Copper(I)-Catalyzed N-O Bond Formation through Vinyl Nitrene Mediated Pathway under Mild Conditions

Article abstract of DOI:10.1021/acs.joc.8b00605

Copper(I)-catalyzed N-O bond formation reactions through vinyl nitrene-mediated pathway were described. The reactions of N-alkoxylbenzamides and 2H-azirines afforded α-amino oxime ethers in good to excellent yields at room temperature, which involved the

Full text of DOI:10.1021/acs.joc.8b00605

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Article
Copper(I)-Catalyzed N-O Bond Formation through
Vinyl Nitrene-Mediated Pathway under Mild Conditions
Feifei Wu, Min Zhang, Wei Zhou, Wanzhi Chen, Miaochang Liu, and Huayue Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00605 • Publication Date (Web): 14 May 2018
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Copper(I)-Catalyzed
N-O
Bond
Formation
through
Vinyl
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Nitrene-Mediated Pathway under Mild Conditions
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Feifei Wu,† Min Zhang,† Wei Zhou,† and Wanzhi Chen*,†, Miaochang Liu*,‡ and Huayue Wu‡
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†Department of Chemistry, Zhejiang University, Hangzhou 310027, China
‡College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, 325027, China.
Eꢀmail: chenwzz@zju.edu.cn mcl@wzu.edu.cn
;
ABSTRACT: Copper(I)ꢀcatalyzed NꢀO bond formation reactions through vinyl nitreneꢀmediated
pathway were described. The reactions of Nꢀalkoxylbenzamides and 2Hꢀazirines afforded αꢀamino
oxime ethers in good to excellent yields at room temperature, which involved the cleavage of CꢀN and
NꢀO bonds, and the construction of new NꢀO and CꢀN bonds. It offers an efficient, regioꢀ and
stereoselective synthetic route for αꢀamino oxime ethers.
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INTRODUCTION
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Nitrogenꢀoxygen single bonds have been found in many biologically active
compounds.1 They exist in both aromatic Nꢀheterocycles such as isoxazoles,
benzisoxazoles, furazans, 1,2ꢀazines, 1,2ꢀoxazines, and nonaromatic chain compounds
like Nꢀhydroxylamine, oximes, and Nꢀoxides. These compounds show promising
biological activities, such as antifungal, antiꢀinflammatory and analgesic, as well as
antiꢀhistamine effects.2 For example, Orysastrobin is used to control the leaf and
panicle blast (Magnaporthe grisea) and sheath blight (Thanatephorus cucumeris) in
rice.3 SCH 206272 is a potent and orally active tachykinin NK1, NK2, and NK3
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receptor antagonist (Figure 1).4
Cl
O
O
N
N
O
N
Cl
N
N
O
O
N
N
O
H
N
O
N
N
O
O
H
Cl
Cl
Orysastrobin
SCH 206272
Figure 1. Representative examples of αꢀamino oxime ethers.
Typically, the NꢀO moieties are constructed from the derivation of the starting
materials with preꢀexisting NꢀO bonds such as hydroxylamines and nitro compounds.
Although amine Nꢀoxides and pyridine Nꢀoxides are easily accessible through direct
oxidation with peroxides,5 metalꢀcatalyzed direct NꢀO coupling has been scarcely
studied. Usually, the known NꢀO bond formation approaches involve oxidative NꢀO
coupling. Oxidation of βꢀaminoketones by PhI(OAc)2 could afford
isoxazolo[3,4ꢀd]primidineꢀ4,6ꢀdione derivatives due to NꢀO bond formation.6
Cuꢀcatalyzed oxidative NꢀO bond formation between amides and organic nitriles led
to 1,2,4ꢀoxadiazoles using O2 as the oxidant.7 FeBr2 catalyzed reaction of aryl and
vinyl azides with ketone resulted in 2,1ꢀbenzisoxazoles.8 It was believed that azide
was activated via coordination of the terminal Nꢀatom to iron(II), then the activated
azide was attacked by Oꢀatom of ketone, and finally N2 lost. Reactions of
orthoꢀhydroxyaryl N–H ketimines with NCS or NaClO yielded 2ꢀ and 3ꢀsubstituted
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benzisoxazoles through N–Cl imine intermediate.9 Reactions of aldehydes or ketones
with TMSN3 in the presence of ZrCl4 or TfOH afforded benzisoxazoles after nitrogen
extrusion via an intramolecular nucleophilic substitution of azido methanolate
complex or imine diazonium ion.10 The above described synthetic approaches are
restricted to synthesize heterocyclic compounds containing NꢀO bonds. The
construction of NꢀO bonds in chain compounds has seldom been studied.
Transition metal catalyzed reactions of 2Hꢀazirines11 have been used to
synthesize indoles,12 amides,13 oxime ethers,14 and 1,2,3ꢀtriazole derivatives15. These
transformations usually involve nitrene intermediate. We envisioned that Nꢀalkoxyl
benzamide containing a fissionable NꢀO bond would react with vinyl nitrene to form a
new NꢀO bond.16 Herein we describe copper(I)ꢀcatalyzed difunctionalization of
2Hꢀazirines offering αꢀamino oxime ethers through vinyl nitreneꢀmediated pathway
under mild conditions in good to excellent yields.17
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RESULTS AND DISCUSSION
Table 1. Optimization of Reaction Conditionsa
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Entry
Catalyst
Base
(1 equiv.)
