Palladium-Catalyzed Acylation Reactions: A One-Pot Diversified Synthesis of Phthalazines, Phthalazinones and Benzoxazinones

Article abstract of DOI:10.1002/ejoc.201800159

A sequential one-pot strategy for the diversified synthesis of phthalazines, phthalazinones and benzoxazinones was presented. This strategy proceeds through [Pd]-catalyzed acylation and nucleophilic cyclocondensation with dinucleophilic reagents. This process was based on direct coupling with simple bench-top aldehydes without the assistance of directing group and without activating the carbonyl group. The process is highly advantageous because it employs simple nitrogen-based nucleophiles, and non-toxic and readily accessible aldehydes as the carbonyl source. Most importantly, the strategy was applied to the one-pot synthesis of PDE-4 inhibitor.

Full text of DOI:10.1002/ejoc.201800159

A Journal of
Accepted Article
Title: Palladium-Catalyzed Acylations: A One-pot Diversified Synthesis
of Phthalazines, Phthalazinones and Benzoxazinones
Authors: Suchand Basuli and Gedu Satyanarayana
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800159
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800159
Supported by

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
Palladium-Catalyzed Acylations: A One-Pot Diversified Synthesis
of Phthalazines, Phthalazinones and Benzoxazinones
Basuli Suchand and Gedu Satyanarayana*[a]
Dedication ((optional))
Abstract: A sequential one-pot strategy for the diversified synthesis
of phthalazines, phthalazinones and benzoxazinones, was presented.
This strategy proceeds via [Pd]-catalyzed acylation and nucleophilic
cyclocondensation with dinucleophilic reagents. This process was
based on direct coupling with simple bench-top aldehydes, without the
assistance of directing group and without activating the carbonyl
group. The process is highly advantageous, as, it employs simple
nitrogen based nucleophiles, and non-toxic & readily accessible
aldehydes as the carbonyl source. Most importantly, the strategy was
applied to the one-pot synthesis of PDE-4 inhibitor.
Introduction
Heterocyclic compounds are vital and ubiquitous in nature.[1] Thus,
development of efficient synthetic processes to accomplish them
is indispensable. In particular, the nitrogen based heterocyclic
molecules have gained an exceptional importance in medicinal
chemistry. Particularly, dinitrogen containing phthalazinones have
been utilized to cure various diseases, for example, hepatitis B,
arrhythmia, asthma, diabetes, cardiovascular and vascular
hypertension (Figure 1).[2] In addition, benzoxazinone derivatives
Figure 1: Representative examples of bioactive phathalazinones/phathalazine.
are another important class of heterocycles that exhibit interesting
physiological and pharmaceutical activities, such as, anticancer,
antimalarial, antifungal, antitubercular, phytotoxic, antiviral,
antifeedant, anti-HIV and antibacterial.[3] While phthalazines are a
special class of heterocyclic compounds,[4] having medicinal and
biological significance (Figure 1).[5]
Owing to their interesting structural features and broad spectrum
of biological activities, synthetic community has established some
interesting strategies on their synthesis. In 1893, Gabriel et al first
synthesized the phthalazine using substitution of 1,2-bis-
dichloromethylbenzene by ring-closing reaction of ortho-
carbonylbenzaldehyde with hydrazine.[6] Commonly, phthalazines
have been achieved by using multistep procedures, such as, ring
closing or ring enlargement or aromatization of 1,2-dihydro- or
1,2,4,5- tetrahydrophthalazines.[7] They were also synthesized by
employing the Diels-Alder reaction of 1,2,4,5-tetrazines with
arynes/arenes or pyridazino[4,5-d]pyridazine with enamines.[8] H.
A. Wegner et al presented the synthesis of phthalazines and
pyridazino aromatics starting from aromatic aldehydes via
directed ortho-lithiation strategy.[9] While synthesis of
phthalazinones was established by cyclocondensation and
cycloaddition reactions.[10] Recently, the research group of Xiao-
Feng Wu reported the carbonylative synthesis of phthalazinones
from 2-bromobenzaldehydes and hydrazines, in which CO was
used as the carbonylating source.[11] On the other hand, L. K.
Reddy and Baburajan et al made use of Mo(CO)6 and Co2(CO)8
as an alternative sources of CO, respectively.[12] Orru et al
disclosed [Pd]-catalyzed isocyanide insertion to give
phathalazinones,[13] while, to the best of our knowledge, there
was only one report on the synthesis of benzoxazinones by
[a]
Indian Institute of Technology (IIT) Hyderabad, Kandi – 502 285,
Sangareddy District, Telangana, INDIA
Fax: +91(40) 2301 6032
E-mail: gvsatya@iith.ac.in
Home page:
https://sites.google.com/site/gsresearchgrouphomepage/home
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
Huanfeng Jiang and co-workers via [Pd]-catalyzed carbonylation
of aromatic oximes.[14]
Sequential one-pot transformations are very essential for
chemical synthesis,[15] as they enable the formation of more than
one bond, thereby facilitating the formation of products with
sufficient complexity. Also, they are economically and ecologically
viable processes, as they save time, energy and reduce amount
of waste formation. Additionally, they are beneficial by reducing
tedious isolation and purification steps of the intermediate
product(s). Transition-metal-catalysis proved to be powerful tool
for the efficient construction of C−C and C−heteroatom bonds.[16]
We anticipated that a sequential one-pot synthesis of nitrogen
containing heterocycles could be feasible using [Pd]-catalyzed
direct acylation with aldehydes and cyclocondensation with
dinucleophilic agents (Scheme 1). It was also envisaged that
simple bench-top aldehydes could serve as non-toxic acyl source.
As part of our ongoing research in the development of new
synthetic methodologies catalyzed by transition metals,[17] very
recently, [Pd]-catalyzed direct acylation of iodoarenes with
aldehydes without the aid of functional group was reported by
us.[18] Subsequently, we have shown the effectiveness of this
concept, for a one-pot synthesis of indenones via [Pd]-catalyzed
direct acylation and intramolecular aldol condensation.[19] Later,
the efficacy of the concept was further proven by one-pot
synthesis of lactams.[20] Encouraged by these outcomes, herein,
we describe an efficient one-pot synthesis of phthalazines
through [Pd]-catalyzed direct acylation of ortho-iodoaryl ketones
with aldehydes and nucleophilic cyclocondensation with
hydrazine hydrate. In addition, sequential one-pot formation of
phthalazinones have been accomplished upon acylation of ortho-
iodoaryl esters and cyclocondensation with hydrazine hydrates.
Further, the synthesis of N-substituted phathalizinones has also
been explored. Furthermore, this concept has been successfully
extended to the one-pot synthesis of benzoxazinones using
hydroxylamine as the nucleophile for condensation. Remarkably,
this protocol enabled the one-pot synthesis of PDE-4 inhibitor.
Scheme 1: Anticipated one-pot synthetic route to heterocylic products.
Results and Discussion
In order to initiate the synthetic explorations, for the preparation
of phthalazine 3aa, ortho-iodoacetophenone 1a and
butyraldehyde 2a, were chosen as the model substrates. Thus,
acylation was performed using our earlier established conditions
[i.e. Pd(OAc)2 (5 mol%), Ag2O (1.2 equiv), TBHP in H2O (5 equiv),
120 C, 14 h]. After confirming the formation of diketone
intermediate 4aa by thin-layer-chromatography (TLC), the
cyclocondensation with dinucleophilic hydrazine hydrate was
explored, under various conditions. Addition of hydrazine hydrate
to the diketone intermediate 4aa along with the base triethylamine
(2 equiv) with no additional solvent, furnished the desired
phthalazine product 3aa, in moderate yield (Table 1, entry 1).
While the reaction with the base K2CO3 was found to be inferior
(Table 1, entry 2). On the other hand, in the absence of base and
solvent, the product 3aa was obtained in poor yields (Table 1,
entry 3). Slight improvement was seen with additional amount of
solvent DMF in the presence of K2CO3 (Table 1, entry 4). More or
less same yield of product 3aa was obtained without base (Table
1, entry 5). Yield deviation was negligible even by decreasing the
temperature of the reaction from 100 C to 50 C (Table 1, entry
6), so, there is not that much effect of high temperature.
Improvement in the yield was noticed by increasing equivalents of
hydrazine hydrate in DMF solvent (Table 1, entries 7). Only slight
improvement was noted by using MeOH as solvent (Table 1, entry
8). Interestingly, 3aa was obtained in 55% yield in EtOH solvent
(Table 1, entries 9). Further, slight improvement of the product
3aa was obtained with 10 equiv of hydrazine hydrate in methanol
solvent (Table 1, entry 10). Upon increasing the temperature to
75 C, yield has been improved to 62% (Table 1, entries 11).
While the reaction with 10 equiv of hydrazine hydrate in ethanol
at 50 C, gave 3aa in 64% yield (Table 1, entry 12). Gratifyingly,
ethanol was found to be a better solvent than methanol and
furnished the phthalazine 3aa, in 67% overall yield, with 10 and 5
equiv of hydrazine hydrate at 75 C, for 6 h, respectively (Table 1,
entries 13 & 14). Whereas, the product 3aa yield was decreased,
when 2 equiv of hydrazine hydrate was used (Table 1, entry 15).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
Table 1: Optimization study for one-pot formation of phthalazine 3aa via the diketone 4aa.[a]
Entry
1.
2.
3
N2H4H2O (equiv)
Base (2 equiv)
Solvent (2.0 mL)
Temp (C)
120
100
100
100
100
50
Time (h)
Yield 3aa (%)[b]
2.0
NEt3
-
6
40
30
30
44
43
42
47
50
55
58
62
64
67
67
53
2.0
K2CO3
-
6
2.0
-
-
12
10
10
12
10
15
8
4
2.0
K2CO3
DMF
DMF
DMF
DMF
MeOH
EtOH
MeOH
MeOH
EtOH
EtOH
EtOH
EtOH
5
2.0
-
-
-
-
-
-
-
-
-
-
-
6
2.0
7
4.0
50
8
4.0
50
9
4.0
50
10
11
12
13
14
15
10.0
10.0
10.0
10.0
5.0
50
10
8
75
50
8
75
6
75
6
2.0
75
14
[a] Unless otherwise mentioned, all the reactions were carried out by using 98.0 mg (0.40 mmol) of ortho-iodoketone 1a and aldehyde 2a (115.0 mg, 1.6 mmol). [b]
Isolated yields of chromatographically pure products.
With the established conditions in hand, [(1) for acylation: 1a (1.0
equiv), 2a (4.0 equiv), Pd(OAc)2 (5 mol %)/Ag2O (1.2 equiv),
aqueous TBHP (5.0 equiv) at 120 C for 14 h; (2) for nucleophilic
cylcocondensation: hydrazine hydrate (5 equiv), EtOH (2 mL), 75
C, for 6 h (Table 1, entry 13)], to check the scope and limitations
for the one-pot formation of phthalizine 3aa, the acylation and in-
situ nucleophilic cyclocondensation was explored. Thus, after
confirming the formation of acylation product upon coupling of
ortho-iodoarylketones 1a-1e with aldehydes 2a-2n, the hydrazine
hydrate and ethanol were added to the reaction mixture, under
the established conditions. Delightfully, the reaction was found to
be smooth and quite successful with very good substrate scope,
and furnished a diversified phthalazine products 3aa-3ef (Table
2). For example, ortho-iodoacetophenone 1a coupling with
aliphatic aldehydes 2a-2c and subsequent cyclocondensation
was amenable, and delivered the products 3aa-3ac (Table 2).
