Synthesis of 4-alkylsulfanylphthalazin-1(2H)-ones via palladium catalyzed sulfanylation of substituted 4-bromophthalazin-1(2H)-ones

Article abstract of DOI:10.1016/j.tet.2016.10.022

The synthesis of a series of new alkylsulfanyl phthalazinone and phthalazine derivatives is described. The target compounds were efficiently synthesized in a four step sequence, consisting of (1) cyclization of 2-formylbenzoic acid with hydrazine hydrate to form phthalazinone, (2) the direct bromination of phthalazinone core with KBr₃, (3) alkylation of the obtained 4-bromolactam (Mitsunobu procedure) to make N- and also O-alkyl derivatives and finally (4) palladium-catalyzed coupling reactions of 2-alkyl-4-bromophthalazinone and 1-alkyloxy-4-bromophthalazine derivatives with aliphatic mercaptanes. Furthermore, the synthesis of 2-methyl-8-(propan-2-yl)sulfanyl-pyrido[3,4-d]pyridazin-1(2H)-one from 2-methyl-pyrido[3,4-d]pyridazin-1(2H)-one via bromination reaction with KBr₃and subsequent sulfanylation by isopropyl mercaptan under catalyzed coupling reaction conditions is also described.

Full text of DOI:10.1016/j.tet.2016.10.022

Accepted Manuscript
Synthesis of 4-alkylsulfanylphthalazin-1(2H)-ones via palladium catalyzed
sulfanylation of substituted 4-bromophthalazin-1(2H)-ones
Zbigniew Malinowski, Emilia Fornal, Beata Sierocińska, Renata Czeczko, Monika
Nowak
PII:
S0040-4020(16)31044-4
10.1016/j.tet.2016.10.022
TET 28163
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 July 2016
Revised Date: 28 September 2016
Accepted Date: 10 October 2016
Please cite this article as: Malinowski Z, Fornal E, Sierocińska B, Czeczko R, Nowak M, Synthesis
of 4-alkylsulfanylphthalazin-1(2H)-ones via palladium catalyzed sulfanylation of substituted 4-
bromophthalazin-1(2H)-ones, Tetrahedron (2016), doi: 10.1016/j.tet.2016.10.022.
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ACCEPTED MANUSCRIPT
Graphical Abstract
SR2
N
N
R1
a)
Pd coupling
X
N
Pd coupling
University of Łódź, Faculty of Chemistry,
Department of Organic Chemistry,
Tamka 12 Str., 91-403 Łódź, Poland.
EMF Lab, Paderewskiego 14/44 Str., 20-860 Lublin, Poland.
University of Life Sciences in Lublin,
Department of Chemistry,
Akademicka 15 Str., 20-950 Lublin, Poland.
O
SR2
N
N
N
NH
R1
b)
SR2
O
N
O
c
X = CH, N; R1 = Me, sBu, Pentan-2-yl, Neomenthyl;
R2 = Pr, iPr, sBu, 2Py, Cy, Bn
N
OR1

ACCEPTED MANUSCRIPT
Synthesis of 4-alkylsulfanylphthalazin-1(2H)-ones via palladium catalyzed
sulfanylation of substituted 4-bromophthalazin-1(2H)-ones
Zbigniew Malinowski,a* Emilia Fornal,b
Beata Sierocińska,a Renata Czeczko,c Monika Nowaka
a) University of Łódź, Faculty of Chemistry, Department of Organic Chemistry,
Tamka 12 Str., 91-403 Łódź, Poland.
b) EMF Lab, Paderewskiego 14/44 Str., 20-860 Lublin, Poland.
c) University of Life Sciences in Lublin, Department of Chemistry,
Akademicka 15 Str., 20-950 Lublin, Poland.
Keywords:
Phthalazinones, Bromination, Mitsunobu reaction, Palladium catalyzed coupling reaction,
Sulfanylation
Abstract
The synthesis of a series of new alkylsulfanyl phthalazinone and phthalazine derivatives
was is described. The target compounds were efficiently synthesized in a four step sequence
steps reaction, consisting of (1) cyclization of 2-formylbenzoic acid with hydrazine hydrate to
form phthalazinone, (2) the direct bromination of phthalazinone core with KBr3, then (3) the
alkylation reactions of the obtained 4-bromolactam (Mitsunobu procedure) to make N- and
also O-alkyl derivatives and finally (4) the palladium-catalyzed coupling reactions of 2-alkyl-
4-bromophthalazinone and 1-alkyloxy-4-bromophthalazine derivatives with aliphatic
mercaptanes. Furthermore, the synthesis of 2-methyl-8-(propan-2-yl)sulfanyl-pyrido[3,4-
d]pyridazin-1(2H)-one from 2-methyl-pyrido[3,4-d]pyridazin-1(2H)-one via bromination
reaction with KBr3 and subsequent sulfanylation by isopropyl mercaptan under catalyzed
coupling reaction conditions was is also described.
Corresponding authors. Fax: +4842 6786583; E-mail addresses: zbigmal@uni.lodz.pl (Z.
Malinowski)
1

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1. Introduction
Phthalazin-1(2H)-ones and phthalazines are nitrogen heterocycles which have aroused
great interest since over many years, due to their important biological and pharmacological
properties,1 as well as due to their significance in other fields, such as e.g. new in materials
chemistry.2 It has been shown that phthalazinone derivatives exhibit diverse biological
activities, e.g. antidiabetic,3 anticancer,4 antiasthmatic,5 anti-inflammatory, analgesic6 or
antimicrobial7 activities. Some of them have been used in medicine to treat cancer (Olaparib)
or diabetes (Zopolrestat).8 In the recent years, much attention was devoted to the studies on
the synthetic methods and properties of 4-substituted (alkyl, heteroaryl, amino) phthalazin-
1(2H)-ones.9-11 On the other hand, to date, the phthalazinones or phthalazines containing
sulfide or sulfone functional groups are a relatively little-studied class of compounds.
However, the literature review proves that some of them have shown interesting properties,
e.g. mesitylphthalazine I (Fig. 1) has exhibited a good antimicrobial activity against
Escherichia coli and Staphylococcus aureus (MIC = 12.5 µg/mL),12 phthalazine II has
exhibited a high cytotoxic activity (IC50 = 2.3
µM) against human breast cancer cell line
(MCF-7)13 and tert-butylsulfanylphthalazinone III has shown an activity as a modulator of
KCNQ potassium channel.14
AcO
S
S
Me
N
S
Me
S
N
N
Me
N
N
Cl
N
N
O
Me
Me
NH
O
Me
Br
I
II
III
Fig. 1. Biologically tested phthalazinone and phthalazine derivatives containing sulfanyl
moiety.
In continuing our work in on the synthesis of new polyazanaphthalene derivatives
(phthalazinones, azaphthalazinones, quinazolinones),15 and also taking into consideration the
importance of sulfanyl compounds, among other things as biologically active molecules,16
already partially mentioned above, we wished to present the investigate a route for the
synthesis of 2-substituted-4-alkylsulfanylphthalazinones using palladium catalyzed C-S
coupling reactions. The first report describing the palladium catalyzed C-S bond formation
reaction was presented towards the end of 1970s by Migita.17 Since then, many reviews
describing the sulfanyl derivatives formation in reactions of aromatic halogenated species
2

ACCEPTED MANUSCRIPT
with various thiols have been published,18 however these type of transformations were not
used to the synthesis of phthalazinones, containing C-S bonds. As a key intermediate for our
research, we chose 4-bromophthalazin-1(2H)-one (3, Scheme 1). Literature examples of the
synthesis of 3, usually involved condensation of phthalic anhydride with unsubstituted
hydrazine, and next dibromination of formed phthalazine-1,4-dione, followed by
monohydrolysis.11 So far, synthetic utilities of 4-bromo- and also 4-triflate- phthalazinone
derivatives were have been demonstrated, e.g. in a palladium or copper catalyzed coupling
reactions with amines, aryl- (heteroaryl-) boronic acids or with aryl- (alkyl-) acetylenes.11,17 19
2. Results and discussion
The planned synthetic route toward 4-bromophthalazinone (3) consisted of the two-
steps, as shown in Scheme 1 (Path A). The first step involved the condensation of 2-
formylbenzoic acid (1) with hydrazine hydrate, in boiling propan-1-ol, yielding phthalazin-
1(2H)-one (2), in 77% yield.18 20 In the next stage lactam 2 was subjected to bromination
reaction with various agents, combinations of reagents19 21 such as e.g. NBS/FeCl3 in MeCN,
Br2 in AcOH, Br2/FeBr3 in CCl4 or Br2/Na2CO3 in THF. Unfortunately, in most instances the
results were not satisfying; only when NBS/FeCl3 in MeCN and Br2/Na2CO3 in THF were
used the target bromo derivative 3 formed in a little amount (as judged by 1H NMR, TLC). ,
what made these methods useless in the further synthesis of target compounds. A literature
survey revealed that Br2-KBr various tribromide reagents, particularly potassium tribromide,
can be an effective reagent agents for bromination of heterocyclic compounds.20 22 The
treatment of phthalazin-1(2H)-one (2) with Br2-KBr in water as an environmentally friendly
solvent, afforded a regioselectivity brominated product 3, in a satisfactory yield (45%).
Moreover, an attempt to carry out the bromination of phthalazinone core The use of Br2-KBr
in an acetate buffer solution resulted in an increase in a yield of 3 (66%). The bromo
derivative 3 was isolated from the post reaction mixture using flash chromatography. In
addition to lactam 3, every time some amount of starting phthalazinone 2 was also isolated
from the crude material. The position substitution of the bromine atom in 4 position of
1
pyridazinone moiety was supported confirmed by H NMR spectroscopy. The spectrum of 3
revealed the absence of the singlet signal at 8.36 ppm (DMSO-d6) of 4-H H-4 pyridazinone
proton, characteristic of an unsubstituted phthalazinone 2.
Furthermore, it was found that we observed that also 2-methylaphthalazin-1(2H)-one (5)
(Scheme 1, Path B), also underwent the reaction bromination with potassium tribromide in
3

