Multicomponent synthesis of 4-aminophthalazin-1(2 H)-ones by palladium-catalyzed isocyanide insertion

Article abstract of DOI:10.1021/jo401131p

4-Aminophthalazin-1(2H)-ones (APOs) are underexplored heterocyclic compounds with promising and diverse biological activities. The classical synthesis of these compounds is tedious and does not allow the regioselective introduction of substituents. Here,

Full text of DOI:10.1021/jo401131p

Article
pubs.acs.org/joc
Multicomponent Synthesis of 4‑Aminophthalazin-1(2H)‑ones by
Palladium-Catalyzed Isocyanide Insertion
Tjøstil Vlaar,† Pieter Mampuys,‡ Madeleine Helliwell,§ Bert U. W. Maes,*,‡ Romano V. A. Orru,*,†
and Eelco Ruijter*,†
†Department of Chemistry & Pharmaceutical Sciences and Amsterdam Institute for Molecules Medicines and Systems (AIMMS),
VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
‡Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium
§School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
S
* Supporting Information
ABSTRACT: 4-Aminophthalazin-1(2H)-ones (APOs) are under-
explored heterocyclic compounds with promising and diverse
biological activities. The classical synthesis of these compounds
is tedious and does not allow the regioselective introduction of
substituents. Here, we present our full studies on the Pd-catalyzed
cross-coupling of substituted o-(pseudo)halobenzoates and
hydrazines with isocyanide insertion allowing straightforward
access to diversely substituted APOs. We illustrate the advantages
of this method compared to other approaches and describe
solutions for the limitations we encountered. In addition, we
have developed efficient diversifications of this heterocyclic
scaffold that allow access to more diverse APOs as well as
novel heterocyclic scaffolds.
can be employed, and the resulting N2 position can be
functionalized later on, thereby extending the sequence to five
steps (Scheme 1, route B). In addition, selective introduction of
substituents on the phenyl ring (4, R1) is difficult in both routes
A and B because condensation with substituted hydrazine and
monodehydroxyhalogenation both proceed with very poor
regioselectivity.
Palladium-catalyzed cross-coupling reactions have become
essential tools for the mild and selective construction of C−C
bonds.7 Isocyanides (2, Scheme 1), which are isoelectronic with
carbon monoxide, have emerged as powerful C1 building
blocks in palladium catalysis during the last couple of years.8
Isocyanides readily undergo transformations similar to carbon
monoxide9 but offer a distinct advantage for introducing diver-
sity because they possess a variable group at nitrogen. As a
result, palladium-catalyzed isocyanide insertion reactions offer
a vast potential for the efficient and flexible synthesis of valuable
nitrogen-containing heterocycles.10 We have recently ex-
ploited this reactivity in a novel palladium-catalyzed coupling of
o-(pseudo)halobenzoates (1), isocyanides (2) and hydrazines
(3) that produces APOs in a more step- and atom-economic
manner than the above-mentioned conventional methods
INTRODUCTION
■
Novel and underexplored heterocyclic scaffolds exhibiting
valuable biological activity are vital for the drug discovery and
development process. Efficient synthetic approaches toward
such scaffolds are instrumental to the rapid synthesis and
evaluation of these compounds. Multicomponent reactions
(MCRs)1 and cascade reactions2 are important tools to meet
these goals, because several bond forming steps are combined
in a single reaction vessel. As a result, fewer synthetic steps
are required for the construction of a given target molecule.
4-Aminophthalazin-1(2H)-ones (APOs, 4)3 have recently shown
promising activity as Aurora A kinase inhibitors and human A3
adenosine receptor antagonists (Scheme 1).4 In addition, they
have shown potential as PARP (poly(ADP-ribose) polymerase)
inhibitors, which are associated with cancer treatment, and
for the treatment of inflammatory and autoimmune diseases.5
Despite this promising precedence, APOs have remained rather
unexplored, most likely due to their tedious linear synthesis and
the lack of new and regioselective approaches for synthesizing
substituted APOs.4a,6 The typical synthesis (Scheme 1, route A)
starts from phthalic anhydride and is a multistep process that
consists of condensation with hydrazine (I), dehydroxyhaloge-
nation (II), and Buchwald−Hartwig amination (III).4a This
sequence is highly inefficient for variation at the N2 position
(4, R3) due to the poor commercial availability of substituted
hydrazines and the early incorporation of this group in the
synthesis. To circumvent this, unsubstituted hydrazine (R = H)
Received: May 23, 2013
Revised: June 14, 2013
Accepted: June 14, 2013
© XXXX American Chemical Society
A
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Scheme 1. Biologically Active 4-Aminophthalazin-1(2H)-ones and Routes of Synthesis
(Scheme 1, routes A and B) and allows, for the first time,
regioselective introduction of substituents (Scheme 1, route C).11,12
The reaction was unfortunately limited to tertiary aliphatic
isocyanides and worked the best for unsubstituted hydrazines.
Herein, we report the full details of this reaction and strategies
to overcome the limitations of our approach, resulting in a two-
or three-step sequence that selectively introduces substituents
on all positions of the APO scaffold.
nucleophilic aromatic substitution by hydrazine. Interestingly, the
yield of 4b increased significantly when the reaction time was
reduced to just 2 min (from 62% to 80%), suggesting undesired
Pd-catalyzed reactions of the aryl chloride occurred on the
reaction product. It is important to note that the medicinally
important fluoro- and trifluoromethyl substituents could be
smoothly incorporated,14 but the yields were modest (4c and
4d). A naphthalene-fused derivative (4e) and a methyl-substituted
APO (4f) were obtained in excellent yield (99% and 95%,
respectively). Electron-rich methyl o-(pseudo)halobenzoates
undergo the desired reaction extremely well, affording the
corresponding APOs 4g−4k in excellent yield, but reactions
are sometimes slower, requiring 15 min reaction time (4j and
4k). Substrate 1i, containing a free amino group, was not fully
consumed under the reaction conditions. The reaction tolerates
heterocyclic substrates, as exemplified by the conversion of the
pyridine analog 1l to aza-APO 4l in 84% yield. Azaphthalazi-
nones lacking the 4-amino group very recently received attention
as human histamine H1 receptor antagonists.15
The main limitation in scope with respect to the benzoate
(1) is the availability or straightforward access to this building
block. We were therefore pleased to find that methyl 2-bromo-
4-fluorobenzoate (1c), which can be obtained in one step from
the commercially available corresponding carboxylic acid, is an
excellent substrate for nucleophilic aromatic substitution reac-
tions with amines. Benzoates 1j and 1k were readily obtained in
the manner described in Scheme 2. Considering the fact that
amines are prevalent in biologically active molecules, this is an
important handle for introducing additional functionality.
Next, we explored the substrate scope of the other two com-
ponents of this reaction and were disappointed to find low yields
when monosubstituted hydrazines were employed (Table 1).
We reasoned this might be due to the difference in basicity
between different hydrazines and resolved this issue by the
RESULTS AND DISCUSSION
■
We previously established optimal conditions for the conver-
sion of methyl 2-bromobenzoate to 4-(tert-butylamino)phthalazin-
1(2H)-one (4a) using hydrazine monohydrate and tert-butyl
isocyanide as reagents.11 Hydrazine not only is used as a reactant
but also acts as a base to neutralize the generated hydrobromic
acid. Bidentate phosphine ligands proved essential for high
yields, with Xantphos being most effective. Furthermore,
dimethyl sulfoxide (DMSO) was the only solvent in which
the reaction performed well, and microwave irradiation heating
proved more effective than conventional heating.13 With these
optimized conditions, 4a is readily obtained within 5 min in
excellent yield (Table 1, 98%). The reaction can be extended to
the corresponding aryl iodide and aryl triflate, but the aryl
chloride provides a much lower yield of 4a. Diverse substitution
(e.g., Cl, CF3, NH2, F, and OMe) on the methyl o-halobenzoate
(1) was well tolerated on various positions and led to the
isolation of the corresponding products 4b−4k in moderate to
excellent yields. The structure of compound 4b was un-
ambiguously established by X-ray crystallography (see Figure S1
in the Supporting Information). Electron-poor methyl benzoates
(1) are typically converted in moderate yield (4b−4d). This is
probably due to compatibility issues as the aryl chloride (1b)
might undergo competitive oxidative addition, and methyl
2-bromo-4-fluorobenzoate (1c) is an excellent substrate for
B
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a
Table 1. Substrate Scope of the Pd-Catalyzed MCR toward 4-Aminophthalazin-1(2H)-ones
a
Conditions: ArX (0.50 mmol), isocyanide (0.75 mmol), hydrazine monohydrate (1.05 mmol), Pd(OAc)2 (2 mol %), and Xantphos (4 mol %) in
DMSO (2.5 mL) for 5 min at 150 °C (μW). Yields refer to isolated products. Compounds 4a, 4b, 4e−i, and 4m−r were reported by us previously.11
b
c
d
Reaction time: 2 min. Reaction time: 15 min. Conditions as under a but using a substituted hydrazine (1.25 mmol) and i-Pr2NH (1.50 mmol).