Notably, the one-pot reaction of 1a and 1b was also compatible
with benzaldehydes 2e, 2k-2m bearing simple to electron rich
aromatic
ring
(Table
2,
3al-3bk).
Further,
ortho-
iodobenzophenones 1c-1e, were also smoothly transformed into
the corresponding products, under standard reaction conditions
(Table 2, 3cn-3ef). Significantly, the reaction was amenable with
heteroaromatic systems (Table 2, 3cn & 3ef). Notably, the
strategy was also compatible with bromobenzaldehyde 2j and
thus would permit further functionalizations, under transition metal
catalysis (Table 2, 3dj).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
Table 2: Scope of the synthetic study for one-pot synthesis of phthalazines 3aa-3ef.[a]
[a] Isolated yields of chromatographically pure products.
Further, to emphasize the importance of the present method, it
was aimed at the one-pot synthesis of phthalazinones. For this
purpose, ortho-iodobenzoate 1f was identified as the suitable
starting material. Thus, acylation of ortho-iodomethylbenzoate 1f
with aliphatic aldehydes 2a-2d and subsequent condensation with
nitrogen based nucleophlies was carried out, under the
established conditions. Gratifyingly, the desired phthalazinones
5fa-5fd were obtained as the exclusive products (Table 3). In
addition, the reaction was also smooth with benzaldehydes 2e-2i,
2l ranging from simple, electron rich and electron deactivating
aromatic rings (Table 3, 5fe-5fl), thus, emphasizing the
importance of the present protocol.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
Table 3: One-pot synthesis of phthalazinones 5fa-5fl. [a]
[a] Isolated yields of chromatographically pure products.
Further, to demonstrate the synthetic utility of the present strategy, exploring the reaction under different conditions, it was realized
it was planned for the one-pot synthesis of N-substituted
phthalazinones. This could be achieved upon subjecting the
acylated dicarbonyl intermediate to N-protected hydrazine
hydrochloride analogs 8. Thus, after monitoring the formation of
ketone intermediate by TLC, the reaction mixture was treated with
different hydrazine analogs 8a-8e, to drive subsequent
cyclocondensation. To our delight, as anticipated, the strategy
was smooth with aliphatic aldehydes 2a-2c, under stablished
conditions (Table 4, 6faa-6fbe). However, the reaction was
sluggish when aromatic aldehydes were employed as the
acylating agents. This may be due to the fact that N-arylated
hydrazines are somewhat less nucleophilic than that of simple
hydrazine hydrate. Moreover, the corresponding ketone
intermediate generated from aromatic aldehydes is less
electrophilic than aliphatic ones. Hence, it is necessary to
optimize the conditions, for the formation of corresponding N-
substituted phthalazinones with aromatic aldehydes. After
that conc. H2SO4 (10 equiv), as an additive was best to drive the
cyclocondensation step. Further, these modified optimized
conditions enable the synthesis of N-substituted phthalazinones
(Table 4, 6fea-6fhe).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
Table 4: One-pot synthesis of N-substituted phthalazinones 6faa-6fhe. [a]
[a] Isolated yields of chromatographically pure products.
phenylhydrazine hydrochloride 8a (Scheme 2). Gratifyingly, the
target product PDE-4 inhibitor 6fla was obtained in 59% overall
yield.
Furthermore, to reveal the importance of present method, it was
aimed at the one-pot synthesis of PDE-4 inhibitor. Thus, ortho-
iodomethylbenzoate 1f was subjected to acylation with
veratraldehyde 2l and subsequent condensation with
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
Scheme 2: One-pot synthesis of PDE-4 inhibitor 6fla.
Moreover, to establish the diversity of this protocol, one-pot
synthesis of benzoxazinones was aimed. Thus, in-situ formed
ketones were reacted with hydroxylamine hydrochloride.
Delightfully, as presumed, the benzoxazinones 7fa-7fd were
accomplished, in moderate to fair yields (Table 5). It is worth
mentioning that the reaction was sluggish when attempts were
made with aromatic aldehydes as acylating agents. This could be
due to less nucleophilic nature of hydroxylamine hydrochloride. In
addition, the acylated aromatic ketones are slightly less reactive
than aliphatic ones.
and benzoxazinones. The whole process proceeds through [Pd]-
catalyzed intermolecular acylation and nucleophilic condensation
with dinucleophiles. Simple bench-top aldehydes and nitrogen
based nucleophiles were employed, as non-toxic sources. This
process was relied upon direct coupling with aldehydes, without
the activation of the carbonyl group and no directing group
assistance is needed. Significantly, the effectiveness of strategy
has been established by one-pot synthesis of PDE-4 inhibitor.
Experimental Section
Table 5: One-pot synthesis of benzoxazinones 7fa-7fd. [a]
IR spectra were recorded on a FTIR spectrophotometer. 1H NMR spectra
were recorded on 400 MHz spectrometer at 295 K in CDCl3; chemical
shifts (δ ppm) and coupling constants (Hz) are reported in standard fashion
with reference to either internal standard tetramethylsilane (TMS) (δH
=0.00 ppm) or CHCl3 (δH = 7.25 ppm). 13C NMR spectra were recorded on
100 MHz spectrometer at RT in CDCl3; chemical shifts (δ ppm) are
reported relative to CHCl3 [δC = 77.00 ppm (central line of triplet)]. In the
13C NMR, the nature of carbons (C, CH, CH2 and CH3) was determined by
recording the DEPT-135 spectra. In the 1H-NMR, the following
abbreviations were used throughout: s = singlet, d = doublet, t = triplet, q
= quartet, qui =quintet, sept = septet, dd = doublet of doublet, m = multiplet
and br. s = broad singlet. High-resolution mass spectra (HR-MS) were
recorded on Q-TOF electron spray ionization (ESI) mode and atmospheric
pressure chemical ionization (APCI) modes. Melting points were
determined on an electrothermal melting point apparatus and are
uncorrected.
All small scale reactions were carried out using Schlenk tube. Reactions
were monitored by TLC on silica gel using a combination of hexane and
ethyl acetate as eluents. Reactions were generally run under argon or a
nitrogen atmosphere. Solvents were distilled prior to use; petroleum ether
with a boiling range of 60 to 80 C was used. Acme’s silica-gel (60–120
mesh) was used for column chromatography (approximately 20 g per one
gram of crude material).
[a] Isolated yields of chromatographically pure products.
The aldehydes 2a-n which have been used are commercially available.
The ortho-iodoester 1f is commercially available.
The following ortho-iodo ketone 1a-e was synthesized from 10a-d which is
reported (Table 6, see supporting information).
Conclusions
In summary, a sequential one-pot method was developed for the
efficient and diversified synthesis of phthalazines, phthalazinones
GP-1 [General procedure for preparation of 3/5]:
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
GP-1 was carried out with ortho-iodoketone/ortho-iodoester 1a-f (98.0-
135.0 mg, 0.40 mmol) and aldehyde 2a-n (115.0-313.0 mg, 1.6 mmol) in
the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg, 0.48 mmol)
and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and allowed the
reaction mixture to stir at 120 C for 12-20 h. Progress of the reaction was
monitored by TLC till the ortho-iodoketone/ ortho-iodoester 1a-f was
completed. Then the reaction mixture was removed from oil bath and allow
to reach room temperature. Then added ethanol (2 ml) and hydrazine
mono hydrate (99.0 mg, 1.99 mmol) and allowed the reaction mixture
stirred at 75 C for 6-10 h. Progress of the products 3/5 formation was
monitored by TLC till the reaction was completed. The reaction mixture
was quenched by the addition of aqueous NaHCO3 solution and then
extracted with ethyl acetate (3  15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4) and filtered. Evaporation of
the solvent under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl acetate)
furnished the products 3/5 (50.0-106.0 mg, 43-72 %). The products 3al,
3am, 3de and 5fa-5fl are reported in literature.[21]
GP-4 [General procedure for preparation of 7]:
GP-4 was carried out with ortho-iodoester 1f (105.0 mg, 0.40 mmol) and
aldehyde 2a-d (115.0-179.0 mg, 1.6 mmol) in the presence of Pd(OAc)2
(5.0 mg, 5 mol %), Ag2O (111.3 mg, 0.48 mmol) and 70% aqueous solution
of TBHP (257.1 mg, 2.0 mmol) and allowed the reaction mixture to stir at
120 C for 12-20 h. Progress of the reaction was monitored by TLC till the
ortho-iodoester 1f was completed. Then the reaction mixture was removed
from oil bath and allow to reach room temperature. Then added ethanol (2
ml) and hydroxylamine hydrochloride (138.0 mg, 2.0 mmol) and allowed
the reaction mixture stirred at 75 C for 6-10 h. Progress of the products 7
formation was monitored by TLC till the reaction was completed. The
reaction mixture was quenched by the addition of aqueous NaHCO3
solution and then extracted with ethyl acetate (3  15 mL). The organic
layers were washed with saturated NaCl solution, dried (Na2SO4) and
filtered. Evaporation of the solvent under reduced pressure and purification
of the crude material by silica gel column chromatography (petroleum
ether/ethyl acetate) furnished the products 7 (46.0-52.0 mg, 50-63 %). The
products 7fa are reported in literature.[14]
GP-2 [General procedure (condition A) for preparation of 6faa-6fbe]:
1-methyl-4-propylphthalazine (3aa): GP-1 was carried out with ortho-
iodoketone 1a (98.0 mg, 0.40 mmol) and aldehyde 2a (115.0 mg, 1.6
mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg,
0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 14 h. Progress of the
reaction was monitored by TLC till the ortho-iodoketone 1a was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
6 h. Progress of the products 3aa formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
3aa (50.0 mg, 67 %). [TLC control (petroleum ether/ethyl acetate 95:05),
Rf(1a)=0.80, Rf(3aa)=0.30, UV detection]. IR (MIR-ATR, 4000–600 cm-1):
GP-2 was carried out with ortho-iodoester 1f (105.0 mg, 0.40 mmol) and
aldehyde 2a-c (115.0-160.0 mg, 1.6 mmol) in the presence of Pd(OAc)2
(5.0 mg, 5 mol %), Ag2O (111.3 mg, 0.48 mmol) and 70% aqueous solution
of TBHP (257.1 mg, 2.0 mmol) and allowed the reaction mixture to stir at
120 C for 12-18 h. Progress of the reaction was monitored by TLC till the
ortho-iodoester 1f was completed. Then the reaction mixture was removed
from oil bath and allow to reach room temperature. Then added ethanol (2
ml) and N-protected hydrazine hydrochloride 8 (410.0-623.0 mg, 2.8
mmol) and allowed the reaction mixture stirred at 75 C for 10-12 h.