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water, to give exclusively the monobrominated product 4, substituted at 4 position of
pyridazinone ring, in 60 % yield. On the other hand, the introduction of the nitrogen atom into
the benzene ring condensed with pyridazinone moiety so significantly changed the reactivity
of obtained system that . 2-methylpyridopyridazin-1(2H)-one 821 23 (Scheme 1, Path C) ,
under the same reaction conditions, underwent bromination reaction only in the pyridine ring,
leading to afforded 8-bromo derivative 9, in 52% yield.
Path B
N
iv
v
N
Me
O
(45%)
5
O
i
COOH
Br
O
Br
N
Path A
ii
1
X
N
iii
N
N
NH
NH
Me
vi
OH
N
O
O
2
7
(X = CH 77%)
(X = N 70%)
3
4
N
(45% - Method A)
(66% - Method B)
Ph
(85% - Path A, Method A)
(40% - Path A, Method B)
(60% - Path B)
O
6
N
N
N
viii
N
N
N
vii
Me
Me
Path C
O
(55%)
O
(52%)
Br
8
9
Reagents and conditions: Path A: i) NH2NH2, PrOH, ∆, ii) Method A: Br2, KBr, H2O, ∆, Method B: Br2, KBr, acetate buffer,
∆; iii) Method A: MeI, K2CO3, acetone, ∆, Method B: MeI, K2CO3, acetone, MW; Path C B: iv) MeI, K2CO3, acetone, MW,
v) Br2, KBr, H2O, ∆; Path D C: vi) NH2NH2, ∆, vii) MeI, KOH, methanol, ∆, viii) Br2, KBr, H2O, ∆.
Scheme 1. The direct bromination reaction of phthalazinone 2, N-methylphthalazinone 5 and
N-methylpyridopyridazinone 8 with KBr3.
The mechanism of reaction KBr3 with 2, 5 and particularly with 8 is not obvious and
demands additional studies but . it can be assumed that in the case of halogenation of lactam
2, its lactim tautomeric form22 24 plays the a significant role. and The possible mechanism of
this transformation could be similar to the one proposed for the bromination reaction of
cinnolin-4(1H)-oneꢀ4-hydroxycinnoline with bromine in AcOH or in AcOK/AcOH .23
Likewise as for 2, the bromination process of cinnolinone also which proceeds selectively in
the heterocyclic ring and leads to the formation of 3-bromo derivative cinnolinone.25 On the
other hand, phthalazinones could be treated like acyl hydrazones, which bromination leads to
4

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the replacement of the methine hydrogen and the formation of the corresponding hydrazonoyl
bromides.24 26
Nevertheless, the detailed mechanismtic investigations of these transformations demand
additional studies and were not our main aim.
Two synthetic routes were employed for The important part of our studies was the
synthesis of the N-substituted phthalazinones and pyridopyridazinones. The conversion of 2H-
pyridazin-3-one derivatives into corresponding N-alkyl substituted products (Scheme 1 and
Table 1). was performed using two synthetic routes (Scheme 1, Table 1).
The first approach involved the reactions of lactams 2, 3, 8 with alkyl halides. It is known that
phthalazinones as well as their azaanalogues can exist in two tautomeric forms
(lactamꢀlactim) and thereby can be alkylated at the nitrogen or at the oxygen atom to
produce both N- and O-substituted products, depending on the reaction conditions. On the
other hand, it is known that It was found that potassium salts of phthalazinones selectively
react with methyl iodide or ethyl iodide at the lactam nitrogen atom while their silver salts
give mainly O-alkyl phthalazines.22 24 Thus, N-Methyl lactams 4 and 5 were prepared by
direct alkylation of phthalazinones 2, 3 with methyl iodide in the presence of K2CO3/dry
acetone under microwave or conventional heating conditions (Scheme 1, Path A, B).15
Unexpectedly, carrying out the reactions under MW conditions (55 oC, 3.5 h) turned out to be
less effective than conventional heating and the products 4, 5 were obtained in only moderate
yields (40% and 45%, respectively). The change of the reaction conditions (60 oC, 8 h) led to
an increase in a yield of 4 up to 85%. Carrying out the reaction in dry acetone at 55 oC for 3.5
h under microwave conditions allow derivatives 4 (40%), 5 (45%) to be obtained in moderate
yields. A considerable improvement of the yield of N-methyl lactam 4 (85%) was achieved
when the reaction was carried out under conventional heating conditions.
2-Methylpyridopyridazinone 8 was prepared from pyridopyridazinone 7 according to
previously described procedure (MeI, KOH/MeOH) in 55% yield.21 23 The formation of N-
methylated products was confirmed on the base basis of their FTIR spectra, which exhibited
bands in the region 1648–1665 cm–1 attributable to C=O group of lactams.
Alternatively, the synthesis of alkyl 4-bromophthalazinone derivatives was performed using
the Mitsunobu reaction.
In the second approach the alkylation of phthalazine core was carried out under
Mitsunobu reaction conditions. In our earlier paper, we have demonstrated an the
effectiveness of this procedure as a synthetic tool for the alkylation of phthalazinone moieties
5

ACCEPTED MANUSCRIPT
with the primary N-protected-aminoalcohols.25 27 In the present work, we focused on the
application of secondary alcohols, like butan-2-ol, pentan-2-ol and (–)-menthol. It is well-
known that in the case of secondary alcohols that the Mitsunobu reaction proceeds with the
inversion of configuration at the stereogenic center and thus, the employ use of menthol leads
28
to neomenthyl derivatives.26
Before attempting to synthesize N-alkylated
bromophthalazinones 13-15 (Table 1), we there was investigated the behavior of
unsubstituted phthalazinone 2 in the condensations with the mentioned secondary alcohols.
All tests reactions were carried out in the presence of TPP and DEAD,25,27 27,29 at room
temperature, in THF as solvent and were completed within 24 hours. At the beginning First,
we applied the procedure described by Knaac27 29 (Experimental, Table 1, Method A); the
analysis of the obtained post-reaction mixtures indicated the presence of Mitsunobu products,
DEAD-H2, triphenylphosphine oxide, unreacted starting compounds and others unidentified
substances. Despite the fact that reactions mainly coursed at the phthalazinone nitrogen atom
the outcomes were moderate and products 10a-12a were isolated only in 30–48% yields
(Table 1, Entry 1, 2, 3, 5, Method A). On the other hand, it is possible that also corresponding
O-derivatives 10b¸11b and 12b were formed in trace amounts (1H NMR), but they were not
isolated. Next, we examined the effectiveness of an alkylation of phthalazinone 2 using
30
modified Sammakia28
procedure conditions (Experimental, Table 1, Method B).
Compounds 10a and 11a were received with meaningful better results (72% and 85%,
respectively) but . unexpectedly, neomenthyl derivative 12a was separated isolated in only
30% yield. The obtained results clearly showed that Therefore, in some cases, changes of in
the reaction temperature as well as the order of reagent addition, can result in an increase of
Mitsunobu products yields.
Finally, the condensations of 4-bromophthalazin-1(2H)-one (3) with butan-2-ol, pentan-2-ol
and (–)-menthol secondary alcohols were performed using the second procedure (Method B,
Table 1) the same reaction conditions as for 2 (Method B) and led to the formation of product
mixtures of N-alkyl-bromophthalazinones 13a-15a and O-alkyl-bromophthalazines 13b-15b
(Table 1), in which the former largely predominated.
Compounds 13a-15a, 13b and 15b were separated by flash chromatography and identified by
NMR and HRMS spectroscopy. Only, the phthalazine 14b was isolated in the mixture with
14a. The total yields of obtained products 13a,b, 14a,b, and 15a,b were 54%, 31% and 57%,
respectively.
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Table 1. The alkylation reaction of phthalazinones 2, 3 under
Mitsunobu reaction conditions.
R1
R1
N
N
N
NH
OH
O
2
R1 = H; R1 = Br
3
R2-OH
DEAD, TPP
THF, rt, 24 h
R1
R1
N
N
N
N
+
R2
O
O
R2
10a
-
15a
10b
-
15b
Yield (%)a
Method A Method B
Entry
Compound
10a
R1
R2
Me
Me
1
2
H
H
30
48
72
85
Me
11a
Me
Me
3
H
40
30
12a
Me
Me
Me
Me
4
5
6
7
Br
Br
Br
Br
–
–
–
–
48
6
13a
13b
14a
14b
Me
Me
Me
Me
28
3b
Me
Me
Me
8
9
Br
Br
–
29
28
15a
15b
Me
Me
Me
Me
–
Me
a Yield was given for isolated product after silica gel chromatography;
b Mixture with 14a (1H NMR).
The structures of N-, O- isomeric alkyl derivatives 13-15 were explicitly characterized based
1
on the comparison of H NMR spectra. The major diagnostic value in the identification of
phthalazinone and phthalazine derivatives had the chemical shifts of H-8 aromatic proton and
7

