Synthesis of N -(2-(Methylamino)ethyl) Derivatives of 2 H -Phthalazin-1-ones

Article abstract of DOI:10.1080/00397911.2014.944269

A series of new alkyl, tosyl, acetyl, and tert-butoxycarbonyl derivatives of 2-(2-aminoethyl)-phthalazinones were efficiently synthesized by reaction of lactams with N-Boc-, N-acetyl-, or N,O-ditosyl derivatives of N-methylethanolamine in the presence of

Full text of DOI:10.1080/00397911.2014.944269

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Synthesis of N-(2-(Methylamino)ethyl)
Derivatives of 2H-Phthalazin-1-ones
Zbigniew Malinowski a , Aleksandra K. Szcześniak a , Wanda Pakulska
b , Dariusz Sroczyński c , Elżbieta Czarnecka b & Jan Epsztajn a
a Faculty of Chemistry, Department of Organic Chemistry ,
University of Łódź , Łódź , Poland
b Faculty of Pharmacy, Department of Pharmacodynamics , Medical
University of Łódź , Łódź , Poland
c Faculty of Chemistry, Department of Inorganic and Analytical
Chemistry , University of Łódź , Łódź , Poland
Accepted author version posted online: 08 Aug 2014.Published
online: 15 Oct 2014.
To cite this article: Zbigniew Malinowski , Aleksandra K. Szcześniak , Wanda Pakulska , Dariusz
Sroczyński , Elżbieta Czarnecka & Jan Epsztajn (2014) Synthesis of N-(2-(Methylamino)ethyl)
Derivatives of 2H-Phthalazin-1-ones, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 44:24, 3572-3581, DOI:
10.1080/00397911.2014.944269
To link to this article: http://dx.doi.org/10.1080/00397911.2014.944269
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Synthetic Communications1, 44: 3572–3581, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.944269
SYNTHESIS OF N-(2-(METHYLAMINO)ETHYL)
DERIVATIVES OF 2H-PHTHALAZIN-1-ONES
1
Zbigniew Malinowski, Aleksandra K. Szczesniak,
1
´
2
3
2
´
Wanda Pakulska, Dariusz Sroczynski, Elz˙bieta Czarnecka,
and Jan Epsztajn1
1Faculty of Chemistry, Department of Organic Chemistry,
´ ´ ´ ´
University of Łodz, Łodz, Poland
2Faculty of Pharmacy, Department of Pharmacodynamics,
´ ´ ´ ´
Medical University of Łodz, Łodz, Poland
3Faculty of Chemistry, Department of Inorganic and Analytical Chemistry,
´ ´ ´ ´
University of Łodz, Łodz, Poland
GRAPHICAL ABSTRACT
Abstract A series of new alkyl, tosyl, acetyl, and tert-butoxycarbonyl derivatives of
2-(2-aminoethyl)-phthalazinones were efficiently synthesized by reaction of lactams with
N-Boc-, N-acetyl-, or N,O-ditosyl derivatives of N-methylethanolamine in the presence
of MeONa or under Mitsunobu reaction conditions. Selected compounds were converted
into corresponding 2-[2-(methylamino)ethyl]phthalazinones in good yields.
Keywords Alkylation; amines; Mitsunobu reaction; phthalazinones; rotamers
INTRODUCTION
2H-Pyridazin-3-ones and their benzo- (phthalazinones) and pyrido- (pyridopir-
ydazinones) derivatives demonstrate a wide spectrum of biological properties. Com-
pounds of these type show an interesting pharmacological action (e.g., adenosine A1
receptor antagonist I,[1] antinociceptive agents II,[2–4] a1-adrenoreceptors antagonist
III,[5,6] and nonprostanoid PGI2 agonist IV[7]; Fig. 1).
Especially interesting group of 2H-pyridazin-3-one derivatives are compounds
substituted at the lactam nitrogen atom by x-aminoalkyl group. These type of
Received May 22, 2014.
Address correspondence to Zbigniew Malinowski, Faculty of Chemistry, Department of Organic
´
Chemistry, University of Łodz, Tamka 12 Street, 91-403 Łodz, Poland. E-mail: zbigmal@uni.lodz.pl
´
´
´
3572