Scheme 2. Synthesis of Substrates 1j and 1k
addition of diisopropylamine as additional base. Aromatic hydrazines
work reasonably well under these modified conditions (4m−4p),
and methyl hydrazine provided 30% of reaction product 4q.
The isocyanide input is, unfortunately, limited to tertiary aliphatic
isocyanides; only tert-butyl isocyanide and 1,1,3,3-tetramethylbutyl
isocyanide provided the desired product.
To make further diversification possible, we envisioned a
“deprotection” strategy. Removal of the tert-butyl group of the
4-(tert-butylamino)phthalazin-1(2H)-ones (4) should give
APOs with a free amino group (5). Pleasingly, the acid-mediated
removal of the tert-butyl group proceeds in excellent yields using
conditions developed by Guchhait (Table 2).16 The deal-
kylation can be performed without intermediate purification
of the 4-(tert-butylamino)phthalazin-1(2H)-one (4), although
a solvent switch to n-butanol was required. Also, scale-up of this
one-pot, two-stage procedure was successful in demonstrating
that practical quantities can be obtained via this approach. The
reaction proceeds well on a 4 mmol scale, but the required
reaction times for the multicomponent reaction are typically
longer. For example, while 7-methoxy-substituted APO 4h was
obtained within 5 min on a 0.5 mmol scale (Table 1), 30 min
were required for high yields on a 4 mmol scale (Step 1, 5e,
Table 2). In general, electron-rich methyl 2-(pseudo)-
halobenzoates (1) need prolonged reaction times to allow full
conversion and proceed in excellent yield (5d−5f). The chloro-
substituted APO 5c was obtained in optimal yield after just 2
min and required intermediate purification before dealkylation
due to formation of side products (vide supra). Finally,
N2-substituted APOs, as exemplified by the synthesis of 5g, could
also be obtained via this one-pot, two-stage procedure using
phenylhydrazine as the reagent in the presence of iPr2NH as
the base.
C
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a
Table 2. Substrate Scope of the One-Pot MCR and De-tert-Butylation Strategy
a
Step 1 conditions: ArX (4.0 mmol), t-BuNC (6.0 mmol), H2NNH2·H2O (8.4 mmol), Pd(OAc)2 (2 mol %), and Xantphos (4 mol %) in DMSO
(20 mL) for 5 min at 150 °C (μW). Step 2 conditions: HBF4 (48 wt % in H2O, 4.0 mmol), and n-BuOH (16 mL) for 20 min at 160 °C (μW). Yields
b
refer to isolated products. Compound 5a was reported by us previously.11 Reaction time for step 1: 2 min. Purification was necessary after step 1.
c
d
e
Reaction time for step 1: 15 min. Reaction time for step 1: 30 min. Conditions as under a but using phenylhydrazine (10 mmol) and i-Pr2NH
(12 mmol).
a
Table 3. Substrate Scope of the N2 Alkylation of APOs
a
Conditions: 4-aminophthalazin-1(2H)-one (0.5 mmol), alkyl halide (0.5 mmol), and NaH (60% in oil, 0.5 mmol) in dry DMF (3.5 mL) was stirred
at RT for 20 h. Yields refer to isolated products. Compound 6a was reported by us previously.11
With the dealkylated 4-aminophthalazin-1(2H)-ones (5a−5g)
in hand, we set out to develop a strategy to access a broad
range of decorated APOs by further functionalization. Two
difficulties were apparent: (1) the APOs (5a−5g) are very polar
and only dissolve in DMSO or DMF, and (2) differentiation
between the N2 position and the 4-amino group is necessary.
We have previously reported an N2 methylation of 4-
aminophthalazin-1(2H)-one 5a using methyl iodide and
sodium hydride delivering 6a in 80% yield (Table 3).11 This
selective alkylation was further applied by benzylation and
allylation of 5c and 5e, yielding APOs 6b and 6c, respectively.
APOs with an aryl group at the N2 position are the most
studied class of 4-aminophthalazin-1(2H)-ones in medicinal
chemistry and typically show increased pharmaceutical
potential compared to that of N2-alkylated APOs.4 They are,
however, difficult to access using traditional methods that rely
on aryl hydrazines (Scheme 1) because of the poor commercial
availability of substituted hydrazines. We therefore explored a
selective N2 arylation with readily available aryl iodides under
transition metal catalysis. Pleasingly, we found that a copper
catalyst is able to differentiate between the N2 and 4-amino
positions to furnish 2-arylated APOs under conditions derived
from a procedure developed by Buchwald et al.17 APO 5a was
arylated with p-iodotoluene to yield product 7a in 72% yield,
whereas only 7% of the double arylation product (8) was
isolated (Table 4). Several electronically diverse aryl iodides
coupled in good yield and with similar selectivities (7b−7d),
and even 4-iodopyridine worked well (7e). We did not
optimize the reaction for each substrate specifically but rather
focused on one robust set of conditions that allows the smooth
D
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a
Table 4. Substrate Scope of the N2 Arylation of APOs
a
Conditions: 4-aminophthalazin-1(2H)-one (0.50 mmol), aryl iodide (0.75 mmol), Cs2CO3 (1.25 mmol), CuI (6 mol %), and ( )-trans-1,2-
b
diaminocyclohexane (40 mol %) in dry DMF (1 mL) at 110 °C for 20 h. Yields refer to isolated products. 7% of double arylation product was
isolated. 27% of double arylation product was isolated.
c
conversion of a broad scope of APOs and aryl iodides. We then
tested a range of substituted APOs and found good yields in
most cases. For example, a 7-methoxy or 6-methyl group had
no pronounced effect on the yield (7f and 7g). In contrast, a
chloro substituent decreased the yield significantly (7h),
presumably due to the competing reaction of copper catalyst
with the aryl chloride. A 5-methoxy group resulted in low con-
version, and just 16% of product 7i was isolated. We speculate
that bidentate coordination of copper to the methoxy and
amino groups inhibits catalysis. Finally, a 6-morpholino group
was tolerated, and product 7j was obtained in 58% yield.
Surprisingly, in this specific case, a significant amount of double
arylation product was found.
Table 5. Substrate Scope of the Groebke−Bienayme−
́
a
Blackburn MCR with APOs
Considering the fact that the discovery of new molecular
scaffolds is essential to meet the contemporary demand for
improved materials and pharmaceuticals, we used the dealkylated
APOs (5) as input in the complexity-generating Groebke−
Bienayme−
́
Blackburn MCR (Table 5).18 The resulting
imidazo-[2,1-a]phthalazin-6-ones (9) are unexplored scaffolds
and accessible in just 2 steps by this double MCR approach.
The reaction proceeds in higher yields if p-toluenesulfonic acid
is employed as mediator instead of ammonium chloride, which
we reported previously.11 The scope was evaluated and revealed
that several APOs can be used as substrates, and both electron
rich and electron poor aldehydes are tolerated.
a
Conditions: 4-aminophthalazin-1(2H)-one (0.50 mmol), p-toluene-
sulfonic acid monohydrate (0.25 mmol), aldehyde (0.60 mmol), and
isocyanide (0.55 mmol) in dry DMSO (2.5 mL) at 70 °C for 20 h.
Yields refer to isolated products. Compound 9a was reported by us
previously.11
Finally, when we treated 4a with phosphoryl chloride in
acetonitrile, we found conversion toward N-(tert-butyl)-4-
chlorophthalazin-1-amine (10) in a modest 48% yield (Scheme 3).