ACCEPTED MANUSCRIPT
methine proton of alkyl substituent, attached to carbon adjacent to nitrogen or oxygen atom.
In the case of 13a-15a, the H-8 proton signals were appreciably more downfield shifted (≈ 8.4
ppm), than in the instance of corresponding O-derivatives 13b-15b (≈ 8.1 ppm) (≈ 8.4 ppm
and ≈ 8.1 ppm, respectively), while the methine protons of alkyl groups were more upfield
shifted for N-derivatives. For example, for O-derivative 15b the methine proton signal was
observed at ≈ 5.92 ppm, while for 15a at ≈ 5.43 ppm. Furthermore, in the 13C NMR spectra of
10b-12b 13b-15b signals corresponding to the carbon of O-Csp3 and Csp2-O moiety were
observed at ≈ 74 ppm and ≈ 160 ppm, respectively. Whereas for N-derivatives 13a-15a,
signals of N-Csp3 and C=O carbon atoms appeared at ≈ 53 ppm and ≈ 159 ppm, respectively.
Likewise as in the case of N-methyl derivatives, the FTIR spectra of the N-substituted lactams
13a, 14a, 15a showed shown the presence of C=O band at in the range 1653–1660 cm–1
characteristic of the lactam carbonyl group, which were was absent in the FTIR spectra of
13b, 14b and 15b.
From achieved reaction results (Table 1) it become clear that the chemical nature of
phthalazinones as ambident nucleophiles as well as alcohols can have an influence on the
course of the Mitsunobu reaction and on the ratio of formed N-, O- isomeric products. In
particular, we have found, that the bromine atom at the 4-position of the pyridazinone moiety
in 3 clearly increased the formation of O-alkylated phthalazine in comparison with an
unsubstituted phthalazinone. In addition, in this case an amount of the produced phthalazine
derivative depended also on the kind of alcohol used for alkylation of 3 process (Table 1,
Entry 8, 10, 12, 5, 7, 9) and it was the largest for (–)-menthol.
A similar dual behavior of various ambident nucleophilic components in Mitsunobu reaction,
was well documented in the literature,29 31 but a lucid an explanation of this phenomenon and
especially the prediction of the amounts of formed products is still problematic. The Hard and
Soft Acids and Bases (HSAB) concept30 32 is one of more popular theory used for describing
reactivity of ambident nucleophiles., but its direct and uncritical application to organic
chemistry should be circumspect due to sometimes erroneous deductions to which it can
lead.31 According to the HSAB principle, an intermediate formed from alcohol in Mitsunobu
reaction, as hard electrophilic species should be preferentially attacked by harder nucleophilic
atom (oxygen), but our experimental data showed shown the softer nucleophilic site in the
ambident phthalazinone anion was mainly alkylated (Tables 1 and 2). Mayr31 33 as well
Fletcher32 34 have written in your papers paid attention that Marcus theory better describes the
behavior of amide type species in alkylation process. Despite the fact that, the value of
8

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intrinsic barrier prefers the oxygen attack (it is slight lower than for nitrogen), the course of
reaction through the nitrogen atom is thermodynamically favoured (amides are typically 80
kJ/mol more stable than their tautomers).33,34 and it is in accordance with our experiment
results. Thus, direct and uncritical application of the HSBA theory to organic chemistry can
lead to wrong conclusions and it should be treated with caution.33
On the other hand, the HSAB-theory can be with give good results when applied to explain
the influence of the alcohol (their its hardness or softness, in fact) on the distribution of
isomeric N-/O- alkylated products in the Mitsunobu reaction obtained from 3. Based on the
methodology presented by Meier33 35 we closer examined the experimental data obtained for
4-bromoderivatives 13-15 (Tables 1 and 2). Approximately, the hardness/softness of an
intermediate formed from alcohol in Mitsunobu reaction can be assessed based on the 13C
NMR chemical shift of the corresponding HC-OH alcohol carbon atom attached to the
hydroxyl group.33 35 The more the HC-OH carbon atom signal is downfield, the harder it is
likely to be and harder more O- derivative should be also appeared. a carbocation-like center
of an alcohol intermediate
Table 2. The ratio of N-/O- alkylation of lactam 3.
N-/O-
HC-OH
(ppm)a
Entry
Alcohol
Lactam alkylation
ratiob
HO
1
2
67.0
68.5
95:5
Me
Me
Me
Me
HO
92:8
3
OH
Me
Me
3
71.7
62:38
Me
a
-
13C NMR chemical shift of HC-OH-carbon atom of alcohol;
b - The ratio of the formed N- and O- alkylated products was
determined by 1H NMR analysis of the crude mixture.
The obtained values of chemical shifts of HC-OH carbon for pentan-2-ol, butan-2-ol
and (–)-menthol (Table 2) were as follows: 67.0, 68.5 and 71.7 ppm. These data implied that
the C-1 carbon atom of menthol should be harder than the C-2 carbon atoms of butan-2-ol or
pentan-2-ol and thereby, (–)-menthol can form more O- alkylated product. Indeed, these
predictions are in conformity with experimental data.
The observed ratio of the formed O-alkylated 1-bromophthalazine to N-alkylated 4-
bromophthalazinone increased from 5:95 (pentan-2-ol), 8:92 (butan-2-ol) to 38:62 ((-)-
9

ACCEPTED MANUSCRIPT
menthol). Therefore, the well thought out use of HSAB or Marcus theories can supply to
conclusions in accordance with experimental data.
In the next step bromolactams 4, 9, 13a, 14a and 15a (Scheme 2) were subjected to the
palladium cross-coupling reaction with mercaptanes with a view to synthesize target 2-alkyl-
4-sulfanyl- and 2-alkyl-8-sulfanyl- derivatives.
The first report describing the palladium catalyzed C-S bond formation reaction was
presented towards the end of 1970s by Migita.34 Since then, many reviews describing the
sulfanyl derivatives formation in reactions of aromatic halogenated species with various thiols
have been published in the literature,35 however these type of transformations were not used
to the synthesis of phthalazinones, containing C-S bonds.
To optimization of the reaction conditions for the palladium-catalyzed synthesis of sulfanyl
derivatives, we initially investigated the reaction of 4-bromo-2-methylphthalazin-1(2H)-one 4
with isopropyl mercaptan in the presence of Pd(OAc)2 as a palladium source and phosphine
ligand, like: XantPhos, DPEPhos, DavePhos (Table 3).
Table 3. Optimization of the C-S coupling reaction conditions.
Me
S
Me
R1
Br
SH
N
N
N
N
Pd/L/DIPEA
1,4-dioxane
+
Me
Me
R1
O
O
3
4
R1 = H
R1 = Me
16 R1 = H
17 R1 = Me
Yield (%)a
Pd/L ratio
Entry
R1
L
Pd
(mol%)
10 / 10
10 / 10
30 / 30
30 / 30
30 / 30
30 / 30
16
17
1
2
3
4
5
6
Me
Me
Me
Me
Me
H
DavePhos
XantPhos
DavePhos
XantPhos
DPEPhos
XantPhos
Pd(OAc)2
–
–
NR
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
NR
10
84b
78
–
–
–
–
16
Reaction conditions: 4-bromophthalazinone
3
(0.209 mmol) or 4-bromo-2-
methylphthalazinone 4 (0.209 mmol), isopropyl thiol (0.418 mmol), DIPEA (0.7 mL), 1,4-
dioxane (5 mL), 100 oC (26 h);
a Yield determined by 1H NMR analysis of crude reaction mixture;
b Yield of isolated product;
NR - No reaction.
10

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Cy2P
PPh2
PPh2
PPh2
PPh2
O
O
NMe2
Me Me
DavePhos
DPEPhos
XantPhos
When the combination of Pd(OAc)2 with DavePhos (Entry 1), or Pd(OAc)2 with
XantPhos (Entry 2) in the ratio 10 mol%/10 mol% as catalytic system were used to for the
coupling 4 with mercaptan, the production of 17 was not observed. The Further investigations
showed that the an increased an amount of Pd(OAc)2 and DavePhos up to 30 mol%/30 mol%
(Entry 3) resulted in the production of 17, which was observed in 10% yield by 1H NMR. In
the presence of Pd(OAc)2 and XantPhos used in the same ratio (Entry 4) sulfide 17 was
formed as the major product, and finally was isolated in 84% yield. The replacement of the
XantPhos by DPEPhos led to a slight decrease in the reaction yield (78%, 1H NMR, Entry 5).
Although both catalytic systems worked, Pd(OAc)2/XantPhos proved to be more productive
and gave the higher yield of the target product 17. Moreover, in this case the starting lactam 4
was observed only in trace amount, in the crude reaction mixtures by 1H NMR.
In addition, we it was observed that the corresponding 4-bromophthalazinone 3 (Entry
6) also underwent sulfanylation in the presence of Pd(OAc)2/XantPhos system in the ratio 30
mol%/30 mol% and gave 16, in 16% (1H NMR) yield. Attempts to separation of 16 by flash
chromatography was were failed, and finally it was obtained as a mixture with 3 and
characterized by 1H NMR spectroscopy.
Based on the results presented in Table 3, bromolactams 4, 9, 13a, 14a were subjected
to coupling reactions with various mercaptanes. As can be seen from Scheme 2, the palladium
catalyzed sulfanylation of 4, 9, 13a and 14a proceeded excellent with primary as well as
secondary aliphatic mercaptanes. Unexpectedly, 2-mercaptopyridine was unreactive towards
4 and product 18 was not observed. The target alkylsulfanyl derivatives 17, 19-22, 24 were
isolated in 75–92% yields. The reaction of 13a with propyl mercaptan surprisingly processed
in lower yield than in other cases and derivative 23 was isolated in 39% yield.
11