N-[2-(METHYLAMINO)ETHYL]PHTHALAZINONES
3573
Figure 1. Structures of biologically active 2H-pyridazin-3-one derivatives I–V.
compounds can exhibit analgesic as well as nonsteroidal anti-inflammatory activity
Va–c.[8–11]
In our previous articles we have described methodologies for the synthesis of
novel (dimethylamino)methyl- and 2-(dimethylamino)ethyl- derivatives of phthalazi-
nones and pyridopyridazinones (Scheme 1).[11,12] The synthetic methods applied in
the preparation of these compounds were based on the Mannich reaction and on
the reaction of lactams 1 with 2-chloro-N,N-dimethylethanamine.
RESULTS AND DISCUSSION
In this article, we present methods for the preparation of 2-(N-methylami-
no)ethyl- derivatives of phthalazinones. Starting lactams 1 were synthesized from
the appropriate 3-hydroxyisoindolinones or ketoacids upon reaction with hydrazine
monohydrate, according to previously described methods.[11–14]
Our preliminary studies have shown that preparation of 2-(x-aminoalkyl)
phthalazinones by reaction of corresponding 2-halogenethylamines 4 (Scheme 2)
with lactams 1 is not effective. If primary or secondary x-halogenalkylamines 4a,b
were used to react with phthalazinones 1, the outcomes were rather poor.[15]

3574
Z. MALINOWSKI ET AL.
Scheme 1. Synthesis of (N,N-dimethylamino)alkyl phthalazinones 2 and 3.[11,12]
N-Alkylated products 5 were formed in trace amounts only, if at all. The formation
of compounds 5 was observed by NMR spectroscopy and they were not isolated in
individual form. Therefore, practical application of the x-halogenalkylamines as
alkylating agents is limited and determined by the degree of substitution of amine
nitrogen atom. In practice, this methodology plays a significant role in preparation
of 2-(N,N-dialkylamino)ethyl-lactam derivatives type 3,[11] solely (Scheme 1).
Based on these results, we focused on the synthesis of selected N-(2-ami-
noethyl)- phthalazinone derivatives substituted on the amine nitrogen atom by alkyl,
tosyl, acetyl, and tert-butoxycarbonyl group. These derivatives can be effortlessly
converted into the desired secondary amines (N-methylamines).[16,17] Easily access-
ible derivatives of 2-(methylamino)ethanol, types 6, 7, and 8 (Fig. 2),[18–20] were used
as x-aminoethylating agents.
Synthesis of N-2-(methylamino)ethyl lactams type 10 was carried out using two
approaches as shown in Scheme 3. Initially, benzenesulfonamides 9 were synthesized,
as precursors of corresponding 2-(methylamino)ethyl derivatives 10.
Phthalazinones 1 after treatment with MeONa were converted into amides 9 by
reaction with ditosylated 2-(methylamino)ethanol, in 40–64% yields. In the second

N-[2-(METHYLAMINO)ETHYL]PHTHALAZINONES
3575
Scheme 2. Studies of synthesis of 2-(N-methylamino)ethyl- and 2-aminoethylphthalazinones 5.
stage benzenesulfonamides 9 were hydrolyzed to corresponding amines 10 by heating
with concentrated H2SO4 (110 ꢀC). Desired amines were obtained in 56–78% yields.
The structures of compounds 9 and 10 were determined by infrared (IR), 1H NMR,
and elemental analysis or mass spectroscopy (Table 1).
Unexpectedly, synthesis of amine 10d via hydrolysis of appropriate N-tosyl
derivative with H2SO4 ended in failure. For this reason, the synthesis of amine
10d was carried out using the Mitsunobu reaction[21,22] as a key step, followed by
deprotecion of the amine group. Alkylation of phthalazinone 1 with N-
Boc-protected 2-(metylamino)ethanol using standard Mitsunobu conditions (TPP,
DEAD) gave carbamic acid derivatives 11e in satisfactory yields (Scheme 3). Cleav-
age of the Boc protecting group of compound 11e with hydrochloric acid at rt gave
the secondary amine 10d in 55% yield. This protocol was successfully applied to
Figure 2. Structures of x-aminoethylating agents.