Progress of the products 6 formation was monitored by TLC till the reaction
was completed. The reaction mixture was quenched by the addition of
aqueous NaHCO3 solution and then extracted with ethyl acetate (3  15
mL). The organic layers were washed with saturated NaCl solution, dried
(Na2SO4) and filtered. Evaporation of the solvent under reduced pressure
and purification of the crude material by silica gel column chromatography
(petroleum ether/ethyl acetate) furnished the products 6faa-6fbe (65.0-
106.0 mg, 57-61 %).

max=2938, 1710, 1682, 1594, 1452, 1282, 1081, 904, 728 cm-1. 1H NMR
(CDCl3, 400 MHz): δ=8.09-8.03 (m, 2H, Ar-H), 7.86-7.84 (m, 2H, Ar-H),
3.29-3.25 (m, 2H), 2.94 (s, 3H, CH3), 1.92-1.86 (m, 2H), 1.05 (t, J = 7.3 Hz,
3H, CH3), ppm. 13C NMR (CDCl3, 100 MHz): δ=159.4 (s, Ar-C=N), 156.1
(s, Ar-C=N), 131.7 (d, Ar-CH), 131.6 (d, Ar-CH), 126.2 (s, Ar-C), 125.3 (s,
Ar-C), 124.9 (d, Ar-CH), 124.5 (d, Ar-CH), 34.9 (t, –CH2–), 22.7 (t, –CH2–),
19.7 (q, CH3), 14.2 (q, CH3) ppm. HR-MS (ESI+) m/z calculated for
[C12H15N2]+=[MH]+: 187.1230; found 187.1236.
GP-3 [General procedure (condition B) for preparation of 6fea-6fhe]:
GP-3 was f carried out with ortho-iodoester 1f (105.0 mg, 0.40 mmol) and
aldehyde 2e-h (169.0-198.0 mg, 1.6 mmol) in the presence of Pd(OAc)2
(5.0 mg, 5 mol %), Ag2O (111.3 mg, 0.48 mmol) and 70% aqueous solution
of TBHP (257.1 mg, 2.0 mmol) and allowed the reaction mixture to stir at
120 C for 12-20 h. Progress of the reaction was monitored by TLC till the
ortho-iodoester 1f was completed. Then the reaction mixture was removed
from oil bath and allow to reach room temperature. Then added ethanol (2
ml), conc. H2SO4 (0.39 ml, 4.0 mmol) and N-protected hydrazine
hydrochloride 8 (410.0-623.0 mg, 2.8 mmol) and allowed the reaction
mixture stirred at 75 C for 40-48 h. Progress of the products 6 formation
was monitored by TLC till the reaction was completed. The reaction
mixture was quenched by the addition of aqueous NaHCO3 solution and
then extracted with ethyl acetate (3  15 mL). The organic layers were
washed with saturated NaCl solution, dried (Na2SO4) and filtered.
Evaporation of the solvent under reduced pressure and purification of the
crude material by silica gel column chromatography (petroleum ether/ethyl
acetate) furnished the products 6fea-6fhe (67.0-86.0 mg, 50-64 %). The
products 6fea, 6feb, 6fec, 6fed are reported in literature.[22, 12b]
1-butyl-4-methylphthalazine (3ab): GP-1 was carried out with ortho-
iodoketone 1a (98.0 mg, 0.40 mmol) and aldehyde 2b (137.0 mg, 1.6
mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg,
0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 12 h. Progress of the
reaction was monitored by TLC till the ortho-iodoketone 1a was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
8 h. Progress of the products 3ab formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
3ab (52.0 mg, 65 %). [TLC control (petroleum ether/ethyl acetate 95:05),
Rf(1a)=0.80, Rf(3aa)=0.30, UV detection]. IR (MIR-ATR, 4000–600 cm-1):
1-methyl-4-(3,4,5-trimethoxyphenyl)phthalazine (3am): GP-1 was
carried out with ortho-iodoketone 1a (98.0 mg, 0.40 mmol) and aldehyde
2m (314.0 mg, 1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %),
Ag2O (111.3 mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1
mg, 2.0 mmol) and allowed the reaction mixture to stir at 120 C for 20 h.
Progress of the reaction was monitored by TLC till the ortho-iodoketone 1a
was completed. Then the reaction mixture was removed from oil bath and
allow to reach room temperature. Then added ethanol (2 ml) and hydrazine
mono hydrate (99.0 mg, 1.99 mmol) and allowed the reaction mixture
stirred at 75 C for 8 h. Progress of the products 3am formation was
monitored by TLC till the reaction was completed. The reaction mixture
was quenched by the addition of aqueous NaHCO3 solution and then
extracted with ethyl acetate (3  15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4) and filtered. Evaporation of
the solvent under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl acetate)
furnished the products 3am (82.0 mg, 66 %).

max=2936, 1720, 1684, 1590, 1451, 1280, 1189, 943, 705 cm-1. 1H NMR
(CDCl3, 400 MHz): δ=8.08-8.02 (m, 2H, Ar-H), 7.86-7.83 (m, 2H, Ar-H),
3.30-3.27 (m, 2H), 2.93 (s, 3H, CH3), 1.87-1.79 (m, 2H), 1.52-1.43 (m, 2H),
0.95 (t, J = 7.3 Hz, 3H, CH3), ppm. 13C NMR (CDCl3, 100 MHz): δ=159.6
(s, Ar-C=N), 156.0 (s, Ar-C=N), 131.6 (d, Ar-CH), 131.5 (d, Ar-CH), 126.1
(s, Ar-C), 125.2 (s, Ar-C), 124.9 (d, Ar-CH), 124.5 (d, Ar-CH), 32.8 (t, –
CH2–), 31.5 (t, –CH2–), 22.8 (t, –CH2–), 19.7 (q, CH3), 13.9 (q, CH3) ppm.
HR-MS (ESI+) m/z calculated for [C13H17N2]+=[MH]+: 201.1386; found
201.1382.
1-methyl-4-pentylphthalazine (3ac): GP-1 was carried out with ortho-
iodoketone 1a (98.0 mg, 0.40 mmol) and aldehyde 2c (160.0 mg, 1.6
mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg,
0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 15 h. Progress of the
reaction was monitored by TLC till the ortho-iodoketone 1b was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
8 h. Progress of the products 3ac formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
3ac (51.0 mg, 60 %). [TLC control (petroleum ether/ethyl acetate 95:05),
Rf(1a)=0.80, Rf(3ac)=0.30, UV detection]. IR (MIR-ATR, 4000–600 cm-1):
5-methyl-8-phenyl-[1,3]dioxolo[4,5-g]phthalazine (3be): GP-1 was
carried out with ortho-iodoketone 1b (116.0 mg, 0.40 mmol) and aldehyde
2e (169.0 mg, 1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %),
Ag2O (111.3 mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1
mg, 2.0 mmol) and allowed the reaction mixture to stir at 120 C for 18 h.
Progress of the reaction was monitored by TLC till the ortho-iodoketone
1b was completed. Then the reaction mixture was removed from oil bath
and allow to reach room temperature. Then added ethanol (2 ml) and
hydrazine mono hydrate (99.0 mg, 1.99 mmol) and allowed the reaction
mixture stirred at 75 C for 10 h. Progress of the products 3be formation
was monitored by TLC till the reaction was completed. The reaction
mixture was quenched by the addition of aqueous NaHCO3 solution and
then extracted with ethyl acetate (3  15 mL). The organic layers were
washed with saturated NaCl solution, dried (Na2SO4) and filtered.
Evaporation of the solvent under reduced pressure and purification of the
crude material by silica gel column chromatography (petroleum ether/ethyl
acetate) furnished the products 3be (106.0 mg, 68 %). [TLC control
(petroleum ether/ethyl acetate 95:05), Rf(1a)=0.80, Rf(3be)=0.30, UV
detection]. IR (MIR-ATR, 4000–600 cm-1): max=2930, 1705, 1680, 1595,
1453, 1283, 1085, 912, 705 cm-1. 1H NMR (CDCl3, 400 MHz): δ=7.63-7.61
(m, 2H, Ar-H), 7.50-7.49 (m, 3H, Ar-H), 7.31 (s, 1H, Ar-H), 7.22 (s, 1H, Ar-
H), 6.13 (s, 2H, -OCH2O-), 2.91 (s, 3H, CH3) ppm. 13C NMR (CDCl3, 100
MHz): δ=158.1 (s, Ar-C=N), 155.1 (s, Ar-C=N), 151.4 (s, 2 × Ar-C), 136.6
(s, Ar-C), 129.7 (d, 2 × Ar–CH), 128.9 (d, Ar-CH), 128.4 (d, 2 × Ar–CH),
124.7 (s, Ar-C), 123.3 (s, Ar-C), 103.1 (d, Ar–CH), 102.3 (t, –CH2–), 101.1
(d, Ar–CH), 20.0 (q, CH3) ppm. HR-MS (ESI+) m/z calculated for
[C16H13N2O2]+=[MH]+: 265.0972; found 265.0973.

max=2938, 1719, 1687, 1612, 1460, 1280, 1081, 914, 705 cm-1. 1H NMR
(CDCl3, 400 MHz): δ=8.09-8.03 (m, 2H, Ar-H), 7.86-7.84 (m, 2H, Ar-H),
3.30-3.26 (m, 2H), 2.94 (s, 3H, CH3), 1.89-1.81 (m, 2H), 1.46-1.33 (m, 4H),
0.88 (t, J = 7.0 Hz, 3H, CH3), ppm. 13C NMR (CDCl3, 100 MHz): δ=159.6
(s, Ar-C=N), 156.0 (s, Ar-C=N), 131.6 (d, Ar-CH), 131.5 (d, Ar-CH), 126.2
(s, Ar-C), 125.2 (s, Ar-C), 124.9 (d, Ar-CH), 124.5 (d, Ar-CH), 33.1 (t, –
CH2–), 31.8 (t, –CH2–), 29.1 (t, –CH2–), 22.5 (t, –CH2–), 19.7 (q, CH3),
13.9 (q, CH3) ppm. HR-MS (ESI+) m/z calculated for [C14H19N2]+=[MH]+:
215.1543; found 215.1537.
1-(3,4-dimethoxyphenyl)-4-methylphthalazine (3al): GP-1 was carried
out with ortho-iodoketone 1a (98.0 mg, 0.40 mmol) and aldehyde 2l (265.0
mg, 1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3
mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol)
and allowed the reaction mixture to stir at 120 C for 20 h. Progress of the
reaction was monitored by TLC till the ortho-iodoketone 1a was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
10 h. Progress of the products 3al formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products 3al
(76.0 mg, 68 %).