ꢀ
Solvent
Yieldb (%)
(10 mol%)
Pd(OAc)2
Pd(OAc)2
{Cp*RhCl2}2
Pd(OAc)2
MnBr(CO)5
CuI
1
2
DCE
DCE
84
99
75
0
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K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
3
DCE
4
methanol
DCE
5
54
99(97)
0
6
DCE
7
ꢀ
DCE
8c
9d
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CuI
DCE
93
89
87
92
68
7
CuI
DCE
Cu(OAc)2
CuCl2
DCE
DCE
Cu(OTf)2
CuI
DCE
DMF
Toluene
CuI
75
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (0.02 mmol), base (0.2 mmol) in 2
mL of solvent at room temperature for 12 h; b Yields determined by H NMR analysis using
1
CH2Br2 as the internal standard and isolated yields shown in parentheses; CuI (5 % mmol); d CuI
c
(2 % mmol).
Initially, we started our work by taking Nꢀmethoxylbenzamide 1a and
3ꢀphenylꢀ2Hꢀazirine 2a as the model substrates using Pd(OAc)2 catalyst to optimize
the reaction conditions. The optimization results were shown in Table 1. At a loading
of 10 mol% of the palladium catalyst, we were pleased to find that αꢀamino oxime
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ether 3a was obtained in 84% yield in DCE at room temperature based on H NMR
analysis (Table 1, entry 1). Addition of K2CO3 could further promote the reaction, and
3a could be almost quantitatively obtained (Table 1, entry 2). {Cp*RhCl2}2 was also
active, and 3a was afforded in 75% yield under the same conditions (Table 1, entry 3).
When protonic solvent methanol was used, the reaction was totally inhibited (Table 1,
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entry 4). MnBr(CO)5 could also catalyse the reaction, and 3a was obtained in a
moderate yield (Table 1, entry 5). To our surprise, the cheap copper(I) salt was quite
efficient to give 3a in a quantitative yield (Table 1, entry 6). Without metal catalysts
the reaction did not proceed (Table 1, entry 7). When 2ꢀ5 mol% of CuI was used, the
yield of 3 was slightly decreased (Table 1, entries 8 and 9). Other copper catalysts
such as Cu(OAc)2, CuCl2, and Cu(OTf)2 are less efficient than CuI (Table 1, entries
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1
10ꢀ12). The H NMR spectral analysis showed that in solution only the anti isomer
was formed. The structures of 3a and 3b were further identified by Xꢀray
crystallography, which were presented in Figure S1 in the Supporting Information.
Table 2. Scope of 2Hꢀazirinesa,b
aReaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), CuI (0.02 mmol), K2CO3 (0.2 mmol) in 2 mL of DCE at room
temperature for 12 h. b Isolated yields.
With optimized conditions in hand, we continued to explore the substrate scope of
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the reaction. Various Nꢀalkoxylamides containing both electronꢀdonating and
electronꢀwithdrawing groups were examined (Table 2). The results showed that both
electronꢀdonating and electronꢀwithdrawing groups at their aromatic rings were
tolerated. NꢀMethoxylbenzamides bearing methyl groups at oꢀ, mꢀ, and pꢀpositions
were quite reactive, and in such cases 3 were obtained in more than 83% yields.
NꢀMethoxylbenzamides containing halogen substituents are also good reaction
partners giving αꢀamino oxime ethers 3e, 3f, and 3g in good to excellent yields.
Reactions of two Nꢀmethoxynaphthalenecarboxamides 1m and 1n with 2Hꢀazirine
afforded 3m and 3n in 61% and 88% yields, respectively. Unexpectedly, the
substrates having 4ꢀtꢀBu and 4ꢀOMe are less reactive, and the corresponding products
3c and 3d were produced in only 60% and 52% yields, respectively. Heterocyclic
compounds containing N, O, and S did not show negative effect, and 3o, 3p, and 3q
were isolated in 62, 93, and 80% yields, respectively. Aliphatic amides
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Nꢀmethoxyꢀ2ꢀmethylꢀ2ꢀphenylpropanamide
1r
and
Nꢀmethoxycyclopropanecarboxamide 1s could participate in the reaction, and 3r and
3s were isolated in moderate yields. Bulkier Nꢀtꢀbutoxylbenzamide 1u also showed
good reactivity, and the reactivity was not affected by the steric hindrance.
Table 3. Scope of 2Hꢀazirinesa,b
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aReaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), CuI (0.02 mmol), K2CO3 (0.2 mmol) in 2 mL of DCE at
room temperature for 12 h. bIsolated yield.
Subsequently, the reactions of various 2Hꢀazirines 2 with Nꢀmethoxylbenzamide 1a
were further investigated (Table 3). Generally, 3ꢀphenylꢀ2Hꢀazirine derivatives
having an alkyl, F, Br substituents proceeded smoothly to give the desired products in
good to excellent yields. However, the chlorineꢀcontaining 2Hꢀazirine showed
relatively lower activity, and 3w was isolated in only 46% yield. In addition, the
disubstituted azirine, 2,3ꢀdiphenylꢀ2Hꢀazirine 1z, gave the corresponding products 3z
in 70% yield. In addtion, 3ꢀalkylꢀ2Hꢀazirine was also compatible, and 3aa was
afforded from (3ꢀmethylꢀ2Hꢀazirinꢀ2ꢀyl)(phenyl)methanone in 53% yield.
