4-HO-TEMPO-Catalyzed Redox Annulation of Cyclopropanols with Oxime Acetates toward Pyridine Derivatives

Article abstract of DOI:10.1021/acscatal.9b00832

A 4-HO-TEMPO-catalyzed redox strategy for the synthesis of pyridines through the annulation of cyclopropanols and oxime acetates has been developed. This protocol features good functional group tolerance and high chemoselectivity and also promises to be efficient for the late-stage functionalization of skeletons of drugs and natural products. Mechanism studies indicate that the reaction involves the in situ generated α,β-unsaturated ketones and imines as the key intermediates, which are derived from cyclopropanols and oxime acetates via a TEMPO/TEMPOH redox cycle, respectively. The pyridine products are formed as a result of annulation of enones with imines followed by TEMPO-catalyzed oxidative aromatization by excess oxime acetates. This method not only realizes the TEMPO-catalyzed redox reaction but also broadens the frontiers for TEMPO in catalysis.

Full text of DOI:10.1021/acscatal.9b00832

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Article
4-HO-TEMPO-Catalyzed Redox Annulation of Cyclopropanols
with Oxime Acetates toward Pyridine Derivatives
Jun-Long Zhan, Meng-Wei Wu, Dian Wei, Bang-Yi Wei, Yu Jiang, Wei Yu, and Bing Han
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 28 Mar 2019
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Page 1 of 9
ACS Catalysis
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4-HO-TEMPO-Catalyzed Redox Annulation of Cyclopropanols
with Oxime Acetates toward Pyridine Derivatives
Jun-Long Zhan,† Meng-Wei Wu,† Dian Wei, Bang-Yi Wei, Yu Jiang, Wei Yu, and Bing Han*
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State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou, 730000, People’s Republic of China
ABSTRACT: A 4-HO-TEMPO-catalyzed redox strategy for the synthesis of pyridines through the annulation of cyclopropanols
and oxime acetates has been developed. This protocol features good functional group tolerance, high chemoselectivity, and also
promises to be efficient for the late-stage functionalization of skeletons of drugs and natural products. Mechanism studies indicate
that the reaction involves the in-situ generated α,β-unsaturated ketones and imines as the key intermediates, which derived from
cyclopropanols and oxime acetates via a TEMPO/TEMPOH redox cycle, respectively. The pyridine products are formed as a result
of annulation of enones with imines followed by TEMPO-catalyzed oxidative aromatization by excess oxime acetates. This method
not only realizes the TEMPO-catalyzed redox reaction, but also broadens the frontiers for TEMPO in catalysis.
KEYWORDS: nitroxyl radical catalysis • pyridines • redox reaction • iminyl radical • enones • annulation
works for the synthesis of polysubstituted pyridines from
INTRODUCTION
oxime esters and α,β-unsaturated aldehydes/ketimines under
copper catalysis (Scheme 2a and 2b).8a,b In 2018, Li and co-
workers further investigated the Cu-catalyzed synthesis of
fluoroalkylated pyridines from oxime acetates and β-CF3-
substituted α,β-unsaturated ketones (Scheme 2c).8c
Previous transition metal-mediated processes
TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl),1 a well-known
persistent nitroxyl radical, has found extensive applications in
organic synthesis,2 polymer chemistry,3 biochemistry,4 and
material science5 in past decades. Due to its
intermediate valence, TEMPO shows redox properties which
could be further oxidized to the corresponding oxoammonium
species TEMPO+ (cycle I) as well as undergoes a 1e−/1H+
reduction to hydroxylamine TEMPOH (cycle II) (Scheme 1).
Consequently, TEMPO and TEMPO+ salts have been widely
used as oxidants in organic reactions. Recently, more and
more attention has been paid to the strategy of employing
TEMPO as a catalyst in the oxidation reaction by using extra
oxidants2k-u or electrooxidation2v-z to recycle TEMPO.
However, most of those catalytic reactions rely on the
oxidative property of TEMPO, the reduction of substrates by
hydroxylamine TEMPOH has remained largely unappreciated.
TEMPO-mediated redox reactions, where both TEMPOH and
TEMPO are active catalysts to react with the substrates, have
not been reported so far to our knowledge.
