Iron(iii)-catalyzed selective N-O bond cleavage to prepare tetrasubstituted pyridines and 3,5-disubstituted isoxazolines from: N -vinyl-α,β-unsaturated ketonitrones

Article abstract of DOI:10.1039/c8gc00630j

An iron(iii)-catalyst controlled cyclization and selective N-O bond cleavage of N-vinyl-α,β-unsaturated nitrones has been achieved under mild conditions to access tetrasubstituted pyridines and 3,5-disubstituted isoxazolines in moderate to good yields. The tetrasubstituted pyridines were afforded with FeCl₃ as a catalyst while using FeCl₃·6H₂O combined with 1,10-phenanthroline delivered isoxazolines. The regioselectivity for cyclization of styrenyl groups in N-vinyl-α,β-unsaturated nitrones was completely different during the formation of pyridines and isoxazolines. A rational mechanism for the formation of pyridines and isoxazolines was proposed based on the further control experimental studies. The isoxazolines can be converted to a novel bidentate N-ligand over four steps and an epoxypyridine scaffold was obtained from N-vinyl nitrone when copper(ii) acetate in combination with the prepared bidentate N-ligand was used.

Full text of DOI:10.1039/c8gc00630j

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Iron(III)-Catalyzed Selective N−O Bond Cleavage to Prepare
Tetrasubstituted Pyridines and 3,5-Disubstituted Isoxazolines
from N-Vinyl-ɑ,β-Unsaturated Ketonitrones
Received 00th January 20xx,
Accepted 00th January 20xx
Chun-Hua Chen, Qing-Yan Wu, Cui Wei, Cui Liang, Gui-Fa Su*, and Dong-Liang Mo*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An iron(III)-catalyst controlled cyclization and selective N−O bond cleavage of N-vinyl-ɑ,β-unsaturated nitrones has been
achieved under mild conditions to access tetrasubstituted pyridines and 3,5-disustituted isoxazolines in moderate to good
yields. The tetrasubstituted pyridines were afforded under FeCl3 as catalyst while using FeCl3•6H2O combined with 1,10-
phenanthroline delivered isoxazolines. The regioselectivity for cyclization of styrenyl groups in N-vinyl-ɑ,β-unsaturated
nitrones was completely different during the formation of pyridines and isoxazolines. A rational mechanism for the
formation of pyridines and isoxazolines was proposed based on the further control experimental studies. The isoxazolines
can be converted to a novel bidentate N-ligand over four steps and an epoxypyridine scaffold was obtained from N-vinyl
nitrone when copper(II) acetate combanied with the prepared bidentate N-ligand was used.
unsaturated nitrones could go through a O-atom transfer
reaction to afford ɑ,β-epoxyketimines under copper(I) chloride
combined with 1,10-phenanthroline (1,10-Phen) (Scheme 1-
Introduction
Diversity-oriented synthesis (DOS) is an efficient strategy
that not only is crucial to the generation of spatially diverse
chemical libraries for biological screening from a single
material, but also improves the synthetic efficiency and
simplifies the operations.1 Controlling reaction selectivity is an
important and challenging topic that rapidly builds molecular
complexity and has been employed for the synthesis of
complicated molecules in both target- and diversity-oriented
syntheses.2 Examples of substrate-, reagent-, solvent-, and
catalyst-controlled divergent cascade process that lead to
either skeletally or stereochemically distinct products are
known, however, the use of catalyst to control the reaction
selectivity is one of the most appealing strategies.3-7 Therefore,
to explore a new and efficient catalyst-oriented method
toward important chemical libraries for biological screening
from simple molecules is desirable.
A).10 An isoxazoline intermediate and a sequence of N−O bond
cleavage were proposed, but the intermediate has not yet
been isolated and completely characterized. We envisioned
that according to the proposed isoxazoline intermediate,
different types of catalysts and the substituted groups on N-
atom of nitrones might control the sequential N−O bond
cleavage.
A) Copperꢀcatalyzed Oꢀatom transfer reaction of Nꢀaryl nitrones to epoxyketimines
Ar2
Ar
Ar
O
O
N
CuCl / 1,10ꢀPhen
MeCN, 80 °C
N
Ar
N
Ar2
Ar1
Ar1
Ar2
[Cu]
O
Ar1
30 examples
80ꢀ99% yields
Proposed
B) This work, Iron(III)ꢀcontrolled NꢀO bond cleavage to access pyridines and isoxazolines
R1
R2
[Fe]
N
R2
Nitrone, one of the most important 1,3-dipoles in
cycloaddition reactions, has been extensively used in diverse
organic synthesis and total synthesis.8 In particular, ɑ,β-
unsaturated nitrones have attracted much attention in recent
years due to the rich chemistry of the double bonds.9 In 2013,
Anderson and coworker firstly reported that N-aryl-ɑ,β-
R2
Ar2
O
Ar1
Ar2
[Fe]
O
R1
Ar1
N
N
R1
O
[Fe]/1,10ꢀPhen
N
Ar2
[Fe]
Ar1
Ar2
Ar1
Scheme 1. Strategies to control the selectivity of N−O bond cleavage
Recently, N-vinyl nitrone has become a new type of nitrone
in organic synthesis due to its new reactivity and
conversions.11 During our studies of N-vinyl nitrones,12 we
surmised that N-vinyl-ɑ,β-unsaturated nitrones might also
undergo an intramolecular attack to form isoxazoline
intermediate, which then afforded pyridine or isoxazoline
scaffolds by further conversion of the double bond on N-atom
after N−O bond cleavage (Scheme 1-B). The pyridine and
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: gfysglgx@163.com; moeastlight@mailbox.gxnu.edu.cn
Electronic Supplementary Information (ESI) available: Experimental details and
characterization of all compounds and copies of 1H and 13C NMR for new
compounds. CCDC 1819200; 1819201. For ESI and crystallographic data in CIF. See
DOI: 10.1039/x0xx00000x
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isoxazoline units are two important N-heterocycles that are improved the yield of product 2a to 65% (Table 1, entry 11).
