Transition Metal Catalyzed C-H bond Activation/Functionalization and Annulation of Phthalazinones

Abstract

Phthalazinones and their higher congeners are commonly prevalent structural motifs that occur in natural products, bioactive molecules, and pharmaceuticals. In the past few decades, transition-metal-catalyzed reactions have received an overwhelming response from organic chemists as challenging organics and heterocycles could be built with ease. Currently, the synthesis of phthalazinones largely depends on transition-metal catalysis, especially by palladium-catalyzed carbonylation. Further, the dominance of transition-metal catalysts was realized from the phthalazinones viewpoint, as nitrogen and oxygen atoms endowed upon them act as directing groups to facilitate diverse C-H activation/functionalization/annulation reactions. This highlight describes the various synthetic methods used to access phthalazinones and functionalize them by reacting with various coupling partners via chelation assistance strategy involving C(sp2)-H/N-H bond activation in the presence of transition-metal (Rh, Ru, Pd, and Ir) catalysts. The mechanisms of sulfonylation, halogenation, acylmethylation, alkylation, and annulation reactions are discussed.

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Organic &
Biomolecular Chemistry
REVIEW
Cite this: DOI: 10.1039/d1ob01616d
Received 17th August 2021,
Accepted 31st August 2021
DOI: 10.1039/d1ob01616d
rsc.li/obc
Transition-metal-catalyzed C–H bond activation/
functionalization and annulation of
phthalazinones
Chandrasekaran Sivaraj, Alagumalai Ramkumar, Nagesh Sankaran and
Thirumanavelan Gandhi *
Phthalazinones and their higher congeners are commonly prevalent structural motifs that occur in natural
products, bioactive molecules, and pharmaceuticals. In the past few decades, transition-metal-catalyzed
reactions have received an overwhelming response from organic chemists as challenging organics and
heterocycles could be built with ease. Currently, the synthesis of phthalazinones largely depends on tran-
sition-metal catalysis, especially by palladium-catalyzed carbonylation. Further, the dominance of tran-
sition-metal catalysts was realized from the phthalazinones viewpoint, as nitrogen and oxygen atoms
endowed upon them act as directing groups to facilitate diverse C–H activation/functionalization/annula-
tion reactions. This highlight describes the various synthetic methods used to access phthalazinones and
functionalize them by reacting with various coupling partners via chelation assistance strategy involving
C(sp
2
)–H/N–H bond activation in the presence of transition-metal (Rh, Ru, Pd, and Ir) catalysts. The
mechanisms of sulfonylation, halogenation, acylmethylation, alkylation, and annulation reactions are
discussed.
Introduction
Heterocycles are ubiquitous motifs embodied in natural pro-
ducts,
1
biologically active molecules,
2
and pharmaceuticals.
3
More specifically, nitrogen-containing heterocycles have a
repertoire of potential motifs that find application in medic-
inal chemistry.
4
Along this line, dinitrogen-containing com-
pounds, particularly phthalazinones, have been found to be
promising clinical candidates. Phthalazinones exhibit diverse
roles in treating several diseases, such as diabetes,
5,6
hepatitis
B,
7
vascular hypertension,
8,9
asthma,
10,11
arrhythmia,
12
and
cancer, and serve as antiallergic and antihistaminic drugs.
11,13
Additionally, some of their derivatives show anti-inflammatory
activity, such as vascular endothelial growth factor (VEGF)
inhibition,
14
poly(ADPribose) polymerase-1 (PARP-1) inhi-
bition,
15
and liphosphodiesterase-4 (PDE-4) inhibition
16
(Fig. 1). Owing to their intriguing structural architecture and
versatile biological activities, phthalazinone synthesis has
gained immense attention from synthetic and medicinal che-
mists. Traditionally, phthalazinones have been synthesized by
cyclocondensation, cycloaddition, reduction, and biotrans-
formation methods.
17
Currently, transition-metal catalysts play
a pivotal role in the synthesis of phthalazinone derivatives
involving multicomponent reactions, carbonylative cycliza-
tion,
18
intermolecular acylation
19
and nucleophilic conden-
sation.
20
Abundant medicinally valuable phthalazinones are
accessed by late-stage multiple and divergent C–H bond acti-
Fig. 1 Phthalazinone containing biological active compounds.
Department of Chemistry, School of Advanced Sciences, Vellore Institute of
Technology, Vellore 632014, Tamil Nadu, India. E-mail: velan.g@vit.ac.in
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vation/functionalization/annulation from their parent
compounds.
This review mainly highlights the recent advances in the
selective C–H bond activation/functionalization and annula-
tion of phthalazinones with various coupling partners, such as
alkenes, alkynes, amides, propargyl alcohols, isocyanides, and
sulfonyl chloride. To confine the breadth of this review, Rh-,
Ru-, Pd-, and Ir-catalyzed transformations were considered.
Major attention has been devoted towards the C–C, C–X (Cl,
Br, I), C–N, and C–S bond formation overlaying arylation, alkyl-
ation, alkenylation, alkynylation, sulfonylation, amidation,
halogenation, and subsequent annulations strategies.
Regioselectivity, substrate scope, and insightful mechanistic
aspects are discussed in detail. As a result, we anticipate that
this discussion will serve as a reference tool for synthetic che-
mists who are interested in the chemistries of phthalazinones.
Recent advances in the synthesis of phthalazinones
A great surge in the development and synthesis of phthalazi-
nones was witnessed in the last decade, with a variety of
organic precursors subjected to different reactions, such as
carbonylation, cyclocondensation, and cycloaddition, to access
a wide scope of phthalazinone derivatives. In 2011, Orru and
co-workers reported the synthesis of 4-aminophthalazin-1-
(2H)-ones 4via cross-coupling of o-(pseudo)halobenzoates and
hydrazines with isocyanide by Pd catalysis (2 mol%) in micro-
wave medium. They were the first to disclose the three-com-
ponent reaction involving methyl o-bromobenzoate, isocya-
nides and free hydrazines. In this reaction, a variety of ligands
and solvents were screened, but XantPhos as the ligand
(4 mol%) and DMSO as the solvent were most effective. In
addition to aryl bromides, aryl iodides and triflates provided
products 4a–fin moderate to good yields after 5 min of micro-
wave irradiation (Scheme 1).
