The facile construction of the phthalazin-1(2H)-one scaffold via copper-mediated C-H(sp2)/C-H(sp) coupling under mild conditions

Article abstract of DOI:10.3762/bjoc.11.177

A novel strategy for the construction of the phthalazin-1(2H)-one scaffold has been developed by means of a copper-mediated cascade C-H/C-H coupling and intramolecular annulations and a subsequent facile hydrazinolysis. This C-H activation transformation proceeds smoothly with wide generality, good functional tolerance and high stereo- And regioselectivity under mild conditions. Through the removal of the directing group, the resulting moiety could easily be transformed into the phthalazin-1(2H)-one scaffold, which is known to be a privileged moiety and a bioactive nucleus in pharmaceuticals.

Full text of DOI:10.3762/bjoc.11.177

The facile construction of the phthalazin-1(2H)-one scaffold
via copper-mediated C–H(sp2)/C–H(sp) coupling
under mild conditions
Wei Zhu, Bao Wang, Shengbin Zhou and Hong Liu*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 1624–1631.
CAS Key Laboratory of Receptor Research, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi
Road, Shanghai 201203, P. R. China
doi:10.3762/bjoc.11.177
Received: 22 May 2015
Accepted: 11 August 2015
Published: 14 September 2015
Email:
Hong Liu* - hliu@mail.shcnc.ac.cn
Associate Editor: J. P. Wolfe
*
Corresponding author
©
2015 Zhu et al; licensee Beilstein-Institut.
Keywords:
License and terms: see end of document.
C–H activation; copper; phthalazin-1(2H)-one
Abstract
A novel strategy for the construction of the phthalazin-1(2H)-one scaffold has been developed by means of a copper-mediated
cascade C–H/C–H coupling and intramolecular annulations and a subsequent facile hydrazinolysis. This C–H activation transfor-
mation proceeds smoothly with wide generality, good functional tolerance and high stereo- and regioselectivity under mild condi-
tions. Through the removal of the directing group, the resulting moiety could easily be transformed into the phthalazin-1(2H)-one
scaffold, which is known to be a privileged moiety and a bioactive nucleus in pharmaceuticals.
Introduction
The phthalazin-1(2H)-one scaffold represents an important class (PDE4) inhibitor and is undergoing phase II trials [10].
of privileged structures and has been widely found in numerous Although several methods have been developed for the syn-
biologically active compounds and drug molecules [1-6]. For thesis of phthalazin-1(2H)-one derivatives, these approaches
example (Figure 1), azelastine is a selective histamine antago- mainly rely on the use of prefunctionalized benzoic acid, such
nist, which is recommended for the treatment of both seasonal as phthalic anhydride or 2-formylbenzoic acid, as starting ma-
allergic rhinitis (SAR) and nonallergic vasomotor rhinitis terials and suffer from low yields, poor regioselectivity and
(
VMR) [7]. As the lead of a series of poly ADP ribose poly- scope limitations [11,12]. Therefore, there is still a need for
merase (PARP) inhibitors, olaparib has been approved by the synthetic chemists to develop efficient and expedient routes for
FDA as a potential treatment for germline BRCA mutated the construction of the phthalazin-1(2H)-one scaffold.
(
gBRCAm) advanced ovarian cancer [8]; another PARP
inhibitor, talazoparib, is undergoing phase III trials [9]. Mean- During the last decade, the transition metal-mediated C–H acti-
while, TA-7906 has been developed as a phosphodiesterase-4 vation reaction has emerged as one of the most important and
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Beilstein J. Org. Chem. 2015, 11, 1624–1631.
Figure 1: Representative structures of biologically important phthalazin-1(2H)-ones.
powerful methodologies for the formation of carbon–carbon bond construction and simultaneous annulations under milder
bonds in a single synthetic operation [13-16]. From the view- conditions with less equivalents of copper salts and oxygen
point of practicality and feasibility, increasing attention was atmosphere at a lower temperature (80 °C). Even more impor-
paid to develop cheap and easily available transition metals, tant, the resulting products could be smoothly transformed into
such as copper, to realize direct C–H functionalization [17]. preconceived 4-benzylphthalazin-1(2H)-one derivatives with
Miura and Yu successfully demonstrated a novel protocol for the removal of the directing group by treatment with hydrazine
the direct C–H/C–H coupling with combinations of copper salts hydrate and sodium hydroxide.
and N,N’-dual coordinated directing groups [18-22]. By the
employment of a similar approach, our group reported a Results and Discussion
straightforward route to the isoquinolinone scaffold via copper- We initiated our investigation of the direct carbon–carbon
mediated C–H(sp2)/C–H(sp3) coupling [23].
