Synthesis of α-aminooxy amides through [3 + 3] cycloaddition and Sc(OTf)3-catalyzed double C-N bond cleavage in a one-pot reaction

Article abstract of DOI:10.1039/d0ob01788d

Various α-aminooxy amides bearing a quaternary carbon at the α-position were prepared in good to excellent yields under mild reaction conditions from N-vinyl nitrones and α-bromohydroxamates. The N-vinyl nitrones tolerate a wide range of N-vinyl fluorenone nitrones and N-vinyl isatin nitrones. Mechanistic studies show that the reaction initially proceeds through [3 + 3] cycloaddition between N-vinyl nitrones and aza-oxyallyl cations generated from α-bromohydroxamates to afford six-membered N,O-heterocycles, followed by double C-N bond cleavage in the presence of the Sc(OTf)3 catalyst. A selective N-O bond cleavage of the obtained α-aminooxy amides is also realized under Fe/NH4Cl conditions. Furthermore, gram-scalable preparations of α-aminooxy amides are easily achieved. This journal is

Full text of DOI:10.1039/d0ob01788d

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DOI: 10.1039/D0OB01788D
ARTICLE
Synthesis of α-Aminooxy Amides through [3+3] Cycloaddition and
Sc(OTf)3-Catalyzed Double C-N Bond Cleavage in One-Pot Reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Yan Luo, Chun-Hua Chen, Fan Zhu, and Dong-Liang Mo*
DOI: 10.1039/x0xx00000x
Various α-aminooxy amides bearing a quaternary carbon at the α-position were prepared in good to excellent yields under
mild reaction conditions from N-vinyl nitrones and α-bromohydroxamates. The N-vinyl nitrones tolerate a wide range of N-
vinyl fluorenone nitrones and N-vinyl isatin nitrones. Mechanistic studies show that the reaction initially undergoes [3+3]
cycloaddition between N-vinyl nitrones and aza-oxyallyl cations generated from α-bromohydroxamates to afford six-
membered N,O-heterocycles, and then take place double C-N bond cleavage in the presence of Sc(OTf)3 catalyst. A
selective N-O bond cleavage of the obtained α-aminooxy amides is also realized by Fe/NH4Cl conditions. Furthermore,
gram
scalable
preparations
of
α-aminooxy
amides
are
easily
achieved.
NHFmoc
Introduction
O
O
HN
O
R3
OAc
O
R1
The introduction of an aminooxy functional group to the -
position of a carbonyl compound has attracted great attention
in synthetic chemistry and medicine because the formation of
C-O-NR2 linkage is an important and useful building block in
various natural products and pharmaceuticals.1 The α-
aminooxy carbonyl compounds can be not only converted to
α-hydroxy ketones and 1,2-diols by reduction, but also
extensively served as an efficient tool for various applications
in carbohydrates and glycoconjugates due to their unusual
conformational properties of N-O bonds.2 Peptides containing
an aminooxy group, namely α-aminooxy peptides, usually
show a great biological activities due to their novel secondary
structure including hydrogen-bonded turns or N-O turns.3 In
particular, the oxime ether group offers very attractive
approaches for drug design in a variety of pharmaceutical
preparation and pesticides, which exhibit excellent anticancer
and anti-inflammatory activities, and larvicidal activities
against pest (Figure 1).4 Therefore, development of new
methods toward the introduction of an aminooxy group to the
-position of a carbonyl compound will be desirable.
O
O
H
N
H
N
H
O
AcO
AcO
R2
N
N
OAc
CO2t-Bu
Me
O
HNO donors
MeS
Glycopeptide
R
R
O
O
N
R1
R3
R2
N
H
H
H
O
Me
N
H
N
N
H
H
O
Me
O
O
N
O
CO2Et
Glycine receptor antagonist
antiproliferative activity
Figure 1. Selected examples containing α-aminooxy carbonyl groups
Methods for the preparation of α-aminooxy carbonyl
compounds have been extensively developed in the last
decades.5 For examples, nucleophilic substitution of α-
halocarbonyl compounds with N-hydroxyphthalimides or
oximes was the one of the most used strategies to prepare α-
aminooxy carbonyl compounds (Scheme 1-A).6 However, This
conventional method was always favorable to no substituent
or one subsituent at the α-position of the α-halocarbonyl
compounds. The α-halocarbonyl compounds bearing
a
quaternary carbon at the α-position usually failed and occured
elimination reaction of halides in some cases. Recently,
Yamamoto and coworkers found that a Lewis acid-catalyzed
regioselective synthesis of α-aminooxy ketones by N-nitroso
aldo reaction of enolate compounds while α-hydroxyamino
ketones were obtained without adding catalyst (Scheme 1-B).7
Although it figured out the preparation of α-aminooxy
carbonyl compounds containing α-quaternary carbons at the
a. State Key Laboratory for Chemistry and Molecular Engineering of Medicinal
Resources, Ministry of Science and Technology of China; School of Chemistry and
Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin
541004, China. E-mail: moeastlight@mailbox.gxnu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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ARTICLE
Journal Name
α-position, it still suffered from the addition regioselectivity of Results and discussion
View Article Online
N-nitrosobenzene in some enantioselective catalytic systems.8
From the above examples we can see, some elegant methods
toward the preparation of α-aminooxy carbonyl compounds
have been developed, but the development of novel and mild
methods is still required, especially for the preparation of α-
Initially, N-vinyl fluorenone nitDroOnI:e10.1013a9/D0aOnBd01788αD-
bromohydroxamate 2a were chosen as model substrates. As
shown in Table 1, nitrone 1a reacting with 2a under K2CO3 as
base in MeCN at room temperature did not afford α-(9-
fluorenylideneaminooxy)amide 3aa in the absence of catalyst
and only the [3+3] cycloadduct was obtained (Table 1, entry 1).
Adding PdCl2 and RhCl3 delivered 3aa in 59% and 65% yields,
respectively (Table 1, entries 2-3). But product 3aa was not
observed when CuI, AgOTf, and Mn(OAc)2 were used as
catalysts (Table 1, entries 4-6). Pleasingly, Adding 10 mol% of
Sc(OTf)3 as the catalyst afforded 3aa in 93% yield (Table 1,
entry 7). Solvent screening showed that DCE gave 3aa in 64%
yield while lower yields were obtained in toluene, THF, and
DMF (Table 1, entries 8-11). To our surprise, the most used
hexafluoroisopropanol (HFIP) solvent in aza-oxyallyl cation
chemistry only delivered 3aa in 10% yield owing to the easy
decomposition of N-vinyl fluorenone nitrone to 9-fluorenone
in HFIP (Table 1, entry 12). The effect of base was also tested.
Good yields of 3aa were obtained with inorganic bases, such as
Na2CO3, Cs2CO3, and KOH, while organic base such as NEt3
gave 3aa only in 14% yield (Table 1, entries 13-16). The
reaction temperature was also evaluated. Increasing the
temperature to 60 °C and 80 °C decreased the yield of 3aa to
83% and 81%, respectively, and further decreased to 58% at
100 °C (Table 1, entries 17-19). When 2a was decreased to 1.0
equiv., product 3aa was only obtained in 80% yield and nitrone
1a was recovered perhaps owing to the -elimination of 2a to
form ,-unsaturated amide in the presence of base (Table 1,
entry 20). Therefore, the optimal conditions for preparing 3aa
was Sc(OTf)3 (10 mol%) as catalyst and K2CO3 as base in MeCN
at room temperature.
aminooxy carbonyl compounds containing
a quaternary
carbon at the α-position because the 3D structure of the
quaternary carbon sometimes improves the biological activies.
Recently, nitrone served as 1,3-dipole, has attracted great
interest due to its efficient transformations in the
cycloaddition reaction in organic synthesis.9 The [3+3]
cycloaddition of nitrones with aza-oxyallyl cations has been
successfully developed to prepare 1,2,4-oxadiazinan-5-ones
before.10,11 During the studies of cycloaddition of N-vinyl
fluorenone nitrones in our group,12 we found that N-vinyl
nitrones and aza-oxyallyl cations underwent [3+3]
cycloaddition to afford various spirofluorenyl-1,2,4-
oxadiazinan-5-ones under the metal-free conditions in good
yields.12b Further studies showed that the [3+3] cycloaddition
and sequential Sc(OTf)3 catalyzed double C-N bond cleavage of
six-membered heterocyclic adducts could afford α-aminooxy
carbonyl compounds bearing a quaternary carbon at the α-
position in a one-pot reaction (Scheme 1-C). The N-vinyl
nitrones were easily prepared by the copper-mediated cross-
coupling reaction of oximes with vinylboronic acids under mild
reaction conditions.13 Herein, we report a novel method
toward the synthesis of α-aminooxy amides through [3+3]
cycloaddition and Sc(OTf)3-catalyzed double C-N bond
cleavage in a one-pot reaction under mild reaction conditions.