21
In the following year, Beller’s
group elegantly described the Pd-catalyzed synthesis of phtha-
lazinones 8via carbonylative coupling of 2-bromobenzalde-
hyde with methylhydrazine under CO (10 bar) in the presence
of DBU (1 mmol). The investigation of different ligands and
solvents demonstrated that dppf ligand (2 mol%) and DMSO
were the most effective for the carbonylation reaction, provid-
ing product 8a in 52% yield. Additionally, when MgSO
4
(1 mmol) was used as an additive, an improvement in the yield
was observed (60–61%). Notably, an excess of MgSO
4
decreased
the product yield to only 46%. This strategy tolerates different
functional groups, such as electron-releasing and -withdrawing
groups (Scheme 2).
22
In the same year, Gu and co-workers
demonstrated the one-pot synthesis of phthalazinones 10 via
intramolecular amidation of 2-carboxybenzaldehyde and
hydrazines catalyzed by ultrathin, highly active and stable Pt
nanowires (Scheme 3).
23
In 2013, Reddy et al. reported the
microwave-assisted Pd-catalyzed synthesis of phthalazinones
12a–ffrom o-bromoarylaldehydes, Mo(CO)
6
(2.50 mmol), and
From left to right: A. Ramkumar, Thirumanavelan Gandhi,
C. Sivaraj and Nagesh Sankaran
C. Sivaraj was born in T. Puliyankulam, Tamil Nadu, India, in
1997. He completed his Bachelor’s and Master’s degree
(Chemistry) at The American College, Madurai (2014–2019). He
worked as a project assistant under Dr K. Namitharan at SRM
University, Kattankulathur, Chennai. Currently, he is pursuing his
Ph.D. under the supervision of Dr G. Thirumanavelan at VIT,
Vellore, India. His research work focuses on the C–H bond
functionalization of organic molecules via transition metal-cata-
lyzed C–H bond activation.
A. Ramkumar was born in Madathupatti, Tamil Nadu, India, in
1996. He completed his Bachelor’s and Master’s degrees
(Chemistry) at Devanga Arts College, Aruppukottai. He is pursuing
his Ph.D. under the supervision of Dr G. Thirumanavelan at VIT,
Vellore, India. His research work focuses on the C–H bond
functionalization of organic molecules via transition metal-cata-
lyzed C–H bond activation.
Nagesh Sankaran was born and raised in Enusonai, located in
the northern part of Tamil Nadu, India. He completed his
Bachelor’s degree at Arignar Anna Arts and Science College,
Krishnagiri, Tamil Nadu. Then he moved to VIT, Vellore, to begin
his Master’s degree. With a keen interest towards research, he
started working from the first semester onwards in the group of
Dr G. Thirumanavelan, where he worked on the manipulation of
bench-stable N-heterocyclic carbene complexes towards C–H bond
activation/functionalization to form new C–C, C–N, C–O and C–X
bonds. Additionally, he works on sustainable base metal-catalyzed
reactions and alkali metal-mediated reactions.
Thirumanavelan Gandhi studied chemistry at the
Muthurangam Govt Arts College, Vellore (1997–1999) and
received his Ph.D. in 2005 from the Indian Institute of Science,
Bengaluru, under the supervision of Prof. Balaji R. Jagirdar. He
pursued his postdoctoral studies (2006–2008) at Johns Hopkins
University, Baltimore, with Prof. Kenneth D. Karlin. He served as
a senior scientist in Cookson India Research Centre (Alent plc),
Bengaluru (2009–2010). He started his academic career at Vellore
Institute Technology, Vellore, in 2011 wherein currently he is an
Associate Professor. His research interest is focused on the develop-
ment of metal–NHC catalysts and sustainable synthetic
methodologies.
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arylhydrazines via carbonylation in the presence of Cs
2
CO
3
(3 mmol) in dioxane at 140 °C. In this reaction, di-1-adaman-
tyl-n-butylphosphine (BuPAd
2
) (0.2 mmol) was used as the
ligand, which enhanced the yield of the product (70–75%).
The attraction of this methodology is the use of molybdenum
hexacarbonyl Mo(CO)
6
as the CO source, giving an alternative
source of toxic CO gas in the presence of the Pd catalyst
(Scheme 4).
24
In 2014, Ahmed and co-workers revealed the syn-
thesis of N-substituted phthalazinones 14a–cand 4-substituted
phthalazinones 16a–cfrom 2-bromobenzaldehydes and 2-bro-
mobenzophenones, respectively, with different hydrazines via
condensation and intramolecular carbonylative cyclization by
Pd catalysis (5 mol%) in the presence of DBU (1.25 mmol).
Ligand 1,1′-bis(diphenylphosphino)ferrocene (dppf) (6 mol%)
improved the yield of the desired product. The highlights of
this methodology include short reaction time (3 h at 90 °C),
molecular sieves as an additive (significantly increased the
yield of the product (80–86%), minimal waste and Co
2
(CO)
8
as
the carbonyl source (Scheme 5).
25
In the same year, Deng et al.
published the one-pot synthesis of phthalazinones 19a–ffrom
2-halomethyl benzoates, paraformaldehyde, and aryl hydra-
zines by Pd catalysis in the presence of K
2
CO
3
. The optimal
conditions for this reaction are Pd(TFA)
2
(5 mol%), XantPhos
Scheme 1 Pd-catalyzed synthesis of 4-aminophthalazin-1(2H)-ones by
isocyanide insertion.
Scheme 2 Palladium-catalyzed carbonylative synthesis of
phthalazinones.
Scheme 3 Synthesis of phthalazinones from salicylic aldehyde and
hydrazines.
Scheme 4 Microwave assisted Pd-catalyzed synthesis of
phthalazinones.
Scheme 5 Synthesis of N-substituted phthalazinones.
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(10 mol%) and K
2
CO
3
(0.24 mmol) in toluene at 160 °C. The
key attraction of this methodology is the utilization of parafor-
maldehyde, which is a low toxicity and low cost easy to operate
C
1
source. Notably, various functional groups, such as –CH
3
,
–CH
2
CH
3
,–C(CH
3
)
3
,–OCH
3
,–OCF
3
(electron-donating groups)
and –F, –Cl, –CN (electron-withdrawing groups), at the para
position in substrates were tolerated and resulted in good
yields. However, meta or ortho substituents decreased the
desired product yield due to steric effects (Scheme 6).