coupling of N-(quinolin-8-yl)benzamide (1a) and phenylacety-
lene (2a). After extensive attempts, 3-benzylidene-2-(quinolin-
In light of previous works, we envisioned the construction of 8-yl)isoindolin-1-one (3a) was formed in 18% yield via the
the phthalazin-1(2H)-one scaffold by the hydrazinolysis of combination of Cu(OAc)2 and Li2CO3 in DMF under an
precursor 3, which could be afforded by copper-mediated oxygen atmosphere (Table 1, entry 1). As shown in Table 1,
C–H(sp2)/C–H(sp) direct coupling and sequential annulations various bases, copper(II) salts and solvents were screened for
(
Scheme 1). During our exploration, however, You reported a the best reaction conditions. With Cu(OAc)2 as the transition
similar C–H activation transformation system at high tempera- metal and DMF as the solvent at 90 °C under oxygen atmos-
ture (120 °C) with excessive copper salts (3 equivalents). In phere, we tested the impact of various inorganic bases and
addition, failure to remove the directing group partly prevented K2CO3 proved to be the most efficient promoter (Table 1,
the practicality and application of the transformation [22]. entries 1–7). The subsequent evaluation of copper salts revealed
Herein, we reveal a copper-mediated direct C–H(sp2)-C–H(sp) that Cu(OAc)2 gave the best yield (Table 1, entries 8–11). The
Scheme 1: The construction of phthalazin-1(2H)-one scaffold via C–H activation.
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Table 1: Optimization of reaction conditions.a
Entry
Copper salt
Base
Solvent
Yieldb
1
2
3
4
5
6
7
8
9
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2’H2O
Cu(CF3COO)2
CuF2
Li2CO3
Na2CO3
K2CO3
Cs2CO3
KOAc
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
iPrOH
DCE
DMF
DMF
DMF
DMF
DMF
18%
43%
78%
74%
31%
16%
27%
70%
Trace
17%
6%
t-BuONa
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
10
11
12
13
14
CuI
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
68%
n.r.
n.r.
15c
16d
17e
76%
24%
38%
81%
75%
18f
1
9f,g
aReaction conditions: 1a (0.4 mmol), 2a (0.8 mmol), copper salts (0.4 mmol), bases (0.8 mmol), DMF (2 mL), 90 °C ,12 h, O2; byield of isolated pro-
duct. c24 h; dsealed tube without oxygen; ecopper salts (0.08 mmol); f80 °C; gair, 18 h.
effect of different solvents on the transformation was also electron-donating groups (–Me, –OCF3,) at the para-position
investigated. DMSO was slightly inferior to DMF, while the use were well compatible with good yields (3b, 3c), while the intro-
of the aprotic solvent iPrOH and the nonpolar solvent DCE was duction of a methoxy group led to a slight decrease in the yield
ineffective (Table 1, entries 12–14). The extension of the reac- (3d). Electron-poor benzamides (–CF3, –COOMe) worked well
tion time could not provide higher yield (Table 1, entry 15). The under the transformation system and gave good yields (3e, 3f).
absence of oxygen or a decrease in the amount of Cu(OAc)2 led Notably, halides and an ethenyl group were tolerated under the
to dramatic reductions in yields (Table 1, entries 16 and 17). standard reaction conditions (3g–3i), which could undergo
Gratifyingly, the temperature screening showed that the trans- further elaboration. The C–H activation of meta-substituted
formation yield was further enhanced by reducing the reaction benzamides occurred predominantly at less sterically congested
temperature to 80 °C (Table 1, entry 18). The reaction could sites (3j, 3k). A ortho-substituted and a tetrahydronaphthalene
also be conducted under the atmosphere of air (Table 1, entry derivative worked well, respectively, and provided moderate
1
9). In addition, single-crystal X-ray diffraction of 3a showed yields (3l, 3m).
that the Z-isomer of the alkene is preferentially formed [24].
We also tested a variety of terminal alkynes as coupling part-
Next, the scope of 8-aminoquinoline benzamides and the gener- ners with N-(quinolin-8-yl)benzamides (Scheme 3). Both elec-
ality of this process were investigated under the optimized tron-rich (–Me) and electron-poor (–CN, –F) ethynylbenzene
conditions. As shown in Scheme 2, most of the examined proceeded smoothly under this transformation system with good
substrates (1b–1m) provided the corresponding products yields (3n–3t). The halogeno- and cyano-substituted ethynyl-
(
3b–3m) in moderate to good yields. Benzamides with weak benzenes exhibited good tolerance under the reaction condi-
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Beilstein J. Org. Chem. 2015, 11, 1624–1631.