Scheme 1. Gram scale and further transformation experiments
The optimized reaction conditions were suitable for gramꢀscale preparation. For
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example, when 10 mol% CuI was used, the reaction of 2b (0.990 g) and 1a (0.702 g)
was conducted at room temperature for twelve hours, the desired product 3b (1.236 g)
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was isolated in 73% yield. We found that treatment of 3b with Cu(OAc)2 2H2O at 100
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oC
resulted
in
antiꢀsyn
isomerization,
and
the
syn
isomer
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(Z)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)ꢀ4ꢀmethylbenzamide 4 was obtained in 28%
yield, and 3b was recovered in 68% yield (Scheme 1). Treatment of 3b with
CF3COOH
resulted
in
isomerization
and
partial
hydrolysis
to
4ꢀmethylꢀNꢀ(2ꢀoxoꢀ2ꢀphenylethyl)benzamide 5. In the presence of CF3COOH or BF3,
only the hydrolysed product αꢀaminoketone 5 was isolated in 53% yield.
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Scheme 2. Control experiments.
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Figure 2. A possible reaction pathway
To explore the possible mechanism, a few control experiments were performed
under the standard conditions (Scheme 2). In the presence of a radical scavenger
2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO), the reaction of 1a and 2a afforded 3a
in 82% yield, indicating that the radical pathway could be excluded. When 2 equiv. of
tꢀBuONa was added, the reaction of 1a and 2a gave 3a in 94% yield. The reaction of
1a and 2a in the presence of 2 equiv. of 4ꢀ(tertꢀbutyl)benzamide did not give the
mixtures of 3a and 3c. In addition, the reaction of benzamide and 2a in the presence
of 2 equiv. of CH3ONa did not result in the formation of 3a. These results illustrate
that the reaction is not proceeded via substitution reaction. It was also found that
when NꢀmethoxyꢀNꢀmethylbenzamide was used in the reaction, no product was
generated. The reaction of Nꢀphenylacetamide and phthalimide with azirine did not
occur under the same reaction conditions, and the starting materials could be
recovered, indicating that the reaction was not initiated by nucleophilic addition of
amidate to C=N bond and subsequent ringꢀopening. Based on these observations, a
possible reaction pathway was proposed and depicted in Figure 2. In the presence of a
base, Cu(I) Nꢀalkoxylamidate complex I would be expected upon deprotonation of
Nꢀalkoxylamide. Intramolecular oxidative addition of NꢀO bond toward Cu(I) would
occur to give Cu(III) intermediate II.18 The Cu(III) species was captured by
2Hꢀazirine 2, and subsequent rearrangement would result in the formation of
Cu(nitrene) amidate intermediate III. Insertion of nitrene into the CuꢀO bond gave
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species IV. Intermediate V was afforded through 1,3ꢀmigration.19,20 Reductive
elimination would finally generate product 3.
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In conclusion, the reaction of Nꢀmethoxylbenzamides and 2Hꢀazirines was
developed leading to αꢀamino oxime ethers in good to excellent yields under mild
conditions. It involved copper(I)ꢀcatalyzed NꢀO bond formation through vinyl
nitreneꢀmediated pathway. The αꢀamino oxime ethers could be afforded at 100%
atom economy with excellent regioselectivity and stereoselectivity. Further
exploration of a detailed mechanism and relevant reactions involving 2Hꢀazirines is
currently underway.
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EXPERIMENTAL SECTION
General remarks
Reagents were obtained from commercial sources and used without further
purification. Solvents were dried and stored over 4 Ǻ molecular sieves under nitrogen.
Reactions were carried out under nitrogen using standard Schlenk technique unless
otherwise noted. Flash column chromatography was performed on silca gel 300 and
thinꢀlayer chromatography on GF 254 plates. Melting points were determined with an
1
13
Electrothermal apparatus and are uncorrected. H NMR and C NMR spectra were
recorded in CDCl3 at 400 and 100 MHz, respectively, using the solvents as internal
standard. Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, dd = doublet of doublet, dt = doublet of triplet, br = broad.
Jꢀvalues are in Hz. Commercially obtained reagents were used without further
purification. NꢀMethoxybenzamides 1 and 2Hꢀazirines 2 were prepared according to
literatures.21, 22
General procedure for synthesis of 3. To a flameꢀdried flask were added
Nꢀalkoxylamide 1 (0.2 mmol, 1.0 equiv), CuI (0.02 mmol, 0.1 equiv) and K2CO3 (0.2
mmol 1.0 equiv). Then, DCE (2.0 mL) and 2 (0.4 mmol, 2.0 equiv) were added
subsequently. The reaction mixture was stirred for 12 hours at room temperature. The
crude product was purified by silica gel chromatography (petroleum ether:ethyl
acetate = 3:1) to afford the desired product 3.
(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)benzamide (3a): White solid; mp: 129ꢀ130
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ºC; yield: 52 mg, 97%; 1H NMR (400 MHz, CDCl3): δ = 7.80ꢀ7.78 (m, 2H), 7.55ꢀ7.37
13
(m, 8H), 7.07 (br, 1H), 4.51 (d, J = 4.8 Hz, 2H), 3.92 (s, 1H); C NMR (100 MHz,
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CDCl3): δ = 167.2, 151.7, 134.3, 131.6, 131.5, 129.7, 128.6, 128.4, 128.0, 127.0, 62.5,
43.4; HRMS (EIꢀTOF) m/z: [M]+ calcd for C16H16N2O2 268.1212; Found 268.1215.