A) Nucleophilic substitution of -halocarbonyl compounds
R2
O
O
R3
R2
R1
N
R1
base
Table 1. Optimization of the Reaction Conditions.a
N
OH
+
R3
O
R
R
R4
X
O
Me
O
Me
Me
R4
OBn
Me
N
N
H
X = Cl, Br, I, OH
O
R1 = R2 = H, work well
R1 = H, R2 ¹ H, work well
R1  H, R2  H, failed
O
Me
Me
N
OBn
N
H
cat (10%)
+
Br
base, solvent, rt
B) Lewis acid-catalyzed N-nitroso aldo reaction of enolate compounds
O
2a
Lewis acid
R1
1a
O
Ar
3aa
N
H
OR
O
R2 R3
major
Ar
N
R2
R1
R3
O
OH
N
without catalyst
R1
Ar
R = SiMe3, SnBu3. COCl3
R3
major
R2
C) This work, [3+3] cycloaddition and sequential C-N bond cleavage in one pot
R4
Me
O
R3
O
"one-pot"
R4
O
OR5
HN OR5
R3
base
Me
N
O
+
N
H
N
Br
Sc(OTf)3
R1
R2
R1
R2
R3
R4
Me
O
Sc(OTf)3
[3+3]
base
N
O
C-N cleavage
Me
N
R1
OR5
R2
Scheme 1. Strategies for preparing α-aminooxy carbonyl compounds
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 3 of 11
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
entry
cat
-
PdCl2
RhCl3
CuI
base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
solvent
3aa%b
-
59
65
<5
View Article Online
DOI: 10.1039/D0OB01788D
O
O
Me
1
2
3
4
5
6
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Me
Me
OBn
Me
OBn
R
N
H
O
N
H
2a
N
O
N
Br
Sc(OTf)3 (10 mol%)
K2CO3, MeCN, rt
AgOTf
Mn(OAc)2
<5
<5
1
3aa
7
8
Sc(OTf)3
Sc(OTf)3
K2CO3
K2CO3
MeCN
DCE
93
64
Ph
Et
Et
O
Et
O
O
9
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
toluene
THF
31
21
<5
10
78
N
N
N
10
11
12
13
DMF
HFIP
1c
1b
1d
3aa, 36%
MeCN
3aa, 80%
3aa, 65%
14
15
16
17
18
19
20
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Cs2CO3
KOH
NEt3
K2CO3
K2CO3
K2CO3
K2CO3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
56
64
14
83c
81d
58e
80f
n-Bu
Me
N
O
Ph
O
O
N
N
1e
1f
1g
3aa, 0% (88%)a
3aa, 51%
3aa, 0% (72%)a
Scheme 2. The N-substituent effect of nitrones 1 on the formation of 3aa.
(Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol, 2.0 equiv.), Sc(OTf)3 (10 mol%),
K2CO3 (0.4 mmol, 2.0 equiv.), MeCN (2.0 mL), 12-48 h, isolated yield; a the yield
of its [3+3] cycloadduct.)
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol, 2.0 equiv.), catalyst (10
mol%), base (0.4 mmol, 2.0 equiv.), solvent (2.0 mL), 12−24 h; isolated yield;
ran at 60 °C; d ran at 80 °C; e ran at 100 °C; f 2a (0.2 mmol, 1.0 equiv.).
b
c
Since the N-vinyl group of nitrone 1a was dropped after the
reaction completed, various N-substituted groups of nitrones 1
were explored to study the effect on the yield of 3aa under the
optimal conditions. As shown in Scheme 2, N-vinyl groups of
nitrone, including monosubstituted, linear and cyclic
disubstituted vinyl groups (1b-1e), all these N-vinyl moieties
delivered desired product 3aa in good yields under the
standard conditions. However, nitrones 1f bearing N-methyl
group and 1g bearing N-phenyl group did not afford 3aa even
after 48 h, and only delivered their [3+3] cycloadducts in 72%
and 88% yields in the presence of Sc(OTf)3, respectively. These
results suggested that only the N-vinyl groups of [3+3]
cycloadducts from N-vinyl nitrones smoothly underwent C-N
bond cleavage.
Next, the substrate scope of nitrones
1 and α-
bromohydroxamates was evaluated to prepare α-
2
aminooxyamides 3 (Scheme 3). It was found that a wide range
of α-bromohydroxamates 2 reacting with nitrone 1a were
smoothly converted to α-(9-fluorenylideneaminooxy)amides
3ab-3ao in moderate to excellent yields under the standard
conditions. The structure of compound 3 was confirmed by X-
ray diffraction analysis of compound 3al.14 The R5 group could
be present with different alkyloxy and aryloxy groups.
Pleasingly, the R5 group was compatible with vinyl and alkynyl
groups (3ah-3ak). When the R3 group was methyl or ethyl
substituent and the R4 group was hydrogen, N-benzyloxy -
bromoamides (2m and 2n) produced 3am and 3an in 86% and
89% yields, respectively, while 2o with a phenyl in R3 group
gave 3ao only in 26% yield. The 9-fluorenone nitrones also
tolerated bromo group in the both aryl groups of fluorenone
and afforded 3ha and 3ia in 85% and 95% yields, respectively.
However, a 1:1 E/Z ratio of N-vinyl fluorenone nitrone 1h with
only one bromo group afforded product 3ha with 1:1 E/Z
isomer ratio of the C=N bond, which might be owing to the 1:1
diastereomers of its cycloaddition product suggesting that the
diastereoselectivity of cycloaddition product had a great
impact on the E/Z ratio of α-aminooxy amides. To our surprise,
2p bearing R3 and R4 groups with hydrogen and 2q with a N-
phenyl group did not deliver the desired product 3ap and 3aq
under the standard conditions because these two substrates
did not produce their [3+3] cycloaddition intermediates, which
might be owing to these substituted groups cannot stabilize
the aza-oxyallyl cations. This method provides
a good
approach to access -aminooxy hydroxamates bearing two or
three substituents at the -position of a carbonyl group.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
Journal Name
O
View Article Online
O
Me
R4
Me
DOI: 10.1039/D0OB01788D
R3
N
R5
Me
Me
OBn
N
O
N
H
O
O
Me
O
O
N
Me
Me
H
O
R4
R3
OBn
R5
N
Sc(OTf)3 (10 mol%)
K2CO3, MeCN, rt
N
H
N
+
Me
N
H
R1
R2
2a
Br
Br
R6
O
R6
O
2
N
Sc(OTf)3 (10 mol%)
K2CO3, MeCN, rt
1
N
R7
3
R7
O
O
Me
O
Me
O
4
5 (E/ Z)
Ar = 4-MeOC6H4, 3ab, 74%
Ar = 4-BrC6H4, 3ac, 68%
Ar = 4-FC6H4
Ar = 4-CF3C6H4, 3ae, 60%
Ar = 3-MeC6H4
Ar = 2-MeC6H4
Me
N
O
O
Me
N
Ar
N
H
N
H
O
O
Me
O
Me
,
3ad, 61%
Me
Me
Me
OBn
Me
OBn
,
,
3af, 52%
3ag, 36%
N
H
OBn
N
H
N
O
O
H
O
3ah, 90%
N
N
N
Me
O
MeO
O
Me
O
Me
O
R
O
O
O
Me
N
O
O
Me
N
N
H
N
H
N
H
Ph
N
H
N
H
R = H, 3ai, 71%
R = Me, 3aj, 66%
4a, 1.5:1
4b, 5:1
4c, 10:1
5aa, 92%, 2:1
5ba, 50%, 10:1
5ca, 74%, 10:1
3ak, 56%
O
O
O
Me
Me
Me
O
Me
Me
Me
Me
O
OBn
OBn
OBn
N
H
N
H
H
O
N
Me
OMe
O
N
H
O
H
O
R3
N
OBn
N
H
O
N
N
N
N
R3 = Me, 3am, 86%
R3 = Et, 3an, 89%
R3 = Ph, 3ao, 26%
O
O
O
N
N
N
H
Me
4e, 5:1
5ea, 50%, 5:1
Ph
4f, 5:1
5fa, 99%, 3:1
Me
3al, 98%
4d, 2:1
5da, 56%, 2:1
O
O
O
Me
O
O
Me
Me
OBn
OBn
Me
N
Ph
Me
N
N
H
Me
N
OBn
N
H
Scheme 4. Scope of N-vinyl isatin nitrone 4 for the preparation of 5. (Reaction
conditions: 4 (0.2 mmol), 2a (0.4 mmol, 2.0 equiv.), Sc(OTf)3 (10 mol%), K2CO3
(0.4 mmol, 2.0 equiv.), MeCN (2.0 mL), 12-18 h, isolated yield, E/Z ratio of the
C=N bond.)
