Studying the reactivity of (phthalazin-1(2H)-on-2-yl)methyl trichloroacetimidate towards different C- and O-nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2009.09.068

A simple and efficient synthesis of phthalazin-1(2H)-one 2-substituted derivatives is achieved in very good yields via reaction of a phthalazinone-trichloroacetimidate with various C- and O-nucleophiles such as aromatic, heteroaromatic and olefinic reagen

Full text of DOI:10.1016/j.tetlet.2009.09.068

Tetrahedron Letters 50 (2009) 6646–6650
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studying the reactivity of (phthalazin-1(2H)-on-2-yl)methyl
trichloroacetimidate towards different C- and O-nucleophiles
b
c
Ahmed O. H. El Nezhawy a, , Samir T. Gaballah , Mohamed A. A. Radwan
*
a Chemistry of Natural and Microbial Products Department, National Research Center, Dokki, Cairo, Egypt
b Photochemistry Department, National Research Center, Dokki, Cairo, Egypt
c Applied Organic Chemistry Department, National Research Center, Dokki, Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 May 2009
Revised 3 September 2009
Accepted 11 September 2009
Available online 16 September 2009
A simple and efficient synthesis of phthalazin-1(2H)-one 2-substituted derivatives is achieved in very
good yields via reaction of a phthalazinone–trichloroacetimidate with various C- and O-nucleophiles
such as aromatic, heteroaromatic and olefinic reagents, sugars and cholesterol in CH2Cl2 in the presence
of a catalytic amount of trimethylsilyl trifluoromethanesulfonate (TMSOTf).
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Trichloroacetimidate
C-Nucleophiles
O-Nucleophiles
N-Phthalazinone
Trimethylsilyl trifluoromethanesulfonate
(TMSOTf)
The synthesis of new compounds and testing their biological
and pharmacological activities are the major goals of drug develop-
ment projects. Nitrogen-containing heterocyclic compounds have
received much attention as shown by the numerous studies pub-
lished on their applicability in different areas, especially as
drugs.1,2 Phthalazines are examples of nitrogen heterocycles that
possess exciting biological properties.3–5 They form the structural
profile for several biologically active compounds and hence they
are considered as important key elements. Several reports in the
literature have focused on the pharmacology of phthalazine deriv-
atives. These reports have resulted in a great number of contribu-
tions in diverse areas of interest.6–11 Phthalazines have been
reported to possess anticonvulsant,12 cardiotonic13 and vasorelax-
ant activities.14,15 Additionally, phthalazines have recently been
reported to potentially inhibit serotonin reuptake and are consid-
ered as anti-depression agents.16
tumour agents and showed moderate activities against the
Caucasian breast adenocarcinoma MCF7 cell line.17,18
Several approaches have been reported in the literature for the
synthesis of phthalazinones.12,19 Generally, phthalazines are syn-
thesized from either phthalic anhydride derivatives, 2-aryl-3-
hydroxyinden-1-ones, or b-diketones via condensation with
hydrazine hydrate by either heating20 or applying microwave irra-
diation.15 However, these routes could not be used for the intro-
duction of N-methylenyl substitution. Trichloroacetimidate has
been shown to be a good leaving group leading to C–O bond forma-
tion and is used extensively in carbohydrate research.21 Recently,
new methodologies have been developed for C–C bond formation
via reaction of trichloroacetimidate derivatives with C-nucleo-
philes in the presence of Lewis acids.22,23 This inspired us to inves-
tigate the addition of a methylenyl moiety at the N-2 position of
phthalazinone using the trichloroacetimidate approach.
As a part of our ongoing research on drug discovery, we needed
to develop a facile and rapid synthetic pathway to new drug-like
small organic molecules containing the phthalazinone moiety.
Our research in this area has resulted in the synthesis of a series
of indole–pyrimidine (meridianin D analogues) and phthalazi-
none–amino acid conjugates. These conjugates were tested as anti-
In this Letter, we present an efficient procedure for the synthe-
sis of N-substituted phthalazinones. Starting with phthalazin-
1(2H)-one (1), we synthesized the corresponding trichloroacetim-
idate 3 as a key product. This compound was subsequently reacted
with a variety of C- and O-nucleophiles in the presence of TMSOTf
to produce a series of new phthalazinone derivatives.