5-(3-methoxyphenyl)-8-methyl-[1,3]dioxolo[4,5-g]phthalazine (3bk):
GP-1 was carried out with ortho-iodoketone 1b (116.0 mg, 0.40 mmol) and
aldehyde 2k (218.0 mg, 1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5
mol %), Ag2O (111.3 mg, 0.48 mmol) and 70% aqueous solution of TBHP
(257.1 mg, 2.0 mmol) and allowed the reaction mixture to stir at 120 C for
15 h. Progress of the reaction was monitored by TLC till the ortho-
iodoketone 1b was completed. Then the reaction mixture was removed
from oil bath and allow to reach room temperature. Then added ethanol (2
ml) and hydrazine mono hydrate (99.0 mg, 1.99 mmol) and allowed the
reaction mixture stirred at 75 C for 7 h. Progress of the products 3bk
formation was monitored by TLC till the reaction was completed. The
reaction mixture was quenched by the addition of aqueous NaHCO3
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
solution and then extracted with ethyl acetate (3  15 mL). The organic
layers were washed with saturated NaCl solution, dried (Na2SO4) and
filtered. Evaporation of the solvent under reduced pressure and purification
of the crude material by silica gel column chromatography (petroleum
ether/ethyl acetate) furnished the products 3bk (74.0 mg, 63 %). [TLC
control (petroleum ether/ethyl acetate 95:05), Rf(1a)=0.80, Rf(3bk)=0.30,
UV detection]. IR (MIR-ATR, 4000–600 cm-1): max=2932, 1719, 1676,
1590, 1451, 1280, 1189, 914, 708 cm-1. 1H NMR (CDCl3, 400 MHz): δ=
7.40 (t, J = 7.8 Hz, 1H, Ar-H), 7.29 (s, 1H, Ar-H), 7.25 (s, 1H, Ar-H), 7.19-
7.16 (m, 2H, Ar-H), 7.01 (dd, J = 8.3 Hz and 2.4 Hz, 1H, Ar-H), 6.12 (s, 2H,
-OCH2O-), 3.83 (s, 3H, -OCH3), 2.90 (s, 3H, CH3) ppm. 13C NMR (CDCl3,
100 MHz): δ=159.6 (s, 2 × Ar-C), 158.0 (s, Ar-C=N), 155.2 (s, Ar-C=N),
151.3 (s, 2 × Ar-C), 138.0 (s, Ar-C), 129.4 (d, Ar–CH), 124.7 (s, Ar-C),
123.2 (s, Ar-C), 122.1 (d, Ar–CH), 115.0 (d, Ar–CH), 115.0 (d, Ar–CH),
103.1 (d, Ar–CH), 102.3 (t, –CH2–), 101.1 (d, Ar–CH), 55.3 (q, CH3), 20.1
(q, CH3) ppm. HR-MS (ESI+) m/z calculated for [C17H15N2O3]+=[MH]+:
295.1077; found 295.1070.
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
3de (74.0 mg, 59 %).
1-(4-methoxyphenyl)-4-(p-tolyl)phthalazine (3df): GP-1 was carried out
with ortho-iodoketone 1d (135.0 mg, 0.40 mmol) and aldehyde 2f (192.0
mg, 1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3
mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol)
and allowed the reaction mixture to stir at 120 C for 15 h. Progress of the
reaction was monitored by TLC till the ortho-iodoketone 1d was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
8 h. Progress of the products 3df formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
3df (85.0 mg, 65 %). [TLC control (petroleum ether/ethyl acetate 95:05),
Rf(1a)=0.80, Rf(3df)=0.30, UV detection]. IR (MIR-ATR, 4000–600 cm-1):
1-phenyl-4-(thiophen-2-yl)phthalazine (3cn): GP-1 was carried out with
ortho-iodoketone 1c (123.0 mg, 0.40 mmol) and aldehyde 2n (179.0 mg,
1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3
mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol)
and allowed the reaction mixture to stir at 120 C for 18 h. Progress of the
reaction was monitored by TLC till the ortho-iodoketone 1c was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
8 h. Progress of the products 3cn formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
3cn (46.0 mg, 43 %). [TLC control (petroleum ether/ethyl acetate 95:05),
Rf(1a)=0.80, Rf(3cn)=0.30, UV detection]. IR (MIR-ATR, 4000–600 cm-1):

max=2938, 1720, 1685, 1509, 1455, 1286, 1087, 935, 730 cm-1. 1H NMR
(CDCl3, 400 MHz): δ=8.17-8.13 (m, 2H, Ar-H), 7.83-7.81 (m, 2H, Ar-H),
7.78-7.76 (m, 2H, Ar-H), 7.69 (d, J = 8.3 Hz, 2H, Ar-H), 7.38 (d, J = 7.8 Hz,
2H, Ar-H), 7.10 (d, J = 8.8 Hz, 2H, Ar-H), 3.91 (s, 3H, -OCH3), 2.48 (s, 3H,
Ar-CH3) ppm. 13C NMR (CDCl3, 100 MHz): δ=160.5 (s, Ar-C), 158.7 (s, Ar-
C=N), 158.4 (s, Ar-C=N), 139.2 (s, Ar-C), 133.5 (s, Ar-C), 131.7 (d, Ar-CH),
131.6 (d, 2 × Ar–CH), 130.1 (d, 2 × Ar–CH), 129.2 (d, 2 × Ar–CH), 128.8
(s, Ar-C), 126.6 (d, Ar-CH), 126.5 (d, Ar-CH), 126.0 (s, Ar-C), 125.9 (s, Ar-
C), 114.0 (d, 2 × Ar–CH), 55.4 (q, CH3), 21.4 (q, CH3) ppm. HR-MS (ESI+)
m/z calculated for [C22H19N2O]+=[MH]+: 327.1492; found 327.1490.

max=2943, 1713, 1689, 1590, 1451, 1287, 1189, 923, 711 cm-1. 1H NMR
1-(3-bromophenyl)-4-(4-methoxyphenyl)phthalazine (3dj): GP-1 was
carried out with ortho-iodoketone 1d (135.0 mg, 0.40 mmol) and aldehyde
2j (115.0 mg, 1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %),
Ag2O (111.3 mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1
mg, 2.0 mmol) and allowed the reaction mixture to stir at 120 C for 20 h.
Progress of the reaction was monitored by TLC till the ortho-iodoketone
1d was completed. Then the reaction mixture was removed from oil bath
and allow to reach room temperature. Then added ethanol (2 ml) and
hydrazine mono hydrate (99.0 mg, 1.99 mmol) and allowed the reaction
mixture stirred at 75 C for 8 h. Progress of the products 3dj formation was
monitored by TLC till the reaction was completed. The reaction mixture
was quenched by the addition of aqueous NaHCO3 solution and then
extracted with ethyl acetate (3  15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4) and filtered. Evaporation of
the solvent under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl acetate)
furnished the products 3dj (97.0 mg, 62 %). [TLC control (petroleum
ether/ethyl acetate 95:05), Rf(1a)=0.80, Rf(3dj)=0.30, UV detection]. IR
(MIR-ATR, 4000–600 cm-1): max=2940, 1705, 1687, 1589, 1451, 1287,
1182, 904, 728 cm-1. 1H NMR (CDCl3, 400 MHz): δ=8.21-8.11 (m, 1H, Ar-
H), 8.08-8.04 (m, 1H, Ar-H), 7.95 (t, J = 1.7 Hz, 1H, Ar-H), 7.88-7.85 (m,
2H, Ar-H), 7.78-7.67 (m, 4H, Ar-H), 7.45 (t, J = 7.8 Hz, 1H, Ar-H), 7.11 (d,
J = 8.8 Hz, 2H, Ar-H), 3.91 (s, 3H, -OCH3) ppm. 13C NMR (CDCl3, 100
MHz): δ=160.7 (s, Ar-C), 159.0 (s, Ar-C=N), 157.3 (s, Ar-C=N), 138.4 (s,
Ar-C), 133.0 (d, Ar-CH), 132.3 (d, Ar–CH), 132.1 (d, Ar–CH), 132.0 (d, Ar–
CH), 131.6 (d, 2 × Ar–CH), 130.0 (d, Ar–CH), 128.7 (d, Ar–CH), 128.5 (s,
(CDCl3, 400 MHz): δ=8.55 (d, J = 8.8 Hz, 1H, Ar-H), 8.13 (d, J = 8.8 Hz,
1H, Ar-H), 7.94-7.83 (m, 2H, Ar-H), 7.80-7.77 (m, 2H, Ar-H), 7.73-7.72 (m,
1H, Ar-H), 7.61-7.54 (m, 4H, Ar-H), 7.27-7.25 (m, 1H, Ar-H) ppm. 13C NMR
(CDCl3, 100 MHz): δ=158.6 (s, Ar-C=N), 152.8 (s, Ar-C=N), 139.0 (s, Ar-
C), 136.2 (s, Ar-C), 132.3 (d, Ar-CH), 132.0 (d, Ar–CH), 130.2 (d, 2 × Ar–
CH), 129.7 (d, Ar–CH), 129.3 (d, Ar–CH), 129.0 (d, Ar–CH), 128.5 (d, 2 ×
Ar–CH), 127.6 (d, Ar–CH), 126.8 (d, Ar–CH), 125.9 (s, Ar-C), 125.8 (d,
Ar-CH), 125.2 (s, Ar-C) ppm. HR-MS (ESI+) m/z calculated for
[C18H13N2S]+=[MH]+: 289.0794; found 289.0790.
1-(4-methoxyphenyl)-4-phenylphthalazine (3de): GP-1 was carried out
with ortho-iodoketone 1d (135.0 mg, 0.40 mmol) and aldehyde 2e (169.0
mg, 1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3
mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol)
and allowed the reaction mixture to stir at 120 C for 16 h. Progress of the
reaction was monitored by TLC till the ortho-iodoketone 1d was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
10 h. Progress of the products 3de formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
Ar-C), 126.8 (d, Ar-CH), 126.0 (d, Ar-CH), 125.8 (s, Ar-C), 125.7 (s, Ar-C),
122.6 (s, Ar-C), 114.1 (d, 2 × Ar–CH), 55.4 (q, CH3) ppm. HR-MS (ESI+)
m/z calculated for [C21H16BrN2O]+=[MH]+: 391.0441; found 391.0445.
4-butylphthalazin-1(2H)-one (5fb): GP-1 was carried out with ortho-
iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2b (137.0 mg, 1.6 mmol)
in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg, 0.48
mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 12 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
6 h. Progress of the products 5fb formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
5fb (52.0 mg, 65 %). [TLC control (petroleum ether/ethyl acetate 50:50),
Rf(1f)=1.0, Rf(5fb)=0.30, UV detection].
1-(thiophen-2-yl)-4-(p-tolyl)phthalazine (3ef): GP-1 was carried out with
ortho-iodoketone 1e (125.0 mg, 0.40 mmol) and aldehyde 2f (192.0 mg,
1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3
mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol)
and allowed the reaction mixture to stir at 120 C for 18 h. Progress of the
reaction was monitored by TLC till the ortho-iodoketone 1e was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
9 h. Progress of the products 3ef formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
3ef (68.0 mg, 56 %). [TLC control (petroleum ether/ethyl acetate 95:05),
Rf(1a)=0.80, Rf(3ef)=0.30, UV detection]. IR (MIR-ATR, 4000–600 cm-1):
4-pentylphthalazin-1(2H)-one (5fc): GP-1 was carried out with ortho-
iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2c (160.0 mg, 1.6 mmol)
in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg, 0.48
mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 14 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
6 h. Progress of the products 5fc formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
5fc (64.0 mg, 62 %). [TLC control (petroleum ether/ethyl acetate 50:50),
Rf(1f)=1.0, Rf(5fc)=0.30, UV detection].