N
H
H
O
O
O
N
N
Br
Br
Br
3ia, 95% (1:1)a
3ap, 0%
3aq, 0%
3ha, 85%
Interestingly, treating N-vinyl nitrone 1a with 2a for 12 h
under the optimal conditions and then adding with Fe powder
and NH4Cl in a mixed solvent of EtOH and H2O at 80 C
smoothly afforded -(9-fluorenylideneaminooxy)amide 6aa in
68% yield.15 The structure of 6aa was determined by its X-ray
diffraction analysis.14 As shown in Scheme 5, different types of
Scheme 3. Substrate scope of nitrones 1 and α-bromohydroxamates 2 for the
preparation of compounds 3. (Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol,
2.0 equiv.), Sc(OTf)3 (10 mol%), K2CO3 (0.4 mmol, 2.0 equiv.), MeCN (2.0 mL), 12-
18 h, isolated yield; a E/Z ratio of the C=N bond.)
In addition to N-vinyl fluorenone nitrones, N-vinyl isatin
nitrones 4 were also tested. As shown in Scheme 4, aryl moiety
of isatin nitrones bearing methoxy and methyl groups (4b-4d)
were applicable to this cascade reaction, affording the
corresponding -aminooxy hydroxamates in moderate yields
(5ba-5da). The R7 group was compatible with both free NH and
N-protecting groups. For examples, nitrones bearing N-R7 with
Me and Ph groups, resulted in 5ea and 5fa in 50% and 99%
yields, respectively. The E/Z ratios of C=N bond of compounds
5 were ranging from 2:1 to 10:1, which might have correlations
with the nitrone E/Z-geometry. For examples, a 1.5:1 E/Z ratio
of 4a delivered 5aa with a 2:1 E/Z ratio, however, 4b with 5:1
E/Z ratio afforded 5ba with 10:1 E/Z ratio.
nitrones
and
α-bromohydroxamates
produced
the
corresponding amides (6am, 6ha, and 6ia) in moderate yields.
These results showed that the reaction underwent both C-N
and N-OBn bond cleavage, while the N-O bond of nitrone
remained, showing that the adjacent acyl group allows the N-
OBn bond to be more labile in cleavage.
O
R4
Me
R3
NH2
O
Me
N
O
O
Sc(OTf)3 (10 mol%)
K2CO3, MeCN, rt
N
R4
R3
OBn
+
N
R1
R1
R2
H
then adding Fe/NH4Cl
EtOH/H2O, 80 °C
Br
R2
2
1
6
NH2
NH2
NH2
Me
NH2
Me
Me
Me
N
Me
Me
O
O
Me
O
O
O
O
O
O
N
N
N
Br
Br
Br
6aa, 68%
6am, 64%
6ha, 58%
6ia, 52% (E/ Z = 1:1)
Scheme 5. Scope of nitrone 1 for the preparation of 6 in two steps in one pot.
(Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol, 2.0 equiv.), Sc(OTf)3 (10 mol%),
K2CO3 (0.4 mmol, 2.0 equiv.), MeCN (2.0 mL), 12 h; Then, adding Fe/NH4Cl and
EtOH/H2O, 80 C for 3-6 h; isolated yield.)
4 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
To better understand the mechanism for the formation of -
(9-fluorenylideneaminooxy) hydroxamates, control
View Article Online
Me
Me
DOI: 10.1039/D0OBO01788D
O
O
O
Ph
N
experiments were performed (Scheme 6). When N-vinyl
nitrone 1j and 2a were carried out in the absence of Sc(OTf)3
catalyst, [3+3] cycloadduct 7ja was obtained in 85% yield,
which was then conducted under the Sc(OTf)3-catalyzed
conditions affording 3aa in 91% yield accompanied by
acetophenone in 92% yield (Scheme 6-1 and 6-2). These
results indicated that the vinyl group of compound 7ja was
converted to ketone by hydrolysis. Interestingly, when
compound 7ja was performed in dry MeCN under N2
atmosphere, 3aa was only obtained in 16% yield while 90%
yield was obtained by adding additional 2.0 equiv. of water
(Scheme 6-3). These results showed that water promoted the
C-N bond clveage step. However, the additional water in one-
pot reaction was not required because the water was
produced during the formation of aza-oxyallyl cation in the
presence of K2CO3. When 9-fluoreone oxime and 2a were
subjected to the standard conditions, product 3aa was not
observed, even though the temperature was increased to 120
C (Scheme 6-4), suggesting that the nucleophilic substitution
of α-bromohydroxamate 2 with oxime is difficult. Treating 3aa
with Fe/NH4Cl reduction conditions afforded 6aa in 68% yield,
which indicated that 6aa was generated from 3aa by N-O bond
reduction (Scheme 6-5). To know more about the formation of
E/Z ratio of compound 5 in Scheme 4, we performed the
hydrolysis of 3aa with HCl in dioxane to generate α-aminooxy
amides in situ, then condensation with isatin to afford
compound 5aa in 85% yield with a 3:1 E/Z ratio (Scheme 6-6).
This easy hydrolysis also offers a method to prepare other
types of α-aminooxy amides by condensation with various
ketones.
Me
Me
N
N
OBn
K2CO3
OBn
+
N
H
1)
MeCN, rt
85% yield
Ph
Br
2a
1j
7ja
Me
O
O
Me
Me
N
Me
OBn
+
O
O
O
N
H
N
N
Sc(OTf)3
K2CO3, MeCN, rt
OBn
Ph
Me
92%
2)
Ph
3aa, 91%
7ja
Me
Me
N
O
O
N
Sc(OTf)3
K2CO3 rt
OBn
3aa
,
3)
Ph
dry MeCN, under N2, 16% yield
dry MeCN / H2O (2.0 equiv.), under N2, 90% yield
7ja
OH
Me
O
O
Me
OBn
w/o Sc(OTf)3
K2CO3
O
N
N
H
Me
Me
N
OBn
N
+
H
4)
Br
MeCN, rt -120 °C
2a
3aa, 0%
Me
O
Me
O
O
Me
Me
OBn
N
H
O
NH2
N
N
Fe/NH4Cl
5)
EtOH/H2O, 80 °C
68% yield
3aa
6aa
O
N
Me
O
Me
Me
OBn
O
Me
OBn
N
H
Me
6)
O
N
H
O
N
O
Me
H2
Isatin
HCl/dioxane
OBn
N
H
O
MeOH
N
in situ
NH
3aa
5aa
85% yield,
= 3:1
E/ Z
Scheme 6. Control experiments
Based on the above experimental results, a possible
mechanism for the formation of 3aa from N-vinyl nitrone 1a
and α-bromohydroxamate 2a was proposed (Scheme 7). α-
Bromohydroxamate 2a produced aza-oxyallyl cation
A
accompanied by water in the presence of K2CO3, which
underwent [3+3] cycloaddition with nitrone 1a to provide six-
membered N,O-heterocycle 7. Then, compound 7 took place
C-N bond cleavage in the presence of Lewis acid catalyst
Sc(OTf)3 and water to afford intermediate B and N-vinyl moiety
was converted to the corresponding ketone by hydrolysis.
Finally, C-N bond cleavage of B and sequential H-migration via
intermediate C gave product 3aa.
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
chromatography was performed on 0.25 mm extVriaewhAartricdle sOinlilicnae
gel plates with UV254 fluorescent indicator. Chromatography
Me Me
O
O
DOI: 10.1039/D0OB01788D
O
O
Me
Me
OBn
Me
OBn
was performed using with 300-400 mesh silica gel (SiO2).