Thus, commercially available phthalazin-1(2H)-one (1) was ini-
tially transformed into 2-(hydroxymethyl)phthalazin-1(2H)-one
(2)24 via reaction with formaldehyde in ethanol at reflux. The
trichloroacetimidate 325 was synthesized by reacting 2 with
* Corresponding author. Tel.: +20 2 37753491; fax: +20 2 33370931.
E-mail address: nzhawy7@yahoo.com (A.O.H. El Nezhawy).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.068

A. O. H. El Nezhawy et al. / Tetrahedron Letters 50 (2009) 6646–6650
6647
O
O
HCHO, EtOH,
reflux, 7-8 h
Cl3CCN, DBU
CH2Cl2, r.t.
NH
N
N
N
OH
1
2 (91%)
C-Nu (4-10),
TMSOTf, CH2Cl2,
-40 to -78 oC
O
O
NH
O CCl3
N
N
Nu
N
N
NH2
3 (89%)
11-18
CCl3
O
Scheme 1. The reaction of phthalazinone trichloroacetimidate with C-nucleophiles.
trichloroacetonitrile in dry dichloromethane in the presence of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) (Scheme 1). The reaction
ran smoothly at room temperature and was terminated after com-
plete consumption of the starting materials as indicated by TLC.
Trichloroacetimidate 3 was further reacted with electron-rich
aromatic C-nucleophiles 4–1026 in the presence of trimethylsilyl
trifluoromethanesulfonate (TMSOTf) as catalyst to afford the corre-
sponding adducts 11–18 in high yields (Table 1).
with 3 to afford a mixture of two inseparable stereoisomers 30a
and 30b in a 1:1 ratio as determined by 1H NMR spectroscopy.
Table 1
Reaction of C-nucleophiles 4–10 with trichloroacetimidate 3
Entry
C-Nucleophile
Product
11a
11b
12
Yield % (Ratio)
89 (3:2)
F
O
O
O
F
As fluorobenzene (4) has two equivalent o- and one p-position
susceptible to attack, two inseparable regioisomers were obtained
which were assigned as the o- and the p-products 11a and 11b. The
1H NMR spectrum showed two singlets at 5.74 and 5.71 ppm for
the CH2-linker protons in a ratio of 3:2. The singlet at 5.74 ppm
was assigned to the o-regioisomer and the singlet at 5.71 ppm to
the p-regioisomer. 1-Bromo-2,4-dimethoxybenzene (5) has two
equivalent nucleophilic sites (C-3 and C-5) and accordingly, two
products 12 and 13 were obtained, in comparable 40% and 47%
yields. The 1H NMR spectra of 12 and 13 allowed differentiation
between the two regioisomers. Compound 12 showed two dou-
blets assigned to the two neighbouring aromatic protons at 6.59
(d, J = 8.9 Hz) and 7.45 (d, J = 8.9 Hz) ppm, while 13 showed two
singlets at 6.48 and 7.29 ppm assigned to the two separate aro-
matic protons. Anisole (6) has two equivalent o- and one p-position
which are possible nucleophilic sites. Reaction of 6 gave insepara-
ble regioisomers 14a and 14b in an isomeric ratio of 2:1 (o/p-iso-
meric ratio) as determined by 1H NMR spectroscopy. Although
TLC of the reaction mixture of 1,3-dimethoxybenzene (7) with 3
showed two spots, only one major product 1527 was isolated.
Silylated reagents have also proved to effect C–C bond forma-
tion.22,28,29 Thus, trichloroacetimidate 3 was reacted with different
silylated reagents including, 1-phenyltrimethylsiloxyethene (8), 3-
trimethylsilylprop-1-ene (9) and trimethyl(vinyl)silane (10) in the
presence of TMOSTf to give, respectively, products 16, 17 and 18
(Table 1). These compounds were characterized by 1H and 13C
NMR spectroscopies. The mechanism of the nucleophilic substitu-
tion reaction of trichloroacetimidate with C- and O-nucleophiles
has been studied previously.30 In all cases, trichloroacetamide
was obtained as a by-product.