In this case, the tert-butyl group serves as a protecting group
to prevent homocoupling of the reaction product. Such
4-chlorophthalazin-1-amines are classically obtained from
1,4-dichlorophthalazines and readily undergo nucleophilic aromatic
substitution by amines to furnish 1,4-diaminophthalazines (11).19
Our route allows regioselective amine introduction when
substituents are present on the phenyl ring and therefore
avoids the tedious separation of regioisomers. Furthermore,
4-chlorophthalazin-1-amines have also been used as substrates for
Pd-catalyzed cross-coupling reactions, as exemplified by Suzuki
reactions, furnishing medicinally interesting arylphthalazines (12).20
CONCLUSION
■
We have developed a multicomponent reaction toward 4-
aminophthalazin-1(2H)-ones that, unlike other methods, allows
E
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Scheme 3. Dehydroxychlorination of 4a
(d, J = 10 Hz, C), 122.0 (d, J = 24.6 Hz, CH), 114.7 (d, J = 21.4 Hz,
CH), 52.7 (CH3).
the regioselective introduction of functional groups on the
C5−C8 positions. A one-pot MCR/dealkylation strategy over-
comes the limited scope with respect to the isocyanide input and
provides opportunities for scaffold postdiversification. The poor
commercial availability of monosubstituted hydrazines promp-
ted us to develop procedures for regioselective N2 function-
alization that avoids the use of these reagents and allows
straightforward access to both N-arylated and N-alkylated
APOs. Additionally, we have used APOs as input in Groebke−
Methyl 2-Bromo-5-(trifluoromethyl)benzoate (1d). A solu-
tion of 2-bromo-5-(trifluoromethyl)benzoic acid21 (1.93 g, 7.1 mmol,
1 equiv) in dry MeOH (22.5 mL) under an N2 atmosphere was cooled
to 0 °C. SOCl2 (1.09 mL, 15 mmol, 2.1 equiv) was slowly added, and
then the mixture was refluxed for 5 h. The reaction mixture was con-
centrated in vacuo, dissolved in DCM, washed twice with NaHCO3
(aq, saturated), and dried (Na2SO4). Purification by flash chromatog-
raphy using cyclohexane/EtOAc (50:1 > 1:9) afforded 1.88 g of a
1
Bienayme−
́
Blackburn MCRs to obtain new and highly func-
yellow oil (93%). H NMR (500 MHz, DMSO-d6): δ 8.05 (d, J =
2.1 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 2.3, 8.4 Hz, 1H), 3.89
(s, 3H). 13C NMR (125 MHz, DMSO-d6): δ 164.9 (C), 135.2 (CH),
133.3 (C), 129.3 (q, J = 3.4 Hz, CH), 128.5 (q, J = 32.9 Hz, C), 127.4
(q, J = 3.7 Hz, CH), 124.9 (C), 123.3 (q, J = 273 Hz, C), 52.9 (CH3).
Methyl 2-Bromo-4-morpholinobenzoate (1j). Methyl 2-bromo-
4-fluorobenzoate (1c, 2.32 g, 10 mmol, 1 equiv) and morpholine
(4.37 mL, 50 mmol, 5 equiv) were dissolved in DMSO (10 mL), and
the solution was stirred at 120 °C for 140 min. Subsequently, the
reaction mixture was partitioned between EtOAc and H2O. The
aqueous layer was extracted with EtOAc (3 times). The combined
organic extracts were dried (Na2SO4), filtered, and concentrated in
vacuo. Purification by flash chromatography using EtOAc/cyclohexane
(1:3) afforded 2.73 g of an off-white solid (91%). Mp: 75.5−76.5 °C
(decomposition). 1H NMR (500 MHz, CDCl3): δ 7.84 (d, J = 8.5 Hz,
1H), 7.11 (d, J = 2.5 Hz, 1H), 6.79 (dd, J = 2.5, 9.0 Hz, 1H), 3.87 (s,
3H), 3.84 (t, J = 5.0 Hz, 4H), 3.27 (t, J = 5.0 Hz, 4H). 13C NMR (125
MHz, CDCl3): δ 166.0 (CH), 153.7 (CH), 133.4 (C), 124.4 (CH),
120.5 (CH), 119.8 (C), 112.5 (C), 66.6 (CH2), 52.1 (CH3), 47.6
(CH2). HRMS (ESI) m/z: calcd for C12H14NO3BrNa [M + Na]+
322.0049, found 322.0035.
tionalized scaffolds in just two synthetic steps. Finally, we have
shown that 4-aminophthalazin-1(2H)-ones can be converted to
4-chlorophthalazin-1-amines, which are interesting intermedi-
ates toward medicinally relevant products.
EXPERIMENTAL SECTION
■
General Comments. Unless stated otherwise, all solvents and
commercially available reagents were used as received. Noncommercial
starting materials were prepared as described below or according to
literature procedures. The microwave reactions were performed in a
sealed vessel using either a CEM Discover or a Biotage Initiator Plus,
and the reaction temperatures were measured using IR. Reaction times
refer to the hold time at the desired set temperature. H and 13C
1
(attached proton test) nuclear magnetic resonance (NMR) spectra
were recorded at ambient temperature using the residual solvent as an
internal standard (1H δ 2.50 ppm and 13C{1H} δ 39.52 ppm for
DMSO-d6 and 1H δ 7.26 ppm and 13C{1H} δ 77.16 ppm for CDCl3).
Chemical shifts (δ) are given in parts per million, and coupling
constants (J) are quoted in hertz. Resonances are described as s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br
(broad) or combinations thereof. Electrospray ionization (ESI) high-
resolution mass spectrometry was carried out in positive ion mode
(capillary potential of 4500 V) with TOF analysis. Flash chromatog-
raphy was performed on SiO2 (particle size 40−63 μm, pore diameter
60 Å) using the indicated eluent.
Methyl 2-Bromo-4-fluorobenzoate (1c). 2-Bromo-4-fluoro-
benzoic acid (4.38 g, 20 mmol, 1 equiv) and dry MeOH (60 mL) were
added to a three-necked flask under an N2 atmosphere. The solution
was cooled to 0 °C, and SOCl2 (2.9 mL, 40 mmol, 2 equiv) was added.
The mixture was heated to reflux for 100 min and then concentrated in
vacuo. The residue was dissolved in DCM, and the solution was
washed twice with NaHCO3 (aq, saturated). The organic layer was
dried (Na2SO4), filtered, and concentrated in vacuo to give 4.30 g of a
colorless oil (92%). 1H NMR (500 MHz, CDCl3): δ 7.88 (dd, J = 8.8,
6.0 Hz, 1H), 7.41 (dd, J = 8.3, 2.5 Hz, 1H), 7.08 (m, 1H), 3.92 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 165.7 (C), 164.0 (d, J = 257 Hz,
C), 133.5 (d, J = 9.3 Hz, CH), 128.1 (d, J = 3.5 Hz, C), 123.3
Methyl 2-Bromo-4-((4-fluorobenzyl)amino)benzoate (1k).
Methyl 2-bromo-4-fluorobenzoate (1c, 1.16 g, 5 mmol, 1 equiv),
4-fluorobenzylamine (0.86 mL, 7.5 mmol, 1.5 equiv), and triethylamine
(1.4 mL, 10 mmol, 2 equiv) were dissolved in dry DMSO (10 mL). The
reaction mixture was stirred at 120 °C for 5 h and then cooled and
partitioned between EtOAc and H2O. The aqueous layer was extracted
with EtOAc (3 times), and the combined organic extracts were dried
(Na2SO4), filtered, and concentrated in vacuo. Purification by flash
chromatography using EtOAc/cyclohexane (1:9 > 1:1) gave 1.15 g of
1
an off-white solid (74%). Mp: 73.6−74.9 (decomposition). H NMR
(500 MHz, DMSO-d6): δ 7.65 (d, J = 8.8 Hz, 1H), 7.39−7.35 (m, 2H),
7.27 (t, J = 6.0 Hz, 1H), 7.19−7.14 (m, 2H), 6.87 (d, J = 2.2 Hz, 1H),
6.61 (dd, J = 2.3, 8.8 Hz, 1H), 4.32 (d, J = 5.9 Hz, 2H), 3.72 (s, 3H).
13C NMR (125 MHz, DMSO-d6): δ 165.1 (C), 161.3 (d, J = 243 Hz,
C), 152.4 (C), 135.0 (d, J = 2.7 Hz, C), 133.3 (CH), 129.2 (d, J =
8.2 Hz, CH), 123.3 (C), 116.8 (CH), 116.1 (C), 115.2 (d, J = 21.5 Hz,
CH), 110.6 (CH), 51.6 (CH3), 44.9 (CH2). HRMS (ESI) m/z: calcd
for C15H14BrFNO2 [M + H]+ 338.0186, found 338.0180.
