Palladium-Catalyzed Direct ortho-C–H Bond Sulfonylation and Halogenation of Phthalazine-1,4-diones

Article abstract of DOI:10.1002/ejoc.201901055

The regio- and chemo-selective Pd-catalyzed C–H activation methods have been successfully reported for directed C–H sulfonation and halogenation of pyridazinedione with arylsulfonyl chlorides and N-halosuccinimide, respectively. These protocols are compatible with a range of various functional groups and exhibit excellent regio-selectivity under mild reaction conditions by use of inexpensive and readily accessible reagents.

Full text of DOI:10.1002/ejoc.201901055

A Journal of
Accepted Article
Title: Palladium‐Catalyzed Direct ortho-C-H Bond Sulfonylation and
Halogenation of Phthalazine-1,4-diones
Authors: Minoo Dabiri, Noushin Farajinia Lehi, Chiman Osmani, and
Siyavash Kazemi Movahed
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901055
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901055
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10.1002/ejoc.201901055
European Journal of Organic Chemistry
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-
Palladium Catalyzed Direct ortho-C-H Bond Sulfonylation and
Halogenation of Phthalazine-1,4-diones
Minoo Dabiri,* Noushin Farajinia Lehi, Chiman Osmani, and Siyavash Kazemi Movahed
Abstract: The regio- and chemo-selective Pd-catalyzed C−H
activation methods have been successfully reported for directed C−H
sulfonation and halogenation of pyridazinedione with arylsulfonyl
chlorides and N-halosuccinimide, respectively. These protocols are
compatible with a range of various functional groups on substrates
and exhibit excellent regio-selectivity under mild reaction conditions
by use of inexpensive and readily accessible reagents.
Introduction
In the past decade, with the ever-increasing need for efficient,
atom-economical and green-sustainable processes, the
tremendous amount of attention has been paid to the construction
of C-C or C-heteroatom linkages directly from two simple C−H
and C-halogen bonds for organic synthesis. Undoubtedly, direct,
selective and catalytic functionalization of ubiquitous C–H bonds
has opened a revolutionary direction to green, clean and efficient
synthetic methods as it allows to minimize the steps of synthetic
manipulations and reduces undesired byproducts.[1–4]
Figure 1. Representative examples of bioactive compounds with
pyridazinedione structural motif.
To the best of our knowledge, pyridazinedione-directed C−H
functionalization has been mainly limited to C−C bonds formation
with Ir, Rh, and Ru catalysts (Scheme 1). In 2016, two groups of
Gandhi[17] and Perumal[18] independently reported the using of
phthalazindiones as easily accessible structures in the synthesis
of phthalazino[2,3-a]cinnolines via Ru and Rh catalyzed
dehydrogenative coupling reactions, respectively (Scheme 1a
and 1b). Gogoi disclosed a RuII-catalyzed annulation reaction
between 2-phenylphthalazinediones and alkynes for the
synthesis of substituted quinazolines (Scheme 1c).[19] Shang
reported Ir-catalyzed the consecutive C−H bond activation,
carbene insertion, and condensation annulation processes for the
Despite many efforts in the introduction of a varied range of
directing groups for the selective C-H bond functionalization,[5] the
developing this scope to heterocyclic scaffolds, especially N-
heterocycles is still a challenging subject in organic and medicinal
chemistry due to their biological importance.[6–8] Pyridazinedione
derivatives constitute a prominent category of N-heterocyclic
compounds, which were classically served as intermediates in the
preparation of insecticide and acaricide substances and
ectoparasiticide drugs. They have also been utilized in the
polymer industry, and exhibited as bioactive scaffolds due to their
neurokinin-1 (substance P) antagonistic[9] (Fig. 1A), anti-tumor
(Fig. 1B),[10] anti-inflammatory (Fig. 1C and D)[11] and anxiolytic
activities (Fig. 1E)[12]. Recently, pyridazinediones have found a
wide application in expanding drug-like molecules and the site-
synthesis
of
phthalazino[2,3-a]cinnolinedione
derivatives
(Scheme 1d).[20] Sakhuja developed two efficient Rh(III)-
catalyzed additive-modulated strategies for the synthesis of
unprecedented hydroxy-dihydroindazolo[1,2-b]phthalazines and
phthalazino[2,3-a]cinnolines by using 2-arylphthalazine-1,4-
diones and α-diazo carbonyl compounds (Scheme 1e).[21] Ji
introduced the synthesis of indazolo[1,2-b]phthalazinedione
structures via Rh(III)-catalyzed [4 + 1] annulation of propargyl
alcohols with pyridazinedione scaffolds by C−H activation
(Scheme 1f).[22] Recently also, Kianmehr reported RuII catalyzed
oxidative alkenylation of pyridazinediones with acrylates followed
by intramolecular cyclization of the resulting indazolo[1,2-
b]phthalazines derivatives (Scheme 1g).[23]
[13–16]
selective manipulation of peptides and proteins.
Consequently, the development of novel and highly efficient
approaches to construct and modify these versatile structures is
highly desirable from both laboratory and industrial syntheses
point of view.
To continue our research interest aiming at N-heterocycle
directed C-H bond functionalization of arenes,[24–27] herein, we
report the first Pd-catalyzed C−H activation/sulfonylation and
halogenation reactions of phthalazindiones. These approaches
afford predominantly mono-functionalized products under mild
and oxidant-free reaction conditions using a palladium catalytic
system and readily accessible and inexpensive reagents as
functional group sources (Scheme 1h).