3576
Z. MALINOWSKI ET AL.
Scheme 3. Synthesis of compounds 9, 10, and 11. Reagents and conditions: (i) (a) MeONa=MeOH, D
30 min, (b) TsOCH2CH2N(Me)Ts (6), D 7 h; (ii) H2SO4, D 6 h; (iii) Mitsunobu procedure: (a) TPP, DEAD,
ꢁ10 ꢀC, (b) HOCH2CH2N(Me)R3 7 or 8, rt 20 h; (iv) HCl (20%aq), MeOH, rt 30 h.
Table 1. Synthesis of compounds 9, 10, and 11
Entry
Compound
R1
R2
R3
Yield (%)
1
2
9a
9b
H
H
—
—
50
45
64
47
40
45
78
65
56
55
30
45
55
50
55
Me
Ph
H
3
9c
9d
H
—
—
4
4-(MeO)-C6H4
H
5
9e
9f
4-Cl-C6H4
2Py
H
H
—
—
6
MeO
H
7
10a
10b
10c
10d
11a
11b
11c
11d
11e
—
—
8
Me
Ph
H
9
H
—
—
10
11
12
13
14
15
2Py
H
MeO
H
Ac
Boc
Ac
Boc
Boc
H
Ph
H
H
Ph
2Py
H
MeO
preparation of N-(tert-butoxycarbonyl) derivatives 11b,d and N-acetyl analogs 11a,c
using N-(2-hydroxyethyl)-N-methylacetamide as a starting material, too. Therefore,
presented methods for synthesis of N-methylaminoethyl derivatives of phthalazi-
nones are complementary to one another but application of Mitsunobu method-
ology allows the reaction to be carried out under milder conditions.
CONCLUSIONS
In conclusion, we described an efficient synthesis of new N-substituted phthalazi-
nones derivatives containing (2-fmethyl[(4-methylphenyl)sulfonyl]aminogethyl)- and

N-[2-(METHYLAMINO)ETHYL]PHTHALAZINONES
3577
f2-[(tert-butoxy carbonyl)(methyl)amino]ethylg- moiety by reaction of series
phthalazinones with readily accessible 2-(methylamino)ethanol derivatives. This,
coupled with an effective conversion of compounds 9 and 11 to the corresponding
2-[2-(methylamino)ethyl]-2H-phthalazin-1-ones 10, should allow to access a wide variety
of these types of compounds.
EXPERIMENTAL
The melting points were determined on a Boetius hot-stage apparatus and are
1
uncorrected. H NMR spectra were recorded at 200 MHz and 13C NMR spectra at
50 MHz on a Varian Gemini 200 BB spectrometer with tetramethylsilane (TMS) as
an internal reference. IR spectra were recorded on a Nexus FT-IR spectrometer.
Mass spectra analyses were performed on a MAT95-Finnigan mass spectrometer.
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
visualized using an ultraviolet lamp.
Commercially available (Aldrich, Fluka) hydrazine monohydrate, N,N,N0,
N0-tetramethylethylenediamine, triphenylphosphite (TPP), diethyl azodicarboxylate
(DEAD), 2-acetylbenzoic acid, and 2-benzoilbenzoic acid were used without further
purification. Tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl
immediately before use. x-Aminoethylating agents 6, 7, and 8 were prepared by stan-
dard methods[18–20] from the commercially available 2-(methylamino)ethanol.
2H-Phthalazin-1-ones 1 were prepared according to an already reported
procedure from appropriate 3-hydroxy-1H-isoindolin-1-ones or ketoacids.[11–14]
General Procedure for Preparation of Benzenesulfonamides 9
2H-Phthalazin-1-one 1 (0.0153 mol) was added to a solution of sodium meth-
oxide (0.0165 mol) in dry MeOH (70 ml). The mixture was heated to boiling for
30 min. Afterward, toluene-4-sulfonic acid 2-[methyl-(toluene-4-sulfonyl)-amino]-
ethyl ester (6) (0.0230 mol) was added and heating was continued for the next 7 h.
After this time, the mixture was cooled to ambient temperature. The separated pro-
duct was filtrated off, washed with dry methanol, and purified by crystallization or
column chromatography.
The FTIR spectra of the benzenesulfonamides 9 displayed characteristic
absorption of the C O in the region 1640–1650 cmꢁ1. Besides, bands of SO2 between
=
1
1150 and 1340 cmꢁ1 were observed. The H NMR spectra of amides 9 showed the
presence of two singlets at 2.31–2.34 ppm and 2.91–2.93 ppm corresponding to
methyl group of 4-toluenesulfonyl moiety and N-Me protons, respectively. The
signals of the ethylene bridge were displayed as two triplets at 4.36–4.50 and
3.51–3.59 ppm.
4,N-Dimethyl-N-[2-(1-oxo-4-phenyl-1H-phthalazin-2-yl)-ethyl]
benzenesulfonamide (9c)
ꢁ1
Yield 64%; mp 128–131 ꢀC (MeOH); FT-IR (KBr, cm ) n: 1654 (C O), 1336,
=
1163 (SO2); 1H NMR (200 MHz, CDCl3, ppm) d: 8.46–8.51 (m, 1H, 8-ArH),