1
N
N
4
F
O
Br
Br
N
N
O
O
2
3
4
41
O
5
O
O
Br
O
N
N
47
O
O
13
N
N
O
90 (2:1)
6
14a
O
N
Next, we directed our attention towards the reaction of 3 with
several O-nucleophiles under the conditions reported above
(Scheme 2). Amongst the O-nucleophiles that were tested, reactiv-
ity towards trichloroacetimidate decreased for primary, secondary
and aromatic hydroxy groups. Reactions between 3 and primary
alcohols such as 19 and 20 afforded readily the corresponding
ethers 2731 and 2832 in high yields (Table 2). Another primary alco-
hol, N-hydroxymethylphthalimide (21), similarly underwent
etherification on reaction with 3 to afford 29. Analogously, the
secondary alcohol 2-allyl-3-hydroxyisoindolin-1-one (22) reacted
N
O
O
14b
15
O
N
N
89
O
O
O
7
(continued on next page)

6648
A. O. H. El Nezhawy et al. / Tetrahedron Letters 50 (2009) 6646–6650
Table 1 (continued)
O-Nu (19-26),
TMSOTf, CH2Cl2,
-40 to -78 oC
O
Entry
C-Nucleophile
Product
Yield % (Ratio)
N
N
O-Nu
3
O
O
O
O
Si
O
N
N
NH2
CCl3
5
89
90
86
27-34
O
16
17
18
8
Scheme 2. The reaction of phthalazinone trichloroacetimidate with O-
nucleophiles.
Si
N
N
6
Etherification of secondary alcohols 23 and 24 was successfully
performed under similar conditions to afford the
the ether 31 (5.44 ppm, s, 1H, H-1) and an inseparable mixture of
the - and b-anomers of 32 (4.75–4.98 ppm, m, 1H, H-1), respec-
tively, in good yields. It was noticed that the dimethoxytrityl group
(DMT) of 23 was cleaved during the reaction. Similarly, cholesterol
(25) reacted with 3 to afford 33 in 84% yield. The reaction between
trichloroacetimidate 3 and the hydroxy group of heteroaromatic
system 26 gave 34 in high yield. The structures of products 27–
34 were confirmed by 1H and 13C NMR spectroscopies.
a-anomer of
9
a
Si
N
N
7
10
Table 2
Reaction of O-nucleophiles 19–26 with trichloroacetimidate 3
Entry
O-Nucleophile
Product
Yield %
90
O
O
HO
O
N
N
O
1
O
O
27
28
29
19
O
O
HO
O
N
N
O
O
2
3
88
89
O
O
O
20
O
O
N
N
N
N
HO
O
O
21
O
O
N
O
N
4
5
6
86
75
86
HO
N
N
O
30a, 30b
22
ODMT
O
OH
O
O
O
O
HO
O
N
N
O
O
31
32
23
OAc
OAc
OAc
OAc
O
O
O
HO
N
O
OAc
OAc
N
24

A. O. H. El Nezhawy et al. / Tetrahedron Letters 50 (2009) 6646–6650
6649
Table 2 (continued)
Entry
O-Nucleophile
Product
Yield %
H
7
84
H
O
H
H
H
H
N
N
O
HO
25
33
O
HO
N
N
O
N
8
90
N
26
34
17. Radwan, M. A. A.; El-Sherbiny, M. Bioorg. Med. Chem. 2007, 15, 1206.
18. El Nezhawy, A. O. H.; Radwan, M. A. A.; Gaballah, S. T. ARKIVOC, 2009, xii,
119–130.
In conclusion, a facile and efficient method for the preparation
of novel 1-N-phthalazin-1(2H)-one derivatives is reported via reac-
tions of a phthalazine–trichloroacetimidate derivative with various
aromatic, heteroaromatic and olefinic reagents, sugars and choles-
terol in CH2Cl2 in the presence of a catalytic amount of trimethyl-
silyl trifluoromethanesulfonate (TMSOTf).
ˇ
19. Vina, D.; del Olmo, E.; Lopez-Perez, J. L.; Feliciano, A. S. Tetrahedron 2009, 65,
1574–1580.