present in number of natural and pharmacological The yield of product 2a was dropped either at lower or higher
a
compounds and display a wide range of biological activity reaction temperature (Table 1, entries 12-13). To our surprise,
(Figure 1).13 Both two scaffolds have not only been used as a mixture of pyridine 2a and isoxazoline 3a was afforded in 10%
powerful building blocks in organic synthesis but also played and 31% yields by using FeCl3 with 1,10-Phen (L1) and
extensively as versatile N-ligands in catalysis.14 Therefore, to isoxazoline 3a was obtained as the major product (Table 1,
develop efficient methods, especially for the general, practical entry 14). Almost the same result was obtained when i-PrOH
and environmentally benign synthetic methods to prepare was replaced by MeCN (Table 1, entry 15). Moreover, using
pyridine and isoxazoline units remain desirable. Many elegant FeCl3•6H2O and ligand L1 could further increase the total yield
and efficient strategies to prepare pyridine and isoxazoline of products 2a and 3a (Table 1, entry 16). These results
scaffolds were developed in the past decades.15,16 However, demonstrated that the iron-catalysts might control the N-O
most of these methods suffered from harsh reaction bond cleavage. Inspired by these results, the effect of solvents
conditions, expensive metals, and various starting materials. was next examined by using FeCl3•6H2O and 1,10-Phen (L1).
There are no examples reported to prepare both pyridine and The solvent screening revealed that isoxazoline 3a was
isoxazoline units from a single starting material, which limited furnished in moderate to good yields as the major product in
the synthetic efficiency and diversity of products. Although most solvents, such as toluene, DMF, and THF except that DCE
Anderson group has reported a metal-free synthesis of delivered lower yield (Table 1, entries 17-20). It was shown
polysubstituted pyridines from N-vinyl-ɑ,β-unsaturated that THF was the best solvent resulting product 3a in 79% yield
nitrones, high temperature (at 140 °C) was required and the (Table 1, entry 20). Other bidentate N-ligands L2-L4 were also
scope and diversity of products were limited because there tested (Table 1, entries 21-23). Ligand L2 afforded lower yield
were no catalyst to control.17 As the most abundant transition of product 3a while ligands L3 and L4 furnished product 3a
metal on earth, using iron catalysts in synthetic chemistry has smoothly in 73% and 71% yields, respectively. When the
clear advantages because of the inexpensive, nontoxic, and reaction temperature was lowered to 60 °C, product 3a was
environmentally benign properties of iron species.18 However, also obtained in 75% yield (Table 1, entry 24). Further lowering
there was few report that iron-catalyst can be used to control temperature decreased the yield of 3a obviously and no
the selectivity of N−O bond cleavage. Herein, we reported an reaction occurred at room temperature (Table 1, entry 25).
iron(III)-controlled N−O bond cleavage and oriented synthesis Other iron, copper or palladium catalysts were also evaluated.
of tetrasubstituted pyridines and isoxazolines from N-vinyl-ɑ,β- Iron(III) combined with OTf anion furnished product 3a in
unsaturated nitrones.