F
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General Procedure for the MCR Toward 4-Aminophthalazin-
1(2H)-ones (4). A microwave tube was flame-dried under a flow of
argon before addition of Pd(OAc)2 (2.2 mg, 0.01 mmol, 2 mol %) and
Xantphos (11.6 mg, 0.02 mmol, 4 mol %). Dry DMSO (2.5 mL) was
added to the catalyst, and the resulting mixture was stirred.
Subsequently, isocyanide (0.75 mmol, 1.5 equiv), methyl benzoate
(0.50 mmol, 1 equiv), and hydrazine monohydrate (51 μL, 1.05 mmol,
2.1 equiv) were added in this order. The tube was then placed in the
microwave reactor and heated at 150 °C for 5 min unless indicated
otherwise. The crude reaction mixture was filtered through a short
plug of silica (EtOAc) and then concentrated in vacuo. Remaining
DMSO was removed by freeze-drying. The crude product was purified
by flash chromatography using the eluent specified below. Products 4a,
4b, 4e, 4f, 4g, 4h, 4i, and 4r and the synthesis of the corresponding
starting materials have been reported by us previously.11
an off-white solid (84%). Mp: 218.0−220.2 (decomposition). 1H
NMR (400 MHz, DMSO-d6): δ 11.86 (s, 1H), 9.50 (s, 1H), 8.94 (d,
J = 4.8 Hz, 1H), 8.02 (t, J = 4.8 Hz, 2H), 6.07 (s, 1H), 1.44 (s, 9H).
13C NMR (100 MHz, DMSO-d6): δ 156.2 (C), 150.5 (CH), 147.2
(CH), 143.0 (C), 133.6 (C), 120.1 (C), 118.4 (CH), 51.1 (C), 28.5
(CH3). HRMS (ESI) m/z: calcd for C11H15N4O [M + H]+ 219.1240,
found 219.1254.
General Procedure for the One-Pot MCR/Dealkylation
Sequence toward 4-Aminophthalazin-1(2H)-ones (5). A micro-
wave tube was flame-dried under a flow of Ar before addition of
Pd(OAc)2 (18.0 mg, 0.08 mmol, 2 mol %) and Xantphos (92.6 mg,
0.16 mmol, 4 mol %). Dry DMSO (20 mL) was added to the catalyst,
and the resulting mixture was stirred. Subsequently, tert-butyl iso-
cyanide (0.68 mL, 6.0 mmol, 1.5 equiv), methyl benzoate (4.0 mmol,
1 equiv), and hydrazine monohydrate (0.41 mL, 8.4 mmol, 2.1 equiv)
were added in this order. The tube was sealed, placed in the microwave
reactor, and heated at 150 °C for 5 min unless indicated otherwise.
The reaction mixture was then concentrated in vacuo, and the remain-
ing DMSO was removed by freeze-drying. (Note: Traces of DMSO led
to an unpleasant smell along with lower yields during dealkylation. We
found cofreeze-drying with H2O helpful to remove all traces of
DMSO.) The resulting solid was suspended in n-BuOH (16 mL), and
HBF4 (48 wt.% in H2O, 0.52 mL, 4 mmol, 1 equiv) was added sub-
sequently. The reaction mixture was heated in the microwave reactor
at 160 °C for 20 min, resulting in a suspension of the product as HBF4
salt and palladium black. This product was dissolved in DMSO,
and the solution was applied to 30 g of activated DOWEX 50WX2
(50−100 mesh). HBF4 was washed off with H2O (wash until pH = 7),
and impurities were removed by eluting with MeOH. Then, the
product was removed from the column by washing in succession with
NH3 (25% in H2O) and MeOH. The solution was concentrated in
vacuo, and the resulting solid was further purified by trituration to
yield analytically pure product.
Modifications for monosubstituted hydrazines: 2.5 equiv of
hydrazine derivative and iPr2NH (210 μL, 1.5 mmol, 3 equiv) was
added. Products 4m, 4n, 4o, 4p, and 4q have been reported by us
previously.11
4-(tert-Butylamino)-6-fluorophthalazin-1(2H)-one (4c). Pre-
pared from methyl 2-bromo-4-fluorobenzoate (1c). Flash chromatog-
raphy using EtOAc/cyclohexane (1:2 > 1:1) gave 44 mg of a yellow
1
solid (37%). Mp: 210.2−212.2 °C (decomposition). H NMR (500
MHz, DMSO-d6): δ 11.63 (s, 1H), 8.26 (dd, J = 6.0, 9.0 Hz, 1H), 8.06
(dd, J = 2.0, 10.5 Hz, 1H), 7.64 (dt, J = 2.5, 9.0 Hz, 1H), 5.78 (s, 1H),
1.42 (s, 9H). 13C NMR (125 MHz, DMSO-d6): δ 164.6 (d, J = 250 Hz,
C), 156.8 (C), 143.3 (d, J = 2.5 Hz, C), 129.8 (d, J = 8.8 Hz, CH),
128.1 (d, J = 8.8 Hz, C), 125.3 (d, J = 1.3 Hz, C), 119.1 (d, J = 22.6 Hz,
CH), 109.5 (d, J = 23.9 Hz, CH), 51.0 (C), 28.6 (CH3). HRMS
(ESI) m/z: calcd for C12H15FN3O [M + H]+ 236.1194, found
236.1192.
4-(tert-Butylamino)-7-(trifluoromethyl)phthalazin-1(2H)-one
(4d). Prepared from methyl 2-bromo-5-(trifluoromethyl)benzoate
(1d). Flash chromatography using EtOAc/cyclohexane/NEt3 (10:90:2 >
33:66:2) gave 61 mg of a yellow solid (42%). Mp: 200.0−202.2 °C
4-Aminophthalazin-1(2H)-one (5a). Prepared from methyl 2-
bromobenzoate. Trituration with DCM gave 556 mg of an off-white
1
1
(decomposition). H NMR (500 MHz, DMSO-d6): δ 11.88 (s, 1H),
solid (86%). Mp: 266.6−268.9 °C (decomposition). H NMR (500
8.44−8.40 (m, 2H), 8.22 (dd, J = 1.5, 8.5 Hz, 1H), 6.00 (s, 1H), 1.43 (s,
9H). 13C NMR (125 MHz, DMSO-d6): δ 156.6 (C), 143.3 (C), 130.7
(q, J = 32.8 Hz, C), 128.8 (C), 128.7 (q, J = 3.5 Hz, CH), 128.5 (C),
125.6 (CH), 123.6 (q, J = 273 Hz, C), 123.1 (q, J = 4.0 Hz, CH),
51.1 (C), 28.5 (CH3). HRMS (ESI) m/z: calcd for C13H14F3N3NaO
[M + Na]+ 308.0981, found 308.0954.
MHz, DMSO-d6): δ 11.50 (s, 1H), 8.21 (dd, J = 1.0, 8.0 Hz, 1H), 8.05
(d, J = 7.5 Hz, 1H), 7.88 (dt, J = 1.0, 7.5 Hz, 1H), 7.80 (t, J = 8.0 Hz,
1H), 5.98 (s, 2H). 13C NMR (125 MHz, DMSO-d6): δ 158.1 (C),
146.1 (C), 132.9 (CH), 131.6 (CH), 128.4 (C), 126.1 (CH), 125.0
(C), 123.9 (CH). HRMS (ESI) m/z: calcd for C8H7N3ONa [M + Na]+
184.0481, found 184.0484.
4-(tert-Butylamino)-6-morpholinophthalazin-1(2H)-one (4j).
Prepared from methyl 2-bromo-4-morpholinobenzoate (1j). Reaction
time: 15 min. Flash chromatography using EtOAc/cyclohexane (1:2)
gave 145 mg of an off-white solid (96%). Mp: >230 °C (decomposition).
1H NMR (500 MHz, DMSO-d6): δ 11.24 (s, 1H), 8.01 (d, J = 9.0 Hz,
1H), 7.37 (dd, J = 2.5, 9.0 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 5.62 (s,
4-Amino-6-methylphthalazin-1(2H)-one (5b). Prepared from
methyl 2-trifluoromethanesulfonyloxy-4-methylbenzoate. Trituration
with Et2O gave 629 mg of a light yellow solid (90%). Mp: 285.8−
1
289.5 °C (decomposition). H NMR (500 MHz, DMSO-d6): δ 11.41
(s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.62 (dd, J = 1.0, 8.0 Hz,
1H), 5.89 (s, 2H), 2.49 (s, 3H). 13C NMR (125 MHz, DMSO-d6):
δ 158.1 (C), 146.0 (C), 143.0 (C), 132.1 (CH), 126.1 (C), 126.1
(CH), 125.0 (C), 123.7 (CH), 21.5 (CH3). HRMS (ESI) m/z: calcd
for C9H9N3ONa [M + Na]+ 198.0638, found 198.0635.
