Cu-Mediated Stereoselective [4+2] Annulation between N-Hydroxybenzimidoyl Cyanide and Norbornene

Article abstract of DOI:10.1021/acs.joc.8b01081

A Cu-mediated stereoselective [4+2] annulation between N-hydroxybenzimidoyl cyanides and norbornene (NBE) has been developed for the synthesis of 4H-1,2-oxazin-4-ones. The reaction proceeds through sequentially forming C-O/C-C bonds. The advantage of this reaction includes high stereoselectivity, excellent yields, as well as simple and mild reaction conditions. A total of 26 examples are presented along with some control experiments.

Full text of DOI:10.1021/acs.joc.8b01081

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Article
Cu-Mediated Stereoselective [4+2] Annulation Between
N-Hydroxybenzimidoyl Cyanide and Norbornene
Kui Liu, Zhen-Bang Chen, Fang-Ling Zhang, Chun Qian,
Shou-Wei Tao, Qiong Ming Xu, and Yong-Ming Zhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01081 • Publication Date (Web): 15 Jun 2018
Downloaded from http://pubs.acs.org on June 15, 2018
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Cu-Mediated Stereoselective [4+2] Annulation
Between N-Hydroxybenzimidoyl Cyanide and
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Norbornene
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Kui Liu, Zhen-Bang Chen, Fang-Ling Zhang, Chun qian, Shou-Wei Tao
Qiong-Ming, Xu and Yong-Ming Zhu*
College of Pharmaceutical Sciences, Soochow University, Suzhou,
215123, China
ABSTRACT: A Cu-mediated stereoselective [4+2] annulation between
N-hydroxybenzimidoyl cyanides and norbornene (NBE) has been
developed for the synthesis of 4H-1,2-oxazin-4-ones. The reaction
proceeds through sequentially forming C-O/C-C bond. The advantage of
this reaction includes high stereoselectivity, excellent yields, as well as
simple and mild reaction conditions. A total of 26 examples are presented
along with some control experiments.
Introduction
Cycloaddition, in which multiple bonds are formed in a single step, has
become increasingly popular among synthetic chemists not only owing to
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the advantages of a high degree of regioselectivity and stereoselectivity,
atom economy, but the rapid assembly of complex and diverse carbo- and
heterocyclic systems.1-4 Particular members of the cycloaddition family
are [2 + 2], [3 + 2] and [4 + 2] variants.5 Since the initial work of Diels
and Alder, the utility of [4+2] cycloaddition in formation of
six-membered rings has been widely explored. Besides, norbornene (NBE)
and norbomadiene (NBD) are an important class of organic molecules
which have been widely applied in cycloaddition, especially in the homo
Diels-Alder (HDA) reaction.6 However, these classical approaches suffer
from cost of the catalytic systems, various competing cycloaddition
reactions, and lower yield. Therefore, it is of considerable interest to
develop a low-cost metals catalytical cycloaddition reaction of NBE and
NBD which selectively generate single cycloadducts in high yield.
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Oximes and their derivatives are valuable synthetic building blocks as
they can be easily transformed into ketones,7 amides,8 and nitriles.9
Moreover, they can also serve as internal oxidants and have been used as
substrates for transition-metal-catalyzed C−H activation.10 Nevertheless,
the most achievements mainly focus on the utility of oximes as the
precursors of 1, 3-dipolar for the synthesis of oxygen/nitrogen-containing
compounds.11 Only a few examples of cycloaddition of oximes have been
reported. For instance, in 2012, Cheng12 reported nickel-catalyzed
cycloaddition of ortho-iodoketoximes and ortho-iodoketimines with
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alkynes for synthesis of isoquinolines and isoquinolinium salts (Scheme
1a). At the same year, Rodríguez-Borges13 presented boron-mediated
cycloadditions between methyl glyoxylate oxime and cyclopentadiene or
cyclopentene for synthesis of isoxazolidine (Scheme 1b). In 2016, Deng
and Jiang14 developed palladium-catalyzed cycloaddition of aryloxime
with vinyl azides for the synthesis of isoquinolines (Scheme 1c). On the
other hand, oxazin-4-ones are important heterocyclic scaffolds that occur
in many natural products, pharmaceuticals and materials.15 Seminal work
by the group of Li reported [4+2] annulation of arylalkynes with
tert-butyl nitrite to assemble benzo[e][1,2]oxazin-4-ones (Scheme 1d).16
Given the N-hydroxybenzimidoyl cyanides have never been previously
reported as substrates for NBE cycloaddition. Herein, we report a new
Cu-mediated [4+2] annulation protocol to assemble [1, 2]oxazin-4-ones
(Scheme 1e), where NBE serve as 2-carbon units for reaction with
N-hydroxybenzimidoyl cyanides through the formation of C=O double
bond, C-C single bond and C-O single bond.
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Scheme 1. Cycloaddition of Oximes
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Results and discussion
Initial studies began with employing N-hydroxybenzimidoyl cyanide (1a),
and NBE (2) as the standard substrates in the presence of Pd(OAc)2 (5%
mmol), Cu(OTf)2 (1.5 equiv) and Cs2CO3 (2 equiv) in toluene for 24 h,
and the desired product was obtained in 55% yield (Table 1, entry 1). It
should be noted that this reaction is highly stereoselective, with the
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product existing only as cis-conformers. The result was validated by
NOESY analysis. In NOESY, there has correlation between the
hydrogens H-C4a and H-C8a, and the coupling constants between
hydrogens H-C4a and H-C8a is 5.3 Hz (see supporting information). The
product is a racemate, which was supported by the test of optical rotations.