Unless otherwise noted, all reagents and solvents were
obtained from commercial sources and, where appropriate,
purified prior to use. N-Vinyl fluorenone nitrones 1a-1j13a, N-
vinyl nitrones 4a-4f13b, α-bromohydroxamates 2a-2q16, and
7ja12b, were prepared according to the literature methods and
their spectral data matched literature values.
General procedure for the synthesis of α-(9-
fluorenylideneaminooxy) amides 3: In a 25 mL round-bottom
flask was charged with Sc(OTf)3 (10 mol%), N-vinyl fluorenone
nitrones 1 (0.2 mmol), -bromohydroxamates 2 (0.4 mmol, 2.0
equiv.), and K2CO3 (0.4 mmol, 2.0 equiv.). Then, MeCN (2.0 mL)
was added. The resulting mixture was stirred vigorously at
room temperature for 12−24 h (monitored by TLC). At this
time, the solvent was removed under reduced pressure and
the crude product was purified by flash column
chromatography (the crude residue was dry loaded with silica
gel, 1/4 to 1/2, ethyl acetate/petroleum ether) to provide α-
aminooxy amides 3.
N
N
K2CO3
1a
OBn
N
N
Me
H
[3+3]
Br
Me
Me
2a
A
KBr + H2O +CO2
7
O
Sc(OTf)3
Me
O
O
Me
H2
O
Me
Me Me
O
Me
Me
N
O
HN OBn
Me
N
O
Sc(OTf)3
C-N cleavage HN
H-migration
O
H
N
N
OBn
OBn
3aa
C
B
Scheme 7. Proposed mechanism
The scalability of this Sc(OTf)3-catalyzed cascade reaction
was then evaluated (Scheme 8). When 1.0 g of nitrone 1a was
reacted with 2a under Sc(OTf)3 conditions, product 3aa was
obtained in 91% yield (1.4 g). Treating 1.0 g of nitrone 1a with
2a and sequential reduction by Fe/NH4Cl conditions, delivered
6aa in 58% yield (0.65 g). These easy gram scale performances
allow these compounds more potential applications in organic
synthesis and their biological activity studies.
2-(9H-Fluoren-9-ylideneaminooxy)-N-(benzyloxy)-2-
methylpropanamide (3aa). A white solid, 0.072 g, 93% yield.
Mp: 90−91 °C; 1H NMR (400 MHz, DMSO): δ 11.20 (s, 1H), 8.26
(d, J = 7.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.6 Hz,
1H), 7.69 (d, J = 7.6 Hz, 1H), 7.55−7.52 (m, 1H), 7.49−7.45 (m,
1H), 7.41−7.32 (m, 4H), 7.28−7.24 (m, 3H), 4.78 (s, 2H), 1.60 (s,
6H); 13C NMR (100 MHz, DMSO): δ 170.5, 152.4, 141.3, 140.2,
136.3, 135.2, 132.0, 130.9, 130.1, 130.0, 129.6, 128.9, 128.8,
128.7, 128.6, 121.9. 121.1, 120.9, 83.8, 77.2, 24.7; IR (thin film)
3456, 3022, 2924, 1494, 1448, 1363, 1187, 964 cm−1; HRMS
(ESI) m/z calcd for C24H23N2O3 (M+H)+ 387.1703, found
387.1693.
OBn
HN
NH2
Me
Me
Me
Me
Me
O
O
O
2a
O
2a
O
Me
N
N
N
Sc(OTf)3
Sc(OTf)3
K2CO3, MeCN, rt
then Fe/NH4Cl
3aa
1.4 g, 91% yield
1a
6aa
1.0 g, 4.0 mmol
0.65 g, 58% yield
Scheme 8. Gram scale preparations
2-(9H-Fluoren-9-ylideneaminooxy)-N-(4-methoxybenzyloxy)-
2-methylpropanamide (3ab). A white solid, 0.062 g, 74% yield.
Mp: 81−82 °C; H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H), 8.03
Conclusions
1
We have developed an efficient method for the synthesis of
α-aminooxy amides in good to excellent yields through [3+3]
cycloaddition and Sc(OTf)3-catalyzed double C-N bond
cleavage in one pot reaction from N-vinyl nitrones and α-
bromohydroxamates. The present method features mild
reaction coniditions, broad substrate scope, easily available
starting materials, new application of N-vinyl nitrones, and
(d, J = 7.5 Hz, 1H), 7.59−7.54 (m, 3H), 7.39−7.33 (m, 2H),
7.23−7.19 (m, 2H), 7.16 (d, J = 8.0, 2H), 6.54 (d, J = 8.5, 2H),
4.76 (s, 2H), 3.56 (s, 3H), 1.65 (s, 6H); 13C NMR (125 MHz,
CDCl3): δ 171.9, 159.8, 153.6, 141.8, 140.3, 135.1, 131.5, 130.9,
130.4, 130.0, 129.1, 128.3, 128.1, 127.0, 122.0, 120.0, 119.9,
113.7, 84.7, 77.8, 55.0, 24.6, 24.5; IR (thin film) 3454, 2926,
1637, 1451, 1098, 961 cm−1; HRMS (ESI) m/z calcd for
C25H25N2O4 (M+H)+ 417.1809, found 417.1806.
preparation of α-aminooxy carbonyl group bearing
quaternary carbon at the α-position.
a
2-(((9H-Fluoren-9-ylidene)amino)oxy)-N-((4-bromobenzyl)
oxy)-2-methylpropanamide (3ac). A white solid, 0.064 g, 68%
1
yield. Mp: 94−95 °C; H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H),
Experimental
8.10 (d, J = 7.6 Hz, 1H), 7.67−7.60 (m, 3H), 7.47−7.40 (m, 2H),
7.31 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 6.0 Hz, 1H), 7.22 (d, J = 8.4
Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 4.83 (s, 2H), 1.71 (s, 6H); 13C
NMR (100 MHz, CDCl3): δ 172.2, 153.7, 141.8, 140.3, 134.9,
133.9, 131.6, 131.5, 130.6, 130.5, 129.9, 129.0, 128.3, 128.1,
122.8. 121.8, 120.2, 120.1, 84.6, 24.5; IR (thin film) 3404, 2924,
1680, 1450, 1164, 960 cm−1; HRMS (ESI) m/z calcd for
C24H22BrN2O3 (M+H)+ 465.0808, found 465.0807.
1H NMR and 13C NMR spectra were recorded at ambient
temperature using 400 MHz and 500 MHz spectrometers. The
data are reported as follows: chemical shift in ppm from
internal tetramethylsilane on the  scale, multiplicity (br =
broad, s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet), coupling constants (Hz), and integration. High
resolution mass spectra were acquired on an LTQ FT
spectrometer, and were obtained by peak matching. Melting
points are reported uncorrected. Analytical thin layer
2-(((9H-Fluoren-9-ylidene)amino)oxy)-N-((4-fluorobenzyl)
oxy)-2-methylpropanamide (3ad). A white solid, 0.049 g, 61%
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
yield. Mp: 110−111 °C; H NMR (400 MHz, CDCl3): δ 8.68 (s,
ARTICLE
1
(E)-2-(((9H-Fluoren-9-ylidene)amino)oxy)-N-(cinnamyloxy)-
View Article Online
1H), 8.12 (d, J = 7.6 Hz, 1H), 7.68−7.62 (m, 3H), 7.48−7.40 (m, 2-methylpropanamide (3ai). A yellow soDliOd,I:010.0.150839g/,D70O1%B0y17ie88ldD.
1
2H), 7.29−7.26 (m, 4H), 6.79−6.74 (m, 2H), 4.85 (s, 2H), 1.72 (s, Mp: 76−77 °C; H NMR (400 MHz, CDCl3): δ 8.85 (s, 1H), 8.19
6H); 13C NMR (100 MHz, CDCl3): δ 172.2, 164.0 (d, J = 245.8 (d, J = 7.6 Hz, 1H), 7.66−7.56 (m, 3H), 7.44−7.35 (m, 2H),
Hz), 153.7, 141.9, 140.3, 135.0, 131.7, 131.1, 131.0, 130.8 (d, J 7.26−7.18 (m, 7H), 6.60 (d, J = 16.0 Hz, 1H), 6.30−6.23 (m, 1H),
= 3.6 Hz), 130.6, 130.0, 129.1, 128.3, 128.1, 121.9. 120.2, 4.55 (d, J = 6.8 Hz, 2H), 1.73 (s, 6H); 13C NMR (100 MHz, CDCl3):
120.1, 115.5, 115.2, 84.6, 24.6; IR (thin film) 3672, 2924, 1510, δ 172.2, 153.8, 141.8, 140.3, 136.4, 135.9, 135.0, 131.6, 130.4,
1259, 1038, 971 cm−1; HRMS (ESI) m/z calcd for C24H22FN2O3 130.0, 129.1, 128.5, 128.3, 128.1, 128.0, 126.6, 122.6, 121.9,
(M+H)+ 405.1609, found 405.1608.
