Ru(II)-Catalyzed C-H Hydroxyalkylation and Mitsunobu Cyclization of N-Aryl Phthalazinones

Article abstract of DOI:10.1021/acs.joc.9b03228

Ruthenium(II)-catalyzed C(sp²)-H functionalization of N-Aryl phthalazinones with a range of aldehydes and activated ketone is described. Initial formation of hydroxyalkylated phthalazinones and subsequent Mitsunobu cyclization provided facile access to biologically relevant indazolophthalazinones. The utility of this method is highlighted by synthetic transformations into a series of potentially bioactive scaffolds.

Full text of DOI:10.1021/acs.joc.9b03228

Subscriber access provided by Universite du Quebec a Montreal (UQAM)
Article
Ru(II)-Catalyzed C–H Hydroxyalkylation and
Mitsunobu Cyclization of N-Aryl Phthalazinones
Kunyoung Kim, Sang Hoon Han, Daeun Jeoung, Prithwish Ghosh, Saegun
Kim, Seung Jun Kim, Jin-Mo Ku, Neeraj Kumar Mishra, and In Su Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03228 • Publication Date (Web): 06 Jan 2020
Downloaded from pubs.acs.org on January 6, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 15
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ru(II)-Catalyzed C–H Hydroxyalkylation and Mitsunobu Cyclization
of N-Aryl Phthalazinones
a
a
a
a
a
Kunyoung Kim, Sang Hoon Han, Daeun Jeoung, Prithwish Ghosh, Saegun Kim, Seung Jun
a
b,
a,
a,
Kim, Jin-Mo Ku, * Neeraj Kumar Mishra, * and In Su Kim *
a
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
b
Biocenter, Gyeonggido Business & Science Accelerator (GBSA), Suwon 16229, Republic of Korea
KEYWORDS: Arylphthalazinones, C–H functionalization, Hydroxyalkylation, Mitsunobu cyclization, Ruthenium.
2
ABSTRACT: Ruthenium(II)-catalyzed C(sp )–H functionalization of N-aryl phthalazinones with a range of aldehydes and
activated ketone is described. Initial formation of hydroxyalkylated phthalazinones and subsequent Mitsunobu cycliza-
tion provided facile access to biologically relevant indazolophthalazinones. The utility of this method is highlighted by
synthetic transformations into a series of potentially bioactive scaffolds.
Introduction
With great advances in catalytic C–H functionaliza-
tion, recent efforts have been devoted to the generation
of tetracyclic phthalazine derivatives from the reaction
5
Phthalazine is a ubiquitous structural core found in a
range of natural products, pharmaceuticals, and function-
1
between N-aryl phthalazinones and π-unsaturated com-
al materials. Particularly, this class of compounds has
6a
6b
pounds. For example, Gandhi and Perumal inde-
pendently described the annulative formations of
[6,6,6,6]-tetracyclic cinnolinophthalazinones using N-aryl
phthalazinones and alkynes. Recently, the synthetic
routes for [6,6,5,6]-tetracyclic indazolophthalazinones
attracted great attention by virtue of their diverse biologi-
cal properties such as antitumor, anti-inflammatory, anti-
hypertensive, anticonvulsant, and antimicrobial. There-
fore, the ability to synthesize substituted phthalazines is
2
important from the perspective of furthering medicinal,
7a
agrochemical, and other chemical entities.3 Notably,
were reported by using α-diazo carbonyls, propargylic
7
b
4b
alcohols, and alkenes under Rh(III) catalysis (Scheme
).
[6,6,5,6]-tetracyclic phthalazine derivatives including in-
dazolophthalazinones are of recent interest in medicinal
1
Scheme 1. N-Aryl Phthalazinones in C–H Functionali-
zation
chemistry due to their remarkable antitumor and anti-
inflammatory activities (Figure 1).4
Figure 1. Selected Examples of Bioactive Phthalazines
The polar π-bonds of carbonyl compounds were ex-
plored in C–H functionalization events under transition-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 15
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
metal catalysis, leading to the formation of various heter-
ocyclic molecules. In continuation of our recent works
10
AgNTf
AgNTf
AgNTf
AgNTf
AgNTf
AgNTf
-
2
2
2
2
2
2
(10), NaOAc (30)
(10), NaOAc (30)
(10), NaOAc (30)
(10), NaOAc (30)
(10), NaOAc (30)
(10)
MeCN
MeOH
toluene
DCE
43
8
11
N.R.
75
on the synthesis of biologically active scaffolds based on
12
5c
C–H functionalization, we herein disclose the synthesis
of indazolophthalazinones via the Ru(II)-catalyzed site-
selective C–H hydroxyalkylation of N-aryl phthalazinones
with aldehydes and activated ketone followed by intramo-
lecular cyclization under Mitsunobu conditions.
13c
14d
15e
16e
17f
78
DCE
N.R.
25
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
DCE
DCE
88
AgNTf
2
(10), NaOAc (30)
DCE
92
a
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), [Ru(p-
cymene)Cl (2.5 mol %), additive (quantity noted), DCE (1 mL)
under air at 40 C for 20 h in pressure tubes. Yield by flash column
Result and discussions
]
2 2
o
b
Optimization of reaction conditions was initially per-
formed by coupling of N-aryl 2,3-dihydrophthalazine-1,4-
dione 1a with ethyl glyoxalate (2a), as shown in Table 1.
We were pleased to observe the coupling reaction under
cationic Ru(II) catalysis in DCE under mild reaction con-
c
chromatography.
[Cp*RhCl
2
]
2
(2.5 mol %) instead of [Ru(p-
(5 mol %) instead of [Ru(p-
d
cymene)Cl
cymene)Cl
cymene)Cl
2
]
]
2
2
.
.
[Cp*Co(CO)I
2
]
e
2
[Ru(p-cymene)(OAc) ] (5 mol %) instead of [Ru(p-
2
f
2
]
2
. Scale-up experiment: 1a (1 g, 4 mmol) was used.
o
Scheme 2. Substrate Scopea
dition (40 C), affording the hydroxyalkylated N-aryl
phthalazinone 3a in 48% yield (Table 1, entry 1). Screening
of acetate additives was found to be more effective in this
transformation (Table 1, entries 2–7). Particularly, a
NaOAc additive displayed dramatically increased reactivi-
ty to provide 3a in 96% yield (Table 1, entry 5). A control
experiment revealed the pivotal role of a cationic Ru(II)
catalyst for the formation of 3a (Table 1, entry 8). Evalua-
tion of solvent effect indicated that DCE was found to be
a most suitable reaction media (Table 1, entries 9–12). No-
tably, Rh(III) and Co(III) catalysts were found to be less
reactive or unsuccessful (Table 1, entries 13 and 14). In
O
R2
+
O
R2
R1
[Ru(p-cymene)Cl2]2
2.5 mol %)
R1
O
(
N
N
AgNTf2 (10 mol %)
H
R
NH
H
NH
HO
2
a (R = CO2Et)
b-2f (R = Ar)
R
NaOAc (30 mol %)
DCE, 40 °C, 20 h
2
O
a-1n
O
2g (R = H)
1
3a-3t, %b
Cl
Me
CF3
O
O
O
O
O
N
N
N
NH
HO
NH
NH
CO2Et
CO2Et
HO
CO2Et
CF3
HO
O
3a, 96%
3b, 99%
3c, 80%
Me
addition, the reaction using
cymene)(OAc) ] catalyst in the presence of AgNTf
ed in the significantly decreased formation of 3a (Table 1,
entry 15). Interestingly, the use of [Ru(p-cymene)(OAc)
catalyst without AgNTf provided 3a in 88% yield (Table 1,
entry 16). These results revealed that a neutral [Ru(p-
cymene)(OAc) ] catalyst might be an active species in the
a
synthesized [Ru(p-
R
Me
O
O
O
2
2
result-
N
N
N
NH
HO
NH
NH
HO
CO2Et
CO2Et
2
]
2
CO Et
HO
O
O
O
2
3e, 95% (R = Me)
3h, 95%
3d, 81%
3
f, 97% (R = F)
3g, 85% (R = Cl)
R
2
O
O
NO2 O
catalytic cycle, and the role of silver salts might accelerate
N
N
N
the formation of an active catalyst by the removal of chlo-
NH
HO
NH
HO
NH
CO2Et
CO Et
CO2Et
2
HO
9
rine anion. It should be noted that this transformation
O
O
O
3j, 83% (R = F)
k, 42% (R = Me)
was compatible with a scale-up experiment (1 g, 4 mmol)
to give 3a in 92% yield (Table 1, entry 17).
Table 1. Optimization for Reaction Conditionsa
3i, 98%
3l, 69%
3
O
O
O
N
N
N
NH
HO
NH
NH
CO2Et
CO2Et
O
HO
HO
R
3o, 71% (R = NO )c
3p, 51% (R = CO Me)
3q, 31% (R = CF3)
O
O
2
3m, 72%
3
n, 97%
c
2
c
O
O
O
N
N
N
yield(%)b
NH
HO
NH
Br
entry
additive (mol %)
solvent
NH
HO
OH
O
O
1
AgNTf
AgNTf
AgNTf
AgNTf
AgNTf
AgNTf
2
2
2
2
2
2
(10)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
48
82
68
62
96
71
O
r, 60%c
3s, 85%c NO2
3t, 42%c
3
NO2
2
3
4
5
6
7
8
9
2
(10), Cu(OAc) (30)
a
Reaction conditions: 1a–1n (0.2 mmol), 2a, 2b–2f and 2g (0.6 mmol),
(10), AgOAc (30)
(10), LiOAc (30)
(10), NaOAc (30)
(10), KOAc (30)
(10), NaOAc (30)
[
Ru(p-cymene)Cl
2
]
2
(2.5 mol %), AgNTf
2
(10 mol %), NaOAc (30
o
b
mol %), DCE (1 mL) under air at 40 C for 20 h in pressure tubes.
c
Yield by flash column chromatography. The reaction was carried
out by using 5 mol % of [Ru(p-cymene)Cl
2
]
2
under N atmosphere.
2
AgSbF
NaOAc (30)
AgNTf (10), NaOAc (30)
6
82
72
59
With the optimal reaction conditions in hand, the
scope of 2-aryl 2,3-dihydrophthalazine-1,4-diones with 2a
was examined (Scheme 2). meta-Substituted compounds
2
ACS Paragon Plus Environment

Page 3 of 15
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1b–1d with both electron-rich and electron-deficient
groups were found to be viable substrates in this reaction,
providing the desired products 3b–3d in high yields. The
complete site-selectivity was observed at less hindered C–
H bonds. Additionally, a range of para-substituted
phthalazinones 1e–1i was coupled with 2a to deliver the
corresponding products 3e–3i in 85–98% yields. It should
be noted that mono-hydroxyalkylated adducts were ex-
clusively formed in all cases. This reaction was also toler-
able with ortho-substituted substrate 1j, affording the
desired product 3j in 83% yield. Moreover, a sterically
congested N-aryl 2,3-dihydrophthalazine-1,4-dione 1k also
reacted with 2a to afford 3k in a moderate yield (42%). In
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Synthesis of Indazolophthalazinonesa
O
O
R2
N
N
R2
N
R1
R1
DEAD, PPh3
R3
NH
HO R4
CH2Cl2, rt, 12 h
4 R3
R
O
O
6a-6u, %b
3a-3u
R
Me
O
addition, 8-NO
2
-N-aryl phthalazinone 1l and N-aryl ben-
O
O
O
R
zophthalazinone 1m participated in this coupling reaction
to furnish 3l (69%) and 3m (72%), respectively. It is note-
worthy that the construction of functionalized N-aryl pyr-
idazinone 3n is of interest owing to the wide spectrum of
pharmaceutical and agrochemical activities of pyridazi-
none derivatives.1 Moreover, electron-deficient aryl alde-
hydes 2b–2f were compatible for this transformation to
generate the corresponding products 3o–3s. Paraformal-
dehyde 2g as an abundant one-carbon feedstock was also
exploited in the Ru(II)-catalyzed hydroxymethylation
N
N
Me
N
N
N
N
O
O
OEt
OEt
O
OEt
O
O
6e, 85% (R = Me)
6f, 96% (R = F)
6g, 91% (R = Cl)
6
6
a, 91% (R = Cl)
b, 90% (R = Me)
6c, 92% (R = CF )
6d, 82%
0
6h, 94% (R = CF )
3
3
R
O
NO2
O
O
N
N
N
N
N
N
O
O
OEt
O
O
OEt
O
OEt
11
O
reaction to provide 3t in 42% yield under the current
reaction conditions. It is noted that electron-rich (het-
ero)aryl aldehydes (2-thiophenecarboxaldehyde, p-
anisaldehyde), enal (trans-cinnamaldehyde), aliphatic
aldehydes (n-hexanal, cyclohexanecarboxaldehyde), and
benzylic aldehyde (2-phenylacetaldehyde) provided un-
satisfactory results (< 10% yield) under the current reac-
tion conditions (data not shown). In addition, activated
ketone 2h underwent the C–H hydroxymethylation reac-
tion to afford 3u in 65% yield (Scheme 3). However, other
activated ketones such as benzil, ethyl benzoylformate,
ethyl pyruvate, and 4-chloro-2,2,2-trifluoroacetophenone
proved to be unsuccessful substrates in this transfor-
mation.
6
i, 95% (R = H)
6l, 82%
6m
, 94%
6
j, 90% (R = F)
O
6k, 65% (R = Me)
O
O
N
N
N
N
N
N
O
O
O
OEt
O
R
6
n, 72%
O2N
6o, 77% (R = NO2)
O
6p, 75% (R = CO2Me)
6r, 49%
6
q, 76% (R = CF3)
N
N
O
O
N
N
N
N
O
Br
CO2Et
F3C
O
O2N
O
6s, 86%
6t, 50%
6u, N.R.
a
Scheme 3. Hydroxymethylation using Activated Ke-
tone
Reaction conditions: 3a–3u (0.2 mmol), DEAD (1.2 equiv.), PPh
equiv.), CH Cl (1 mL) under N atmosphere at room temperature for
2 h in reaction tubes. b Yield by flash column chromatography.
3
(3
2
2
2
1
O
O
[
Ru(p-cymene)Cl2]2
5 mol %)
Subsequently, hydroxyalkylated phthalazine-1,4-diones
O
(
N
N
3a–3u were employed in the intramolecular cyclization
for the formation of indazolophthalazinones, and the re-
sults are shown in Scheme 5. After screening of 3a under
various reaction conditions, we found that the Mitsunobu
reaction can be efficiently attributed to the annulation
reaction, delivering the corresponding product 6a in 91%
OEt AgNTf2 (10 mol %)
+
2
CO Et
HO CF3
NH
H
F3C
NH
O
NaOAc (30 mol %)
DCE, 60 °C, 20 h
O
O
1i
2h
3u, 65%
unsuccessful activated ketones
O
O
O
O
Ph
OEt
OEt
F3C
Ph
Ph
H3C
yield. It is noted that other reaction conditions, such as
O
O
O
Cl
13
oxidative cyclization using Ag
2
CO
3
,
acid-mediated cy-
To explore the C–H hydroxyalkylation of N-protected
N-aryl phthalazinone, the coupling reaction between 4a
and 2a was conducted under the current reaction condi-
tions (Scheme 4). No formation of 5a was detected, pre-
sumably due to no generation of a nitrogen-assisted
ruthenacycle(II) intermediate.1
clization), and S 2-type cyclization by O-mesylation, were
N
found to be unsuccessful (see the Supporting Information
for details). Thus, the Mitsunobu condition was employed
for the formation of indazolophthalazinones (6a–6m and
6o–6t) and indazolopyridazinone 6n in acceptable yields.
The structure of 6c was confirmed by X-ray crystallo-
graphic analysis (see Supporting Information for details).
2
Scheme 4. Control Experiment
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 15
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
However, the formation of 6u was unsuccessful under the
the presence of NaOAc to afford 3i in 92% yield (Scheme
current reaction conditions, presumably due to the steric
environment of a tertiary alcohol. It should be noted that
this protocol provides an efficient route for the construc-
tion of indazolophthalazinone and indazolopyridazinone
derivatives containing carboxylate, aryl, and methylene
functionality at the C13-position.
