Palladium-catalyzed benzo[d]isoxazole synthesis by C-H activation/[4 + 1] annulation

Article abstract of DOI:10.1039/c3sc53228c

We report a palladium-catalyzed intermolecular [4 + 1] annulation pathway for N-phenoxyacetamides with aldehydes to form 1,2-benzisoxazoles. By activating the C-H bonds ortho to phenol-derived O-N bonds, the method enables the simultaneous construction of C-C and CN bonds in 1,2-benzisoxazoles with the O-N bonds intact. The method has been successfully applied to the synthesis of active pharmaceutical intermediates, such as risperidone.

Full text of DOI:10.1039/c3sc53228c

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Palladium-catalyzed benzo[d]isoxazole synthesis
by C–H activation/[4 + 1] annulation†
Cite this: Chem. Sci., 2014, 5, 1574
Pingping Duan,a Yunfang Yang,a Rong Ben,b Yiyong Yan,a Lu Dai,a Mei Hong,a
a
a
a
ab
*
*
*
Yun-Dong Wu, Dongqi Wang, Xinhao Zhang and Jing Zhao
We report a palladium-catalyzed intermolecular [4 + 1] annulation pathway for N-phenoxyacetamides with
aldehydes to form 1,2-benzisoxazoles. By activating the C–H bonds ortho to phenol-derived O–N bonds,
the method enables the simultaneous construction of C–C and C]N bonds in 1,2-benzisoxazoles with the
O–N bonds intact. The method has been successfully applied to the synthesis of active pharmaceutical
intermediates, such as risperidone.
Received 25th November 2013
Accepted 19th December 2013
DOI: 10.1039/c3sc53228c
www.rsc.org/chemicalscience
rst example that introduces a Pd(II)-catalyzed intermolecular
C–H activation route for the simultaneous construction of C–C
Introduction
and C]N bonds in 1,2-benzisoxazoles.
Transition metal-catalyzed C–H activation–annulation reac-
tions have become some of the most important and powerful
methods in organic synthesis.1 The direct insertion of unsatu-
rated molecules via C–H bond transformation offers many
efficient syntheses in an atom-economic fashion. Thanks to
their commercial availability and low cost, aldehydes are widely
used as coupling partners in metal-catalyzed C–H functionali-
zations.2 Several recent reports have utilized aldehydes in
directed transition metal-catalyzed annulations (Scheme 1),
which enabled the simultaneous formation of C–C and
C–heteroatom bonds.3 Specically, there are three reports
highlighting a [4 + 1] annulation strategy involving aldehydes.
Ellman et al. demonstrated a highly efficient Rh(III)-catalyzed
reaction between azobenzenes and aldehydes to yield
substituted N-aryl-2H-indazoles (Scheme 1a).3a Kim et al.
reported the synthesis of 3-hydroxyisoindolin-1-ones via a
Rh(III)-catalyzed cascade reaction.3b Zhao and co-workers
recently reported improved Pd(II)-catalyzed reaction conditions
(Scheme 1b).3c
Results and discussion
The initial reaction of N-phenoxyacetamide (1a) and p-tol-
ualdehyde (2a) was carried out in the presence of 10 mol%
Pd(TFA)2 and 4 equiv. tert-butyl hydroperoxide (TBHP) at
80 ꢀC in THF under N2 atmosphere, affording the desired
product 3aa in 31% yield (Table 1, entry 1). The crystal
structure of product 3aa is shown in Table 2.6 Other oxidants
such as Ag salts, K2S2O8 and Cu(OAc)2 did not promote the
desired reaction (see Table S1†). We also examined different
additives and found that acids and bases did not improve the
reaction yield (see Table S1†). A variety of solvents were
screened. DMSO improved the yield to 59% (entry 3) and
t-AmOH was proved to be the most effective solvent, affording
the product in 75% yield (entry 5), indicating that the solvent
Many natural products and pharmaceuticals, such as ris-
peridone and zonisamide, contain 1,2-benzisoxazoles as a key
fragment.4 We hypothesized that N-phenoxyacetamides5 might
react with aldehydes to form 1,2-benzisoxazoles using a catalytic
[4 + 1] annulation strategy (Scheme 1c). Herein we report the
aShenzhen Key Lab of Nano-Micro Material Research, School of Chemical Biology and
Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, 518055,
China. E-mail: jingzhao@pkusz.edu.cn
bInstitute of Chemistry and BioMedical Sciences, State Key Laboratory of
Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing,
210093, China
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data for all new compounds. CCDC 963147. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c3sc53228c
Scheme 1 Heterocycle formation through [4 + 1] annulation.