1H), 3.78 (t, J = 4.5 Hz, 4H), 3.37 (t, J = 4.5 Hz, 4H), 1.43 (s, 9H). 13
C
NMR (125 MHz, DMSO-d6): δ 157.6 (C), 153.7 (C), 143.6 (C), 127.6
(CH), 127.2 (C), 119.4 (C), 117.6 (CH), 105.6 (CH), 65.9 (CH2), 50.8
(C), 47.2 (CH2), 29.0 (CH3). HRMS (ESI) m/z: calcd for C16H23N4O2
[M + H]+ 303.1816, found 303.1801.
4-Amino-7-chlorophthalazin-1(2H)-one (5c). Prepared from
methyl 2-bromo-5-chlorobenzoate. Reaction time for MCR step:
2 min. The intermediate 4-(tert-butylamino)-7-chlorophthalazin-1(2H)-
one (4b) was purified by flash chromatography using EtOAc/cyclohexane
(1:2) to yield 468 mg of a solid, which was then subjected to the standard
dealkylation conditions. Trituration with DCM afforded 257 mg of 5c as a
4-(tert-Butylamino)-6-((4-fluorobenzyl)amino)phthalazin-
1(2H)-one (4k). Prepared from methyl 2-bromo-4-((4-fluorobenzyl)-
amino)benzoate (1k). Reaction time: 15 min. Flash chromatography using
EtOAc/cyclohexane/MeOH/NEt3 (2:1:0:0 > 93:0:5:3) gave 153 mg of an
1
1
off-white solid (90%). Mp: 181.2−185.2 °C (decomposition). H NMR
yellow solid (33%). Mp: 301.0−304.6 °C (decomposition). H NMR
(400 MHz, DMSO-d6): δ 11.05 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.44
(dd, J = 5.6, 8.4 Hz, 2H), 7.16 (t, J = 8.8 Hz, 2H) 7.08 (t, J = 5.6 Hz, 1H),
7.00 (dd, J = 2.0, 8.8 Hz, 1H), 6.88 (d, J = 1.6 Hz, 1H), 5.23 (s, 1H), 4.43
(d, J = 6.0 Hz, 2H), 1.41 (s, 9H). 13C NMR (125 MHz, DMSO-d6): δ
161.3 (d, J = 243 Hz, C), 157.8 (C), 152.0 (C), 143.4 (C), 135.4 (d, J =
2.5 Hz, C), 129.5 (d, J = 8.8 Hz, CH), 127.7 (C), 127.4 (CH), 117.4 (C),
117.2 (CH), 115.1 (d, J = 20.1 Hz, CH), 101.6 (CH), 50.7 (C), 45.3
(CH2), 28.8 (CH3). HRMS (ESI) m/z: calcd for C19H22FN4O [M + H]+
341.1772, found 341.1753.
(400 MHz, DMSO-d6): δ 11.66 (s, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.10 (d,
J = 8.8 Hz, 1H), 7.97 (dd, J = 2.0, 8.8 Hz, 1H), 6.07 (s, 2H). 13C NMR
(125 MHz, DMSO-d6): δ 157.0 (C), 145.8 (C), 136.2 (C), 133.0 (CH),
130.0 (C), 126.6 (CH), 125.4 (CH), 123.6 (C). HRMS (ESI) m/z: calcd
for C8H6ClN3ONa [M + Na]+ 218.0092, found 218.0090.
4-Amino-5-methoxyphthalazin-1(2H)-one (5d). Prepared from
methyl 2-trifluoromethanesulfonyloxy-3-methoxybenzoate. Reaction
time for the MCR step: 15 min. Trituration with DCM gave 563 mg
1
of an off-white solid (74%). Mp: >240 °C (decomposition). H NMR
4-(tert-Butylamino)pyrido[4,3-d]pyridazin-1(2H)-one (4l).
Prepared from 3-bromopyridine-4-carboxylic acid methyl ester (1l).
Flash chromatography using EtOAc/cyclohexane (2:1) gave 91 mg of
(400 MHz, DMSO-d6): δ 11.50 (s, 1H), 7.81 (dd, J = 1.2, 8.0 Hz, 1H),
7.74 (t, J = 8.0 Hz, 1H), 7.47 (dd, J = 1.2, 8.0 Hz, 1H), 6.07 (s, 2H),
3.99 (s, 3H). 13C NMR (125 MHz, DMSO-d6): δ 157.2 (C), 156.1 (C),
G
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145.3 (C), 132.2 (CH), 130.4 (C), 118.3 (CH), 114.9 (CH), 114.3 (C),
56.5 (CH3). HRMS (ESI) m/z: calcd for C9H9N3O2Na [M + Na]+
214.0587, found 214.0583.
38.0 (CH3). HRMS (ESI) m/z: calcd for C9H10N3O [M + H]+
176.0818, found 176.0822.
2-Benzyl-4-amino-7-chlorophthalazin-1(2H)-one (6b). Pre-
pared from benzyl bromide. Flash chromatography using EtOAc/
DCM/NEt3 (50:50:2 > 80:20:2) gave 96 mg of a white solid (67%).
Mp: 207.0−207.6 °C (decomposition). 1H NMR (500 MHz, DMSO-d6):
δ 8.21 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 9.0 Hz, 1H), 7.98 (dd, J =
2.5, 8.5 Hz, 1H), 7.33−7.24 (m, 5H), 6.31 (s, 2H), 5.14 (s, 2H). 13C
NMR (125 MHz, DMSO-d6): δ 155.8 (C), 145.8 (C), 137.7 (C),
136.6 (C), 133.0 (CH), 129.6 (C), 128.4 (CH), 127.6 (CH), 127.2
(CH), 126.5 (CH), 125.9 (CH), 123.2 (C), 53.0 (CH2). HRMS (ESI)
m/z: calcd for C15H13ClN3O [M + H]+ 286.0742, found 286.0740.
2-Allyl-4-amino-7-methoxyphthalazin-1(2H)-one (6c). Prepared
from allyl bromide. Flash chromatography using EtOAc/DCM/NEt3
(50:50:2 > 66:33:2) gave 82 mg of an off-white solid (71%). Mp:
138.5−141.3 °C (decomposition). 1H NMR (500 MHz, DMSO-d6): δ
8.02 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 3.0 Hz, 1H), 7.45 (dd, J = 2.5,
9.0 Hz, 1H), 6.09 (s, 2H), 5.93 (m, 1H), 5.11 (m, 2H), 4.55 (d, J =
5.5 Hz, 2H), 3.92 (s, 3H). 13C NMR (125 MHz, DMSO-d6): δ 161.5 (C),
156.3 (C), 146.0 (C), 133.6 (CH), 130.0 (C), 126.1 (CH), 121.4
(CH), 118.1 (C), 116.7 (CH2), 107.6 (CH), 55.7 (CH), 52.0 (CH2).
HRMS (ESI) m/z: calcd for C12H14N3O2 [M + H]+ 232.1081, found
232.1083.
4-Amino-7-methoxyphthalazin-1(2H)-one (5e). Prepared from
methyl 2-bromo-5-methoxybenzoate. Reaction time for the MCR step:
30 min. The product was obtained as an off-white solid (537 mg,
70%). Mp: >230 °C (decomposition). 1H NMR (500 MHz, DMSO-d6):
δ 11.46 (s, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 3.0 Hz, 1H),
7.44 (dd, J = 2.5, 9.0 Hz, 1H), 5.88 (s, 2H), 3.91 (s, 3H). 13C NMR
(125 MHz, DMSO-d6): δ 161.2 (C), 158.0 (C), 146.1 (C), 130.3 (C),
126.0 (CH), 121.5 (CH), 118.7 (C), 107.2 (CH), 55.7 (CH3). HRMS
(ESI) m/z: calcd for C9H9N3O2Na [M + Na]+ 214.0587, found
214.0583.