7, eq. 3). However, in the absence of NaOAc, no formation
of 3i was detected (Scheme 7, eq. 4). These results suggest
that complex A’ might be a possible precursor for a Ru-
OAc intermediate A in the catalytic cycle.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 7. Mechanistic Investigations
(
25%D)
Scheme 6. Synthetic Transformations
no deuteration
D/H
O
O
standard conditions
CD3CO2D (5 equiv)
N
N
(1)
NH H/D
NH
H
0 oC, 20 h
(25%D)
4
O
O
O
1
i
no deuteration deuterio-1i, 89%
O
N
[
Ru(p-cymene)Cl2]2
100 mol %)
(
N
H
N
(
2)
Cl
NH
H
NaOAc (300 mol %)
DCE, 40 C, 20 h
Ru
L
O
o
O
O
1
i
A', 45%
(L = p-cymene)
O
N
A' (5 mol %)
NaOAc (30 mol %)
N
(3)
(4)
DCE, 40 oC, 20 h
NH
HO
NH
H
H
CO2Et
2a (3 equiv)
O
O
O
1i
3i, 92%
O
A' (5 mol %)
DCE, 40 oC, 20 h
2a (3 equiv)
N
N
To illustrate the synthetic potential of hydroxyalkylated
phthalazine-1,4-diones, the radical-mediated C–N bond
formation reaction of 3i was first performed with
NH
HO
NH
CO2Et
O
O
without NaOAc
1i
3i, N.R.
PhI(OAc) , and the hydroxyl-containing adduct 7a was
2
Based on the reported literatures on the Ru(II)-
formed in 30% yield (Scheme 6). The structure of 7a was
confirmed by X-ray crystallographic analysis (see the
Supporting Information for details). Hydrolysis of 6i with
16
catalyzed C–H functionalizations and preliminary mech-
anistic investigations, a plausible reaction mechanism is
outlined (Scheme 8). Phthalazine-1,4-dione 1i undergoes
KOH in H O provided (1H)-indazole (7b) in 38% yield. In
2
the ligand exchange with
a
monomeric [Ru(p-
addition, reduction of 6i in the presence of LAH gave in-
dazolophthalazine derivative 7c in 31% yield. Furthermore,
cymene)(OAc) ] catalyst to deliver an intermediate A,
2
which is alternatively generated from isolable intermedi-
ate A’ in the initial stage. Next, an intermediate A delivers
the ruthenacycle complex B through C–H bond activation.
Coordination of 2a and subsequent migratory insertion
affords a ruthenacycle species D, which can be protonated
to furnish hydroxyalkylated adduct 3i and [Ru(p-
7e as a privileged anti-inflammatory core was obtained via
decarboxylation of 6i and subsequent benzylic oxidation
of 7d.
To gain
deuterium-labelling experiment was performed (Scheme
, eq. 1). A remarkable deuterium incorporation (25% D)
at ortho-C−H bonds of deuterio-1i was observed in the
presence of CD CO D, which indicates that the C−H bond
a preliminary mechanistic insight, the
7
cymene)(OAc) ] as an active catalyst. Intramolecular
2
Mitsunobu cyclization provides tetracyclic indazoloph-
thalazinone 6i.
3
2
cleavage step might be a reversible. Importantly, no H/D
exchange was observed at ortho-C−H bonds on
phthalazine-1,4-dione framework, suggesting the site-
selectivity of our developed method. In addition, a
isolable ruthenium complex A’ was obtained in 45% yield
Scheme 8. Proposed Reaction Mechanism
by the reaction between [Ru(p-cymene)Cl
2
2
] (100 mol %)
and NaOAc (300 mol %), as shown in eq. 2. The structure
of complex A’ was confirmed by NMR analysis and X-ray
crystallographic data (see Supporting Information for
details).1 To confirm whether complex A’ is an off-cycle
4
15
intermediate, we performed the reaction of 1i with 2a in
ACS Paragon Plus Environment

Page 5 of 15
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
bottom flask charged with phthalic anhydride (7 mmol, 100
mol %), and 10% HCl (105 mL) was added aryl hydrazine (7
mmol, 100 mol %). The reaction mixture was allowed to stir
o
for 9 h at 120 C under reflux condition. The resulting solid
was filtered, washed with water, and recrystallized from eth-
6
anol to afford the desired N-aryl phthalazinones.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
-(3-Chlorophenyl)-2,3-dihydrophthalazine-1,4-dione (1a):
o
1
1
.31 g (68%); white solid; mp = 239.0–242.2 C; H NMR (400
MHz, CD OD) δ 8.39 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 7.6 Hz,
H), 7.98–7.89 (m, 2H), 7.77 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H),
3
1
13
1
7.46 (t, J = 8.4 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H); C{ H} NMR
(175 MHz, DMSO-d ) δ 157.5, 150.7, 142.9, 133.8, 132.7, 132.6,
130.1, 129.1, 126.9, 126.8, 125.6, 124.7, 124.3; IR (KBr) υ 3732,
394, 3164, 1740, 1644, 1588, 1475, 1430, 1341, 1261, 1203, 1031, 773
6
3
-
1
+
cm ; HRMS (quadrupole, EI) calcd for C14
72.0353, found 272.0348.
-(m-Tolyl)-2,3-dihydrophthalazine-1,4-dione (1b): 1.34
9 2 2
H ClN O [M]
2
2
g
o
1
(
76%); white solid; mp = 223.3–226.5 C; H NMR (400 MHz,
CD OD) δ 8.38 (dd, J = 7.6, 0.8 Hz, 1H), 8.12 (dd, J = 8.0, 0.8
Hz, 1H), 7.97–7.88 (m, 2H), 7.46 (s, 1H), 7.42 (d, J = 8.0 Hz,
3
13
1
1
H), 7.36 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H); C{ H}
NMR (175 MHz, DMSO-d ) δ 157.2, 150.3, 141.7, 137.7, 133.5,
6
132.4, 129.2, 128.2, 127.6, 126.8, 126.4, 124.6, 124.1, 123.0, 20.9; IR
(KBr) υ 3733, 3512, 3067, 1735, 1624, 1570, 1556, 1487, 1457, 1366,
-
1
1
(
343, 1321, 1250, 1237, 1163, 1089, 1073, 1028, 911, 781 cm ; HRMS
+
quadrupole, EI) calcd for C15H12N2O2 [M] 252.0899, found
Conclusion
2
52.0894.
In conclusion, we disclosed the Ru(II)-catalyzed C–H
hydroxyalkylation of N-aryl phthalazinones with a range
of aldehydes. Notably, this method provides a facile route
for the construction of biologically relevant indazoloph-
thalazinones by intramolecular Mitsunobu cyclization. A
wide range of substrate scopes and broad functional
group tolerance were observed. Furthermore, a series of
transformations demonstrate great potential for applica-
tions in medicinal chemistry.
2
-(3-(Trifluoromethyl)phenyl)-2,3-dihydrophthalazine-1,4-
o
dione (1c): 0.643 g (30%); orange solid; mp = 249.0–252.2 C;
H NMR (400 MHz, CD
1
3
OD) δ 8.40 (dd, J = 7.6, 0.4 Hz, 1H),
8
.11 (dd, J = 8.0, 1.2 Hz, 1H), 8.10 (s, 1H), 8.05–7.97 (m, 1H),
13
1
7
.96–7.91 (m, 2H), 7.69–7.66 (m, 2H); C{ H} NMR (100 MHz,
CD OD) δ 160.3, 153.1, 143.8, 134.9, 133.7, 132.1 (q, JC-F = 32.0
3
Hz), 130.5, 130.4, 130.2, 128.2, 126.3, 125.7, 125.4 (q, JC-F = 269.7
Hz), 124.7 (q, JC-F = 3.6 Hz), 123.5 (q, JC-F = 4.0 Hz); IR (KBr) υ
3732, 3421, 3062, 1721, 1662, 1535, 1542, 1482, 1456, 1333, 1311,
-
1
1
258, 1123, 1080, 1070, 1025, 912, 786 cm ; HRMS (quadrupole,
+
EXPERIMENTAL SECTION
General Information. Commercially available reagents
were used without additional purification, unless otherwise
stated. Sealed tubes (13 × 100 mm ) were purchased from
Fischer Scientific and dried in oven for overnight and cooled
at room temperature prior to use. Thin layer chromatog-
raphy was carried out using plates coated with Kieselgel 60
EI) calcd for C H F N O [M] 306.0616, found 306.0611.
15
9
3
2
2
2-(3,4-Dimethylphenyl)-2,3-dihydrophthalazine-1,4-dione
o
1
(1d): 1.02 g (55%); brown solid; mp = 221.4–224.5 C; H NMR
(400 MHz, CD OD) δ 8.36 (dd, J = 7.2, 0.8 Hz, 1H), 8.10 (dd, J
= 8.0, 1.2 Hz, 1H), 7.95–7.87 (m, 2H), 7.38 (s, 1H), 7.31 (dd, J =
2
3
13
1
8.0, 2.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 2.31 (s, 6H); C{ H}
NMR (100 MHz, CD OD) δ 160.0, 152.9, 140.8, 138.1, 137.3,
3
F
254 (Merck). For flash column chromatography, E. Merck
134.7, 133.6, 130.7, 130.6, 128.1, 126.4, 125.6, 124.4, 19.8, 19.5; IR
(KBr) υ 3723, 3329, 3165, 1737, 1640, 1588, 1498, 1454, 1347, 1288,
Kieselgel 60 (230–400 mesh) was used. Nuclear magnetic
1
13
1
-1
resonance spectra ( H and C{ H} NMR) were recorded on a
Bruker Unity 700, 500 and 400 spectrometers in CDCl3,
CD OD, CD COCD , and DMSO-d solution and chemical
3 3 3 6
shifts are reported as parts per million (ppm). Resonance
patterns are reported with the notations s (singlet), d (dou-
blet), t (triplet), dd (doublet of doublets), td (triplet of dou-
blets), q (quartet), p (pentet), and m (multiplet). Coupling
constants (J) are reported in hertz (Hz). IR spectra were rec-
orded on a Varian 2000 Infrared spectrophotometer and are
1231, 1196, 1092, 1070, 1025, 807 cm ; HRMS (quadrupole, EI)
+
calcd for C16
H
14
N
2
O
2
[M] 266.1055, found 266.1050.
2-(p-Tolyl)-2,3-dihydrophthalazine-1,4-dione (1e): 1.09
g
o
1
(
62%); yellow solid; mp = 230.8–233.4 C; H NMR (400 MHz,
CD OD) δ 8.37 (dd, J = 7.2, 0.4 Hz, 1H), 8.11 (d, J = 6.8 Hz, 1H),
.96–7.88 (m, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz,
3
7
2
13
1
6
H), 2.40 (s, 3H); C{ H} NMR (175 MHz, DMSO-d ) δ 157.3,
1
1
1
50.3, 139.3, 136.3, 133.4, 132.4, 129.2, 128.8, 126.8, 125.7, 124.6,
24.1, 20.7 ; IR (KBr) υ 3734, 3165, 3032, 1736, 1641, 1598, 1509,
-1
reported as cm . High-resolution mass spectra (HRMS) were
recorded on a JEOL JMS-600 spectrometer.
-1
494, 1365, 1240, 1203, 1092, 1065, 1024, 873, 811 cm ; HRMS
+
(quadrupole, EI) calcd for C15
H
12
N
2
O
2
[M] 252.0899, found
General procedure and characterization data for the synthe-
sis of N-aryl phthalazinones (1a–1n). To an oven-dried round
252.0894.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 15
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2-(4-Fluorophenyl)-2,3-dihydrophthalazine-1,4-dione
(1f):
.07 g (60%); light yellow solid; mp = 243.1–246.3 C; H NMR
400 MHz, CD OD) δ 8.37 (dd, J = 7.6, 0.8 Hz, 1H), 8.11 (d, J =
.4 Hz, 1H), 7.96–7.88 (m, 2H), 7.69–7.65 (m, 2H), 7.21 (t, J =
17.2; IR (KBr) υ 3735, 3651, 3406, 1642, 1589, 1490, 1324, 1246,
o
1
-1
1
(
8
8
1032, 908, 810 cm ; HRMS (quadrupole, EI) calcd for
+
3
C
15
H
12
N
2
O
2
[M] 252.0899, found 252.0894.
8-Nitro-2-phenyl-2,3-dihydrophthalazine-1,4-dione
.396 g (20%); yellow solid; mp = 260.0–263.2 C; H NMR
(1l):
13
1
.4 Hz, 2H); C{ H} NMR (100 MHz, CD
3
OD) δ 162.9 (d, JC-F
=
=
o
1
0
2
8
44.1 Hz), 160.2, 152.9, 139.4, 134.8, 133.6, 130.5, 129.0 (d, JC-F
.7 Hz), 128.1, 126.4, 125.7, 116.2 (d, JC-F = 23.0 Hz); IR (KBr) υ
733, 3165, 1737, 1643, 1555, 1508, 1423, 1358, 1508, 1423, 1358,
(
(
(
400 MHz, CD
3
OD) δ 8.58 (dd, J = 7.6, 1.2 Hz, 1H), 8.07–7.99
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
m, 2H), 7.66 (d, J = 7.6 Hz 2H), 7.50 (t, J = 7.6, Hz, 2H), 7.39
t, J = 7.2 Hz, 1H); C{ H} NMR (100 MHz, CD OD) δ 158.2,
3
3
13
1
-
1
1321, 1292, 1231, 1213, 1151, 1094, 1056, 1027, 975, 850, 826 cm ;
1
1
48.4, 142.6, 134.1, 132.4, 130.8, 129.7, 128.9, 128.6, 127.3, 127.0,
26.9; IR (KBr) υ 3765, 3526, 1740, 1647, 1622, 1545, 1354, 1239,
+
HRMS (quadrupole, EI) calcd for C14
H
9
FN
2
O
2
[M] 256.0648,
found 256.0643.
-1
1032, 832 cm ; HRMS (quadrupole, EI) calcd for C14
[M] 283.0593, found 283.0588.
H
9
N
3
O
4
+
2-(4-Chlorophenyl)-2,3-dihydrophthalazine-1,4-dione (1g):
o
1
1.11 g (58%); white solid; mp = 255.6–258.6 C; H NMR (400
MHz, CD OD) δ 8.38 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 7.2 Hz,
H), 7.97–7.89 (m, 2H), 7.70–7.68 (m, 2H), 7.49–7.47 (m, 2H);
2
-Phenyl-2,3-dihydrobenzo[g]phthalazine-1,4-dione (1m):
3
o
1
0.525 g (26%); light yellow solid; mp = 290.2–292.8 C; H
NMR (500 MHz, DMSO-d ) δ 8.99 (s, 1H), 8.68 (s, 1H), 8.36–
.31 (m, 2H), 7.81–7.75 (m, 2H), 7.69–7.66 (m, 2H), 7.52–7.49
m, 2H), 7.39–7.35 (m, 1H); C{ H} NMR (125 MHz, DMSO-d
δ 163.4, 157.6, 134.5, 133.9, 130.5, 130.3, 129.4, 129.1, 128.9, 128.6,
28.4, 128.3, 127.4, 126.9, 126.0, 125.4; IR (KBr) υ 3765, 3650,
1
6
1
3
1
C{ H} NMR (175 MHz, DMSO-d
32.5, 131.1, 129.1, 128.3, 127.4, 126.9, 124.6, 124.2; IR (KBr) υ 3723,
638, 3165, 2969, 1736, 1640, 1562, 1490, 1363, 1256, 1153, 1092,
6
) δ 157.4, 150.5, 140.5, 133.7,
8
(
1
13
1
6
)
3
-1
1
9 2 2
031, 821 cm ; HRMS (quadrupole, EI) calcd for C14H ClN O
1
+
[
M] 272.0353, found 272.0348.