(a)
R3
CuI (20 mol %)
CHO
R4
NOAc
R2
R2
R1
R4
R2NH HClO4
DMSO, 60 o
+
+
C
R1
R3
N
(b)
R3
R4
R3
N
[Cu(MeCN)4]PF6 (5 mol %)
NaHSO3 (1 equiv)
NOAc
R2
R2
R4
R5
NTs
DMSO, 60 o
C
R1
R5
R1
CF3
(c)
(d)
O
NOAc
CuCl (20 mol %)
DMSO, 60 o
+
+
R2
R1
C
F3C
R1
R2
R1
N
R2
R4
N3
R4
R3
Mn(acac)3 (1.7 equiv)
MeOH, then HOAc
R1
R2
HO
R3
N
Our nitroxyl radical-catalyzed redox strategy
(e)
+ e, + H+
R2
R1
+ e
O
cat. TEMPO
N
O
N
O
N
- e, - H+
redox cycle
- e
R2
N
R2
in situ generated
NH2
R1
[3+3]
annulation
HO
I
OH
redox cycle
II
R4
R3
TEMPO
+
TEMPOH
TEMPO+
TEMPO
TEMPOH
oxidation
NH
NOAc
R4
R1
R3
Scheme 1. Redox Cycles of TEMPO.
redox
R3
R3
R4
R4
Pyridine scaffolds have attracted widespread attention
because they are not only common moieties in natural
products and drug molecules, but also play important roles in
TEMPO catalyzed redox reaction
both TEMPOH and TEMPO as active catalysts




in-situ generated enones and imines metal-free, additive-free broad substrate scope


pyridine synthesis in one pot
good functional group tolerance
high chemoselectivity


Scheme 2. Strategies for Pyridines Synthesis via [3+3]
Annulation.
functional
materials,
coordination
chemistry
and
organic catalysis.6 So far, various synthetic approaches have
been developed to access pyridine scaffolds.7 Very recently,
the [3+3]-type condensation reaction has been proved to be a
practical strategy for constructing pyridine derivatives.7b,7e-
Cyclopropanols, due to their intrinsic strain energy and
ready availability, serves as valuable C3 synthons in organic
synthesis.9 During the last decades, many efforts have been
made to synthesize β-functionalized carbonyl compounds from
cyclopropanols10 via transition-metal mediated oxidative ring-
opening (Scheme 3). For instance, Chiba reported an
impressive Mn(OAc)3-mediated [3+3] annulation for the
g,8,10a,10b
Among them, oxime esters as the C2N1 synthons as
well as the internal oxi-dants have been utilized for the
synthesis of structurally di-verse pyridines skeletons. For
example, in 2013 and 2017, Yoshikai reported two elegant
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ACS Catalysis
synthesis of pyridines using cyclopropanols and vinyl azides
Page 2 of 9
no better result was obtained. In addition, the loading amount
of catalyst was also explored. When the amount of 4-HO-
TEMPO was increased to 30 mol %, there is no significant
improvement on the yield of 3a. When the amount of 4-HO-
TEMPO was decreased to 10 mol %, on the other hand, a
slight decreasing in yield was observed (Table 1, entries 11
and 12). No reaction took place in the absence of 4-HO-
TEMPO (Table 1, entry 13). When the protocol was
performed under air, the reaction was obviously suppressed
(Table 1, entry 14). TEMPO could also catalyze this reaction
to give the desired 3a in comparable yield (Table 1, entry 15).
However, 4-HO-TEMPO was a better option considering its
low volatility and easy separability.