lower yield while iron(II) catalyst combined with either Cl or
OTf anions did not promote the reaction (Table 1, entries 26-
28). Product 3a was not observed while pyridine 2a was
obtained in 10% and 6% yields by using copper(II) acetate or
copper(I) chloride combined with 1,10-Phen (L1) as catalysts
(Table 1, entries 29-30). 23% yield of product 3a was afforded
without product 2a when the copper was replaced by Pd(OAc)2
(Table 1, entry 31). Therefore, the optimal reaction conditions
for preparing pyridine 2a were using 20 mol% of FeCl3 with 3Å
MS as additive in i-PrOH at 80 °C (Table 1, entry 11). The
optimal conditions for preparing isoxazoline 3a was using 20
mol% of FeCl3•6H2O and 40 mol% of 1,10-Phen (L1) in THF at
80 °C (Table 1, entry 20).19
O
OH
Me
Ph
OH
O
N
OMe
MeO2
C
CO2Et
CF3
COOH
OH
Me
N
Me
N
N
HO
Vitamin B6
Antidiabetic properties
Herbicide
Fatty acid binding protein inhibitors
N
O
O
Me
HN
O
N
N
Me
Me
O2
N
Me
N
DNA methyltransferase 1 inhibitor
Antibacterial agent
O
Figure 1. Bioactive compounds containing pyridine and isoxazoline units
Table 1. Optimization of the Reaction Conditions.a
Results and Discussion
Me
Me
Initially, N-vinyl-ɑ,β-unsaturated nitrone 1a was chosen as
the model substrate to evaluate the cyclization and N−O bond
cleavage process. When nitrone 1a was heated in THF at 80 °C
for 24 h without adding catalyst, product 2a or 3a was
observed less than 5% yield and nitrone 1a was almost
recovered (Table 1, entry 1). Addition of 20 mol% of FeCl3 and
FeCl3•6H2O afforded pyridine 2a as a major product in 39%
and 33% yields, respectively (Table 1, entries 2-3). The solvent
screening revealed that using alcohols as solvents, such as
MeOH, t-BuOH or i-PrOH, gave higher yields of product 2a
compared to THF, MeCN, toluene, DCE, and DMSO (Table 1,
entries 8-10 vs entries 2-7). The reaction delivered pyridine 2a
in 56% yield in i-PrOH (Table 1, entry 10). Addition of 3Å MS
O
Me
Ph
N
O
N
Ph
cat. / L
Me
N
+
solvent, T
Ph
Ph
Ph
Ph
1a
2a
3a
Me
Me
Me
Me
Me
N
N
N
N
N
N
N
N
Me
L1
L2
L3
L4
2 | J. Name., 2012, 00, 1-3
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yields (Table 2, 2ac-ak). However, monosubstituted linear N-
vinyl nitrone 1ab failed to furnish pyridine 2ab and
decomposed to dibenzylideneacetone. For cyclic vinyl group
on N-atom of nitrone, the ring size did not affect the yield of
pyridines much (Table 2, 2ae-ag). Interestingly, compounds
2ai-ak were obtained in good yields even through there were
substituents presented on the six-membered ring, such as
acetal, t-Bu or phenyl groups. The introduction of an acetal
group onto the six-membered ring was particularly appealing
(Table 2, 2ai), because this group could be removed by
entry
1
cat. / L
solvent
T (°C)
2a%b
3a%b
-
THF
THF
80
80
80
80
80
80
80
80
80
80
80
70
100
80
80
80
80
80
80
80
80
80
80
60
25
80
80
80
80
80
80
<5
39
33
30
38
24
27
46
51
56
65
58
64
10
14
18
15
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
10
6
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
31
38
43
26
60
63
79
32
73
71
75
<5
24
<5
<5
<5
<5
23
2
FeCl3
3
4
5
6
7
8
FeCl3•6H2O
FeCl3
THF
MeCN
toluene
DCE
FeCl3
FeCl3
FeCl3
DMSO
MeOH
t-BuOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
MeCN
MeCN
DCE
FeCl3
9
FeCl3
10
11c
12c
13c
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
FeCl3
deprotection to provide
manipulation.
a synthetic handle for further
FeCl3
FeCl3
Table 2. The scope of preparing tetrasubstituted pyridines
for N-vinyl nitrones 1 a,b
2
FeCl3
.
FeCl3 / L1
FeCl3 / L1
R4
R3
R3
FeCl3•6H2O / L1
FeCl3•6H2O / L1
FeCl3•6H2O / L1
FeCl3•6H2O / L1
FeCl3•6H2O / L1
FeCl3•6H2O / L2
FeCl3•6H2O / L3
FeCl3•6H2O / L4
FeCl3•6H2O / L1
FeCl3•6H2O / L1
Fe(OTf)3 / L1
FeCl2 / L1
R4
R2
O
FeCl3 (20 mol%)
N
N
toluene
DMF
THF
R1
3 Å MS, i-PrOH, 80 °C
R1
R2
2
1
Me
Me
Me
N
THF
Me
Me
Ph
Me
X
N
N
THF
R
THF
R
R
THF
X
THF
R = H,
R = 4ꢀOMe, 2b (23%)
R = 4ꢀMe, 2c (56%)
R = 4ꢀCF3
R = 4ꢀBr, 2e (58%)
R = 2ꢀBr, 2f (54%)
2a, (65%)
R = H,
2i (74%)
X = O, 2g (47%)
X = S, 2h (53%)
R = 4ꢀOMe, 2j (65%)
R = 4ꢀBr, 2k (67%)
THF
, 2d (53%)
THF
Fe(OTf)2 / L1
Cu(OAc)2 /L1
CuCl / L1
THF
Me
R = 4ꢀOMe, 2l (50%)
R = 4ꢀBr, 2m (61%)
THF
Me
N
R = 4ꢀCF3, 2n (60%)
THF
R = 4ꢀNO2, 2o (62%)
R = 3ꢀBr, 2p (76%)
R = 2ꢀBr, 2q (58%)
Ph
Pd(OAc)2 / L1
THF
<5
R
2n
a Reaction conditions: 1a (0.2 mmol), cat. (20 mol%), L (40 mol%), solvent (2 mL),
80 °C, 7−24 h; b Isolated yield; c 3Å MS (200 mg) was added.