max=3003, 1709, 1679, 1632, 1534, 1451, 1283, 1089, 924, 719 cm-1. 1H
NMR (CDCl3, 400 MHz): δ=8.53 (d, J = 7.8 Hz, 1H, Ar-H), 8.17-8.15 (m,
1H, Ar-H), 7.93-7.83 (m, 2H, Ar-H), 7.73-7.69 (m, 3H, Ar-H), 7.59 (dd, J =
4.8 Hz and 0.9 Hz , 1H, Ar-H), 7.38 (d, J = 7.8 Hz, 2H, Ar-H), 7.26 (dd, J =
4.8 Hz and 3.9 Hz , 1H, Ar-H), 2.48 (s, 3H, Ar-CH3 ppm. 13C NMR (CDCl3,
100 MHz): δ=158.5 (s, Ar-C=N), 152.6 (s, Ar-C=N), 139.3 (s, Ar-C), 139.0
(s, Ar-C), 133.3 (s, Ar-C), 132.2 (d, Ar-CH), 131.9 (d, Ar–CH), 130.1 (d, 2
× Ar–CH), 129.6 (d, Ar–CH), 129.2 (d, 2 × Ar–CH), 128.8 (d, Ar–CH),
127.6 (d, Ar–CH), 126.8 (d, Ar–CH), 125.8 (s, Ar-C), 125.7 (d, Ar-CH),
125.2 (s, Ar-C), 21.4 (q, CH3) ppm. HR-MS (ESI+) m/z calculated for
[C19H14N2NaS]+=[MNa]+: 325.0770; found 325.0773.
4-propylphthalazin-1(2H)-one (5fa): GP-1 was carried out with ortho-
iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2a (115.0 mg, 1.6 mmol)
in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg, 0.48
mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 14 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
6 h. Progress of the products 5fa formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
5fa (48.0 mg, 64 %). [TLC control (petroleum ether/ethyl acetate 50:50),
Rf(1f)=1.0, Rf(5fa)=0.30, UV detection].
4-cyclohexylphthalazin-1(2H)-one (5fd): GP-1 was carried out with
ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2d (179.0 mg, 1.6
mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg,
0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 13 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
7 h. Progress of the products 5fc formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
5fd (91.2 mg, 68 %).[TLC control (petroleum ether/ethyl acetate 50:50),
Rf(1f)=1.0, Rf(5fc)=0.30, UV detection].
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
4-phenylphthalazin-1(2H)-one (5fe): GP-1 was carried out with ortho-
iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2e (169.0 mg, 1.6 mmol)
in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg, 0.48
mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 14 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
6 h. Progress of the products 5fe formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
5fe (63.0 mg, 71 %). [TLC control (petroleum ether/ethyl acetate 20:80),
Rf(1f)=1.0, Rf(5fe)=0.30, UV detection].
0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 18 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
6 h. Progress of the products 5fh formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
5fh (55.0 mg, 57 %). [TLC control (petroleum ether/ethyl acetate 20:80),
Rf(1f)=1.0, Rf(5fh)=0.30, UV detection].
4-(3-chlorophenyl)phthalazin-1(2H)-one (5fi): GP-1 was carried out with
ortho- iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2i (224.0 mg, 1.6
mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg,
0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 17 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
9 h. Progress of the products 5fi formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products 5fi
(102.0 mg, 60 %). [TLC control (petroleum ether/ethyl acetate 20:80),
Rf(1f)=1.0, Rf(5fi)=0.30, UV detection].
4-(p-tolyl)phthalazin-1(2H)-one (5ff): GP-1 was carried out with ortho-
iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2f (192.0 mg, 1.6 mmol)
in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg, 0.48
mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 19 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
8 h. Progress of the products 5ff formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products 5ff
(60.0 mg, 63 %). [TLC control (petroleum ether/ethyl acetate 20:80),
Rf(1f)=1.0, Rf(5ff)=0.30, UV detection].
4-(3,4-dimethoxyphenyl)phthalazin-1(2H)-one (5fl): GP-1 was carried
out with ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2l (265.0
mg, 1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3
mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol)
and allowed the reaction mixture to stir at 120 C for 20 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
8 h. Progress of the products 5fl formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products 5fl
(81.0 mg, 72 %).[TLC control (petroleum ether/ethyl acetate 20:80),
Rf(1f)=1.0, Rf(5fl)=0.20, UV detection].
4-(naphthalen-1-yl)phthalazin-1(2H)-one (5fg): GP-1 was carried out
with ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2g (249.0 mg,
1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3
mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol)
and allowed the reaction mixture to stir at 120 C for 17 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydrazine mono hydrate
(99.0 mg, 1.99 mmol) and allowed the reaction mixture stirred at 75 C for
9 h. Progress of the products 5fg formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
5fg (69.0 mg, 63 %).[TLC control (petroleum ether/ethyl acetate 20:80),
Rf(1f)=1.0, Rf(5fg)=0.30, UV detection].
2-phenyl-4-propylphthalazin-1(2H)-one (6faa): GP-1 was followed with
ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2a (115.0 mg, 1.6
mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg,
0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 14 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and N-protected hydrazine
4-(4-fluorophenyl)phthalazin-1(2H)-one (5fh): GP-1 was carried out with
ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2h (198.0 mg, 1.6
mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
hydrochloride 8a (410.0 mg, 2.8 mmol) and allowed the reaction mixture
stirred at 75 C for 8 h. Progress of the products 6faa formation was
monitored by TLC till the reaction was completed. The reaction mixture
was quenched by the addition of aqueous NaHCO3 solution and then
extracted with ethyl acetate (3  15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4) and filtered. Evaporation of
the solvent under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl acetate)
furnished the products 6faa (106.0 mg, 61 %). [TLC control (petroleum
ether/ethyl acetate 95:05), Rf(1f)=0.60, Rf(6faa)=0.50, UV detection]. IR
(MIR-ATR, 4000–600 cm-1): max=3030, 1719, 1678, 1595, 1451, 1283,
1182, 914, 718, 675 cm-1.1H NMR (CDCl3, 400 MHz): δ= 8.54 (d, J = 7.8
Hz, 1H, Ar-H), 7.84-7.77 (m, 3H, Ar-H), 7.70-7.68 (m, 2H, Ar-H), 7.48 (t, J
= 7.8 Hz, 2H, Ar-H), 7.37-7.33 (m, 3H, Ar-H), 2.99-2.95 (m, 2H), 1.89-1.79
(m, 2H), 1.06 (t, J = 7.3 Hz, 3H, CH3), ppm. 13C NMR (CDCl3, 100 MHz):
δ=159.0 (s, C=O), 147.1 (s, Ar-C=N), 142.0 (s, Ar-C), 133.1 (d, Ar-CH),
131.3 (d, Ar-CH), 129.1 (s, Ar-C), 128.6 (d, 2 × Ar-CH), 128.6 (s, Ar-C),
127.7 (d, Ar-CH), 127.4 (d, Ar-CH), 125.6 (d, 2 × Ar-CH), 124.5 (d, Ar-CH),
34.2 (t, –CH2–), 21.4 (t, –CH2–), 13.9 (q, CH3) ppm. HR-MS (ESI+) m/z
calculated for [C17H17N2O]+=[MH]+: 265.1335; found 265.1331.
(MIR-ATR, 4000–600 cm-1): max=3012, 1704, 1685, 1593, 1453, 1284,
1189, 914, 700 cm-1.1H NMR (CDCl3, 400 MHz): δ= 8.54 (dd, J = 7.5 Hz
and 1.2 Hz, 1H, Ar-H), 7.84-7.82 (m, 2H, Ar-H), 7.79-7.76 (m, 1H, Ar-H),
7.68 (dd, J = 7.5 Hz and 1.2 Hz, 2H, Ar-H), 7.50-7.46 (m, 2H, Ar-H), 7.38-
7.33 (m, 2H, Ar-H), 3.01-2.97 (m, 2H), 1.84-1.77 (m, 2H), 1.47-1.35 (m,
4H), 0.91 (t, J = 7.3 Hz, 3H, CH3) ppm. 13C NMR (CDCl3, 100 MHz):
δ=159.0 (s, C=O), 147.4 (s, Ar-C=N), 142.0 (s, Ar-C), 133.1 (d, Ar-CH),
131.3 (d, Ar-CH), 129.1 (s, Ar-C), 128.6 (d, 2 × Ar-CH), 128.6 (s, Ar-C),
127.7 (d, Ar-CH), 127.4 (d, Ar-CH), 125.7 (d, 2 × Ar-CH), 124.5 (d, Ar-CH),
32.3 (t, –CH2–), 31.6 (t, –CH2–), 27.8 (t, –CH2–), 22.4 (t, –CH2–), 14.0 (q,
CH3) ppm. HR-MS (ESI+) m/z calculated for [C19H21N2O]+=[MH]+:
293.1648; found 293.1643.
4-butyl-2-tosylphthalazin-1(2H)-one (6fbe): GP-2 was followed with
ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2b (137.0 mg, 1.6
mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg,
0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 14 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and N-protected hydrazine
hydrochloride 8e (623.0 mg, 2.8 mmol) and allowed the reaction mixture
stirred at 75 C for 10 h. Progress of the products 6fbe formation was
monitored by TLC till the reaction was completed. The reaction mixture
was quenched by the addition of aqueous NaHCO3 solution and then
extracted with ethyl acetate (3  15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4) and filtered. Evaporation of
the solvent under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl acetate)
furnished the products 6fbe (86.0 mg, 60 %). [TLC control (petroleum
ether/ethyl acetate 95:05), Rf(1f)=0.60, Rf(6fbe)=0.50, UV detection]. IR
(MIR-ATR, 4000–600 cm-1): max=3010, 1700, 1682, 1509, 1451, 1285,
1084, 938, 716 cm-1.1H NMR (CDCl3, 400 MHz): δ=8.35-8.32 (m, 1H, Ar-
H), 8.08 (d, J = 8.3 Hz, 2H, Ar-H), 7.84-7.80 (m, 1H, Ar-H), 7.77-7.75 (m,
1H, Ar-H), 7.72-7.68 (m, 1H, Ar-H), 7.33 (d, J = 7.8 Hz, 2H, Ar-H), 3.00-
2.97 (m, 2H), 2.41 (s, 3H, Ar-CH3), 1.79-1.72 (m, 2H), 1.51-1.42 (m, 2H),
0.97 (t, J = 7.5 Hz, 3H, CH3) ppm. 13C NMR (CDCl3, 100 MHz): δ=158.2
(s, C=O), 148.2 (s, Ar-C=N), 145.5 (s, Ar-C), 134.5 (s, Ar-C), 134.3 (d, Ar-
CH), 131.8 (d, Ar-CH), 129.5 (d, 2 × Ar-CH), 129.3 (d, 2 × Ar-CH), 128.5
(s, Ar-C), 127.8 (d, Ar-CH), 125.0 (d, Ar-CH), 32.2 (t, –CH2–), 29.8 (t, –
CH2–), 22.5 (t, –CH2–), 21.7 (q, CH3), 13.8 (q, CH3) ppm. HR-MS (ESI+)
m/z calculated for [C19H21N2O3S]+=[MH]+: 357.1267; found 357.1271.