26
In
2018, Satyanarayana’s group reported the one-pot synthesis of
phthalazines 22 and benzoxazinones through Pd-catalyzed acy-
lation and nucleophilic cyclocondensation with dinucleophilic
reagents in the presence of TBHP. In this reaction, the alde-
hyde acts as an acylating agent in the presence of the Pd cata-
lyst (5 mol%) and TBHP (5 equiv.) as an oxidant (Scheme 7).
27
To circumvent some drawbacks in the previously reported tra-
ditional synthesis of phthalazinones, a greener alternative was
devised by Gao and co-workers in 2018, which involves the syn-
thesis of 2,3-dihydro-phthalazine-1,4-dione 25 via oxidation-
cyclization of benzyl alcohol and hydrazine in the presence of
the eco-friendly catalyst PPaba@Fe
2
O
3
/[Ru(bpy)
3
]
2+
(PPaba =
poly(p-aminobenzoic acid-aniline). This photocatalysis reac-
tion demands the use of [Ru
II
(bpy)
3
]
2+
(0.1 M, 200 µL), polymer
united metal nanospheres PPaba-Fe
2
O
3
(200 mg), and an LED
lamp (450–550 nm) (Scheme 8).
28
In 2019, Zhong et al. pub-
lished the synthesis of phthalazinones 28 using phthalaldehy-
dic acid, 2-acyl-benzoic acid, and substituted hydrazine.
During this reaction, no catalysts or solvents were used,
although different solvents, such as acetonitrile, ethyl acetate,
THF, toluene, trichloromethane, and dioxane, were examined.
Interestingly, solvent-free conditions increased the product
yield (99%) and shortened the reaction time (20–60 min).
Notably, a variety of functional groups, such as hydroxyethyl,
bulky groups, substituted phenyl, and heterocyclic groups,
were tolerated in the reaction and improved the product yield
(98–100%). Interestingly, this methodology displayed chemo-
selectivity and atom economy under mild temperatures
(Scheme 9).
29
C–H activation and functionalization of phthalazinones
In recent times, the transition-metal-catalyzed strategy has
turned into a fully-fledged tool for synthesizing challenging
organics, especially bioactive heterocycles. As an added advan-
tage, the transition-metal-catalyzed strategy provides an eco-
friendly and step-economical pathway compared to the conven-
tional methods. Heterocycles bestowed with heteroatoms
commonly act as chelation-assisted directing groups to orches-
trate the activation and functionalization of C(sp
2
)–H bonds by
the transition-metal catalyst. Overwhelmingly, directing the
Scheme 6 Pd-catalyzed synthesis of phthalazinones from 2-halo-
methyl benzoates, paraformaldehyde, and aryl hydrazines.
Scheme 8 Ru-catalyzed synthesis of 2,3-dihydro-phthalazine-1,4-
dione.
Scheme 7 Pd-catalyzed one-pot synthesis of phthalazinones.
Scheme 9 Synthesis of phthalazinones from 2-acyl-benzoic acid, and
substituted hydrazines.
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catalyst to a specific site results in regioselective products
involving sequential C–C/C–N/C–S bond formations.
30
Phthalazin-1(2H)-one
C8-Functionalization. In 2016, Huestis reported the Rh(III)-
catalyzed C–H functionalization of 1-(2H)-phthalazinones at
the C8 position using olefins, alkynes, and N-iodosuccinimide
as coupling partners via oxidative alkenylation, hydroarylation
and iodination, respectively. To narrow down the suitable cata-
lyst, a variety of metal catalysts, such as rhodium(III), iridium
(III), and cobalt(III), were tested, but the Rh(III) catalyst [Cp*Rh
(MeCN)
3
](SbF
6
)
2
(5 mol%) was found to be very effective and
afforded C8-substituted phthalazinones in good yield. As
shown in Scheme 10a, acrylates react readily with phthalazi-
nones via oxidative C–H alkenylation of 1-(2H)-phthalazinones
at C8 in the presence of the oxidant copper(II) acetate (2.1
equiv.) to afford alkenylated phthalazinones 31a–b.In
addition, vinyl sulfones react smoothly to yield 31b (76%).
When diphenylacetylene 32 was used as a coupling partner, it
underwent functionalization at C8 in 29 via a hydroarylation
pathway in the presence of [Cp*Rh(MeCN)
3
](SbF
6
)
2
(5 mol%)
and acetic acid (5 equiv.) to deliver the desired product 33a in
high yield (86%) (Scheme 10b). Iodination at the C8 position
in 29 is effected by N-iodosuccinimide, which acts as an iodi-
nating agent and results in 8-iodo-2-methyl-1(2H)-phthalazi-
none 35a in 55% yield plus 35% recovered starting material
(RSM) (Scheme 10c).
31
Alkynylation. In 2020, Chen et al. disclosed the mono- and
di-alkynylation of 4-aryl phthalazin-1-(2H)-one using bromoa-
cetylenes via C–H bond activation by a Rh(III) catalyst. The opti-
mized conditions for monoalkynylation 38 are 3 mol% of
[Cp*RhCl
2
]
2
as the catalyst and Ag
2
CO
3
(1.0 equiv.) as the silver
salt in DCE at 100 °C for 12 h under air (Scheme 11a). Further
different additives (silver salts and bases) were tested under
similar conditions. Interestingly, adding a catalytic amount of
AgSbF
6
(20 mol%) resulted in good yields of the dialkynylated
product 39 (Scheme 11b). Notably, various functional groups,
such as –Me, –OMe, –OEt, –F, and –Cl, were tolerated in the
selective monoalkynylation reaction. Functional groups at the
para position (71–79%) were more effective than at the meta
(78%) and ortho positions (62%) in 36.
32
Alkenylation. In 2014, Xu’s group reported the C–H alkenyla-
tion of 4-aryl phthalazin-1-(2H)-one 40 using alkyne 41 in the
presence of [Ru(p-cymene)Cl
2
]
2
(10 mol%) in DMF at 120 °C
under O
2
atmosphere to give alkenylated product 42 in good
yield (84%) (Scheme 12).