3578
Z. MALINOWSKI ET AL.
7.82–7.72 (m, 3H, Ph, ArH), 7.67–7.52 (m, 7H; Ph, Ar, TsH), 7.15 (m, 2H, TsH),
4.48 (t, 2H, CH2, J ¼ 6.0 Hz), 3.59 (t, 2H, CH2, J ¼ 6.0 Hz), 2.93 (s, 3H, NMe),
2.31 (s, 3H, TsMe); 13C NMR (50 MHz, CDCl3, ppm) d: 159.1, 142.9, 135.0,
134.9, 132.7, 131.2, 129.4, 129.0, 128.5, 127.9, 127.0, 126.6, 48.1, 34.8, 21.4. Anal.
calcd. for (C24H23N3O3S): C, 66.49; H, 5.35; N, 9.69; S, 7.40%. Found: C, 66.45;
H, 5.42; N, 9.73; S, 7.47%.
General Procedure for Preparation of Acetyl- and tert-Butoxycarbonyl-
Derivatives of 2-[(Methylamino)ethyl]-2H-phthalazin-1-ones 11
(Mitsunobu Procedure)
The Mitsunobu reaction was carried out under argon. DEAD (0.0102 mol,
solution in toluene c ꢂ 40%) was slowly added to a stirred solution of TPP
(0.0102 mol) in dry THF (10 ml) at ꢁ10 ꢀC. Then a solution of phthalazinone 1
(0.0068 mol) in THF (44 ml) was added dropwise. The whole lot was mixed for
15 min at ꢁ10 ꢀC and next the appropriate derivative of N-methylethanolamine 7
or 8 (0.00748 mol) in THF (5 ml) was added at ꢁ10 ꢀC. The mixture was stirred
during 2 h at ꢁ10 ꢀC, after which time the reaction mixture was warmed to ambient
temperature and stirred in this condition for 20 h. All volatile materials were removed
under reduced pressure, ethyl ether (20 ml) was added to the residue, and the whole
lot was stirred for 0.5 h at ambient temperature. The separate white solid was col-
lected by flirtation and washed with ether, and the filtrate was evaporated to dryness.
The residue was subjected to column chromatography to give the pure product 11.
1H NMR spectra of compounds 11 showed doubled singlets of methyl groups
connected with nitrogen atoms and derived from acetyl or tert-butoxycarbonyl
moieties. This fact may indicate that amides 11 coexist as mixtures of rotamers.[23]
N-Methyl-N-[2-(1-oxo-4-phenyl-1H-phthalazin-2-yl)-ethyl]-acetamide
(11c)
Yield: 55%; mp 138–140 ꢀC; Rf ¼ 0.12 (CH2Cl2-acetone ¼ 9:1); FT-IR (KBr,
1
cmꢁ1) n: 1652, 1649 (C O); H NMR (200 MHz, CDCl3, ppm, mixture of rotamers)
=
d: 8.53–8.50 (m, 1H, ArH), 7.81–7.72 (m, 3H, ArH), 7.61–7.50 (m, 5H, ArH), 4.50
(m, 2H, CH2), 3.93–3.77 (m, 2H, CH2), 3.04, 3.02 (2 ꢃ s, 3H, NMe, two rotamers),
2.02, 1.97 (2 ꢃ s, 3H, Ac-Me, two rotamers); 13C NMR (50 MHz, CDCl3, ppm, mix-
ture of rotamers) d: 171.1, 170.9, 159.4, 159. 3, 147.8, 147.1, 135.1, 134.8, 133.1,
132.8, 131.7, 131.3, 129.4, 129.3, 129.0, 128.7, 128.6, 127.1, 126.7, 49.0, 48.6, 46.2,
36.7, 33.5, 21.7, 20.9. Anal. calcd. for C19H19N3O2: C, 71.01; H, 5.96; N, 13.07%.
Found: C, 70.88; H, 5.99; N, 12.81%.
General Procedure for Preparation of 2-[(Methylamino)ethyl]-2H-
phthalazin-1-ones 10
Method A: Hydrolysis of benzenesulfonamides 9. The benzenesulfona-
mide 9 (0.0106 mol) and H2SO4 (98%, 0.0318 mol) were heated up to 100–110 ꢀC over
a period of 6 h. After this time the reaction mixture was cooled to ambient
temperature, alkalized with 20% aqueous solution of NaOH, and next extracted with