More surprisingly, with stoichiometric copper, this reaction could still
proceed very smoothly without palladium, leading to more green and
economic synthetic chemistry (Table 1, entries 2 and 3). Screening of
various bases revealed that NaOAc was optimal to give the target product
in 62% yield (Table 1, entries 4-10). Compared with CuCl2·2H2O, other
copper source such as Cu(OAc)2, Cu(TFA)2, and CuI resulted in
diminished yields (Table 1, entries 11-14). Subsequently, other solvents
were also tested to improve the yield further. However, none of them
were superior to toluene (Table 1, entries 15-18). Gratifyingly, the yield
was dramatically improved to 81% when DCE/ toluene (v:v=1:1) was
used as a mixed solvent (Table 1, entry 19). Replacing the CuCl2·2H2O
by AgOAc led to decrease in the yield (Table 1, entry 20). The reaction
was entirely hampered after CuCl2·2H2O was switched to FeCl3 or ZnCl2
(Table 1, entries 21 and 22). The decrease in the amount of CuCl2·2H2O
to 1 equiv was not beneficial to the formation of 2a (Table 1, entry 23).
Further investigation found that using catalytic CuCl2·2H2O (20%) with
K2S2O8 (2 equiv) or O2 as the oxidant were less effective (Table 1 entries
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24 and 25)
Table 1. Optimization of Reaction Conditionsa
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Entry
[Cu]
base
solvent
Yield(%)b
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2
Cu(OTf)2
-
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
NaOAc
KF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
55c
n.d
57
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Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
4
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7
K3PO4
HCOONa
Et3N
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trace
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-
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Cu(OAc)2
Cu(TFA)2
CuI
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
toluene
toluene
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63
15
70
41
toluene
CuCl2·2H2O
CuCl2·2H2O
toluene
1.4-dioxane
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CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
AgOAc
NaOAc
NaOAc
NaOAc
THF
DMF
DCE
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NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
DCE/ Tol
DCE/ Tol
DCE/ Tol
DCE/ Tol
DCE/ Tol
DCE/ Tol
DCE/ Tol
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FeCl3
n.d
n.d
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ZnCl2
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
47d
39e
aGeneral conditions: the reactions were run on a 0.5 mmol scale in
solvent (2 mL), NBE (1 equiv.), [Cu] (1.5 equiv.), base (2 equiv.) under
nitrogen in a sealed tube at 100oC for 24 h. Isolated yields. 5% mol
b
c
d
Pd(OAc)2 were added. Using 20% CuCl2·2H2O and 2 equiv. K2S2O8.
eUsing 20% CuCl2·2H2O and purged with O2.
With the optimized conditions in hand, we examined the scope of this
[4+2] annulation protocol with a wide range of oximes (Table 2). Various
N-hydroxybenzimidoyl cyanides with electron-neutral (2q, 2j) or
electron-donating (2d-2g, 2n) or electron–withdrawing groups (2b, 2c, 2h,
2i etc) reacted smoothly with NBE, and moderate to good yields were
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achieved. However, due to the effect of steric hindrance,
N-hydroxybenzimidoyl cyanides with substituted o-methyl (2l) and o-
halogen (2k, 2m) afforded lower yields. It is noted that heterocyclic
substrates were less compatible with this reaction. Product 2r was still
obtained in 27% yield from an electron-rich cyclic substrate such as
N-hydroxythiophene-3-carbimidoyl cyanide, while no product was
detected using an electron-deficient heteroatomic ring as substrate, e.g.
N-hydroxypicolinimidoyl cyanide (2t).
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Table
2.
[4+2]
cycloadditions
of
various
substituted
N-hydroxybenzimidoyl cyanide with NBE a, b.
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aAll reactions were performed under nitrogen on a 0.5 mmol scale in
DCE/Tol (v:v=1:1, 2 mL), NBE (1 equiv.), CuCl2·2H2O (1.5 equiv.),
NaOAc (2 equiv.) in a sealed tube at 100oC for 24 h. bIsolated yields.
Further experiments were conducted to examine the compatibility of this
reaction with respect to other olefins. As shown in table 3, the
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norbomadiene (NBD), as active as NBE, could transform to
corresponding products by reacting with electron-poor or electron-rich
N-hydroxybenzimidoyls cyanides, but the N-hydroxybenzimidoyl
cyanides with electron-donating groups (3b, 3e) gived much better results
than the substrates with electron-withdrawing groups (3c, 3d). However,
when cyclopentene was employed, the corresponding cyclization product
3f was obtained with only 21% yield. Unfortunately, the annulation of
cyclohexene (3aa) and its other synthetic equivalents (1-decene 3ab,
(Z)-1,2-diphenylethene 3ac) failed, and the phenylacetylene (3ad) also
showed a sluggish reaction.
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Table 3. [4+2] cycloadditions of various olefins
N-hydroxybenzimidoyl cyanidea, b
with
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aAll reactions were performed under nitrogen on a 0.5 mmol scale in
DCE/Tol (v:v=1:1, 2 mL), norbomadiene (1 equiv.), CuCl2·2H2O (1.5
b
equiv.), NaOAc (2 equiv.) in a sealed tube at 100oC for 24 h. Isolated
yields.
Finally, some control experiments were performed to gain some insight
into the reaction mechanism. Firstly, under the optimal conditions, a trace
amount of 2a was observed using the N-acetoxybenzimidoyl cyanide as
the substrate, indicating that –OH is necessary in this transformation
(route a in scheme 2). In the absence of the NBE, 4a was obtained, which
showed that –CN could be hydrolyzed easily under this condition (route b
in scheme 2). Additionally, considering the precedent literatures,17 we
envisioned that whether the reaction proceed through the radical pathway.
However,
when
a
radical-trapping
reagent
TEMPO
(2,2,6,6-tetramethyl-1-oxylpiperidine) was added, the reaction still went
on under the optimal conditions, manifesting that the reaction did not
proceed by the radical pathway (route c in scheme 2).
Scheme 2. Control experiments
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On the basis of the above results, a plausible mechanism for the [4+2]
cycloaddition was proposed in scheme 3. Initially, the splitting of the
O−H bond of –OH occured under the effect of base to generate
intermediate A. Owing to the intermediate A has no choice to the two
carbons of the C-C double bond of the NBE, so it could attacked NBE
from two directions and given the intermediates B and C (path a and path
b). Subsequent nucleophilic addition of the intermediates B and C gives
the intermediates D and E. Finally, the intermediates D and E are
hydrolyzed to form the product, which is a racemate.