33
Phthalazine-1,4-diones
Sulfonylation and halogenation. In 2019, Movahed et al. pub-
lished the Pd-catalyzed direct ortho-C–H bond sulfonylation
and halogenation of phthalazine-1,4-diones using arylsulfonyl
chlorides and N-halosuccinimide, respectively, via cross-coup-
ling method. The sulfonylated products 45 were formed with
the combination of Pd(OAc)
2
(10 mol%) and K
2
CO
3
(2.0 equiv.)
Scheme 10 Rhodium(III)-catalyzed C–H Functionalization of 1-(2H)-
phthalazinones at C8.
Scheme 11 Rh(III)-catalyzed C–H mono- and dialkynylation of 4-aryl
phthalazin-1(2H)-one.
Scheme 12 Ru-catalyzed C–H alkenylation of 4-aryl phthalazin-1(2H)-
ones.
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in DCE at 120 °C for 24 h (Scheme 13a). No reaction occurred
in the absence of K
2
CO
3
and decreasing the amount of catalyst
from 10 to 5 mol% led to a lowering of the yield and increasing
the catalytic load to 15 mol% did not show significant
improvement in the yield. The quantity of sulfonyl chloride
governs the product formation—an excess of sulfonyl chloride
led to good yields. Notably, 43 bearing an electron-rich group
(p-Me) furnishes higher yield (77% yield) than those analogs
bearing an electron-withdrawing substituent (p-Br and p-Cl).
However, substituents at the ortho position deter the reaction
due to the steric hindrance. In Scheme 13b, bromination of
2-phenyl-2,3-dihydrophthalazine-1,4-dione is shown. The opti-
mized conditions for bromination of 43 are Pd(OAc)
2
(10 mol%), p-toluenesulfonic acid (p-TSA) (0.5 equiv.), and
N-bromosuccinimide (NBS) (1.2 equiv.) (acts as bromine
source and an oxidant) in DCE at 100 °C. Notably, the elec-
tron-releasing group p-CH
3
was tolerated better than electron-
withdrawing ones and functional groups at the ortho position
reduce the yield owing to the steric effect. However, chlori-
nation and iodination of 43 under similar reaction conditions
afforded an inferior yield (Scheme 13). The proposed mecha-
nism is the phthalazinediones first coordinate with the Pd(II)
catalyst via ortho-selective cyclometallation to generate five-
membered palladacycle 14A, followed by oxidative coupling of
aryl sulfonyl chloride or N-halosuccinimde with 14A to form
either dimeric Pd(III) or monomeric Pd(IV)14B. Finally, pro-
ducts 45 or 47 were obtained via reductive elimination
(Scheme 14).
34
Acylmethylation. In 2019, Sakhuja’s group reported the ortho-
C(sp
2
)–H acylmethylation of N-arylphthalazine-1,4-diones 43
with α-carbonyl sulfoxonium ylides 48 using a Ru catalyst to
give 2-(ortho-acylmethylaryl)-2,3-dihydrophthalazine-1,4-diones
49 (Scheme 15a). Interestingly, cinnoline-8,13-diones 50 and
51 were prepared by reaction of 49 with Lawesson’s reagent
and BF
3
·OEt
2
, respectively. The optimized conditions for 49
are 5 mol% of [RuCl
2
(p-cymene)]
2
as the catalyst with KPF
6
(50 mol%) as an additive in EtOH at 80 °C for 12 h under a N
2
atmosphere. Notably, various functional groups, such as Me, F,
Cl, and Br, at meta and para positions in 43 were tolerated and
resulted in improved 49a–49c (79–80%). Furthermore, varying
functional groups on aroyl sulfoxonium ylides 48 also afforded
products in 73–85% yields. The ortho-acylmethylated product
49 undergoes intramolecular cyclization in the presence of
Lawesson’s reagent (2 equiv.) in toluene at 110 °C for 12 h to
give phthalazino-fused cinnolines 50a–c.Different functional
groups, such as electron-donating and electron-withdrawing
groups, were tolerated in this intramolecular cyclization reac-
tion with good yields (Scheme 15b). Another cyclization reac-
tion was explored, which was effected by the combination of
BF
3
·OEt
2
(2 equiv.) and DMSO with 49 to yield cyclized pro-
ducts 51a–c(Scheme 15c). In this reaction, DMSO act as a
methylene source under BF
3
·OEt
2
-mediated conditions.
Examples bearing electron-donating and electron-withdrawing
groups were tolerated. The plausible mechanism details acyl-
methylation as well as the other two cyclization processes,
which are commonly initiated by [RuX
2
(p-cymene)] (generated
from dissociation of dimeric [RuX
2
(p-cymene)]
2
in the pres-
ence of KPF
6
). The reaction of [RuX
2
(p-cymene)] with 43
resulted in the five-membered ruthenacycle 16A via C–H acti-
vation. Addition of sulfoxonium ylide 48 to 16A leads to the
formation of ruthenium α-oxo carbene species 16B with the
elimination of DMSO. Thereafter, migratory insertion of the
activated carbene into the Ru–aryl bond furnishes the six-
membered ruthenacycle 16C. Eventually o-acylmethylated
product 49 was dispelled, via protonolysis of the Rh–N and
Rh–C bonds and concomitant catalyst regeneration. The
Lawesson’s reagent-mediated cyclization part starts with the
thionation of 49 with Lawesson’s reagent to afford o-thioacyl-
Scheme 14 A plausible mechanism for ortho-C–H functionalization of
2-aryl-2,3dihydrophthalazine-1,4-diones.
Scheme 13 Pd-catalyzed direct ortho-C–H bond sulfonylation and
halogenation of phthalazine-1,4-diones.
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methylated 2-arylphthalazine-1,4-dione 16D, which on intra-
molecular nucleophilic attack by the amide group followed by
H
2
S elimination generates 50. In the BF
3
·OEt
2
-mediated cycli-
zation part, initially DMSO was activated by BF
3
·OEt
2
to gene-
rate an electrophilic thionium ion which on encountering 49
gives alkylsulfurized intermediate 16E. Further, 16E underwent
demethylthioation to give iminium species 16F, which finally
furnished 51 via intramolecular cyclization of 16G mediated by
BF
3
(Scheme 16).
