]; Analysis Calcd. For C22H17BrN2: C,
67.88; H, 4.40; N, 7.20%. Found: C, 67.79; H, 4.48; N, 7.28%.
H, 4.82; N, 11.82%. Found: C, 74.17; H, 4.89; N, 11.93%.
Acknowledgements
The authors gratefully acknowledge SAIF, Punjab University
Chandigarh for providing all the spectroscopic and analytical
75 data. Rahila and P.Rai are grateful to the CSIR, New Delhi for
the award of Senior Research Fellowship (SRF) and H. Sagir to
UGC, New Delhi for the award of Junior Research Fellowship.
20 3l. 4-(1,4-dihydro-1,3-diphenylpyridazin-4-yl)benzonitrile
IR(KBr, cmꢀ1): νmax = 3061, 2927, 2229, 1655, 1599, 1499, 1366,
1273, 1243, 1193, 1127, 844, 756, 692. 1H NMR (400 MHz,
CDCl3) δ (ppm) = 7.74ꢀ7.62 (m, 6H, ArH), 7.42ꢀ7.40 (m, 5H,
ArH), 7.36ꢀ7.32 (m, 2H, ArH), 7.19ꢀ7.14 (t, J = 7.2 Hz, 1H,
25 ArH), 6.97 (d, J = 8.1 Hz, 1H, ꢀNꢀCH=Cꢀ), 5.21 (dd, J = 8.1, 5.6
Hz, 1H, ꢀC=CHꢀCꢀ), 4.51 (d, J = 5.6 Hz, 1H, ꢀCꢀCHꢀCꢀ). 13C
NMR (100 MHz, CDCl3) δ (ppm) = 147.7, 143.2, 134.2, 132.9,
131.1, 131.8, 130.0, 129.3, 128.3, 127.6, 125.7, 124.3, 121.4,
118.1, 116.3, 111.4, 36.7. MS (EI) m/z 335 [M+]; Analysis
30 Calcd. For C23H17N3: C, 82.36; H, 5.11; N, 12.53%. Found: C,
82.50; H, 5.26; N, 12.42%.
Notes and references
Laboratory of Green synthesis, Department of Chemistry, University of
80 Allahabad, Allahabad-211002, India; E-mail: dr.irsiddiqui@gmail.com
1
Reviews (a) C. J. Li, Chem. Rev. 2005, 105, 3095; (b) J. G.
Hernandez, E. Juaristi, Chem. Soc. Rev., 2012, 48, 5396; (c) J.
Mlynarski, J. Paradowska, Chem. Soc. Rev., 2008, 37, 1502; (d) R. N.
Butler, A. G. Coyne, Chem. Rev. 2010, 110, 6302.
85
90
2
(a) Y. Gu, Green Chem., 2012, 14, 2091; (b) J. Mlynarski, S. Baś,
Chem. Soc. Rev., 2014, 43, 577; (c) Z. N. Tisseh, M. Dabiri, M.
Nobahar, H. R. Khavasi, A. Bazgir, Tetrahedron, 2012, 68, 1769; (d)
J. Pinto, V. L. M. Silva, A. M. G. Silva, A. M. S. Silva, J. C. S.
Costa, L. B. M. N. F. Santos, R. Enes, J. A. S. Cavaleiro, A. A. M. O.
S. Vicented, J. A. C. Teixeira, Green Chem., 2013, 15, 970; (e) U. M.
Lindström, Organic Reactions in Water: Principles, Strategies and
Applications, 1st ed.; Blackwell Publishing: Oxford, 2007.
M. B. Gawande, V. D. B. Bonifacio, R. Luque, P. S. Branco, R. S.
Varma, Chem. Soc. Rev., 2013, 42, 5522 and references therein
(a) W.ꢀC. Lee, H.ꢀC. Shen, W.ꢀP. Hu, W.ꢀS. Lo, C. Murali, J. K.
Vandavasi, J.ꢀJ. Wang, Adv. Synth. Catal., 2012, 354, 2218; (b) Y.
Yan, Y. Zhang, C. Feng, Z. Zha, Z. Wang, Angew. Chem., Int. Ed.,
2012, 51, 8077; (c) G. Ramachandran, N. S. Karthikeyan, P.
Giridharan, K. I. Sathiyanarayanan, Org. Biomol. Chem., 2012, 10,
5343; (d) G. R. Reddy, T. R. Reddy, S. C. Joseph, K. S. Reddy, M.
Pal, RSC Adv., 2012, 2, 3387.