Scheme 3. Plausible Mechanism for the Synthesis of 2a
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Conclusions
In summary， we have developed a novel Cu-mediated [4+2] annulation
of N-hydroxybenzimidoyl with NBE for the synthesis of
[1,2]oxazin-4-ones. This method allows to access the [1,2]oxazin-4-ones
skeletons by the formation of C=O bond, C-C bond and C-O bond. This
synthetic protocol is characterized by commercially available reagents,
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excellent yields, as well as simple and mild reaction conditions. Further
studies toward detailed mechanism and applications of this methodology
are currently underway.
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EXPERIMENTAL SECTION
General Information. Reagents were purchased from commercial
suppliers. All solvents were dried and freshly distilled. TLC was
performed on silica HSGF254 plates. Melting points were determined
with a digital melting-point apparatus. NMR spectra were run in a
solution of deuterated chloroform (CDCl3) with tetramethylsilane (TMS)
1
as the internal standard and were reported in parts per million (ppm). H
and 13C NMR spectra were obtained at 400/101 MHz (1H/13C),
respectively. High-resolution mass spectra (HRMS) analyses were carried
out on a chemical ionization (CI) apparatus using time-of-flight (TOF)
mass spectrometry. Optical rotations were measured with automatic
polarimeter.
Preparation of Hydroximoyl Cyanides
All hydroximoyl cyanides are known compounds that were synthesized
from commercially available acetonitriles according to the procedure that
follows: a solution of isopentyl nitrite (1.5 equiv, 15 mmol) in ethyl
alcohol (3 mL) was added dropwise to a solution of acetonitriles (10
mmol) and sodium ethoxide (1.5 equiv, 15 mmol) in ethyl alcohol (5 mL)
at 0 °C. Once the addition was completed, the mixture was allowed to
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warm to room temperature. After stirring for 8-10 h, the reaction mixture
was diluted with water and extracted with EtOAc three times. The
organic fractions were combined, dried with anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified by flash
chromatography on silica gel using petroleum ether/EtOAc as the eluent
to afford the desired products.
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General Procedure for Synthesis of the 4H-1,2-oxazin-4-ones
1 (0.5 mmol), Norbornylene (0.5 mmol), CuCl2·2H2O (1.5 equiv,
0.75mmol), NaOAc (2 equiv, 1 mmol) were added into a 15 mL sealed
tube equipped with a magnetic stirring bar. The mixture was stirred in
DCE/Tol (v:v=1:1, 2 mL) under Nitrogen at 100 °C for 24 h. After
completion, the reaction mixture was diluted with EtOAc and then
filtered. The residue was purified on a silica gel column using petroleum
ether/EtOAc as the eluent to give the pure target products.
(±)-(4a,5,8,8a)-3-phenyl-4a,5,6,7,8,8a-hexahydro-4H-5,8-methanobenzo[
e][1,2]oxazin-4-one (2a): EtOAc/petroleum ether =1/20. white solid (97
mg, 80% yield). [α]D28 = 0.574 (c = 0.4g/100ml, CHCl3). Mp: 120-124 oC.
1H NMR (400 MHz, CDCl3) δ 8.49 – 8.39 (m, 2H), 7.50 – 7.40 (m, 3H),
4.18 (t, J = 5.3 Hz, 1H), 2.97 (s, 1H), 2.74 – 2.64 (m, 2H), 1.85 – 1.74 (m,
1H), 1.72 – 1.61 (m, 1H), 1.37 (d, J = 4.1 Hz, 2H), 1.25 (d, J = 9.0 Hz,
13
2H). C NMR (101 MHz, CDCl3) δ 199.2, 140.5, 130.8, 128.2, 127.5,
125.3, 77.6, 52.1, 40.1, 39.8, 31.6, 28.1, 25.4. HRMS (ESI-TOF) m/z: [M
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+ H]+ Calcd for C15H16NO2 242.1182; found 242.1182.
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(±)-(4a,5,8,8a)-3-(4-fluorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-meth
anobenzo[e][1,2]oxazin-4-one (2b) : EtOAc/petroleum ether =1/20.
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White solid (118 mg, 91% yield). Mp: 143-145 C. H NMR (400 MHz,
CDCl3) δ 8.59 – 8.53 (m, 2H), 7.16 – 7.09 (m, 2H), 4.20 (d, J = 5.9 Hz,
1H), 2.97 (d, J = 4.7 Hz, 1H), 2.70 (t, J = 5.8 Hz, 2H), 1.86 – 1.76 (m,
1H), 1.69 (dd, J = 9.6, 5.6 Hz, 1H), 1.43 – 1.33 (m, 2H), 1.23 (s, 2H). 13C
NMR (101 MHz, CDCl3) δ 199.3, 165.0, 162.5, 139.7, 130.0 (d, JCF = 8.4
Hz), 121.8 (d, JCF = 3.3 Hz), 115.6, 115.4, 77.7, 52.3, 40.2, 39.9, 31.7,
28.2, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H15FNO2
260.1088; found 260.1084.
(±)-(4a,5,8,8a)-3-(4-(trifluoromethyl)phenyl)-4a,5,6,7,8,8a-hexahydro-4
H-5,8-methanobenzo[e][1,2]oxazin-4-one (2c) : EtOAc/petroleum ether
=1/20. White solid (136 mg, 88% yield). Mp: 196-198 oC. 1H NMR (400
MHz, CDCl3) δ 8.60 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 4.23 (d,
J = 5.8 Hz, 1H), 2.97 (s, 1H), 2.73 (d, J = 4.6 Hz, 2H), 1.87 – 1.76 (m,
13
1H), 1.74 – 1.63 (m, 1H), 1.44 – 1.33 (m, 2H), 1.25 (s, 2H). C NMR
(101 MHz, CDCl3) δ 198.9, 139.6, 132.6, 132.2, 131.9, 131.6, 128.7,
127.7, 125.2 (d, JCF = 3.9 Hz), 122.5, 78.2, 52.3, 40.2 (d, JCF = 15.7 Hz),
31.7, 28.1, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H15F3NO2
310.1056; found 310.1048.
