Palladium-catalyzed synthesis of 4-aminophthalazin-1(2h)-ones by isocyanide insertion

Article abstract of DOI:10.1021/ol202784d

Palladium-catalyzed cross-coupling of a wide range of substituted o-(pseudo)halobenzoates and hydrazines with isocyanide insertion followed by lactamization efficiently affords 4-aminophthalazin-1(2H)-ones that are difficult to obtain regioselectively by

Full text of DOI:10.1021/ol202784d

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6496–6499
Palladium-Catalyzed Synthesis of
4-Aminophthalazin-1(2H)-ones by
Isocyanide Insertion
Tjøstil Vlaar,† Eelco Ruijter,*,† Anass Znabet,† Elwin Janssen,† Frans J. J. de Kanter,†
Bert U. W. Maes,§ and Romano V. A. Orru*,†
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, and Organic Synthesis,
Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020
Antwerp, Belgium
r.v.a.orru@vu.nl; e.ruijter@vu.nl
Received October 17, 2011
ABSTRACT
Palladium-catalyzed cross-coupling of a wide range of substituted o-(pseudo)halobenzoates and hydrazines with isocyanide insertion followed by
lactamization efficiently affords 4-aminophthalazin-1(2H)-ones that are difficult to obtain regioselectively by classical methods.
Efficient access to libraries of functionalized hetero-
cycles for lead discovery and optimization is essential for
drug development and relies heavily on combinatorial
chemistry and high-speed synthesis. In this respect, multi-
component reactions (MCRs)1 are valuable tools, since
they allow rapid generation of complex and structurally
diverse heterocycles.2 4-Aminophthalazin-1(2H)-ones
(APOs, 2) are exceptional and structurally interesting
heteroaromatics3 that have shown potential as anticancer
agents4 and in the treatment of autoimmune and inflam-
matory diseases.5 In addition, they have been identified as
PARP inhibitors.6 Very recently, 2-phenyl APOs have
been reported as a decorable scaffold for the design of
human A3 adenosine receptor antagonists.7 Vatalanib
(Scheme 1), a promising drug candidate in clinical trials
for the treatment of several types of cancer,8 can be pre-
pared from APOs. Despite this promising precedence,
APOs have only scarcely been studied, which might be
explained by the tedious linear synthesis starting from
† VU University Amsterdam.
§ University of Antwerp.
€
ꢀ
(1) (a) Domling, A. Chem. Rev. 2006, 106, 17. (b) Zhu, J.; Bienayme,
€
H. Multicomponent Reactions; Wiley-VCH: Weinheim, 2005. (c) Domling,
A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (d) Orru, R. V. A.; de
Greef, M. Synthesis 2003, 1471. (e) Ruijter, E.; Scheffelaar, R.; Orru,
R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6324.
(4) Prime, M. E.; Courtney, S. M.; Brookfield, F. A.; Marston, R. W.;
Walker, V.; Warne, J.; Boyd, A. E.; Kairies, N. A.; von der Saal, W.;
Limberg, A.; Georges, G.; Engh, R. A.; Goller, B.; Rueger, P.; Rueth,
M. J. Med. Chem. 2010, 54, 312.
(2) (a) Akritopoulou-Zanze, I. Curr. Opin. Chem. Biol. 2008, 12, 324.
(b) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51.
(3) For reviews on the synthesis, functionalization, and applications
ꢁ
of phthalazines, see: (a) Tisler, M.; Stanovnik, B. In Comprehensive
(5) Michael, G. D.; Matthias, R. US2007/219195 A1, 2007.
(6) Mevellec, L. A.; Mertens, J. C.; Kennis, L. E. J.; van Dun, J. A. J.;
Wouters, W. B. L.; Somers, M. V. F. WO2006/3147 A1, 2006.
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Daniele, S.; Trincavelli, L.; Martini, C.; Paoletta, S.; Moro, S. J. Med.
Chem. 2011, 54, 2102.
Heterocyclic Chemistry I; Katritzky, A. R., Rees, C. W., Boulton, A. J.,
McKillop, A., Eds.; Elsevier: 1984; Vol. 3, p 1. (b) Coates, W. J. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Boulton, A. J., Eds.; Elsevier: 1996; Vol. 6, p 1. (c) Haider,
N.; Holzer, W. In Science of Synthesis; Yamamoto, Y., Ed.; Thieme: 2004;
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Vol. 16, p 315. (d) Maes, B. U. W.; Lemiere, G. L. F. In Comprehensive
Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven,
E. F. V., Taylor, R. J. K., Aitken, A., Eds.; Elsevier: 2008; Vol. 8, p 1.
(8) Scott, E. N.; Meinhardt, G.; Jacques, C.; Laurent, D.; Thomas,
A. L. Expert Opin. Invest. Drugs 2007, 16, 367.
r
10.1021/ol202784d
Published on Web 11/15/2011
2011 American Chemical Society