[a]
Prof. Dr. M. Dabiri, N. F. Lehi, C. Osmani, Dr. S. K. Movahed
Faculty of Chemistry and Petroleum Sciences
Shahid Beheshti University
Tehran Province, Tehran, District 1, Daneshjou Boulevard,
1983969411
E-mail: m-dabiri@sbu.ac.ir
Homepage: http://facultymembers.sbu.ac.ir/dabiri/
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201901055
European Journal of Organic Chemistry
FULL PAPER
desired cross-coupling product 3aa in 42% yield using 1,4-
dioxane as a solvent in the presence of Pd(OAc)2 (10 mol %) and
K2CO3 (2 eq.) (Table 1, entry 1). First, the effect of various
solvents, such as toluene, CH3CN, EtOH, dimethylformamide
(DMF), and 1,2-dichloroethane (DCE) was screened (Table 1,
entries 2-6). DCE was found to be a more effective solvent
compared to the other solvents, affording 3aa in 69% yield (Table
1, entry 6). Control experiments revealed that the additive played
a crucial role in this transformation and no reaction occurred in
the absence of K2CO3 (Table 1, entry 7). Among the general bases,
such as K2CO3, NaHCO3, NaOAc, Na2CO3, Cs2CO3, the best
result was obtained by using two equivalents of K2CO3 (Table 1,
entries 6, 8- 11). Inspired by the work of Cui and Wu about the
generation of the aryl sulfonyl radicals,[40] the K2CO3 was replaced
by K2S2O8 as an oxidant in reaction condition, but the reaction did
not proceed (Table 1, entry 12). Furthermore, the other common
additives including AgOAc and Cu(OAc)2 were tested and no
improvement in yields was observed (Table 1, entries 13-14).
Trying the reaction in the absence of catalyst was completely
failed (Table 1, entry 15). Thus, Pd(OAc)2, PdCl2, Cu(OAc)2 and
Co(OAc)2 were examined to catalyze this transformation, in which
Pd(OAc)2 was the best choice for C-H sulfonation (Table 1,
entries 16-18). Decreasing the catalyst loading from 10 to 5 mol%
led to a lower yield of 57% (Table 1, entry 19) and increasing the
loading of catalyst to 15 mol%, did not show significant
improvement in the yield (Table 1, entry 20). The optimum
reaction temperature was found to be 120oC and lowering the
temperature (80 oC) reduced the product yield (Table 1, entry 21).
As well as, the excess of sulfonyl chloride was essential, and
decreasing the amount of sulfonyl chloride from 2 mmol to the
stoichiometric ratio of 1a and 2a led to insufficient outcome
product (Table 1, entry 22).
Table 1. Optimization of the C-H sulfonation conditions[a]
Scheme 1. Approaches for the C-H Activation of phthalazinedione with Different
Coupling Partners
Results and Discussion
At the outset of our study, we disclose a direct Pd(II)-catalyzed C-
H bond activation followed by cross-coupling with aryl sulfonyl
chlorides to produce a N-heterocyclic aromatic sulfones, as these
structures have proven to be important structural motifs in a wide
range of pharmaceutical molecules, including inhibitors of
polynucleotide repeat-associated RNA,[28] prevention of heart
Entry
1
Catalyst (mol%)
Pd(OAc)2(10)
Solvent
Additive (eq.)
K2CO3 (2)
Yield[b]
(%)
1,4-
Dioxane
42
failure,[29] anti-tumor,[30] antiviral,[31,32] antibacterial[33]
,
bone
2
3
4
5
6
Pd(OAc)2(10)
Pd(OAc)2(10)
Pd(OAc)2(10)
Pd(OAc)2(10)
Pd(OAc)2(10)
PhCH3
CH3CN
EtOH
DMF
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
63
disorders[34]. On the other hand, they are useful synthetic
intermediates in organic reactions such as Ramberg-Bäcklund
rearrangement[35,36] and Julia olefination[37,38]. Inspired by the work
of Sun[39], We initiated our investigation on the model reaction of
41
12
Trace
69
2-phenyl-2,3-dihydrophthalazine-1,4-dione
(1a)
with
benzenesulfonyl chloride (2a) to optimize the critical reaction
parameters (Table 1). To our delight, the reaction gave the
DCE
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10.1002/ejoc.201901055
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7
Pd(OAc)2(10)
Pd(OAc)2(10)
Pd(OAc)2(10)
Pd(OAc)2(10)
Pd(OAc)2(10)
Pd(OAc)2(10)
Pd(OAc)2(10)
Pd(OAc)2(10)
-
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
-
trace
33
Table 2. Scope of substrats for sulfonylation reaction[a]
8
NaHCO3 (2)
NaOAc (2)
Na2CO3 (2)
Cs2CO3 (2)
K2S2O8 (1.1)
AgOAc (2)
Cu(OAc)2 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
9
21
10
11
12
13
14
15
16
17
18
19
20
21[c]
22[d]
62
54
Trace
29
19
n.r
PdCl2 (10)
17
Cu(OAc)2 (10)
Co(OAc)2 (10)
Pd(OAc)2(5)
Pd(OAc)2(15)
Pd(OAc)2(10)
Pd(OAc)2(10)
Trace
Trace
57
72
49
38
[a]
2-phenyl-2,3-dihydrophthalazine-1,4-dione
(1a)
(1
mmol),
benzenesulfonyl chloride (2a) (2 mmol), Catalyst (X mol%), Additive (Y eq.),
Temp. = 120 °C, Time = 24h. [b] Isolated yield. [c] Temp. = 80 °C. [d] 2a (1
mmol)
Using the optimal reaction conditions, the scope and generality of
the reaction was investigated (Table 2). Initially, 2-phenyl-2,3-
dihydrophthalazine-1,4-dione (1a) was subjected to sulfonylation
with a variety of substituted arylsulfonyl chlorides (2) under the
optimum reaction conditions. In general, arylsulfonyl chlorides
bearing various electron-donating and electron-withdrawing
groups did not affect this transformation significantly (Table 2,
3aa-3ag). However, the presence of electron-withdrawing
substituents (such as p-Br, p-Cl, m-NO2, 2,4,6-trichloro) led to
inferior yields (Table 2, 3ac,3ad, 3af, and 3ag). Additionally, the
slight influence of the steric effect was observed (Table 2, 3ag).