(±)-(4a,5,8,8a)-3-(4-methoxyphenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-me
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thanobenzo[e][1,2]oxazin-4-one (2d) : EtOAc/petroleum ether =1/15.
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White solid (122 mg, 90% yield). Mp: 120-123 C. H NMR (400 MHz,
CDCl3) δ 8.55 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.1 Hz, 2H), 4.17 (d, J =
5.9 Hz, 1H), 3.84 (s, 3H), 2.97 (d, J = 4.2 Hz, 1H), 2.67 (dd, J = 12.7, 4.3
Hz, 2H), 1.84 – 1.74 (m, 1H), 1.72 – 1.62 (m, 1H), 1.43 – 1.31 (m, 2H),
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1.27 – 1.17 (m, 2H). C NMR (101 MHz, CDCl3) δ 199.6, 161.3, 140.0,
129.3, 118.2, 113.6, 77.1, 55.3, 52.2, 40.1, 39.8, 31.6, 28.1, 25.4. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C16H18NO3 272.1287; found
272.1293.
(±)-(4a,5,8,8a)-3-(p-tolyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-methanobenz
o[e][1,2]oxazin-4-one (2e) : EtOAc/petroleum ether =1/20. White solid
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(110 mg, 86% yield). Mp: 140-143 C. H NMR (400 MHz, CDCl3) δ
8.38 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 4.19 (d, J = 5.7 Hz,
1H), 2.98 (d, J = 3.6 Hz, 1H), 2.73 – 2.66 (m, 2H), 2.39 (s, 3H), 1.86 –
1.75 (m, 1H), 1.67 (ddd, J = 12.8, 10.2, 5.9 Hz, 1H), 1.44 – 1.32 (m, 2H),
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1.29 – 1.20 (m, 2H). C NMR (101 MHz, CDCl3) δ 199.5, 141.4, 140.6,
129.0, 127.5, 122.6, 77.5, 52.3, 40.2, 39.9, 31.7, 28.2, 25.5, 21.8. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C16H18NO2 256.1338; found
256.1314.
(±)-(4a,5,8,8a)-3-(benzo[d][1,3]dioxol-5-yl)-4a,5,6,7,8,8a-hexahydro-4H
-5,8-methanobenzo[e][1,2]oxazin-4-one (2f) : EtOAc/petroleum ether
=1/15. Light yellow solid (88 mg, 62% yield). Mp: 169-171 oC. 1H NMR
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(400 MHz, CDCl3) δ 8.18 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 6.88 (d, J =
8.4 Hz, 1H), 6.00 (s, 2H), 4.16 (d, J = 5.8 Hz, 1H), 2.96 (d, J = 3.6 Hz,
1H), 2.70 – 2.63 (m, 2H), 1.84 – 1.74 (m, 1H), 1.72 – 1.63 (m, 1H), 1.42
– 1.31 (m, 2H), 1.21 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 199.5, 149.5,
147.4, 140.0, 123.1, 119.4, 108.3, 107.6, 101.5, 77.2, 52.2, 40.2, 39.9,
31.7, 28.2, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H16NO4
286.1080; found 286.1082.
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(±)-(4a,5,8,8a)-3-(4-(tert-butyl)phenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-
methanobenzo[e][1,2]oxazin-4-one (2g) : EtOAc/petroleum ether =1/25.
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White solid (123 mg, 83% yield). Mp: 161-164 C. H NMR (400 MHz,
CDCl3) δ 8.38 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 11.4 Hz, 2H), 4.20 (d, J =
5.7 Hz, 1H), 2.98 (d, J = 3.5 Hz, 1H), 2.69 (d, J = 6.6 Hz, 2H), 1.86 –
1.75 (m, 1H), 1.68 (ddd, J = 16.3, 10.1, 5.9 Hz, 1H), 1.35 (d, J = 21.9 Hz,
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11H), 1.23 (s, 2H). C NMR (101 MHz, CDCl3) δ 199.5, 154.4, 140.8,
127.5, 125.4, 122.6, 77.5, 52.33, 40.2, 39.9, 35.1, 31.7, 31.2, 28.2, 25.6.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H25NO2 298.1808; found
298.1811.
(±)-(4a,5,8,8a)-3-(4-bromophenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-meth
anobenzo[e][1,2]oxazin-4-one (2h) : EtOAc/petroleum ether =1/20. Light
yellow solid (144 mg, 90% yield). Mp: 164-166 oC. 1H NMR (400 MHz,
CDCl3) δ 8.42 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 4.19 (d, J =
5.8 Hz, 1H), 2.98 (d, J = 3.8 Hz, 1H), 2.70 (d, J = 6.4 Hz, 2H), 1.86 –
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1.76 (m, 1H), 1.75 – 1.65 (m, 1H), 1.44 – 1.33 (m, 2H), 1.24 (s, 2H). C
NMR (101 MHz, CDCl3) δ 199.2, 139.8, 131.7, 128.9, 125.3, 124.4, 77.9,
52.3, 40.3, 40.0, 31.8, 28.2, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C15H15BrNO2 320.0287; found 320.0295.
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(±)-(4a,5,8,8a)-3-(4-chlorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-meth
anobenzo[e][1,2]oxazin-4-one (2i). : EtOAc/petroleum ether =1/20.
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White solid (105 mg, 76% yield). Mp: 147-148 C. H NMR (400 MHz,
CDCl3) δ 8.49 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 4.20 (d, J =
5.8 Hz, 1H), 2.98 (d, J = 3.5 Hz, 1H), 2.70 (d, J = 6.4 Hz, 2H), 1.87 –
1.77 (m, 1H), 1.69 (ddd, J = 16.9, 10.3, 3.8 Hz, 1H), 1.44 – 1.33 (m, 2H),
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1.24 (s, 2H). C NMR (101 MHz, CDCl3) δ 199.3, 139.8, 136.8, 128.9,
128.7, 123.9, 77.9, 52.3, 40.3, 40.0, 31.7, 28.2, 25.5. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C15H15ClNO2 276.0792; found 276.0790.