as the substrates (Scheme 2d).10a,10b The proposed reaction
mechanism involves the formation of β-keto alkyl radical
intermediates derived from Mn(OAc)3-mediated oxidative
radical ring-opening of cyclopropanols, followed by radical
addition to vinyl azides and annulation. Despite these
achievements, however, transformations of cyclopropanols
through new routes, such as the oxidative dehydrogenation to
α,β-unsaturated ketones, has been rarely reported.11 During the
course of our research on radical-promoted heterocycle
synthesis,12 we found that TEMPO can promote the oxidative
ring-opening of cyclopropanols to give α,β-unsaturated
ketones, with TEMPO being reduced to TEMPOH. When an
oxime ester was present in the reaction system, it can be
reduced by the in situ generated TEMPOH to the
corresponding imine. The thus formed imines then underwent
[3+3] annulation with the ,β-unsaturated ketones generated
in the previous step to afford dihydropyridines which were
further oxidized to yield pyridine products (Scheme 2e). The
whole process takes the form of oxidative annulation between
cyclopropanols and oxime esters. As both TEMPO and its
reduced form TEMPOH were involved in the process, only a
catalytic amount of TEMPO is required to guarantee a
complete conversion. To the best of our knowledge, this work
represents the first example of the TEMPO-catalyzed redox
reaction, where both TEMPOH and TEMPO are active
catalysts. Moreover, although transition metal-mediated ring-
opening of cyclopropanols9a,10 and N-O bond cleavage of
oxime esters13 have been well studied, realization of these
reactions under metal-free conditions have been rarely
reported.14 This reaction also represents the first example of
TEMPO-promoted radical ring-opening of cyclopropanols as
well as the first case of TEMPOH-induced N-O bond cleavage
of oxime esters. As TEMPO is a nontoxic oxidant and readily
available, this method is expected to find applications in the
synthesis of pharmaceutically important pyridine compounds.
Notably, the present method is suitable for the synthesis of
2,6-disubstituted or 2,3,6-trisubstituted pyridines. These types
of pyridines are not easily accessible via annulation of
terminal enones and ketoxime esters.8a-d Herein we report
these results.
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Table 1. Optimization of the Reaction Conditionsa
4-HO-TEMPO (x mol %)
solvent, Ar, 120 oC, 36 h
NOR
HO
Ph
Ph
N
Ph
Ph
1a
2
3a
(2.5 equiv)
4-HO-TEMPO
(x mol %)
yield
(%)b
entry
R
solvent
1
2
Ac
Ac
Ac
Ac
Ac
Ac
Piv
20
20
20
20
20
20
20
20
20
20
30
10
0
toluene
DCE
29
42
53
73
43
78
74
75
50
43
79
70
0
3
1,4-dioxane
DMF
4
5
DMA
6
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
7
8
isobutyryl
9
Bz
10
11
12
13
14c
15d
3,5-dinitro-Bz
Ac
Ac
Ac
Ac
Ac
20
＜10
20
78
aAll reactions were carried out by stirring 1a (0.3 mmol), 2a (2.5
equiv) and 4-HO-TEMPO (x mol %) in solvent (1.5 mL) for 36 h
under Ar unless noted otherwise. bYield of isolated product.
O
O
MLn
O
via
or
R
OH
cReaction was carried out under air. TEMPO (20 mol %) was
R
d
R
R
FG
used instead of 4-HO-TEMPO.
homoenolates
β-keto alkyl radical
FG: Br, I, N3, SCN, Cl, F, NR1R2, CF3, CF2X, aryl, alkynyl, etc.
With the optimal conditions established, the synthetic scope
of this reaction was investigated next. Variation on oxime
acetates was first tested, and the results were summarized in
Scheme 4. It can be seen that para-substituted acetophenone
oxime acetates with a wide variety of electronic properties
reacted very well with 1a under the indicated conditions to
give the desired pyridines 3a-k in good to excellent yields,
exhibiting good tolerance of functional groups such as fluoro,
chloro, bromo, iodo, trifluoromethyl, nitro, and ether. When
m-Me and o-Me substituted counterparts were used, the
annulation products 3l and 3m were obtained in 73% and 35%
yields, respectively, indicating an obvious steric effect. 3,4-
Disubstituted aceto-phenone oxime acetate was also converted
to the expected product 3n in 62% yield. In addition, 1-
naphthyl and 2-thienyl incorporated oxime acetates
participated well in the reaction and gave the desired pyridines
3o and 3p in good yields. Notably, oxime acetates involving
α- or γ-keto ester were also compatible in the present protocol,
affording the corresponding ester substituted pyridines 3q and
3r in moderate yields. Moreover, oxime acetates derived from
Scheme 3. Transition Metal Mediated Ring-Opening
Transformations of Cyclopropanol Derivatives.