R3
Me
R4
Me
X
N
N
n
N
Ph
Ph
With the optimized reaction conditions in hand (Table 1,
Ph
Ph
Ph
entry 11), a variety of N-vinyl nitrones
1
were investigated for
. As shown
R3 = H, R4 = nꢀBu, 2ab (<5%)
R3 = Et, R4 = Et, 2ac (59%)
R3 = Ph, R4 = Et, 2ad (45%)
n = 1, 2ae (46%)
n = 2, 2af (52%)
n = 3, 2ag (52%)
X = O, 2r (67%)
X = S, 2s (74%)
the scope of preparing tetrasubstituted pyridines
2
in Table 2, various 2,4,5,6-tetrasubstituted pyridines with
electron-donating and electron-withdrawing groups were
O
R
O
O
N
obtained
in
moderate
yields
when
symmetric
N
N
dibenzylideneacetone-derived N-vinyl nitrones were used, but
Ph
Ph
Ph
Ph
Ph
Ph
nitrone 1b with a methoxy group gave pyridine 2b only in 23%
2ai (56%)
2ah (38%)
R = tꢀBu, 2aj (59%)
R = Ph, 2ak (57%)
yield (Table 2, 2a-f). The reaction also tolerated heteroaryl
a Reaction conditions: 1 (0.2 mmol), FeCl3 (20 mol%), 3Å MS (200 mg), i-PrOH (2 mL),
groups such as 2-furanyl and 2-thienyl giving pyridines 2g and
2h in 47% and 53% yields, respectively. The vinyl groups at 2-
position of pyridines would allow these compounds more
potential transformations in organic synthesis. The scope of N-
vinyl chalcone nitrones was also evaluated. Both aryl groups of
chalcone nitrones were compatible with electron-donating and
electron-withdrawing groups at ortho, meta, and para
80 °C, 12−15 h; b Isolated yield.
We subsequently investigated the substrate scope for
preparing isoxazolines using the optimal conditions (Table 1,
entry 20). As shown in Table 3, a wide range of N-vinyl nitrones
proceeded smoothly to provide various isoxazolines in good
yields. N-vinyl nitrones 1a-f with both electron-rich and
electron-deficient styrenyl functional groups having ortho,
meta, and para substitution patterns were tolerated under the
optimized conditions and afforded the desired isoxazolines in
moderate to good yields (Table 3, 3a-f). To our delight, the
reaction was compatible with 2-furanyl and 2-thienyl groups
on the nitrones, and the corresponding isoxazolines 3g and 3h
were obtained in 76% and 78% yields, respectively. When
asymmetric N-vinyl chalcone nitrones were tested, the aryl
positions (Table 2, 2i-q). The structure of pyridine
further confirmed by the X-ray diffraction analysis of
compound 2n 20
The E/Z ratio for chalcone nitrone 1i-q have
2 was
.
little effect on the yields of 2i-q because the E/Z isomer of vinyl
nitrones were interconvertible under thermal conditions.21 The
vinyl moieties on N-atom of nitrones were also tested.
Disubstituted linear and cyclic N-vinyl nitrones proceeded
smoothly to afford 2,4,5,6-tetrasubstituted pyridines in good
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bearing electron-donating and electron-withdrawing groups methoxy group was subjected to 20 mol% of FeCl3 in i-PrOH at
delivered the corresponding isoxazolines in good to excellent 80 °C, product 2v was afforded in 40% yield and the
yields (Table 3, entries 3i-q). Interestingly, N-vinyl chalcone regioselectivity of cyclization was observed with a 5:1 ratio
nitrones 1i-q, always used with an E/Z ratio of the C=N bond (Scheme 3-1). However, 1:1 E/Z ratio of nitrone 1w with
from 3:1 to 15:1, did not affect the formation of isoxazolines trifluoromethyl group delivered product 2w in 52% yield and
much and both of E/Z isomers could be converted to the regioselectivity of cyclization was observed with a 1:3 ratio.
isoxazolines.21 The structure of isoxazoline
confirmed by X-ray diffraction analysis of compound 3m 20
3
was further The major isomers of 2v and 2w were determined by their
N- NOESY spectra. This regioselectivity of cyclization under iron(III)
.
Vinyl nitrones containing 2-furanyl and 2-thienyl groups catalyst was completely different from metal-free thermal
afforded the desired isoxazolines 3r and 3s in 82% and 86% conditions.17 In this case, cyclization for the formation of
yields, respectively, which provided an alternative method to pyridines was favorable for styrenyl group with an electron-
access double heterocyclic compounds.
donating group in nitrone. For the formation of isoxazolines,
for N-vinyl when nitrone 1v with methoxy group and 1w with
trifluoromethyl group at 4-position of styrenyl group were
subjected to 20 mol% of FeCl3 6H2O with 1,10-Phen in THF at
Table 3. The scope of preparing isoxazolines
nitrone 1 a,b
3
a
.
•
Me
Me
80 °C, products 3v and 3w were obtained in 69% and 60%
yields, respectively (Scheme 3-2). The regioselectivity of
cyclization for the styrenyl group is 1:1 ratio, which suggested
that the electron-donating or electron-withdrawing groups did
not affect the regioselectivity of cyclization for isoxazoline
formation.