4-Amino-6-morpholinophthalazin-1(2H)-one (5f). Prepared
from methyl 2-bromo-4-morpholinobenzoate (1j). Reaction time for
the MCR step: 30 min. Trituration with Et2O gave 946 mg of an off-
1
white solid (96%). Mp: >250 °C (decomposition). H NMR (500
MHz, DMSO-d6): δ 11.15 (s, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.40 (dd,
J = 2.5, 9.0 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 5.84 (s, 2H), 3.77 (t, J =
4.5 Hz, 4H), 3.36 (m, 4H). 13C NMR (125 MHz, DMSO-d6): δ 158.2
(C), 153.7 (C), 145.9 (C), 127.5 (CH), 126.4 (C), 119.3 (C), 118.0
(CH), 106.0 (CH), 65.9 (CH2), 47.2 (CH2). HRMS (ESI) m/z: calcd
for C12H15N4O2 [M + H]+ 247.1190, found 247.1192.
General Procedure for the N2 Arylation of 4-Aminophthalazin-
1(2H)-ones. A Schlenk tube was charged with 4-aminophthalazin-
1(2H)-one (0.5 mmol, 1 equiv), CuI (5.7 mg, 6 mol %), Cs2CO3
(411 mg, 1.25 mmol, 2.5 equiv), and aryl iodide (0.75 mmol, 1.5 equiv).
The Schlenk tube was put under vacuum and backfilled with Ar (3 times).
Subsequently, a stock solution of ( )-trans-1,2-cyclohexanediamine in
DMF (0.2 mM, 1 mL, 0.20 mmol, 40 mol %) was added. The tube was
sealed and placed in an oil bath for 24 h at 110 °C. The crude reaction
mixture was filtered through a short plug of silica (EtOAc) and then
concentrated in vacuo. The crude product was purified by flash
chromatography using the eluent specified below.
4-Amino-2-phenylphthalazin-1(2H)-one (5g). A microwave
tube was flame-dried under a flow of Ar before addition of Pd(OAc)2
(18.0 mg, 0.08 mmol, 2 mol %) and Xantphos (92.6 mg, 0.16 mmol,
4 mol %). Dry DMSO (20 mL) followed by iPr2NH (1.69 mL,
12 mmol, 3 equiv) was added to the catalyst, and the resulting mixture
was stirred. Subsequently, tert-butyl isocyanide (0.68 mL, 6 mmol,
1.5 equiv), methyl 2-bromobenzoate (0.56 mL, 4 mmol, 1 equiv), and
phenyl hydrazine (0.98 mL, 10 mmol, 2.5 equiv) were added in this
order. The tube was sealed, placed in the microwave reactor, and
heated at 150 °C for 5 min. The reaction mixture was concentrated
in vacuo, and the remaining DMSO was removed by freeze-drying.
The resulting solid was suspended in n-BuOH (16 mL), and HBF4
(48 wt.% in H2O, 0.52 mL, 4 mmol, 1 equiv) was added subsequently.
The reaction mixture was heated in the microwave reactor at 160 °C
for 20 min. The mixture was concentrated in vacuo, and the residue
was dissolved in EtOAc and washed with 1 M NaOH. Subsequently,
the water layer was extracted with EtOAc (3 times), and the combined
organic extracts were dried (Na2SO4). Flash chromatography using
EtOAc/cyclohexane/NEt3 (33:66:2 > 50:50:2) afforded 470 mg of an
2-(p-Tolyl)-4-aminophthalazin-1(2H)-one (7a). Flash chroma-
tography using EtOAc/cyclohexane (1:2 > 2:1) gave 91 mg of product
as an off-white solid (72%) along with 13 mg (7%) of double arylation
1
product 8a. Product 7a. Mp: 209.8−210.4 °C (decomposition). H
NMR (500 MHz, DMSO-d6): δ 8.31 (dd, J = 0.5, 8.0 Hz, 1H), 8.13 (d,
J = 8.0 Hz, 1H), 7.93 (dt, J = 1.5, 8.0 Hz, 1H), 7.87 (dt, J = 1.5, 8.0 Hz,
1H), 7.51 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 6.28 (s, 2H),
2.35 (s, 3H). 13C NMR (125 MHz, DMSO-d6): δ 156.7 (C), 146.2
(C), 139.9 (C), 135.9 (C), 133.1 (CH), 131.7 (CH), 129.0 (CH),
128.6 (C), 127.0 (CH), 125.6 (CH), 124.5 (C), 124.0 (CH), 20.7
(CH3). HRMS (ESI) m/z: calcd for C15H13N3ONa [M + Na]+
1
off-white solid (50%). Mp: >160 °C (decomposition). H NMR (400
MHz, DMSO-d6): δ 8.32 (dd, J = 1.2, 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz,
1H), 7.95 (t, J = 7.2 Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.64 (dd, J =
1.2, 8.8 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 6.30
(s, 2H). 13C NMR (125 MHz, DMSO-d6): δ 156.8 (C), 146.3 (C),
142.3 (C), 133.1 (CH), 131.8 (CH), 128.5 (C), 128.2 (CH), 127.0
(CH), 126.7 (CH), 125.8 (CH), 124.6 (C), 124.0 (CH). HRMS (ESI)
m/z: calcd for C14H11N3ONa [M + Na]+ 260.0794, found 260.0790.
General Procedure for the N2 Alkylation of 4-Aminophthalazin-
1(2H)-ones. A flame-dried Schlenk tube under an N2 atmosphere was
charged with 4-aminophthalazin-1(2H)-one (0.5 mmol, 1 equiv) and
dry DMF (3.5 mL). Subsequently, NaH (60% in mineral oil, 20 mg,
0.5 mmol, 1 equiv) was added, and the reaction mixture was stirred for
1 h at room temperature. Then the alkyl halide (0.5 mmol, 1 equiv)
was added. After stirring for 20 h at room temperature, the reaction
mixture was concentrated in vacuo. The residue was partitioned
between EtOAc and H2O, and the layers were separated. The water
layer was extracted with EtOAc (3 times), and the combined organic
layers were dried (Na2SO4). The product was purified using flash
chromatography with the eluent specified below.
1
274.0951, found 274.0945. Product 8a. H NMR (400 MHz, CDCl3):
δ 8.70−8.68 (m, 1H), 7.91−7.87 (m, 3H), 7.74 (d, J = 8.4 Hz, 2H), 7.42
(d, J = 8.4 Hz, 2H), 7.36 (t, J = 4.0 Hz, 3H), 7.20 (d, J = 8.4 Hz, 2H),
6.52 (s, 1H), 2.49 (s, 3H), 2.40 (s, 3H). 13C NMR (125 MHz, CDCl3):
δ 158.1 (C), 141.8 (C), 139.9 (C), 138.4 (C), 137.0 (C), 133.1 (CH),
132.0 (C), 131.8 (CH), 129.8 (C), 129.7 (CH), 129.3 (CH), 128.7
(CH), 125.4 (C), 125.3 (CH), 122.1 (CH), 119.4 (CH), 21.3 (CH3),
20.9 (CH3). HRMS (ESI) m/z: calcd for C22H20N3O [M + H]+
342.1601, found 342.1599.
2-(4-Methoxyphenyl)-4-aminophthalazin-1(2H)-one (7b).
Flash chromatography using EtOAc/cyclohexane (1:2 > 2:1) gave
99 mg of product as an off-white solid (74%). Mp: 208.6−209.6 °C
1
(decomposition). H NMR (500 MHz, DMSO-d6): δ 8.30 (dd, J =
1.0, 8.0 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.93 (dt, J = 1.0, 8.0 Hz,
1H), 7.86 (dt, J = 1.0, 8.0 Hz, 1H), 7.53 (dd, J = 2.0, 7.0 Hz, 2H), 7.00
(dd, J = 2.0, 7.0 Hz, 2H), 6.27 (s, 2H), 3.80 (s, 3H). 13C NMR (125
MHz, DMSO-d6): δ 157.7 (C), 156.7 (C), 146.1 (C), 135.4 (C), 133.0
(CH), 131.7 (CH), 128.6 (C), 127.0 (CH), 126.9 (CH), 124.5 (C),
124.0 (CH), 113.7 (CH), 55.3 (CH3). HRMS (ESI) m/z: calcd for
C15H13N3O2Na [M + H]+ 290.0900, found 290.0900.