Then, the influence of substitutions on the N-aryl ring moiety of
the 2-aryl-2,3-dihydrophthalazine-1,4-diones (1a-d) was explored.
In general, the electronic properties of the substituents on the N-
aryl ring moiety affected the yields (Table 2, 3ba-3da). In general,
N-aryl ring moiety bearing an electron-donating substituent
(p−Me) generally was more reactive and produced higher yield
(77% yield) (Table 2, 3ba) than those analogs bearing an
electron-withdrawing substituent (p−Br and p−Cl) (Table 2, 3ca-
3da and 3cb-3cf). It is worth noting that the halo-substituents
remained intact in the reaction conditions, as these substituents
offer good opportunities for further useful functionalization.
However, the reaction did not occur 3eb when the ortho-methyl
substituted 2-phenyl-2,3-dihydrophthalazine-1,4-dione (1f) was
used, probably due to the steric hindrance.
[a] 2-aryl-2,3-dihydrophthalazine-1,4-dione (1) (1 mmol), arylsulfonyl
chloride (2) (2 mmol), Pd(OAc)2 (10 mol%), K2CO3 (2 eq.), Temp. = 120 °C,
Time = 24h. [b] Isolated yield.
The C−H sulfonylation results prompted an examination of other
forms
of
C−H
functionalization
of
the
2-aryl-2,3-
dihydrophthalazine-1,4-diones (1). Halogenation was chosen
basis on of the further manipulation potential of derived products.
After considerable trials on the bromination of 2-phenyl-2,3-
dihydrophthalazine-1,4-dione (1a) under various conditions (see
Table-S1), the use of N-bromosuccinimide (NBS) as bromine
source and an oxidant reagent, catalytic Pd(OAc)2 and p-
toluenesulfonic acid (p-TSA) as an acidic additive in DCE solvent
at 100 °C proved optimal. With the optimized conditions in hand,
the scope of the reaction was evaluated. It was observed that the
substrate with an electronic-donor group (p-CH3) of the N-aryl ring
provided better outcome (Table 3, 4b) than electronic-
withdrawing ones probably due to the electrophilic C–H activation
(Table 3, 4c and 4d). It was noteworthy that the halo substitution
could be remained unaffected under the reaction conditions to
give the desired products. However, The substrate bearing a
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10.1002/ejoc.201901055
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methyl group at the ortho-position of the aryl ring (1f) resulted in
the decreased yield (39%), due to steric effects (Table 3, 4e). The
optimal reaction was also applied to chlorination and iodination of
2-aryl-2,3-dihydrophthalazine-1,4-diones. It was found that under
similar conditions, iodinated products could be obtained in lower
yields than their brominated counterpart (Table 3, 4f) and the
analogous chlorination reaction with N-chlorosuccinimide (NCS)
produced inferior results (Table 3, 4g, 4h). From these results, it
is evident that the reactivity of the halogenation follows the order:
bromination> iodination> chlorination.
Table 3. Scope of substrats for halogenation reaction[a]
Scheme 2. A plausible mechanism for ortho-C-H functionalization of 2-aryl-2,3-
dihydrophthalazine-1,4-diones.
Conclusions
In summary, we have developed convenient methods for direct C-
H
bond sulfonylation and halogenation of 2-aryl-2,3-
dihydrophthalazine-1,4-diones from readily available aryl sulfonyl
chlorides and N-halosuccinimides, respectively, as starting
materials. The reactions provide regio- and mono-selective
access to a variety of substituted phthalazine-1,4-diones. The use
and application of the reported protocols in the synthesis of
biologically important related molecules may be anticipated.
[a] 2-aryl-2,3-dihydrophthalazine-1,4-dione (1) (1 mmol), NXS (1.2 eq.),
Pd(OAc)2 (10 mol%), p-TSA (0.5 eq.), DCE (3 mL), Temp. = 100 °C, Time =
12 h, [b] Isolated yield.
Experimental Section
In accordance with the previous reports, a possible reaction
mechanism is shown in Scheme 2. The reaction was probably
initiated by ortho-selective cyclometalation on phthalazinediones
by Pd(II) and generated the five-membered palladocycle
(intermediate A). The oxidative coupling of aryl sulfonyl chloride
or N-halosuccinimde was proposed to form either dimeric Pd(III)
or monomeric Pd(IV) (intermediate B). Finally, the final product
was obtained via reductive elimination.
General Information. All starting materials and solvents were purchased
from Merck and Sigma. Melting points were measured on an
Electrothermal 9100 apparatus. Mass spectra were recorded on an Agilent
Technology (HP) 5973 Network Mass Selective Detector operating at an
ionization potential of 20 eV and 70 eV. IR spectra were recorded on a
Bomem MB-Series FT-IR spectrophotometer. The products were purified
by thin layer chromatography (MERCK Silica Gel 60). 1H and 13C-NMR
Spectra: were recorded on Bruker DRX 300 and 75 MHz. Elemental
analysis of products was performed using an Elementar Analysensysteme
GmbH VarioEL CHNS.