35
Amidation. In 2020, Kim and co-workers demonstrated the
site-selective amidation of N-aryl phthalazinones using dioxa-
zolones as amide sources via C–N bond formation by Rh(III)
catalysis. This amidation reaction proceeds with the following
reaction conditions: [RhCp*Cl
2
]
2
(2.5 mol%) as the catalyst
with AgSbF
6
(10 mol%) and NaOAc (30 mol%) as additives at
80 °C in DCE for 14 h under air in pressure tubes to furnish
the product 53. Most importantly, functional groups at the
para and meta positions afforded site selectivity, i.e.,ortho pro-
ducts 53a–f, in good yields compared to the sterically con-
gested ortho substituents. Further, post-modification of ami-
dated N-aryl phthalazinone 53 was achieved by using POCl
3
,
PhI(OAc)
2
and NaOH via intramolecular cyclization, N–N bond
formation and deprotection of a benzoyl group, affording poly-
cyclic benzotriazino phthalazinone 54 (41%), 1-(m-toluoyl)ben-
zotriazole 55 (38%) and 2-amino aryl phthalazinone 56 (86%),
respectively (Scheme 17). Based on control studies and the lit-
erature, the authors proposed a possible mechanism
(Scheme 18), whereby an active catalyst [RhCp*(OAc)
2
] is gener-
ated by the reaction of cationic Cp*Rh(III) with NaOAc via
ligand exchange. Then, phthalazine-1,4-dione 43 coordinates
with [RhCp*(OAc)
2
] to form an intermediate 18A, which con-
verts to five-membered cyclometallated complex 18B via C–H
activation. Incoming 52 coordinates with 18B to furnish 18C,
and subsequent insertion of nitrene species furnishes a six-
membered Rh(III)-amido species 18D with the elimination of
CO
2
. Eventually, protonation leads to the desired product 53
and regeneration of the active catalyst [RhCp*(OAc)
2
].
36
Alkylation. Very recently, the same group reported the ortho-
alkylation of N-aryl phthalazinones using maleimides in the
presence of a Rh(III) catalyst to yield the desired product 58.
The optimal conditions are [RhCp*Cl
2
]
2
(2.5 mol%), AgSbF
6
(10 mol%), and AcOH (500 mol%) in DCM under air at 80 °C
for 12 h. Notably, various functional groups (Me, –CF
3
,NO
2
)at
the para and meta positions tolerated the reaction conditions,
while ortho substituents gave poor yields due to steric hin-
drance. Interestingly, unprotected maleimide afforded the
desired product 58a in 86% yield (Scheme 19). Bismaleimide
furnished 58f (49%) with high mono-selectivity under the
optimal reaction conditions. The mechanistic study revealed
that the cationic Rh(III) complex activates the C–H bond in
N-aryl phthalazinone 43 to afford a five-membered rhodacycle
intermediate 20A. Coordination of maleimide 57 and sub-
sequent migratory insertion results in the seven-membered
rhodacycle intermediate 20C via 20B. Eventually, after protona-
tion with AcOH, the desired product 58 was released with the
regeneration of the Rh(III) catalyst (Scheme 20).
37
Transition-metal-catalyzed annulation reactions in
phthalazinones
Transition-metal-catalyzed annulation reactions are the most
demanding synthetic techniques for building diversely functio-
nalized carbocycles and heterocycles.
38
Phthalazine-1,4-dione
Propargyl alcohols. In 2016, our group reported the synthesis
of cinnolinediones 60 via regioselective deoxy-oxidative annu-
lation of 2-phenyl-2,3-dihydrophthalazine-1,4-dione with
primary and secondary propargyl alcohols in the presence of a
Ru catalyst. In this protocol, [RuCl
2
(p-cymene)]
2
(5 mol%) is
used as the catalyst, KPF
6
(30 mol%) as the co-catalyst, and Cu
(OAc)
2
(2.0 equiv.) as the oxidant in CH
3
COOH at 110 °C for
Scheme 15 Ru-catalyzed o-acylmethylation and Lawesson’s reagent
and BF
3
·OEt
2
-mediated cyclization.
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Scheme 16 Plausible mechanism for o-acylmethylation and Lawesson’s reagent and BF
3
·OEt
2
-mediated cyclization.
Scheme 17 Rh-catalyzed amidation of N-aryl phthalazinones.
Scheme 18 Proposed reaction mechanism for Rh-catalyzed amidation of N-aryl phthalazinones using dioxazolones.
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8 h. Electron-donating and electron-withdrawing groups at the
para/meta positions of phthalazine-1,4-dione and propargyl
alcohols tolerated the reaction better than ortho substituents
to give regioselective deoxy-oxidative annulated products in
good yields. Unfortunately, attempts with a tertiary propargyl
alcohol afforded an unidentified product and were thus futile
(Scheme 21). From the series of control experiments and
based on earlier literature reports, a plausible mechanism was
outlined (Scheme 22). Initially, coordination of 2-phenyl-2,3-
dihydrophthalazine-1,4-dione 43 with Ru(II) catalyst 22A was
effected by C–H activation to generate ruthenacycle 22B,to
which the regioselective insertion of the alkyne (in situ-formed
propargylic ester) results in a seven-membered Ru(II) species
22C. This on isomerization in the presence of acid generates
intermediate 22D. Further, 22D is rearranged to a new Ru(II)
species 22E via aγ-deoxygenation step. A seven-membered Ru
(II) species 22F is formed with the removal of –OAc, and finally
an oxidative annulated product is generated.
39
In 2018, Ji and
co-workers published the [4 + 1] annulation of propargyl alco-
hols with phthalazinones to yield polycyclic compounds 62
bearing a quaternary carbon center in the presence of a Rh(III)
catalyst under air. The optimized conditions involve
[Cp*RhCl
2
]
2
(5 mol%) and NaOAc (1 equiv.) in PhCl at 90 °C in
air. This strategy applied to substrates bearing electron-rich
and electron-deficient groups at different positions in 43 with
good yield. Notably, electron-releasing groups (–Me and –OMe)
in the para position of 43 offered the corresponding products
62a and 62b in good yields (77 and 69%), and a fluoro group
at the meta position gave the desired product 62d with exclu-
sive regioselectivity. However, a methoxyl group at the meta
position afforded 62c with an 88 : 12 ratio of regioisomers.