N-[2-(METHYLAMINO)ETHYL]PHTHALAZINONES
3579
CH2Cl2 (3 ꢃ 30 ml). The combined extracts were dried over MgSO4 and concentrated
to dryness. The amine was separated by column chromatography.
Method B: Hydrolysis of tert-butyl methyl[2-(1-oxo-1H-phthalazin-2-yl)
ethyl]-carbamates 11. Carbamate 11 (0.00275 mol) was added to a solution of
HClaq (20%, 36 ml). The mixture was stirred for 30 h at room temperature. Next
reaction mixture was alkalized with 20% aqueous solution of NaOH and extracted
with CH2Cl2 (3 ꢃ 50 ml). The combined extracts were dried over MgSO4 and concen-
trated under vacuum. The amine was isolated by column chromatography.
In the case of amines 10 FTIR spectra showed NH bands at ꢂ3320 cmꢁ1 and
1
strong C O bands at 1652 cmꢁ1. In the H NMR spectra of amines 10 (Scheme 3)
=
the signals of the 2-(methylamino)ethyl moiety were displayed as two triplets at
ꢂ4.42 and ꢂ3.11 ppm corresponding to CH2 protons of ethylene chain, whereas
the protons of NMe and NH groups exhibited as two singlets between 1.52 and
2.51 ppm.
2-[2-(Methylamino)-ethyl]-4-phenyl-2H-phthalazin-1-one (10c). Yield: 56%
(method A); mp 96–98 ꢀC; Rf ¼ 0.01 (AcOEt–MeOH ¼ 1:1 next MeOH); FT-IR
(KBr, cmꢁ1) n: 1652 (C O), 3332 (NH). 1H NMR (200 MHz, CDCl3, ppm) d:
=
8.57–8.53 (m, 1H, ArH), 7.82–7.76 (m, 3H, ArH), 7.62–7.53 (m, 6H, ArH), 4.49
(t, 2H, CH2, J ¼ 6.1 Hz), 3.16 (t, 2H, CH2, J ¼ 6.1 Hz), 2.51 (s, 3H, NMe), 2.29 (s,
1H, NH); 13C NMR (50 MHz, CDCl3, ppm) d: 159.2, 146.9, 135.0, 132.6, 131.2,
129.3, 128.9, 128.4, 127.0, 126.5, 50.3, 50.2, 36.1. Anal. calcd. for (C17H17N3O): C,
73.10; H, 6.13; N, 15.04%. Found: C, 73.11; H, 5.98; N, 15.11%.
6-Methoxy-2-[2-(methylamino)-ethyl]-4-(pyridin-2-yl)-2H-phthalazin-1-
one (10d). Yield: 55% (method B); mp 94–96 ꢀC; Rf ¼ 0.0 (AcOEt next MeOH);
FT-IR (KBr, cmꢁ1) n: 1652 (C O), 3316 (NH); 1H NMR (200 MHz, CDCl3,
=
ppm) d: 8.75–7.24 (m, 1H, ArH), 8.42 (d, 1H, ArH, J ¼ 8.8 Hz), 7.95–7.86 (m, 3H,
ArH), 7.42–7.28 (m, 2H, ArH), 4.44 (t, 2H, CH2, J ¼ 6.1 Hz), 3.88 (s, 3H, OMe),
3.10 (t, 2H, CH2, J ¼ 6.1 Hz), 2.47 (s, 3H, NMe), 1.52 (brs, 1H, NH); 13C NMR
(50 MHz, CDCl3, ppm) d: 162.9, 159.3, 154.9, 148.4, 143.3, 137.1, 130.4, 128.9,
124.2, 123.4, 121.9, 120.2, 108.6, 55.5, 50.3, 50.2, 36.0. Anal. calcd. for
(C17H18N3O2): C, 65.79; H, 5.85; N, 18.05%. Found: C, 65.52; H, 5.78; N, 17.93%.
FUNDING
This work was financially supported by the Polish Ministry of Science and
´ ´
Higher Education, Grant No. 3 T09A 015 29 and University of Łodz.
SUPPORTING INFORMATION
Full experimental details, 1H and 13C NMR, and IR spectra can be accessed on
the publisher’s website.

3580
Z. MALINOWSKI ET AL.
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