General procedure for the Synthesis of substituted 2-aryl-2,3-
dihydrophthalazine-1,4-diones:
A
mixture of phthalic anhydride (1.0 mmol) and arylhydrazine
hydrochloride (1.0 mmol) in HCl (10%) (15 mL) was refluxed for 12 h. The
reaction mixture was cooled to room temperature, resulting from solid was
collected by filtration and washed with water and then recrystallized from
ethanol to afford pure desired 2-aryl-2,3-dihydrophthalazine-1,4-dione
derivatives.[41]
General procedure for sulfonylation of 2-aryl-2,3-dihydrophthalazine-
1,4-diones:
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A sealed tube (10 mL) that contained 2-aryl-2,3-dihydrophthalazine-1,4-
diones 1 (1.0 mmol), arylsulfonyl chlorides 2 (1.2 mmol), Pd(OAc)2 (10
mol%), K2CO3 (2 eq.) and DCE (3.0 mL) was stirred at 120 ℃ and
monitored by TLC. After the completion of the reaction, the reaction
mixture was cooled to room temperature and concentrated under reduced
pressure. The organic phase was extracted with water and EtOAc. The
organic layer was further washed with brine solution. Afterward, the
organic layer was separated and dried over anhydrous Na2SO4 and
concentrated under reduced pressure. Finally, purification was
accomplished by thin-layer chromatography to afford the desired product.
2.44 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 158.21, 146.85, 143.75,
141.04, 135.05, 134.17, 132.43, 130.73, 129.65, 129.20, 128.94, 128.52,
128.23, 127.86, 125.95, 125.85, 124.95, 124.18, 21.66; MS (m/z): 392
(M+); Anal. Calcd for C21H16N2O4S: C, 64.27; H, 4.11; N, 7.14. Found: C,
64.23; H, 4.04; N, 7.08.
2-(2-((4-bromophenyl)sulfonyl)phenyl)-2,3-dihydrophthalazine-1,4-
dione (3ac): White solid, Yield: 61%, mp: 165-167 °C; IR (KBr) (νmax /cm-
1): 1674, 1595, 1319, 1196, 1072; 1H NMR (300 MHz, DMSO-d6) δ 8.36 (d,
J = 7.6 Hz, 1H), 8.13 – 7.89 (m, 6H), 7.44 (dt, J = 11.8, 6.7 Hz, 3H), 7.34
(d, J = 8.2 Hz, 2H). 13C NMR (75 MHz, DMSO-d6) δ 158.23, 143.62, 140.98,
135.12, 134.65, 133.45, 131.13, 130.18, 129.74, 128.95, 127.91, 125.86,
124.83, 124.16; MS (m/z): 457 (M+); Anal. Calcd for C20H13BrN2O4S: C,
52.53; H, 2.87; N, 6.13. Found: C, 52.40; H, 2.85; N, 6.18.
General procedure for halogenation of 2-aryl-2,3-dihydrophthalazine-
1,4-diones:
To a sealed tube (10 mL) were added the 2-aryl-2,3-dihydrophthalazine-
1,4-diones (1 mmol), NXS (1.2 mmol), Pd(OAc)2 (0.1 mmol), p-TSA (0.5
equiv.) and the DCE solvent (3 mL) in turn. The reaction mixture was
stirred at 100 °C, and the reaction progress was monitored using TLC.
After the completion of the reaction, the reaction mixture was cooled to
room temperature and concentrated under reduced pressure. The organic
phase was extracted with water and EtOAc. The organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated. Finally, purification
was accomplished by thin-layer chromatography to afford the
corresponding product.
2-(2-((4-chlorophenyl)sulfonyl)phenyl)-2,3-dihydrophthalazine-1,4-
dione (3ad): White solid, Yield: 59%, mp: 134-138 °C; IR (KBr) (νmax /cm-
1): 1647, 1572, 1347, 1188, 1035; 1H NMR (300 MHz, DMSO-d6) δ 8.35 (d,
J = 7.5 Hz, 1H), 8.08 (t, J = 7.6 Hz, 3H), 7.89 (dd, J = 16.3, 7.7 Hz, 2H),
7.68 (dt, J = 21.1, 6.7 Hz, 4H), 7.33 (d, J = 8.4 Hz, 2H); 13C NMR (75 MHz,
DMSO-d6) δ 158.18, 144.01, 140.24, 135.93, 135.49, 135.18, 134.29,
131.89, 130.40, 129.63, 129.12, 128.11, 127.79, 125.95, 124.87, 120.93;
MS (m/z): 412 (M+); Anal. Calcd for C20H13ClN2O4S: C, 58.19; H, 3.17; N,
6.79. Found: C, 58.16; H, 3.26; N, 6.78.
2-phenyl-2,3-dihydrophthalazine-1,4-dione (1a): White solid, Yield:
76%, mp: 214-217 °C (lit.[42] mp: 215 °C); 1H NMR (300 MHz, DMSO-d6) δ
11.85 (s, 1H), 8.35 – 8.26 (m, 1H), 7.97 (dtd, J = 19.7, 8.2, 7.2, 3.6 Hz,
3H), 7.64 (d, J = 7.8 Hz, 2H), 7.49 (t, J = 7.8 Hz, 2H), 7.42 – 7.31 (m, 1H).