(±)-(4a,5,8,8a)-3-([1,1'-biphenyl]-4-yl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-
methanobenzo[e][1,2]oxazin-4-one (2j) : EtOAc/petroleum ether =1/20.
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White solid (128 mg, 81% yield). Mp: 210-213 C. H NMR (400 MHz,
CDCl3) δ 8.58 (d, J = 7.9 Hz, 2H), 7.67 (dd, J = 28.0, 7.7 Hz, 4H), 7.49 –
7.33 (m, 3H), 4.23 (d, J = 5.6 Hz, 1H), 3.01 (s, 1H), 2.73 (d, J = 5.6 Hz,
2H), 1.86 – 1.63 (m, 2H), 1.39 (s, 2H), 1.26 (s, 2H). 13C NMR (101 MHz,
CDCl3) δ 199.5, 143.4, 140.4, 140.4, 129.0, 128.0, 128.0, 127.3, 127.0,
124.4, 77.7, 52.4, 40.3, 40.0, 31.8, 28.2, 25.6. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C21H20NO2 318.1495; found 318.1508.
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(±)-(4a,5,8,8a)-3-(2,4-dichlorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-
methanobenzo[e][1,2]oxazin-4-one (2k) : EtOAc/petroleum ether =1/20.
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White solid (76 mg, 49% yield). Mp: 162-165 C. H NMR (400 MHz,
CDCl3) δ 7.51 (d, J = 1.3 Hz, 1H), 7.34 (dd, J = 8.3, 1.4 Hz, 1H), 7.27 (t,
J = 6.4 Hz, 1H), 4.26 (d, J = 5.5 Hz, 1H), 2.97 (d, J = 3.6 Hz, 1H), 2.83 –
2.70 (m, 2H), 1.87 – 1.77 (m, 1H), 1.75 – 1.64 (m, 1H), 1.44 – 1.34 (m,
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2H), 1.33 – 1.23 (m, 2H). C NMR (101 MHz, CDCl3) δ 197.3, 143.0,
137.3, 135.3, 132.3, 130.3, 127.4, 123.1, 78.8, 53.0, 40.0, 39.8, 31.9, 28.2,
25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H14Cl2NO2 310.0402;
found 310.0403.
(±)-(4a,5,8,8a)-3-(o-tolyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-methanobenz
o[e][1,2]oxazin-4-one (2l) : EtOAc/petroleum ether =1/20. White solid
(42 mg, 33% yield). Mp: 147-150 oC. 1H NMR (400 MHz, CDCl3) δ 7.39
– 7.19 (m, 4H), 4.24 (s, 1H), 2.98 (s, 1H), 2.75 (d, J = 14.6 Hz, 2H), 2.21
13
(s, 3H), 1.75 (dd, J = 36.3, 10.3 Hz, 2H), 1.43 – 1.28 (m, 4H). C NMR
(101 MHz, CDCl3) δ 198.5, 145.9, 138.5, 130.7, 130.5, 129.7, 125.7,
124.1, 78.1, 52.8, 39.9, 39.7, 31.8, 28.1, 25.5, 20.4. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C16H18NO2 256.1338; found 256.1340.
(±)-(4a,5,8,8a)-3-(2-fluorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-meth
anobenzo[e][1,2]oxazin-4-one (2m) : EtOAc/petroleum ether =1/20.
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White solid (63 mg, 49% yield). Mp: 123-124 C. H NMR (400 MHz,
CDCl3) δ 7.51 – 7.42 (m, 2H), 7.25 (dd, J = 13.2, 5.7 Hz, 1H), 7.17 (t, J =
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9.1 Hz, 1H), 4.28 (d, J = 5.6 Hz, 1H), 2.99 (d, J = 3.6 Hz, 1H), 2.82 –
2.71 (m, 2H), 1.89 – 1.76 (m, 1H), 1.74 – 1.65 (m, 1H), 1.37 (dd, J = 24.4,
8.2 Hz, 3H), 1.33 – 1.23 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 197.6,
161.6, 159.1, 141.2, 132.5 (d, JCF = 8.5 Hz), 130.7 (d, JCF = 3.2 Hz),
124.3 (d, JCF = 3.4 Hz), 116.5, 116.3, 113.0 (d, JCF = 15.1 Hz), 78.6, 52.8,
40.1, 39.9, 31.7, 28.2, 25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C15H15FNO2 260.1088; found 260.1091.
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(±)-(4a,5,8,8a)-3-(3,5-dimethylphenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-
methanobenzo[e][1,2]oxazin-4-one (2n) : EtOAc/petroleum ether =1/20.
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White solid (121 mg, 90% yield). Mp: 152-154 C. H NMR (400 MHz,
CDCl3) δ 8.03 (s, 2H), 7.09 (s, 1H), 4.19 (d, J = 5.6 Hz, 1H), 2.98 (s, 1H),
2.73 – 2.65 (m, 2H), 2.36 (s, 6H), 1.79 (d, J = 8.7 Hz, 1H), 1.68 (t, J =
14.1 Hz, 1H), 1.44 – 1.33 (m, 2H), 1.28 – 1.20 (m, 2H). 13C NMR (101
MHz, CDCl3) δ 199.5, 141.1, 137.9, 132.7, 125.3, 125.1, 77.6, 52.2, 40.2,
39.9, 31.7, 28.2, 25.5, 21.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C17H20NO2 270.1495; found 270.1499.
(±)-(4a,5,8,8a)-3-(3-chlorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-meth
anobenzo[e][1,2]oxazin-4-one (2o) : EtOAc/petroleum ether =1/20.