-(4-(Trifluoromethyl)phenyl)-2,3-dihydrophthalazine-1,4-
dione (1h): 0.6 g (28%); light orange solid; mp = 293.3–296.2
3
055, 2919, 1710, 1648, 1619, 1594, 1496, 1455, 1408, 1348, 1298,
-1
2
1031, 902, 865 cm ; HRMS (quadrupole, EI) calcd for
C
+
18
H
12
N
2
O
2
[M] 288.0899, found 288.0894.
o
1
C; H NMR (700 MHz, DMSO-d
6
) δ 11.97 (s, 1H), 8.32 (ddd, J
1
-Phenyl-1,2-dihydropyridazine-3,6-dione (1n): 0.764
g
= 7.8, 1.2, 0.5 Hz, 1H), 8.02 (dd, J = 7.7, 0.7 Hz, 1H), 7.99–7.97
o
1
(
58%); light orange solid; mp = 267.1–269.8 C; H NMR (400
MHz, CD OD) δ 7.58–7.56 (m, 2H), 7.46 (t, J = 8.0 Hz, 2H),
7.38 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 12.0 Hz, 1H), 7.04 (d, J = 8.0
13
1
(
m, 3H), 7.94–7.92 (m, 1H), 7.86 (d, J = 8.4 Hz, 2H); C{ H}
NMR (175 MHz, DMSO-d ) δ 157.6, 150.8, 144.9, 133.8, 132.6,
29.1, 126.9, 126.7 (q, JC-F = 32.2 Hz), 125.9, 125.5 (q, JC-F = 3.5
Hz), 125.6, 124.3, 124.1 (q, JC-F = 270.4 Hz); IR (KBr) υ 3722,
3
6
1
13
1
Hz, 1H); C{ H} NMR (100 MHz, CD
3
OD) δ 160.8, 155.3, 142.9,
1
34.6, 129.7, 129.1, 129.0, 126.7; IR (KBr) υ 3764, 3407, 3067,
3
501, 3165, 2943, 1742, 1701, 1656, 1581, 1561, 1496, 1424, 1323,
-1
2
943, 1711, 1661, 1602, 1567, 1489, 1253, 1221, 1122, 1042, 835 cm ;
-1
1
256, 1161, 1122, 1062, 1023, 858, 829 cm ; HRMS (quadrupole,
+
HRMS (quadrupole, EI) calcd for C10
H
8
N
O
2 2
[M] 188.0586,
+
9 3 2 2
EI) calcd for C15H F N O [M] 306.0616, found 306.0611.
found 188.0581.
2
-Phenyl-2,3-dihydrophthalazine-1,4-dione (1i): 1.03 g (62%);
General procedure and characterization data for the hy-
droxyalkylation of N-aryl phthalazinones (3a–3u). To an ov-
en-dried sealed tube charged with 2-(3-chlorophenyl)-2,3-
dihydrophthalazine-1,4-dione (1a) (54.5 mg, 0.2 mmol, 100
o
1
light white solid; mp = 215.0–217.5 C; H NMR (400 MHz,
CD OD) δ 8.37 (dd, J = 7.2, 0.4 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H),
3
7.97–7.88 (m, 2H), 7.66–7.63 (m, 2H), 7.45 (t, J = 7.6 Hz, 2H),
7.37 (t, J = 7.6 Hz, 1H); 13C{ H} NMR (100 MHz, CD
1
3
OD) δ
mol %), [Ru(p-cymene)Cl
AgNTf (7.8 mg, 0.02 mmol, 10 mol %), NaOAc (4.9 mg, 0.06
mmol, 30 mol %) and ethyl 2-oxoacetate (~50% in toluene)
2 2
] (3.1 mg, 0.005 mmol, 2.5 mol %),
1
1
1
60.1, 152.9, 143.2, 134.7, 133.6, 130.6, 129.6, 128.6, 128.1, 127.1,
2
26.4, 125.6; IR (KBr) υ 3850, 3504, 3062, 2905, 1640, 1595, 1571,
489, 1454, 1429, 1361, 1324, 1252, 1205, 1162, 1092, 1064, 1026,
(
2a) (122.5 mg, 0.6 mmol, 300 mol %) was added DCE (1 mL).
-
1
8
67, 848 cm ; HRMS (quadrupole, EI) calcd for C14
H
10
N
2
O
2
o
The reaction mixture was allowed to stir for 20 h at 40 C.
The reaction mixture was diluted with EtOAc (2 mL) and
concentrated in vacuo. The residue was purified by flash col-
umn chromatography (EtOAc/n-hexanes = 1:1 to 1.5:1) to af-
ford 3a (72.2 mg) in 96% yield.
+
[
M] 238.0742, found 238.0737.
2
-(2-Fluorophenyl)-2,3-dihydrophthalazine-1,4-dione
(1j):
.717 g (40%); white solid; mp = 250.2–253.1 C; H NMR (400
OD) δ 8.36 (dd, J = 7.6, 0.4 Hz, 1H), 8.14 (d, J = 8.0
o
1
0
MHz, CD
3
Hz, 1H), 8.01–7.90 (m, 2H), 7.55 (td, J = 7.6, 1.5 Hz, 1H), 7.50–
Ethyl
(S)-2-(4-chloro-2-(1,4-dioxo-3,4-dihydrophthalazin-
7.46 (m, 1H), 7.34–7.26 (m, 2H); 13C{ H} NMR (100 MHz,
1
2
(1H)-yl)phenyl)-2-hydroxyacetate (3a): 72.2 mg (96%); light
pink solid; mp = 88.2–91.4 C; H NMR (400 MHz, CD OD) δ
3
CD
3
OD) δ 160.1, 158.8 (d, JC-F = 249.7 Hz), 153.1, 135.0, 133.7,
31.4 (d, JC-F = 7.8 Hz), 130.8 (d, JC-F = 12.8 Hz), 130.4, 130.0,
27.9, 126.6, 125.8, 125.7 (d, JC-F = 3.8 Hz), 117.4 (d, JC-F = 19.9
o
1
1
1
8.37 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.98 (t, J = 7.2
Hz, 1H), 7.94–7.90 (m, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.51 (d, J =
Hz); IR (KBr) υ 3839, 3066, 1642, 1573, 1552, 1496, 1457, 1371,
8
.4 Hz, 1H), 7.48 (s, 1H), 5.33 (s, 1H), 4.03–3.95 (m, 1H), 3.88–
-
1
1
343, 1322, 1238, 1213, 1109, 1093, 1060, 1024, 883, 802 cm ;
13
1
3
.80 (m, 1H), 0.97 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz,
CD OD) δ 173.3, 160.6, 153.4, 141.7, 136.6, 135.1, 135.0, 133.7,
30.5, 130.3, 130.1, 129.7, 128.0, 126.8, 125.9, 70.2, 62.6, 14.0; IR
+
HRMS (quadrupole, EI) calcd for C14
H
9
FN
2
O
2
[M] 256.0648,
3
found 256.0643.
1
2
-(o-Tolyl)-2,3-dihydrophthalazine-1,4-dione (1k): 0.759 g
(KBr) υ 2394, 1746, 1714, 1696, 1644, 1583, 1559, 1528, 1498, 1457,
o
1
-1
(
43%); light yellow solid; mp = 211.7–214.5 C; H NMR (400
1327, 1091, 1024 cm ; HRMS (orbitrap, ESI) calcd for
+
MHz, CD
3
OD) δ 8.37 (dd, J = 8.0, 0.8 Hz, 1H), 8.16 (d, J = 8.0
C
18
H
15ClN
2
O
5
Na [M+Na] 397.0564, found 397.0562.
Ethyl (S)-2-(2-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-4-
methylphenyl)-2-hydroxyacetate (3b): 70.2 mg (99%); white
Hz, 1H), 8.01–7.90 (m, 2H), 7.37–7.33 (m, 4H), 2.18 (s, 3H);
1
3
1
C{ H} NMR (175 MHz, DMSO-d
6
) δ 157.0, 150.3, 140.9, 134.9,
1
33.5, 132.5, 130.4, 129.0, 128.3, 127.9, 126.7, 126.5, 124.8, 124.3,
o
1
3
solid; mp = 184.1–187.3 C; H NMR (700 MHz, CD OD) δ
ACS Paragon Plus Environment

Page 7 of 15
The Journal of Organic Chemistry
1
2
3
4
-
1
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
8.37–8.35 (m, 1H), 8.13 (d, J = 4.8 Hz, 1H), 7.96 (td, J = 7.7, 1.3
Hz, 1H), 7.91 (td, J = 7.7, 1.2 Hz, 1H), 7.58 (d, J = 4.8 Hz, 1H),
.31 (d, J = 4.8 Hz, 1H), 7.22 (s, 1H), 5.26 (s, 1H), 4.02–3.98 (m,
1497, 1424, 1326, 1268, 739 cm ; HRMS (orbitrap, ESI) calcd
+
for C18
Ethyl
2(1H)-yl)phenyl)-2-hydroxyacetate (3g): 63.8 mg (85%); white
H
15FN
2
O
5
Na [M+Na] 381.0857, found 381.0857.
7
(S)-2-(5-chloro-2-(1,4-dioxo-3,4-dihydrophthalazin-
1
H), 3.88–3.83 (m, 1H), 2.39 (s, 3H), 0.99 (t, J = 4.4 Hz, 3H);
1
3
1
C{ H} NMR (175 MHz, CD
3
OD) δ 173.8, 160.6, 153.2, 140.7,
o
1
solid; mp = 100.6–103.8 C; H NMR (500 MHz, CD
.36 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 7.3 Hz, 1H), 7.98 (td, J = 7.7,
.4 Hz, 1H), 7.92 (td, J = 7.6, 1.3 Hz, 1H), 7.76 (d, J = 2.4 Hz,
H), 7.48 (dd, J = 8.4, 2.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 5.35
s, 1H), 4.01 (dq, J = 10.7, 7.1 Hz, 1H), 3.93–3.74 (m, 1H), 0.96 (t,
J = 7.1 Hz, 3H); C{ H} NMR (125 MHz, CD OD) δ 173.1, 160.5,
3
153.3, 139.7, 139.2, 135.7, 135.0, 133.7, 131.3, 130.3, 130.0, 128.9,
128.0, 126.7, 125.8, 70.2, 62.7, 14.0; IR (KBr) υ 2378, 1735, 1694,
3
OD) δ
1
1
1
40.4, 134.9, 134.5, 133.7, 130.8, 130.4, 130.1, 129.3, 128.0, 126.7,
25.8, 70.6, 62.4, 20.9, 14.0; IR (KBr) υ 2455, 1714, 1588, 1507,
8
1
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
268, 1193, 1059, 1024, 794 cm ; HRMS (orbitrap, ESI) calcd for
+
C
19
H
18
N
2
O
5
Na [M+Na] 377.1108, found 377.1108.
(
13
1
Ethyl (S)-2-(2-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-4-
(trifluoromethyl)phenyl)-2-hydroxyacetate (3c): 65.2 mg
o
1
(80%); yellow solid; mp = 162.5–165.6 C; H NMR (500 MHz,
CD OD) δ 8.38 (d, J = 7.9 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1H),
.05–7.90 (m, 3H), 7.81 (dd, J = 8.3, 1.4 Hz, 1H), 7.77 (s, 1H),
.45 (s, 1H), 4.01 (dq, J = 10.8, 7.2 Hz, 1H), 3.85 (dq, J = 10.7, 7.1
-
1
3
1661, 1559, 1497, 1488, 1446, 1270, 1092, 781 cm ; HRMS (or-
+
8
bitrap, ESI) calcd for C18
H
15ClN
2
O
5
Na [M+Na] 397.0561,
5
found 397.0562.
1
3
1
Hz, 1H), 0.96 (t, J = 7.1 Hz, 3H); C{ H} NMR (125 MHz,
CD OD) δ 172.9, 160.6, 153.4, 142.0, 141.2, 135.1, 133.8, 132.1 (q,
C-F = 33.3 Hz), 130.3, 129.9, 128.1, 126.9 (q, JC-F = 3.7 Hz), 126.7,
26.6 (q, JC-F = 3.6 Hz), 125.9, 125.1 (q, JC-F = 269.8 Hz), 70.4,
Ethyl (S)-2-(2-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-5-
trifluoromethyl)phenyl)-2-hydroxyacetate (3h): 77.6 mg
95%); orange solid; mp = 180.7–183.5 C; H NMR (500 MHz,
OD) δ 8.36 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H),
.09 (d, J = 1.6 Hz, 1H), 7.98 (td, J = 7.7, 1.3 Hz, 1H), 7.92 (td, J
7.7, 1.2 Hz, 1H), 7.78 (dd, J = 8.3, 2.0 Hz, 1H), 7.63 (d, J = 8.2
Hz, 1H), 5.46 (s, 1H), 3.98 (dq, J = 10.8, 7.1 Hz, 1H), 3.83 (dq, J
= 10.8, 7.1 Hz, 1H), 0.93 (t, J = 7.1 Hz, 3H); C{ H} NMR (125
MHz, CD OD) δ 172.9, 160.5, 153.3, 143.7, 139.1, 135.1, 133.8,
131.9 (q, JC-F = 32.7 Hz), 130.7, 130.2, 127.1, 126.9 (q, JC-F = 271.0
Hz), 126.8 (q, JC-F = 3.5 Hz), 126.6, 126.4, 126.0 (q, JC-F = 3.5 Hz),
70.2, 62.7, 13.9; F NMR (470 MHz, CD
3
(
(
J
1
6
o
1
CD
3
19
3
2.3, 13.9; F NMR (470 MHz, CD OD) δ −64.5; IR (KBr) υ
8
=
2395, 1746, 1713, 1645, 1590, 1458, 1424, 1328, 1269, 1170, 1075,
-
1
1024, 943 cm ; HRMS (orbitrap, ESI) calcd for
+
C
19
H
15
3
F N
2
O
5
Na [M+Na] 431.0827, found 431.0825.
13
1
Ethyl
(S)-2-(2-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-
3
4
,5-dimethylphenyl)-2-hydroxyacetate (3d): 59.3 mg (81%);
orange sticky oil; H NMR (700 MHz, CD
1
3
OD) δ 8.36 (ddd, J =
19
7
.9, 1.3, 0.6 Hz, 1H), 8.14 (ddd, J = 7.9, 1.3, 0.6 Hz, 1H), 7.96 (td,
J = 7.7, 1.3 Hz, 1H), 7.91 (td, J = 7.6, 1.3 Hz, 1H), 7.45 (s, 1H),
.17 (s, 1H), 5.23 (s, 1H), 4.00 (dq, J = 10.8, 7.1 Hz, 1H), 3.90–
.82 (m, 1H), 2.34 (s, 3H), 2.30 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H);
3
OD) δ −64.5; IR (KBr)
υ 2384, 1724, 1717, 1554, 1434, 1388, 1328, 1275, 1221, 1128, 1085,
741 cm ; HRMS (orbitrap, ESI) calcd for C19
409.1006, found 409.1006.
-1
+
7
16 3 2 5
H F N O [M+H]
3
13
1
3
C{ H} NMR (175 MHz, CD OD) δ 173.9, 160.6, 153.3, 139.1,
Ethyl
(S)-2-(2-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-
yl)phenyl)-2-hydroxyacetate (3i): 66.8 mg (98%); white solid;
mp = 176.2–179.2 C; H NMR (400 MHz, CDCl ) δ 8.42 (dd, J
3
= 7.6, 1.3 Hz, 1H), 7.99 (dd, J = 8.0, 0.8 Hz, 1H), 7.88–7.74 (m,
2H), 7.54 (dd, J = 5.9, 3.4 Hz, 1H), 7.43 (dq, J = 7.2, 3.9 Hz, 2H),
7.35 (dd, J = 6.0, 3.3 Hz, 1H), 5.22 (s, 1H), 4.05–3.95 (m, 1H),
3.95–3.85 (m, 1H), 0.99 (t, J = 7.1 Hz, 3H); C{ H} NMR (100
MHz, CDCl ) δ 172.3, 159.0, 152.6, 138.2, 136.0, 133.7, 133.1, 129.8,
129.7, 129.6, 129.3, 128.7, 127.7, 125.2, 70.5, 61.9, 13.7; IR (KBr) υ
139.0, 138.1, 134.8, 134.5, 133.7, 130.5, 130.4, 128.1, 126.8, 125.8,
70.7, 62.4, 49.9, 19.6, 19.4, 14.1; IR (KBr) υ 2427, 1745, 1715, 1636,
o
1
-
1
1
578, 1564, 1540, 1508, 1458, 1396, 1265, 1076, 1020, 730 cm ;
+
HRMS (orbitrap, ESI) calcd for C20
H
N
21 2
O
5
[M+H] 369.1445,
found 369.1445.
13
1
Ethyl (S)-2-(2-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-5-
methylphenyl)-2-hydroxyacetate (3e): 67.4 mg (95%); light
3
o
1
yellow solid; mp = 107.1–110.3 C; H NMR (700 MHz, CD
3
OD)
-
1
δ 8.36 (d, J = 7.3 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.96 (td, J =
2432, 1714, 1685, 1607, 1552, 1502, 1325, 1228, 1028, 741 cm ;
HRMS (orbitrap, ESI) calcd for C18
+
7
7
.7, 1.3 Hz, 1H), 7.91 (td, J = 7.8, 1.2 Hz, 1H), 7.53 (s, 1H), 7.31–
.25 (m, 2H), 5.28 (s, 1H), 4.01 (dq, J = 10.8, 7.1 Hz, 1H), 3.86
H
17
2
N O
5
[M+H] 341.1132,
found 341.1129.