O
N
O
FeCl3—6H2O (20 mol%)
R2
N
1,10ꢀPhen (40 mol%)
THF, 80 °C
R1
R1
R2
1
3
O
O
N
N
O
N
Ph
R
X
R
1) Studies of regioselectivity for formation of pyridine 2
Me
R
X
Me
R = H,
3a, (79%)
R = H,
R = 4ꢀOMe, 3j (81%)
R = 4ꢀF, 3u (72%)
R = 4ꢀBr, 3k (82%)
3i (98%)
N
R = 4ꢀOMe, 3b (51%)
R = 4ꢀMe, 3c (72%)
R = 4ꢀCF3, 3d (66%)
R = 3ꢀBr, 3t (76%)
R = 2ꢀBr, 3f (80%)
X = O, 3g (76%)
X = S, 3h (78%)
Ph
Me
a
X
O
FeCl3 (20 mol%)
Me
N
+
Me
O
X
N
3Å MS, iꢀPrOH, 80 °C
Me
Ph
O
R = 4ꢀOMe, 3l (68%)
Ph
N
N
R = 4ꢀBr,
3m (75%)
Ph
R = 4ꢀCF3, 3n (83%)
X
R = 3ꢀBr,
R = 2ꢀBr,
3p (78%)
3q (86%)
Ph
X = O, 3r (82%)
X = S, 3s (86%)
R
X = OMe, 1v (E/ Z = 1:1)
X = CF3 1w (E/Z = 1:1)
3m
b
,
X
a Reaction conditions:
THF (2 mL), 80 °C, 7−15 h; b Isolated yield.
1 (0.2 mmol), FeCl3•6H2O (20 mol%), 1,10-Phen (40 mol%),
X = OMe, 2v (40%, a/b = 5:1)
X = CF3, 2w (52%, a/b = 1:3)
2) Studies of regioselectivity for formation of isoxazoline 3
O
N
X
Obviously, the vinyl substituent on N-atom of nitrone was
dropped during the formation of isoxazolines. Therefore,
substituents on N-atom were evaluated. As shown in Scheme 2,
both monosubstituted linear N-vinyl nitrone 1ab and cyclic N-
vinyl nitrone 1af proceed smoothly to afford isoxazoline 3a in
82% yield. These results revealed that the vinyl substituents on
N-atom did not have a great effect on the formation of
isoxazolines.
Me
Ph
a
O
Me
N
O
FeCl3—6H2O (20 mol%)
N
+
Ph
1,10ꢀPhen (40 mol%)
THF, 80 °C
Ph
b
X
X
X = OMe, 1v (E/Z = 1:1)
X = CF3, 1w (E/Z = 1:1)
X = OMe, 3v (69%, a/b = 1:1)
X = CF3, 3w (60%, a/b = 1:1)
Scheme 3. Exploration of regioselectivity for forming pyridines and isoxazolines
Some control experiments were conducted to gain some
information on the reaction mechanism (Scheme 4). When
nitrone 1a was conducted under FeCl3 in i-PrOH with radical
trapping reagent TEMPO, 36% yield of pyridine 2a was
nꢀBu
O
N
FeCl3•6H2O (20 mol%)
O
Ph
N
1,10ꢀPhen (40 mol%)
THF, 80 °C
1)
Ph
Ph
Ph
3a, 82%
obtained (Scheme 4-1). However, an isoxazole product
afforded in 61% yield when 1a reacted with TEMPO under
FeCl3 6H2O with 1,10-Phen (Scheme 4-2). The isoxazoline 3a
was converted to isoxazole in 29% yield in the presence of
FeCl3 6H2O with 1,10-Phen and TEMPO (Scheme 4-3), which
suggested that isoxazole might be generated from
4 was
1ab
•
O
N
O
N
2)
Ph
4
FeCl3•6H2O (20 mol%)
1,10ꢀPhen (40 mol%)
THF, 80 °C
Ph
Ph
Ph
•
1af
3a, 82%
4
isoxazoline 3a. These results revealed that the formation of
Scheme 2. The reactivity of substituents on N-atom of nitrones
both pyridines and isoxazolines did not involve a radical
process. When N-vinyl nitrone 1al was conducted under FeCl3
•
Next, the regioselectivity of cyclization for the formation of
pyridines and isoxazolines were studied (Scheme 3). For the
formation of pyridines, when 1:1 E/Z ratio of nitrone 1v with a
6H2O with 1,10-Phen, product 3a was obtained in 49% yield
accompanied by 79% yield of acetophenone which might be
4 | J. Name., 2012, 00, 1-3
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produced by hydrolysis from the vinyl group on N-atom of Scheme 4-4. Iron(III) catalyst might play as a Lewis acid to
nitrone (Scheme 4-4). When nitrone 1a ran under FeCl3 with promote these cyclization reactions.
1,10-Phen in THF with addition of 1.0 equiv of D2O, the yield of
R4
R4
R3
R4
R3
3a was obtained in 69% and the deuterated ratio of methylene
group in 3a was 50% and 30%. The NOESY spectra of
compound D-3a showed that D (50%) was cis relationship with
phenyl group (Scheme 4-5). These results suggested that the
protonolysis step was an intermolecular scratching. When N-
aryl nitrone 1am was subjected to the pyridine formation
conditions, enaminoketone 2am was obtained in 26% yield
(Scheme 4-6). This result indicated that enaminoketone might
be the key intermediate for the formation of pyridines.