Sterically hindered substrates, such as ortho-methyl, did not
respond under the optimized conditions. In addition, various
functional groups, like naphthyl, thiophenyl, benzyl, and
ethyl, on the phenyl moiety of propargyl alcohols also provided
the annulated products in good yields (Scheme 23). A plausible
mechanistic route for this chemical transformation involves
the generation of the active catalyst Cp*Rh(OAc)
2
via ligand
exchange with sodium acetate (Scheme 24). The five-mem-
bered rhodacycle intermediate 24A was formed by reaction
between 43 and the active catalyst via C–H bond activation.
Then successive coordination of 61 to the metal followed by
migratory insertion leads to intermediate 24B. Subsequently,
the abstraction of the allylic proton by the rhodium complex
affords allene intermediate 24C. Eventually, 24C undergoes
sequential reductive elimination and enol–keto tautomerism
to give the desired product 62.
40
Scheme 19 Rh(III)-catalyzed C–H functionalization phthalazinone with
succinimide.
Scheme 20 Plausible mechanism for Rh(III)-catalyzed C–H functionali-
zation of N-aryl phthalazinones using maleimides.
Scheme 21 Ru-catalyzed regio-selective deoxy-oxidative annulation.
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Alkynes. In 2016, Perumal et al. demonstrated the synthesis
of cinnolines via dehydrogenative C–H/N–H functionalization
of N-phenyl phthalazinone with alkynes by a Rh(III) catalyst.
This transformation was performed in the presence of
2.5 mol% of [Cp*RhCl
2
]
2
, 10 mol% of AgSbF
6
, and 1 equiv. of
Cu(OAc)
2
.H
2
Oint-AmOH at 100 °C under a N
2
atmosphere for
6 h to afford phthalazino[2,3-a]cinnolines 64. The substrate
scope based on N-phenylphthalazinones and alkynes was
explored, resulting in good yields of 64a–f(80–92%). Moreover,
unsymmetrical alkynes were tested in this transformation,
affording the single regioisomeric products 64d and 64e in
85% and 78% yield, respectively. This methodology was suit-
Scheme 22 A plausible mechanism for Ru-catalyzed regio-selective deoxy-oxidative annulation of 2-phenyl-2,3-dihydrophthalazine-1,4-dione
with primary and secondary propargyl alcohols.
Scheme 23 Rh-catalyzed [4 + 1] annulation of phthalazinones with
propargyl alcohols.
Scheme 24 A plausible mechanistic route for Rh-catalyzed [4 + 1]
annulation of phthalazinones with propargyl alcohols.
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able for symmetrical aliphatic alkynes 64f as well (yield 98%)
(Scheme 25). The synthesized annulated products exhibited
good fluorescence properties in solid and aggregation states;
imaging of various cancer cell lines was also performed. The
following plausible mechanism is proposed, starting with the
removal of –Cl–from [RhCp*Cl
2
]
2
effected by the intervention
of AgSbF
6
to generate the active [Rh
III
] catalyst. This [Rh
III
]
readily coordinates with 43, and assists the C–H activation to
form cyclometallated intermediate 26A. Next, insertion of 63
into the Rh–CPh bond of 26A with regioselectivity results in a
seven-membered species 26C via 26B. Eventually annulated
product 64 is released via a reductive elimination, and Rh(III)is
regenerated under air (Scheme 26).
41
Gogoi et al. demonstrated
the Ru(II)-catalyzed C–H activation and annulation of 2-phenyl-
dihydrophthalazinediones 43 using alkynes 65. Surprisingly,
the alkyne triple bond participates in annulation to generate
biologically important substituted quinazolines 66 in the pres-
ence of [RuCl
2
(p-cymene)]
2
(5 mol%), Cu(OAc)
2
·H
2
O (1.0
equiv.), DPPP [1,3-bis-(diphenylphosphino)propane]
(10 mol%) and K
2
CO
3
(1 equiv.) in t-AmOH at 90 °C for 8 h.
Electron-donating and electron-withdrawing substituents,
such as Me,
i
Pr, OMe, CF
3
, F, and Cl, at the para position of
the 2-phenyl ring in 43 afforded good yields (66a in 80% yield),
and substituents such as Me, F, and Cl at the meta position
provided highly regioselective products (66b in 75% yield).
Moreover, both symmetrical and unsymmetrical alkynes furn-
ished the desired product in good yield. Notably, Br- and aryl
heteroarylsubstituted unsymmetrical alkynes afforded regio-
selective products 66d and 66e, respectively (Scheme 27).
Based on their control studies and the reported literature, a
possible mechanism was proposed (Scheme 28). The active Ru
(II) catalyst 28A reacts with 43 to generate cyclometallated
species 28B, then the seven-membered Ru(II) complex 28C was
formed by insertion of the alkyne into the C–Ru bond in 28B.
This on further oxidation by cleavage of the N–N bond gener-
ates Ru(IV) complex 28D. Thereafter, indole derivative 28E is
produced via reductive elimination. The activation at the C-2
position in the indole moiety furnishes Ru complex 28F, which
on subsequent reductive elimination, in the presence of Cu
(OAc)
2
,affords a seven-membered amide 28G with simul-
taneous regeneration of 28A. Eventually, 28G undergoes intra-
molecular cyclization, leading to diazacyclopropane azulene
28H, which further undergoes another intramolecular
rearrangement and elimination to 66.
42
Olefins. Kianmehr and co-workers published the oxidative
C–H bond alkenylation of N-aryl phthalazinediones with acry-
lates via intramolecular cyclization by ruthenium catalysis.
Scheme 25 Rh-catalyzed synthesis of cinnolines via dehydrogenative
C–H/N–H Functionalization.
Scheme 26 A plausible mechanism for Rh-catalyzed synthesis of cin-
nolines via dehydrogenative C–H/N–H functionalization.
Scheme 27 Ru-catalyzed annulation of 2-phenyldihydrophthalazine-
diones using alkynes.
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This reaction was carried out in water in the presence of
[RuCl
2
(p-cymene)]
2
(5 mol%), KPF
6
(10 mol%), and Cu
(OAc)
2
·H
2
O (1.0 equiv.) to give the annulated product 68.
Impressively, substituents such as fluoro-, bromo-, and methyl-
bearing substrates tolerated the reaction condition and exhibi-
ted improved yields (Scheme 29). The authors proposed the
following plausible catalytic cycle, (Scheme 30) where the five-
membered ruthenacycle 30A was generated by N–H-assisted C–
H bond activation in 43 by an active Ru catalyst. Afterwards,
the π-coordinated acylate undergoes migratory insertion and
subsequent β-hydride elimination to give 30C. Further, inter-
mediate 30D is formed via reductive elimination, which under-
goes an intramolecular aza-Michael addition reaction to afford
68.