(dd, J = 10.7, 7.1 Hz, 1H), 2.43 (s, 3H), 0.99 (t, J = 7.1 Hz, 3H);
Ethyl (S)-2-(2-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-3-
fluorophenyl)-2-hydroxyacetate (3j): 59.5 mg (83%, 1.4:1 mix-
ture of rotamers); white solid; mp = 85.3–88.5 C; H NMR
(500 MHz, CD OD) δ 8.37 (dt, J = 8.0, 1.4 Hz, 1.7H), 8.15 (d, J
= 7.5 Hz, 1.7H), 8.01–7.97 (m, 1.8H), 7.95–7.91 (m, 1.8H), 7.58–
.49 (m, 3.7H), 7.29 (dddd, J = 11.0, 9.6, 8.2, 1.4 Hz, 1.7H), 5.44
(s, 1H), 5.21 (s, 0.7H), 4.09–4.04 (m, 0.8H), 4.02–3.98 (m, 1H),
3.97–3.91 (m, 0.7H), 1.07 (t, J = 7.0 Hz, 2.2H), 0.92 (t, J = 7.0
3
Hz, 3H); C{ H} NMR (125 MHz, CD OD) δ 173.2, 173.1, 160.7,
159.4 (d, JC-F = 246.4 Hz), 159.2 (d, JC-F = 248.9 Hz), 153.6, 153.5,
140.5, 140.1, 135.2, 135.0, 133.8, 133.7, 131.6 (d, JC-F = 8.6 Hz), 131.5
(d, JC-F = 8.6 Hz), 130.2, 129.9, 128.0, 127.9, 126.8 (d, JC-F = 1.5
Hz), 126.7 (d, JC-F = 1.0 Hz), 126.0, 125.9, 124.9 (d, JC-F = 3.3 Hz),
124.3 (d, JC-F = 3.4 Hz), 117.2 (d, JC-F = 20.4 Hz), 116.8 (d, JC-F
20.3 Hz), 70.9 (d, JC-F = 2.5 Hz), 69.6 (d, JC-F = 2.3 Hz), 62.7,
13
1
C{ H} NMR (175 MHz, CD
3
OD) δ 173.7, 160.6, 153.2, 140.5,
138.1, 137.1, 134.8, 133.7, 130.8, 130.4, 129.8, 129.5, 128.0, 126.7,
o
1
1
1
C
25.8, 70.7, 62.4, 21.3, 14.0; IR (KBr) υ 2352, 1728, 1558, 1498,
3
-1
385, 1328, 1296, 742 cm ; HRMS (orbitrap, ESI) calcd for
+
19
H
19
N
2
O
5
[M+H] 355.1289, found 355.1286.
7
Ethyl (S)-2-(2-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-5-
fluorophenyl)-2-hydroxyacetate (3f): 69.5 mg (97%); white
o
1
13
1
solid; mp = 190.8–193.9 C; H NMR (700 MHz, DMSO-d
6
) δ
1
7
2
1.89 (s, 1H), 8.28 (d, J = 7.7 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H),
.99 (td, J = 7.6, 1.2 Hz, 1H), 7.96–7.92 (m, 1H), 7.52–7.42 (m,
H), 7.30 (td, J = 8.3, 3.0 Hz, 1H), 6.40 (brs, 1H), 5.21 (brs, 1H),
3.92–3.80 (m, 1H), 3.75–3.60 (m, 1H), 0.79 (t, J = 7.1 Hz, 3H);
1
3
1
C{ H} NMR (100 MHz, CD
Hz), 160.6, 153.2, 140.5 (d, JC-F = 8.1 Hz), 136.6, 135.0, 133.7, 131.7
d, JC-F = 8.8 Hz), 130.4, 128.0, 126.7, 125.8, 116.7 (d, JC-F = 23.1
Hz), 115.5 (d, JC-F = 24.4 Hz), 70.2, 62.6, 13.9; 19F NMR (470
MHz, CD OD) δ −114.4; IR (KBr) υ 2372, 1736, 1711, 1654, 1559,
3
OD) δ 173.1, 163.9 (d, JC-F = 245.5
=
19
(
62.6, 14.1, 13.9; F NMR (470 MHz, CD
IR (KBr) υ 2362, 1725, 1711, 1602, 1558, 1473, 1328, 1266, 1105,
3
OD) δ −123.2, −123.7;
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 15
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
1
1095 cm ; HRMS (orbitrap, ESI) calcd for C18
[
H
15FN
2
O
5
Na
(brs, 1H), 8.32 (brs, 1H), 8.15–7.82 (m, 6H), 7.66–7.21 (m, 5H),
+
13
1
M+Na] 381.0858, found 381.0857.
6.03 (s, 1H), 5.29 (d, J = 4.5 Hz, 1H); C{ H} NMR (100 MHz,
CDCl ) δ 159.5, 152.3, 151.1, 147.6, 140.7, 134.5 (two carbons
3
Ethyl (S)-2-(2-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-3-
methylphenyl)-2-hydroxyacetate (3k): 29.8 mg (42%, 1.9:1
mixture of rotamers); white solid; mp = 199.8–202.8 C; H
NMR (700 MHz, CD OD) δ 8.38 (dddd, J = 7.9, 3.9, 1.2, 0.5 Hz,
.5H), 8.18–8.16 (m, 1.5H), 8.00 (tdd, J = 8.0, 4.4, 1.3 Hz, 1.5H),
.94 (tdd, J = 7.4, 4.2, 1.3 Hz, 1.5H), 7.55 (d, J = 7.0 Hz, 0.5H),
.51 (d, J = 7.7 Hz, 1H), 7.42 (td, J = 7.7, 3.4 Hz, 1.6H), 7.37–
.36 (m, 1.5H), 5.22 (s, 0.5H), 5.11 (s, 1H), 4.09–4.05 (m, 1H),
4.04–4.01 (m, 0.5H), 4.09–4.05 (m, 1H), 3.95 (dq, J = 10.8, 7.1
Hz, 1H), 3.84 (dq, J = 10.7, 7.1 Hz, 0.5H), 2.14 (s, 4.9H), 1.08 (t,
J = 7.0 Hz, 3H), 0.97 (t, J = 7.0 Hz, 1.6H); 13C{ H} NMR (175
overlapped), 133.4, 130.3, 129.8 (two carbons overlapped),
129.5, 128.4, 128.1, 127.9, 125.9, 125.2, 123.7, 79.3; IR (KBr) υ 2397,
o
1
-
1
1
(
746, 1713, 1660, 1558, 1540, 1402, 1350, 1223, 1131 cm ; HRMS
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
orbitrap, ESI) calcd for C21
H
16
N
3
O
5
[M+H] 390.1085, found
1
3
90.1087.
7
7
7
Methyl
(R)-4-((2-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-
yl)phenyl)(hydroxy)methyl)benzoate (3p): 40.9 mg (51%);
o
1
white solid; mp = 132.4–135.4 C; H NMR (400 MHz,
CD COCD ) δ 8.33 (brs, 1H), 8.08 (d, J = 7.7 Hz, 1H), 8.03–
7.86 (m, 3H), 7.76 (brs, 2H), 7.51 (brs, 1H), 7.47–7.37 (m, 3H),
3
3
1
13
1
MHz, CD
3
OD) δ 173.7, 173.6, 160.6, 160.0, 153.7, 153.6, 139.5,
7.34 (d, J = 8.1 Hz, 2H), 5.98 (s, 1H), 3.82 (s, 3H); C{ H} NMR
(100 MHz, CD COCD ) δ 167.1, 159.6, 151.2, 149.9, 140.9, 134.4,
1
1
1
39.3, 138.1, 137.8, 137.6, 137.5, 135.0, 134.9, 133.8, 133.7, 132.0,
31.9, 130.5, 130.4, 130.3, 130.2, 128.1, 127.2, 126.9, 126.7, 125.9,
25.8, 122.1, 120.3, 71.2, 70.6, 62.5, 62.4, 17.7, 17.6, 14.1, 14.0; IR
KBr) υ 2335, 1741, 1725, 1575, 1498, 1368, 1267, 1198, 1092, 1024,
19 2 5
73 cm ; HRMS (orbitrap, ESI) calcd for C19H N O [M+H]
3
3
133.3, 130.4, 129.8 (two carbons overlapped), 129.7, 129.6, 129.2
(two carbons overlapped), 128.0, 127.5 (two carbons over-
lapped), 125.9, 125.2, 79.3, 52.2; IR (KBr) υ 2372, 1748, 1720,
1669, 1644, 1576, 1540, 1496, 1436, 1367, 1280, 1208, 1108, 1017
(
8
-1
+
-1
+
3
55.1289, found 355.1288.
cm ; HRMS (orbitrap, ESI) calcd for C23
H
19
N
2
O
5
[M+H]
403.1289, found 403.1288.
Ethyl (S)-2-hydroxy-2-(2-(8-nitro-1,4-dioxo-3,4-
dihydrophthalazin-2(1H)-yl)phenyl)acetate (3l): 53.2 mg
(69%); green liquid; H NMR (500 MHz, CD
= 7.8, 1.3 Hz, 1H), 8.09 (dd, J = 7.8, 1.3 Hz, 1H), 8.05 (t, J = 7.8
Hz, 1H), 7.73 (dd, J = 7.3, 1.9 Hz, 1H), 7.51 (dtd, J = 14.4, 7.3, 1.7
Hz, 2H), 7.44 (dd, J = 7.6, 1.6 Hz, 1H), 5.33 (s, 1H), 4.05 (dq, J =
0.8, 7.1 Hz, 1H), 3.95–3.85 (m, 1H), 1.03 (t, J = 7.1 Hz, 3H);
C{ H} NMR (125 MHz, CD
37.4, 134.3, 132.1, 130.8, 130.4, 130.3, 129.5, 129.2, 128.7, 124.3,
17.6, 70.6, 62.6, 14.1; IR (KBr) υ 2371, 1746, 1713, 1659, 1644,
558, 1457, 1375, 1281, 1198, 1130, 1071 cm ; HRMS (orbitrap,
ESI) calcd for C18
408.0806.
(R)-2-(2-(Hydroxy(4-
(trifluoromethyl)phenyl)methyl)phenyl)-2,3-
1
3
OD) δ 8.58 (dd, J
dihydrophthalazine-1,4-dione (3q): 25.6 mg (31%); light brown
o
1
3 3
solid; mp = 219.2–221.1 C; H NMR (500 MHz, CD COCD ) δ
10.32 (brs, 1H), 8.42–8.22 (m, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.98
1
(t, J = 7.3 Hz, 1H), 7.94–7.86 (m, 1H), 7.69–7.51 (m, 2H), 7.50–
1
3
1
13
1
3
OD) δ 173.6, 149.2, 148.4, 140.1,
7.10 (m, 6H), 6.02 (s, 1H), 5.17 (brs, 1H); C{ H} NMR (125
MHz, CD COCD ) δ 159.6, 151.3, 146.1, 140.9, 134.4, 133.3, 131.4,
1
1
1
3
3
130.6 (q, JC-F = 36.6 Hz), 130.3, 129.7 (two carbons overlapped),
129.6, 129.3 (two carbons overlapped), 127.9 (two carbons
overlapped), 125.9, 125.3 (q, JC-F = 270.1 Hz), 125.2, 124.3 (q, JC-F
-1
15 3 7
H N NaO
[M+Na]+ 408.0802, found
19
= 3.6 Hz), 123.7, 71.2; F NMR (470 MHz, CD
3
OD) δ −63.5; IR
(
KBr) υ 2485, 1749, 1714, 1659, 1650, 1558, 1539, 1449, 1377, 1327,
Ethyl
(S)-2-(2-(1,4-dioxo-3,4-dihydrobenzo[g]phthalazin-
-
1
1
223, 1165, 1074 cm ; HRMS (orbitrap, ESI) calcd for
2(1H)-yl)phenyl)-2-hydroxyacetate (3m): 56.2 mg (72%); white
solid; mp = 241.5–244.4 C; H NMR (400 MHz, DMSO-d
1.92 (brs, 1H), 8.97 (s, 1H), 8.70 (s, 1H), 8.37–8.33 (m, 2H),
.82–7.77 (m, 2H), 7.74–7.71 (m, 1H), 7.52–7.43 (m, 3H), 6.15
+
o
1
C
22
H
16
3
F N
2
O
3
[M+H] 413.1108, found 413.11068.
6
) δ
1
7
(R)-2-(2-(Hydroxy(3-nitrophenyl)methyl)phenyl)-2,3-
dihydrophthalazine-1,4-dione (3r): 46.7 mg (60%); white solid;
o
1
(
0
brs, 1H), 5.27 (s, 1H), 3.89–3.81 (m, 1H), 3.74–3.66 (m, 1H),
3 3
mp = 246.7–249.6 C; H NMR (400 MHz, CD COCD ) δ 8.29
13
1
.78 (t,
J
=
9.0 Hz, 3H); C{ H} NMR (175 MHz,
(s, 1H), 8.06–8.04 (m, 2H), 7.97–7.89 (m, 3H), 7.62 (d, J = 6.8
Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.50–7.44 (m, 2H), 7.41–7.35
CDCl
3
+CD
3
OD) δ 172.2, 159.3, 153.2, 138.5, 136.1, 134.9, 134.5,
13
1
1
29.4, 129.3, 129.2, 128.9, 128.8, 128.6, 128.5, 126.1, 124.6, 121.7,
120.7, 118.1, 69.7, 61.6, 30.4; IR (KBr) υ 2821, 1749, 1649, 1622,
1482, 1407, 1389, 1288, 1211, 1191, 933 cm ; HRMS (orbitrap,
ESI) calcd for C22
Ethyl
yl)phenyl)-2-hydroxyacetate (3n): 56.2 mg (97%); off white
solid; mp = 80.5–83.4 C; H NMR (400 MHz, CD
.67 (m, 1H), 7.54–7.43 (m, 2H), 7.36–7.28 (m, 1H), 7.23 (d, J =
3 3
(m, 2H), 6.04 (s, 1H); C{ H} NMR (175 MHz, CD COCD ) δ
161.6, 154.7, 151.9, 148.8, 147.1, 141.7, 141.1, 134.3, 133.9, 133.2,
130.4, 129.9, 129.7, 129.5, 128.7, 127.9, 125.4, 122.5, 121.9, 116.8,
49.8; IR (KBr) υ 2050, 1712, 1700, 1507, 1447, 1411, 1369, 1331,
-1
+
H
18
N
2
NaO
5
[M+Na] 413.1108, found 413.1108.
-
1
1
C
268, 1194, 1072 cm ; HRMS (orbitrap, ESI) calcd for
(S)-2-(2-(3,6-dioxo-3,6-dihydropyridazin-1(2H)-
+
21
H
15
N
3
NaO
5
[M+Na] 412.0904, found 412.0906.
o
1
3
OD) δ 7.73–
(R)-2-(2-((3-Bromo-5-nitrophenyl)(hydroxy)methyl)phenyl)-
2,3-dihydrophthalazine-1,4-dione (3s): 79.5 mg (85%); white
7
9
o
1
.8 Hz, 1H), 7.06 (d, J = 9.8 Hz, 1H), 5.26 (s, 1H), 4.11 (dq, J =
0.8, 7.2 Hz, 1H), 3.97 (dq, J = 10.8, 7.1 Hz, 1H), 1.15 (t, J = 7.1
3 3
solid; mp = 229.6–232.9 C; H NMR (400 MHz, CD COCD ) δ
1
8.30 (d, J = 5.6 Hz, 1H), 8.06–8.05 (m, 2H), 8.01–7.91 (m, 3H),
7.71 (d, J = 7.2 Hz, 1H), 7.67 (s, 1H), 7.52 (p, J = 7.0 Hz, 2H),
13
1
Hz, 3H); C{ H} NMR (100 MHz, CD
3
OD) δ 173.5, 161.2, 155.3,
40.6, 137.1, 134.4, 130.4, 130.2, 129.6, 129.3, 129.2, 70.5, 62.5,
4.2; IR (KBr) υ 2376, 1735, 1681, 1576, 1540, 1457, 1412, 1263,
13
1
1
7.41 (d, J = 7.2 Hz, 1H), 6.04 (s, 1H); C{ H} NMR (100 MHz,
1
CD COCD ) δ 151.4, 149.4, 149.2, 146.7, 140.8, 136.4, 136.3, 134.5,
3
3
-1
1109, 1076, 1028, 846 cm ; HRMS (orbitrap, ESI) calcd for
133.5, 130.2, 130.0, 129.9, 129.8, 129.7, 127.9, 125.8, 125.4, 122.7,
121.2, 121.1, 49.8; IR (KBr) υ 2474, 1713, 1702, 1682, 1613, 1556,
+
C
14
H
15
N
2
O
5
[M+H] 291.0976, found 291.0976.