2-(2-(m-tolylsulfonyl)phenyl)-2,3-dihydrophthalazine-1,4-dione (3ae):
White solid, Yield: 68%, mp: 105-109 °C; IR (KBr) (νmax /cm-1): 1682, 1597,
1319, 1176; 1H NMR (300 MHz, DMSO-d6) δ 8.36 (d, J = 7.8 Hz, 1H), 8.05
(dt, J = 15.3, 7.9 Hz, 2H), 7.90 (dd, J = 16.3, 10.9 Hz, 3H), 7.61 (dt, J =
15.8, 7.7 Hz, 2H), 7.50 – 7.34 (m, 4H), 2.33 (s, 3H). 13C NMR (75 MHz,
DMSO-d6) δ 158.21, 143.86, 141.07, 140.26, 136.39, 135.44, 135.07,
134.19, 130.16, 129.68, 129.31, 128.99, 128.25, 127.88, 126.22, 125.85,
124.90, 124.13, 21.01; MS (m/z): 392 (M+); Anal. Calcd for
C21H16BrN2O4S: C, 64.27; H, 4.11; N, 7.14. Found: C, 64.30; H, 4.09; N,
7.09.
2-(p-tolyl)-2,3-dihydrophthalazine-1,4-dione (1b): White solid, Yield:
79%, mp: 221-223 °C (lit.[43] mp: 225 °C); 1H NMR (300 MHz, DMSO-d6) δ
11.79 (s, 1H), 8.33 – 8.27 (m, 1H), 8.03 – 7.87 (m, 3H), 7.50 (d, J = 8.0 Hz,
2H), 7.27 (d, J = 8.1 Hz, 2H), 2.35 (s, 3H).
2-(4-bromophenyl)-2,3-dihydrophthalazine-1,4-dione (1c): White solid,
Yield: 65%, mp: 257-259°C (lit.[41] mp: 260-261 °C); 1H NMR (300 MHz,
DMSO-d6) δ 11.95 (s, 1H), 8.30 (d, J = 7.6 Hz, 1H), 8.07 – 7.87 (m, 4H),
7.74 – 7.60 (m, 5H).
2-(2-((3-nitrophenyl)sulfonyl)phenyl)-2,3-dihydrophthalazine-1,4-
dione (3af): White solid, Yield: 53%, mp: 156-160 °C; IR (KBr) (νmax /cm-
1): 1649, 1576, 1535, 1354, 1197; 1H NMR (300 MHz, DMSO-d6) δ 8.37 (s,
1H), 8.25 (dd, J = 23.4, 7.6 Hz, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.90 (dd, J =
14.3, 7.5 Hz, 2H), 7.69 (q, J = 8.5 Hz, 3H), 7.46 (d, J = 7.3 Hz, 2H), 7.34
(d, J = 7.0 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) δ 150.23, 147.66, 142.56,
133.67, 132.46, 130.30, 128.72, 127.20, 126.31, 123.94, 120.55; MS
(m/z): 423 (M+); Anal. Calcd for C20H13N3O6S: C, 56.74; H, 3.09; N, 9.92.
Found: C, 56.71; H, 3.15; N, 9.90.
2-(4-chlorophenyl)-2,3-dihydrophthalazine-1,4-dione (1d): White solid,
Yield: 52%, mp: 255-258 °C (lit.[41] mp: 262-264 °C); 1H NMR (300 MHz,
DMSO-d6) δ 11.94 (s, 1H), 8.31 (d, J = 7.6 Hz, 1H), ), 8.04 – 7.95 (m, 3H),
7.72 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H).
2-(o-tolyl)-2,3-dihydrophthalazine-1,4-dione (1e): White solid, Yield:
52%, mp: 211-213°C (lit.{43} mp: 207 °C)1H NMR (300 MHz, DMSO-d6) δ
11.85 (s, 1H), 8.31 (s, 1H), 8.01 (d, J = 22.2 Hz, 3H), 7.38 (s, 4H), 2.13 (s,
3H).
2-(2-((2,4,6-trichlorophenyl)sulfonyl)phenyl)-2,3-dihydrophthalazine-
1,4-dione (3ag): White solid, Yield: 43%, mp: 167-171 °C; IR (KBr) (νmax
/cm-1): 1671, 1593, 1316, 1193, 1132,1067; 1H NMR (300 MHz, DMSO-d6)
δ 8.40 – 8.24 (m, 3H), 8.04 (td, J = 11.9, 10.0, 6.2 Hz, 3H), 7.65 (d, J = 7.6
Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.43 – 7.35 (m, 3H), 7.19 (d, J = 4.1 Hz,
1H); 13C NMR (75 MHz, DMSO-d6) δ 158.16, 143.60, 140.92, 135.21,
134.00, 133.80, 132.29, 131.89, 131.69, 130.42, 129.84, 128.88, 128.82,
126.40, 125.56, 124.40; MS (m/z): 480 (M+); Anal. Calcd for
C20H11Cl3N2O4S: C, 49.87; H, 2.30; N, 5.82. Found: C, 49.86; H, 2.36; N,
5.77.