4-butyl-2-phenylphthalazin-1(2H)-one (6fba): GP-1 was followed with
ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2b (137.0 mg, 1.6
mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg,
0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 14 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and N-protected hydrazine
hydrochloride 8a (410.0 mg, 2.8 mmol) and allowed the reaction mixture
stirred at 75 C for 6 h. Progress of the products 6fba formation was
monitored by TLC till the reaction was completed. The reaction mixture
was quenched by the addition of aqueous NaHCO3 solution and then
extracted with ethyl acetate (3  15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4) and filtered. Evaporation of
the solvent under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl acetate)
furnished the products 6fba (64.0 mg, 58 %). [TLC control (petroleum
ether/ethyl acetate 95:05), Rf(1f)=0.60, Rf(6fba)=0.50, UV detection].
2,4-diphenylphthalazin-1(2H)-one (6fea): GP-3 was followed with ortho-
iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2e (169.0 mg, 1.6 mmol)
in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg, 0.48
mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 14 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml), conc. H2SO4 (0.39 ml, 4.0
mmol) and N-protected hydrazine hydrochloride 8a (410.0 mg, 2.8 mmol)
and allowed the reaction mixture stirred at 75 C for 45 h. Progress of the
products 6fea formation was monitored by TLC till the reaction was
completed. The reaction mixture was quenched by the addition of aqueous
NaHCO3 solution and then extracted with ethyl acetate (3  15 mL). The
organic layers were washed with saturated NaCl solution, dried (Na2SO4)
and filtered. Evaporation of the solvent under reduced pressure and
purification of the crude material by silica gel column chromatography
(petroleum ether/ethyl acetate) furnished the products 6fea (76.0 mg,
64 %). [TLC control (petroleum ether/ethyl acetate 95:05), Rf(1f)=0.60,
Rf(6fea)=0.50, UV detection].
4-pentyl-2-phenylphthalazin-1(2H)-one (6fca): GP-2 was followed with
ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2c (160.0 mg, 1.6
mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg,
0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 14 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and N-protected hydrazine
hydrochloride 8a (410.0 mg, 2.8 mmol) and allowed the reaction mixture
stirred at 75 C for 10 h. Progress of the products 6fca formation was
monitored by TLC till the reaction was completed. The reaction mixture
was quenched by the addition of aqueous NaHCO3 solution and then
extracted with ethyl acetate (3  15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4) and filtered. Evaporation of
the solvent under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl acetate)
furnished the products 6fca (67.0 mg, 57 %). [TLC control (petroleum
ether/ethyl acetate 95:05), Rf(1f)=0.60, Rf(6fca)=0.50, UV detection]. IR
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
2-(4-fluorophenyl)-4-phenylphthalazin-1(2H)-one (6feb): GP-3 was
followed with ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2e
(169.0 mg, 1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O
(111.3 mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0
mmol) and allowed the reaction mixture to stir at 120 C for 14 h. Progress
of the reaction was monitored by TLC till the ortho-iodoester 1f was
completed. Then the reaction mixture was removed from oil bath and allow
to reach room temperature. Then added ethanol (2 ml), conc. H2SO4 (0.39
ml, 4.0 mmol) and N-protected hydrazine hydrochloride 8b (455.0 mg, 2.8
mmol) and allowed the reaction mixture stirred at 75 C for 30 h. Progress
of the products 6feb formation was monitored by TLC till the reaction was
completed. The reaction mixture was quenched by the addition of aqueous
NaHCO3 solution and then extracted with ethyl acetate (3  15 mL). The
organic layers were washed with saturated NaCl solution, dried (Na2SO4)
and filtered. Evaporation of the solvent under reduced pressure and
purification of the crude material by silica gel column chromatography
(petroleum ether/ethyl acetate) furnished the products 6feb (70.0 mg,
55 %). [TLC control (petroleum ether/ethyl acetate 95:05), Rf(1f)=0.60,
Rf(6feb)=0.50, UV detection].
4-(4-fluorophenyl)-2-tosylphthalazin-1(2H)-one (6fhe): GP-3 was
followed with ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2h
(198.0 mg, 1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O
(111.3 mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0
mmol) and allowed the reaction mixture to stir at 120 C for 16 h. Progress
of the reaction was monitored by TLC till the ortho-iodoester 1f was
completed. Then the reaction mixture was removed from oil bath and allow
to reach room temperature. Then added ethanol (2 ml), conc. H2SO4 (0.39
ml, 4.0 mmol) and N-protected hydrazine hydrochloride 8e (623.0 mg, 2.8
mmol) and allowed the reaction mixture stirred at 75 C for 48 h. Progress
of the products 6fhe formation was monitored by TLC till the reaction was
completed. The reaction mixture was quenched by the addition of aqueous
NaHCO3 solution and then extracted with ethyl acetate (3  15 mL). The
organic layers were washed with saturated NaCl solution, dried (Na2SO4)
and filtered. Evaporation of the solvent under reduced pressure and
purification of the crude material by silica gel column chromatography
(petroleum ether/ethyl acetate) furnished the products 6fhe (79.0 mg,
50 %). [TLC control (petroleum ether/ethyl acetate 95:05), Rf(1f)=0.60,
Rf(6fhe)=0.50, UV detection]. IR (MIR-ATR, 4000–600 cm-1): max=2937,
1719, 1685, 1590, 1451, 1284, 1082, 935, 708 cm-1.1H NMR (CDCl3, 400
MHz): δ=8.42-8.40 (m, 1H, Ar-H), 8.12 (d, J = 8.3 Hz, 2H, Ar-H), 7.79-7.75
(m, 2H, Ar-H), 7.67-7.60 (m, 3H, Ar-H), 7.35 (d, J = 8.3 Hz, 2H, Ar-H), 7.25-
7.20 (m, 3H, Ar-H), 2.42 (s, 3H, Ar-CH3) ppm. 13C NMR (CDCl3, 100 MHz):
δ=164.9 (d, Ar-C-F, J = 249 Hz), 157.8 (s, C=O), 147.3 (s, Ar-C=N), 145.8
(s, Ar-C), 134.3 (d, Ar-CH), 134.3 (s, Ar-C), 132.2 (d, Ar-CH), 131.6 (d, Ar-
CH), 131.5 (d, Ar-CH), 130.3 (s, Ar-C), 129.6 (d, 2 × Ar-CH), 129.5 (d, 2 ×
Ar-CH), 129.3 (s, Ar-C), 128.9 (s, Ar-C), 127.8 (d, Ar-CH), 127.2 (d, Ar-
CH), 116.0 (d, Ar-CH), 115.8 (d, Ar-CH), 21.7 (q, CH3) ppm. HR-MS (ESI+)
m/z calculated for [C22H19N2O3S]+=[MH]+: 391.1111; found 391.1109.
2-(4-chlorophenyl)-4-phenylphthalazin-1(2H)-one (6fec): GP-3 was
followed with ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2e
(169.0 mg, 1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O
(111.3 mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0
mmol) and allowed the reaction mixture to stir at 120 C for 14 h. Progress
of the reaction was monitored by TLC till the ortho-iodoester 1f was
completed. Then the reaction mixture was removed from oil bath and allow
to reach room temperature. Then added ethanol (2 ml), conc. H2SO4 (0.39
ml, 4.0 mmol) and N-protected hydrazine hydrochloride 8c (501.0 mg, 2.8
mmol) and allowed the reaction mixture stirred at 75 C for 43 h. Progress
of the products 6feb formation was monitored by TLC till the reaction was
completed. The reaction mixture was quenched by the addition of aqueous
NaHCO3 solution and then extracted with ethyl acetate (3  15 mL). The
organic layers were washed with saturated NaCl solution, dried (Na2SO4)
and filtered. Evaporation of the solvent under reduced pressure and
purification of the crude material by silica gel column chromatography
(petroleum ether/ethyl acetate) furnished the products 6fec (80.0 mg,
60 %). [TLC control (petroleum ether/ethyl acetate 95:05), Rf(1f)=0.60,
Rf(6fec)=0.50, UV detection].
[12b]
4-(3,4-dimethoxyphenyl)-2-phenylphthalazin-1(2H)-one
(6fla)
:
GP-3 was followed with ortho-iodoester 1f (105.0 mg, 0.40 mmol) and
aldehyde 2l (265.0 mg, 1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5
mol %), Ag2O (111.3 mg, 0.48 mmol) and 70% aqueous solution of TBHP
(257.1 mg, 2.0 mmol) and allowed the reaction mixture to stir at 120 C for
20 h. Progress of the reaction was monitored by TLC till the ortho-iodoester
1f was completed. Then the reaction mixture was removed from oil bath
and allow to reach room temperature. Then added ethanol (2 ml), conc.
H2SO4 (0.39 ml, 4.0 mmol) and N-protected hydrazine hydrochloride 8a
(410.0 mg, 2.8 mmol) and allowed the reaction mixture stirred at 75 C for
45 h. Progress of the products 6fla formation was monitored by TLC till the
reaction was completed. The reaction mixture was quenched by the
addition of aqueous NaHCO3 solution and then extracted with ethyl acetate
(3  15 mL). The organic layers were washed with saturated NaCl solution,
dried (Na2SO4) and filtered. Evaporation of the solvent under reduced
pressure and purification of the crude material by silica gel column
chromatography (petroleum ether/ethyl acetate) furnished the products
6fla (84.0 mg, 59 %). [TLC control (petroleum ether/ethyl acetate 85:15),
Rf(1f)=0.90, Rf(6fla)=0.30, UV detection].
2-(4-bromophenyl)-4-phenylphthalazin-1(2H)-one (6fed): GP-3 was
followed with ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2e
(169.0 mg, 1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O
(111.3 mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0
mmol) and allowed the reaction mixture to stir at 120 C for 14 h. Progress
of the reaction was monitored by TLC till the ortho-iodoester 1f was
completed. Then the reaction mixture was removed from oil bath and allow
to reach room temperature. Then added ethanol (2 ml), conc. H2SO4 (0.39
ml, 4.0 mmol) and N-protected hydrazine hydrochloride 8d (625.0 mg, 2.8
mmol) and allowed the reaction mixture stirred at 75 C for 46 h. Progress
of the products 6feb formation was monitored by TLC till the reaction was
completed. The reaction mixture was quenched by the addition of aqueous
NaHCO3 solution and then extracted with ethyl acetate (3  15 mL). The
organic layers were washed with saturated NaCl solution, dried (Na2SO4)
and filtered. Evaporation of the solvent under reduced pressure and
purification of the crude material by silica gel column chromatography
(petroleum ether/ethyl acetate) furnished the products 6fed (86.0 mg,
57 %). [TLC control (petroleum ether/ethyl acetate 95:05), Rf(1f)=0.60,
Rf(6fed)=0.40, UV detection].