-
1
1
C
532, 1506, 1457, 1347, 1210 cm ; HRMS (orbitrap, ESI) calcd for
(R)-2-(2-(Hydroxy(4-nitrophenyl)methyl)phenyl)-2,3-
dihydrophthalazine-1,4-dione (3o): 55.3 mg (71%); white solid;
mp = 213.1–216.2 C; H NMR (400 MHz, CD COCD ) δ 10.27
3 3
+
21
H
14BrN
3
NaO
5
[M+Na] 490.0009, found 490.0005.
o
1
ACS Paragon Plus Environment

Page 9 of 15
The Journal of Organic Chemistry
1
2
3
4
5
+
2-(2-(Hydroxymethyl)phenyl)-2,3-dihydrophthalazine-1,4-
HRMS (orbitrap, ESI) calcd for C19
found 337.1180.
17 2 4
H N O [M+H] 337.1183,
1
dione (3t): 22.8 mg (42%); yellow liquid; H NMR (500 MHz,
CD OD) δ 8.37–8.35 (m, 1H), 8.15–8.14 (m, 1H), 7.98 (td, J =
.7, 1.4 Hz, 1H), 7.92 (td, J = 7.6, 1.3 Hz, 1H), 7.66 (d, J = 7.0 Hz,
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
Ethyl
(S)-6,11-dioxo-3-(trifluoromethyl)-6,11-dihydro-13H-
indazolo[1,2-b]phthalazine-13-carboxylate (6c): 71.8 mg (92%);
white solid; mp = 194.6–197.3 C; H NMR (700 MHz, CDCl
δ 8.70 (s, 1H), 8.47–8.45 (m, 1H), 8.40–8.38 (m, 1H), 7.93–7.89
7
1
7
H), 7.49 (td, J = 7.5, 1.4 Hz, 1H), 7.43 (td, J = 7.6, 1.5 Hz, 1H),
o
1
3
)
.38 (dd, J = 7.8, 1.3 Hz, 1H), 4.54 (s, 2H); 13C{ H} NMR (175
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MHz, CD
3
OD) δ 160.3, 153.2, 140.4, 139.6, 134.9, 133.7, 130.3,
(
6
m, 2H), 7.69 (d, J = 7.7 Hz, 1H), 7.58 (dd, J = 7.7, 0.7 Hz, 1H),
1
29.9, 129.1, 129.0, 128.8, 127.9, 126.7, 125.8, 61.1; 19F NMR (470
13
1
.24 (s, 1H), 4.36–4.28 (m, 2H), 1.31 (t, J = 7.0 Hz, 3H); C{ H}
) δ 165.1, 155.1, 154.8, 137.4, 134.1, 134.0,
33.2 (q, JC-F = 32.9 Hz), 129.7, 128.2, 127.9, 127.7, 125.5, 123.7,
123.4 (q, JC-F = 271.3 Hz), 123.2 (q, JC-F = 3.9 Hz), 113.2 (q, JC-F
3.9 Hz), 63.1, 62.7, 14.1; 19F NMR (470 MHz, CDCl
) δ −62.9; IR
3
MHz, CD OD) δ −72.4, −73.1, −79.1; IR (KBr) υ 2519, 1756, 1714,
NMR (175 MHz, CDCl
3
-
1
1660, 1607, 1558, 1507, 1457, 1400, 1222 cm ; HRMS (orbitrap,
1
+
ESI) calcd for C15
H
13
N
2
O
3
[M+H] 269.0921, found 269.0920.
=
Ethyl
2-(2-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-
3
yl)phenyl)-3,3,3-trifluoro-2-hydroxypropanoate (3u): 53.2 mg
(KBr) υ 2372, 1761, 1750, 1655, 1646, 1445, 1380, 1324, 1264, 1205,
1173, 1124, 1023 cm ; HRMS (orbitrap, ESI) calcd for
o
1
-1
(
65%); Grey solid; mp = 177.5–180.3 C; H NMR (400 MHz,
DMSO-d ) δ 11.8 (brs, 1H), 8.25 (dd, J = 19.0, 7.5 Hz, 1H), 8.03–
.91 (m, 3H), 7.77 (brs, 1H), 7.62–7.59 (m, 2H), 7.49–7.47 (m,
+
6
C
19
H
F
14 3
2
N O
4
[M+H] 391.0900, found 391.0897.
7
1
Ethyl
(S)-2,3-dimethyl-6,11-dioxo-6,11-dihydro-13H-
indazolo[1,2-b]phthalazine-13-carboxylate (6d): 57.5 mg
82%); light orange solid; mp = 230.1–233.2 C; H NMR (700
MHz, CDCl ) δ 8.45–8.44 (m, 1H), 8.38–8.37 (m, 1H), 8.22 (s,
H), 7.87 (dtd, J = 20.2, 7.3, 1.4 Hz, 2H), 7.30 (s, 1H), 6.10 (s,
H), 4.32–4.25 (m, 2H), 2.35 (s, 3H), 2.31 (s, 3H), 1.29 (t, J = 7.0
Hz, 3H); C{ H} NMR (175 MHz, CDCl ) δ 166.2, 155.1, 154.2,
3
139.6, 135.3, 135.2, 133.7, 133.5, 130.2, 128.2, 127.7, 127.5, 123.6,
119.5, 116.9, 62.7, 62.6, 20.4, 19.9, 14.1; IR (KBr) υ 2396, 1750,
13
1
H), 7.28 (s, 1H), 3.94–3.75 (m, 2H), 1.04–0.96 (m, 3H); C{ H}
NMR (100 MHz, DMSO-d ) δ 166.8, 160.1, 150.0, 140.1, 134.1,
32.6, 132.5, 132.3, 131.2, 130.9, 130.6, 129.2, 128.0, 126.8, 126.6 (q,
6
o
1
(
1
J
3
19
C-F = 3.0 Hz), 124.3, 78.3, 62.1, 13.3; F NMR (470 MHz,
OD) δ −72.4, −73.1, −79.1; IR (KBr) υ 2619, 1758, 1711, 1664,
1604, 1578, 1501, 1459, 1389, 1367, 1291, 1217, 1189, 1139, 1099,
1
1
CD
3
13
1
-
1
1
C
025, 956, 918, 750 cm ; HRMS (orbitrap, ESI) calcd for
+
19
H
15
3
F N
2
NaO
5
[M+Na] 431.0825, found 431.0827.
-1
General procedure and characterization data for the synthe-
sis of indazolophthalazinones (6a–6t). To an oven-dried
sealed tube charged with ethyl (S)-2-(4-chloro-2-(1,4-dioxo-
,4-dihydrophthalazin-2(1H)-yl)phenyl)-2-hydroxyacetate
3a) (75.0 mg, 0.2 mmol, 100 mol %), diethyl azodicarbox-
ylate (41.8 mg, 0.24 mmol, 120 mol %) and tri-
phenylphosphine (157.4 mg, 0.6 mmol, 300 mol %) was add-
1653, 1644, 1603, 1576, 1385, 1330, 1281, 1206, 1194 cm ; HRMS
+
(orbitrap, ESI) calcd for C20
H
19
N
2
O
4
[M+H] 351.1340, found
351.1338.
3
(
Ethyl (S)-2-methyl-6,11-dioxo-6,11-dihydro-13H-indazolo[1,2-
b]phthalazine-13-carboxylate (6e): 57.2 mg (85%); white solid;
o
1
mp = 185.4–188.2 C; H NMR (700 MHz, CDCl
3
) δ 8.46–8.41
(
(
(
m, 1H), 8.40–8.34 (m, 1H), 8.26 (d, J = 8.3 Hz, 1H), 7.89–7.83
m, 2H), 7.35–7.34 (m, 1H), 7.30 (dt, J = 8.4, 0.7 Hz, 1H), 6.12
s, 1H), 4.35–4.23 (m, 2H), 2.41 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H);
C{ H} NMR (175 MHz, CDCl ) δ 166.0, 155.0, 154.1, 136.6, 134.9,
3
133.6, 133.5, 131.1, 130.2, 128.2, 127.7, 127.5, 123.4, 122.1, 115.8, 62.8,
62.7, 21.3, 14.1; IR (KBr) υ 2377, 1750, 1713, 1643, 1606, 1559, 1533,
508, 1490, 1458, 1372, 1222, 1131, 1024, 825 cm ; HRMS (or-
2
ed dichloromethane (1 mL) under N atmosphere. The reac-
tion mixture was allowed to stir for 12 h at room temperature.
The reaction mixture was diluted with EtOAc (2 mL) and
concentrated in vacuo. The residue was purified by flash col-
umn chromatography (n-hexanes/EtOAc = 4:1) to afford 6a
13
1
(
65.2 mg) in 91% yield.
-1
1
+
Ethyl (S)-3-chloro-6,11-dioxo-6,11-dihydro-13H-indazolo[1,2-
bitrap, ESI) calcd for C19
337.1182.
H
17
N
2
O
4
[M+H] 337.1183, found
b]phthalazine-13-carboxylate (6a): 65.2 mg (91%); white solid;
o
1
mp = 186.5–189.5 C; H NMR (700 MHz, CDCl
3
) δ 8.46–4.45
Ethyl (S)-2-fluoro-6,11-dioxo-6,11-dihydro-13H-indazolo[1,2-
b]phthalazine-13-carboxylate (6f): 65.6 mg (96%); white solid;
(
7
m, 2H), 8.45 (dd, J = 1.9, 0.8 Hz, 1H), 8.39–8.37 (m, 1H),
.92–7.88 (m, 2H), 7.48 (dd, J = 7.7, 0.7 Hz, 1H), 7.30 (dd, J =
o
1
mp = 158.9–161.6 C; H NMR (700 MHz, CDCl
3
) δ 8.45–8.44
8.1, 1.9 Hz, 1H), 6.14 (s, 1H), 4.33–4.27 (m, 2H), 1.30 (t, J = 7.0
(
7
m, 1H), 8.40 (dd, J = 8.9, 4.5 Hz, 1H), 8.38–8.37 (m, 1H),
.90–7.86 (m, 2H), 7.28 (ddd, J = 7.4, 2.5, 1.1 Hz, 1H), 7.22 (tdd,
J = 8.8, 2.6, 0.8 Hz, 1H), 6.16 (s, 1H), 4.35–4.28 (m, 2H), 1.32 (t,
Hz, 3H); 1 C{ H} NMR (175 MHz, CDCl
3
1
3
) δ 165.5, 155.1, 154.7,
137.8, 136.6, 134.0, 133.9, 129.8, 128.3, 127.9, 127.7, 126.4, 123..9,
20.4, 116.4, 62.9, 62.5, 14.1; IR (KBr) υ 2385, 1864, 1748, 1652,
636, 1604, 1560, 1527, 1457, 1382, 1204, 1128, 1024, 891 cm ;
1
1
13
1
J = 7.7 Hz, 3H); C{ H} NMR (175 MHz, CDCl
(d, JC-F = 246.0 Hz), 155.1, 154.3, 133.7 (d, JC-F = 18.4 Hz), 133.3
d, JC-F = 2.1 Hz), 129.9, 128.2, 127.8, 127.6, 123.7 (d, JC-F = 9.5
Hz), 117.6, 117.5 (d, JC-F = 3.9 Hz), 117.4, 110.7 (d, JC-F = 26.3 Hz),
3
) δ 165.3, 160.6
-
1
+
HRMS (orbitrap, ESI) calcd for
57.0637, found 357.0637.
Ethyl (S)-3-methyl-6,11-dioxo-6,11-dihydro-13H-indazolo[1,2-
b]phthalazine-13-carboxylate (6b): 60.7 mg (90%); white sol-
C
18
H
14ClN
2
O
4
[M+H]
(
3
19
3
63.0, 62.6 (d, JC-F = 2.5 Hz), 14.1; F NMR (470 MHz, CDCl ) δ
−114.2; IR (KBr) υ 2371, 1793, 1748, 1718, 1655, 1560, 1541, 1397,
1261, 1196, 1119, 1021, 1004, 959 cm ; HRMS (orbitrap, ESI)
o
1
-1
id; mp = 201.2–204.1 C; H NMR (700 MHz, CDCl
.45 (m, 1H), 8.39–8.38 (m, 1H), 8.27 (s, 1H), 7.90–7.85 (m,
H), 7.43 (d, J = 7.7 Hz, 1H), 7.13 (ddd, J = 7.8, 1.6, 0.8 Hz, 1H),
6.13 (s, 1H), 4.33–4.25 (m, 2H), 2.46 (s, 3H), 1.29 (t, J = 7.7 Hz,
3
) δ 8.47–
+
8
2
calcd for C18
H
14FN
2
O
4
[M+H] 341.0932, found 341.0929.
Ethyl (S)-2-chloro-6,11-dioxo-6,11-dihydro-13H-indazolo[1,2-
b]phthalazine-13-carboxylate (6g): 65.2 mg (91%); white solid;
mp = 160.4–163.2 C; H NMR (400 MHz, CDCl ) δ 8.46–8.43
3
(m, 1H), 8.39–8.37 (m, 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.92–7.86
(m, 2H), 7.54 (s, 1H), 7.50–7.48 (m, 1H), 6.16 (s, 1H), 4.33 (q, J
3H); 1 C{ H} NMR (175 MHz, CDCl
3
1
) δ 166.1, 155.1, 154.5, 141.2,
37.2, 133.7, 133.6, 130.2, 128.3, 127.8, 127.6, 127.1, 122.6, 119.3,
16.6, 62.7, 62.6, 21.8, 14.1; IR (KBr) υ 2392, 1758, 1649, 1575,
o
1
3
1
1
1
-
1
417, 1368, 1275, 1195, 1166, 1120, 1096, 1041, 1022, 998 cm ;
13
1
=
7.1 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 15
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CDCl
3
) δ 165.4, 155.1, 154.5, 135.6, 133.8, 133.9, 131.7, 130.8, 129.9,
3
CDCl ) δ 8.66 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 8.1 Hz, 1H), 8.01
1
2
28.2, 127.9, 127.7, 123.6, 123.4, 117.0, 63.1, 62.5, 14.1; IR (KBr) υ
365, 1754, 1714, 1649, 1606, 1507, 1466, 1409, 1367, 1325, 1275,
(t, J = 7.9 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.56 (q, J = 7.9 Hz,
2H), 7.37 (t, J = 7.6 Hz, 1H), 6.15 (s, 1H), 4.48–4.09 (m, 2H),
-1
13
1
1
C
168, 1126, 1022 cm ; HRMS (orbitrap, ESI) calcd for
1.30 (t, J = 7.1 Hz, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 165.2,
+
18
H
14ClN
2
O
4
[M+H] 357.0637, found 357.0636.
152.3, 150.8, 149.4, 136.5, 134.4, 131.7, 130.8, 130.3, 127.2, 127.0,
1
1
23.2, 122.0, 119.4, 116.2, 63.1, 63.0, 14.1; IR (KBr) υ 2392, 1747,
Ethyl
(S)-6,11-dioxo-2-(trifluoromethyl)-6,11-dihydro-13H-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
713, 1673, 1636, 1560, 1508, 1438, 1400, 1352, 1267, 1221 cm ;
indazolo[1,2-b]phthalazine-13-carboxylate (6h): 73.2 mg
+
o
1
HRMS (orbitrap, ESI) calcd for C18
390.0697, found 390.0697.