2-(2-(phenylsulfonyl)phenyl)-2,3-dihydrophthalazine-1,4-dione (3aa):
White solid, Yield: 69%, mp: 125-128°C, IR (KBr) (νmax /cm-1): 1671, 1593,
1312, 1167; 1H NMR (300 MHz, DMSO-d6) δ 8.35 (d, J = 7.6 Hz, 1H), 8.12
– 7.82 (m, 5H), 7.68 (q, J = 8.9, 8.3 Hz, 2H), 7.54 – 7.26 (m, 5H); 13C NMR
(75 MHz, DMSO-d6) δ 158.19, 143.75, 141.01, 135.81, 135.50, 135.04,
134.17, 130.33, 129.66, 129.11, 128.96, 128.86, 128.21, 128.10, 127.87,
125.94, 125.83, 124.87, 124.10; MS (m/z): 378 (M+); Anal. Calcd for
C20H14N2O4S: C, 63.48; H, 3.73; N, 7.40; Found: C, 63.38; H, 3.78; N, 7.46.
2-(4-methyl-2-(phenylsulfonyl)phenyl)-2,3-dihydrophthalazine-1,4-
dione (3ba): White solid, Yield: 77%, mp: 128-130 °C; IR (KBr) (νmax /cm-
1): 1672, 1596, 1318, 1194; 1H NMR (300 MHz, DMSO-d6) δ 8.38 – 8.29
(m, 1H), 8.11 – 7.98 (m, 4H), 7.93 – 7.83 (m, 2H), 7.70 (t, J = 7.7 Hz, 2H),
7.23 (s, 4H), 2.34 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 158.18, 143.63,
138.60, 137.67, 135.82, 135.49, 134.99, 134.13, 130.34, 129.63, 129.36,
2-(2-tosylphenyl)-2,3-dihydrophthalazine-1,4-dione (3ab): White solid,
Yield: 73%, mp: 130-133°C; IR (KBr) (νmax /cm-1): 1668, 1510, 1313, 1168;
1H NMR (300 MHz, DMSO-d6) δ 8.35 (d, J = 7.5 Hz, 1H), 8.12 – 7.96 (m,
3H), 7.92 (d, J = 8.5 Hz, 2H), 7.55 – 7.41 (m, 5H), 7.39 – 7.32 (m, 2H),
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10.1002/ejoc.201901055
European Journal of Organic Chemistry
FULL PAPER
129.09, 128.10, 127.84, 125.94, 125.58, 124.86, 124.08, 21.12; MS (m/z):
392 (M+); Anal. Calcd for C21H16BrN2O4S: C, 64.27; H, 4.11; N, 7.14.
Found: C, 64.24; H, 4.07; N, 7.15.
C20H12BrN3O6S: C, 47.82; H, 2.41; N, 8.37. Found: C, 47.93; H, 2.36; N,
8.35.
2-(2-bromophenyl)-2,3-dihydrophthalazine-1,4-dione (4a): White solid,
Yield: 71%, mp: 212-215 °C; IR (KBr) (νmax /cm-1): 1644, 1580, 1079; 1H
NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.29 (d, J = 7.7 Hz, 1H), 8.09
– 7.89 (m, 3H), 7.81 (d, J = 8.0 Hz, 1H), 7.67 – 7.49 (m, 2H), 7.43 (t, J =
7.7 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 157.50, 151.99, 141.61,
133.97, 133.27, 132.56, 130.70, 129.07, 128.73, 127.05, 126.30, 125.10,
122.28; MS (m/z): 317 (M+); Anal. Calcd for C14H9BrN2O2: C, 53.02; H,
2.86; N, 8.83. Found: C, 53.04; H, 2.91; N, 8.94.
2-(4-bromo-2-(phenylsulfonyl)phenyl)-2,3-dihydrophthalazine-1,4-
dione (3ca): White solid, Yield: 51%, mp:137-141 °C; IR (KBr) (νmax /cm-
1): 1661, 1613, 1311, 1168; 1062. 1H NMR (300 MHz, DMSO-d6) δ 8.37 (d,
J = 7.6 Hz, 1H), 8.09 – 7.94 (m, 3H), 7.66 – 7.41 (m, 7H), 7.32 (d, J = 4.6
Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 158.30, 141.46, 137.71, 135.22,
134.19, 133.97, 130.23, 129.18, 129.00, 128.91, 128.51, 128.41, 128.10,
127.77, 126.48, 126.15, 125.93, 40.76; MS (m/z): 458 (M+); Anal. Calcd
for C20H13BrN2O4S: C, 52.53; H, 2.87; N, 6.13. Found: C, 52.61; H, 2.82;
N, 6.08.
2-(2-bromo-4-methylphenyl)-2,3-dihydrophthalazine-1,4-dione (4b):
White solid, Yield: 76%, mp: 256-259 °C; IR (KBr) (νmax /cm-1): 1644, 1551,
1072; 1H NMR (300 MHz, DMSO-d6) δ 8.27 (dd, J = 7.3, 1.6 Hz, 1H), 8.09
– 7.87 (m, 4H), 7.63 (d, J = 1.8 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.33 (dd,
J = 8.0, 1.8 Hz, 1H), 2.38 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 157.62,
150.85, 140.84, 138.76, 134.15, 133.42, 132.96, 130.21, 129.63, 129.35,
127.17, 124.83, 121.88, 20.82; MS (m/z): 331 (M+); Anal. Calcd for
C15H11BrN2O2: C, 54.40; H, 3.35; N, 8.46. Found: C, 54.48; H, 3.42; N,
8.43.