2-(9H-Fluoren-9-ylideneaminooxy)-2-methyl-N-(4-
120.1, 120.0, 84.7, 24.6; IR (thin film) 3689, 2924, 1740, 1451,
1267, 965 cm−1; HRMS (ESI) m/z calcd for C26H25N2O3 (M+H)+
(trifluoromethyl)benzyloxy)propanamide (3ae). A white solid, 413.1860, found 413.1858.
0.054 g, 60% yield. Mp: 101−102 °C; 1H NMR (400 MHz, DMSO-
(E)-2-(((9H-Fluoren-9-ylidene)amino)oxy)-2-methyl-N-((2-
d6): δ 11.05 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.89−7.83 (m, 2H), methyl-3-phenylallyl)oxy) propanamide (3aj). A yellow oil,
1
7.67 (d, J = 7.6 Hz, 1H), 7.60−7.50 (m, 5H), 7.48 (t, J = 14.8 Hz, 0.056 g, 66% yield. H NMR (400 MHz, CDCl3): δ 8.82 (s, 1H),
1H), 7.39−7.31 (m, 2 H), 4.88 (s, 2 H), 1.59 (s, 6H); 13C NMR 8.20 (d, J = 7.6 Hz, 1H), 7.64−7.59 (m, 2H), 7.56 (d, J = 7.2 Hz,
(100 MHz, DMSO-d6): δ 170.7, 152.5, 141.3, 141.1, 140.2, 1H), 7.44−7.40 (m, 1H), 7.37−7.33 (m, 1H), 7.27−7.16 (m, 5H),
135.1, 132.0, 131.0, 130.1, 130.0, 129.9, 129.3, 128.9, 128.7, 7.09 (d, J = 7.2 Hz, 2H), 6.45 (s, 1H), 4.43 (s, 2H), 1.91 (s, 3H),
128.6 (q, J = 269.7 Hz), 126.0, 125.4 (q, J = 3.6 Hz), 123.3, 1.74 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 172.1, 153.8, 141.9,
121.9, 121.1, 121.0, 120.6, 83.8, 76.2, 24.6; IR (thin film) 3451, 140.3, 136.6, 134.9, 132.4, 131.5, 131.0, 130.4, 130.0, 129.1,
2928, 1659, 1481, 1167, 964 cm−1; HRMS (ESI) m/z calcd for 128.8, 128.7, 128.2, 128.0, 126.7, 121.9, 120.1, 120.0, 84.7,
C25H22F3N2O3 (M+H)+ 455.1577, found 455.1575.
2-(((9H-Fluoren-9-ylidene)amino)oxy)-2-methyl-N-((3-
82.9, 24.7, 15.8; IR (thin film) 3696, 2989, 2368, 1451, 1275,
961 cm−1; HRMS (ESI) m/z calcd for C27H27N2O3 (M+H)+
methylbenzyl)oxy)propanamide (3af). A yellow oil, 0.042 g, 427.2016, found 427.2013.
52% yield. 1H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 8.11 (d, J =
2-(9H-Fluoren-9-ylideneaminooxy)-2-methyl-N-(prop-2-
7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.62−7.59 (m, 2H), ynyloxy)propanamide (3ak). A white solid, 0.037 g, 56% yield.
1
7.47−7.38 (m, 2H), 7.28−7.26 (m, 2H), 7.14 (s, 1H), 7.10 (d, J = Mp: 92−93 °C; H NMR (400 MHz, CDCl3): δ 9.02 (s, 1H), 8.18
6.4 Hz, 1H), 7.00−6.97 (m, 2H), 4.87 (s, 2H), 2.16 (s, 3H), 1.72 (d, J = 7.6 Hz, 1H), 7.67 (d, J =8.0 Hz, 1H), 7.61 (d, J = 7.6 Hz,
(s, 6H); 13C NMR (100 MHz, CDCl3): δ 172.0, 153.6, 141.9, 1H), 7.55 (d, J = 7.6Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.35 (t, J =
140.3, 138.2, 135.0, 134.8, 131.5, 130.4, 130.0, 129.7, 129.4, 7.6 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.22-7.19 (m, 1H), 4.48 (d, J
129.1, 128.3, 128.1, 126.2, 122.0, 120.1, 119.9, 84.6, 24.6, = 2.0 Hz, 2H), 2.16 (s, 1H), 1.68 (s, 6H); 13C NMR (125 MHz,
21.1; IR (thin film) 3317, 2926, 1678, 1452, 1264, 960 cm−1; DMSO-d6): δ 170.6, 152.5, 141.3, 140.2, 135.2, 134.6, 132.0,
HRMS (ESI) m/z calcd for C25H25N2O3 (M+H)+ 401.1860, found 130.9,130.0, 128.9, 122.0, 121.0, 120.9, 83.8, 79.0, 78.9, 62.7,
401.1859.
24.7; IR (thin film) 3454, 2971, 2094, 1637, 1080, 974, 617
cm−1; HRMS (ESI) m/z calcd for C20H19N2O3 (M+H)+ 335.1390,
2-(((9H-Fluoren-9-ylidene)amino)oxy)-2-methyl-N-((2-
methylbenzyl)oxy)propanamide (3ag). A yellow oil, 0.029 g, found 335.1389.
36% yield. 1H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 8.13 (d, J =
2-(9H-Fluoren-9-ylideneaminooxy)-N-methoxy-2-methyl
7.6 Hz, 1H), 7.67−7.61 (m, 3H), 7.47−7.39 (m, 2H), 7.30−7.26 propanamide (3al). A white solid, 0.061g, 98% yield. Mp:
(m, 3H), 7.21 (d, J = 7.6, 1H), 7.08−7.06 (m, 2H), 6.90−6.86 (m, 142−143 °C; 1H NMR (500 MHz, CDCl3): δ 8.80 (s, 1H), 8.14 (d, J
1H), 4.95 (s, 2H), 2.39 (s, 3H), 1.72 (s, 6H); 13C NMR (100 MHz, = 9.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H),
CDCl3): δ 172.2, 153.7, 141.9, 140.3, 138.1, 135.1, 132.8, 131.6, 7.51 (d, J = 9.0 Hz, 1H), 7.38 (t, J = 9.0 Hz, 1H), 7.31 (t, J = 8.5
130.6, 130.5, 130.4, 130.1, 129.1, 128.9, 128.3, 128.1, 125.6, Hz, 1H), 7.25 (t, J = 9.0 Hz, 1H), 7.19 (t, J = 9.0 Hz, 1H), 3.65 (s,
122.0, 120.1, 119.9, 84.7, 24.6, 18.9; IR (thin film) 3598, 2989, 3H), 1.63 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 172.5, 153.9,
1462, 1276, 1261, 750 cm−1; HRMS (ESI) m/z calcd for 141.9, 140.3, 135.0, 131.6, 130.5，130.1, 129.2, 128.3, 128.1,
C25H25N2O3 (M+H)+ 401.1860, found 401.1859.
122.0, 120.1, 120.0, 84.6, 64.3, 24.6; IR (thin film) 3264, 2929,
2-(9H-Fluoren-9-ylideneaminooxy)-N-(allyloxy)-2-
2805, 1921, 1661, 1482, 956 cm−1; HRMS (ESI) m/z calcd for
methylpropanamide (3ah). A white solid, 0.060 g, 90% yield. C18H19N2O3 (M+H)+ 311.1390, found 311.1389.