ACCEPTED MANUSCRIPT
R4
S
N
N
R2
R1
R4-SH, DIPEA
O
17
-
24
Pd(OAc)2, XantPhos
X
N
N
1,4-dioxane, 100 oC, 26 h
R2
R3
O
N
N
N
4
,
13a
,
14a
X = CH, R1 = Br, R2 = Me, sBu, Pentan-2-yl, R3 = H
R2
9
X = N, R1 = H, R2 = Me, R3 = Br
S
O
R4
25
Me
N
Me
S
Me
Me
S
S
Me
Me
N
N
N
N
N
N
Me
O
O
O
17 (84%)
18 (0%)
19 (75%)
Me
S
Me
S
S
N
N
N
N
N
N
Me
Me
Me
O
O
O
Me
20 (92%)
21 (79%)
22 (78%)
Me
Me
S
S
N
N
N
N
N
N
N
Me
Me
S
O
Me
O
Me
O
Me
Me
Me
23 (39%)
24 (90%)
25 (81%)
Scheme 2. Synthesis of sulfanyl phthalazinone and pyridopyridazinone derivatives.
Apart from bromophthalazinones, 1-bromophthalazines may be also transformed into
sufanyl derivatives. The treatment of 15a as well, 15b with sec-butyl mercaptan in the
presence of the previously used catalytic system led to alkylsulfanylphthalazinone 26 and
alkylsulfanylphthalazine 27 (Scheme 3) in 82% and 36% yields, respectively.
1
Sulfanylderivatives 26, 27 were obtained as mixtures of two diastereomers (dr = 1:1, H
NMR) each, due to the presence of an additional stereogenic center from the sec-butyl thiol.
s
Curiously, the coupling reactions of bromoderivatives 15a, 15b with Bu-SH proceeded
without any diastereoselectivity effect, despite the presence of the neomenthyl moiety in both
molecules.
12

ACCEPTED MANUSCRIPT
Br
Br
N
N
N
NH
O
OH
3
Mitsunobu
reaction
Me
Me
Me
Me
S
Br
O
Br
S
sBu-SH, DIPEA
sBu-SH, DIPEA
Me
Me
Me
Me
N
N
Pd(OAc)2, XantPhos
N
N
N
N
N
Pd(OAc)2, XantPhos
1,4-dioxane, 100 oC, 26 h
1,4-dioxane, 100 oC, 26 h
N
O
Me
O
Me
O
Me
Me
Me
Me
Me
Me
26a
,
b
(82%)
27a,b (36%)
15a
15b
Scheme 3. Synthesis of neomenthyl derivatives 26, 27.
Successful synthesis of 25 and 27 has confirmed our conjectures that the described
above strategy could be a useful tool for modifications of various heterocyclic systems.
The proposed structures of all new compounds were confirmed using spectroscopic analyses
(NMR, FTIR and HRMS).
3. Conclusion
In conclusion, we have demonstrated an efficient synthesis of 2-alkyl-4-alkylsulfanyl
phthalazinones 17, 19-24, 26 and 1-alkyloxy-4-alkylsulfanyl phthalazine 27 via the direct
bromination of phthalazin-1(2H)-one (2) with potassium tribromide, followed by alkylation of
4-bromophthalazinone 3 with methyl iodide or selected secondary alcohols in the presence of
TPP and DEAD (Mitsunobu reaction) and further palladium-catalyzed sulfanylation of
lactams 4, 13a-15a and phthalazine 15b with aliphatic mercaptanes. Furthermore, we have
demonstrated that 2-methylphthalazinone 5 and 2-methylazaphthalazinone 8 can be also
brominated with KBr3, thereby providing for the possibility of the further synthesis of new
compounds under metal catalyzed coupling reactions.
4. Experimental section
1
Melting points were determined on a Boetius hot stage apparatus and were uncorrected. H,
13C NMR spectra were recorded on a Bruker Advance III spectrometer at 600 MHz and 150
MHz respectively. The residual CDCl3 or DMSO-d6 signal was used for reference (CDCl3 at
13

ACCEPTED MANUSCRIPT
1
7.26 ppm or DMSO-d6 at 2.50 ppm for H NMR and CDCl3 at 77.16 ppm or DMSO-d6 at
39.52 ppm for 13C NMR).36 2D Homonuclear 1H, 1H COSY spectra and heteronuclear 1H, 13C
COSY spectra (HSQC and HMBC) were used to assign the proton and carbon signals. IR
spectra were recorded on a Nexus FT-IR spectrometer. Microwave reactions were performed
in a Synthos 3000 microwave reactor from Anton Paar. LC/HRMS analyses were performed
using an Agilent Technologies HPLC 1200 coupled to an Agilent Technologies 6530
Accurate Mass Q-TOF LC-MS mass spectrometer equipped with a JetStream Technology ion
source housed in the Institute of Nuclear Chemistry and Technology, Warsaw, Poland
(internal mass calibration was enabled, reference ions of m/z 121.0509 and 922.0098 were
used) in the case of compounds 3, 4, 9, 13a, 14a, 15a, 15b, 10a, 11a, 12a, 17, 19, 21 and
using an Agilent Technologies HPLC 1200 coupled to an Agilent Technologies 6538 UHD
Accurate Mass Q-TOF LC-MS mass spectrometer equipped with a HPLC chip-cube ion
source housed in The Children’s Memorial Health Institute, Warsaw, Poland (internal mass
calibration was unenabled) for compounds 13b, 20, 22, 23, 24, 25, 26, 27. The analytical thin
layer chromatography tests (TLC) were carried out on Merck silica gel plates (Kiselgel 60
F254, layer thickness 0.2 mm) and the spots were visualised using UV lamp. The flash
column chromatography purifications were performed on Fluka silica gel (Silica gel 60,
0.035-0.070 mm). All reactions with organopalladium compounds were performed under an
argon atmosphere using standard Schlenk technique. Tetrahydrofuran (THF) and 1,4-dioxane
were distilled from sodium benzophenone ketyl prior to use. Commercially available
reagents: 2-formylbenzoic acid, hydrazine monohydrate, N-bromosuccinimide (NBS), methyl
iodide (MeI), butan-2-ol, pentan-2-ol, (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol ((–)-
menthol), benzyl mercaptan, propyl mercaptan, (sec-butyl mercaptan, isopropyl mercaptan,
cyclohexyl
azodicarboxylate (DEAD), N,N-diisopropylethyl amine (DIPEA), palladium(II) acetate
(Pd(OAc)2), 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), 2-
dicyclohexylphosphino-20-(N,N-dimethylamino)biphenyl (DavePhos), (oxydi-2,1-
mercaptan,
2-mercaptopyridine,
triphenylphosphine
(TPP),
diethyl
phenylene)-bis-(diphenylphosphine) (DPEPhos) were purchased from Sigma-Aldrich and
were used without further purification.
4.1. Synthesis of phthalazin-1(2H)-one (2).
A mixture of 2-formylbenzoic acid (1) (1.00 g, 6.66 mmol) and hydrazine monohydrate (3
mL), in propan-1-ol (15 mL) was heated with stirring under reflux for 8 h. After the
14

ACCEPTED MANUSCRIPT
completion of the reaction (TLC check) the mixture was cooled and all volatile materials were
removed under reduced pressure. To the residue water was added and neutralized with acetic
acid. The separated solid was collected by filtration, washed with water and then dried by
vacuum suction to give the pure product 2.
o
o
White solid; Yield: 750 mg, 77%; Mp: 186–187 C, (lit. 182–184 C37); FTIR (KBr):
ν =
1
3162, 3103, 1659 (C=O), 1559, cm–1; H NMR (600 MHz, CDCl3):
δ = 10.75 (s, 1H, NH),
8.45 (d, J = 7.9 Hz, 1H, 8 Ar-H), 8.18 (s, 1H, 4-pyrid), 7.87–7.83 (m, 1H, Ar-H), 7.81–7.78
(m, 1H, Ar-H), 7.73 (d, J = 7.9 Hz, 1H, 5 Ar-H); 1H NMR (600 MHz, DMSO-d6):
= 12.62
δ
(s, 1H, NH), 8.36 (s, 1H, 4-pyrid), 8.22 (d, J = 7.8 Hz, 1H, 8 Ar-H), 7.94–7.90 (m, 2H, Ar-H),
13
7.87–7.82 (m, 1H, Ar-H); C NMR (150 MHz, DMSO-d6):
δ = 159.6 (C=O), 138.2, 133.6,
131.7, 129.9, 127.5, 126.7, 125.3 ppm.
4.2. General procedure for the reaction of phthalazinones 4 (Path A) and 5 (Path B) with
methyl iodide
Method A.
A mixture of 4-bromophthalazin-1(2H)-one (3) (0.50 g, 2.22 mmol), potassium carbonate
(0.92 g, 6.66 mmol) in dry acetone (20 mL) was heated to boiling for 30 min and next methyl
iodide (0.47 g, 3.33 mmol) was added. The reaction mixture was heated and stirred under
reflux for 8 h.
Method B.
A mixture phthalazin-1(2H)-one (2) (0.50 g, 3.42 mmol), caesium carbonate (1.34 g, 4.11
mmol) in dry acetone (20 mL) was charged to PTFE tubes, sealed in ceramic cases and placed
in the rotor. The reaction mixture was heated to 55 oC, held for 0.5 h at 55 oC and then cooled
o
to 25 C. In the next step the methyl iodide (0.56 g, 0.23 mL, 3.77 mmol) was added and the
reaction was continued at 55 oC for 3.5 h.
After cooling to room temperature the separated solid was collected by filtration and washed
with acetone (5 mL). The filtrate was concentrated under reduced pressure and then the crude
product was purified by flash chromatography.
4.2.1. 4-Bromo-2-methylphthalazin-1(2H)-one (4) (Path A). White solid; Yield: 451 mg, 85%
(Method A), 327 mg, 40% (Method B); Mp: 101–104 oC; Rf (CHCl3) = 0.34; FTIR (KBr):
ν =
3036, 2906, 1652 (C=O), 1572 cm–1; 1H NMR (600 MHz, DMSO-d6):
δ = 8.29 (d, J = 7.9 Hz,
15