43
Very recently, Sakhuja et al. disclosed the reductive [4 + 2]
Scheme 28 A possible mechanism for Ru-catalyzed annulation of 2-phenyldihydrophthalazinediones using alkynes.
Scheme 29 Ru-catalyed annulation of N-aryl phthalazinedione with
acrylates.
Scheme 30 A plausible mechanism for Ru-catalyzed annulation fo
N-aryl phthalazinediones with acrylates.
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annulation of 2-aryl-2,3 dihydrophthalazine-1,4-diones 43 with
nitroolefins 69 in the presence of a Rh catalyst, as shown in
Scheme 31. The optimized reaction conditions to prepare
phthalazino[2,3-a]cinnolines 70 are [Cp*RhCl
2
]
2
(2.5 mol%)
and NaOAc (0.5 equiv.) in EtOH at 80 °C for 6 h under a N
2
atmosphere. In this methodology, electron-donating groups
(4-CH
3
,4-
i
Pr, and 3-NH
2
) at the meta and para positions and
disubstitution in 43 are better tolerated than electron-with-
drawing groups (2-Br, 4-NO
2
, and 4-CN). Additionally, nitroole-
fins containing heterocyclic moieties, such as thiophene,
furan, and indole, also afford their respective annulated pro-
ducts in good yield. Based on the authors’controlled studies
and previous literature, a plausible reaction mechanism is pro-
posed. Initially, the active catalyst [Cp*Rh
III
(OAc)
2
] is formed
from dimeric precursor [Cp*RhCl
2
]
2
in the presence of NaOAc.
Further, 43 reacts with the Rh catalyst via N–H assistance to
produce species 32A. The five-membered rhodacycle 32C is
generated by C–H activation and possibly through the SEAr
mechanism via 32B. Next, 69 coordinates to 32C and its sub-
sequent insertion into the Rh–CAr bond furnishes new species
32E via 32D. Afterward, 32E is transformed to 32F via acetate-
ion-mediated demetallation concomitant with the protonation
reaction. Then active Rh
III
species is regenerated for the next
catalytic cycle. Finally, dehydration in 32F leads to 70
(Scheme 32).
44
Diazo-compounds. In 2018, Shang’s group disclosed the syn-
thesis of phthalazino[2,3-a]cinnoline-8,13-diones 72 via Ir(III)-
catalyzed C–H bond activation/annulation of cyclic amides 43
with cyclic 2-diazo-1,3-diketones 71. This methodology
demands (IrCp*Cl
2
)
2
(2 mol%) and AgSbF
6
(20 mol%) as cata-
lysts and is performed in DCE at 100 °C for 14 h. Impressively,
various functional groups, such as Me,
t
Bu, F, Cl, and Br, on
the N-phenyl group in 43 furnished the desired products in
good to excellent yields. Notably, sterically hindered ortho-sub-
stituted substrates tolerated the reaction conditions and
afforded products 72b and 72c in good yields (81 and 82%).
Additionally, acyclic 72e and five-membered cyclic 1,3-carbo-
nyl-2-diazo compound 72f were isolated in excellent yields
(92% and 86%, respectively) (Scheme 33).
45
In the same year,
Sakhuja and co-workers reported two unique Rh(III)-catalyzed
additive-driven [4 + 1] and [4 + 2] annulations of
N-arylphthalazine-1,4-dione with α-diazo carbonyl compounds.
Scheme 32 A possible mechanism for Rh-catalyed annulation of
2-aryl-2,3 dihydrophthalazine-1,4-diones.
Scheme 33 Ir(III)-catalyzed C–H bond activation/annulation of cyclic
amides with 1,3-diketone-2-diazo.
Scheme 31 Rh-catalyzed annulation of 2-aryl-2,3 dihydrophthalazine-
1,4-diones.
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The additive utilized for the synthesis of [4 + 1] annulated
product hydroxy-dihydroindazolo-fused phthalazines 74 is
CsOAc (50 mol%) and the catalyst is [Cp*RhCl
2
]
2
(2.5 mol%) in
DCEatRTfor16–18 h under air. However, when AgSbF
6
is used,
surprisingly, the [4 + 2] annulated product is isolated at elevated
temperature (110 °C). Further, electronically differentiated sub-
stituents(H,Me,F,Cl,Br)atdifferent positions on 43 afford the
desired [4 + 1] annulation products 74a–cin good yields.
Moreover, functional groups at the meta position are better toler-
ated than those at the para and ortho positions (Scheme 34a).
From the [4 + 2] annulation viewpoint, diverse substituents (H,
Me,F,Cl,andBr)onthephenylgroupin43 were better tolerated
than strong electron-withdrawing groups (m-NO
2
,m-CF
3
,
p-COOEt, or p-CN) (Scheme 34b). A plausible mechanism is pro-
posed based on their controlled experiments and previous litera-
ture reports; classically, both [4 + 1] and [4 + 2] annulations were
initiated by active Rh(III) species ([Cp*RhX
2
]); X = OAc or SbF
6
.
This active Rh(III) species reacts with 43 to form rhodacyclic com-
pound 35A via C–H activation. Further, 35A on carbene insertion
gives 35B, followed by migratory insertion to give 35C.Theinter-
mediate 35C on subsequent protonolysis generates 35E via 35D
along with the regeneration of the active Rh(III) species.
Afterwards, two different pathways are proposed for the [4 + 1]
and [4 + 2] annulation processes. In path a, intermediate 35E
undergoes intramolecular nucleophilic addition followed by de-
hydration to afford the [4 + 2] annulation product 75 (in the pres-
ence of AgSbF
6
). In path b (in the presence of CsOAc), intermedi-
ate 35F is formed from 35E via proton abstraction. Further,
oxygen insertion in 35F generates a superoxide ionic species
35G, which on the elimination of R
3
COO-furnishes intermediate
35H. Eventually, intermediate 35H undergoes intramolecular
nucleophilic addition to afford [4 + 1] annulation product 74
(Scheme 35).