Mp: 133−134 °C; 1H NMR (400 MHz, CDCl3): δ 8.72 (s, 1H), 8.14
2-(9H-Fluoren-9-ylideneaminooxy)-N-(benzyloxy)propan
(d, J = 7.6 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.58 (d, J = 7.2 Hz, amide (3am). A white solid, 0.064g, 86% yield. Mp: 100−101
1H), 7.53 (d, J = 7.2 Hz, 1H), 7.39 (t, J = 7.2 Hz, 1H), 7.32 (t, J = °C; 1H NMR (400 MHz, CDCl3): δ 8.57 (s, 1H), 7.97 (d, J = 7.2 Hz,
7.2 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.22−7.17 (m, 1H), 1H), 7.57−7.52 (m, 3H), 7.38−7.31 (m, 2H), 7.23−7.15 (m, 4H),
5.87−5.77 (m, 1H), 5.21 (d, J = 17.2 Hz, 1H), 5.11 (d, J = 10.4 Hz, 7.04−7.03 (m, 3H), 4.90−4.80 (m, 3H), 1.61 (d, J = 6.8 Hz, 3H);
1H), 4.30 (d, J = 6.0 Hz, 1H), 1.64 (s, 6H); 13C NMR (100 MHz, 13C NMR (100 MHz, CDCl3): δ 169.4, 154.0, 141.8, 140.4, 134.8,
CDCl3): δ 172.1, 153.8, 141.8, 140.3, 135.0, 131.8, 131.6, 130.4, 134.6, 131.6, 130.5, 130.0, 129.1, 129.0, 128.7, 128.4, 128.3,
130.0, 129.1, 128.2, 128.0, 121.9, 120.9, 120.1, 119.9, 84.6, 128.1, 122.0, 120.0, 119.9, 80.9, 78.3, 17.4; IR (thin film) 3204,
77.2, 24.6; IR (thin film) 3220, 2971, 1654, 1495, 1448, 963 2988, 1666, 1448, 1045, 974 cm−1; HRMS (ESI) m/z calcd for
cm−1; HRMS (ESI) m/z calcd for C20H21N2O3 (M+H)+ 337.1547, C23H21N2O3 (M+H)+ 373.1547, found 373.1532.
found 337.1535.
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Organic & Biomolecular Chemistry
Page 8 of 11
ARTICLE
2-(9H-Fluoren-9-ylideneaminooxy)-N-(benzyloxy)butan
amide (3an). A white solid, 0.069 g, 89% yield. Mp: 136−137 gel, 1/4 to 1/2, ethyl acetate/petroleum ether) to provide α-
°C; 1H NMR (400 MHz, CDCl3): δ 8.57 (s, 1H), 7.95 (d, J = 7.6 Hz, aminooxy amides 5.
Journal Name
chromatography (the crude residue was dry loaded with silica
View Article Online
DOI: 10.1039/D0OB01788D
1H), 7.58−7.50 (m, 3H), 7.36−7.29 (m, 2H), 7.21−7.14 (m, 4H),
N-(Benzyloxy)-2-methyl-2-(((2-oxoindolin-3-ylidene)amino)
7.03−7.01 (m, 3H), 4.86−4.73 (m, 3H), 2.09−1.91 (m, 2H), 1.03 oxy)propanamide (5aa). A white solid, 0.065 g, 92% yield. (E/Z
(t J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.8, 154.0, = 2:1), Mp: 77-78 °C ; Major isomer: 1H NMR (400 MHz, DMSO-
141.7, 140.3, 134.8, 134.7, 131.6, 130.5, 130.0, 129.1, 129.0, d6): δ 10.92 (s, 1H), 10.80 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H),
128.6, 128.4, 128.3, 128.1, 122.0, 120.1, 119.9, 85.9, 78.3, 7.36−7.33 (m, 3H), 7.32−7.30 (m, 3H), 7.01−6.98 (m, 1H), 6.86
24.9, 9.6; IR (thin film) 3475, 3199, 2971, 1670, 1449, 976 (d, J = 8.0 Hz, 1H), 4.78 (s, 2H), 1.51 (s, 6H); 13C NMR (100 MHz,
cm−1; HRMS (ESI) m/z calcd for C24H23N2O3 (M+H)+ 387.1703, DMSO-d6): δ 170.2, 158.5, 144.5, 143.0, 136.1, 132.4, 129.5,
found 387.1686.
2-(9H-Fluoren-9-ylideneaminooxy)-N-(benzyloxy)-2-phenyl
128.7, 128.6, 122.4, 121.4, 119.5, 110.9, 84.8, 77.2, 24.5;
Minor isomer: H NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H),
1
acetamide (3ao). A white solid, 0.023 g, 26% yield. Mp: 10.81 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.39−7.36 (m, 3H),
107−108 °C; 1H NMR (400 MHz, CDCl3): δ 8.69 (s, 1H), 7.95 (d, J 7.35−7.32 (m, 3H), 7.05−7.02 (m, 1H), 6.90 (d, J = 8.0 Hz, 1H),
= 6.4 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.56−7.52 (m, 2H), 7.46 4.77 (s, 2H), 1.55 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ
(d, J = 4.4 Hz, 2H), 7.35−7.33 (m, 4H), 7.22−7.18 (m, 3H), 170.0, 164.2, 145.4, 143.9, 136.2, 133.6, 129.6, 128.8, 128.7,
7.16−7.12 (m, 2H), 7.07−7.06 (m, 3H), 5.80 (s, 1H), 4.85−4.82 128.6, 122.6, 116.3, 110.9, 84.8, 77.2, 24.6; IR (thin film) 3637,
(m, 2H); 13C NMR (125 MHz, DMSO-d6): δ 166.3, 153.4, 141.4, 2963, 1729, 1261, 1097, 970 cm−1; HRMS (ESI) m/z calcd for
140.4, 136.3, 136.1, 134.7, 132.5, 131.3, 129.9, 129.8, 129.6, C19H20 N3O4 (M+H)+ 354.1448, found 354.1449.
129.4, 129.2, 129.1, 128.9. 128.8, 128.7, 127.8, 122.0, 121.2,
N-(Benzyloxy)-2-(((5-methoxy-2-oxoindolin-3-ylidene)
121.1, 84.2, 77.3; IR (thin film) 3432, 2925, 1668, 1448, 1025, amino)oxy)-2-methylpropanamide (5ba). (E/Z = 10:1), A white
1
997 cm−1; HRMS (ESI) m/z calcd for C28H23N2O3 (M+H)+ solid, 0.038 g, 50% yield. Mp: 155-156 °C; Major isomer: H
435.1703, found 435.1694.
N-(Benzyloxy)-2-(2,7-dibromo-9H-fluoren-9-ylidene
NMR (400 MHz, CDCl3): δ 9.96 (s, 1H), 8.05 (s, 1H), 7.42−7.41
(m, 2H), 7.30−7.26 (m, 3H), 7.12 (d, J = 1.6 Hz, 1H), 6.90−6.87
aminooxy)-2-methylpropanamide (3ha). A yellow solid, 0.092 (m, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.98 (s, 2H), 3.82 (s, 3H), 1.67
1
g, 85% yield. Mp: 145−146 °C; H NMR (400 MHz, CDCl3): δ (s, 6H); 13C NMR (100 MHz, CDCl3): δ 170.6, 159.0, 156.0,
8.52 (s, 1H), 8.13 (s, 1H), 7.64−7.63 (m, 1H), 7.51−7.32 (m, 4H), 145.1, 135.1, 134.6, 129.2, 128.6, 128.4, 119.7, 118.5, 111.3,
7.24−7.23 (m, 2H), 7.08−7.07 (m, 3H), 4.85 (s, 2H), 1.64 (s, 6H); 106.7, 85.9, 78.2, 55.9, 24.0; IR (thin film) 3686, 2995, 1699,
13C NMR (100 MHz, CDCl3): δ 171.4, 151.6, 139.6, 138.1, 136.4, 1487, 1163, 980 cm−1; HRMS (ESI) m/z calcd for C20H22N3O5
134.8, 134.4, 133.4, 132.1, 131.0, 129.1, 128.7, 128.4, 125.2, (M+H)+ 384.1554, found 384.1556.
122.2, 122.1. 121.3, 121.2, 85.4, 78.2, 24.5; IR (thin film) 3341,
N-(Benzyloxy)-2-methyl-2-(((5-methyl-2-oxoindolin-
2923, 1690, 1430, 1165, 972 cm−1; HRMS (ESI) m/z calcd for 3ylidene) amino)oxy)propanamide (5ca). (E/Z = 10:1), A
C24H21Br2N2O3 (M+H)+542.9901, found 542.9902.