4-propyl-1H-benzo[d][1,2]oxazin-1-one (7fa): GP-4 was carried out with
ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2a (115.0 mg, 1.6
mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg,
0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 14 h. Progress of the
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydroxylamine
hydrochloride (138.0 mg, 2.0 mmol) and allowed the reaction mixture
stirred at 75 C for 7 h. Progress of the products 7fa formation was
monitored by TLC till the reaction was completed. The reaction mixture
was quenched by the addition of aqueous NaHCO3 solution and then
extracted with ethyl acetate (3  15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4) and filtered. Evaporation of
the solvent under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl acetate)
furnished the products 7fa (46.0 mg, 63 %). [TLC control (petroleum
ether/ethyl acetate 95:05), Rf(1f)=0.60, Rf(7fa)=0.50, UV detection].
ether/ethyl acetate 95:05), Rf(1f)=0.60, Rf(7fc)=0.50, UV detection]. IR
(MIR-ATR, 4000–600 cm-1): max=2945, 2876, 1819, 1710, 1680, 1599,
1457, 1280, 1089, 930, 708 cm-1.1H NMR (CDCl3, 400 MHz): δ= 8.38 (dd,
J = 7.8 Hz and 0.98 Hz, 1H, Ar-H), 7.91 (td, J = 7.5 Hz and 1.4 Hz, 1H, Ar-
H), 7.83 (td, J = 7.5 Hz and 1.4 Hz, 1H, Ar-H), 7.71 (d, J = 8.3 Hz, 1H, Ar-
H), 2.94-2.91 (m, 2H), 1.81-1.74 (m, 2H), 1.47-1.31 (m, 4H), 0.90 (t, J =
7.0 Hz, 3H, CH3) ppm. 13C NMR (CDCl3, 100 MHz): δ=163.8 (s, C=O),
155.9 (s, Ar-C=N), 135.3 (d, Ar-CH), 133.4 (d, Ar-CH), 128.8 (d, Ar-CH),
126.9 (s, Ar-C), 124.9 (d, Ar-CH), 122.7 (d, Ar-CH), 31.5 (t, –CH2–), 30.5
(t, –CH2–), 27.1 (t, –CH2–), 22.3 (t, –CH2–), 13.9 (q, CH3) ppm. HR-MS
(ESI+) m/z calculated for [C13H16NO2]+=[MH]+: 218.1176; found 218.1180.
4-cyclohexyl-1H-benzo[d][1,2]oxazin-1-one (7fd): GP-4 was carried out
with ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2d (179.0 mg,
1.6 mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3
mg, 0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol)
and allowed the reaction mixture to stir at 120 C for 12 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydroxylamine
hydrochloride (138.0 mg, 2.0 mmol) and allowed the reaction mixture
stirred at 75 C for 12 h. Progress of the products 7fd formation was
monitored by TLC till the reaction was completed. The reaction mixture
was quenched by the addition of aqueous NaHCO3 solution and then
extracted with ethyl acetate (3  15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4) and filtered. Evaporation of
the solvent under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl acetate)
furnished the products 7fd (46.0 mg, 50 %). [TLC control (petroleum
ether/ethyl acetate 95:05), Rf(1f)=0.60, Rf(7fd)=0.50, UV detection]. IR
(MIR-ATR, 4000–600 cm-1): max=2930, 1719, 1680, 1593, 1450, 1287,
1089, 934, 718 cm-1.1H NMR (CDCl3, 400 MHz): δ= 8.38 (dd, J = 7.8 Hz
and 0.98 Hz, 1H, Ar-H), 7.90 (td, J = 7.7 Hz and 1.2 Hz, 1H, Ar-H), 7.81
(td, J = 7.2 Hz and 1.4 Hz, 1H, Ar-H), 7.75 (d, J = 8.3 Hz, 1H, Ar-H), 3.09-
3.02 (m, 1H), 2.04-2.01 (m, 2H), 1.93-1.88 (m, 2H), 1.81-1.61 (m, 3H),
1.49-1.28 (m, 3H) ppm. 13C NMR (CDCl3, 100 MHz): δ=163.7 (s, C=O),
158.7 (s, Ar-C=N), 135.2 (d, Ar-CH), 133.2 (d, Ar-CH), 128.9 (d, Ar-CH),
126.5 (s, Ar-C), 124.4 (d, Ar-CH), 122.8 (d, Ar-CH), 39.6 (d, –CH–), 31.2
(t, 2 ×–CH2–), 26.4 (t, 2 ×–CH2–), 25.9 (t, –CH2–) ppm. HR-MS (ESI+) m/z
calculated for [C14H16NO2]+=[MH]+: 230.1176; found 230.1172.
4-butyl-1H-benzo[d][1,2]oxazin-1-one (7fb): GP-4 was carried out with
ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2b (137.0 mg, 1.6
mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg,
0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 13 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydroxylamine
hydrochloride (138.0 mg, 2.0 mmol) and allowed the reaction mixture
stirred at 75 C for 8 h. Progress of the products 7fb formation was
monitored by TLC till the reaction was completed. The reaction mixture
was quenched by the addition of aqueous NaHCO3 solution and then
extracted with ethyl acetate (3  15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4) and filtered. Evaporation of
the solvent under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl acetate)
furnished the products 7fb (45.0 mg, 56 %). [TLC control (petroleum
ether/ethyl acetate 95:05), Rf(1f)=0.60, Rf(7fb)=0.50, UV detection]. IR
(MIR-ATR, 4000–600 cm-1): max=2981, 1690, 1682, 1601, 1543, 1460,
1247, 1089, 914, 713 cm-1.1H NMR (CDCl3, 400 MHz): δ= 8.37 (dd, J = 7.8
Hz and 1.4 Hz, 1H, Ar-H), 7.91 (td, J = 7.7 Hz and 1.2 Hz, 1H, Ar-H), 7.83
(td, J = 7.7 Hz and 1.2 Hz, 1H, Ar-H), 7.71 (d, J = 7.8 Hz, 1H, Ar-H), 2.95-
2.91 (m, 2H), 1.79-1.68 (m, 3H), 1.50-1.45 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H,
CH3) ppm. 13C NMR (CDCl3, 100 MHz): δ=163.8 (s, C=O), 155.9 (s, Ar-
C=N), 135.3 (d, Ar-CH), 133.4 (d, Ar-CH), 128.8 (d, Ar-CH), 126.9 (s, Ar-
C), 124.9 (d, Ar-CH), 122.7 (d, Ar-CH), 30.2 (t, –CH2–), 29.5 (t, –CH2–),
22.4 (t, –CH2–), 13.7 (q, CH3) ppm. HR-MS (ESI+) m/z calculated for
[C12H14NO2]+=[MH]+: 204.1019; found 204.1023.
Acknowledgements ((optional))
We are grateful to the Council of Scientific and Industrial
Research [(CSIR), No. 02(0262)/16/EMR-II], New Delhi, for
financial support. S.B. thanks MHRD, New Delhi, for the award of
a research fellowship.
4-pentyl-1H-benzo[d][1,2]oxazin-1-one (7fc): GP-4 was carried out with
ortho-iodoester 1f (105.0 mg, 0.40 mmol) and aldehyde 2c (160.0 mg, 1.6
mmol) in the presence of Pd(OAc)2 (5.0 mg, 5 mol %), Ag2O (111.3 mg,
0.48 mmol) and 70% aqueous solution of TBHP (257.1 mg, 2.0 mmol) and
allowed the reaction mixture to stir at 120 C for 14 h. Progress of the
reaction was monitored by TLC till the ortho-iodoester 1f was completed.
Then the reaction mixture was removed from oil bath and allow to reach
room temperature. Then added ethanol (2 ml) and hydroxylamine
hydrochloride (138.0 mg, 2.0 mmol) and allowed the reaction mixture
stirred at 75 C for 10 h. Progress of the products 7fc formation was
monitored by TLC till the reaction was completed. The reaction mixture
was quenched by the addition of aqueous NaHCO3 solution and then
extracted with ethyl acetate (3  15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4) and filtered. Evaporation of
the solvent under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl acetate)
furnished the products 7fc (52.0 mg, 60 %). [TLC control (petroleum
Keywords One-pot reaction • Acylation • Cyclocondensation • Phthalazines
• Phthalazinones • Benzoxazinones • PDE-4 inhibitor
[1] (a) R. Grote, Y. Chen, A. Zeeck, Z. Chen, H. Zahner, P. Mischnick-
Lubbecke, W. A. Konig, J. Antibiot. 1988, 41, 595–601. (b) J. Y. Cho, H. C.
Kwon, P. G. Williams, P. R. Jensen, W. Fenical, Org. Lett. 2006, 8, 2471–
2474. (c) M. J. Winter, L. A. Jansma, M. T. Handel, S. B. Moore, Angew.
Chem., Int. Ed. 2009, 48, 767–770. (d) E. Vitaku, D.T. Smith, J. T. Njardarson,
J. Med. Chem. 2014, 57, 10257-10274.
[2]
(a) N. Vila, P. Besada, T. Costas, M. C. Costas-Lago, C. Terán, E. J.
Med. Chem. 2014.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
doi:10.1016/j.ejmech.2014.11.043. (b) A. Csámpai, K. Körmendy, P.
Sohár, F. Ruff, Tetrahedron 1989, 45, 5539–5548. (c) B. J. Sutherland,
P. J. Freeman, A. Williams, J. Appl. Microbiol. Biotechnol. 1998, 49, 445–
449. (d) N. Haider, K. J. Käferböck, P. Mátyus, Heterocycles 1999, 51,
2703–2710. (e) O. D. Morgan, D. W. Ollis, P. S. Stanforth, Tetrahedron
2000, 56, 5523–5534. (f) P. Franck, S. Hostyn, B. Dajka-Halász, A.
Polonka-Bálint, K. Monsieurs, P. Mátyus, W. U. B. Maes, Tetrahedron
2008, 64, 6030–6037. (g) H. O. A. El Nezhawy, T. S. Gaballah, A. A. M.
Radwan, Tetrahedron Lett. 2009, 50, 6646–6650. (h) M. V. Outerbridge,
M. S. Landge, H. Tamaki, B. Török, Synthesis 2009, 1801–1806. (i) W.
Li, H. Li, Z. Li, Tetrahedron Lett. 2010, 51, 5448–5450. (j) D. Poli, D.
Catarzi, V. Colotta, F. Varano, G. Filacchioni, S. Daniele, L. Trincavelli,
C. Martini, S. Paoletta, S. Moro, J. Med. Chem. 2011, 54, 2102–2113.
[3] (a) K. Jing, Y. Jia-Ping, L. Zhong-Yuan, L. Qi-Li, L. H. Sheng Li, G. W. Wang,
J. Org. Chem. 2017, 82 (23), 12715–12725. (b) Y. Xu, W. Hu, X. Tang,
J, Zhao, W. Wu, H. Jiang, Chem. Commun. 2015, 51, 6843-6846. (c) K.
Hiramatsu, T. Honjo, V. Rauniyar, F. D. Toste, ACS Catal. 2016, 6, 151–
154. (d) Z. Nie, C. Perretta, J. Lu, Y. Su, S. Margosiak, K. S. Gajiwala, J.
Cortez, V. Nikulin, K. M. Yager, K. Appelt, S. Chu, J. Med. Chem. 2005,
48, 1596–1609. (e) H. Ü. Kaniskan, K. D. Konze, J. Jin, J. Med. Chem.