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White solid (113 mg, 82% yield). Mp: 165-167 C. H NMR (400 MHz,
CDCl3) δ 8.54 (s, 1H), 8.38 (d, J = 7.4 Hz, 1H), 7.45 – 7.35 (m, 2H), 4.21
(d, J = 5.8 Hz, 1H), 2.97 (d, J = 3.8 Hz, 1H), 2.71 (d, J = 5.7 Hz, 2H),
1.80 (dd, J = 10.9, 3.2 Hz, 1H), 1.69 (dd, J = 11.6, 7.8 Hz, 1H), 1.44 –
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1.32 (m, 2H), 1.24 (s, 2H). C NMR (101 MHz, CDCl3) δ 198.9, 139.5,
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134.4, 130.9, 129.6, 127.2, 127.0, 125.5, 78.0, 52.3, 40.2, 40.0, 31.7, 28.2,
25.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H15ClNO2 276.0792;
found 276.0788.
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(±)-(4a,5,8,8a)-3-(4-(trifluoromethoxy)phenyl)-4a,5,6,7,8,8a-hexahydro-4
H-5,8-methanobenzo[e][1,2]oxazin-4-one (2p) : EtOAc/petroleum ether
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=1/20. White solid (73 mg, 45% yield). Mp: 125-128 C. H NMR (400
MHz, CDCl3) δ 8.59 (d, J = 8.9 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 4.23 (d,
J = 5.8 Hz, 1H), 2.99 (d, J = 3.8 Hz, 1H), 2.72 (d, J = 4.8 Hz, 2H), 1.86 –
1.77 (m, 1H), 1.74 – 1.65 (m, 1H), 1.41 (t, J = 9.0 Hz, 2H), 1.26 (d, J =
9.9 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 199.1, 150.4, 139.5, 129.4,
124.0, 121.7, 120.4, 77.9 52.3, 40.2, 40.0, 31.7, 28.1, 25.4. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C16H15F3NO3 326.1005; found
326.1006.
(±)-(4a,5,8,8a)-3-(naphthalen-2-yl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-met
hanobenzo[e][1,2]oxazin-4-one (2q) : EtOAc/petroleum ether =1/20.
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White solid (143 mg, 98% yield). Mp: 184-185 C. H NMR (400 MHz,
CDCl3) δ 9.12 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 7.4 Hz, 1H),
7.90 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 7.4 Hz, 1H), 7.56 – 7.49 (m, 2H),
4.26 (d, J = 4.5 Hz, 1H), 3.04 (s, 1H), 2.76 (s, 2H), 1.83 (d, J = 10.8 Hz,
1H), 1.71 (s, 1H), 1.42 (s, 2H), 1.31 – 1.25 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ 199.6, 140.7, 134.3, 132.8, 129.4, 128.5, 127.9, 127.8, 127.7,
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126.5, 123.8, 122.9, 77.8, 52.4, 40.3, 40.1, 31.8, 28.3, 25.6. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C19H18NO2 292.1338; found
292.1339.
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(±)-(4a,5,8,8a)-3-(thiophen-3-yl)-4a,5,6,7,8,8a-hexahydro-4H-5,8-metha
nobenzo[e][1,2]oxazin-4-one (2r) : EtOAc/petroleum ether =1/20. White
solid (33mg, 27% yield). Mp: 143-145 oC. 1H NMR (400 MHz, CDCl3) δ
8.97 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 5.0 Hz, 1H), 7.40 – 7.36 (m, 1H),
4.21 (d, J = 5.7 Hz, 1H), 2.98 (d, J = 3.7 Hz, 1H), 2.70 (d, J = 5.8 Hz, 2H),
1.84 – 1.76 (m, 1H), 1.73 – 1.66 (m, 1H), 1.38 (d, J = 4.4 Hz, 2H), 1.22 (s,
13
2H). C NMR (101 MHz, CDCl3) δ 198.8, 138.4, 129.1, 126.0, 125.9,
125.2, 77.3, 52.5, 40.1, 39.8, 31.8, 28.2, 25.5. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C13H14NO2S 248.0746; found 248.0749.
(±)-4-((4a,5,8,8a)-4-oxo-4a,5,6,7,8,8a-hexahydro-4H-5,8-methanobenzo[
e][1,2]oxazin-3-yl)benzonitrile (2s) : EtOAc/petroleum ether =1/20.
o
1
White solid (68mg, 51% yield). Mp: 113-115 C. H NMR (400 MHz,
CDCl3) δ 8.64 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 4.25 (d, J =
5.7 Hz, 1H), 2.99 (d, J = 3.3 Hz, 1H), 2.75 (d, J = 4.3 Hz, 2H), 1.82 (dd, J
= 12.5, 2.7 Hz, 1H), 1.72 (dd, J = 11.2, 7.7 Hz, 1H), 1.41 (s, 2H), 1.26 (d,
13
J = 5.6 Hz, 2H). C NMR (101 MHz, CDCl3) δ 198.9, 139.1, 132.1,
129.6, 127.7, 118.5, 113.9, 78.4, 52.4, 40.3, 40.2, 31.8, 28.2, 25.5. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C16H15N2O2 267.1134; found
267.1140.
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(±)-(4a,5,8,8a)-3-phenyl-4a,5,8,8a-tetrahydro-4H-5,8-methanobenzo[e][
6
7
1,2]oxazin-4-one (3a) : EtOAc/petroleum ether =1/25. White solid (75mg,
8
9
o
63% yield). Mp: 125-127 C. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J =
10
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14
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2.9 Hz, 2H), 7.44 (s, 3H), 6.41 (d, J = 2.4 Hz, 1H), 6.26 (d, J = 2.1 Hz,
1H), 4.30 (d, J = 4.6 Hz, 1H), 3.51 (s, 1H), 3.24 (s, 1H), 2.85 (d, J = 4.2
13
Hz, 1H), 1.77 – 1.65 (m, 1H), 1.47 (d, J = 10.1 Hz, 1H). C NMR (151
MHz, CDCl3) δ 197.9, 142.1, 140.4, 135.6, 130.9, 128.3, 127.7, 125.6,
77.5, 51.2, 45.3, 44.9, 42.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C15H14NO2 240.1025; found 240.1028.