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Table 1 Optimization of reaction conditionsa,b
yields. Various aliphatic aldehydes could also form the
desired products under standard conditions. Simple aliphatic
aldehydes, such as butyraldehyde (2q), offered the desired
product in 63% yield and branched isobutyraldehyde (2r)
gave the corresponding product in 40% yield. The cycloalkane
carboxaldehydes such as cyclohexanecarboxaldehyde (2s)
and cyclopentanecarboxaldehyde (2t) participated in the
coupling reaction to furnish products in 41% and 64%
yield, respectively. The coupling reaction was facile enough
that the cyclopropyl ring was kept intact when cyclo-
propanecarboxaldehyde (2u) reacted with N-phenoxy-
acetamide to afford the 3-cyclopropyl-1,2-benzisoxazole in
51% yield.
The scope of the substituents on N-phenoxyacetamide was
also investigated (Table 3). N-Phenoxyacetamides with either
electron-rich or electron-decient substituents proceeded
smoothly. A variety of functionalities including methoxyl,
uoro, chloro and bromo groups were tolerable. The meta-
substituted N-phenoxyacetamides were annulated only at the
less hindered ortho positions. The complete regiospecicity
suggested again that the steric effect is important (3ca,
3ea–3ha). When the substitutions on the N-phenoxy-
acetamides were para (3ga, 3ha) to the newly formed carbon–
carbon bond, the yields were higher than when the substi-
tutions were in meta positions (3ia, 3ja). This might be
attributed to the competing inductive effect and resonance
stabilization, which could also explain the tendency of the
yield, 3ha > 3ga > 3fa.
Entry
Solvent
X
Yield [%]
1c
2c
3c
4c
5c
6
THF
1,4-Dioxane
DMSO
t-BuOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
4
4
4
4
4
4
4
3
31
46
59
46
75
85
73
80
88
N.R.
7d
8
9
10
2.5
—
a
Determined by GC analysis using mesitylene as an internal standard.
All reactions were kept in a dark place. c Reaction at 80 ꢀC. d 5 mol%
b
Pd(TFA)2.
plays a key role in the reaction. Gratifyingly, by lowering the
ꢀ
reaction temperature to 60 C, the yield was improved to 85%
(entry 6). When the catalyst loading was lowered from 10
mol% to 5 mol%, the yield was obviously reduced from 85%
to 73% (entry 7). Using 2.5 equiv. TBHP in place of 4 equiv.
TBHP (entry 9) had no obvious impact on the yield. In the
absence of TBHP, no product was observed (entry 10). Even-
tually we set the standard reaction conditions to be Pd(TFA)2
(10 mol%) and TBHP (2.5 equiv.) in t-AmOH under nitrogen
at 60 ꢀC.
Mechanism
A kinetic isotope effect experiment was carried out between
equimolar amounts of deuterio-1a and N-phenoxyacetamide 1a
with aldehyde 2a under standard conditions for one hour. It
gave a KH/KD ratio of 3.2, indicating that C–H bond cleavage was
involved in the product determining step (eqn (1)).7
Next, we explored the substrate scope for aldehydes
(Table 2). The reaction went well for diverse substrates
including aromatic, heterocyclic, and aliphatic aldehydes.
When benzaldehyde derivatives were used as the starting
materials, electron-donating substitution groups such as
methyl (2a, 2b, 2c) and methoxyl (2e, 2f, 2g) afforded the
corresponding products in moderate to high yields ranging
from 56% to 90%, while electron-withdrawing groups such as
ester (2i), triuoromethyl (2k) and naphthyl (2n) gave prod-
ucts in yields ranging from 64% to 76%. With the same
substitution group, the yield was typically highest when the
para-position of the phenyl ring was occupied, and lowest for
the ortho-substituted benzaldehyde (3aa > 3ab > 3ac, 3ae > 3af
> 3ag). This trend held true for different substitution groups
of the same electron-withdrawing category on the phenyl ring
(3ai, 3aj > 3ak > 3al), indicating that steric hindrance might
play a key role in the reaction. This transformation tolerated
dual-substitution, such that 3,5-dimethoxybenzaldehyde (2h)
and 3,5-dichlorobenzaldehyde (2m) proceeded smoothly to
afford products in 53% and 48% yield, respectively. Hetero-
cyclic aldehydes such as furfural (2o) and 2-thio-
phenecarboxaldehyde (2p) proceeded smoothly in moderate
(1)
To probe the catalytic mechanism, we carried out a model
reaction with 10 mol% Pd(TFA)2 or 1 equiv. Pd(TFA)2 in the
absence of TBHP. No desired product was detected, suggesting
that the mechanism is a Pd(II)–Pd(IV)–Pd(II) catalytic cycle
instead of a Pd(II)–Pd(0)–Pd(II) cycle. When we added a radical
scavenger to the reaction, such as 2,2,6,6-tetramethylpiperidin-
1-oxyl (TEMPO),8 the reaction rate was suppressed in a dose-
dependent manner from GC analysis. Thus radical intermedi-
ates might be involved in the mechanism. When the substrate
(1k) was treated with 10 mol% Pd(TFA)2 in t-AmOH at 60 ꢀC
under N2, it was exclusively converted to the corresponding
product 3ad, indicating that 1k was likely to be the intermediate
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Table 2 Scope of aldehydesa,b
Table 3 Scope of N-phenoxyacetamidesa,b
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), t-AmOH (1 ml).