20. Blicke, F. F.; Swisher, R. D. J. Am. Chem. Soc. 1934, 56, 923–925.
21. Schmidt, R. R.; Kinzy, W. In Adv. Carbohydr. Chem. Biochem.; Horton, D., Ed.;
Academic Press: San Diego, New York Boston, London, Sydney, Tokyo, Toronto,
1994; pp 21–123.
22. Ali, I. A. I.; El Ashry, E. S. H.; Schmidt, R. R. Eur. J. Org. Chem. 2003, 4121–4131.
23. Li, C.; Li, W.; Wang, J. Tetrahedron Lett. 2009, 50, 2533–2535.
Supplementary data
24. Synthesis of 2-(hydroxymethyl)phthalazin-1(2H)-one (2). To
a solution of
phthalazin-1(2H)-one (5.0 g, 34.2 mmol) in dry ethanol (30 mL) was added
formaldehyde (27 mL, 35–37%) and the mixture was stirred at reflux for 7 h.
The solvent was removed under reduced pressure and the crude material was
chromatographed on silica gel eluting with EtOAc/MeOH (9.5:0.5, v/v) to afford
2 as a white powder (yield: 5.47 g, 91%). 1H NMR (270 MHz, CDCl3): d = 5.34 (br
s, 1H, OH), 5.66 (s, 2H, CH2, linker), 7.60–7.78 (m, 3H, Ar), 8.12 (s, 1H, Ar), 8.35
(m, 1H, Ar). Anal. Calcd for C9H8N2O2 (176.17): C, 61.36; H, 4.58; N, 15.90.
Found: C, 61.31; H, 4.54; N, 15.86.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.068.
References and notes
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25. Synthesis of (1-oxophthalazin-2(1H)-yl)methyl 2,2,2-trichloroacetimidate (3). To a
solution of 2-(hydroxymethyl)phthalazin-1(2H)-one (2) (0.88 g, 5 mmol) in dry
CH2Cl2 (35 mL) were added sequentially trichloroacetonitrile (5 mL, 50 mmol)
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2 h and then concentrated under reduced pressure. The resulting residue was
purified using silica gel pad filtration, eluting with 5% Et3N in CH2Cl2 and the
eluent was evaporated to dryness to give trichloroacetimidate 3 as a pale-
yellow oil (yield: 1.43 g, 89%). 1H NMR (270 MHz, CDCl3): d = 6.29 (s, 2H, CH2),
7.64–7.83 (m, 3H, Ar), 8.15 (s, 1H, Ar), 8.39 (d, J = 7.4 Hz, 1H, Ar), 8.56 (s, 1H,
NH). 13C NMR (66.2, MHz, CDCl3) d = 93.4, 126.2, 127.0, 127.5, 129.6, 131.9,
133.8, 138.9, 159.5, 161.4. Anal. Calcd for C11H8Cl3N3O2 (320.56): C, 41.21; H,
2.52; Cl, 33.18; N, 13.11. Found: C, 41.15; H, 2.55; Cl, 33.24; N, 13.15.
26. General synthetic procedure for the reaction between trichloroacetimidate and C-
and O-nucleophiles. A solution of 3 (0.48 g 1.5 mmol) and the appropriate
nucleophile (1.5 mmol) in dry CH2Cl2 (25 mL) was cooled to À78 °C and stirred
until complete dissolution of the reactants. The solution was treated with
TMSOTf (33 mL, 0.15 mmol) and the reaction mixture was further stirred for
20–120 min at the same temperature. The reaction was then quenched by
adding sodium bicarbonate (solid) and the reaction mixture was filtered and
finally concentrated. The crude material was chromatographed on silica gel,
with gradient elution with hexanes/EtOAc.
4. Carling, R. W.; Moore, K. W.; Street, L. J.; Wild, D.; Isted, C.; Leeson, P. D.;
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Martiny-Baron, G.; Mestan, J.; Rösel, J.; Sills, M.; Stover, D.; Acemoglu, F.; Boss,
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Ganazzoli, F. Bioorg. Med. Chem. 2005, 13, 4425–4433.