(±)-(4a,5,8,8a)-3-(4-methoxyphenyl)-4a,5,8,8a-tetrahydro-4H-5,8-metha
nobenzo[e][1,2]oxazin-4-one (3b) : EtOAc/petroleum ether =1/25. White
solid (103mg, 76% yield). Mp: 130-132 oC. 1H NMR (400 MHz, CDCl3)
δ 8.54 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.42 (s, 1H), 6.28 (s,
1H), 4.30 (d, J = 5.6 Hz, 1H), 3.85 (s, 3H), 3.52 (s, 1H), 3.24 (s, 1H),
2.85 (d, J = 5.4 Hz, 1H), 1.69 (d, J = 9.9 Hz, 1H), 1.46 (d, J = 10.1 Hz,
13
1H). C NMR (101 MHz, CDCl3) δ 198.3, 161.4, 141.7, 140.4, 135.7,
129.6, 118.5, 113.8, 77.1, 55.5, 51.3, 45.3, 44.9, 42.2. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C16H16NO3 270.1131; found 270.1122.
(±)-(4a,5,8,8a)-3-(4-(trifluoromethyl)phenyl)-4a,5,8,8a-tetrahydro-4H-5,
8-methanobenzo[e][1,2]oxazin-4-one (3c) : EtOAc/petroleum ether
o
1
=1/25. White solid (86mg, 56% yield). Mp: 130-132 C. H NMR (400
MHz, CDCl3) δ 8.60 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 6.47 –
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6.42 (m, 1H), 6.32 – 6.27 (m, 1H), 4.36 (d, J = 5.7 Hz, 1H), 3.54 (s, 1H),
3.28 (s, 1H), 2.92 (d, J = 5.6 Hz, 1H), 1.73 (d, J = 10.2 Hz, 1H), 1.48 (d,
8
9
13
J = 10.2 Hz, 1H). C NMR (101 MHz, CDCl3) δ 197.5, 141.0, 140.6,
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135.6, 132.2 (d, JCF = 32.7 Hz), 128.9, 127.9, 125.3 (q, JCF = 3.8 Hz),
122.5, 78.1, 51.4, 45.5, 45.9, 42.2. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C16H13F3NO2 308.0899; found 308,0897.
(±)-(4a,5,8,8a)-3-(3-chlorophenyl)-4a,5,8,8a-tetrahydro-4H-5,8-methano
benzo[e][1,2]oxazin-4-one (3d) : EtOAc/petroleum ether =1/25. White
solid (59mg, 43% yield). Mp: 129-131 oC. 1H NMR (400 MHz, CDCl3) δ
8.54 (s, 1H), 8.38 (d, J = 7.4 Hz, 1H), 7.40 (dd, J = 13.6, 5.7 Hz, 2H),
6.44 (dd, J = 5.0, 2.7 Hz, 1H), 6.31 – 6.26 (m, 1H), 4.33 (d, J = 5.7 Hz,
1H), 3.53 (s, 1H), 3.26 (s, 1H), 2.89 (d, J = 5.5 Hz, 1H), 1.72 (d, J = 10.1
Hz, 1H), 1.46 (d, J = 10.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 197.5,
140.9, 140.5, 135.6, 134.5, 131.0, 129.7, 127.4, 127.3, 125.7, 77.9, 51.3,
45.5, 45.0, 42.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H13ClNO2
274.0636; found 274.0626.
(±)-(4a,5,8,8a)-3-(benzo[d][1,3]dioxol-5-yl)-4a,5,8,8a-tetrahydro-4H-5,8
-methanobenzo[e][1,2]oxazin-4-one (3e) : EtOAc/petroleum ether =1/25.
o
1
White solid (115mg, 81% yield). Mp: 178-180 C. H NMR (400 MHz,
CDCl3) δ 8.16 (d, J = 27.5 Hz, 2H), 6.90 (s, 1H), 6.42 (s, 1H), 6.28 (s,
1H), 6.01 (s, 2H), 4.29 (s, 1H), 3.51 (s, 1H), 3.24 (s, 1H), 2.84 (s, 1H),
13
1.69 (s, 1H), 1.45 (s, 1H). C NMR (101 MHz, CDCl3) δ 198.1, 149.6,
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147.5, 141.6, 140.4, 135.7, 123.3, 119.6, 108.4, 107.8, 101.6, 77.1, 51.2,
45.3, 44.9, 42.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H14NO4
284.0924; found 284.0920.
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(±)-(4a,7a)-3-phenyl-5,6,7,7a-tetrahydrocyclopenta[e][1,2]oxazin-4(4aH
1
)-one (3f) : EtOAc/petroleum ether =1/25. yellow oil (23mg, 21%). H
NMR (400 MHz, CDCl3) δ 8.45 (dd, J = 6.7, 3.3 Hz, 2H), 7.45 (dd, J =
5.2, 2.1 Hz, 3H), 4.72 (t, J = 7.0 Hz, 1H), 3.24 (dd, J = 9.1, 6.7 Hz, 1H),
2.53 (dd, J = 14.3, 6.3 Hz, 1H), 2.23 (dd, J = 12.7, 6.1 Hz, 1H), 1.83 (dtd,
13
J = 35.0, 13.0, 6.6 Hz, 3H), 1.44 – 1.29 (m, 1H). C NMR (101 MHz,
CDCl3) δ 200.6, 139.3, 130.8, 128.3, 127.5, 125.5, 77.0, 48.9, 30.9, 30.1,
22.7. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H14NO2 216.1027;
found 216.1027.
ASSOCIATED
1
13
Supporting Information Figures giving 2D NMR spectra and H, C
NMR spectra.
AUTHOR INFORMATION
Corresponding Authors
*(Yong-Ming
Zhu)
E-mail:
zhuyongming@suda.edu.cn;
fax:
(+86)-512-67166591.
Notes
The authors declare no competing financial interest.
References
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(1) (a) Remy, R.; Bochet, C. G. Arene−Alkene Cycloaddition. Chem. Rev.