N-(Benzyloxy)-2-(2-bromo-9H-fluoren-9-ylideneaminooxy)-
yellow solid, 0.054 g, 74% yield. Mp: 169-170 °C; Major isomer:
1H NMR (400 MHz, CDCl3): δ 10.00 (s, 1H), 8.48 (s, 1H),
2-methylpropanamide (3ia). A yellow solid, 0.102 g, 95% yield. 7.41−7.40 (m, 3H), 7.28−7.27 (m, 3H), 7.13 (d, J = 8.0 Hz, 1H),
Mp: 114−115 °C; One isomer: 1H NMR (400 MHz, CDCl3): δ 8.56 6.76 (d, J = 7.6 Hz, 1H), 4.97 (s, 2H), 2.34 (s, 3H), 1.66 (s, 6H);
(s, 1H), 8.17 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.53−7.50 (m, 2H), 13C NMR (100 MHz, CDCl3): δ 170.7, 159.2, 145.0, 138.7, 135.1,
7.47−7.43 (m, 2H), 7.25−7.19 (m, 6H), 4.85 (s, 2H), 1.65 (s, 6H); 132.6, 132.5, 129.2, 128.6, 128.4, 122.1, 119.0, 110.4, 85.7,
13C NMR (100 MHz, CDCl3): δ 171.8, 152.7, 140.9, 139.4, 136.8, 78.2, 24.0, 21.0; IR (thin film) 3689, 2963, 1707, 1296, 1041,
134.9, 134.7, 133.2, 132.1, 130.7, 129.2, 128.7, 128.4, 125.1, 816 cm−1; HRMS (ESI) m/z calcd for C20H22N3O4 (M+H)+
1
122.1, 121.8, 121.3,120.2, 85.0, 78.3, 24.5; Another isomer: H 368.1605, found 368.1604.
NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 7.66 (s, 1H), 7.57−7.55
N-(Benzyloxy)-2-methyl-2-(((7-methyl-2-oxoindolin-3-
(m, 2H), 7.41−7.33 (m, 3H), 7.09−7.03 (m, 6H), 4.85 (s, 2H), ylidene)amino)oxy)propanamide (5da). (E/Z = 2:1), A yellow
1
1.64 (s, 6H);13C NMR (100 MHz, CDCl3): δ 171.7, 152.6, 140.6, solid, 0.041 g, 56% yield. Mp: 114-115 °C ; Major isomer: H
139.1, 134.8, 134.2, 133.2, 131.7, 129.7, 129.1, 128.6, 128.4, NMR (400 MHz, CDCl3): δ 9.87 (s, 1H), 8.14 (s, 1H), 7.43−7.40
125.1, 122.1, 121.7, 121.2, 120.0, 85.0, 78.1, 24.5; IR (thin film) (m, 3H), 7.29−7.26 (m, 3H), 7.18 (d, J = 7.6 Hz, 1H), 7.01−6.98
3214, 2926, 1672, 1440, 1154, 965 cm−1; HRMS (ESI) m/z calcd (m, 1H), 4.95 (s, 2H), 2.24 (s, 3H), 1.66 (s, 6H); 13C NMR (100
for C24H22BrN2O3 (M+H)+ 465.0814, found 465.0793.
MHz, CDCl3): δ 170.6, 159.0, 145.0, 139.5, 135.1, 133.2, 129.2,
General procedure for the synthesis of α-(9- 128.5, 128.4, 123.0, 119.6, 119.2, 118.7, 85.9, 78.2, 24.0, 15.8;
isatinlideneaminooxy) amides 5: In a 25 mL round-bottom minor isomer: 1H NMR (400 MHz, CDCl3): δ 8.62 (s, 1H), 8.39 (s,
flask was charged with Sc(OTf)3 (10 mol%), N-vinyl isatin 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.41−7.39 (m, 3H), 7.28−7.26 (m,
nitrones 4 (0.2 mmol), -bromohydroxamate 2a (0.4 mmol, 2H), 7.20−7.16 (m, 1H), 6.95−6.91 (m, 1H), 4.96 (d, J = 12.0 Hz,
2.0 equiv.), and K2CO3 (0.4 mmol, 2.0 equiv.). Then, MeCN (2.0 2H), 2.26 (s, 3H), 1.71 (s, 6H); 13C NMR (100 MHz, CDCl3): δ
mL) was added. The resulting mixture was stirred vigorously at 170.8, 164.3, 140.8, 134.9, 134.6, 129.4, 128.7, 128.5, 125.5,
room temperature for 12−24 h (monitored by TLC). At this 123.1, 123.0, 119.8, 115.5, 86.3, 78.3, 24.0, 16.0; IR (thin film)
time, the solvent was removed under reduced pressure and 3635, 2928, 1709, 1262, 1016, 981 cm−1; HRMS (ESI) m/z calcd
the crude product was purified by flash column for C20H22N3O4 (M+H)+ 368.1605, found 368.1609.
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
N-(Benzyloxy)-2-methyl-2-(((1-methyl-2-oxoindolin-3-
7.54−7.51 (m, 1H), 7.46−7.40 (m, 2H), 7.34−7.31 (m, 1H),
View Article Online
ylidene)amino)oxy)propanamide (5ea). (E/Z = 5:1), A white 7.20−7.17 (m, 2H), 1.60 (s, 6H); 13C NMR (125 MHz, DMSO-d6):
DOI: 10.1039/D0OB01788D
1
solid, 0.037 g, 50% yield. Mp: 94-95 °C; Major isomer: H NMR δ 175.7, 152.2, 141.3, 140.2, 135.2, 132.0, 130.8, 130.1, 129.9,
(400 MHz, CDCl3): δ 10.01 (s, 1H), 7.59 (d, J = 7.2 Hz, 1H), 129.0, 128.7, 121.9, 121.0, 120.9, 84.2, 24.7; IR (thin film)
7.44−7.40 (m, 3H), 7.27−7.25 (m, 3H), 7.11−7.07 (m, 1H), 6.84 3431, 2925, 1651, 1390, 1025, 997 cm−1; HRMS (ESI) m/z calcd
(d, J = 8.0 Hz, 1H), 4.96 (s, 2H), 3.21 (s, 3H), 1.65 (s, 6H); 13C for C17H17N2O2 (M+H)+ 281.1285, found 281.1279.
NMR (100 MHz, CDCl3): δ 170.6, 162.7, 145.0, 135.0, 133.2,
2-(9H-Fluoren-9-ylideneaminooxy)propanamide (6am).
A
1
131.9, 129.3, 128.6, 128.3, 127.8, 123.1, 115.2, 108.7, 86.3, yellow solid, 0.034 g, 64% yield. Mp: 75−76 °C; H NMR (500
1
78.2, 26.1, 24.5; minor isomer: H NMR (400 MHz, CDCl3): δ MHz, DMSO-d6): δ 8.31 (d, J = 7.5 Hz, 1H), 7.90 (d, J = 7.0 Hz,
8.68 (s, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.40−7.37 (m, 3H), 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.55−7.52
7.27−7.25 (m, 3H), 7.04−7.00 (m, 1H), 6.84 (d, J = 8.0 Hz, 1H), (m, 1H), 7.48−7.39 (m, 3H), 7.37−7.31 (m, 1H), 7.26 (s, 1H),
4.92 (s, 2H), 3.23 (s, 2H), 1.71 (s, 6H); 13C NMR (100 MHz, 4.82 (q, J = 6.5 Hz, 1H), 1.53 (d, J = 6.5 Hz, 3H); 13C NMR (125
CDCl3): δ 170.6, 162.7, 144.8, 135.0, 133.2, 131.9, 129.2, MHz, DMSO-d6): δ 173.7, 152.5, 141.2, 140.3, 135.0, 132.1,
128.4, 128.3, 127.8, 123.0, 115.2, 108.6, 86.3, 78.2, 25.8, 24.0; 131.0, 130.1, 130.0, 129.1, 128.7, 121.9, 121.1, 121.0, 80.8,
IR (thin film) 3406, 2984, 2314, 1601, 1164, 672 cm−1; HRMS 17.9; IR (thin film) 3429, 2925, 1649, 1025, 996 cm−1; HRMS
(ESI) m/z calcd for C20H21N3O4 (M+H)+ 368.1605, found (ESI) m/z calcd for C16H15N2O2 (M+H)+ 267.1128, found
368.1608.
267.1123.