ACCEPTED MANUSCRIPT
1H, 8 Ar-H), 8.06–8.00 (m, 1H, Ar-H), 7.98–7.92 (m, 2H, Ar-H), 3.71 (s, 3H, Me); 13C NMR
(150 MHz, CDCl3):
δ = 158.2 (C=O), 134.4, 133.2, 129.6, 128.1, 127.7, 127.5, 126.7, 38.9
ppm; HRMS (ESI) m/z: calcd for C9H8BrN2O [M + H]+ 238.9814, found 238.9813.
4.2.2. 2-Methylphthalazin-1(2H)-one (5) (Path B). White solid; Yield: 247 mg, 45% (Method
B); Mp: 111–114 oC, (lit. 112–114 oC37); Rf (CHCl3/AcOEt/PE 6:1:1.5) = 0.46; FTIR (KBr):
ν
1
= 3036, 2942, 1641 (C=O), 1590 cm–1; H NMR (600 MHz, DMSO-d6):
δ = 8.40 (s, 1H, 4-
pyrid), 8.25 (d, J = 8.0 Hz, 1H, Ar-H), 7.96–7.89 (m, 2H, Ar-H), 7.88–7.83 (m, 1H, Ar-H),
3.72 (s, 3H, Me); 13C NMR (150 MHz, DMSO-d6):
δ = 158.7 (C=O), 137.8, 133.4, 132.1,
129.6, 127.0, 126.8, 125.6, 39.0 ppm.
4.3. Synthesis of 2-methylpyrido[3,4-d]pyridazin-1(2H)-one (8)21,23
N-Methylpyridopyridazinone 8, pyridopirydazinone 7 and hydroxyazaisoindolinone 6 were
prepared according to the procedure reported in literature 21.
4.3.1. 2-methylpyrido[3,4-d]pyridazin-1(2H)-one (8) (Path C). Canary yellow solid; Yield:
197 mg, 55%; Mp: 175–177 oC (lit. 180–182 oC21 23); FTIR (KBr):
ν
= 1665 (C=O) cm–1; 1H
NMR (600 MHz, CDCl3): δ = 9.14 (s, 1H, 5 A-H), 8.96 (d, J = 5.3 Hz, 1H, 7 Ar-H), 8.25 (s,
1H, 4-pyrid), 8.20 (d, J = 5.3 Hz, 1H, 8 Ar-H), 3.87 (s, 3H, Me); 13C NMR (150 MHz,
CDCl3): δ = 158.4, 151.3, 149.6, 135.6, 132.8, 124.4, 119.00, 39.9 ppm.
4.4. General procedure for bromination of phthalazinones 2, 5 and pyridopyridazinone 8
Synthesis of compounds 3 (Path A), 4 (Path B) and 9 (Path C).
The reaction was carried out in a round-bottom flask fitted with a magnetic stirrer bar. To a
suspension of phthalazin-1(2H)-one (2) or 2-methylphthalazin-1(2H)-one (5) or
pyridopyridazinone 8 (6.84 mmol) in water (55 mL) (Method A) or in the acetate buffer
solution pH = 5.8 (55 mL) (Method B), was added potassium bromide (8.44 mmol) and
bromine (8.44 mmol) at an ambient temperature. The mixture was then stirred for 6 h at an
ambient temperature, and next the whole was heated to boiling and stirred for 25 h until the
bromine colour entirely disappeared. After cooling to an ambient temperature (in the case of 9
the mixture was adjusted to pH 7 with saturated NaHCO3) the separated solid was collected
by filtration and washed with water (5 mL). The crude product was purified by flash
chromatography.
16

ACCEPTED MANUSCRIPT
4.4.1. 4-Bromophthalazin-1(2H)-one (3) (Path A). White solid; Yield: 693 mg, 45% (Method
o
o
A), 1.02 g, 66 % (Method B); Mp: 279–281 C, (lit. 277–279 °C,20 22 273 C38); Rf
(DCM/AcOEt/Hex 6:1:1) = 0.24; FTIR (KBr): = 3022, 2931, 2892, 1671, 1659 (C=O),
1581 cm–1; 1H NMR (600 MHz, DMSO-d6):
= 12.94 (s, 1H, NH), 8.26 (d, J = 7.9 Hz, 1H, 8
Ar-H), 8.06–8.01 (m, 1H, Ar-H), 7.97–7.91 (m, 2H, Ar-H); 13C NMR (150 MHz, DMSO-d6):
= 159.1 (C=O), 134.8, 133.1, 129.9, 129.4, 128.2, 127.6, 126.5 ppm; HRMS (ESI) m/z:
ν
δ
δ
calcd for C8H6BrN2O [M + H]+ 224.9658, found 224.9658.
4.4.2. 4-Bromo-2-methylphthalazin-1(2H)-one (4) (Path B). White solid; Yield: 981 mg, 60%
(Method A); Mp: 101-104 oC; Rf (AcOEt/Hex 1:1) = 0.6.
4.4.3. 8-Bromo-2-methylpyrido[3,4-d]pyridazin-1(2H)-one (9) (Path C). Cream solid; Yield:
o
854 mg, 52% (Method A); Mp: 220–222 C; Rf (AcOEt/Hex 10:3) = 0.56; FTIR (KBr):
ν =
1
3062, 2927, 1653 (C=O) cm–1; H NMR (600 MHz, DMSO-d6): δ = 9.22 (s, 1H, 5 Ar-H),
13
9.08 (s, 1H, 7 Ar-H), 8.54 (s, 1H, 4-pyrid), 3.70 (s, 3H, Me); C NMR (150 MHz, DMSO-
d6): δ = 155.8 (C=O), 154.1, 149.6, 135.4, 129.0, 126.0, 116.6, 39.5 ppm; HRMS (ESI) m/z:
calcd for C8H7BrN3O [M + H]+ 239.9767, found 239.9765.
4.5. General procedure for the Mitsunobu reaction of phthalazin-1(2H)-ones 2 and 3 with the
secondary alcohols. Synthesis of compounds 10-15.
Method A
The Mitsunobu reaction was carried out under argon. Diethyl azodicarboxylate (1.03 mmol,
solution in toluene c ≈ 40%) was slowly added to a stirred solution of triphenylphosphine
o
o
(1.03 mmol) in dry THF (10 mL) at the temperature between –10 C and –5 C. Then a
solution of phthalazinone 2 (0.684 mmol) in THF (10 mL) was added dropwise. The whole lot
was mixed for 15 min at this temperature and next the appropriate alcohol (0.753 mmol) in
THF (5 mL) was added at –10 - –5 oC. The mixture was stirred during 2 h at this conditions,
after which time the reaction mixture was warmed to ambient temperature and stirred in this
conditions for 24 h. All volatile materials were removed under reduced pressure, ethyl ether
(5 mL) was added to the residue, and the whole lot was stirred for 0.5 h at an ambient
temperature. The separate white solid was collected by flirtation and washed with ether, and
17

ACCEPTED MANUSCRIPT
the filtrate was evaporated to dryness. The product was separated and purified by flash
chromatography.
Method B
The Mitsunobu reaction was carried out under argon. To a round bottom flask were added
phthalazinone 2 or 3 (1.78 mmol), alcohol (2.67 mmol), triphenylphosphine (2.67 mmol) and
o
THF (40 mL). Then, the solution was cooled to the temperature –20 C for 15 min. and
diethyl azodicarboxylate (2.67 mmol, solution in toluene c ≈ 40%) was added dropwise to the
solution. The reaction was stirred at –20 oC for 1 h, and then the cold bath allowed to slowly
warm to an ambient temperature and stirred in this conditions for 24 h. All volatile materials
were removed under reduced pressure, diethyl ether (15 mL) was added to the residue, and the
whole lot was stirred for 0.5 h at an ambient temperature. The separate white solid was
collected by flirtation and washed with ether, and the filtrate was evaporated to dryness. The
product was separated and purified by flash chromatography.
4.5.1. 2-(Butan-2-yl)phthalazin-1(2H)-one (10a). Straw oil; Yield: 41.5 mg, 30% (Method A),
259 mg, 72% (Method B); Rf (AcOEt/Hex 1:3) = 0.5; FTIR (thin film):
ν = 3044, 2968, 2933,
1
1644 (C=O), 1591 cm–1; H NMR (600 MHz, CDCl3): δ = 8.43 (d, J = 7.8 Hz, 1H, 8 Ar-H),
8.20 (s, 1H, 4-pyrid), 7.80–7.71 (m, 2H, Ar-H), 7.67 (d, J = 8.2 Hz, 1H, 5 Ar-H), 5.38–5.06
(m, 1H, N-CH), 1.95–1.86 (m, 1H, CH2), 1.77–1.68 (m, 1H, CH2), 1.37 (d, J = 6.8 Hz, 3H,
13
Me), 0.84 (t, J = 7.4 Hz, 3H, Me); C NMR (150 MHz, CDCl3): δ = 159.6 (C=O), 137.7,
133.0, 131.5, 129.4, 128.0, 127.1, 125.9, 54.1 (N-CH), 28.4, 19.4, 10.9 ppm; HRMS (ESI)
m/z: calcd for C12H15N2O [M + H]+ 203.1179, found 203.1179.
4.5.2. 2-(Pentan-2-yl)phthalazin-1(2H)-one (11a). Yellow oil; Yield: 71.0 mg, 48% (Method
A), 327 mg, 85% (Method B); Rf (Hex/AcOEt 3:1) = 0.56; FTIR (thin film):
ν = 3051, 2960,
1
2331, 1653 (C=O), 1589 cm–1; H NMR (600 MHz, CDCl3): δ = 8.44 (d, J = 7.8 Hz, 1H, 8
Ar-H), 8.21 (s, 1H, 4-pyrid), 7.81–7.77 (m, 1H, Ar-H), 7.77–7.72 (m, 1H, Ar-H), 7.68 (d, J =
8.0 Hz, 1H, 5 Ar-H), 5.37–5.27 (m, 1H, N-CH), 1.97–1.87 (m, 1H, CH2), 1.71–1.62 (m, 1H,
CH2), 1.38 (d, J = 6.7 Hz, 3H, Me), 1.35–1.28 (m, 1H, CH2), 1.25–1.17 (m, 1H, CH2), 0.90 (t,
13
J = 7.4 Hz, 3H, Me); C NMR (150 MHz, CDCl3): δ = 159.5 (C=O), 137.7, 133.0, 131.5,
129.4, 128.0, 127.2, 125.9, 52.4 (N-CH), 37.6, 19.8, 19.7, 14.0 ppm; HRMS (ESI) m/z: calcd
for C13H17N2O [M + H]+ 217.1335, found 217.1331.
18