2015, 58, 1596–1629.
[12] (a) K. P. Rao, A. K. Basak, P. K. Deb, S. Sharma, L. K. Reddy, Tetrahedron
Lett. 2013, 54, 3694–3696.
(b) A. S. Suresh, P. Baburajan, M.
Ahmed, Tetrahedron Lett. 2014, 55, 3482–3485.
[13] T. Vlaar, E. Ruijter, A. Znabet, E. Janssen, F. J. J. De Kanter, B. U. W.
Maes, R. V. a Orru, Org. Lett. 2011, 13, 6496–6499.
[14] H. Wang, Y. Liu, M. Li, H. Huang, H. M. Xu, R. J. Hong, H. Shen, Chem.
Commun. 2015, 51, 6843–6846.
[15] (a) L. Bai, Y. Yuan, J. Liu, J. Wu, L. Han, H. Wang, Y. Wang, X. Luan,
Angew. Chemie - Int. Ed. 2016, 55, 6946–6950; (b) M. Pérez-Gómez, L.
Navarro, I. Saura-Llamas, D. Bautista, M. Lautens, J. A. García-López,
Organometallics 2017, 36, 4465–4476; (c) R. Das, G. S. Kumar, M.
Kapur, European J. Org. Chem. 2017, 5439–5459; (d) H. Yoon, M. Rölz,
F. Landau, M. Lautens, Angew. Chemie - Int. Ed. 2017, 56, 10920–
10923; e) Z. Zuo, H. Wang, L. Fan, J. Liu, Y. Wang, X. Luan, Angew.
Chemie - Int. Ed. 2017, 129, 1–6;( f) M. Pérez-Gómez, J. A. García-
López, Angew. Chemie - Int. Ed. 2016, 55, 14389–14393;( g) K. Naveen,
S. A. Nikson, P. T. Perumal, Adv. Synth. Catal. 2017, 359, 2407–
2413;( h) M. He, J. F. Soulé, H. Doucet, ChemCatChem 2014, 6, 1824–
1859.
[4] (a) J. S. Suh, N. H. Jang, D. H. Jeong, M. Moskovits J. Phys. Chem. 1996,
100, 805–813. (b) M. Rashidi, S. M. Nabavizadeh, A. Zare, S. Jamali, R.
J. Puddephatt, Inorg. Chem. 2010, 49, 8435–8443. (c) B. Herberich, G.
Q. Cao, P. P. Chakrabarti, J. R. Falsey, L. Pettus, R. M. Rzasa, A. B.
Reed, A. Reichelt, K. Sham, M. Thaman, R. P. Wurz, S. Xu, D. Zhang,
F. Hsieh, M. R. Lee, R. Syed, V. Li, D. Grosfeld, M. H. Plant, B. Henkle,
L. Sherman, S. Middleton, L. M. Wong, A. S. Tasker, J. Med. Chem. 2008,
51, 6271–6279. (d) M. Mori, N. Rath, C. Gobble, J. Chickos, A. A.
Samarov , S. P. Verevkin, J. Chem. Eng. Data. 2016, 61, 370–379. (e)
V. J. Cee, L. B. Schenkel, B. L. Hodous, H. L. Deak, H. N. Nguyen, P. R.
Olivieri, K. Romero, A. Bak, X. Be, S. Bellon, T. L. Bush, A. C. Cheng, G.
Chung, S. Coats, P. M. Eden, K. Hanestad, P. L. Gallant, Y. Gu, X.
Huang, R. L. Kendall, M. J. Lin, M. J. Morrison, V. F. Patel, R. Radinsky,
P. E. Rose, S. Ross, J. R. Sun, J. Tang, H. Zhao, M. Payton, S. D. G.
Meyer, J. Med. Chem. 2010, 53, 6368–6377. (f) G. H. Birnberg, A. S.
Tomcufcik, J. B. Press, J. Org. Chem. 1982, 47, 5389–5391. (g) K. P.
Chan, A. S. Hay, J. Org. Chem. 1995, 60, 3131–3134.
[16] (a) T. Moragas, CA. Correa, R. Martin, Chem. A Eur. J. 2014, 20, 1–18;
(b) T. Xu, H. Alper, Org. Lett. 2015, 17, 4526–4529. (c) K. T. Neumann,
S. R. Laursen, A. T. Lindhardt, B. Bang-Andersen, T. Skrydstrup, Org.
Lett. 2014, 16, 2216–2219. (d) P. Xie, Y. Xie, B. Qian, H. Zhou, C. Xia,
H. Huang, J. Am. Chem. Soc. 2012, 134, 9902–9905. (e) W. M. Cheng,
R. Shang, H.Z. Yu, Y. Fu, Chem. - A Eur. J. 2015, 21, 1–6. (f) R. J.
Wakeham, J. E. Taylor, S. D. Bull, J. A. Morris, J. M. J. Williams, Org.
Lett. 2013, 15, 702–705. (g) K. Dong, X. Fang, R. Jackstell, G. Laurenczy,
Y. Li, M. Beller, J. Am. Chem. Soc. 2015, 137, 6053–6058; (h) X. Li, X.
Li, N. Jiao, J. Am. Chem. Soc. 2015, 137, 9246–9249. (i) L. Chu, J. M.
Lipshultz, D. W. C. MacMillan, Angew. Chem., Int. Ed. 2015, 54, 7929–
7933. (j) B. Tang, R. Song, C. Wu, Y. Liu, M. Zhou, W. Wei, G. Deng, J.
Am. Chem. Soc. 2010, 132, 8900–8902. (k) Q. Y. Toh, A. McNally, S.
Vera, N. Erdmann, M. J. Gaunt, J. Am. Chem. Soc. 2013, 135, 3772–
3775. (l) Z. Yin, P. Sun, J. Org. Chem. 2012, 77, 11339–11344. (m) X.
Jia, S. Zhang, W. Wang, F. Luo, J. Cheng, Org. Lett. 2009, 11, 3120–
3123. (n) M. Li, H. Ge, Org. Lett. 2010, 12, 3464–3467.
[5] (a) M. S. Moreno, F. G. Contreras, P. Navarro, C. Marín, F. Olmo, M. J. R.
Yunta, A. M. Sanz, M. J. Rosales, C. Cano, L. Campayo, J. Med. Chem.
2012, 55, 9900–9913. (b) D. A. Leinwand, S. M. Lefkowitz, H. C. Brenner,
J. Am. Chem. Soc. 1985, 107, 6179–6183. (c) V. L. Alverez, S. G. Hadley,
J. Phys. Chem. 1972, 76, 3937–3940. (d) L. K. Thompson, A. W. Hanson,
B. S. Ramaswamy, Inorg. Chem. 1984, 23, 2459–2465.
[17] (a) L. Mahendar, J. Krishna, A. G. K. Reddy, B. V. Ramulu, G.
Satyanarayana, Org. Lett. 2012, 14, 628–631; b) L. Mahendar, G.
Satyanarayana, J. Org. Chem. 2014, 79, 2059–2074; c) L. Mahendar, G.
Satyanarayana, J. Org. Chem. 2015, 80, 7089–7098; (d) D. R. Kumar,
G. Satyanarayana, Org. Lett. 2015, 17, 5894–5897; (e) J. Krishna, A. G.
K. Reddy, G. Satyanarayana, Adv. Synth. Catal. 2015, 357, 3597–3610;
(f) L. Mahendar, G. Satyanarayana, J. Org. Chem. 2016, 81, 7685–7691;
(g) A. G. K. Reddy, G. Satyanarayana, J. Org. Chem. 2016, 81, 12212-
12222; (h) K. Ramesh, G. Satyanarayana, J. Org. Chem. 2017, 82, 4254-
4264; (i) B. Suchand, G. Satyanarayana, Eur. J. Org. Chem. 2017, 26,
3886–3895. (J) K. Ramesh, G. Satyanarayana, Green Chem. 2018,
Advance Article.
[6] (a) S. Gabriel, A. Neumann, Ber. Dtsch. Chem. Ges. 1893, 26, 521–527. (b)
S. Gabriel, G. Pinkus, Ber. Dtsch. Chem. Ges. 1893, 26, 2210–2216.
[7] (a) R. N. Patel, In Chemistry of Heterocyclic Compounds: A Series of
Monographs; Castle, R. N., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ,
USA; Vol. 27, pp 323760. (b) D. D. Brown, J. Cinnolines and
Phthalazines: Supplement II, Volume 64; Chemistry of Heterocyclic
Compounds: A Series Of Monographs; 2005
[8] (a) N. Haider, C. Loll, J. Heterocycl. Chem. 1994, 31, 357–360. (b) N. Haider,
Tetrahedron 1991, 47, 3959–3968. (c) (a) D. Margetic, Y. Murata, K.
Komatsu, Z. Marinic, Helv. Chim. Acta 2009, 92, 298–312. (b) M.
Girardot, R. Nomak, K. J. Snyder, J. Org. Chem. 1998, 63, 10063–10068.
(d) G. Seitz, R. Hoferichter, R. Mohr, Angew. Chem., Int. Ed. 1987, 26,
332–334.
[18] B. Suchand, G. Satyanarayana, J. Org. Chem. 2016, 81, 6409-6423.
[19] B. Suchand, G. Satyanarayana, J. Org. Chem. 2017, 82, 372-381.
[20] B. Suchand, G. Satyanarayana, Eur. J. Org. Chem. 2017, asap, doi:
10.1002/ejoc.201701250.
[21] (a) K. Harikrishna, R. Mukkamala, B. Hinkelmann, F. Sasse, I. A. Singh,
Eur. J. Org. Chem. 2014, 5, 1066–1075. (b) M. F. Ismail, F. A. El-Bassioy,
H. A. Younes, Tetrahedron 1984, 40, 2983-2984. (c) M. Yamaguchi, K.
Kamei, T. Koga, M. Akima, T. Kuroki, N. Ohi, J. Med. Chem. 1993, 36,
4052-4060. (d) G. R. Dhage, S. R. Deshmukha, S. R. Thopate, RSC Adv.
2015, 5, 33377-33384.
[9]
S. N. Kessler, H. A. Wegner, Org. Lett. 2012, 14, 3268–3271.
[10] (a) L. Shi, L. Hu, J. Wang, X. Cao, H. Gu, Org. Lett. 2012, 14, 1876-1879.
(b) K. Viktor, M. Petrove, S. Andrej, K. Shubin, Tetrahedron, 2006, 62,
10018-10030.
[11] X. F. Wu, H. Neumann, S. Neumann, M. Beller, Chem. - A Eur. J. 2012,
18, 8596–8599.
[22] K. Bowden, A. Brownhill, F. Malik, Faisal, Journal of the Serbian Chemical
Society 1997, 62, 951-955.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800159
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here: max.
width: 5.5 cm; max. height: 5.0 cm))
Layout 2:
FULL PAPER
Basuli Scuhand and Gedu
Satyanarayana *
Page No. – Page No.
Palladium-Catalyzed Acylations: A
One-pot Diversified Synthesis of
Phthalazines, Phthalazinones and
Benzooxazinones
Text for Table of Contents
This article is protected by copyright. All rights reserved.