N-(Benzyloxy)-2-methyl-2-(((2-oxo-1-phenylindolin-3-
2-(2,7-Dibromo-9H-fluoren-9-ylideneaminooxy)-2-methyl
ylidene)amino)oxy)propanamide (5fa). (E/Z = 3:1), A yellow propanamide (6ha). A white solid, 0.045 g, 58% yield. Mp:
oil, 0.085 g, 99% yield. Major isomer: 1H NMR (400 MHz, 80−81 °C; 1H NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H),
CDCl3): δ 9.88 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.59−7.55 (m, 7.91−7.85 (m, 2H), 7.78 (d, J = 6.8 Hz, 2H), 7.69 (d, J = 8.0 Hz,
2H), 7.49−7.45 (m, 1H), 7.42−7.38 (m, 4H), 7.35−7.31 (m, 1H), 1H), 7.30 (s, 1H), 7.17 (s, 1H), 1.60 (s, 6H); 13C NMR (100 MHz,
7.27−7.26 (m, 3H), 7.15−7.11 (m, 1H), 6.82 (d, J = 8.0 Hz, 1H), DMSO-d6): δ 175.2, 150.0, 139.3, 138.3, 137.0, 134.7, 133.6,
4.93 (s, 2H), 1.68 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 170.5, 132.2, 131.3, 124.4, 123.4, 123.1, 122.0, 122.9, 85.1, 24.5; IR
156.8, 144.2, 143.6, 135.0, 133.4, 131.8, 129.8, 129.2, 128.6, (thin film) 3453, 2924, 1642, 1463, 1110, 819 cm−1; HRMS (ESI)
128.4, 128.3, 126.5, 123.4, 121.5, 118.3, 110.0, 85.9, 78.1, m/z calcd for C17H15 Br2N2O2 (M+H)+ 436.9495, found
1
53.4, 24.0; Minor isomer: H NMR (400 MHz, CDCl3): δ 8.67 (s, 436.9493.
1H), 7.86 (d, J = 7.6 Hz, 1H), 7.58−7.54 (m, 2H), 7.47 (d, J = 7.2
2-(2-Bromo-9H-fluoren-9-ylideneaminooxy)-2-methyl
Hz, 1H), 7.43−7.40 (m, 4H), 7.37−7.33 (m, 1H), 7.29−7.26 (m, propanamide (6ia). (E/Z = 1:1), A white solid, 0.037 g, 52%
3H), 7.08−7.04 (m, 1H), 6.85 (d, J = 7.6 Hz, 1H), 4.94 (s, 2H), yield. Mp: 64-65 °C; One isomer: 1H NMR (400 MHz, DMSO-d6):
1.74 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 170.6, 161.9, 144.9, δ 8.43 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.77−7.73 (m, 2H),
144.8, 135.0, 133.5, 133.1, 129.8, 129.5, 128.7, 128.5, 128.0, 7.57−7.54 (m, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.17−7.16 (m, 3H),
126.5, 123.6, 115.3, 110.0, 86.4, 78.2, 53.4, 24.5; IR (thin film) 1.60 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ 175.4, 151.1,
3654, 2956, 1736, 1303, 1261, 978 cm−1; HRMS (ESI) m/z calcd 140.3, 139.2, 137.3, 134.8, 132.3, 131.7, 129.8, 129.4, 124.3,
for C25H24N3O4 (M+H)+ 430.1761, found 430.1763.
123.0, 121.9, 121.4, 84.6, 24.6; Another isomer: H NMR (400
1
General procedure for the synthesis of compounds 6: In a 25 MHz, DMSO-d6): δ 8.30 (d, J = 7.6 Hz, 1H), 7.87−7.84 (m, 4H),
mL round-bottom flask was charged with Sc(OTf)3 (10 mol%), 7.69−7.64 (m, 2H), 7.49−7.43 (m, 2H), 7.28 (s, 1H), 1.60 (s, 6H);
N-vinyl
fluorenone
nitrones
1
(0.2
mmol),
- 13C NMR (100 MHz, DMSO-d6): δ 175.4, 151.1, 140.3, 139.2,
bromohydroxamates 2 (0.4 mmol, 2.0 equiv.), and K2CO3 (0.4 134.9, 133.4, 132.2, 131.0, 129.7, 129.1, 123.1, 121.9, 121.5,
mmol, 2.0 equiv.). Then, MeCN (2.0 mL) was added. The 121.3, 84.6, 24.5; IR (thin film) 3404, 2960, 1646, 1261, 1095,
resulting mixture was stirred vigorously at room temperature 801, 732 cm−1; HRMS (ESI) m/z calcd for C17H16 BrN2O2 (M+H)+
for 12 h (monitored by TLC). At this time, iron powder (2 359.0390, found 359.0382.
mmol, 10.0 equiv.), ammonium chloride (2 mmol, 10.0 equiv.),
Gram scale preparation of 3aa: Sc(OTf)3 (10 mol%), N-vinyl
and 4.0 mL of EtOH/H2O (1:1) was added under air fluorenone nitrone 1a (1.0 g, 4.0 mmol), -bromohydroxamate
atmosphere. The reaction vessel was stirred vigorously at 80 °C 2a (8.0 mmol, 2.0 equiv.) and K2CO3 (8.0 mmol, 2.0 equiv.)
for 3-6 h (monitored by TLC). The solution was then diluted were dissolved in MeCN (30 mL). Then stirring at room
with water (10 mL) and extracted with DCM (3 × 10 mL). The temperature for 24 h. Purification using medium pressure
combined organic extracts were washed with brine (1 × 10 mL) chromatography (1:2; ethyl acetate: petroleum ether) afforded
and dried with Na2SO4. The solvent was removed under 3aa as a white solid (1.4 g, 91%).
reduced pressure and the crude product was purified flash
Gram scale preparation of 6aa: Sc(OTf)3 (10 mol%), N-vinyl
column chromatography (the crude residue was dry loaded fluorenone nitrone 1a (1.0 g, 4.0 mmol), -bromohydroxamate
with silica gel, 1/4 to 1/2, ethyl acetate/petroleum ether) to 2a (8.0 mmol, 2.0 equiv.) and K2CO3 (8.0 mmol, 2.0 equiv.)
provide compounds 6.
2-(9H-Fluoren-9-ylideneaminooxy)-2-methylpropanamide
were dissolved in MeCN (30 mL). Then the reaction mixture
was stirring at room temperature for 24 h. Then, iron powder
(6aa). A yellow solid, 0.038 g, 68% yield. Mp: 70−71°C; 1H NMR (40 mmol, 10.0 equiv.), ammonium chloride (40 mmol, 10.0
(500 MHz, DMSO-d6): δ 8.33 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 7.5 equiv.), and 40.0 mL of EtOH/H2O (1:1) were added under air
Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), atmosphere. The reaction vessel was stirred vigorously at 80
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for
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(c) Z. Han, S. Chen, F. Zheng, H. Hu, J. Zhang and S. Zhu,
Tetrahedron Lett. 2019, 60, 151188. (d) H. ZenVgi,ewCA.rtZichleuOanlninde
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℃
6
h. Purification using medium pressure
chromatography (1:2; ethyl acetate: petroleum ether) afforded
6aa as a white solid (0.65 g, 58%).
Conflicts of interest
There are no conflicts to declare
6
7
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Acknowledgements
Financial support from National Natural Science Foundation of
China (21871062, 22071035), “Overseas 100 Talents Program”
of Guangxi Higher Education, and “One thousand Young and
Middle-Aged College and University Backbone Teachers
Cultivation Program” of Guangxi, is greatly appreciated.
8
9
Notes and references
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2
3
4
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14 CCDC: 1938292 (3al) and 1938293 (6aa), contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
15 Other reductive conditions were also tested to form 6aa. The
results are listed below: Zn/HOAc (6aa, 0%), Zn/NH4Cl (6aa,
25%).
16 J. Feng, M. Zhou, X. Z. Lin, A. Lu, X. Y. Zhang and M. Zhao,
Org. Lett. 2019, 21, 6245.
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10 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB01788D
Graphic Abstract
R4
O
Me
Me
O
O
R3
R4
Sc(OTf)3 (10 mol%)
K2CO3, MeCN, rt
OR5
O
HN OR5
R3
+
N
N
H
N
Br
R1
R2
R1
R2
25 examples
26-99% yields
E/ Z = 1:1 to 10:1
R
'
R
R1
R2
O
R
N
R'
A [3+3] cycloaddition and Sc(OTf)3-catalyzed double C-N bond cleavage to
synthesize various α-aminooxy amides bearing a quaternary carbon in one pot has
been achieved from N-vinyl nitrones and α-bromohydroxamates.