(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)ꢀ4ꢀmethylbenzamide (3b): White solid; mp:
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1
95ꢀ97 ºC; yield: 53 mg, 94%; H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 7.6 Hz,
2H), 7.54ꢀ7.52 (m, 2H), 7.43ꢀ7.38 (m, 3H), 7.24 (d, J = 7.6 Hz, 2H), 7.00 (br, 1H),
4.51 (d, J = 4.8 Hz, 2H), 3.92 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
167.1, 151.8, 142.0, 131.6, 131.5, 129.7, 129.3, 128.4, 128.0, 127.0, 62.4, 43.3, 21.5;
HRMS (EIꢀTOF) m/z: [M]+ calcd for C17H18N2O2 282.1368; Found 282.1371.
(E)ꢀ4ꢀ(tertꢀbutyl)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)benzamide (3c): White solid;
mp: 108ꢀ110 ºC; yield: 39 mg, 60%; 1H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 8.4
Hz, 2H), 7.55ꢀ7.52 (m, 2H), 7.47ꢀ7.38 (m, 2H), 7.03 (br, 1H), 4.51 (d, 4.8 Hz, 2H),
3.91 (s, 3H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3): δ = 167.1, 155.0, 151.8,
131.6, 131.5, 129.7, 128.4, 128.0, 126.9, 125.6, 62.4, 43.3, 34.9, 31.2; HRMS
(EIꢀTOF) m/z: [M]+ calcd for C20H24N2O2 324.1838; Found 324.1834.
(E)ꢀ4ꢀmethoxyꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)benzamide (3d): White solid; mp:
1
106ꢀ108 ºC; yield: 31 mg, 52%; H NMR (400 MHz, CDCl3): δ = 7.76 (m, 2H),
7.55ꢀ7.52 (m, 2H), 7.44ꢀ7.36 (m, 3H), 6.95ꢀ6.92 (m, 3H), 4.50 (d, J = 4.8 Hz, 2H),
3.92 (s, 3H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 166.7, 162.3, 151.9,
131.6, 129.7, 128.8, 128.4, 128.0, 126.6, 113.8, 62.4, 55.4, 43.3; HRMS (EIꢀTOF)
m/z: [M]+ calcd for C17H18N2O3 298.1317; Found 298.1313.
(E)ꢀ4ꢀfluoroꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)benzamide (3e): White solid; mp:
1
111ꢀ113 ºC; yield: 50 mg, 87%; H NMR (400 MHz, CDCl3): δ = 7.82ꢀ7.78 (m, 2H),
7.54ꢀ7.52 (m, 2H), 7.44ꢀ 7.32 (m, 3H), 7.11 (t, J = 8.4 Hz), 7.03 (b, 1H), 4.5 (d, J =
13
4.8 Hz, 2H), 3.92 (s, 1H); C NMR (100 MHz, CDCl3): δ = 166.1, 164.8 (d, JCF
=
250.4 Hz), 151.6, 131.5, 130.5 (d, JCF = 2.9 Hz), 129.7, 129.4 (d, JCF = 9.0 Hz), 128.4,
128.0, 115.7 (d, JCF = 21.9 Hz), 62.5, 43.4; 19F NMR (376 MHz，CDCl3): δ = ꢀ108.1;
HRMS (EIꢀTOF) m/z: [M]+ calcd for C16H15FN2O2 286.1118; Found 286.1118.
(E)ꢀ4ꢀchloroꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)benzamide (3f): White solid; mp:
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114ꢀ115 ºC; yield: 38 mg, 63 %; 1H NMR (400 MHz, CDCl3): δ = 7.74ꢀ7.72 (m, 2H),
7.54ꢀ7.52 (m, 2H), 7.44ꢀ7.39 (m, 5H), 7.04 (br, 1H), 4.50 (d, J = 4.4 Hz, 2H), 3.92 (s,
3H); 13C NMR (100 MHz, CDCl3): δ = 166.1, 151.5, 137.8, 132.7, 131.4, 129.8,
128.9, 128.4, 128.0, 62.5, 43.4; HRMS (EIꢀTOF) m/z: [M]+ calcd for C16H15ClN2O2
302.0822; Found 302.0818.
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(E)ꢀ4ꢀbromoꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)benzamide (3g): White solid; mp:
138ꢀ140 ºC; yield: 65 mg, 94 %; 1H NMR (400 MHz, CDCl3): δ = 7.67ꢀ7.64 (m, 2H),
7.59ꢀ7.51 (m, 4H), 7.45ꢀ7.37 (m, 3H), 7.05 (s, 1H), 4.49 (d, J = 4.8 Hz, 2H), 3.92 (s,
3H); 13C NMR (100 MHz, CDCl3): δ = 166.2, 151.5, 133.1, 131.8, 131.4, 129.8,
128.6, 128.4, 128.0, 126.3, 62.5, 43.4; HRMS (EIꢀTOF) m/z: [M]+ calcd for
C16H15BrN2O2 346.0317; Found 346.0316.