ACCEPTED MANUSCRIPT
4.5.3. 2-[(1S,2S,5R)-5-Methyl-2-(propan-2-yl)cyclohexyl]phthalazin-1(2H)-one (12a). White
o
solid; Yield: 77.8 mg, 40% (Method A), 152 mg, 30% (Method B); Mp: 144–147 C; Rf
1
(Hex/AcOEt 5:1) = 0.58; FTIR (KBr):
ν
= 3066, 2952, 2930, 1638 (C=O), 1587 cm–1; H
NMR (600 MHz, CDCl3): δ = 8.45 (d, J = 7.9 Hz, 1H, 8 Ar-H), 8.13 (s, 1H, 4-pyrid), 7.80–
7.76 (m, 1H, Ar-H), 7.75–7.71 (m, 1H, Ar-H), 7.66 (d, J = 7.7 Hz, 1H, 5 Ar-H), 5.63–5.38
(m, 1H, N-CH), 2.26–2.15 (m, 1H, CH2), 1.97–1.86 (m, 3H, CH2), 1.78–1.72 (m, 1H, CH2),
1.46–1.35 (m, 3H, CH2), 1.06–0.97 (m, 1H, CH2), 0.86 (d, J = 6.3 Hz, 3H, Me), 0.83–0.80 (m,
6H, 2xMe); 13C NMR (150 MHz, CDCl3): δ = 159.7 (C=O), 135.6, 132.9, 131.2, 129.4,
128.0, 127.2, 125.6, 52.5 (N-CH), 47.0, 40.5, 35.6, 29.3, 25.8, 25.7, 22.8, 21.5, 21.3 ppm;
HRMS (ESI) m/z: calcd for C18H25N2O [M + H]+ 285.1961, found 285.1960.
4.5.4. 4-Bromo-2-(butan-2-yl)phthalazin-1(2H)-one (13a). Yellow oil; Yield: 240 mg, 48%
(Method B), Rf (AcOEt/Hex 1:10) = 0.25; FTIR (thin film):
ν = 3074, 2968, 2933, 1660
1
(C=O), 1576 cm–1; H NMR (600 MHz, CDCl3): δ = 8.44 (dd, J = 7.9, 0.8 Hz, 1H, 8 Ar-H),
7.93 (dd, J = 8.0, 0.5 Hz, 1H, 5 Ar-H), 7.87–7.83 (m, 1H, 7 Ar-H), 7.82–7.77 (m, 1H, 6 Ar-
H), 5.31–4.98 (m, 1H, N-CH), 1.96–1.86 (m, 1H, CH2), 1.79–1.70 (m, 1H, CH2), 1.39 (d, J =
6.7 Hz, 3H, Me), 0.87 (t, J = 7.4 Hz, 3H, Me); 13C NMR (150 MHz, CDCl3): δ = 159.0
(C=O), 133.7, 132.4, 130.0, 129.2, 128.6, 127.8, 127.7, 54.9 (N-CH), 28.4, 19.4, 10.9 ppm;
HRMS (ESI) m/z: calcd for C12H14BrN2O [M + H]+ 281.0284, found 281.0285.
4.5.5. 1-Bromo-4-[(butan-2-yl)oxy]phthalazine (13b). White solid; Yield: 30.0 mg, 6%
(Method B), Mp: 88–90 oC; Rf (AcOEt/Hex 1:10) = 0.32; FTIR (KBr):
ν = 2966, 2919, 1537,
1
1408 cm–1; H NMR (600 MHz, DMSO-d6): δ = 8.21 (d, J = 7.9 Hz, 1H, Ar-H), 8.17–8.10
(m, 2H, Ar-H), 8.11–8.07 (m, 1H, Ar-H), 5.60–5.27 (m, 1H, O-CH), 1.90–1.82 (m, 1H, CH2),
1.82–1.74 (m, 1H, CH2), 1.42 (d, J = 6.2 Hz, 3H, Me), 0.99 (t, J = 7.4 Hz, 3H, Me); 13C NMR
(150 MHz, DMSO-d6): δ = 160.0 (C-O), 142.3, 134.3, 133.9, 128.5, 126.8, 123.3, 121.0, 74.9
(O-CH), 28.3, 18.8, 9.4 ppm; HRMS (ESI) m/z: calcd for C12H14BrN2O [M + H]+ 281.0284,
found 281.0289.
4.5.6. 4-Bromo-2-(pentan-2-yl)phthalazin-1(2H)-one (14a). Yellow oil; Yield: 147 mg, 28%
(Method B), Rf (Hex/AcOEt 5:1) = 0.62; FTIR (thin film):
ν = 3037, 2960, 2931, 1655
1
(C=O), 1576 cm–1; H NMR (600 MHz, CDCl3): δ = 8.44 (dd, J = 7.9, 0.7 Hz, 1H 8 Ar-H),
19

ACCEPTED MANUSCRIPT
7.92 (d, J = 8.0 Hz, 1H, 5Ar-H), 7.87–7.83 (m, 1H, Ar-H), 7.82–7.78 (m, 1H, Ar-H), 5.29–
5.21 (m, 1H, N-CH), 1.95–1.87 (m, 1H, CH2), 1.71–1.62 (m, 1H, CH2), 1.39 (d, J = 6.7 Hz,
13
3H, Me), 1.36–1.29 (m, 1H CH2), 1.29–1.20 (m, 1H CH2), 0.92 (t, J = 7.4 Hz, 3H, Me); C
NMR (150 MHz, CDCl3): δ = 158.8 (C=O), 133.6, 132.3, 129.9, 129.0, 128.5, 127.6, 127.5,
52.9 (N-CH), 37.3, 19.6, 19.5, 13.9 ppm; HRMS (ESI) m/z: calcd for C13H16BrN2O [M + H]+
295.0440, found 295.0438.
4.5.7. 1-Bromo-4-[(pentan-2-yl)oxy]phthalazine (14b). (The crude mixture with 14a after
chromatography); Yellow oil; Yield: 15.8 mg, 3% (1H NMR, Method B), Rf (Hex/AcOEt 5:1)
= 0.59, 0.62; 1H NMR (600 MHz, CDCl3) δ = 8.46–8.42 (m, 1H, Ar-H, 14a), 8.23–8.19 (m,
1H, Ar-H), 8.14–8.11 (m, 1H, Ar-H), 7.96–7.83 (m, 4H, Ar-H, 14a, 14b), 7.82–7.77 (m, 1H,
Ar-H, 14a), 5.69–5.57 (m, 1H, O-CH), 5.28–5.19 (m, 1H, N-CH, 14a), 1.95–1.85 (m, 2H,
CH2, 14a, 14b), 1.74–1.63 (m, 2H, CH2, 14a, 14b), 1.53–1.41 (m, 5H, CH2, Me), 1.39 (d, J =
6.7 Hz, 3H, Me, 14a), 1.36–1.20 (m, 2H, CH2, 14a), 0.96 (t, J = 7.4 Hz, 3H, Me), 0.91 (t, J =
7.4 Hz, 3H, Me, 14a); 13C NMR (150 MHz, CDCl3): δ = 160.5, 158.8 (14a), 142.7, 133.6
(14a), 133.0, 132.7, 132.3 (14a), 129.9 (14a), 129.4, 129.0 (14a), 128.5 (14a), 128.1, 127.7
(14a), 127.6 (14a), 127.3, 123.7, 74.1 (O-CH), 52.9 (14a, N-CH), 38.3, 37.3 (14a), 19.7, 19.6
(14a), 19.5 (14a), 18.7, 14.1, 13.9 (14a) ppm.
4.5.8.
4-Bromo-2-[(1S,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]phthalazin-1(2H)-one
o
(15a). White solid; Yield: 188 mg, 29% (Method B), Mp: 80–82 C; Rf (Hex/ AcOEt 5:1) =
0.60; FTIR (KBr):
ν
= 2951, 2924, 1653 (C=O), 1576 cm–1; 1H NMR (600 MHz, CDCl3): δ =
8.45 (dd, J = 7.9, 0.7 Hz, 1H, 8 Ar-H), 7.92 (d, J = 8.0 Hz, 1H, 5 Ar-H), 7.87–7.84 (m, 1H, 7
Ar-H), 7.81–7.76 (m, 1H, 8 Ar-H), 5.51–5.34 (m, 1H, N-CH), 2.22–2.12 (m, 1H, CH2), 1.97–
1.88 (m, 3H, CH2), 1.79–1.73 (m, 1H CH2), 1.46–1.36 (m, 3H, CH2), 1.05–0.96 (m, 1H,
CH2), 0.89 (d, J = 6.3 Hz, 3H, Me), 0.83 (d, J = 6.3 Hz, 3H, Me), 0.82 (d, J = 6.4 Hz, 3H,
Me); 13C NMR (150 MHz, CDCl3): δ = 159.1 (C=O), 133.7, 132.2, 130.0, 128.6, 127.9,
127.4, 126.8, 53.0 (N-CH), 46.8, 40.3, 35.5, 29.3, 25.5, 25.5, 22.8, 21.4 ppm; HRMS (ESI)
m/z: calcd for C18H24BrN2O [M + H]+ 363.1067, found 363.1065.
4.5.9. 1-Bromo-4-{[(1S,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}phthalazine (15b).
White solid; Yield: 181 mg, 28% (Method B), Mp: 109–112 oC; Rf (Hex/ AcOEt 5:1) = 0.70;
FTIR (KBr):
ν
= 2955, 2919, 1535, 1408 cm–1; 1H NMR (600 MHz, CDCl3): δ = 8.19 (d, J =
20