R4
R3
O
R3
N
FeCl3•6H2O
O
O
[Fe]
N
N
O
N
R2
R2
1,10ꢀPhen
R1
R1
R2
R1
R2
[Fe]
R1
1
F
B
[Fe]
A
R3
FeCl3
H2O
O
R4
R2
R4
R4
HN
R4
R2
N
R2
NH
R1
O
R1
R3
R3
R3
N
R2
O
[Fe]
R1
O[Fe]
C
E
D
[Fe]
R1
G
[Fe] + H2O
H2O
O
R3
R4
R3
Me
R4
R2
Me
O
N
H
N
R2
Me
TEMPO (1.0 equiv)
N
R1
O
R1
FeCl3 (20 mol%)
H
Me
N
2
H
Ph
Ph
Ph
1)
3Å MS, iꢀPrOH, 80 °C
3
Ph
Ph
Scheme 5. Proposed mechanism
2a, 36% yield
1a
Me
Me
TEMPO (1.0 equiv)
O
N
Oxazoline and isoxazole are two important types of N-ligand
and have been extensively applied in transition-metal catalysis.
Hence, a new bidentate N-ligand containing oxazoline and
isoxazole was investigated (Scheme 6-1). Treatment of
isoxazoline 3a under FeCl3 and TBHP, followed with SOCl2,
condensation with L-valinol and cyclization with PPh3 and CCl4
conditions provided ligand L5 and L6 in 53% and 37% yields in
four steps, respectively. The N-ligand L6 was the first time
synthesized. When nitrone 1a was subjected to isoxazoline
formation conditions, pyridine 2a was obtained in 46% yield as
O
O
FeCl3—6H2O (20 mol%)
N
N
2)
1,10ꢀPhen (40 mol%)
THF, 80 °C
Ph
Ph
Ph
Ph
4, 61% yield
1a
O
N
TEMPO (1.0 equiv)
FeCl3—6H2O (20 mol%)
Ph
3)
4)
Ph
Ph
1,10ꢀPhen (40 mol%)
THF, 80 °C
3a
4, 29% yield
O
N
O
O
FeCl3—6H2O (20 mol%)
Ph
Ph
N
+
1,10ꢀPhen (40 mol%)
Ph
THF, 80 °C
Ph
Me
Ph
Ph
79% yield
3a, 49% yield
1al
a major product while an epoxypyridine
5 was afforded in 40%
Me
O
yield and 10% ee accompanied by pyridine 2a in 20% yield
(Scheme 6-2). These results demonstrated that ligand L6
definitely possessed asymmetric induction. Compared to the
optimization by using copper and ligand L1 in Table 1, ligand L6
showed its special catalytic reactivity for N-vinyl nitrone.
FeCl3 (20 mol%)
N
Ph
H(D)
30%
O
1,10ꢀPhen (40 mol%)
NOE
50%
5)
Me
N
Ph
THF, 80 °C
D2O (1.0 equiv)
(D)H
Ph
Me
Ph
1a
D-3a, 69% yield
Me
6)
O
FeCl3 (20 mol%)
3Å MS, iꢀPrOH, 80 °C
1) Synthesis of bidentate Nꢀligand L6 from isoxazoline 3a
N
NH
Ph
O
O
N
Ph
O
Ph
Ph
2) SOCl2
N
Ph
1) FeCl3
TBHP
Ph
N
HOOC
PhCOOH
Me
1am
2am, 26% yield
+
Me
Ph
3a
Scheme 4. Mechanistic studies
H2N
3)
OH
Me
NEt3
Me
O
N
O
4) PPh3/CCl4
Based on the experimental results and literatures on N−O
bond cleavage,22 a plausible mechanism for the formation of
pyridines and isoxazolines from N-vinyl nitrones under iron(III)-
Me
N
+
Me
Ph
O
L6
37% yield
L5
53% yield
catalyst was proposed. As shown in Scheme 5, intermediate
was formed by nitrone coordinated to iron(III), which
occurred an intramolecular attack to give . Intermediate
might undergo a subsequent N−O bond cleavage to result
epoxyketimine , Then, a ring-opening under iron(III)-catalyst
gave enaminoketone D 23
The proceeded an intramolecular
nucleophilic addition of enamine to ketone to afford , which
finally underwent an elimination to provide pyridine and
release iron(III) catalyst and water. Alternatively, isomerisation
of converted to under iron(III) with 1,10-Phen, and then
underwent hydrolysis to form isoxazoline releasing by-
A
2) Application of Nꢀligand L6
Me
1
Me
O
FeCl3•6H2O (20 mol%)
L6 (40 mol%)
Me
N
N
Ph
B
B
O
Me
N
+
Ph
Ph
Ph
THF, 80 °C
Ph
Ph
3a, <5%
C
2a, 46%
1a
Me
Me
Me
Me
.