methyl (E)ꢀ4ꢀ((2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)carbamoyl)benzoate (3h): White
solid; mp: 159ꢀ161 ºC; yield: 56 mg, 86 %; 1H NMR (400 MHz, CDCl3): δ = 8.11 (d,
J = 8.0 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.55ꢀ7.53 (m, 2H), 7.44ꢀ7.38 (m, 3H), 7.14
(br, 1H), 4.52 (d, J = 4.2 Hz, 2H), 3.94 (s, 3H), 3.93 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 166.3, 166.2, 151.4, 138.2, 132.8, 131.4, 129.9, 129.8, 128.4, 128.0,
127.1, 62.5, 52.4, 43.4; HRMS (EIꢀTOF) m/z: [M]+ calcd for C18H18N2O4 326.1267;
Found 326.1274.
(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)ꢀ2ꢀmethylbenzamide (3i): White solid; mp:
109ꢀ110 ºC; yield: 47 mg, 83 %; 1H NMR (400 MHz, CDCl3): δ = 7.56ꢀ7.54 (m, 2H),
7.45ꢀ7.39 (m, 3H), 7.35ꢀ7.29 (m, 2H), 7.21ꢀ7.18 (m, 2H), 6.51 (br, 1H), 4.51 (d, J =
5.2 Hz, 2H) 3.88 (s, 3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 169.7, 151.9,
136.2, 136.1, 131.4, 131.0, 130.0, 129.7, 128.4, 128.1, 126.9, 125.8, 62.4, 43.1, 19.8;
HRMS (EIꢀTOF) m/z: [M]+ calcd for C17H18N2O2 282.1368; Found 282.1364.
(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)ꢀ3ꢀmethylbenzamide (3j): White solid; mp:
1
105ꢀ107 ºC; yield: 53 mg, 94 %; H NMR (400 MHz, CDCl3): δ = 7.62 (s, 1H),
7.55ꢀ7.52 (m, 3H), 7.42ꢀ7.30 (m, 5H), 7.03 (br, 1H), 4.50 (d, J = 4.4 Hz, 2H), 3.92 (s,
3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 167.4, 151.8, 138.5, 134.3, 132.3,
131.5, 129.7, 128.5, 128.4, 128.0, 127.9, 123.9, 62.4, 43.3, 21.4; HRMS (EIꢀTOF)
m/z: [M]+ calcd for C17H18N2O2 282.1368; Found 282.1364.
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(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)ꢀ2,4ꢀdimethylbenzamide (3k): White solid;
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mp: 94ꢀ96 ºC; yield: 31 mg, 52 %; H NMR (400 MHz, CDCl3): δ = 7.55ꢀ7.53 (m,
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2H), 7.44ꢀ7.36 (m, 3H), 7.25 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 7.00 (d, J = 8.4 Hz,
1H), 6.49 (br, 1H), 4.50 (d, J = 4.8 Hz, 2H), 3.88 (s, 3H), 2.37 (s, 3H), 2.32 (3H); 13C
NMR (100 MHz, CDCl3): δ = 169.7, 152.0, 140.1, 136.3, 133.2, 131.9, 131.4, 129.7,
128.4, 128.1, 127.1, 126.4, 62.4, 43.1, 21.3, 19.8; HRMS (EIꢀTOF) m/z: [M]+ calcd
for C18H20N2O2 296.1525; Found 296.1521.
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(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)benzo[d][1,3]dioxoleꢀ5ꢀcarboxamide
(3l):
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White solid; mp: 116ꢀ118 ºC; yield: 49 mg, 79 %; H NMR (400 MHz, CDCl3): δ =
7.54ꢀ7.51 (m, 2H), 7.44ꢀ7.38 (m, 3H), 7.33ꢀ7.26 (m, 2H), 6.94 (br, 1H), 6.82 (d, J =
8.0 Hz, 1H), 6.01 (s, 2H), 4.48 (d, J = 4.8 Hz, 2H) 3.92 (s, 1H); 13C NMR (100 MHz,
CDCl3): δ = 166.4, 151.8, 150.4, 148.0, 131.5, 129.7, 128.5, 128.4, 128.0, 121.7,
108.1, 107.6, 101.7, 62.4, 43.4; HRMS (EIꢀTOF) m/z: [M]+ calcd for C17H16N2O4
312.1110; Found 312.1114.
(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)ꢀ1ꢀnaphthamide (3m): White solid; mp:
1
94ꢀ96 ºC; yield: 39 mg, 61%; H NMR (400 MHz, CDCl3): δ = 8.20ꢀ8.18 (m, 1H),
7.91ꢀ 7.84 (m, 2H), 7.59ꢀ7.57 (m, 3H), 7.51ꢀ7.48 (m, 2H), 7.46ꢀ7.41 (m, 4H), 6.72 (b,
13
1H), 4.62 (d, J = 5.2 Hz, 2H), 3.88 (s, 3H); C NMR (100 MHz, CDCl3): δ = 169.3,
152.0, 134.2, 133.7, 131.5, 130.7, 130.1, 129.7, 128.5, 128.3, 128.2, 127.1, 126.4,
125.4, 125.2, 124.8, 62.4, 43.3; HRMS (EIꢀTOF) m/z: [M]+ calcd for C20H18N2O2
318.1368; Found 318.1365.