RESULTS AND DISCUSSION
We initiated our investigation by stirring 1-phenylcyclo-
propanol (1a, 0.3 mmol) and acetophenone oxime acetate (2a,
2.5 equiv) in the presence of 4-HO-TEMPO (20 mol %) in
toluene under Ar at 120 oC. To our delight, the desired product
2,6-diphenylpyridine 3a was produced in 29% yield (Table 1,
entry 1). To enhance the reaction efficiency, other solvents
such as 1,2-dichloroethane (DCE), 1,4-dioxane, N,N-
dimethylformide (DMF), N,N-dimethylacetamide (DMA) and
dimethylsulfoxide (DMSO) were investigated (Table 1, entries
2-6). Among them, DMSO proved to be superior to other
solvents, and the yield of 3a in DMSO was raised to 78%
(Table 1, entry 6). To further improve the yield of 3a, oxime
esters with different electronic properties including pivaloyl
(Piv), isobutyryl, benzoyl (Bz), 3,5-dinitro-benzoyl (3,5-
dinitro-Bz) were examined (Table 1, entries 7-10). However,
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ACS Catalysis
Scheme 5. Regioselective and Competitive Reactions of
both chain-like and cyclic ketones, such as undecan-6-one,
cyclopentanone, cyclohexanone, cycloheptanone, and
1
Oxime Acetates
2
3
4
5
6
7
8
9
cyclopentadecanone, were all transformed smoothly in the
reaction, delivering 2,3,6-trisubstituted pyridines 3s-w in
medium yields. 3,4-Dihydronaphthalen-1(2H)-one and 6-
methyl-chroman-4-one oxime acetates were also good
candidates for this tactic, providing the fused pyridines 3x and
3y in 88% and 50% yields, respectively. Significantly, the
annulation of nitrogen-containing endocyclic oxime acetate
was also successful, as demonstrated by the formation of 3z in
Next, a series of cyclopropanol derivates were tested, and
the result is shown in Scheme 6. Phenylcyclopropanols with
different substituents on the phenyl ring, such as p-MeO, p-Ph,
p-CF3, p-Cl, m-Cl, and 3,5-dimethoxyl, were transformed very
well under the standard conditions, and the desired pyridines
4b-g were obtained in good to excellent yields. Naphthalene-
2-cyclopropanol and thiophene-3-cyclopropanol also well
participated in the reaction, giving rise to the corresponding
pyridines 4h and 4i in 80% and 85% yield, respectively. Alkyl,
cycloalkyl, and adamantyl substituted cyclopropanol
derivatives were all good redox partners and generated the
desired products 4j-o in 62-83% yields. In addition, piperidyl
substituted cyclopropanol was compatible with this catalytic
system as well and converted into the expected pyridines 4p in
48% yield. Gratifyingly, when 2-ethyl-1-phenylcyclopropanol
was involved in the reaction, 2,3,4,6-tetrasubstituted pyridine
70 % yield.
NOAc
R2
10
11
12
13
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4-HO-TEMPO (20 mol % )
+
R1
DMSO, Ar, 120 o
C
HO
Ph
Ph
Ph
N
3a-z
R1
R2
1a
2a-z
(2.5 equiv)
N
Ph
N
Ph
N
Ph Ph
N
tBu
OMe
3b
3c
3d
, 72%
3a
, 71%
N
, 60%
N
, 76%
4q was produced in 43% yield.
R2
R2
Ph
Ph
N
NOAc
Ph
N
Ph
Ph
4-HO-TEMPO (20 mol %)
DMSO, 120 oC, Ar
+
Cl
Br
F
3f
HO
1b-q
R1
3g
3h
, 82%
, 83%
, 82%
R1
N
3e
, 67%
4b-v
2x
(2.5 equiv)
Ph
I
N
Ph
N
Ph
N
Ph
NO2
N
CF3
N
N
N
3i
3j
3k
3l
, 85%
, 80%
, 81%
N
, 73%
F3C
MeO
Ph
Cl
4b
4c
4d
, 81%
, 76%
, 82%
O
O
S
Ph
Ph
N
Ph
N
Ph
Ph
N
MeO
N
3m
3n
3o, 75%
3p
, 35%
, 62%
, 68%
N
N
N
Cl
CO2Me
OMe
4g
, 70%
4e
4f
, 76%
, 86%
n
Ph
3t
N
Ph
N
CO2Et
Ph
N
, n = 1, 46%
Ph
3u
, n = 2, 51%
3q
, 42%
3r
3s
, 50%
, 48%
N
N
N
3v
, n = 3, 48%
6
S
O
4j
, 74%
4i
, 85%
4h
, 80%
O
N
Ph
N
Ph
N
Ph
N
N
N
N
N
Ph
N
3w
, 53%
3x
3z
, 70%
, 88%
3y
, 50%
4k
4l, 70%
4m
4n
, 76%
, 81%
, 62%
Scheme 4. Scope of oxime acetatesa,b
aAll reactions were carried out by stirring 1a (0.5 mmol), 2 (2.5
equiv) and 4-HO-TEMPO (20 mol %) in DMSO (2.5 mL) for 24-
36 h under Ar unless noted otherwise. bIsolated yield.