phthalic anhydride.4,7 Furthermore, nonsymmetric substi-
tution of the phenyl ring is difficult due to formation of
regioisomers, severely limiting structureÀactivity relation-
ship (SAR) studies of APOs and related heteroaromatics.
Additionally, bulky amino groups are difficult to intro-
duce due to low nucleophilicity.
only 2 mol % of Pd(OAc)2 (entry 3). Lowering the
palladium/ligand ratio to 1:1.1 reduced the yield signifi-
cantly (entry 4). Several ligands were screened (entries 5À7),
indicating that bidentate ligands are essential, and XantPhos
is especially effective. A negative control experiment vali-
dated that a palladium catalyst is required (entry 8). DMSO
proved to be a highly effective solvent, affording the product
in quantitative yield (entry 13). The reaction was equally
efficient when the reaction time was reduced to just 5 min
(entry 14). Microwave irradiation proved clearly superior to
conventional heating (entry 15, preheated oil bath).15,16
After having defined the optimal catalytic system and
reaction conditions, we explored the scope of the reaction
(Scheme 2). In addition to aryl bromides, also aryl iodides
and triflates provided product 2a in excellent yields. Aryl
chlorides, however, proved to be less efficient coupling
partners. Both electron-donating and -withdrawing substi-
tuentsare tolerated on the aryl bromide (2bÀd), although a
5-nitro group did not provide an isolable amount of
product. The amino-substituted substrate 1c was not fully
consumed under the reaction conditions, and the remain-
ing starting material could be isolated. In the case of the
chloro-substituted substrate 1d, a more complex reaction
mixture was observed, presumably due to the competing
oxidative addition of the aryl chloride bond. Products 2c
and 2d are noteworthy, since they allow easy subsequent
modifications to increase molecular diversity. C5- and C6-
substituted APOs (2e, 2f) as well as a naphthalene-fused
derivative (2g) were obtained in excellent to quantitative
yields. The use of substituted hydrazines, however, proved
to be less straightforward. Replacing hydrazine monohy-
drate with phenylhydrazine under the standard conditions
did not lead to product formation. We argued that, since
hydrazine is both a reagent and base in this reaction, the
difference in basicity might be responsible for the observed
results. Accordingly, we examined the use of an additional
base and were delighted to observe product formation
using triethylamine as the base. After optimization we
obtained 2h in 63% yield using iPr2NH (3 equiv).16 Sub-
stitution on the methyl benzoate is still tolerated (2i, 2j),
although a strongly electron-donating methoxy group in
the ortho position decreases the yield. Interestingly, a
change in the electronic character of the aryl hydrazine
has a pronounced effect. Electron-poor para-trifluoro-
methylphenylhydrazine gives 2k in 37% yield, whereas
para-methoxyphenylhydrazine gave only trace amounts of
product. Methylhydrazine can be used, but product 2l was
obtained in poor yield (30%). These N-alkylated and
N-arylated APOs can alternatively be obtained from the
corresponding N-unsubstituted APOs.3
Scheme 1. MCR Approach toward 4-Aminophthalazinones
Palladium-catalyzed iminoacylation by isocyanide in-
sertion isanefficient butrelatively unexplored methodthat
offers significant advantages over the well-known carbon
monoxide insertions,9 such as an additional diversity point
for scaffold decoration and more practical handling.10 It is
therefore not surprising that interest in this field has
increased significantly recently.11 In light of our interest
in employing iminoacylation in palladium-catalyzed cascade
reactions,12,13 we envisioned an MCR approach toward
APOs starting from o-bromobenzoates (1), isocyanides,
and hydrazines (Scheme 1). Hydrazine is a challenging
coupling partner and has only very recently successfully
been used in the BuchwaldÀHartwig reaction.14 We
started our investigations using methyl o-bromobenzoate
(1a), tert-butyl isocyanide, and hydrazine monohydrate as
a benchmark reaction using Pd(OAc)2 (10 mol %) and
XPhos (20 mol %), as the catalytic system, in DMF with
KOAc as the base,13 which did not result in any product
formation under conventional heating. Initial screenings
indicated that employing hydrazine asbotha reagent and a
convenient and cheap base under microwave irradiation
did furnish 2a in 30% yield (Table 1, entry 1). We were
pleased to find that dppf is a much better ligand than
XPhos (entry 2), providing the product in 55% yield with
(9) For Pd-catalyzed carbonylation reactions of aryl halides, see:
€
Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2009,
48, 4114.
(10) (a) Kosugi, M.; Ogata, T.; Tamura, H.; Sano, H.; Migita, T.
Chem. Lett. 1986, 15, 1197. (b) Saluste, C. G.; Whitby, R. J.; Furber, M.
Angew. Chem., Int. Ed. 2000, 39, 4156. (c) Saluste, C. G.; Whitby, R. J.;
Furber, M. Tetrahedron Lett. 2001, 42, 6191. (d) Saluste, C. G.; Crumpler,
S.; Furber, M.; Whitby, R. J. Tetrahedron Lett. 2004, 45, 6995. (e) Tetala,
K. K. R.; Whitby, R. J.; Light, M. E.; Hurtshouse, M. B. Tetrahedron
Lett. 2004, 45, 6991.
The substrate tolerance of the isocyanide was examined
next, which unfortunately revealed that the reaction is
(11) (a) Tobisu, M.; Imoto, S.; Ito, S.; Chatani, N. J. Org. Chem.
2010, 75, 4835. (b) Jiang, H.; Liu, B.; Li, Y.; Wang, A.; Huang, H. Org.
Lett. 2011, 13, 1028. (c) Miura, T.; Nishida, Y.; Morimoto, M.;
Yamauchi, M.; Murakami, M. Org. Lett. 2011, 13, 1429. (d) Wang,
Y.; Wang, H.; Peng, J.; Zhu, Q. Org. Lett. 2011, 13, 4604.
(12) For a review, see: Vlaar, T.; Ruijter, E.; Orru, R. V. A. Adv.
Synth. Catal. 2011, 353, 809.
(15) The temperature in the reaction vessel may be lower than the
temperature of the oil bath, explaining the different conversions ob-
served. For a discussion of microwave heating vs conventional heating in
the Pd-catalyzed synthesis of heterocycles, see: Hostyn, S.; Maes,
B. U. W.; Van Baelen, G.; Gulevskaya, A.; Meyers, C.; Smits, K.
Tetrahedron 2006, 62, 4676.
ꢀꢁ
(13) Van Baelen, G.; Kuijer, S.; Rycek, L.; Sergeyev, S.; Janssen, E.;
de Kanter, F. J. J.; Maes, B. U. W.; Ruijter, E.; Orru, R. V. A. Chem.;
Eur. J. 2011, 17, accepted. DOI: 10.1002/chem.201102468.
(14) Lundgren, R. J.; Stradiotto, M. Angew. Chem., Int. Ed. 2010, 49,
8686.
(16) See the Supporting Information for additional optimization
data.
Org. Lett., Vol. 13, No. 24, 2011
6497

Table 1. Optimization of the Palladium-Catalyzed MCR toward 4-Aminophthalazin-1(2H)-onesa
entry
solvent
ligand
Pd (mol %)
Pd/L ratio
time (min)
conversion (%)b
yield (%)b
1
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
PhMe
THF
X-Phos
dppf
10
10
2
1:2
1:2
1:2
1:1.1
1:2
1:2
1:2
À
20
20
20
20
20
20
20
20
20
20
20
20
20
5
>99%
>99%
>99%
>99%
41%
30%
81%
55%
31%
5%
2
3
dppf
4
dppf
2
5
PPh3
2
6
dppp
2
70%
21%
64%
0%
7
XantPhos
À
2
>99%
39%
8
0
9
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
50%
31%
2%
10
11
12
13
14
15c
2
23%
2
23%
5%
NMP
DMSO
DMSO
DMSO
2
58%
40%
100%
99%
78%
2
>99%
>99%
86%
2
2
5
a Standard reaction conditions: Pd(OAc)2, ligand, methyl o-bromobenzoate (1a, 0.50 mmol), tert-butyl isocyanide (0.75 mmol), hydrazine
monohydrate (1.05 mmol), 2.5 mL indicated solvent, microwave irradiation at 150 °C. b Conversion of methyl o-bromobenzoate, determined by
GC analysis using dodecane as an internal standard. c Conventional heating (oil bath). DMF = N,N-dimethylformamide, THF = tetrahydrofuran,
NMP = N-methylpyrrolidone, DMSO = dimethylsulfoxide.
Scheme 2. Substrate Scope of the Palladium-Catalyzed MCR toward 4-Aminophthalazin-1(2H)-onesa
a Conditions: ArX (0.50 mmol), isocyanide (0.75 mmol), hydrazine monohydrate (1.05 mmol), Pd(OAc)2 (2 mol %), XantPhos (4 mol %) in DMSO
(2.5 mL), 5 min at 150 °C (μW). Yields refer to isolated products. bConditions as under a, but using a substituted hydrazine (1.25 mmol) and i-Pr2NH
(1.5 mmol).
highly specific for tertiary alkyl isocyanides. Although
Walborsky’s reagent provided product 2m in 64% yield,
neither primary and secondary aliphatic nor aromatic
isocyanides gave the desired product. We do not yet have
6498
Org. Lett., Vol. 13, No. 24, 2011

a satisfactory explanation for this high sensitivity. A possi-
bility could be the tendency for less bulky isocyanides to
form stable fully ligated palladium complexes, thereby
inhibiting catalysis.17 Fortunately, the tert-butyl group is
easily removed in a one-pot procedure using Guchhait’s
conditions,18 although a solvent switch is required (Scheme 3).
The unprotected amine 3 is isolated in a very good yield
(84%) at a 4 mmol scale and can subsequently serve as a
platform for diversification. Accordingly, weselectivelyN2-
alkylated amine 3 to obtain the methylated product 4 (80%
zide are formed in the absence of a palladium catalyst
(Table 1, entry 8). It is therefore highly unlikely that
hydrazide formation occurs prior to the isocyanide inser-
tion reaction.
Scheme 4. Proposed Mechanism of the Reaction (ligands on Pd
are omitted for clarity)
yield), which can easily be further modified.7 In addition, we
19
ꢀ
used amine 3 in a GroebkeÀBlackburnÀBienayme MCR,
providing imidazo[2,1a]-phthalazin-6-one 5 in 64% yield
(54% over two steps from commercially available starting
materials). The imidazo-[2,1a]phthalazin-6-one scaffold is
virtually unexplored, and only one simple example has been
reported in the literature so far.20
Scheme 3. One-Pot MCR/Dealkylation Strategy and Subse-
quent Diversification of 3
In summary, we have developed a fast and efficient
palladium-catalyzed MCR toward 4-aminophthalazin-
1(2H)-ones that (unlike existing methods) allows the
straightforward regioselective introduction of substituents
on the phenyl ring. Our method represents the first exam-
ple of a multicomponent reaction combining isocyanides
and free hydrazines as well as one of the few palladium-
catalyzed reactions using hydrazines as reactants.
Although the scope with regard to the hydrazine and
isocyanide inputs is limited, a simple one-pot dealkylation
strategy provides the unprotected APOs in excellent yields.
Subsequent complexity-generating reactions then allow
the construction of functionalized APOs as well as new
molecular scaffolds in a more time- and step-efficient
manner than conventional procedures.
A plausible mechanism for the three-component reac-
tion toward APOs is depicted in Scheme 4. Oxidative
addition of 1a to the Pd(0) catalyst followed by isocyanide
insertion leads to palladium species 7. Coordination of
hydrazine to Pd(II) and subsequent deprotonation fol-
lowed by reductive elimination provides product 9, which
cyclizes and tautomerizes under the reaction conditions to
form product 2a. Alternatively, hydrazide formation by
hydrazinolysis of the ester functional group may occur
first. This is, however, not in accordance with the observed
reaction products when phenylhydrazines are used as
reactants. Furthermore, only trace amounts of the hydra-
Acknowledgment. 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.
(17) For a similar conclusion in nickel catalysis, see: Zhang, M.;
Buchwald, S. L. J. Org. Chem. 1996, 61, 4498.
(18) Guchhait, S. K.; Madaan, C. Org. Biomol. Chem. 2010, 8, 3631.
Supporting Information Available. Detailed experimen-
1
ꢀ
(19) (a) Bienayme, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998, 37,
tal procedures, characterization data, and copies of H
2234. (b) Blackburn, C. Tetrahedron Lett. 1998, 39, 5469. (c) Blackburn,
C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S. Tetrahedron Lett. 1998,
39, 3635. (d) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661.
(20) Carling, W. R.; Ladduwahetty, T.; MacLeod, A. M.; Reeve,
A. J.; Sternfeld, F. US2003/153562 A1, 2003.
and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 24, 2011
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