(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)ꢀ2ꢀnaphthamide (3n): White solid; mp:
1
133ꢀ135 ºC; yield: 56 mg, 88%; H NMR (400 MHz, CDCl3): δ = 8.31 (s, 1H),
7.93ꢀ7.83 (m, 4H), 7.58ꢀ7.51 (m, 4H), 7.45ꢀ7.37 (3H), 7.19 (br, 1H), 4.58 (d, J = 4.8
13
Hz, 2H), 3.94 (s, 3H); C NMR (100 MHz, CDCl3): δ = 167.3, 151.8, 134.8, 132.7,
131.6, 129.7, 129.0, 128.5, 128.4, 128.0, 127.8, 127.7, 127.6, 126.8, 123.6, 62.5, 43.5;
HRMS (EIꢀTOF) m/z: [M]+ calcd for C20H18N2O2 318.1368; Found 318.1370.
(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)ꢀ1ꢀmethylꢀ1Hꢀindoleꢀ3ꢀcarboxamide
(3o):
1
Yellow solid; mp: 144ꢀ146 ºC; yield: 40 mg, 62%; H NMR (400 MHz, CDCl3): δ =
8.00ꢀ7.98 (m, 1H), 7.69 (s, 1H), 7.58ꢀ7.56 (m, 2H), 7.45ꢀ7.35 (m, 4H), 7.32ꢀ7.24 (m,
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2H), 6.94 (b, 1H), 4.58 (d, J = 4.8 Hz, 2H), 3.97 (s, 3H), 3.80 (s, 3H); 13C NMR (100
MHz, CDCl3): δ = 164.7, 152.1, 137.3, 132.9, 131.7, 129.6, 128.4, 128.1, 125.2,
122.5, 121.4, 119.9, 110.7, 110.2, 62.5, 43.1, 33.3; HRMS (EIꢀTOF) m/z: [M]+ calcd
for C19H19N3O2 321.1477; Found 321.1480.
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(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)furanꢀ3ꢀcarboxamide (3p): White solid; mp:
1
102ꢀ103 ºC; yield: 48 mg, 93%; H NMR (400 MHz, CDCl3): δ = 7.95 (s, 1H),
7.53ꢀ7.51 (m, 2H), 7.43ꢀ7.36 (m, 4H), 6.73 (b, 1H), 6.64 (d, J = 0.8 Hz, 1H), 4.56 (d,
J = 4.8 Hz), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 162.3, 151.6, 144.8,
143.8, 131.5, 129.7, 128.4, 128.0, 122.4, 108.3, 62.4, 42.8; HRMS (EIꢀTOF) m/z:
[M]+ calcd for C14H14N2O3 258.1004; Found 258.1003.
(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)benzo[b]thiopheneꢀ3ꢀcarboxamide
(3q):
1
White solid; mp: 111ꢀ112 ºC; yield: 52 mg, 80%; H NMR (400 MHz, CDCl3): δ =
8.34 (d, J = 7.6 Hz, 1H), 7.90 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.57ꢀ7.54 (m, 2H),
7.46ꢀ7.37 (m, 5H), 6.95 (br, 1H), 4.56 (d, J = 4.8 Hz, 2H), 3.92 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ = 163.6, 151.7, 140.3, 136.6, 131.9, 131.5, 129.9, 129.8, 128.5,
128.1, 125.2, 125.1, 124.1, 122.7, 62.5, 43.1; HRMS (EIꢀTOF) m/z: [M]+ calcd for
C18H16N2O2S 324.0932; Found 324.0933.
(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)ꢀ2ꢀmethylꢀ2ꢀphenylpropanamide
(3r):
1
Yellow liquid; yield: 28 mg, 45 %; H NMR (400 MHz, CDCl3): δ = 7.41ꢀ7.36 (m,
5H), 7.33ꢀ7.23 (m, 5H), 5.83 (br, 1H), 4.24 (d, J = 5.2 Hz, 2H), 3.75 (s, 3H), 1.53 (s,
6H); 13C NMR (100 MHz, CDCl3): δ = 177.1, 152.2, 144.7, 131.3, 129.5, 128.6,
128.3, 128.1, 126.9, 126.6, 62.2, 47.0, 42.8, 26.9; HRMS (EIꢀTOF) m/z: [M]+ calcd
for C19H22N2O2 310.1681; Found 310.1682.
(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)cyclopropanecarboxamide (3s): Yellow solid;
mp: 116ꢀ118 ºC; yield: 36 mg, 78 %; 1H NMR (400 MHz, CDCl3): δ = 7.50ꢀ7.48 (m,
2H), 7.42ꢀ7.39 (m, 3H), 6.45 (b, 1H), 4.34 (d, J = 4.8 Hz, 2H), 3.90 (s, 3H), 1.46ꢀ1.40
(m, 1H), 0.99ꢀ0.95 (m, 2H), 0.77ꢀ0.72 (m, 2H); 13C NMR (100 MHz, CDCl3): δ =
173.4, 152.0, 131.6, 129.6, 128.3, 128.0, 62.3, 43.2, 14.7, 7.3; HRMS (EIꢀTOF) m/z:
[M]+ calcd for C13H16N2O2 232.1212; Found 232.1210.