2-(4-chloro-2-(phenylsulfonyl)phenyl)-2,3-dihydrophthalazine-1,4-
dione (3da): White solid, Yield: 47%, mp: 105-110 °C; IR (KBr) (νmax /cm-
1): 1679, 1626, 1311, 1168, 1062; 1H NMR (300 MHz, DMSO-d6) δ 8.34 (d,
J = 7.5 Hz, 1H), 8.08 (d, J = 7.5 Hz, 2H), 7.89 (dd, J = 18.0, 7.7 Hz, 1H),
7.71 (t, J = 7.6 Hz, 1H), 7.61 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.44 – 7.24
(m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 158.21, 143.98, 139.81, 135.47,
134.29, 132.47, 130.38, 129.62, 129.11, 128.95, 128.12, 127.52, 125.95,
124.87, 124.17; MS (m/z): 412 (M+); Anal. Calcd for C20H13ClN2O4S: C,
58.19; H, 3.17; N, 6.79. Found: C, 58.24; H, 3.20; N, 6.71.
2-(2,4-dibromophenyl)-2,3-dihydrophthalazine-1,4-dione (4c): White
solid, Yield: 67%, mp: 211-213 °C; IR (KBr) (νmax /cm-1): 1628, 1533, 1122,
1070; ; 1H NMR (300 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.28 (d, J = 7.7 Hz,
1H), 8.10 (d, J = 2.2 Hz, 1H), 8.04 – 7.92 (m, 3H), 7.77 (dd, J = 8.5, 2.2
Hz, 1H), 7.63 (dd, J = 20.2, 6.1 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ
157.59, 151.00, 135.38, 134.38, 133.15, 132.36, 132.24, 131.76, 129.20,
128.26, 127.20, 124.90, 123.62; MS (m/z): 396 (M+); Anal. Calcd for
C14H8Br2N2O2: C, 42.46; H, 2.04; N, 7.07. Found: C, 42.51; H, 1.99; N,
7.06.
2-(4-methyl-2-tosylphenyl)-2,3-dihydrophthalazine-1,4-dione (3bb):
White solid, Yield: 79%, mp: 120-124 °C; IR (KBr) (νmax /cm-1): 1676, 1593,
1318, 1168; 1H NMR (300 MHz, DMSO-d6 ) δ 8.33 (d, J = 7.6 Hz, 1H), 8.05
(q, J = 9.2, 8.5 Hz, 2H), 7.93 (tt, J = 7.9, 4.3 Hz, 3H), 7.50 (d, J = 7.9 Hz,
2H), 7.23 (s, 3H), 2.44 (s, 3H), 2.35 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
δ 158.20, 146.86, 143.64, 138.64, 137.71, 134.97, 134.10, 132.43, 130.74,
129.62, 129.36, 129.18, 127.83, 125.61, 124.92, 124.14, 21.69, 21.1; MS
(m/z): 406 (M+); Anal. Calcd for C22H18N2O4S: C, 65.01; H, 4.46; N, 6.89.
Found: C, 64.99; H, 4.39; N, 6.78.
2-(2-bromo-4-chlorophenyl)-2,3-dihydrophthalazine-1,4-dione (4d):
White solid, Yield: 53%, mp: 252-255 °C; IR (KBr) (νmax /cm-1): 1644, 1554,
1080, 1040; 1H NMR (300 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.33 – 8.23 (m,
1H), 7.99 (tdd, J = 14.7, 7.8, 3.5 Hz, 4H), 7.73 – 7.59 (m, 2H); 13C NMR
(75 MHz, DMSO) δ 157.64, 151.04, 140.49, 134.42, 133.23, 132.68,
132.03, 129.18, 127.26, 124.93, 123.34; MS (m/z): 352 (M+); Anal. Calcd
for C14H8BrClN2O3: C, 47.83; H, 2.29; N, 7.97. Found: C, 47.91; H, 2.30;
N, 8.01.
2-(4-bromo-2-tosylphenyl)-2,3-dihydrophthalazine-1,4-dione
(3cb):
White solid, Yield: 54%, mp: 134-137°C; IR (KBr) (νmax /cm-1): 1676, 1634,
1310, 1160, 1059. 1H NMR (300 MHz, DMSO-d6) δ 8.40 – 8.30 (m, 1H),
8.12 – 7.90 (m, 4H), 7.72 – 7.62 (m, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.35 (d,
J = 8.5 Hz, 2H), 2.44 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 158.18,
146.94, 144.00, 138.07, 134.26, 132.40, 131.88, 131.26, 130.74, 129.21,
128.51, 127.85, 125.94, 120.94, 118.18, 21.66; MS (m/z): 470 (M+); Anal.
Calcd for C21H15BrN2O4S: C, 53.52; H, 3.21; N, 5.94. Found: C, 53.50; H,
3.10; N, 5.96.
2-bromo-6-methylphenyl)-2,3-dihydrophthalazine-1,4-dione
(4e):
White solid, Yield: 39%, mp: 240-244 °C; IR (KBr) (νmax /cm-1): 1647, 1584,
1458, 1095; 1H NMR (300 MHz, DMSO-d6) δ 8.29 (d, J = 7.2 Hz, 1H), 8.09
(s, 1H), 8.01 – 7.89 (m, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 7.3 Hz,
1H), 7.33 (d, J = 7.7 Hz, 1H), 2.15 (s, 3H); 13C NMR (75 MHz, DMSO) δ
156.82, 151.92, 144.91, 139.65, 18.14, 133.67, 132.37, 130.41, 130.11,
129.94, 126.73, 122.35, 122.34, 17.71; MS (m/z): 330 (M+); Anal. Calcd
for C15H11BrN2O2: C, 54.40; H, 3.35; N, 8.46. Found: C, 54.47; H, 3.38; N,
8.44.