N
N
Ph
N
TsN
4p
, 48%
4o
, 83%
4q
, 43%
To further clarify the reactivity of oxime acetate, we
employed asymmetric 2-heptanone oxime acetate which
possesses two distinct enolizable α-positions to react with 1a.
As shown in Scheme 5a, the reaction resulted in pyridine 3aa
in 47% yield with another possible regioisomer 3ab
undetected, reflecting the internal selectivity of enolizable α-
position rather than the distal selectivity. In addition, the
intermolecular competitive reaction was also conducted as
shown in Scheme 5b. When the mixture of same amount of 2a
and 2x was allowed to react with 1a, the competitive reaction
gave com pound 3x in 86% yield along with a trace amount of
3a, indicating that cyclic oxime acetate 2x is more reactive
than its acyclic counterparts.
Scheme 6. Substrate Scope of Cyclopropanolsa,b
aAll reactions were carried out by stirring 1 (0.5 mmol), 2x (2.5
equiv) and 4-HO-TEMPO (20 mol %) in DMSO (2.5 mL) for 24-
36 h under Ar unless noted otherwise. bIsolated yield.
The present protocol is well suitable for late-stage
functionalization of complex molecules derived from drugs
and natural products (Scheme 7). For instance, cyclopropanols,
which were derived from analgesic and anti-inflammatory
drugs Naproxen and Ibuprofen participated smoothly in this
transformation, yielding the desired products 4r and 4s in
good yields. Product 4r was obtained with partial racemization
when chiral cyclopropanol 1r was used. The racemization may
be due to the fact that 1r was oxidized by 4-HO-TEMPO to
form a chiral enone intermediate, which is easy to racemize at
the α-carbonyl position via enolization, leading to the final
annulation product 4r in partial racemization. Moreover,
alkene-containing cyclopropanols derived from terpenes such
as citronellal and abietic acid were also suitable for this
strategy, affording the desired pyridines 4t and 4u in moderate
yields. When steroid lithocholic acid derivative was allowed to
react under the standard conditions, the corresponding
cyclization product 4v was formed in 87% yield.
(a)
standard
conditions
n-Bu
NOAc
1a
+
+
n-Am
Ph
N
n-Am
Ph
N
3aa
,
47%
2aa
3ab, undetected
, 2.5 equiv
(b)
1a
standard
conditions
NOAc
NOAc
+
+
+
Ph
N
Ph
Ph
N
Ph
3a
, trace
2a
3x, 86%
, 2.5 equiv
2x
, 2.5 equiv
ACS Paragon Plus Environment

ACS Catalysis
results demonstrate that 4-HO-TEMPO could oxidize
Page 4 of 9
1
2
3
4
5
6
7
8
cyclopropanol to produce enone, with itself being reduced to
4-HO-TEMPOH (eq. 1). Notably, although the in-situ
generated enones are unstable in DMSO, they could be further
transformed to pyridines in the presence of ketoximes esters.
In addition, cyclopropanol acetate 12 could neither be
oxidized to produce enone by the treatment with 4-HO-
TEMPO, nor reacted with oxime acetate 2a to produce
pyridine derivative, demonstrating that free hydroxyl group of
cyclopropanol is essential for the reaction (eqs. 3 and 4).
These results also indicate that a hydrogen atom transfer
(HAT) process is involved in the oxidation of cyclopropanols
by 4-HO-TEMPO.
