Copper-catalyzed tandem aryl-halogen hydroxylation and CH2Cl2-based N,O-acetalization toward the synthesis of 2,3-dihydrobenzoxazinones

Article abstract of DOI:10.1039/c7ob00625j

The concise synthesis of 2,3-dihydro-4H-benzo[e][1,3]oxazin-4-ones has been accomplished by copper-catalyzed tandem reactions of o-halobenzamides, LiOH and dichloromethane. The aryl-halogen bond hydroxylation and subsequent N,O-acetalization on CH₂

Full text of DOI:10.1039/c7ob00625j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C7OB00625J
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Copper‐Catalyzed Tandem Aryl‐Halogen Hydroxylation and
CH2Cl2‐Based N,O‐Acetalization Toward the Synthesis of 2,3‐
Dihydrobenzoxazinones
Received 00th January 20xx,
Accepted 00th January 20xx
Xuwen Chen,a Wenyan Haoa and Yunyun Liua,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The concise synthesis of 2,3‐dihydro‐4H‐benzo[e][1,3]oxazin‐4‐ recently, Wang et al developed the aryl‐halogen hydroxylation‐
ones has been accomplished by copper‐catalyzed tandem based tandem reactions for the synthesis of ethers and
reactions of o‐halobenzamides, LiOH and dichloromethane. The benzofurans in water.6 Regardless the notable achievement
aryl‐halogen bond hydroxylation and subsequent N,O‐ reflected by these seminal works, the overall models of
acetalization on CH2Cl2 are enabled under the catalytic conditions tandem reactions initiated by the aryl‐halogen bond
which allowed the generation of C(sp2)‐O, C(sp3)‐O and C(sp3)‐N hydroxylation, especially the reactions providing heterocyclic
bond to the target products.
products, are still rather rare.
2,3‐Dihydro‐4H‐benzo[e][1,3]oxazin‐4‐ones
(2,3‐
Copper‐catalyzed Ullmann C‐O cross‐coupling reaction has
been known as highly efficient and powerful tool in the
construction of aryl/vinyl C‐O bonds. By employing such
transformation, a massive number of oxygen‐containing
molecules such as aryl/vinyl ethers and O‐containing
heterocycles have been successfully synthesized.1 As the
specific version of Ullmann C‐O cross coupling reaction, the
aryl‐halogen bond hydroxylation providing phenol products
has also received broad concern, which has led to the
development of many practical catalytic approaches toward
the hydroxylation of aryl halides.2 However, while most known
efforts have been made in discovering alternative catalytic
methods, the limit on the synthetic application of this
hydroxylation transformation has been ignored. Actually, in
many cases, simply synthesizing phenols from corresponding
aryl halides are not industrially economical. In this regard,
exploring extended application of the aryl‐halogen bond
hydroxylation in the synthesis of organic products with
increased structural complexity is of high significance in terms
of disclosing the synthetic potential of this specific cross‐
coupling process.3 In 2009, You and co‐workers have reported
the copper‐catalyzed synthesis of ethers via the in situ aryl‐
halogen bond hydroxylation and subsequent intermolecular
dihydrobenzoxazinones) are a class of heterocyclic compounds
with enriched biological profiles,7 these heterocyclic
compounds have also been extensively employed as key
building blocks in the synthesis of many other important
organic products.8 Conventionally, 2,3‐dihydrobenzoxazinones
can be accessed via the condensation reactions of o‐hydrozxyl
benzamides with aldehydes and ketones.9 In order to expand
the compound diversity of the synthesis on the basis of the
condensation protocol, some complementary methodologies
have been disclosed in recent years. For example, Taylor et al
developed the tandem deacetalisation–bicyclisation reactions
employing o‐hydroxyl benzoic acids and acetal functionalized
alkyl amines,10 and later on the tandem reactions of o‐hydroxyl
benzoic acids with imines.11 Coates and Mulzer reported the
synthetic methods employing cobalt‐mediated reactions based
on the hydroformylation of dihydroxazines.12 Recently, Maiti
et al reported another interesting route to these heterocyclic
products via copper‐catalyzed intramolecular dehydrogenative
coupling
of
N,N‐dialkyl
functionalized
o‐hydroxyl
benzamides.13 Interesting, all these known method, as
happened in the conventional condensation approach with o‐
hydroxyl benzamides, rely on the transformation of the pre‐
installed hydroxyl group in the substrates. Alternative
synthetic method without using hydroxylated starting
materials, to our knowledge, is not yet available. In the process
of our work in exploring both new synthetic methods based on
the copper‐catalyzed cross‐coupling14 and synthesis using
dichloromethane as methylene donor,15 we wish to report
Williamson
etherification.4
Similar
copper‐catalyzed
hydroxylation and tandem reactions for the synthesis of
functional ether products have also been delevoped.5 More
a. College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, P.R. China. Emai: chemliuyunyun@jxnu.edu.cn
Electronic Supplementary Information (ESI) available: [General experimental
information, full characterization data, 1H and 13C NMR spectra]. See
DOI: 10.1039/x0xx00000x
herein
a
new
synthetic
protocol
toward
2,3‐
dihydrobenzoxazinones by means of the tandem aryl‐halogen
This journal is © The Royal Society of Chemistry 20xx
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hydroxylation and CH2Cl2‐based N,O‐acetalization using o‐ source by providing 3a with much higher yield (entries 16‐17,
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halobenzamides and CH2Cl2.