ACCEPTED MANUSCRIPT
7.9 Hz, 1H, Ar-H), 8.14 (d, J = 7.9 Hz, 1H, Ar-H), 7.96–7.85 (m, 2H, Ar-H), 5.94–5.89 (m,
1H, O-CH), 2.40 (dd, J = 14.5, 2.6 Hz, 1H, CH2), 1.94–1.83 (m, 2H, CH2), 1.76–1.61 (m, 3H,
CH2), 1.24–1.13 (m, 2H, CH2), 1.08–1.00 (m, 1H, CH2), 0.95 (d, J = 6.7 Hz, 3H, Me), 0.89
13
(d, J = 6.7 Hz, 3H, Me), 0.84 (d, J = 6.6 Hz, 3H, Me); C NMR (150 MHz, CDCl3): δ =
160.4, 142.8, 133.2, 132.9, 129.7, 127.5, 123.7, 122.4, 74.4 (O-CH), 47.7, 38.1, 35.2, 29.9,
27.1, 25.6, 22.3, 21.2, 21.1 ppm; HRMS (ESI) m/z: calcd for C18H24BrN2O [M + H]+
363.1067, found 363.1067.
4.6. General procedure for the palladium-catalyzed synthesis of 4-sulfanylphthalazinones 17,
19-26 and 4-sulfanylphthalazine 27.
The reaction was carried out under an argon atmosphere in an oven-dried resealable Schlenk
flask. A resealable Schlenk flask was charged with appropriate 2-substituted-4-
bromophthalazinone 4, 10a-12a or 8-bromo-2-methylpyridopyridazinone 9 or 1-
bromophthalazine 12b (0.418 mmol), 5 mL freshly distilled 1,4-dioxane, Pd(OAc)2 (30
mol%), XantPhos (30 mol%), DIPEA (1.5 mL), and the appropriate mercaptan (0.836 mmol).
The whole mixture was stirred and heated in an oil bath at 100 oC for 26 h. After this time, the
reaction mixture was cooled to an ambient temperature and diluted with 5 mL chloroform.
The solid was removed by filtration and washed with 5 mL chloroform. The filtrate was
concentrated to dryness and the residue was purified by flash chromatography to give pure
product.
4.6.1. 2-Methyl-4-[(propan-2-yl)sulfanyl]phthalazin-1(2H)-one (17). Pale yellow solid; Yield:
o
82.3 mg, 84%, Mp: 80–82,5 C; Rf (AcOEt/CHCl3/PE 1:9:6) = 0.70; FTIR (KBr):
ν = 3072,
2960, 2923, 1648, 1576 cm–1; 1H NMR (600 MHz, CDCl3): δ = 8.43 (d, J = 8.7 Hz, 1H, 8 Ar-
H), 7.90 (d, J = 7.4 Hz, 1H, 5 Ar-H), 7.79–7.70 (m, 2H, Ar-H), 3.96–3.88 (m, 1H, S-CH),
3.83 (s, 3H, N-Me), 1.45 (d, J = 6.8 Hz, 6H, 2×Me); 13C NMR (150 MHz, CDCl3): δ = 159.0
(C=O), 144.2, 132.8, 131.7, 130.0, 127.5, 127.2, 124.6, 39.5, 36.0, 23.1 ppm; HRMS (ESI)
m/z: calcd for C12H15N2OS [M + H]+ 235.0900, found 235.0897.
4.6.2. 4-[(Butan-2-yl)sulfanyl]-2-methylphthalazin-1(2H)-one (19). Light yellow solid; Yield:
o
77.9 mg, 75%, Mp: 40–42 C; Rf (AcOEt/CHCl3/PE 1:9:6) = 0.45; FTIR (thin film):
ν =
1
3067, 2959, 2926, 1652, 1576 cm–1; H NMR (600 MHz, CDCl3): δ = 8.44 (dd, J = 7.0, 2.1
Hz, 1H, 8 Ar-H), 7.93 (dd, J = 7.1, 1.9 Hz, 1H, 5 Ar-H), 7.79–7.71 (m, 2H, Ar-H), 3.84 (s,
21

ACCEPTED MANUSCRIPT
3H, Me), 3.83–3.76 (m, 1H, S-CH), 1.85–1.78 (m, 1H, CH2), 1.76–1.69 (m, 1H, CH2), 1.44
(d, J = 6.8 Hz, 3H, Me), 1.06 (t, J = 7.4 Hz, 3H, Me); 13C NMR (150 MHz, CDCl3): δ = 159.1
(C=O), 144.3, 132.9, 131.7, 130.1, 127.5, 127.2, 124.6, 42.3, 39.5, 29.7, 20.6, 11.6; HRMS
(ESI) m/z: calcd for C13H17N2OS [M + H]+ 249.1056, found 249.1052.
4.6.3. 4-(Cyclohexylsulfanyl)-2-methylphthalazin-1(2H)-one (20). Yellow solid; Yield: 106
mg, 92%; Mp: 111–114 oC; Rf (DCM/AcOEt/Hex 6:1:1) = 0.54; FTIR (KBr):
ν = 3030, 2943,
2918, 1651 (C=O), 1574 cm–1; 1H NMR (600 MHz, CDCl3): δ = 8.45–8.41 (m, 1H, 8 Ar-H),
7.95–7.92 (m, 1H, 5 Ar-H), 7.79–7.71 (m, 2H, Ar-H), 3.84 (s, 3H, Me), 3.80–3.73 (m, 1H, S-
CH), 2.16–2.09 (m, 2H, CH2), 1.84–1.78 (m, 2H, CH2), 1.69–1.62 (m, 1H, CH2), 1.60–1.51
(m, 2H CH2), 1.49–1.41 (m, 2H, CH2), 1.40–1.31 (m, 1H, CH2); 13C NMR (150 MHz,
CDCl3): δ = 159.1 (C=O), 143.9, 132.9, 131.7, 130.2, 127.5, 127.2, 124.7, 44.0, 39.6, 33.3,
26.2, 26.0 ppm; HRMS (ESI) m/z: calcd for C15H19N2OS [M + H]+ 275.1213, found
275.1220.
4.6.4. 4-(Benzylsulfanyl)-2-methylphthalazin-1(2H)-one (21). Beige solid; Yield: 93.2 mg,
o
79%; Mp: 121–123 C; Rf (CHCl3/PE/AcOEt 9:6:1) = 0.54; FTIR (KBr):
ν = 3059, 2925,
1644 (C=O), 1574 cm–1; 1H NMR (600 MHz, CDCl3): δ = 8.45–8.40 (m, 1H, 8 Ar-H), 7.87–
7.81 (m, 1H, 5 Ar-H), 7.80–7.69 (m, 2H, Ar-H), 7.44 (d, J = 7.5 Hz, 2H, Ar-H), 7.36–7.29
(m, 2H, Ar-H), 7.29–7.23 (m, 1H, Ar-H),4.39 (s, 2H, S-CH2), 3.85 (s, 3H, Me); 13C NMR
(150 MHz, CDCl3): δ = 159.1 (C=O), 143.6, 137.1, 132.9, 131.8, 129.4, 129.4, 128.7, 127.6,
127.5, 127.3, 124.2, 39.3, 34.8 ppm; HRMS (ESI) m/z: calcd for C16H15N2OS [M + H]+
283.0900, found 283.0895.
4.6.5. 2-(Butan-2-yl)-4-[(butan-2-yl)sulfanyl]phthalazin-1(2H)-one (22). Brown-yellow oil;
Yield: 94.7 mg, 78%; Diastereoisomers ratio = 1:1; Rf (AcOEt/Hex 1:4) = 0.44; FTIR (thin
film):
ν
= 3056, 2962, 2922, 1652 (C=O), 1575 cm–1; 1H NMR (600 MHz, CDCl3): δ = 8.48–
8.41 (m, 1H, 8 Ar-H), 7.92–7.86 (m, 1H, 5 Ar-H), 7.78–7.69 (m, 2H, Ar-H), 5.27–5.15 (m,
1H, N-CH), 3.85–3.76 (m, 1H, S-CH), 1.96–1.88 (m, 1H, CH2), 1.87–1.81 (m, 1H, CH2),
1.76–1.67 (m, 2H, CH2), 1.47–1.42 (m, 3H, Me), 1.40–1.35 (m, 3H, Me), 1.09–1.04 (m, 3H,
13
Me), 0.88–0.85 (m, 3H, Me); C NMR (150 MHz, CDCl3): δ = 158.7 (C=O), 144.0, 144.0,
132. 8, 131.5, 129.3, 127.6, 127.5, 124.2, 54.1, 41.8, 41.8, 29.7, 29.6, 28.6, 28.5, 20.5, 20.4,
22