(E)ꢀNꢀ(2ꢀ(tertꢀbutoxyimino)ꢀ2ꢀphenylethyl)benzamide (3t): Yellow solid; mp: 93ꢀ95
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ºC; yield: 50 mg, 81%; 1H NMR (400 MHz, CDCl3): δ = 7.81ꢀ7.79 (m, 2H), 7.66ꢀ7.64
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(m, 2H), 7.54ꢀ7.35 (m, 6H), 7.21 (br, 1H), 4.54 (d, J = 4.4 Hz, 2H), 1.35 (s, 9H); C
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NMR (100 MHz, CDCl3): δ = 167.0, 148.8, 134.5, 131.8, 131.5, 129.4, 128.7, 128.3,
128.2, 126.9, 79.4, 43.6, 27.5; HRMS (EIꢀTOF) m/z: [M]+ calcd for C19H22N2O2
310.1681; Found 310.1681.
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(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀ(pꢀtolyl)ethyl)benzamide (3u): White solid; mp: 92ꢀ94 ºC;
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yield: 56 mg, 99 %; H NMR (400 MHz, CDCl3): δ = 7.72ꢀ7.70 (m, 2H), 7.44ꢀ7.34
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(m, 5H), 7.01 (br, 1H), 4.42 (d, J = 4.8 Hz, 2H), 3.84 (s, 1H), 2.28 (s, 1H); C NMR
(100 MHz, CDCl3): δ = 167.1, 151.5, 139.9, 131.6, 129.1, 128.6, 128.5, 128.0, 127.0,
62.4, 43.3, 21.5; HRMS (EIꢀTOF) m/z: [M]+ calcd for C17H18N2O2 282.1368; Found
282.1369.
(E)ꢀNꢀ(2ꢀ(4ꢀfluorophenyl)ꢀ2ꢀ(methoxyimino)ethyl)benzamide (3v): White solid; mp:
128ꢀ130 ºC; yield: 42 mg, 73 %; 1H NMR (400 MHz, CDCl3): δ = 7.80ꢀ7.77 (m, 2H),
7.62ꢀ7.57 (m, 2H), 7.54ꢀ7.50 (m, 1H), 7.47ꢀ7.43 (m, 2H), 7.14ꢀ7.08 (m, 2H), 6.98 (br,
13
1H), 4.52 (d, J = 4.8 Hz, 2H), 3.93 (s, 3H); C NMR (100 MHz, CDCl3): δ = 167.2,
163.1 (d, JCF = 249.2 Hz), 150.6, 134.2, 131.7, 130.4 (d, JCF = 8.3 Hz), 128.7, 127.3
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(d, JCF = 3.3 Hz), 127.0, 115.5 (d, JCF = 21.5 Hz), 62.5, 43.2.; F NMR (376 MHz，
CDCl3): δ = ꢀ110.0; HRMS (EIꢀTOF) m/z: [M]+ calcd for C16H15FN2O2 286.1118;
Found 286.1115.
(E)ꢀNꢀ(2ꢀ(4ꢀchlorophenyl)ꢀ2ꢀ(methoxyimino)ethyl)benzamide (3w): White solid; mp:
1
95ꢀ97 ºC; yield: 28 mg, 46 %; H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 7.6 Hz,
2H), 7.55ꢀ7.52 (m, 3H), 7.46 (t, J = 7.2 Hz, 2H), 7.41 (d, J = 8.8 Hz), 7.03 (br, 1H),
4.52 (d, J = 4.8 Hz, 2H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 167.2, 150.7,
135.7, 134.2, 131.7, 129.7, 129.6, 128.7, 128.6, 127.0, 62.5, 43.1; HRMS (EIꢀTOF)
m/z: [M]+ calcd for C16H15ClN2O2 302.0822; Found 302.0820.
(E)ꢀNꢀ(2ꢀ(4ꢀbromophenyl)ꢀ2ꢀ(methoxyimino)ethyl)benzamide (3x): White solid; mp:
136ꢀ138 ºC; yield: 66 mg, 95 %; 1H NMR (400 MHz, CDCl3): δ = 7.79ꢀ7.77 (m, 2H),
7.55ꢀ7.49 (m, 3H), 7.46ꢀ7.42 (m, 4H), 4.50 (d, J = 4.8 Hz, 1H), 3.92 (s, 1H); 13C
NMR (100 MHz, CDCl3): δ = 167.2, 150.8, 134.2, 131.7, 131.6, 130.1, 129.8, 128.6,
127.0, 124.0, 62.5, 43.1; HRMS (EIꢀTOF) m/z: [M]+ calcd for C16H15BrN2O2
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346.0317; Found 346.0320.
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(E)ꢀNꢀ(2ꢀ(4ꢀ(tertꢀbutyl)phenyl)ꢀ2ꢀ(methoxyimino)ethyl)benzamide (3y): Yellow oil;
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yield: 58 mg, 90 %; H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.4 Hz, 2H),
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7.54ꢀ7.43 (m, 7H), 7.08 (br, 1H), 4.52 (d, J = 4.4 Hz, 2H), 3.93 (s, 3H), 1.32 (s, 9H);
13C NMR (100 MHz, CDCl3): δ = 167.1, 152.9, 151.2, 134.4, 131.5, 128.6, 128.4,
127.9, 127.0, 125.4, 62.5, 43.3, 34.8, 31.2; HRMS (EIꢀTOF) m/z: [M]+ calcd for
C20H24N2O2 324.1838; Found 324.1840.