2-(4-Chlorophenyl)-4-aminophthalazin-1(2H)-one (7c). Flash
chromatography using EtOAc/cyclohexane/NEt3 (25:75:2 > 50:50:2)
gave 109 mg of product as an off-white solid (80%). Mp: 216.3-217.3 °C
(decomposition). 1H NMR (500 MHz, DMSO-d6): δ 8.32 (d,
J = 7.5 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.88
2-Methyl-4-aminophthalazin-1(2H)-one (6a). Prepared from
methyl iodide. Flash chromatography using EtOAc/cyclohexane/NEt3
(80:20:2) gave 70 mg of a white solid (80%). Mp: 161.1−163.2 °C. 1H
NMR (500 MHz, DMSO-d6): δ 8.23 (dd, J = 1.0, 7.5 Hz, 1H), 8.07 (d,
J = 7.5 Hz, 1H), 7.85 (m, 1H), 7.81 (m, 1H), 6.17 (s, 2H), 3.53 (s,
3H). 13C NMR (125 MHz, DMSO-d6): δ 156.8 (C), 145.9 (C), 132.5
(CH), 131.5 (CH), 128.1 (C), 126.4 (CH), 124.5 (C), 123.7 (CH),
H
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(t, J = 7.5 Hz, 1H), 7.73 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H),
6.38 (s, 2H). 13C NMR (125 MHz, DMSO-d6): δ 156.8 (C), 146.5
(C), 141.0 (C), 133.3 (CH), 131.9 (CH), 130.7 (C), 128.4 (C), 128.2
(CH), 127.2 (CH), 127.1 (CH), 124.6 (C), 124.0 (CH). HRMS (ESI)
m/z: calcd for C14H11ClN3O [M + H]+ 272.0585, found 272.0584.
2-(4-Fluorophenyl)-4-aminophthalazin-1(2H)-one (7d). Flash
chromatography using EtOAc/cyclohexane/NEt3 (50:50:2 > 66:33:2)
gave 93 mg of product as an off-white solid (73%). Mp: >225 °C
(decomposition). 1H NMR (500 MHz, DMSO-d6): δ 8.31 (d, J = 8.0 Hz,
1H), 8.14 (d, J = 8.0 Hz, 1H), 7.95 (t, J = 7.0 Hz, 1H), 7.87 (t, J =
7.5 Hz, 1H), 7.69−7.66 (m, 2H), 7.29−7.27 (m, 2H), 6.34 (s, 2H).
13C NMR (125 MHz, DMSO-d6): δ 160.3 (d, J = 244 Hz, C), 156.8
(C), 146.4 (C), 138.6 (d, J = 2.5 Hz, C), 133.2 (CH), 131.8 (CH),
128.4 (C), 127.8 (d, J = 8.8 Hz, CH), 127.0 (CH), 124.6 (C), 124.0
(CH), 115.0 (d, J = 22.6 Hz, CH). HRMS (ESI) m/z: calcd for
C14H11FN3O [M + H]+ 256.0881, found 256.0880.
(d, J = 8.0 Hz, 2H), 7.44 (dd, J = 2.0, 9.0 Hz, 1H), 7.37 (d, J = 2.0 Hz,
1H), 7.22 (d, J = 8.0 Hz, 2H), 6.15 (s, 2H), 3.78 (t, J = 4.5 Hz, 4H),
3.40 (t, J = 4.5 Hz, 4H), 2.34 (s, 3H). 13C NMR (125 MHz, DMSO-d6):
δ 156.8 (C), 153.9 (C), 146.0 (C), 140.0 (C), 135.3 (C), 128.7
(CH), 128.4 (CH) 126.0 (C), 125.3 (CH), 119.1 (C), 118.2 (CH),
105.9 (CH), 65.8 (CH2), 47.1 (CH2), 20.7 (CH3). HRMS (ESI) m/z:
calcd for C19H21N4O2 [M + H]+ 337.1659, found 337.1672. Product
8j. 1H NMR (500 MHz, CDCl3): δ 8.40 (d, J = 9.0 Hz, 1H), 7.61 (d,
J = 8.5 Hz, 2H), 7.31−7.29 (m, 3H), 7.22 (d, J = 8.0 Hz, 2H), 7.08 (d,
J = 8.0 Hz, 2H), 6.99 (d, J = 2.0 Hz,1H), 6.40 (br, 1H), 3.86 (t, J = 4.5
Hz, 4H), 3.33 (t, J = 4.5 Hz, 4H), 2.37 (s, 3H), 2.29 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 158.2 (C), 154.2 (C), 141.7 (C), 139.9 (C),
138.8 (C), 136.6 (C), 131.7 (C), 129.9 (CH), 129.6 (CH), 129.2
(CH), 127.2 (C), 125.2 (CH), 121.2 (C), 119.5 (CH), 119.1 (CH),
104.9 (CH), 67.1 (CH2), 47.9 (CH2), 21.2 (CH3), 20.9 (CH3).
HRMS (ESI) m/z: calcd for C26H27N4O2 [M + H]+ 427.2129, found
427.2133.
2-(4-Pyridinyl)-4-aminophthalazin-1(2H)-one (7e). Flash chro-
matography using EtOAc/MeOH (9:1) gave 70 mg of product as an
off-white solid (59%). Mp: >240 °C (decomposition). H NMR (500
́
General Procedure for the Groebke-Bienayme-Blackburn
1
MCR with 4-Aminophthalazin-1(2H)-ones. A flame-dried Schlenk
tube was charged with 4-aminophthalazin-1(2H)-one (0.5 mmol,
1 equiv) and p-toluenesulfonic acid monohydrate (48 mg, 0.25 mmol,
0.5 equiv) and then purged with N2 (3 times). Dry DMSO (2.5 mL)
was added followed by aldehyde (0.6 mmol, 1.2 equiv) and isocyanide
(0.55 mmol, 1.1 equiv). The reaction mixture was stirred at 70 °C for
20 h. Subsequently, the reaction mixture was concentrated and
partitioned between EtOAc and H2O. The aqueous layer was extracted
with EtOAc (3 times), and the combined organic extracts were washed
with brine, dried (MgSO4), and concentrated in vacuo. The product
was purified using flash chromatography with the eluent specified
below.
MHz, DMSO-d6): δ 8.63 (dd, J = 1.5, 5.0 Hz, 2H), 8.36 (dd, J = 1.0,
8.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.99−7.88 (m, 4H), 6.52 (s,
2H). 13C NMR (125 MHz, DMSO-d6): δ 157.5 (C), 150.0 (CH),
148.6 (C), 146.9 (C), 133.8 (CH), 132.1 (CH), 128.4 (C), 127.3
(CH), 124.5 (C), 124.1 (CH), 118.2 (CH). HRMS (ESI) m/z: calcd
for C13H11N4O [M + H]+ 239.0927, found 239.0912.
2-(p-Tolyl)-4-amino-7-methoxyphthalazin-1(2H)-one (7f).
Flash chromatography using EtOAc/cyclohexane (1:2 > 2:1) gave
86 mg of product as an off-white solid (62%). Mp: >210 °C (decomposi-
tion). 1H NMR (400 MHz, DMSO-d6): δ 8.08 (d, J = 8.8 Hz, 1H), 7.70
(d, J = 2.8 Hz, 1H), 7.51−7.48 (m, 3H), 7.25 (d, J = 8.0 Hz, 2H), 6.16 (s,
2H), 3.94 (s, 3H), 2.35 (s, 3H). 13C NMR (125 MHz, DMSO-d6): δ
162.1 (C), 157.0 (C), 146.6 (C), 140.4 (C), 136.3 (C), 131.0 (C), 129.1
(CH), 126.7 (CH), 126.0 (CH), 122.2 (CH), 118.6 (C), 108.6 (CH),
56.2 (CH3), 21.1 (CH3). HRMS (ESI) m/z: calcd for C16H15N3O2Na
[M + Na]+ 304.1056, found 304.1046.
2-(4-Methoxyphenyl)-4-amino-6-methylphthalazin-1(2H)-one
(7g). Flash chromatography using EtOAc/cyclohexane (1:1 > 2:1)
gave 96 mg of product as an off-white solid (68%). Mp: 239.4−241.2 °C
(decomposition). 1H NMR (500 MHz, DMSO-d6): δ 8.19 (d, J = 8.0 Hz,
1H), 7.95 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 9.0 Hz,
2H), 6.98 (d, J = 9.0 Hz, 2H), 6.19 (s, 2H), 3.79 (s, 3H), 2.52 (s, 3H).
13C NMR (125 MHz, DMSO-d6): δ 157.6 (C), 156.8 (C), 146.0 (C),
143.3 (C), 135.4 (C), 132.8 (CH), 126.7 (CH), 126.3 (C), 124.6 (C),
123.7 (CH), 113.4 (CH), 56.3 (CH3), 21.5 (CH3). HRMS (ESI) m/z:
calcd for C16H16N3O2 [M + H]+ 282.1237, found 282.1219.