13 3 6
H N NaO [M+Na]
(
94%); white solid; mp = 161.7–164.5 C; H NMR (700 MHz,
CDCl ) δ 8.51 (d, J = 8.4 Hz, 1H), 8.47–8.46 (m, 1H), 8.41–8.39
m, 1H), 7.93–7.89 (m, 2H), 7.81 (s, 1H), 7.80–7.79 (m, 1H),
3
(
Ethyl (S)-6,13-dioxo-6,13-dihydro-15H-benzo[g]indazolo[1,2-
13
1
6.23 (s, 1H), 4.38–4.29 (m, 2H), 1.32 (t, J = 7.0 Hz, 3H); C{ H}
NMR (175 MHz, CDCl ) δ 165.3, 155.1, 155.0, 139.5, 134.2, 133.9,
128.5, 128.4, 128.3, 128.2 (q, JC-F = 13.3 Hz), 128.1, 128.0, 127.8,
23.5 (q, JC-F = 270.2 Hz), 120.5 (q, JC-F = 15.4 Hz), 116.1, 63.2,
2.6, 14.1; 19F NMR (470 MHz, CDCl
) δ −62.4; IR (KBr) υ 2340,
756, 1714, 1660, 1652, 1607, 1559, 1508, 1458, 1371, 1322, 1279,
b]phthalazine-15-carboxylate (6m): 69.9 mg (94%); light yel-
o
1
3
3
low solid; mp = 242.1–245.0 C; H NMR (500 MHz, CDCl ) δ
8.99 (s, 1H), 8.92 (s, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.16–8.11 (m,
2H), 7.74–7.71 (m, 2H), 7.57 (d, J = 7.5 Hz, 1H), 7.52 (t, J = 7.5
Hz, 1H), 7.31 (td, J = 7.3, 1.0 Hz, 1H), 4.36–4.26 (m, 2H), 1.31 (t,
1
6
3
13
1
1
1
3
J = 7.0 Hz, 3H); C{ H} NMR (125 MHz, CDCl ) δ 166.1, 155.7,
-1
202, 1165, 1065 cm ; HRMS (orbitrap, ESI) calcd for
155.1, 137.2, 134.9, 134.8, 130.5, 129.7, 129.6, 129.5, 129.4, 129.3,
126.1, 125.5, 123.8, 123.0, 121.9, 116.1, 62.7, 62.6, 14.1; IR (KBr) υ
+
C
19
H
14
3
F N
2
O
4
[M+H] 391.0900, found 391.0897.
2
922, 1749, 1656, 1623, 1603, 1465, 1388, 1288, 1210, 1186, 1022,
Ethyl
(S)-6,11-dioxo-6,11-dihydro-13H-indazolo[1,2-
-1
9
33 cm ; HRMS (orbitrap, ESI) calcd for C22
H
16
N
2
NaO
4
b]phthalazine-13-carboxylate (6i): 61.5 mg (95%); white solid;
mp = 183.1–186.2 C; H NMR (700 MHz, CDCl
+
o
1
[M+Na] 395.1002, found 395.1003.
3
) δ 8.48–8.46
(m, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.40–8.39 (m, 2H), 7.91–7.86
Ethyl
(S)-6,9-dioxo-6,9-dihydro-11H-pyridazino[1,2-
(m, 2H), 7.58–7.57 (m, 1H), 7.54–7.51 (m, 1H), 7.33 (td, J = 7.5,
1.0 Hz, 1H), 6.19 (s, 1H), 4.35–4.28 (m, 2H), 1.31 (t, J = 7.0 Hz,
a]indazole-11-carboxylate (6n): 39.5 mg (72%); yellow liquid;
1
3
H NMR (400 MHz, CDCl ) δ 8.31 (d, J = 8.2 Hz, 1H), 7.56 (d, J
1
3
1
3
H); C{ H} NMR (175 MHz, CDCl
3
) δ 165.9, 155.1, 154.6, 137.1,
= 7.6 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H),
7.08 (d, J = 10.3 Hz, 1H), 7.01 (d, J = 10.3 Hz, 1H), 6.04 (s, 1H),
1
1
1
33.7, 133.6, 130.6, 130.1, 128.3, 127.8, 127.6, 126.3, 123.0, 122.1,
16.1, 62.9, 62.8, 14.1; IR (KBr) υ 2466, 1752, 1693, 1680, 1655,
557, 1465, 1412, 1376, 1290, 1199, 1163, 1023 cm ; HRMS (or-
[M+H]+ 323.1027, found
13
1
4.38–4.20 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H); C{ H} NMR (100
MHz, CDCl ) δ 165.1, 154.0, 153.5, 136.6, 136.5, 133.8, 130.6,
-1
3
bitrap, ESI) calcd for C18
23.1023.
Ethyl (S)-4-fluoro-6,11-dioxo-6,11-dihydro-13H-indazolo[1,2-
b]phthalazine-13-carboxylate (6j): 61.1 mg (90%); light yellow
H
15
N
2
O
4
126.8, 123.0, 121.7, 115.8, 63.0, 62.9, 14.1; IR (KBr) υ 2478, 1744,
-1
3
1715, 1645, 1559, 1466, 1367, 1293, 1195, 1153, 1105, 1029, 843 cm ;
+
HRMS (orbitrap, ESI) calcd for C14
13 2 4
H N O [M+H] 273.0870,
found 273.0870.
o
1
solid; mp = 174.2–177.0 C; H NMR (700 MHz, CDCl
8.42 (m, 1H), 8.31–8.30 (m, 1H), 7.87–7.83 (m, 2H), 7.35 (dt, J =
7.3, 1.2 Hz, 1H), 7.30–7.25 (m, 2H), 6.15 (s, 1H), 4.31–4.23 (m,
2H), 1.26 (t, J = 7.0 Hz, 3H); C{ H} NMR (175 MHz, CDCl
3
) δ 8.43–
(R)-13-(4-Nitrophenyl)-13H-indazolo[1,2-b]phthalazine-6,11-
o
dione (6o): 57.2 mg (77%); yellow solid; mp = 230.1–233.0 C;
1
3
H NMR (400 MHz, CDCl ) δ 8.49 (dd, J = 13.0, 8.0 Hz, 2H),
13
1
3
) δ
8.25 (dd, J = 19.6, 8.1 Hz, 3H), 7.87 (dt, J = 19.9, 7.4 Hz, 2H),
7.54 (dd, J = 13.2, 8.3 Hz, 3H), 7.33–7.23 (m, 1H), 7.18 (d, J = 7.6
1
65.7, 155.8, 153.9, 148.5 (d, JC-F = 257.8 Hz), 133.8, 133.7, 130.0
13
1
(
d, JC-F = 2.5 Hz), 128.4, 128.2, 127.8 (d, JC-F = 6.7 Hz), 127.4,
3
Hz, 1H), 6.81 (s, 1H); C{ H} NMR (100 MHz, CDCl ) δ 155.2,
1
25.7 (d, JC-F = 2.5 Hz), 124.1 (d, JC-F = 12.8 Hz), 119.3 (d, JC-F
=
154.8, 148.0, 144.9, 136.3, 133.8 (two carbons overlapped), 130.3,
129.9, 128.4, 128.3 (two carbons overlapped), 127.8, 127.5, 126.9,
126.7, 124.3 (two carbons overlapped), 123.6, 116.1, 65.1; IR
(KBr) υ 2482, 1753, 1713, 1660, 1645, 1608, 1545, 1508, 1366, 1223,
2.0 Hz), 118.8 (d, JC-F = 17.7 Hz), 63.3, 62.8, 14.0; 1 F NMR (470
9
2
MHz, CDCl
542, 1509, 1452, 1437, 1384, 1319, 1263, 1205 cm ; HRMS (or-
3
) δ −106.9; IR (KBr) υ 2372, 1748, 1636, 1609, 1569,
-1
1
[M+H]+ 341.0932, found
1130 cm ; HRMS (orbitrap, ESI) calcd for C21
-1
H
[M+H]
+
bitrap, ESI) calcd for C18
341.0929.
H
14FN
2
O
4
14
N
3
O
4
372.0979, found 372.0978.
Ethyl (S)-4-methyl-6,11-dioxo-6,11-dihydro-13H-indazolo[1,2-
b]phthalazine-13-carboxylate (6k): 43.9 mg (65%); white sol-
Methyl
(R)-4-(6,11-dioxo-6,11-dihydro-13H-indazolo[1,2-
b]phthalazin-13-yl)benzoate (6p): 57.7 mg (75%); white solid;
o
1
o
1
id; mp = 162.5–165.4 C; H NMR (500 MHz, CDCl
.37 (m, 1H), 8.36–8.31 (m, 1H), 7.89–7.84 (m, 2H), 7.39 (d, J =
.4 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H),
.10 (s, 1H), 4.32–4.20 (m, 2H), 2.63 (s, 3H), 1.26 (t, J = 7.1 Hz,
3
) δ 8.43–
3
mp = 251.8–254.6 C; H NMR (400 MHz, CDCl ) δ 8.48 (dd, J
8
7
= 12.4, 8.0 Hz, 2H), 8.27 (d, J = 7.4 Hz, 1H), 8.02 (d, J = 8.2 Hz,
2H), 7.91–7.78 (m, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 8.2
Hz, 2H), 7.29–7.22 (m, 1H), 7.17 (d, J = 7.6 Hz, 1H), 6.76 (s, 1H),
6
1
3
1
13
1
3H); C{ H} NMR (175 MHz, CDCl
3
) δ 166.5, 156.7, 155.9, 136.3,
3
3.89 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 166.4, 155.0,
1
1
1
33.8, 133.7, 133.5, 130.8, 128.6, 128.0, 127.6, 127.4, 126.9, 124.2,
20.4, 63.4, 62.6, 22.6, 14.1; IR (KBr) υ 2447, 1746, 1714, 1660,
575, 1532, 1507, 1448, 1406, 1354, 1267, 1222, 1130 cm ; HRMS
154.8, 142.9, 136.2, 133.7, 133.6, 130.5, 130.3 (two carbons over-
lapped), 129.9, 129.8, 128.6, 127.8, 127.7, 127.5, 127.2 (two car-
bons overlapped), 126.5, 123.6, 116.0, 65.6, 52.2; IR (KBr) υ
2520, 1713, 1648, 1601, 1574, 1519, 1437, 1411, 1376, 1280, 1105, 1021
-1
+
(orbitrap, ESI) calcd for C19
337.1182.
H
17
N
2
O
4
[M+H] 337.1183, found
-1
+
cm ; HRMS (orbitrap, ESI) calcd for C23
07.1002, found 407.1005.
(R)-13-(4-(Trifluoromethyl)phenyl)-13H-indazolo[1,2-
b]phthalazine-6,11-dione (6q): 59.9 mg (76%); white solid; mp
16 2 4
H N NaO [M+Na]
4
Ethyl
(S)-4-methyl-7-nitro-6,11-dioxo-6,11-dihydro-13H-
indazolo[1,2-b]phthalazine-13-carboxylate (6l): 41.2 mg (54%);
light yellow solid; mp = 210.6–213.4 C; H NMR (400 MHz,
o
1
ACS Paragon Plus Environment

Page 11 of 15
The Journal of Organic Chemistry
1
2
3
4
o
1
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
= 208.3–211.2 C; H NMR (400 MHz, CDCl
1
3
) δ 8.49 (dd, J =
(S)-2-(2-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)phenyl)-2-
hydroxyacetate (3i) (68.1 mg, 0.2 mmol, 100 mol %) and
PhI(OAc) (128.8 mg, 0.4 mmol, 200 mol %) was added DCE
5.6, 7.9 Hz, 2H), 8.28 (d, J = 7.7 Hz, 1H), 7.86 (dq, J = 13.9, 6.9,
6
=
.5 Hz, 2H), 7.66–41 (m, 5H), 7.29 (d, J = 7.5 Hz, 1H), 7.18 (d, J
2
7.6 Hz, 1H), 6.78 (s, 1H); 13C{ H} NMR (100 MHz, CDCl
1
(1 mL). The reaction mixture was allowed to stir for 2 h at 40
3
) δ
o
1
1
J
1
55.2, 154.8, 139.2, 136.2, 133.7, 133.6, 131.3 (q, JC-F = 32.4 Hz),
30.8, 130.0, 129.9, 129.5, 128.7, 127.8, 127.6, 127.5, 126.6, 125.7 (q,
C-F = 3.8 Hz), 124.2 (q, JC-F = 3.9 Hz), 123.8 (q, JC-F = 270.9 Hz),
16.0, 65.5; F NMR (470 MHz, CDCl ) δ −62.9; IR (KBr) υ
3
2459, 1714, 1645, 1557, 1507, 1437, 1407, 1376, 1328, 1182 cm ;
C. The reaction mixture was diluted with EtOAc (3 mL) and
concentrated in vacuo. The residue was purified by flash col-
umn chromatography (n-hexanes/ EtOAc = 3:1) to afford 7a
(20.1 mg) in 30% yield.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
19
-
1
Ethyl
(S)-13-hydroxy-6,11-dioxo-6,11-dihydro-13H-
+
HRMS (orbitrap, ESI) calcd for C22
17.0821, found 417.0824.
13 3 2 2
H F N NaO [M+Na]
indazolo[1,2-b]phthalazine-13-carboxylate (7a): 20.1 mg (30%);
4
o
1
3
orange solid; mp = 124.2–127.1 C; H NMR (500 MHz, CDCl )
(R)-13-(3-Nitrophenyl)-13H-indazolo[1,2-b]phthalazine-6,11-
dione (6r): 36.4 mg (49%); white solid; mp = 268.4–271.5 C;
δ 8.46 (dd, J = 7.9, 1.3 Hz, 1H), 8.41 (d, J = 8.1 Hz, 1H), 8.33 (dd,
J = 7.6, 1.6 Hz, 1H), 7.93–7.83 (m, 2H), 7.63–7.56 (m, 1H), 7.49
(d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 4.37–4.22 (m, 2H),
o
1
H NMR (400 MHz, CDCl
.29 (d, J = 7.3 Hz, 1H), 8.27–8.17 (m, 2H), 7.97–7.82 (m, 2H),
.76 (d, J = 7.7 Hz, 1H), 7.57 (q, J = 8.2 Hz, 2H), 7.32 (t, J = 7.6
Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.85 (s, 1H); C{ H} NMR (100
MHz, CDCl ) δ 155.3, 154.8, 148.6, 140.2, 136.3, 133.8, 133.8,
33.6, 130.3, 130.0, 129.9, 128.4, 127.9, 127.5, 126.9, 126.7, 123.8,
23.6, 122.5, 116.1, 65.2; IR (KBr) υ 2518, 1753, 1714, 1659, 1635,
1605, 1482, 1409, 1348, 1286, 1230, 1109 cm ; HRMS (orbitrap,
ESI) calcd for C21 NaO
[M+Na]+ 394.0798, found
94.0800.
(R)-13-(3-Bromo-5-nitrophenyl)-13H-indazolo[1,2-
b]phthalazine-6,11-dione (6s): 45.2 mg (50%); white solid; mp
246.9–249.8 C; H NMR (500 MHz, CDCl
7.6, 8.0 Hz, 2H), 8.32 (t, J = 1.9 Hz, 1H), 8.26 (d, J = 7.7 Hz,
H), 8.16 (t, J = 1.6 Hz, 1H), 7.93–7.80 (m, 3H), 7.55 (t, J = 7.8
Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.77 (s,
H); C{ H} NMR (125 MHz, CDCl
3
) δ 8.53 (dd, J = 16.3, 7.9 Hz, 2H),
13
1
8
7
3
1.18 (t, J = 7.1 Hz, 3H); C{ H} NMR (125 MHz, CDCl ) δ 167.5,
155.6, 154.2, 136.2, 134.2, 133.8, 131.9, 130.3, 128.3, 128.0, 127.6,
126.5, 124.7, 123.1, 115.9, 89.4, 64.0, 13.9; IR (KBr) υ 2483, 1694,
1
3
1
-1
3
1681, 1556, 1496, 1447, 1420, 1375, 1292, 1253, 1172, 1105 cm ;
+
1
1
HRMS (quadrupole, EI) calcd for C18
14 2 5
H N O [M] 338.0903,
found 338.0906.