At the beginning, the reactions of N‐methyl o‐iodobenzamide temperature failed to afford further improved results (entries
1a, dichloromethane (DCM) and KOH was conducted in the 18‐21, Table 1).
Table 1). Subsequent work in varying theDrOeIa: c10ti.o10n39m/Ce7dOiuBm006a2n5dJ
2
presence of CuBr and 1,10‐phenanthroline wherein the target After the efforts in optimizing reaction conditions, the scope of
product 3a was obtained in 31% yield (entry 1, Table 1). this new synthetic approach was consequently investigated.
Control experiment in the absence of copper catalyst did not According to the reaction process, the synthesis of different
yield 3a (entry 2, Table 1). On the other hand, the entry 2,3‐dihydrobenzoxazinones was performed mainly by varying
without using ligand provided 3a with lower yield (entry 3, the o‐halobenzamide substrates. It was noteworthy that the
Table 1). The variation on the DCM amount indicated that 0.2 present catalytic method exhibited general tolerance to the o‐
mL was the most appropriate (entries 4‐5, Table 2). A class of halobenzamides since the substrates containing functional
different Cu(I) and Cu(II) catalysts were also screened, but no substituent in the phenyl ring and N‐atom (both aryl and alkyl)
copper catalyst better than CuBr was identified (entries 6‐10, all displayed tolerance to the tandem reaction. The
Table 1). In addition, the results from the entries with different employment of both o‐iodo‐ and o‐bromobenzamides in the
catalyst loading suggested that 5 mol% catalyst was favored by reactions showed smooth tolerance to the expect
the reaction (entries 11‐12, Table 1). In order to improve the transformation. On the other hand, the for the reactions using
product yield, some different ligands L2
but no positive result was observed (entries 13‐15, Table 1). afforded corresponding products with higher yiels (3a
‐
L4 were also tested, N‐alkylated benzamides, longer alkyl chain in the N‐atom
3b 3e,
,
,
However, the attempts in using different metal hydroxides 3f and 3h, Table 2). On the other hand, N‐allyl and N‐benzyl
(base) led to the discovery that LiOH was a better hydroxyl benzamides took part in the reaction to provide N‐allyl and N‐
benzyl products with similar yields as those entries using N‐
methyl and N‐ethyl benzamides (3j‐3o, Table 2), and much
Table 1 Optimization on reaction conditionsa
lower yield was observed in the reaction of N‐cyclohexyl
benzamide (3p, Table 2), suggesting that both the electron and
steric effect were crucial in determining the synthetic
efficiency. N‐Aryl benzamides were also applicable starting
materials for the synthesis of N‐arylated products (3q and 3r,
Table 2), but with even lower yield probably because of the
Table2 Synthesis of of different 2,3‐dihydrobenzoxazinones
Entry
1
2
Catalyst
CuBr
no
CuBr
CuBr
CuBr
CuCl
Ligand
L1
L1
no
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
L1
L1
L1
Base
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
NaOH
LiOH
LiOH
LiOH
LiOH
LiOH
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
T (oC)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
90
Yieldb(%)
31
nr
21
14
17
trace
17
11
13
nr
16
22
21
nr
nr
35
57
25
3
4c
5d
6
7
8
9
CuI
CuSO4
Cu(OAc)2
CuO
10
11e
12f
13
14
15
16
17
18
19
20
21
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
DMA
DMSO
DMSO
33
36
42
110
aGeneral conditions: 1a (0.3 mmol), 2 (0.3 mL), copper catalyst (0.015 mmol),
ligand (0.03 mmol), base (2.7 mmol) in solvent (2 mL), stirred at 100 oC in sealed
tube for 12h. DMA = N,N‐dimethyl acetamide; nr = no reaction. bYield of isolated
product based on 1a. cCH2Cl2 (0.2 mL) was used. dCH2Cl2 (0.4 mL) was used. eCuBr
(0.01 mmol) was used. fCuBr (0.02mmol) was used.