Isolated yield.
b
catalytic cycle started from Pd(TFA)2, which was rst ligated to
compound 1 with a concomitant loss of two molecules of tri-
uoroacetic acid. The N–H activation step via TS1-A had a very
low barrier (4.6 kcal molꢁ1), which contributed to the deproto-
nated N-phenoxyacetamide in the intermediate A2. Next, we
proposed that intermediate A4 was obtained via a C–H activa-
tion pathway through a concerted metalation–deprotonation
(CMD) transition state (TS2-A). The CMD step had an activation
energy of about 14.1 kcal molꢁ1, which is the rate-determining
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), t-AmOH (1 ml).
Isolated yields.
b
in the process of the reaction (eqn (2)) (see the ESI† for the
mechanism study in detail).
(2)
On the basis of these observations, a possible mechanism
was proposed, as shown in Scheme 2. Density functional theory
(DFT) studies were conducted to further elucidate the mecha-
nism (Scheme 3). The catalyst Pd(TFA)2 and substrate N-
phenoxyacetamides were taken as the reference points. The Scheme 2 Proposed mechanism of 1,2-benzisoxazole synthesis.
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yield (>95%). Compound 6 was the key intermediate in the
synthesis of pharmaceuticals of risperidone, paliperidone and
iloperidone.10
Conclusions
Taken together, we have developed a novel Pd(II)-catalyzed
intermolecular [4 + 1] annulation pathway for the synthesis of
1,2-benzisoxazoles, utilizing N-phenoxyacetamides and alde-
hydes as starting materials. Interestingly, Lu and co-workers
recently reported Rh-catalyzed directed C–H bond activations
on N-phenoxyacetamides. Their ingenious work suggested that
the O–N functionality acted as an internal oxidant as well as a
directing group.5 In contrast, the O–N bonds were kept intact
and became part of the 1,2-benzisoxazole products in our Pd-
catalyzed system. DFT calculations on our Pd-catalyzed reaction
supported a Pd(II)–Pd(IV)–Pd(II) catalytic cycle involving a
concerted metalation–deprotonation process. Investigations on
developing a wider scope of metal-catalyzed [4 + 1] annulation to
furnish interesting heterocycles are underway and will be
reported in due course.
Scheme 3 The M06 free energy profile for the palladium-catalyzed
benzo[d]isoxazole synthesis. Enthalpies are given in parentheses.
step. Subsequently, the triuoroacetic acid ligand dissociates
and produces a Pd(II) complex A5. The oxidative addition of the
intermediate A5 with an acyl radical, which was generated from
the aldehyde via hydrogen atom abstraction by t-BuOOc (ref. 9)
from TBHP, would generate a Pd(IV) intermediate A6. This
process was calculated to be very exergonic (DG ¼ ꢁ65.3 kcal
molꢁ1). Reductive elimination from intermediate A6 via TS3-A
(DG‡ ¼ 12.0 kcal mo1ꢁ1) allowed for the C–C bond formation
and delivered intermediate A8. Intramolecular nucleophilic
attack occurs via TS4-A to form a palladium alkoxide A9, which
was protonated by triuoroacetic acid to afford the corre-
sponding organic intermediate A10. Finally, deacylation and
dehydration yield the desired product 3 and regenerate the
palladium catalyst. The other two possible mechanisms, an
aldehyde insertion mechanism2c and a nitrogen radical initia-
tion mechanism3c were also studied and found to be unfavor-
able (see ESI†).
Acknowledgements
We thank a referee for an insightful suggestion on the mecha-
nism. This work is nancially supported by grants of the
National Basic Research Program of China (2010CB923303 to
J. Z. and 2013CB911501 to X. Z.), the Doctoral Fund of Ministry
of Education of China, the National Science Foundation of
China (21133002 to Y. W., 21232001 to X. Z., 21302006 to X. Z.),
the Shenzhen Government (JC201104210113A to J. Z.,
SW201110018 to J. Z., KQTD201103 to Y. W.) and the Fok Ying-
Tong Education Foundation, China (132011 to J. Z.).
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The synthetic applicability of our methodology was further
illustrated by the assembly of a 1,2-benzisoxazole compound 6
(Scheme 4). The desired product 5 was obtained conveniently in
40% yield in a single step under standard reaction conditions.
Compound 5 was further deprotected in nearly quantitative
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