-
1
Experimental procedure for the synthesis of (7b). To an ov-
en-dried sealed tube charged with ethyl (S)-2-(2-(1,4-dioxo-
3,4-dihydrophthalazin-2(1H)-yl)phenyl)-2-hydroxyacetate
(6i) (64.5 mg, 0.2 mmol, 100 mol %) and potassium hydrox-
H
13
N
3
4
3
2
ide pellet (39.3 mg, 0.7 mmol, 350 mol %) was added H O (1
o
1
=
3
) δ 8.49 (dd, J =
mL) under air at room temperature. The reaction mixture
o
1
1
was allowed to stir at 100 C for 16 h and cooled to room
temperature. The reaction mixture was quenched with 1 N
HCl to adjust pH = ~7 and extracted with dichloromethane
(10 mL x 3). The organic layer was dried over MgSO , filtered
4
and concentrated in vacuo. The residue was purified by flash
column chromatography (n-hexanes/ EtOAc = 5:1) to afford
7b (8.9 mg) in 38% yield.
13
1
1
1
3
) δ 155.4, 154.7, 149.0, 141.9,
36.3, 136.2, 134.0, 133.9, 130.6, 129.9, 128.3, 127.9, 127.5, 127.0,
126.8, 126.3, 123.6, 123.5, 121.2, 116.2, 64.6; IR (KBr) υ 2470, 1713,
1645, 1603, 1558, 1507, 1465, 1382, 1352, 1275, 1107 cm ; HRMS
-
1
+
(
orbitrap, ESI) calcd for C21
found 471.9905.
13H-Indazolo[1,2-b]phthalazine-6,11-dione (6t): 25.1 mg
50%); white solid; mp = 235.5–238.5 C; H NMR (500 MHz,
CDCl ) δ 8.47–8.42 (m, 2H), 8.42–8.37 (m, 1H), 7.88–7.85 (m,
H), 7.49–7.43 (m, 2H), 7.31 (t, J = 7.5 Hz, 1H), 5.40 (s, 2H);
C{ H} NMR (125 MHz, CDCl
29.9, 129.3, 128.3, 127.7, 127.2, 126.2, 123.5, 123.1, 116.0, 50.6; IR
KBr) υ 2537, 1745, 1714, 1633, 1607, 1559, 1496, 1476, 1440, 1399,
H
12BrN
3
NaO
4
[M+Na] 471.9903,
1H-Indazole (7b): 8.9 mg (38%); light green solid; mp =
o
1
140.0–143.2 C; H NMR (500 MHz, CDCl
3
) δ 8.12 (s, 1H), 7.79–
7.77 (m, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.42–7.39 (m, 1H), 7.20–
o
1
13
1
(
7.17 (m, 1H); C{ H} NMR (125 MHz, CDCl
3
) δ 140.0, 134.6,
3
126.9, 123.1, 121.1, 120.9, 109.8; IR (KBr) υ 2439, 1777, 1752, 1713,
-
1
2
1660, 1541, 1492, 1457, 1367, 1217, 1130, 1076 cm ; HRMS (or-
1
3
1
+
3
) δ 154.9, 154.8, 137.4, 133.5, 133.4,
bitrap, ESI) calcd for C
7
H
N
7 2
[M+H] 119.0604, found 119.0605.
1
Experimental procedure for the synthesis of (7c). To an ov-
en-dried sealed tube charged with ethyl (S)-2-(2-(1,4-dioxo-
(
-1
1330, 1288, 1222, 1129 cm ; HRMS (orbitrap, ESI) calcd for
3
,4-dihydrophthalazin-2(1H)-yl)phenyl)-2-hydroxyacetate
+
C
15
H
10
N
2
NaO
2
[M+Na] 273.0634, found 273.0633.
(
6i) (64.5 mg, 0.2 mmol, 100 mol %) and lithium aluminum
Gram scale experiment. To an oven-dried sealed tube
charged with 2-(3-chlorophenyl)-2,3-dihydrophthalazine-1,4-
dione (1a) (1.0 g, 4.0 mmol, 100 mol %), [Ru(p-cymene)Cl
61.2 mg, 0.1 mmol, 2.5 mol %), AgNTf (155.2 mg, 0.4 mmol,
0 mol %), NaOAc (98.4 mg, 1.2 mmol, 30 mol %) and ethyl
-oxoacetate (~50% in toluene) (2a) (2.45 g, 12 mmol, 300
mol %) was added DCE (20 mL). The reaction mixture was
allowed to stir for 20 h at 40 C. The reaction mixture was
diluted with EtOAc (10 mL) and concentrated in vacuo. The
residue was purified by flash column chromatography
(EtOAc/n-hexanes = 1:1 to 1.5:1) to afford 3a (1.38 g) in 92%
yield. See entry 15 of Table 1 in the manuscript.
hydride (37.9 mg, 1 mmol, 500 mol %) was added THF (1 mL)
o
under N
2
atmosphere at 0 C. The reaction mixture was al-
o
o
2
]
2
lowed to stir at 80 C for 6 h and cooled to 0 C. To the reac-
tion mixture, cold water was added drop wise and the mix-
ture was extracted with EtOAc (15 mL x 3). The combined
organic layers were washed with brine (10 mL x 2), dried over
(
2
1
2
4
MgSO , filtered and concentrated under reduced pressure.
The residue was purified by flash column chromatography
(n-hexanes/ EtOAc = 4:1) to afford 7c (15.5 mg) in 31% yield.
o
(
S)-6,11-Dihydro-13H-indazolo[1,2-b]phthalazine-13-
carbaldehyde (7c): 15.5 mg (31%); orange solid; mp = 153.5–
o
1
1
3
58.4 C; H NMR (700 MHz, CDCl ) δ 10.14 (s, 1H), 7.84 (dd, J
Experimental procedure and characterization data for the
synthesis of hydroxyl-containing indazolophthalazinone ad-
duct (7a). To an oven-dried sealed tube charged with ethyl
= 7.5, 1.5 Hz, 1H), 7.69–7.64 (m, 2H), 7.47 (t, J = 7.7 Hz, 1H),
7.43–7.41 (m, 1H), 7.31–7.26 (m, 2H), 7.11–7.09 (m, 1H), 6.53 (d,
13
1
J = 7.7 Hz, 1H), 6.16 (s, 2H), 4.93 (s, 2H); C{ H} NMR (175
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 15
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
MHz, CDCl
3
) δ 193.7, 148.1, 138.3, 135.1, 134.4, 132.7, 128.1, 127.7,
26.4, 121.9, 121.0, 119.4, 117.5, 63.9, 53.6, 52.1; IR (KBr) υ 2556,
758, 1714, 1659, 1610, 1557, 1506, 1404, 1385, 1299, 1201, 1133,
umn chromatography (EtOAc/n-hexanes = 1:1 to 1.5:1) to af-
ford deuterio-1i (38.1 mg, 79%) as a light yellow solid.
1
1
1
Deuterio-1i: 38.1 mg (79%); light yellow solid; mp = 216.1–
-
1
040, 1004 cm ; HRMS (orbitrap, ESI) calcd for C16
M+H] 251.1184, found 251.1178.
H
15
N
2
O
o
1
3
218.1 C; H NMR (400 MHz, CD OD) δ 8.36 (dd, J = 8.0, 0.8
+
[
Hz, 1H), 8.09 (dd, J = 8.0, 0.8 Hz, 1H), 7.94–7.86 (m, 2H), 7.64
(d, J = 8.0 Hz, 1H), 7.49–7.46 (m, 2H), 7.36 (t, J = 7.2 Hz, 1H);
Experimental procedure for the synthesis of (7d). To an ov-
en-dried sealed tube charged with ethyl (S)-2-(2-(1,4-dioxo-
,4-dihydrophthalazin-2(1H)-yl)phenyl)-2-hydroxyacetate
6i) (64.5 mg, 0.2 mmol, 100 mol %) and 1 N-sodium hydrox-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
3
C{ H} NMR (100 MHz, CD OD) δ 160.1, 152.9, 143.1, 134.7,
3
133.6, 130.6, 129.6, 129.5, 128.6, 128.1, 127.1, 127.0, 126.3, 125.6.
(
Experimental procedure for the synthesis of intermediate A’.
To an oven-dried sealed tube charged with 2-phenyl-2,3-
dihydrophthalazine-1,4-dione (1i) (100.1 mg, 0.42 mmol, 100
ide (0.4 mL, 0.4 mmol, 200 mol %) was added THF (1.5 mL)
under air at room temperature. The reaction mixture was
o
allowed to stir at 100 C for 16 h and cooled to room tempera-
ture. The reaction mixture was quenched with 1 N HCl (0.4
mL) to adjust pH = ~7 and extracted with dichloromethane
mol %), [Ru(p-cymene)Cl
2 2
] (257.2 mg, 0.42 mmol, 100
mol %), and NaOAc (103.4 mg, 1.26 mmol, 300 mol %) was
added DCE (2 mL) under N
2
atmosphere. The reaction mix-
(10 mL x 3). The organic layer was dried over MgSO
4
, filtered
o
ture was allowed to stir for 20 h at 40 C. The reaction mix-
ture was diluted with EtOAc (3 mL) and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy (n-hexanes/EtOAc = 1:1) to afford intermediate A (98.9
mg) in 45% yield.
and concentrated in vacuo. The residue was purified by flash
column chromatography (n-hexanes/ EtOAc = 2:1) to afford
7d (41.1 mg) in 82% yield.
1
3H-Indazolo[1,2-b]phthalazine-6,11-dione (7d): 41.1 mg
o
1
(
82%); white solid; mp = 220.7–223.4 C; H NMR (700 MHz,
CDCl ) δ 8.47–8.44 (m, 2H), 8.41–8.39 (m, 1H), 7.88–7.86 (m,
H), 7.48–7.45 (m, 2H), 7.32 (td, J = 7.5, 0.9 Hz, 1H), 5.41 (s,
2H); C{ H} NMR (175 MHz, CDCl
133.4, 129.9, 129.3, 128.4, 127.7, 127.2, 126.2, 123.5, 123.1, 116.0,
0.6; IR (KBr) υ 2520, 1747, 1714, 1659, 1540, 1507, 1464, 1423,
Intermediate A’: 98.9 mg (45%); orange solid; mp = 280.2–
83.0 C; H NMR (700 MHz, CDCl ) δ 8.32 (d, J = 7.0 Hz, 1H),
3
3
o
1
2
7
2
5
2
.87 (d, J = 7.0 Hz, 1H), 7.72–7.67 (m, 4H), 7.59 (t, J = 7.7 Hz,
H), 7.51 (t, J = 7.7 Hz, 1H), 5.39 (d, J = 5.6 Hz, 1H), 5.09 (d, J =
.6 Hz, 1H), 4.87 (d, J = 4.9 Hz, 1H), 4.65 (d, J = 4.9 Hz, 1H),
13
1
3
) δ 155.0, 154.8, 137.4, 133.6,
5
13
1
2.74–2.68 (m, 1H), 2.16 (s, 3H), 1.24–1.22 (m, 6H); C{ H} NMR
(175 MHz, CDCl ) δ 166.2, 157.8, 140.1, 132.7, 132.1, 130.0, 129.1,
29.0, 128.8, 127.9, 126.7, 126.2, 125.8, 123.7, 102.4, 96.2, 31.5,
-1
1378, 1285, 1206, 1113 cm ; HRMS (orbitrap, ESI) calcd for
3
+
C
15
H
11
N
2
O
2
[M+H] 251.0815, found 251.0811.
1
Experimental procedure for the synthesis of (7e). To an ov-
en-dried sealed tube charged with ethyl (S)-2-(2-(1,4-dioxo-
,4-dihydrophthalazin-2(1H)-yl)phenyl)-2-hydroxyacetate
6i) (64.5 mg, 0.2 mmol, 100 mol %) and NaClO (54.3 mg,
O (4:1, 1 mL) un-
22.2, 18.8; HRMS (orbitrap, ESI) calcd for C24
[M+H] 508.0492, found 508.0491.
H24ClN
2
O
2
Ru
+
3
Experimental procedure for the synthesis of Ru(p-
cymene)(OAc) complex. To an oven-dried sealed tube
charged with [Ru(p-cymene)Cl (122.5 mg, 0.2 mmol, 100
mol %) in DCE (1 mL) was added KOAc (78.5 mg, 0.8 mmol,
00 mol %). The reaction mixture was allowed to stir for 2 h
(
0
2
2
3 2
.6 mmol, 300 mol %) was added CHCl /H
2 2
]
der air at room temperature. The reaction mixture was al-
lowed to stir at 70 C for 5 h and cooled to room temperature.
o
4
The reaction mixture was quenched with saturated Na
solution and extracted dichloromethane (10 mL x 3). The
organic layer was dried over MgSO , filtered, and concen-
trated in vacuo. The residue was purified by flash column
chromatography (n-hexanes/ EtOAc = 2:1) to afford 7e (20.8
mg) in 39% yield.
2
SO
3
o
at 40 C and cooled to room temperature. The reaction mix-
ture was diluted with CH CN (2 mL), filtered through celite
pad and concentrated in vacuo to afford the Ru(p-
cymene)(OAc) complex (113.3 mg) as an orange solid.
Ru(p-cymene)(OAc) CN) δ 5.79 (d,
: 1H NMR (400 MHz, CD
J = 5.6 Hz, 2H), 5.55 (d, J = 6.0 Hz, 2H), 2.15 (s, 3H), 1.75 (s,
3
4
2
2
3
1
3H-Indazolo[1,2-b]phthalazine-6,11,13-trione (7e): 20.8 mg
13
1
6
3
H), 1.29 (d, J = 7.2 Hz, 6H); C{ H} NMR (100 MHz, CD CN)
o
1
(
39%); yellow solid; mp = 271.8–274.6 C; H NMR (400 MHz,
CDCl ) δ 8.58 (dt, J = 8.3, 0.8 Hz, 1H), 8.50–8.49 (m, 1H),
.43–8.41 (m, 1H), 8.07 (ddd, J = 7.7, 1.3, 0.7 Hz, 1H), 7.95–7.90
m, 2H), 7.84 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.48 (ddd, J = 8.0,
δ 183.9, 79.9, 78.4, 32.3, 23.9, 22.7, 18.8.
3
8
(
ASSOCIATED CONTENT
Supporting Information. Unsuccessful results for the cy-
clization of 3a, X-ray crystallographic data of compounds 6c,
13
1
7.3, 0.8 Hz, 1H); C{ H} NMR (175 MHz, CDCl
153.9, 139.2, 136.5, 135.1, 134.7, 129.2, 129.0, 128.9, 128.4, 126.4,
3
) δ 158.1, 154.8,
1
13
19
7
a and intermediate A’, and H, C and F NMR spectra for
1
1
25.4, 116.6, 116.2; IR (KBr) υ 2414, 1753, 1682, 1662, 1603, 1541,
508, 1385, 1282, 1215, 1128, 1106, 1028 cm ; HRMS (orbitrap,
all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
-1
+
ESI) calcd for C15
H
9
N
2
O
3
[M+H] 265.0608, found 265.0605.
Deuterium-labelling experiment. To an oven-dried sealed
tube charged with 2-phenyl-2,3-dihydrophthalazine-1,4-
AUTHOR INFORMATION
Corresponding Authors
dione 1i (47.6 mg, 0.2 mmol, 100 mol %), [Ru(p-cymene)Cl
3.1 mg, 0.005 mmol, 2.5 mol %), AgNTf (7.8 mg, 0.02 mmol,
0 mol %), NaOAc (4.9 mg, 0.06 mmol, 30 mol %) and
CD CO D (64.1 mg, 1.0 mmol, 500 mol %) was added DCE (1
2 2
]
(
1
2
* E-mail for J.M.K.: medichem@gbsa.or.kr.
* E-mail for N.K.M.: neerajchemistry@gmail.com.
* E-mail for I.S.K.: insukim@skku.edu.
3
2
mL). The reaction mixture was allowed to stir for 20 h at 40
o
ORCID
C. The reaction mixture was diluted with EtOAc (2 mL) and
concentrated in vacuo. The residue was purified by flash col-
In Su Kim: 0000-0002-2665-9431
ACS Paragon Plus Environment

Page 13 of 15
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Notes
Selective Formation of γ-Lactams via C–H Amidation Enabled by
Tailored Iridium Catalysts. Science 2018, 359, 1016–1021. (c) Lee,
H.; Kang, D.; Han, S. H.; Chun, R.; Pandey, A. K.; Mishra, N. K.;
Hong, S.; Kim, I. S. Allylic Acetals as Acrolein Oxonium Precur-
sors in Tandem C–H Allylation and [3+2] Dipolar Cycloaddition.
Angew. Chem., Int. Ed. 2019, 58, 9470–9474. (d) Gao, X.; Wang,
P.; Zeng, L.; Tang, S.; Lei, A. Cobalt(II)-Catalyzed Electrooxida-
tive C–H Amination of Arenes with Alkylamines. J. Am. Chem.