27. 2-(2,4-Dimethoxybenzyl)phthalazin-1(2H)-one (15). Yellow solid; mp 93–94 °C;
yield: 0.39 g, 89%. 1H NMR (270 MHz, CDCl3): d 3.74 (s, 3H, OCH3), 3.80, (s, 3H,
OCH3), 5.39 (s, 2H, CH2, linker), 6.43 (dd, J1 = 2.3 Hz, J2 = 8.3 Hz, 1H, Ar), 6.45 (d,
J = 2.3 Hz, 1H, Ar), 7.09 (d, J = 8.3 Hz, 1H, Ar), 7.69–7.76 (m, 3H, Ar), 8.14 (s, 1H,
Ar), 8.42 (d, J = 7.1 Hz, 1H, Ar); 13C NMR (62.5 MHz, CDCl3): d 48.9 (CH2, linker),
55.2 (OCH3), 55.4 (OCH3), 98.5 (Ar), 104.1 (Ar), 117.6 (Ar), 125.8 (Ar), 126.7
(Ar), 127.9 (Ar), 129.5 (Ar), 129.7 (Ar), 131.3 (Ar), 132.8 (Ar), 137.6 (Ar), 158.3
(C–OCH3), 159.4 (C–OCH3), 160.2 (C@O). Anal. Calcd for C17H16N2O3 (296.32):
C, 68.91; H, 5.44; N, 9.45. Found: C, 68.89; H, 5.46; N, 9.47.
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31. 2-[(3,5-Dimethoxybenzyloxy)methyl]phthalazin-1(2H)-one (27). Yellow oil;
yield: 0.44 g, 90%. 1H NMR (270 MHz, CDCl3): d 3.75 (s, 6H, (OCH3)2), 4.70 (s,
2H, CH2, linker), 5.67 (s, 2H, CH2, linker), 6.31 (m, 1H, Ar), 6.53 (d, J = 2.3 Hz, 2H,

6650
A. O. H. El Nezhawy et al. / Tetrahedron Letters 50 (2009) 6646–6650
Ar), 7.65–7.83 (m, 3H, Ar), 8.16 (s, 1H, Ar), 8.45 (d, J = 7.0 Hz, 1H, Ar); 13C NMR
4.80 (s, 2H, CH2, linker), 5.68 (s, 2H, CH2, linker), 7.43 (d, J = 8.1 Hz, 2H, Ar),
7.67–7.86 (m, 3H, Ar), 7.95 (d, J = 8.1 Hz, 2H, Ar), 8.17 (s, 1H, Ar), 8.43 (d,
J = 7.1 Hz, 1H, Ar). 13C NMR (62.5 MHz, CDCl3): d 51.8 (OCH3), 71.0 (CH2, linker),
79.2 (CH2, linker), 126.1 (Ar), 126.9 (Ar), 127.0 (2C, Ar), 127.7 (Ar), 129.2 (Ar),
129.4 (2C, Ar), 129.6 (Ar), 131.8 (Ar), 133.3 (Ar), 138.3 (Ar), 142.9 (Ar), 160.0
(C@O), 166.7 (C@O). Anal. Calcd for C18H16N2O4 (324.33): C, 66.66; H, 4.97; N,
8.64. Found: C, 66.69; H, 4.96; N, 8.65.
(62.5 MHz, CDCl3): d 55.1 (2OCH3), 71.6 (CH2, linker), 79.1 (CH2, linker), 99.8
(Ar), 105.1 (2C, Ar), 126.0 (Ar), 126.9 (Ar), 127.8 (Ar), 129.7 (Ar), 131.7 (Ar),
133.4 (Ar), 138.1 (Ar), 140.0 (Ar), 160.0 (C@O), 160.6 (2COCH3). Anal. Calcd for
C18H18N2O4 (326.35): C, 66.25; H, 5.56; N, 8.58. Found: C, 66.22; H, 5.57; N,
8.57.
32. Methyl 4-{[(1-oxophthalazin-2(1H)-yl)methoxy]methyl}benzoate (28). Colorless
thick oil; yield: 0.43 g, 88%. 1H NMR (270 MHz, CDCl3): d 3.88 (s, 3H, OCH3),