Scheme 2: Copper-mediated reaction of ethynylbenzene with carboxylic acid derivatives. Reaction conditions: 1 (0.4 mmol), 2a (0.8 mmol), Cu(OAc)2
(0.4 mmol), K2CO3 (0.8 mmol), DMF (2 mL), 80 °C , 12 h, O2, isolated yield.
tions (3o, 3p, 3r–3t). Apart from arylalkynes, alkylacetylene microwave irradiation (Scheme 4). Both electron-rich and elec-
and propiolate derivatives were also compatible in the transfor- tron-deficient 4-benzylphthalazin-1(2H)-one derivatives were
mation and gave moderate yields (3u–3w).
obtained in good yields (4b, 4k). The halo-substituted phenyl
moiety was well tolerated under the basic conditions (4p). Alkyl
Finally, the obtained products 3 could be smoothly transformed derivative 3u was compatible in the transformation and gave an
to 4-benzylphthalazin-1(2H)-ones 4 in excellent yields under excellent yield (4u). It was worth mentioning that the simpli-
hydrazinolysis conditions. The directing group quinolin-8- fied process was achieved without silica gel column purifica-
amine was easily removed and recycled by treatment of 3a with tion and the directing moiety quinolin-8-amine could be recov-
hydrazine hydrate and NaOH in EtOH at 120 °C under ered in good yield.
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Beilstein J. Org. Chem. 2015, 11, 1624–1631.
Scheme 3: Copper-mediated reaction of N-(quinolin-8-yl)benzamide with terminal alkynes. Reaction conditions: 1a (0.4 mmol), 2 (0.8 mmol),
Cu(OAc)2 (0.4 mmol), K2CO3 (0.8 mmol), DMF (2 mL), 80 °C ,12 h,O2; isolated yield.
Based on previous works [22,23,25], a copper(II)-mediated Conclusion
C–H functionalization pathway is proposed in Scheme 5. A In conclusion, we have developed a novel strategy for the
base-promoted cupration of the relatively acidic C–H of construction of the phthalazin-1(2H)-one scaffold by means of
ethynylbenzene provides ethynylcopper intermediate M1. The the copper-mediated cascade C–H/C–H coupling and intramole-
following bidentate chelation with 1a yields organocopper(II) cular annulations and a subsequent facile hydrazinolysis. This
complex M2, which undergoes Cu(OAc)2-promoted oxidation C–H activation transformation proceeds smoothly for the
and intramolecular C–H cupration to deliver chelated construction of the isoindolin-1-one scaffold under mild condi-
organocopper(III) intermediate M4. The corresponding product tions with less equivalents of copper salts and a lower tempera-
3
a is formed by the subsequent reductive elimination and ture (80 °C), and exhibits wide generality, good functional
intramolecular annulation. tolerance and high stereo- and regioselectivity. With the
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Beilstein J. Org. Chem. 2015, 11, 1624–1631.
Scheme 4: Hydrazinolysis and removal of the directing group.
Scheme 5: Plausible reaction mechanism.
removal of the directing group, the resulting moiety could be stirred at room temperature for 12 h. The mixture was quenched
easily transformed into the phthalazin-1(2H)-one scaffold by with water and extracted with dichloromethane (3 times). The
treatment with hydrazine hydrate and sodium hydroxide. As the combined organic layer was dried with Na2SO4, concentrated,
phthalazin-1(2H)-one scaffold is identified as a privilege moiety and purified by column chromatography on silica gel (PE/DCM
and bioactive nucleus in pharmaceuticals, this modified proce- 4:1–1:1) to give N-(quinolin-8-yl)benzamide (1a) as a white
dure will be of importance to medicinal chemists.
solid.
Experimental
Copper-mediated coupling of benzamide 1 and alkynyl sub-
General procedure for the synthesis of amides 1 strate 2: The reaction of benzamide 1a with ethynylbenzene
20,22,23,26]: Synthesis of 1a is representative. 8-Aminoquino- (2a) is representative. The dry sealed tube was charged with
[
line (1.0 g, 6.94 mmol) and Et3N (1.2 mL, 8.32 mmol) was N-(quinolin-8-yl)benzamide (1a, 99 mg, 0.4 mmol), ethynyl-
added into dichloromethane (25 mL). The resulting solution benzene (2a, 82 mg, 0.8 mmol), Cu(OAc)2 (73 mg, 0.4 mmol),
was cooled in an ice bath and then benzoyl chloride (0.95 mL, K2CO3 (111 mg, 0.8 mmol) and 2 mL DMF. The resulting mix-
8
.32 mmol) was added drop-wise. The resulting mixture was ture was stirred at 80 °C for 12 hours under oxygen atmosphere
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Beilstein J. Org. Chem. 2015, 11, 1624–1631.
4
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(
(
O2 balloon). The mixture was diluted with dichloromethane
10 mL), filtered through a celite pad, and washed with
dichloromethane (20 mL). The resulting mixture was washed
with water (3 times) and brine. The combined organic layer was
dried with Na2SO4, concentrated, and purified by column chro-
matography on silica gel (DCM/MeOH 200:1–50:1) to give (Z)-
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4
3
0
and recovery of quinolin-8-amine (DG): The synthesis of
a is representative. The microwave tube was charged with (Z)-
-benzylidene-2-(quinolin-8-yl)isoindolin-1-one (3a, 50 mg,
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and washed with 1 M HCl (20 mL, three times). The combined
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Acknowledgements
We gratefully acknowledge financial support from the National
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