3m.
methyl
4-(1,4-dihydro-1,3-diphenylpyridazin-4-
yl)benzoate
35 IR(KBr, cmꢀ1): νmax = 3042, 2955, 1717, 1655, 1598, 1496, 1437,
1366, 1282, 1242, 1192, 1126, 1002, 951, 755, 693. 1H NMR
(400 MHz, CDCl3) δ (ppm) = 8.11ꢀ7.99 (m, 2H, ArH), 7.80ꢀ7.68
(4H, ArH), 7.41ꢀ7.38 (m, 5H, ArH), 7.30ꢀ7.28 (m, 2H, ArH),
7.18ꢀ7.13 (t, J = 7.3 Hz, 1H, ArH), 6.92 (d, J = 7.9 Hz, 1H, ꢀNꢀ
40 CH=Cꢀ), 5.21 (dd, J = 7.9, 5.4 Hz, 1H, ꢀC=CHꢀCꢀ), 4.48 (d, J =
5.4 Hz, 1H, ꢀCꢀCHꢀCꢀ), 3.91 (s, 3H, COOMe). 13C NMR (100
MHz, CDCl3) δ (ppm) = 166.6, 147.5, 143.3, 134.6, 132.0, 131.7,
130.9, 130.0, 129.4, 129.0, 127.8, 127.0, 125.3, 124.1, 121.3,
116.3, 52.0, 36.5. MS (EI) m/z 368 [M+]; Analysis Calcd. For
45 C24H20N2O2: C, 78.24; H, 5.47; N, 7.60%. Found: C, 78.04; H,
5.63; N, 7.44%.
3
4
95
100
105
110
5
6
(a) A. Alizadeh, J. Mokhtari, Tetrahedron, 2013, 69, 6313; (b) F. M.
Moghaddam, M. R. Khodabakhshi, M. Aminaee, Tetrahedron Letters
2014, 55, 4720; (c) J. S. Yadav, G. Narasimhulu, N. Umadevi, Y. V.
Reddy, B.V. Subba Reddy, Tetrahedron Letters 2013, 54, 871.
(a) Chemistry of Heterocyclic Compounds: Pyridazines, Vol. 28 (Ed.:
R. N. Castle), Wiley, New York, 1973; (b) C. G. Wermuth,
MedChemComm. 2011, 2, 935.
3n. 4-(2-fluorophenyl)-1,4-dihydro-1,3-diphenylpyridazine
IR(KBr, cmꢀ1): νmax = 3043, 2927, 1598, 1587, 1492, 1271, 1242,
50 1191, 1143, 1129, 1005, 754, 692. 1H NMR (400 MHz, CDCl3) δ
(ppm) = 7.81ꢀ7.72 (m, 4H, ArH), 7.41ꢀ7.38 (m, 5H, ArH), 7.25ꢀ
7.07 (m, 5H, ArH), 6.90 (d, J = 7.7 Hz, 1H, ꢀNꢀCH=Cꢀ), 5.21 (dd,
J = 7.7, 5.6 Hz, 1H, ꢀC=CHꢀCꢀ), 4.80 (d, J = 5.6 Hz, 1H, ꢀCꢀCHꢀ
Cꢀ). 13C NMR (100 MHz, CDCl3) δ (ppm) = 159.4, 143.6, 134.2,
55 131.9, 131.2, 130.2, 129.7, 129.5, 129.3, 129.4, 127.2, 125.5,
124.8, 124.1, 121.7, 116.4, 115.6, 29.3. MS (EI) m/z 328 [M+];
Analysis Calcd. For C22H17FN2: C, 80.47; H, 5.22; N, 8.53%.
Found: C, 80.59; H, 5.13; N, 8.70%.
7
8
9
G. Frankowiak, H. Meyer, F. Bossert, A. Heise, S. Kazda, K. Stoepel,
R. Towart, E. Wehinger, US 4,348,395, 1982.
G. C. Chiou, Q. S. Yao, T. Okawara, J. Ocul. Pharmacol. 1994, 10,
577.
(a) G. Pitacco et al, Tetrahedron: Asymmetry 2010, 21, 617. (b) H.
Xie, J. Zhu, Z. Chen, S. Li, Y. Wu, Synlett 2012, 23, 935.
115 10 (a) I. R. Siddiqui, P. Rai, Rahila, A. Srivastava, New J. Chem. 2014,
38, 3791; (b) I. R. Siddiqui, P. Rai, Rahila, A. Srivastava, A.
Srivastava, A. Srivastava, New J. Chem. 2013, 37, 3798; (c) I. R.
Siddiqui, A. A. H. Abumhdi, S. Shamim, Shireen, M. A. Waseem,
Rahila, A. Srivastava, A. Srivastava, RSC Advances, 2013, 3, 10173;
120
(d) I. R. Siddiqui, S. Shamim, M. A. Waseem, A. Srivastava, Rahila,
RSC Advances, 2013, 3, 14423.
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Journal Name, [year], [vol], 00–00 | 5

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DOI: 10.1039/C5RA05370F
Table of Content
Molecular iodine catalysed domino cyclization in aqueous medium: A simple and efficient
synthetic route to 1,4-dihydropyridazines
I.R.Siddiqui*, Rahila, Pragati Rai, Hozeyfa Sagir, Malik A Waseem
R
I2
H
N
N
O
N
(10mol%)
N
R
H2O, r.t., 3-4 h
R'
H
Ph
Ph
1
2
R'
3
ꢀ Aqueous solvent
ꢀ Recoverable catalyst
ꢀ No byproduct
An efficient protocol has been developed for the synthesis of dihydropyridazines using molecular
iodine as green catalyst.