2-(4-chloro-2-tosylphenyl)-2,3-dihydrophthalazine-1,4-dione
(3db):
White solid, Yield: 49%, mp: 135-137 °C; IR (KBr) (νmax /cm-1): 1678, 1596,
1310, 1160, 1059; 1H NMR (300 MHz, DMSO-d6) δ 7.75 (dd, J = 8.1, 2.8
Hz, 1H), 7.60 (s, 2H), 7.31 (d, J = 4.5 Hz, 7H), 6.84 (d, J = 2.8 Hz, 1H),
2.43 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 158.19, 146.92, 143.99,
139.82, 135.13, 134.24, 132.47, 132.42, 130.72, 129.57, 129.17, 128.92,
127.87, 127.52, 124.89, 124.18, 21.65; MS (m/z): 426 (M+); Anal. Calcd
for C21H15ClN2O4S: C, 59.09; H, 3.54; N, 6.56. Found: C, 59.08; H, 3.61;
N, 6.58.
2-(2-iodophenyl)-2,3-dihydrophthalazine-1,4-dione (4f): White solid,
Yield: 49%, mp: 254-256 °C; IR (KBr) (νmax /cm-1): 1643, 1582, 1075; 1021;
1H NMR (300 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.34 – 8.24 (m, 1H), 8.09
2-(4-bromo-2-((3-nitrophenyl)sulfonyl)phenyl)-2,3-
– 7.88 (m, 4H), 7.55 (d, J = 4.2 Hz, 2H), 7.24 (dq, J = 8.5, 4.1 Hz, 1H); 13
C
dihydrophthalazine-1,4-dione (3cf): White solid, Yield: 41%, mp: 132-
138 °C; IR (KBr) (νmax /cm-1): 1669, 1595, 1532, 1322, 1175, 1064; 1H NMR
(300 MHz, DMSO-d6) δ 8.74 – 8.62 (m, 2H), 8.55 (t, J = 6.6 Hz, 1H), 8.35
(t, J = 6.4 Hz, 1H), 8.15 – 7.96 (m, 4H), 7.71 – 7.56 (m, 2H), 7.31 (dd, J =
8.3, 5.2 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 158.18, 148.39, 143.98,
140.14, 137.04, 135.04, 134.41, 132.44, 131.89, 130.31, 129.75, 127.86,
124.49, 124.19, 124.02, 121.09; MS (m/z): 501 (M+); Anal. Calcd for
NMR (75 MHz, DMSO-d6) δ 146.04, 143.22, 139.21, 132.98, 131.29,
129.90, 129.51, 128.56, 128.38, 126.67, 126.36, 126.06, 125.95, 99.35;
MS (m/z): 364 (M+); Anal. Calcd for C14H9IN2O2: C, 46.18; H, 2.49; N, 7.69.
Found: C, 46.25; H, 2.55; N, 7.71.
2-(2-chlorophenyl)-2,3-dihydrophthalazine-1,4-dione (4g): White solid,
Yield: 44%, mp: 235-240 °C; IR (KBr) (νmax /cm-1): 1641, 1531, 1080; 1H
NMR (300 MHz, DMSO-d6) δ 8.27 (d, J = 7.6 Hz, 1H), 8.00 (dt, J = 25.1,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901055
European Journal of Organic Chemistry
FULL PAPER
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8.2 Hz, 3H), 7.64 (dt, J = 11.4, 5.7 Hz, 2H), 7.50 (dd, J = 6.2, 3.6 Hz, 2H);
13C NMR (75 MHz, DMSO) δ 156.33, 151.04, 141.75, 137.63, 135.13,
133.09, 129.59, 128.73, 128.04, 127.92, 125.46, 123.61, 123.36.; MS
(m/z): 272 (M+); Anal. Calcd for C14H9ClN2O2: C, 61.67; H, 3.33; N, 10.27.
Found: C, 61.68; H, 3.31; N, 10.23.
[17]
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[19]
[20]
[21]
2-(2-chloro-4-methylphenyl)-2,3-dihydrophthalazine-1,4-dione (4h):
White solid, Yield: 51%, mp: 204-207 °C; IR (KBr) (νmax /cm-1): 1642, 1561,
1091; 1H NMR (300 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.82 (d, J = 19.8 Hz,
3H), 7.42 (d, J = 11.8 Hz, 2H), 7.22 (s, 1H), 2.36 (s, 3H); 13C NMR (75
MHz, DMSO) δ 155.77, 151.60, 139.14, 138.96, 132.26, 131.26, 130.27,
130.15, 129.96, 129.55, 128.59, 126.30, 123.99, 20.81; MS (m/z): 285
(M+); Anal. Calcd for C15H11ClN2O2: C, 62.84; H, 3.87; N, 9.77. Found: C,
62.99; H, 3.96; N, 9.71.
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
Acknowledgments
This work was supported by the Research Council of Shahid
Beheshti University.
Keywords: C−H activation • Palladium • Pyridazinedione •
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[34]
Sulfonylation • Halogenation.
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This article is protected by copyright. All rights reserved.

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European Journal of Organic Chemistry
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C-H functionalization
Noushin Farajinia Lehi, Chiman Osmani,
Siyavash Kazemi Movahed and Minoo
Dabiri*
Page No. – Page No.
The regio-selective Pd-catalyzed C−H sulfonation and halogenation of
pyridazinedione have been successfully reported. This transformation as a viable
tool provides a variety of novel substituted sulfonated and halogenated derivatives
of phthalazinediones in moderate to good yields.
Palladium-Catalyzed ortho C-H Bond
Sulfonylation and Halogenation of
Phthalazine-1,4-diones
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