3-(tert-Butylamino)-2-(4-methoxyphenyl)imidazo[2,1-a]-
phthalazin-6(5H)-one (9a). Flash chromatography using EtOAc/
heptane (1:2 > 2:1) gave 149 mg of product as an off-white solid
(82%). Mp: > 210 °C (decomposition). 1H NMR (400 MHz, DMSO-
d6): δ 12.17 (br, 1H), 8.33 (d, J = 7.9 Hz, 1H), 8.15 (d, J = 8.8 Hz,
2H), 8.10 (d, J = 7.9 Hz, 1H), 7.89 (td, J = 1.0, 8.1 Hz, 1H), 7.67 (td,
J = 1.0, 8.1 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 3.94 (s, 1H), 3.79 (s,
3H), 1.09 (s, 9H). 13C NMR (100 MHz, DMSO-d6): δ 157.9 (C),
156.1 (C), 133.3 (C), 132.9 (CH), 130.9 (C), 128.1 (C), 128.0 (CH),
128.0 (CH), 127.1 (C), 126.6 (C), 125.1 (CH), 121.1 (CH), 117.5
(C), 113.3 (CH), 55.7 (C), 54.9 (CH3), 30.1 (CH3). HRMS (ESI)
m/z: calcd for C21H23N4O2 [M + H]+ 363.1816, found 363.1795.
3-(Cyclohexylamino)-2-(4-methoxyphenyl)-9-methylimidazo-
[2,1-a]phthalazin-6(5H)-one (9b). Flash chromatography using
EtOAc/heptane (1:2 > 2:1) gave 149 mg of product as a white
1
solid (74%). Mp: >170 °C (decomposition). H NMR (400 MHz,
2-(p-Tolyl)-4-amino-7-chlorophthalazin-1(2H)-one (7h). Flash
DMSO-d6): 12.15 (br, 1H), 8.12−8.09 (m, 3H), 7.98 (d, J = 8.4 Hz,
1H), 7.48 (dd, J = 1.2, 8.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 4.13 (d,
J = 6.8 Hz, 1H), 3.80 (s, 3H), 3.17−3.13 (m, 1H), 2.55 (s, 3H), 1.80−
1.14 (m, 11H). 13C NMR (100 MHz, DMSO-d6): δ 157.8 (C), 156.5
(C), 143.5 (C), 130.2 (C), 129.3 (CH), 128.8 (C), 128.6 (C), 127.4
(C), 127.0 (CH), 126.5 (C), 125.2 (CH), 120.6 (CH), 115.1 (C),
113.6, (CH), 55.1 (CH), 55.0 (CH3), 33.3 (CH2), 25.4 (CH2),
24.3 (CH2), 21.5 (CH3). HRMS (ESI) m/z: calcd for C24H27N4O2
[M + H]+ 403.2129, found 403.2106.
chromatography using EtOAc/cyclohexane (1:2) gave 53 mg of prod-
uct as an off-white solid (37%). Mp: >230 °C (decomposition). H
1
NMR (500 MHz, DMSO-d6): δ 8.23 (d, J = 2.0 Hz, 1H), 8.17 (d, J =
9.0 Hz, 1H), 8.02 (dd, J = 2.5, 8.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H),
7.26 (d, J = 8.5 Hz, 2H), 6.37 (s, 2H), 3.94 (s, 3H), 2.35 (s, 3H). 13C
NMR (125 MHz, DMSO-d6): δ 155.6 (C), 145.8 (C), 139.6 (C),
136.7 (C), 136.2 (C), 133.2 (CH), 130.2 (C), 128.7 (CH), 126.5
(CH), 126.2 (CH), 125.5 (CH), 123.2 (C), 20.7 (CH3). HRMS (ESI)
m/z: calcd for C15H12ClN3ONa [M + Na]+ 308.0561, found 308.0557.
2-(p-Tolyl)-4-amino-5-methoxyphthalazin-1(2H)-one (7i).
Flash chromatography using EtOAc/cyclohexane (1:2 > 2:1) gave
23 mg of product as an off-white solid (16%). Mp: >200 °C (decomposi-
2-(4-Bromophenyl)-3-(tert-butylamino)-8-methoxyimidazo-
[2,1-a]phthalazin-6(5H)-one (9c). Flash chromatography using
EtOAc/heptane (1:2 > 2:1) gave 152 mg of product as a white
1
1
solid (69%). Mp: 231.1−233.6 °C (decomposition). H NMR (400
tion). H NMR (500 MHz, DMSO-d6): δ 7.92 (d, J = 8.0 Hz, 1H),
MHz, DMSO-d6): 12.26 (br, 1H), 8.28 (d, J = 8.7 Hz, 1H), 8.20 (d,
J = 8.5 Hz, 2H), 7.57−7.50 (m, 4H), 4.00 (s, 1H), 3.92 (s, 3H), 1.10
(s, 9H). 13C NMR (100 MHz, DMSO-d6): δ 159.3 (C), 155.8 (C),
134.9 (C), 131.8 (C), 131.5 (C), 130.7 (CH), 128.5 (CH), 127.6 (C),
123.2 (CH), 122.4 (CH), 120.6 (C), 119.3 (C), 119.0 (C), 106.3
(CH), 55.9 (C), 55.6 (CH3), 30.4 (CH3). HRMS (ESI) m/z: calcd for
C21H22BrN4O2 [M + H]+ 441.0921, found 441.0902.
N-(tert-Butyl)-4-chlorophthalazin-1-amine (10). 4-(tert-
Butylamino)phthalazin-1(2H)one (4a, 108.6 mg, 0.5 mmol, 1 equiv)
was suspended in dry MeCN (1 mL) under an N2 atmosphere. POCl3
(140 μL, 1.5 mmol, 3 equiv) was added, and the mixture was stirred at
7.80 (t, J = 8.0 Hz, 1H), 7.54−7.52 (m, 3H), 7.25 (d, J = 8.0 Hz, 2H),
6.35 (s, 2H), 4.02 (s, 3H), 2.35 (s, 3H). 13C NMR (125 MHz, DMSO-
d6): δ 156.2 (C), 155.9 (C), 145.3 (C), 139.7 (C), 135.9 (C), 132.8
(CH), 130.7 (C), 128.7 (CH), 125.3 (CH), 119.1 (CH), 115.3 (CH),
113.7 (C), 56.7 (CH3), 20.7 (CH3). HRMS (ESI) m/z: calcd for
C16H16N3O2 [M + H]+ 282.1237, found 282.1233.
2-(p-Tolyl)-4-amino-6-morpholinophthalazin-1(2H)-one (7j).
Flash chromatography using EtOAc/cyclohexane/NEt3 (80:20:2) gave
97 mg of product as an off-white solid (58%) along with 58 mg (27%)
of double arylation product 8j. Product 7j. Mp: >220 °C (decomposition).
1H NMR (500 MHz, DMSO-d6): δ 8.10 (d, J = 9.0 Hz, 1H), 7.50
I
dx.doi.org/10.1021/jo401131p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
60 °C for 22 h. Then, the reaction mixture was cooled, diluted with
EtOAc, washed with NaHCO3 (aq, saturated), H2O, and brine, and
dried (Na2SO4). Flash chromatography using cyclohexane/EtOAc
(3:1) gave 57 mg of product as a white solid (48%). Mp: 176.2−
177.0 °C. 1H NMR (400 MHz, DMSO-d6): 8.48−8.44 (m, 1H),
8.06−7.92 (m, 3H), 6.75 (s, 1H), 1.54 (s, 9H). 13C NMR (100 MHz,
DMSO-d6): δ 153.8 (C), 144.0 (C), 132.7 (CH), 132.2 (CH), 125.3
(C), 124.4 (CH), 123.5 (CH), 120.5 (C), 52.9 (C), 28.4 (CH3).
HRMS (ESI) m/z: calcd for C12H15N3Cl [M + H]+ 236.0949, found
236.0940.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra for all new compounds and
a CIF file for 4b. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: R.V.A.O, r.v.a.orru@vu.nl; B.U.W.M., bert.maes@
ua.ac.be; E.R., e.ruijter@vu.nl.
■
́
̌
(c) van Baelen, G.; Kuijer, S.; Rycek, L.; Sergeyev, S.; Janssen, E.; de
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by The Netherlands
Organization for Scientific Research (NWO) by means of a
TOP grant to R.V.A.O and by the Hercules Foundation. We
thank Elwin Janssen (VU University) for technical assistance,
Sanne Bouwman (VU University) for HRMS measurements,
and Dr. Andreas W. Ehlers (VU University) for NMR spec-
troscopic measurements.
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