D
Me
Ph
Cu(OAc)2 (20 mol%)
Me
+
N
O
E
N
L6 (40 mol%)
N
2
Ph
Ph
Ph
THF, 80 °C
O
Ph
Ph
5
2a
20% yield
1a
40%yield, 10% ee
B
F
Scheme 6. Synthesis and application of bidentate N-ligand L6
3
product ketones, which were supported by the result of
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Journal Name
Science and Technology of China (CMEMR2015-A05), Ministry
of Education of China (IRT_16R15), and “Overseas 100 Talents
Program” of Guangxi Higher Education are greatly appreciated.
Conclusions
We have developed an iron(III) catalyst-controlled
cyclization and selective N−O bond cleavage of N-vinyl-ɑ,β-
unsaturated nitrones to access tetrasubstituted pyridines and
3,5-disubstituted isoxazolines in moderate to good yields. The
reaction tolerated various N-vinyl-ɑ,β-unsaturated nitrones
with functional groups. A new bidentate N-ligand was easily
prepared in 37% yield from isoxazoline over four steps and an
epoxypyridine scaffold was obtained by using copper acetate
combined with the prepared N-ligand. The current strategy
features simple and mild reaction conditions, broad substrate
scope, cheap catalyst-controlled N−O bond cleavage, diversity
of N-heterocycles, and facile to access a chiral bidentate N-
ligand.
Notes and references
1
Selected reviews for diversity-oriented synthesis, see: (a) R.
J. Spandl, M. Díaz-Gavilán, K. M. G. O’Connel, G. L. Thomas,
and D. R. Spring, Chem. Rec. 2008, 8, 129; (b) T. E. Nielsen,
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D. R. Spring, Nat. Commun. 2010,
S. G. Beckmann, and D. R. Spring, Chem. Soc. Rev. 2012, 41
6
, 1149; (d) W. R. J. D. Galloway, A. Isidro-Llobet, and
1
, 80; (e) C. J. O’Connel, H.
,
4444; (f) E. Lenci, G. Menchi, and A. Trabocchi, Org. Biomol.
Chem. 2016, 14, 808; (g) S. Collins, S. Bartlett, F. Nie, H. F.
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2
Selected reviews, see: (a) C.-H. Tung, L.-Z. Wu, L.-P. Zhang,
and B. Chen, Acc. Chem. Res. 2003, 36, 39; (b) A. G.
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2012, 45, 936.
Experimental
General procedure for preparing of pyridines 2: A Teflon-
sealed flask was charged with N-vinyl nitrone
1 (0.2 mmol),
3
4
A review for examples of reagent, substrate, and catalyst
controlled reactions, see: C. Serba, and N. Winssinger, Eur. J.
Org. Chem. 2013, 4195.
FeCl3 (7 mg, 20 mol%), 3Å MS (200 mg) under N2 atmosphere.
i-PrOH (2 mL) was then added via syringe and the reaction
vessel was once again sealed with a Teflon cap. The reaction
mixture was stirred at 25 °C for 5 min and then heated at 80 °C
Selected examples of substrate-controlled reactions, see: (a)
K. C. Nicolaou, B. S. Safina, M. Zak, S. H. Lee, M. Nevalainen,
M. Bella, A. A. Estrada, C. Funke, F. J. Zécri, and S. Bulat, J.
Am. Chem. Soc. 2005, 127, 11159; (b) H.-G. Cheng, C.-B.
Chen, F. Tan, N.-J. Chang, J.-R. Chen, and W.-J. Xiao, Eur. J.
Org. Chem. 2010, 4976; (c) S. Santra, and P. R. Andreana,
Angew. Chem. Int. Ed. 2011, 50, 9418; (d) X. Zhang, X. Song,
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J. Zhang, Org. Lett. 2017, 19, 6526.
Selected examples of reagent-controlled reactions, see: (a)
D. Robbins, A. F. Newton, C. Gignoux, J. C. Legeay, A. Sinclair,
M. Rejzek, C. A. Laxon, S. K. Yalamanchili, W. Lewis, M. A.
O’Connell, and R. A. Stockman, Chem. Sci. 2011, 2, 2232; (b)
R. Halim, L. Aurelio, P. J. Scammells, and B. L. Flynn, J. Org.
Chem. 2013, 78, 4708; (c) J. M. Nogueira, M. Bylsma, D. K.
for 12–15 h until nitrones
1 were consumed completely
(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 on silica gel, 1/50 to 1/20, ethyl acetate/petroleum
ether) to afford tetrasubstituted pyridines 2.
General procedure for preparing isoxazolines 3: A Teflon-
sealed flask was charged with N-vinyl nitrones (0.2 mmol),
5
1
FeCl3•6H2O (11 mg, 20 mol%), 1,10-Phen (15 mg, 40 mol%)
under N2 atmosphere. THF (2 mL) was then added via syringe
and the reaction vessel was once again sealed with a Teflon
cap. The reaction mixture was stirred at 25 °C for 5 min and
Bright, and C. S. Bennett, Angew. Chem. Int. Ed. 2016, 55
8
,
,
then heated at 80 °C for 7–15 h until nitrones
1 were
10008; (d) Y. You, L. Zhang, and S. Luo, Chem. Sci. 2017,
621.
consumed completely (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 on silica gel, 1/50 to 1/20, ethyl
6
Recent examples of solvent-controlled reactions, see: (a) Y.