2 | J. Name., 2012, 00, 1‐3
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aReaction conditions: 1 (0.3 mmol), 2 (0.3 mL, ~16 equiv.), LiOH (2.7 mmol), CuBr
(0.015 mmol), L1 (0.03 mmol) in DMSO (2 mL), stirred at 100 oC in sealed tube for
12h. bYield of isolated product based on 1.
General procedure for the synthesis of productsV3ie.wInArtaicl2e 5OnmlinLe
DOI: 10.1039/C7OB00625J
tube were located o‐halobenzamide
1
(0.3 mmol),
dichloromethane
2 (0.3 mL), LiOH (2.7 mmol), CuBr (0.015
mmol), ligand L1 (0.03 mmol) and DMSO (2 mL). The vessel
was then sealed with Teflon cap and heated up to 100 C and
significantly weaker nucleophilicity of the N‐atom therein.
Additionally, the entry using unsubstituted o‐iodobenzamide
o
stirred at the same temperature for 12 h. After completion
(TLC), the vessel was cooled down to room temperature, and
water (5 mL) was added. The resulting suspension was
extracted with ethyl acetate (10 mL × 3). The organic layer was
combined and dried with anhydrous Na2SO4. After filtration,
the solvent in the acquired solution was removed under
reduced pressure. The residue obtained therein was subjected
to silica gel column chromatography to give pure product by
using mixed ethyl acetate and petroleum ether as eluent (v / v
= 1 : 5).
failed to provide the target NH‐heterocyclic product 3s
.
Notably, 3a was provided with also fair yield when CH2Br2 was
used as alternative substrate of CH2Cl2, indicating that the
halogen source in the dihalomethane did no impact much to
the reaction result. Finally, when
a
different gem‐
dichloroalkane, the 1,1‐dichloroethane was employed to
reaction with 1a and LiOH, the expect 2,3‐
dihydrobenzoxazinone was not formed.
To gain information on the possible reaction process, a control
experiment without employing DCM has been conducted
under standard conditions. As shown in Eq (1), the o‐
iodobenzamide 1f was found to be smoothly transformed into
Acknowledgements
the hydroxylated benzamide 4a
,
indicating that the
This work is financially supported by National Natural Science
Foundation of China (21562024).
hydroxylation of the aryl‐halogen bond is a key transformation
in the product formation.
Notes and references
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Scheme 1 The general process of the copper‐catalyzed tandem reaction
In conclusion, we have realized for the first time the copper‐
catalyzed tandem synthesis of 2,3‐dihydrobenzoxazinones
using o‐halobenzamides, dichloromethane and LiOH as starting
materials. The formation of three new chemical bonds,
including a C(Ar)‐O bond, a C(sp3)‐O bond and a C(sp3)‐N takes
place during the whole reaction process. Besides providing a
facile and new tactic for the synthesis of these important
heterocyclic compounds, the significance of the presence work
also lies in exemplifying the potential of the Ar‐halogen
hydroxylation in the designation of diverse tandem
transformation‐based organic synthesis.
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DOI: 10.1039/C7OB00625J
TOC
The copper-catalyzed tandem reactions consist of Ar-halogen hydroxylation and
N,O-acetalization is designed for concise synthesis of 2,3-dihydrobenzoxazinones.