ACCEPTED MANUSCRIPT
19.7, 19.6, 11.6, 11.6, 11.0, 10.9 ppm; HRMS (ESI) m/z: calcd for C16H23N2OS [M + H]+
291.1526, found 291.1534.
4.6.6. 2-(Butan-2-yl)-4-(propylsulfanyl)phthalazin-1(2H)-one (23). Dark yellow oil; Yield:
45.1 mg, 39%, Rf (Hex/AcOEt 5:1) = 0.44; FTIR (KBr):
ν = 3057, 2964, 2929, 1653 (C=O),
1578 cm–1; 1H NMR (600 MHz, CDCl3): δ = 8.46 (d, J = 7.7 Hz, 1H, 8 Ar-H), 7.88 (d, J = 7.6
Hz, 1H, 5 Ar-H), 7.80–7.71 (m, 2H, Ar-H), 5.26–5.16 (m, 1H, N-CH), 3.16 (t, J = 7.2 Hz, 2H,
S-CH2), 1.95–1.87 (m, 1H, CH2), 1.84–1.78 (m, 2H, CH2), 1.78–1.70 (m, 1H, CH2), 1.38 (d, J
= 6.6 Hz, 3H, NCH-Me), 1.08 (t, J = 7.4 Hz, 3H, Me), 0.87 (t, J = 7.4 Hz, 3H, Me); 13C NMR
(150 MHz, CDCl3): δ = 158.8 (C=O), 143.7, 132.8, 131.6, 129.0, 127.7, 127.5, 124.0, 54.2,
32.0, 28.5, 22.8, 19.6, 13.7, 11.0 ppm; HRMS (ESI) m/z: calcd for C15H21N2OS [M + H]+
277.1369, found 277.1379.
4.6.7. 2-(Pentan-2-yl)-4-(propylsulfanyl)phthalazin-1(2H)-one (24). Brown-orange oil; Yield:
109 mg, 90%, Rf (Hex/AcOEt 5:1) = 0.44; FTIR (thin film):
ν = 3066, 2962, 2931, 1653
1
(C=O), 1578 cm–1; H NMR (600 MHz, CDCl3): δ = 8.44 (d, J = 7.4 Hz, 1H, 8 Ar-H), 7.87
(d, J = 7.7 Hz, 1H, 5 Ar-H), 7.81–7.69 (m, 2H, Ar-H), 5.38–5.22 (m, 1H, N-CH), 3.23–3.06
(m, 2H, S-CH), 1.96–1.87 (m, 1H, CH2), 1.84–1.75 (m, 2H, CH2), 1.69–1.59 (m, 1H, CH2),
1.37 (d, J = 6.6 Hz, 3H, SCH-Me), 1.34–1.27 (m, 1H, CH2), 1.25–1.18 (m, 1H, CH2), 1.08 (t,
13
J = 7.4 Hz, 3H, Me), 0.90 (t, J = 7.4 Hz, 3H, Me); C NMR (150 MHz, CDCl3): δ = 158.6
(C=O), 143.6, 132.8, 131.6, 129.0, 127.6, 127.5, 123.9, 52.4, 37.6, 32.0, 22.8, 19.9, 19.6,
14.1, 13.7 ppm; HRMS (ESI) m/z: calcd for C16H23N2OS [M + H]+ 291.1526, found
291.1536.
4.6.8. 2-Methyl-8-[(propan-2-yl)sulfanyl]pyrido[3,4-d]pyridazin-1(2H)-one (25). Yellow
o
solid; Yield: 79.7 mg, 81%; Mp: 94–96 C; Rf (CHCl3/AcOEt/Hex 6: 1:1) = 0.22; FTIR
(KBr):
ν
= 3076, 2969, 2929, 1644 (C=O), 1594 cm–1; 1H NMR (600 MHz, CDCl3): δ = 8.74
(s, 1H, 5 Ar-H), 8.66 (s, 1H, 7 Ar-H), 8.13 (s, 1H, 4-pyrid), 3.79 (s, 3H, Me), 3.75–3.66 (m,
13
1H, CH), 1.47 (d, J = 6.6 Hz, 6H, 2×Me); C NMR (150 MHz, CDCl3): δ = 158.6 (C=O),
145.1, 142.5, 137.8, 135.4, 128.8, 125.5, 39.8, 34.3, 22.4 ppm; HRMS (ESI) m/z: calcd for
C11H14N3OS [M + H]+ 236.0852, found 236.0852.
23

ACCEPTED MANUSCRIPT
4.6.9. 4-[(Butyl-2-yl)sulfanyl]-2-[(1S,2S,5R)-5-Methyl-2-(propan-2-yl)cyclohexyl]phthalazin-
1(2H)-one (26a, 26b). Brown oil; Yield: 128 mg, 82%; Diastereoisomers ratio = 1:1; Rf
(Hex/AcOEt 5:1) = 0.48; FTIR (thin film):
ν
= 2956, 2924, 1653 (C=O), 1578 cm–1; 1H NMR
(600 MHz, CDCl3): δ = 8.45 (dd, J = 7.7, 1.2 Hz, 1H, 8 Ar-H), 7.97–7.92 (m, 1H, 5 Ar-H),
7.79–7.68 (m, 2H, 6, 7 Ar-H), 5.58–5.52 (m, 1H, O-CH), 3.98–3.65 (m, 1H, S-CH), 2.16–
2.08 (m, 1H, CH2), 1.99–1.63 (m, 6H, CH2), 1.51–1.34 (m, 6H, CH2, Me), 1.10–0.99 (m, 4H,
13
CH2), 0.88–0.84 (m, 3H, Me), 0.84–0.79 (m, 6H, 2xMe); C NMR (150 MHz, CDCl3): δ =
159.0 (C=O), 142.7, 142.6, 132.8, 131.5, 129.5, 129.5, 127.7, 127.7, 127.6, 124.6, 124. 6,
52.5, 52.4, 46.6, 46.5, 41.9, 41.7, 40.5, 40.4, 35.4, 35.4, 29.9, 29.9, 29.8, 29.3, 29.3, 25.9,
25.9, 25.8, 25.8, 22.7, 22.7, 21.5, 21.2, 21.2, 21.1, 20.9, 11.6, 11.6 ppm; HRMS (ESI) m/z:
calcd for C22H33N2OS [M + H]+ 373.2308, found 373.2316.
4.6.10.
4-[(Butan-2-yl)sulfanyl]-1-{[(1S,2S,5R)-5-methyl-2-(propan-2-yl)cyclo-hexyl]oxy}
phthalazine (27a, 27b). White solid; Yield: 79.7 mg, 36%; Diastereoisomers ratio = 1:1; Mp:
>315 oC (decomposition); Rf (AcOEt/Hex 1:10) = 0.68; 1H NMR (600 MHz, DMSO-d6): δ =
8.19–8.16 (m, 1H, Ar-H), 8.06–8.02 (m, 1H, Ar-H), 8.02–7.97 (m, 2H, Ar-H), 5.78–5.72 (m,
1H, O-CH), 4.17–4.07 (m, 1H, S-CH), 2.23 (d, J = 13.6 Hz, 1H, CH2), 1.87–1.55 (m, 7H,
CH2), 1.46–1.40 (m, 3H, Me), 1.25–1.14 (m, 2H, CH2), 1.08–0.98 (m, 4H, CH2, Me), 0.92 (d,
13
J = 6.7 Hz, 3H, Me), 0.86–0.83 (m, 3H, Me), 0.81 (d, J = 6.6 Hz, 3H, Me); C NMR (150
MHz, DMSO-d6): δ = 158.0, 154.0, 133.0, 133.0, 127.3, 123.3, 123.0, 119.1, 72.4, 46.6, 39.9,
39.8, 39.7, 39.5, 39.4, 39.2, 39.1, 29.3, 28.9, 26.4, 24.8, 22.0, 20.8, 20.5, 20.5, 11.3 ppm;
HRMS (ESI) m/z: calcd for C22H33N2OS [M + H]+ 373.2308, found 373.2317.
Acknowledgements
LC/HRMS study was performed using the LC-QTOF instrument funded under the POIG
02.01.00-14-111/09-00 „Centre of Radiochemistry and Nuclear Chemistry for the needs of
nuclear energy and nuclear medicine” project, and the LC-QTOF instrument funded under the
POIG.02.01.00-14-059/09 „Multi-profile modernization of research infrastructure of The
Children’s Memorial Health Institute” project.
The authors are grateful to the University of Łódź for a partial financial support.
References and notes
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