Su, S. Gao, Y. Huang, A. Lin, and H. Yao, Chem. Eur. J. 2015,
21, 15820; (b) M. Miao, Y. Luo, H. Xu, Z. Chen, J. Xu, and H.
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H. Liu, and H. Jiang, Adv. Synth. Catal. 2017, 359, 3509; (d) N.
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Y. More, and M. Jeganmohan, Chem. Commun. 2017, 53
,
9616; (e) J. Jia, A. Yu, S. Ma, Y. Zhang, K. Li, and X. Meng, Org.
Lett. 2017, 19, 6084; (f) P. Ni, B. Li, H. Huang, F. Xiao, and G.-
J. Deng, Green Chem. 2017, 19, 5553; (g) J.-B. Peng, and X.-F.
Wu, Angew. Chem. Int. Ed. 2018, 57, 1152.
Conflicts of interest
There are no conflicts of interest to declare
7
Selected examples of catalyst-controlled reactions, see: (a) B.
R. Balthaser, M. C. Maloney, A. B. Beeler, J. A. Porco Jr., and
J. K. Snyder, Nat. Chem. 2011, 3, 969; (b) G. Valot, J. Garcia,
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Financial support from National Natural Science Foundation of
China (21562005, 21602037, 21462008), Natural Science
Foundation
of
Guangxi
(2015GXNSFCA139001,
2016GXNSFFA380005), State Key Laboratory for Chemistry and
Molecular Engineering of Medicinal Resources, Ministry of
6 | J. Name., 2012, 00, 1-3
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1
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7, 190; (f) I.
12 Some studies of nitrones in our group, see: (a) N. Zou, J.-W. 19 See more optimized reaction conditions for the formation of
Jiao, Y. Feng, C.-H. Chen, C. Liang, G.-F. Su, and D.-L. Mo, Adv. pyridine 2a and isoxazoline 3a in Supporting Information.
Synth. Catal. 2017, 359, 3545; (b) C.-H. Chen, Q.-Q. Liu, X.-P. 20 CCDC: 1819201 (compound 2n and CCDC: 1819200
)
Ma, Y. Feng, C. Liang, C.-X. Pan, G.-F. Su, and D.-L. Mo, J. Org.
Chem. 2017, 82, 6417; (c) X.-P. Ma, J.-F. Zhu, S.-Y. Wu, C.-H.
Chen, N. Zou, C. Liang, G.-F. Su, and D.-L. Mo, J. Org. Chem.
2017, 82, 502; (d) S.-Y. Wu, X.-P. Ma, C. Liang, and D.-L. Mo,
(compound 3m) 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.
J. Org. Chem. 2017, 82, 3232; (e) X.-P. Ma, K. Li, S.-Y. Wu, C. 21 The E/Z ratio for N-vinyl nitrones 1i-q used as follows: 1i
Liang, G.-F. Su, and D.-L. Mo, Green. Chem. 2017, 19, 5761;
(f) X.-P. Ma, W.-M. Shi, X.-L. Mo, X.-H. Li, L.-G. Li, C.-X. Pan, B.
Chen, G.-F. Su, and D.-L. Mo, J. Org. Chem. 2015, 80, 10098;
(g) X.-L. Mo, C.-H. Chen, C. Liang, and D.-L. Mo, Eur. J. Org.
Chem. 2018, 150.
(15:1), 1j (10:1), 1k (8:1), 1l (10:1), 1m (8:1), 1n (3.5:1), 1o
(10:1), 1p (8:1), 1q (8:1). The E/Z isomerisation of N-vinyl
chalcone nitrone 1i was tested. The results showed that E/Z
= 15/1 of nitrone 1i turned to E/Z = 5.8/1 for heating 5.5 h.
And E/Z = 1/1.4 of nitrone 1i turned to E/Z = 7.2/1 for
heating 1.5 h. Please see the spectra in Supporting
Information.
13 (a) L.-H. Zhang, J. C. Chung, T. D. Costello, I. Valvis, P. Ma, S.
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23 Although the enaminoketone
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D was not observed in this
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,
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Green Chemistry
Page 8 of 8
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DOI: 10.1039/C8GC00630J
Graphic Abstract
R4
R3
FeCl3•6H2O (20 mol%)
R4
R2
O
O
N
R3
N
FeCl3 (20 mol%)
N
1,10-Phen (40 mol%)
THF, 80 °C
R2
i-PrOH, 80 °C
R1
R1
R1
R2
20 examples
51-98% yields
26 examples
23-74% yields
Me
Simple and mild conditions
Broad substrate scope
N
N
O
Me
Diversity of N-heterocycles
Ph
O
Cheap catalyst-controlled selectivity
37% yield in four steps
Facile to access a bidentate N-ligand
An iron(III)ꢀcontrolled selective N−O bond cleavage was developed for the synthesis
of tetrasubstituted pyridines and isoxazolines from Nꢀvinylꢀɑ,βꢀunsaturated
ketonitrones.