46
Isocyanates. In 2021, Sakhuja and co-workers reported the
mild, sequential and one-pot Ru(II)-catalyzed C–H amidation
and carbocyclization of 2-phenylphthalazine-1,4-diones 43
using isocyanates 76 as a carbonyl source, which involves C–
C/C–N bond formations. Sequentially, the ortho-amidation pro-
ducts 77 were formed followed by intramolecular nucleophilic
substitution reaction delivered substituted indazolo[1,2-b]
phthalazine-triones 78. To target the ortho-amidation products
77, the combination of [RuCl
2
(p-cymene)]
2
(5 mol%) and
NaOAc (50 mol%) in DCE at 80 °C for 8 h in N
2
atmosphere
was very effective. The prerequisite to isolate the amidation
products 77 is that the N-phenyl group in 43 must possess an
ortho substituent. To effect the carbocyclization, isolated 77
was treated with NaOAc (50 mol%) in DCE at 80 °C for 8 h.
Interestingly, the one-pot sequential carbocyclization was
achieved using milder conditions (40 °C for 4 h) with no ortho
substituents, whereas with ortho substituents (-Me, -Et, -Br)
demands a higher temperature and longer time (120 °C for
6 h). Additionally, disubstituted 78d (3,4-diMe) also tolerated
the reaction conditions with excellent yield. To further high-
light the chemical utility of 78 and 77, they were subjected to
various reactions. The reaction of 78 with LiAlH
4
and
Lawesson’s reagent results in reduced 78g and thioxo-deriva-
tives 78h, respectively. Likewise, 77 subjected with Lawesson’s
reagent and PIDA led to 77e and 77f, respectively (Scheme 36).
Mechanistically, the reaction is believed to be initiated from
the active catalyst [Ru
II
OAc
2
(p-cymene)] which on N–H assist-
ance in 43 forms the new species 37A. Then, the five-mem-
bered ruthenacycle 37B is generated via C–H activation.
Further, coordination of aryl isocyanate 76 with Ru and sub-
sequent migratory insertion of –CvN into Ru–Ar affords 37D
through intermediate 37C. Next, protonolysis of 37D furnishes
ortho-amidated intermediate 77 with the regeneration of the
active Ru(II) species. Finally, intramolecular nucleophilic sub-
stitution provides carbocyclized product 78 (Scheme 37).
47
Aldehydes/ketones. In 2020, Kim’s group reported the Ru(II)-
catalyzed C(sp
2
)–H activation and hydroxyalkylation of N-aryl
Scheme 34 Additive-driven Rh-catalyzed [4 + 1]/[4 + 2] annulations of N-arylphthalazine-1,4-dione.
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phthalazinones 43 with aldehydes 79 and activated ketone 79′
to yield hydroxyalkylated phthalazine-1,4-diones 80.The
intramolecular Mitsunobu cyclization of 80 led to indazo-
lophthalazinones 81 in the presence of diethyl azodicarboxy-
late (DEAD) and PPh
3
. Electron-withdrawing and electron-
donating groups at the ortho/meta/para positions in 43 were
tolerated (80a: 83%, 80b: 99%, and 80c: 97%). Unfortunately,
electron-rich (hetero)aryl aldehydes, aliphatic aldehydes and
benzylic aldehydes provided minuscule amounts of products
(<10% yield). In addition, activated ketone also afforded
hydroxyalkylated product 80a′in 65% yield. Importantly,
N-protected N-aryl phthalazinones do not undergo the C–H
Scheme 35 A plausible mechanism for additive-driven Rh-catalyzed [4 + 1]/[4 + 2] annulations of N-arylphthalazine-1,4-dione.
Scheme 36 Ru-catalyzed C–H amidation and carbocyclization of 2-phenylphthalazine-1,4-diones.
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hydroxyalkylation reaction as they limit the nitrogen-assisted
formation of the ruthenacycle (II) intermediate (Scheme 38).
The plausible mechanism reveals that phthalazine-1,4-dione
43 reacts with the active catalyst [Ru( p-cymene)(OAc)
2
]to
deliver an intermediate 39A, which is also alternatively gener-
ated from isolable intermediate 39A′. Next, the ruthenacycle
39B is formed via C–H bond activation. The carbonyl unit in
79 coordinates to the ruthenium center of 39B,whichonsub-
sequent migratory insertion furnishes a seven-membered
species 39D. Upon protonolysis, the hydroxyalkylated product
80 is released with the regeneration of [Ru(p-cymene)(OAc)
2
].
Furthermore, 80 undergoes Mitsunobu intramolecular cycli-
Scheme 37 A plausible mechanism for Ru-Catalyzed C–H amidation and carbocyclization of 2-phenylphthalazine-1,4-diones.
Scheme 38 Ru-catalyzed C–H hydroxyalkylation and Mitsunobu cyclization of N-aryl phthalazinones.
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zation to provide tetracyclic indazolophthalazinone 81
(Scheme 39).
48
Conclusions
Over the past 6 years, the transition-metal-catalyzed pathway
has provided a tailwind for the easy access of phthalazinone
derivatives via C–H bond activation/functionalization/annula-
tion. Furthermore, this highlight discusses the contribution of
transition-metal catalysis in the synthetic development of
phthalazinones. Ideally, the heteroatoms (O and N) on the
phthalazinone are key units for diverse functionalization with
regioselectivity with the participation of transition-metal cata-
lysts like Rh, Ru, Pd and Ir. Categorically, various functionaliza-
tions, like arylation, alkylation, alkenylation, alkynylation, sulfo-
nylation, amidation, halogenation and C–H annulations with
mechanistic studies have been discussed. Shortly, we can envi-
sage that earth-abundant transition-metal-catalyzed reactions
will play a vital role in the late-stage functionalization of phtha-
lazinones. Besides, ample scope is foreseen to generate highly
substituted and useful phthalazinones. Looking ahead, aug-
menting phthalazinone derivatives with improved processing
and high throughput via more sustainable and greener path-
ways will make this research area more attractive and practical.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The Department of Science and Technology-SERB (EMR/2016/
005461) and the Seed Grant, Vellore Institute of Technology,
Vellore are gratefully acknowledged.
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Scheme 39 A plausible reaction mechanism for Ru-catalyzed C–H hydroxyalkylation and Mitsunobu cyclization of N-aryl phthalazinones.
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