2016, 116, 9816-9849. (b) Pan, G.-H.; Ouyang, X.-H.; Hu, M.; Xie, Y.-X.;
Li, J.-H. Copper-Catalyzed Intermolecular Amino-Alkylation of Alkenes
with α-Bromoalkyl Esters and Amines toward Pyrrolidin-2-ones. Adv.
Synth. Catal. 2017, 359, 2564-2570. (c) Liu, Y.-Y.; Yang, X.-H.; Song,
R.-J.; Luo, S.-L.; Li, J.-H. Oxidative 1,2-carboamination of alkenes with
alkyl nitriles and amines toward γ -amino alkyl nitriles. Nature
Communications. 2017, 8, 14720-14726. (d) Yang, Y.; Song, R.-J.;
Ouyang, X.-H.; Wang, C.-Y.; Li, J.-H.; Luo, S.-L. Iron-Catalyzed
Intermolecular 1,2-Difunctionalization of Styrenes and Conjugated
Alkenes with Silanes and Nucleophiles. Angew. Chem. Int. Ed. 2017, 56,
7916 –7919.
10
11
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16
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47
48
49
50
51
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53
54
55
56
57
58
59
60
(2) Ylijoki, K. E. O.; Stryker, J. M. [5 + 2] Cycloaddition Reactions in
Organic and Natural Product Synthesis. Chem. Rev. 2013, 113,
2244−2266.
(3) (a)Advances in Cycloaddition, Vols. 1–6, JAI, Greenwich, CT, 1988–
1999; (b) W. Carruthers, Cycloaddition Reactions in Organic Synthesis,
Tetrahedron Organic Chemistry Series, Pergamon, Elmsford, NY, 1990;
(c) Cycloaddition Reactions in Organic Synthesis, (Eds.: S.Kobayashi, K.
A. J⌀gensen), Wiley-VCH, Weinheim, 2002; (d) G. Masson, C. Lalli, M.
Benohoud, G. Dagousset. Catalytic Enantioselective [4+2]-Cycloaddition:
A Strategy to Access Aza-Hexacycles. Chem. Soc. Rev. 2013, 42,
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902-923.
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7
8
9
(4) (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Rhodium-Catalyzed
C−C Bond Formation via Heteroatom-Directed C−H Bond Activation.
Chem. Rev. 2010, 110, 624–655. (b) Satoh, T.; Miura, M. Oxidative
Coupling of Aromatic Substrates with Alkynes and Alkenes under
Rhodium Catalysis. Chem. Eur. J. 2010, 16, 11212-11222. (c) Arockiam,
P. B.; Bruneau, C.; Dixneuf, P. H. Ruthenium(II)-Catalyzed C–H Bond
Activation and Functionalization. Chem. Rev. 2012, 112, 5879–5918. (d)
Song, G.-Y.; Wang, F.; Li, X.-W. C–C, C–O and C–N Bond Formation
via Rhodium(III)-Catalyzed Oxidative C–H Activation. Chem. Soc. Rev.
2012, 41, 3651-3678.
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(5) Remy, R.; Bochet, C. G. Arene−Alkene Cycloaddition. Chem. Rev.
2016, 116, 9816-9849.
(6) For homo-Diels-Alder reaction of norbomadienes. Furukawa, J.;
Kobuke, Y.; Sugimoto, T.; Fueno, T. The Role of Attractive Interactions
in Endo-Exo Stereoselectivities of Diels-Alder Reactions. J. Am. Chem.
Soc. 1972, 94, 3633-3635.
(7) Selected papers on oxidation of oximes to produce ketones: (a) Zhou,
X.-T.; Yuan, Q.-L.; Jia, H.-B. Highly Efficient Aerobic Oxidation of
Oximes to Carbonyl Compounds Catalyzed by Metalloporphyrins in the
Presence of Benzaldehyde. Tetrahedron Lett. 2010, 51, 613-617. (b) Kim,
B. R.; Lee, H.-G.; Kim, E. J.; Lee, S.-G.; Yoon, Y.-J. Conversion of
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2-Nitro-4,5-dichloropyridazin-3(2H)-one. J. Org. Chem. 2010, 75, 484–
486. (c) Reddy, M. S.; Narender, M.; Rao, R. Regeneration of Carbonyl
Compounds by Oxidative Cleavage of Oximes with NBS in the Presence
of β-Cyclodextrin in Water. Synth. Commun. 2004, 34, 3875-3881.
(8) Selected papers on the Beckmann rearrangement of oximes to prepare
amides: (a) Hesp, K. D.; Bergman, R. G.; Ellman, J. A. Expedient
Synthesis of N-Acyl Anthranilamides and β-Enamine Amides by the
Rh(III)-Catalyzed Amidation of Aryl and Vinyl C–H Bonds with
Isocyanates. J. Am. Chem. Soc. 2011, 133, 11430–11433. (b) Ramon, R.
S.; Bosson, J.; Díez-Gonz_alez, S.; Marion, N.; Nolan,S. P.
Au/Ag-Cocatalyzed Aldoximes to Amides Rearrangement under Solvent-
and Acid-Free Conditions. J. Org. Chem. 2010, 75, 1197–1202. (c) Betti,
C.; Landini, D.; Maia, A.; Pasi, M. Beckmann Rearrangement of Oximes
Catalyzed by Cyanuric Chloride in Ionic Liquids. Synlett 2008, 6,
908-910. (d) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Highly
Efficient Ruthenium-Catalyzed Oxime to Amide Rearrangement. Org.
Lett. 2007, 9, 3599–3601. (e) Furuya, Y.; Ishihara, K.; Yamamoto, H.
Cyanuric Chloride as a Mild and Active Beckmann Rearrangement
Catalyst. J. Am. Chem. Soc. 2005, 127, 11240–11241.
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(9) Selected papers on dehydration reactions of oximes to produce nitriles:
(a) Enthaler, S.; Weidauer, M.; Schroeder, F. Straightforward
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