O
N
N
N
4r
4s
, 62%, from Ibuprofen
, 63%, ee 48%, from Naproxen
4t
, 57%, from Citronellal
N
H
N
H
H
H
H
9
HO
H
4u
, 40%, from Abietic acid
4v
, 87%, from Lithocholic acid
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60
Scheme 7. Applications of Natural Products and Drug
Moleculesa,b
O
4-HO-TEMPO (3 equiv)
OH
4-HO-TEMPOH
60%
+
DMSO, Ar, 120 oC, 18 h
48% conv.
aAll reactions were carried out by stirring 1 (0.5 mmol), 2x (2.5
equiv), and 4-HO-TEMPO (20 mol %) in DMSO (2.5 mL) for 24-
36 h under Ar unless noted otherwise. bIsolated yield.
Ph
Ph
+
1c
10
, 32%
OH
O
(1)
N
To further explore the practicability of the strategy, gram-
scale synthesis of 3x and its follow-up derivatizations were
conducted. As shown in Scheme 8, the reaction of 1a and 2x
on a gram scale gave 3x in a yield of 82% (1.055 g). Pyridine
3x could be converted to benzo[h]quinoline 5 via oxidative
dehydrogenation. In addition, oxygenation of 3x gave 2-
phenylbenzo[h]quinoline-5,6-dione 6, which could be further
oxidized to dicarboxylic acid 7. Condensation of compound 6
with 1,2-diaminoethane and triformol/NH4OAc yielded the
bioactive fused heterocycles 8 and 9, respectively.15
variations
10
O
10%
t = 36 h
Ph
11
10
, detected by ESI-HRMS
72%
DCE instead of DMSO
O
(2)
complex mixtures
, 34%
+
DMSO, Ar, 120 oC, 36 h
Ph
10
, 0.3 mmol
Ph
4-HO-TEMPO (3 equiv)
no reaction
(3)
(4)
OAc
12
N
NOAc
4-HO-TEMPO (20 mol %)
DMSO, Ar, 120 oC, 24 h
no reaction
+
12
N
Ph
2a
(2.5 equiv)
1a
5 mmol
2x
2.5 equiv
Ph
N
+
8
, 83%
To further elucidate the conversion of cyclopropanols to the
corresponding enones by the oxidation of 4-HO-TEMPO
under the current circumstances, DFT study (details, see SI)
was conducted and the result is shown in Figure 1. The
calculated O-H bond BDE of cyclopropanols 1a is 89.5 kcal
mol-1 which is close to the reported O-H BDE of 4-HO-
TEMPOH (72.2 kcal mol-1)16, indicating that a HAT process
between cyclopropanol 1a and 4-HO-TEMPOH is reasonable
(ΔE, about 17.3 kcal mol-1). Indeed, according to the
calculations, 1a first binds rapidly with 4-HO-TEMPO
through hydrogen bonding to give intermediate INT1, which
then undergoes rate-determining hydrogen atom transfer
(HAT) to form INT2 via TS1. The energy barrier (27.7 kcal
mol-1) for this step is not difficult to overcome at the present
reaction temperature. After INT2 is formed, it would
effortlessly be transformed in to β-keto alkyl radicals INT3
(energy barrier: 1.1 kcal mol-1) via radical ring-opening.
NH2
NH2
4-HO-TEMPO (20 mol %)
DMSO, 120 oC, 36 h
(3 equiv)
MeOH, 70 o
O
C
COOH
H2O2 (2 equiv)
NaOH (2 equiv)
O
CrO3 (2 equiv)
Ac2O, rt, 3 h
Ph
N
Ph
N
THF, H2O, rt
Ph
N
3x
, 82%
(1.055 g)
HOOC
7
6
, 53%
, 98%
(CH2O)3 (3 equiv)
NH4OAc (21 equiv)
DDQ (2 equiv)
toluene, 80 oC, 48 h
AcOH, 100 o
C
HN
N
Ph
N
Ph
N
5
, 70%
9
, 75%
Scheme 8. Gram-scale Synthesis of 3x and Its
Derivatizations.
Grel/kcal mol-1
‡
MECHANISTIC STUDIES
OH
H
N
To gain insights into the reaction mechanism, a series of
control experiments have been conducted as shown in
equations 1-7. First, the oxidation of cyclopropanols by 4-HO-
TEMPO as the redox half reaction in the [3+3] annulation was
investigated. When cyclopropanol 1c was treated with
stoichiometric 4-HO-TEMPO under the standard conditions in
18 h, the reaction gave enone 10 in 32% yield, accompanied
by the generation of 4-HO-TEMPOH in 60% yield under 48%
conversion. Besides, the 4-HO-TEMPO trapping product 11
was also detected by ESI-HRMS (details, see SI). When the
reaction was prolonged to 36 h till cyclopropanol 1c was
completely consumed, the yield of enone 10 was reduced to
10% due to its instability and polymerization in DMSO (eqs. 1
and 2). However, when DCE was used instead of DMSO as
the solvent, the enone 10 was obtained in 72% yield. These
Ph
O
O
‡
TS1
4-HO-
TEMPOH
30.2
Ph
TS2
24.0
O
22.9
Ph
O
INT2
27.7
11.7
O
4-HO-
TEMPO
Ph
2.5
INT3
0.0
OH
N
Ph
OH
INT1
Ph
OH
O
1a
Reaction coordinate
Figure 1. DFT-Computed energy profiles for 4-HO-TEMPO
mediated the generation of β-keto alkyl radical.
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Significantly, the reaction of 1a with 2a could also take
1
2
3
4
place under the catalysis of 4-HO-TEMPOH and gave the
same product 3a in 70% yield, revealing that the reaction
could also be initiated by the reduction of oxime acetate as
well (eq. 6).
5
6
7
NOAc
4-HO-TEMPOH (20 mol %)
DMSO, Ar, 120 oC, 36 h
(6)
+
Ph
OH
Ph
2a
Ph
N
Ph
1a
3a
, 70%
(2.5 equiv)
8
9
Moreover, to confirm that enone was the reaction
intermediate, enone 10 was allowed to react with 2x under the
catalysis of 4-HO-TEMPOH. As expected, the reaction did
take place, giving the corresponding product 4c in 73% yield
(eq. 7). In contrast, the reaction could not take place under the
catalysis of 4-HO-TEMPO.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NOAc
4-HO-TEMPOH (20 mol %)
(7)
10
+
N
DMSO, Ar, 120 oC, 24 h
Ph
2x,
4c
, 73%
1.2 equiv
This result not only indicates that enones could also be used
as an alternative of cyclopropanols to react with ketoxime
acetate for the synthesis of pyridines, but also provides a novel
4-HO-TEMPOH catalyzed redox-neutral reaction. This
modified protocol can be applied to variously substituted
enones, with the pyridine products being generated in
moderate to good yields (Scheme 10). As enones can be
accessed from different precursors from those of
cyclopropanols, this 4-HO-TEMPOH mediated protocol
serves as the complement to that described above. However,
as the terminal enones are liable to polymerize, using
cyclopropanols as substrates is more suitable for the
preparation of 4-unsubstituted pyridines which would
otherwise involve the annulation of terminal enones with
oxime acetates.18
Figure 2. Cyclic voltammograms recorded on a glassy carbon
electrode (the diameter: 3 mm) in 0.1 M solution of n-Bu4NBF4 in
CH3CN. (A) 5 mM 4-HO-TEMPO; (B) 5 mM acetophenone
oxime acetate 2a.
Next, the reduction of oxime acetates by 4-HO-TEMPOH
as another redox half reaction in the [3+3] annulation was
investigated. By cyclic voltammetry experiments (Figure 2),
the half peak reduction potentials of 4-HO-TEMPO and
acetophenone oxime acetate 2a in CH3CN are -1.2 V vs. SCE
(Figure 2A) and -1.9 V vs. SCE (Figure 2B), respectively,
indicating that the direct single electron transfer (SET)
between ketoxime acetate and 4-HO-TEMPOH might be
endoergic. However, it has been well documented that in case
that a SET process is followed or accompanied by a proton
transfer, it can take place as long as the energy gap does not
exceed 1.0 V.17
Subsequent control experiments also confirmed the above
process. When γ,δ-unsaturated oxime acetate 13 was treated
with stoichiometric 4-HO-TEMPOH, the 4-HO-TEMPO-
trapped dihydropyrrole 14 was favorably acquired in 66%
yield (eq. 5). Compound 14 can only be formed via cyclization
of an iminyl intermediate.