Soc. 2018, 140, 4195–4199. (e) Lei, H.; Rovis, T. Ir-Catalyzed In-
termolecular Branch-Selective Allylic C–H Amidation of Unacti-
vated Terminal Olefins. J. Am. Chem. Soc. 2019, 141, 2268–2273.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Research Founda-
tion of Korea (NRF) grant funded by the Korea government
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2
MSIP) (Nos. 2017R1A2B2004786, 2017R1D1A1A09000574,
018M3A9C8021792 and 2019R1A4A2001451).
REFERENCES
(
6) (a) Rajkumar, S.; Savarimuthu, S. A.; Kumaran, R. S.; Naga-
(1) (a) Cho, J. Y.; Kwon, H. C.; Williams, P. G.; Jensen, P. R.;
raja, C.; Gandhi, T. Expedient Synthesis of New Cinnoline Diones
by Ru-Catalyzed Regioselective Unexpected Deoxygenation-
Oxidative Annulation of Propargyl Alcohols with Phthalazinones
and Pyridazinones. Chem. Commun. 2016, 52, 2509–2512. (b)
Mayakrishnan, S.; Arun, Y.; Balachandran, C.; Emi, N.; Murali-
dharan, D.; Perumal, P. T. Synthesis of Cinnolines via Rh(III)-
Catalysed Dehydrogenative C–H/N–H Functionalization: Aggre-
gation Induced Emission and Cell Imaging. Org. Biomol. Chem.
Fenical, W. Azamerone, A Terpenoid Phthalazinone from a Ma-
rine-Derived Bacterium Related to the Genus Streptomyces (Ac-
tinomycetales). Org. Lett. 2006, 8, 2471–2474. (b) Asif, M. Some
Recent Approaches of Biologically Active Substituted Pyridazine
and Phthalazine Drugs. Curr. Med. Chem. 2012, 19, 2984–2991. (c)
Xue, J.; Xin, L.; Hou, J.; Duan, L.; Wang, R.; Wei, Y.; Qiao, J.
Homoleptic Facial Ir(III) Complexes via Facile Synthesis for
High-Efficiency and Low-Roll-Off near-Infrared Organic Light-
Emitting Diodes over 750 Nm. Chem. Mater. 2017, 29, 4775–4782.
(2) (a) Russell, M. G.; Carling, R. W.; Atack, J. R.; Bromidge, F.
A.; Cook, S. M.; Hunt, P.; Isted, C.; Lucas, M.; McKernan, R. M.;
Mitchinson, A.; Moore, K. W.; Narquizian, R.; Macaulay, A. J.;
Thomas, D.; Thompson, S.-A.; Wafford, K. A.; Castro, J. L. Dis-
covery of Functionally Selective 7,8,9,10-Tetrahydro-7,10-ethano-
2
016, 14, 1958–1968.
7) (a) Karishma, P.; Mahesha, C. K.; Agarwal, D. S.; Mandal, S.
(
K.; Sakhuja, R. Additive-Driven Rhodium-Catalyzed [4+1]/[4+2]
Annulations of N-Arylphthalazine-1,4-dione with α-Diazo Car-
bonyl Compounds. J. Org. Chem. 2018, 83, 11661–11673. (b) Wu,
X.; Ji, H. Rhodium-Catalyzed [4+1] Cyclization via C–H Activa-
tion for the Synthesis of Divergent Heterocycles Bearing a Qua-
ternary Carbon. J. Org. Chem. 2018, 83, 4650–4656.
1
,2,4-triazolo[3,4-a]phthalazines as Gabaa Receptor Agonists at
the A3 Subunit. J. Med. Chem. 2005, 48, 1367–1383. (b) Khalil, A.;
Berghot, M.; Gouda, M. Synthesis and Antibacterial Activity of
Some New Heterocycles Incorporating Phthalazine. Eur. J. Med.
Chem. 2009, 44, 4448–4454. (c) Hegab, M. I.; Taleb, N. A. A.;
Hasabelnaby, S. M.; Goudah, A. Synthesis and Anti-
Inflammatory Evaluation of Some Condensed [4-(3,4-
Dimethylphenyl)-1(2H)-oxo-phthalazin-2-yl]acetic Acid Hydra-
zide. Eur. J. Med. Chem. 2010, 45, 1267–1277. (d) Bakale, R. P.;
Naik, G. N.; Mangannavar, C. V.; Muchchandi, I. S.; Shcherbakov,
I.; Frampton, C.; Gudasi, K. B. Mixed Ligand Complex via
Zinc(II)-mediated in situ Oxidative Heterocyclization of Hydro-
chloride Salt of 2-Chlorobenzaldehyde Hydralazine Hydrazone
as Potential of Antihypertensive Agent. Eur. J. Med. Chem. 2014,
73, 38–45. (e) Eldehna, W. M.; Ibrahim, H. S.; Abdel-Aziz, H. A.;
Farrag, N. N.; Youssef, M. M. Design, Synthesis and in vitro Anti-
(
8) (a) Sharma, S.; Mishra, N. K.; Shin, Y.; Kim, I. S. Transi-
tion-Metal-Catalyzed Oxidative and Decarboxylative Acylations
through sp2 C–H Bond Activation. Curr. Org. Chem. 2016, 20,
471–511. (b) Yang, L.; Huang, H. Transition-Metal-Catalyzed Di-
rect Addition of Unactivated C–H Bonds to Polar Unsaturated
Bonds. Chem. Rev. 2015, 115, 3468–3517. (c) Hummel, J. R.; Boerth,
J. A.; Ellman, J. A. Transition-Metal-Catalyzed C–H Bond Addi-
tion to Carbonyls, Imines, and Related Polarized π Bonds. Chem.
Rev. 2017, 117, 9163−9227. (d) Hummel, J. R.; Ellman, J. A. Co-
balt(III)-Catalyzed Synthesis of Indazoles and Furans by C–H
Bond Functionalization/Addition/Cyclization Cascades. J. Am.
Chem. Soc. 2015, 137, 490−498. (e) Chen, X.; Hu, X.; Deng, Y.;
Jiang, H.; Zeng, W. A [4 + 1] Cyclative Capture Access to Indoliz-
2
ines via Cobalt(III)-Catalyzed Csp –H Bond Functionalization.
Org. Lett. 2016, 18, 4742−4745.
tumor
phenyl/benzylphthalazin-1-ones. Eur. J. Med. Chem. 2015, 89,
49–560.
3) For a selected review, see: Han, Y. T.; Jung, J.-W.; Kim, N.-J.
Activity
of
Novel
N-Substituted-4-
(9) (a) Weaver, J. D.; Recio, A. III.; Grenning, A. J.; Tunge, J. A.
Transition Metal-Catalyzed Decarboxylative Allylation and Ben-
zylation Reactions. Chem. Rev. 2011, 111, 1846−1913. (b) Shan, C.;
Zhu, L.; Qu, L.-B.; Bai, R.; Lan, Y. Mechanistic View of Ru-
catalyzed C–H Bond Activation and Functionalization: Compu-
tational Advances. Chem. Soc. Rev. 2018, 47, 7552−7576. (c) Chen,
P.; Sun, Y.; Wu, Y.; Liu, L.; Zhu, J.; Zhao, Y. A Theoretical Study
on the Mechanism of Ruthenium(II)-catalyzed Phosphoryl-
directed ortho-Selective C−H Bond Activations: The Phosphoryl
Hydroxy Group Triggered Ru(II)/Ru(0) Catalytic Cycle. Org.
Chem. Front. 2017, 4, 1482−1492. (d) D’Alterio, M. C.; Yuan, Y.-C.;
Bruneau, C.; Talarico, G.; Gramage-Doria, R.; Poater, A. Base-
controlled Product Switch in the Ruthenium-catalyzed Protode-
carbonylation of Phthalimides: A Mechanistic Study. Catal. Sci.
Technol. 2020, 10, 180−186.
5
(
Recent Advances in the Synthesis of Biologically Active Cin-
noline, Phthalazine and Quinoxaline Derivatives. Curr. Org.
Chem. 2017, 21, 1265–1291.
(4) (a) Zhang, C.; Li, S.; Ji, L.; Liu, S.; Li, Z.; Li, S.; Meng, X. De-
sign, Synthesis and Antitumor Activity of Non-Camptothecin
Topoisomerase I Inhibitors. Bioorg. Med. Chem. Lett. 2015, 25,
4693–4696. (b) Gholamhosseyni, M.; Kianmehr, E. A Rutheni-
um-Catalyzed Alkenylation–Annulation Approach for the Syn-
thesis of Indazole Derivatives via C–H Bond Activation. Org.
Biomol. Chem. 2018, 16, 5973–5978. (c) Lamera, E.; Bouacida, S.;
Borgne, M. L.; Bouaziz, Z.; Bouraiou, A. Sequential MCR/Fisher
Indolization Strategy for the Construction of Polycyclic Carba-
zole Derivatives. Tetrahedron. Lett. 2017, 58, 1305–1307.
(5) For recent selected examples, see: (a) Sambiagio, C.;
Schönbauer, D.; Blieck, R.; Dao-Huy, T.; Pototschnig, G.; Schaaf,
P.; Wiesinger, T.; Zia, M. F.; Wencel-Delord, J.; Besset, T.; Maes,
B. U. W.; Schnürch, M. Chem. Soc. Rev. 2018, 47, 6603–6743. (b)
Hong, S. Y.; Park, Y.; Hwang, Y.; Kim, Y. B.; Baik, M.-H.; Chang, S.
(
10) For selected reviews, see: (a) Baumann, M.; Baxendale, I.
R. An Overview of the Synthetic Routes to the Best Selling Drugs
Containing 6-Membered Heterocycles. Beilstein J. Org. Chem.
2
013, 9, 2265–2319. (b) Asif, M. A Mini Review on Biological Ac-
tivities of Pyridazinone Derivatives as Antiulcer, Antisecretory,
Antihistamine and Particularly Against Histamine H3R. Mini-Rev.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 15
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Med. Chem. 2015, 14, 1093–1103. (c) Singh, J.; Sharma, D.; Bansal,
R. Pyridazinone: An Attractive Lead for Anti-inflammatory and
Analgesic Drug Discovery. Future Med. Chem. 2017, 9, 95–127.
Ruthenium-Catalysed σ-Activation for Remote meta-Selective C–
H Functionalisation. Chem. Soc. Rev. 2017, 46, 7145–7153. (e)
Duarah, G.; Kaishap, P. P.; Begum, T.; Gogoi, S. Recent Advances
in Ruthenium(II)-Catalyzed C−H Bond Activation and Alkyne
Annulation Reactions. Adv. Synth. Catal. 2019, 361, 654–672. (f)
Miura, H.; Terajima, S.; Shishido, T. Carboxylate-Directed Addi-
tion of Aromatic C−H Bond to Aromatic Aldehydes under Ru-
thenium Catalysis. ACS Catal. 2018, 8, 6246–6254.
(11) (a) Zhang, G.-F.; Li, Y.; Xie, X.-Q.; Ding, C.-R. Ru-
Catalyzed Regioselective Direct Hydroxymethylation of (Het-
ero)arenes via C–H Activation. Org. Lett. 2017, 19, 1216–1219. (b)
Wu, Y.; Zhou, B. Ruthenium-Catalyzed Direct Hydroxymethyla-
tion of Aryl C–H Bonds. ACS Catal. 2017, 7, 2213–2217. (c) Lee, S.
H.; Jeong, T.; Kim, K.; Kwon, N. Y.; Pandey, A. K.; Kim, H. S.; Ku,
J.-M.; Mishra, N. K.; Kim, I. S. Ruthenium(II)-Catalyzed Site-
Selective Hydroxymethylation of Indolines with Paraformalde-
hyde. J. Org. Chem. 2019, 84, 2307–2315.
(12) For carbonyl-assisted C–H functionalization of cyclic am-
ides and imides, see: (a) Gao, P.; Guo, W.; Xue, J.; Zhao, Y.; Yuan,
Y.; Xia, Y.; Shi, Z. Iridium(III)-Catalyzed Direct Arylation of C–H
Bonds with Diaryliodonium Salts. J. Am. Chem. Soc. 2015, 137,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2231–12240. (b) Tan, G.; You, Q.; You, J. Iridium-Catalyzed Oxi-
dative Heteroarylation of Arenes and Alkenes: Overcoming the
Restriction to Specific Substrates. ACS Catal. 2018, 8, 8709–8714.
(c) Leitch, J. A.; Wilson, P. B.; McMullin, C. L.; Mahon, M. F.;
Bhonoah, Y.; Williams, I. H.; Frost, C. G. Ruthenium(II)-
Catalyzed C–H Functionalization Using the Oxazolidinone Het-
erocycle as a Weakly Coordinating Directing Group: Experi-
mental and Computational Insights. ACS Catal. 2016, 6, 5520–
5529. (d) Leitch, J. A.; Cook, H. P.; Bhonoah, Y.; Williams, I. H.;
Frost, C. G. Use of the Hydantoin Directing Group in Rutheni-
um(II)-Catalyzed C–H Functionalization. J. Org. Chem. 2016, 81,
1
0081–10087. (e) Ma, W.; Dong, H.; Wang, D.; Ackermann, L.
Late-Stage Diversification of Non-Steroidal Anti-Inflammatory
Drugs by Transition Metal-Catalyzed C–H Alkenylations, Thiola-
tions and Selenylations. Adv. Synth. Catal. 2017, 359, 966–973. (f)
Yuan, Y.-C.; Bruneau, C.; Roisnel, T.; Gramage-Doria, R. Site-
Selective Ruthenium-Catalyzed C–H Bond Arylations with Bo-
ronic Acids: Exploiting Isoindolinones as a Weak Directing
Group. J. Org. Chem. 2019, 84, 12893–12903. (g) Yuan, Y.-C.; Gou-
jon, M.; Bruneau, C.; Roisnel, T.; Gramage-Doria, R. C–H Bond
Alkylation of Cyclic Amides with Maleimides via a Site-Selective-
Determining Six-Membered Ruthenacycle. J. Org. Chem. 2019,
84, 16183–16191.
(13) Sharma, S.; Park, E.; Park, J.; Kim, I. S. Tandem Rh(III)-
Catalyzed Oxidative Acylation of Secondary Benzamides with
Aldehydes and Intramolecular Cyclization: The Direct Synthesis
of 3-Hydroxyisoindolin-1-ones. Org. Lett. 2012, 14, 906–909.
(14) For potential applications of intermediate A’ as bioactive
agents, see: Aman, F.; Hanif, M.; Kubanik, M.; Ashraf, A.; Söhnel,
T.; Jamieson, S. M. F.; Siddiqui, W. A.; Hartinger, C. G. An-
ti-Inflammatory Oxicams as Multi-donor Ligand Systems: pH-
and Solvent-Dependent Coordination Modes of Meloxicam and
Piroxicam to Ru and Os. Chem. Eur. J. 2017, 23, 4893–4902.
(15) Yuan, Y.-C.; Bruneau, C.; Roisnel, T.; Gramage-Doria, R.
Site-Selective Ru-Catalyzed C–H Bond Alkenylation with Biolog-
ically Relevant Isoindolinones: A Case of Catalyst Performance
Controlled by Subtle Stereoelectronic Effects of the Weak Di-
recting Group. Catal. Sci. Technol. 2019, 9, 4711–4717.
(16) For selected reviews, see: (a) Arockiam, P. B.; Bruneau, C.;
Dixneuf, P. H. Ruthenium(II)-Catalyzed C–H Bond Activation
and Functionalization. Chem. Rev. 2012, 112, 5879–5918. (b)
Ackermann, L. Carboxylate-Assisted Ruthenium-Catalyzed Al-
kyne Annulations by C–H/Het–H Bond Functionalizations. Acc.
Chem. Res. 2014, 47, 281–295. (c) Manikandan, R.; Jeganmohan,
M. Recent Advances in the Ruthenium(II)-Catalyzed Chelation-
Assisted C–H Olefination of Substituted Aromatics, Alkenes and
Heteroaromatics with Alkenes via the Deprotonation Pathway.
Chem. Commun. 2017, 53, 8931–8947. (d) Leitch, J. A.; Frost, C. G.
ACS Paragon Plus Environment

Page 15 of 15
The Journal of Organic Chemistry
1
2
3
4
5
6
Table of Contents (TOC)
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment