Synthesis of phthalazinones via palladium(ii)-catalysed intramolecular oxidative C-H/C-H cross-coupling of N′-methylenebenzohydrazides

Article abstract of DOI:10.1039/c3ob40195b

A palladium(ii)-catalysed intramolecular oxidative C-H/C-H cross-coupling of N′-methylenebenzohydrazides to phthalazin-1(2H)-ones has been developed. This cyclization is believed to mechanistically proceed via electrophilic ortho-palladation and subsequen

Full text of DOI:10.1039/c3ob40195b

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Synthesis of phthalazinones via palladium(II)-catalysed
intramolecular oxidative C–H/C–H cross-coupling of
N’-methylenebenzohydrazides†
Cite this: Org. Biomol. Chem., 2013, 11,
2084
Received 29th January 2013,
Accepted 13th February 2013
Takanori Matsuda,* Yuki Tomaru and Yoshiya Matsuda
DOI: 10.1039/c3ob40195b
www.rsc.org/obc
A palladium(II)-catalysed intramolecular oxidative C–H/C–H cross- (Scheme 1): (i) condensation of aroyl chlorides with methyl-
coupling of N’-methylenebenzohydrazides to phthalazin-1(2H)- hydrazine (CHCl3, rt) and (ii) condensation of the resulting
ones has been developed. This cyclization is believed to mechanis- N-methyl aryl hydrazides with paraformaldehyde (toluene,
tically proceed via electrophilic ortho-palladation and subsequent reflux). The N′-methylene hydrazides thus obtained were stable
C-arylation of the carbon–nitrogen double bond.
to air and moisture, which made their utilisation easier.
When treated with 10 mol% Pd(OAc)2 as a catalyst and 1
equiv. of Ag2O as an oxidant at 120 °C in acetic acid under
nitrogen, N′-methylene-p-tolylhydrazide 1a underwent intra-
molecular oxidative C–H/C–H cross-coupling to give phthal-
azinone 2a in 55% yield after 7 h (Table 1, entry 1).7 The use of
PdCl2 led to a lower yield (entry 2), and only traces of the
desired product were formed in the absence of Ag2O (entry 3).
In addition, solvents other than acetic acid were completely
ineffective in this reaction.8 Screening of oxidants revealed
that the organic oxidant, benzoquinone (BQ),9 was the most
suitable for the reaction, giving 2a in good yield (entries
4–6).10
The mechanism for this Pd(II)-catalysed intramolecular oxi-
dative C–H/C–H cross-coupling reaction can be accounted for
by considering a CvN variant of the oxidative Heck-type cycli-
sation (Scheme 2).11 Initially, electrophilic ortho-palladation of
the aryl group of 1 with Pd(OAc)2 leads to cyclometalated ArPd-
(II)OAc intermediate A (or A′),12 and intramolecular carbopalla-
dation onto the CvN bond in a 6-endo fashion generates Pd(II)
amide B. Subsequent β-hydride elimination releases product 2,
and reoxidation of the Pd(0) species with BQ regenerates the
catalytically active Pd(II) concomitantly with the formation of
hydroquinone (HQ).
Pyridazin-3(2H)-ones and phthalazin-1(2H)-ones1 are impor-
tant structural motifs that are encountered in many biologi-
cally active compounds and thus have found important
applications in pharmaceuticals (e.g. azelastine, emorfazone)
and pesticides (e.g. pyridaben, norflurazon). Moreover, phthal-
azinone-containing polymers exhibit a number of advan-
tageous properties, including high thermo-oxidative stability,
mechanical strength, and glass transition temperature.2
Significant progress has recently been made in the area of
transition-metal-catalysed C–H bond functionalisation reac-
tions,3,4 which provide a straightforward and atom-economical
method for transforming otherwise unreactive C–H bonds into
carbon–carbon or carbon–heteroatom bonds. In this context,
oxidative C–H/C–H cross-coupling would be an ideal approach
for forming C–C bonds free of prefunctionalised coupling part-
ners.4 Some carbo- and heterocycles have previously been syn-
thesised by Pd(II)-catalysed cyclisation reactions involving
intramolecular oxidative C–H/C–H cross-coupling;5 however,
this strategy has never been applied to the construction of a
pyridazinone or phthalazinone skeleton. In this paper, we
describe a method for the synthesis of phthalazinones by Pd(II)-
catalysed intramolecular oxidative C–H/C–H cross-coupling of
N′-methylenebenzohydrazides, in which the aromatic and
methylene C–H bonds are cleaved by electrophilic palladation
and β-hydride elimination, respectively.6
With the identified optimal reaction conditions, the scope
of the reaction was assessed using a number of different sub-
strates (Table 2). While phenyl and p-anisyl derivatives 1b and
1c afforded phthalazinones 2b and 2c in 73% and 60% yields,
The N-methyl-N′-methylene aryl hydrazides 1 were prepared
from the corresponding aroyl chlorides in two steps
Department of Applied Chemistry, Tokyo University of Science, 1-3 Kagurazaka,
Shinjuku-ku, Tokyo 162-8601, Japan. E-mail: mtd@rs.tus.ac.jp;
Fax: +81 3 5261 4631
†Electronic supplementary information (ESI) available: Experimental procedures
and characterisation data for new compounds. See DOI: 10.1039/c3ob40195b
Scheme 1
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Table 1 Optimisation of reaction conditionsa
Table 2 Synthesis of phthalazinones 2 by Pd(II)-catalysed intramolecular oxi-
dative C–H/C–H cross-coupling of 1a
Entry
Pd catalyst
Oxidant (equiv.)
Time
Yieldb
Entry
1
1
Equiv. BQ Time 2 (Yieldb)
1
2
3
4
5
6
Pd(OAc)2
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ag2O (1)
Ag2O (1)
None
AgOAc (2)
Cu(OAc)2 (2)
BQ (1.2)
7 h
7 h
24 h
7 h
7 h
2 h
55%
42%
7%
29%
55%
79%
1.2
2
2
3
4
2
5
a 1a (0.200 mmol), Pd catalyst (0.020 mmol, 10 mol%), and oxidant
were reacted at 120 °C in acetic acid (1.0 mL). b Isolated yield.
2
—
2
24
5
6
7
8
1.2
2
2
2
2
7
2
Scheme 2 Proposed mechanism.
2
respectively (entries 1 and 2), hydrazide 1d, carrying a strong
electron-withdrawing nitro group on the phenyl ring, failed to
undergo the cyclisation (entry 3). This result indicated that the
reaction outcome was significantly affected by the electronic
nature of the aryl substituents. p-Bromobenzohydrazide 1e
gave product 2e without deterioration of the C–Br functional-
ity, albeit with diminished yield (entry 4).13 Steric effects were
also seen to play a crucial role in the reactivity. The reaction of
m-tolyl hydrazide 1f occurred site-specifically with C–C bond
formation at the less hindered C(6) position on the aryl group,
affording 7-methylphthalazinone 2f in 85% yield (entry 5).
Similarly, the reaction of 3,4-disubstituted arylhydrazides 1g
and 1h resulted in the exclusive formation of 6,7-disubstituted
products 2g and 2h, respectively (entries 6 and 7). 3,5-Xylyl
and o-tolyl hydrazides 1i and 1j were found to be less reactive
substrates for the reaction because of steric reasons, giving the
corresponding phthalazinones 2i and 2j in low yields (entries
8 and 9). 2-Naphthyl derivative 1k gave benzo[g]phthalazinone
2k in 72% yield via selective cleavage of the C(3)–H bond
9
2
2
2
24
10
11
1.5
—
a 1a (0.200 mmol), Pd(OAc)2 (0.020 mmol, 10 mol%), and BQ (1.2–2
equiv.) were reacted at 120 °C in acetic acid (1.0 mL). b Isolated yield.
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Fig. 1 Unreactive substrates.
Scheme 3 Synthesis of 4-substituted phthalazinones via Heck-type cyclisation.
(entry 10), whereas the 1-naphthyl counterpart gave a complex
mixture of products. The reaction with hydrazine 1l, which
lacked a carbonyl group, failed to afford the corresponding six-
membered product, showing that the reaction is only appli-
cable to hydrazide substrates (entry 11).
The effect of varying the substituents on the nitrogen atoms
was also examined. Unfortunately, neither N-phenyl- or
N-t-butyl hydrazides, nor N′-benzylidene- or N′-ethylidene
hydrazides participated in the cyclisation under the present
reaction conditions (Fig. 1).
To overcome issues arising from the narrow substrate
scope, the Heck-type cyclisation of 2-iodobenzohydrazides 3
was attempted for the synthesis of 4-substituted phthal-
azinones (Scheme 3). In the presence of 20 mol% Pd(OAc)2
and 1 equiv. of AcOK at 130 °C in DMF, 2-iodo-N-methyl-
N′-methylenebenzohydrazide 3a was converted into 2a (R = H)
in 61% yield. The Heck-type cyclisation was applicable to
N′-benzylidene- and N′-ethylidene hydrazides (3m and 3n,
respectively), affording the corresponding 4-phenyl- and
4-methylphthalazinones (2m and 2n, respectively), which were
inaccessible via the oxidative C–H/C–H cross-coupling.
In summary, phthalazin-1(2H)-ones were catalytically syn-
thesised by intramolecular oxidative C–H/C–H cross-coupling
using readily accessible N′-methylenebenzhydrazides 1 and a
catalyst system (Pd(OAc)2, BQ and acetic acid). The mechanism
of the Pd(II)-catalysed cyclisation of 1 was accounted for by the
relatively uncommon Heck-type cyclisation reactions of
carbon–nitrogen double bonds.
Notes and references
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8 Other solvents examined include CF3CO2H, tert-amyl 12 Coordination of the other nitrogen (N′) is also possible.
alcohol, MeOH, water, DMF and toluene.
9 Sublimed BQ was used.
13 No reaction occurred with the corresponding p-chloro-
benzohydrazide.
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