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(E)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ1,2ꢀdiphenylethyl)benzamide (3z): White solid; mp:
150ꢀ152 ºC; yield: 48 mg, 70 %; 1H NMR (400 MHz, CDCl3): δ = 7.84ꢀ7.82 (m, 2H),
7.75 (br and d, J = 6.8 Hz, 1H), 7.53ꢀ7.37 (m, 5H), 7.32ꢀ7.19 (m, 8H), 6.12 (d, J = 7.6
13
Hz, 1H), 3.96 (s, 3H); C NMR (100 MHz, CDCl3): δ = 166.0, 155.1, 138.6, 134.4,
132.0, 131.6, 129.2, 128.7, 128.6, 128.2, 128.1, 128.0, 127.9, 127.1, 62.6, 57.1;
HRMS (EIꢀTOF) m/z: [M]+ calcd for C22H20N2O2 344.1525; Found 344.1524.
(E)ꢀNꢀ(3ꢀ(methoxyimino)ꢀ1ꢀoxoꢀ1ꢀphenylbutanꢀ2ꢀyl)benzamide (3aa): Yellow oil;
yield: 33 mg, 53 %; 1H NMR (400 MHz, CDCl3): δ = 8.13ꢀ8.11 (m, 2H), 7.89ꢀ7.87 (m,
2H), 7.64ꢀ7.60 (m,1H), 7.56ꢀ7.45 (m, 6H), 6.36 (d, J = 7.2 Hz, 1H), 3.83 (s, 3H), 1.87
13
(s, 3H); C NMR (100 MHz, CDCl3): δ = 194.5, 153.0, 134.5, 134.1, 133.7, 132.0,
129.2, 128.7, 128.6, 127.2, 122.3, 62.0, 58.7, 11.9; HRMS (EIꢀTOF) m/z: [M]+ calcd
for C18H18N2O3 310.1317; Found 310.1316.
General procedure for the synthesis of 4. To a seal tube were added 3b (0.2 mmol,
.
1.0 equiv), Cu(OAc)2 H2O (0.4 mmol, 2 equiv), and DCE (2.0 mL). The reaction
o
mixture was stirred for 12 hours at 100 C. The crude product was purified by silica
gel chromatography (petroleum ether: ethyl acetate = 3:1) to afford the desired
product 4.
(Z)ꢀNꢀ(2ꢀ(methoxyimino)ꢀ2ꢀphenylethyl)ꢀ4ꢀmethylbenzamide (4): White solid; mp:
1
135ꢀ137 ºC; yield: 16 mg, 28%; H NMR (400 MHz, CDCl3): δ = 7.85ꢀ7.82 (m, 2H),
7.62 (d, J = 8.0 Hz, 2H), 7.40ꢀ7.38 (m, 3H), 7.22 (d, J = 8.0 Hz, 2H), 6.75 (br, 1H),
4.69 (d, J = 6.0 Hz, 2H), 4.08 (s, 3H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
166.9, 155.8, 142.0, 133.9, 131.4, 129.7, 129.3, 128.7, 127.0, 126.9, 62.6, 36.0, 21.5;
HRMS (EIꢀTOF) m/z: [M]+ calcd for C17H18N2O2 282.1368; Found 282.1367.
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General procedure for the synthesis of 5. Method 1: To a seal tube were added 3b
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(0.2 mmol, 1.0 equiv), CF3COOH (0.4 mmol, 2 equiv), and H2O (20 equiv), and DCE
o
(2.0 mL). The reaction mixture was stirred for 12 hours at 50 C. The crude product
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was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1) to
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afford the desired product 5 (24 mg, 47% yield). Method 2: To a seal tube were added
.
3b (0.2 mmol, 1.0 equiv) and BF3 Et2O (0.4 mmol, 2 equiv). Subsequently, DCE (2.0
o
mL) was added to this tube. The reaction mixture was stirred for 12 hours at 50 C.
The crude product was purified by silica gel chromatography (petroleum ether: ethyl
acetate = 3:1) to afford the desired product 5 (27 mg, 53% yield).
1
4ꢀmethylꢀNꢀ(2ꢀoxoꢀ2ꢀphenylethyl)benzamide (5): White solid; mp: 115ꢀ117 ºC ; H
NMR (400 MHz, CDCl3): δ = 8.05ꢀ8.03 (m, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.65 (t, J =
7.6 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.28ꢀ7.26 (m, 3H), 4.96 (d, J = 4.0 Hz, 2H),
13
2.42 (s, 3H); C NMR (100 MHz, CDCl3): δ = 194.4, 167.4, 142.3, 134.4, 134.3,
131.0, 129.3, 129.0, 128.0, 127.2, 46.9, 21.5; HRMS (EIꢀTOF) m/z: [M]+ calcd for
C16H15NO2 253.1103; Found 253.1099.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: chenwzz@zju.edu.cn
*Eꢀmail: mcl@zju.edu.cn
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information. Spectra of 1H and 13C NMR for new products and crystallographic data
for 3a and 3b. This material is available free of charge via the Internet at http://pubs.acs.org.
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ACKNOWLEDGMENT
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Financial supports from National Natural Science Foundation of China (Nos. 21572203 and
21472140) and Zhejiang Provincial Natural Science Foundation of China (No. LZ16B020001) are
gratefully acknowledged.
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