R2
NOAc
O
4-HO-TEMPOH (20 mol %)
+
DMSO, Ar, 120 o
C
R2
R1
R1
N
15
2a 2x
or
16
Ph
(1.2 equiv)
Ph
Ph
Ph
N
N
Ph
N
Ph
N
16a
16b
, 46%
16d
, 45%
, 73%
16c
, 60%
Ph
CF3
Ph
N
CF3
N
N
Ph
N
Ph
Ph
Br
16f,
16e
25%
, 69%
16g,
90%
16h
, 93%
OTEMP-4-OH
NOAc
Scheme 10. 4-HO-TEMPOH Catalyzed [3+3] Annulationa,b
aAll reactions were carried out by stirring 15 (0.3 mmol), 2 (1.2
equiv) and 4-HO-TEMPOH (20 mol %) in DMSO (1.5 mL) for
24 h under Ar unless noted otherwise. bIsolated yield.
N
4-HO-TEMPOH (1 equiv)
DMSO, Ar, 120 oC, 18 h
(5)
Ph
Ph
13
14
, 66%
Thus, it can be concluded that the N-O bond cleavage of the
oxime acetate in the reaction was effected via SET reduction
by 4-HO-TEMPOH (Scheme 9).
Based on the experimental results and DFT calculation, a
plausible mechanism for the TEMPO-catalyzed redox
annulation is proposed in Scheme 11. Initially, a hydrogen
atom transfer (HAT) process occurs between cyclopropanols 1
and 4-HO-TEMPO to produce the alkoxyl radical A and 4-
HO-TEMPOH.12a,12c The former species subsequently
experiences radical ring-opening to form the carbon radical B,
which is further dehydrogenated by 4-HO-TEMPO to yield
α,β-unsaturated ketone C.2d,2j,12e Meanwhile, the N-O bond
reductive cleavage of oxime acetates 2 occurs by the action of
4-HO-TEMPOH through a SET process19 to give iminyl
radical D, HOAc and 4-HO-TEMPO. D further abstracts H-
O
O
+
120 o
DMSO
C
H
H
O
O
O
N
OH
O
N
OH
+
N
N
O
R
R'
R
R'
N
N
OH
+
HOAc
+
R
R'
Scheme 9. SET Process between Ketoxime Acetates and 4-
HO-TEMPOH.
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Page 6 of 9
atom from 4-HO-TEMPOH to yield imine E and 4-HO-
ACKNOWLEDGMENT
1
2
3
4
5
6
7
8
TEMPO. The former quickly tautomerizes to enamine F
which then nucleophilically adds to enone C to yield the
intermediate G. Annulation of G produces dihydropyridine H,
which is finally oxidative aromatized by 4-HO-TEMPO to
pyridine 3 or 4. Excess oxime acetate serves as a terminal
oxidant to maintain the TEMPO-TEMPOH catalytic cycle.
We thank the National Natural Science Foundation of China (Nos.
21873041, 21632001, and 21422205), the “111” project, the
Program for Changjiang Scholars and Innovative Research Team
in University (IRT-15R28), the Fundamental Research Funds for
the Central Universities (Nos. lzujbky-2016-ct02 and lzujbky-
2016-ct08) for financial support.
4-HO-TEMPOH 4-HO-TEMPO
REFERENCES
R2
R1
HO
N OH
NH
N
R4
R4
(1) For selected reviews including applications of TEMPO in
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R3
R3
9
HO
O
E
4-HO-TEMPOH
1
D
oxidation
reduction
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
- HOAc
NH2
R2
R1
R4
NOAc
R4
R3
F
3
4
or
SET
HAT
HO
N O
R3
A
2
4-HO-TEMPO
R3
NH
R3
O
F
O
R4
R2
R4
R2
annulation
- H2O
O
N
R1
R2
4-HO-
TEMPO
R1
4-HO-
TEMPOH
R2
R1
R1
B
C
H
G
Scheme 11. Proposed Mechanism.
CONCLUSIONS
In summary, a novel and efficient 4-HO-TEMPO-catalyzed
redox approach has been developed for the synthesis of
pyridine derivatives through the [3+3] annulation of
cyclopropanols and oxime acetates under metal-free
conditions. The reaction utilizes the redox cycle of 4-HO-
TEMPO/4-HO-TEMPOH to realize the electron and proton
transfer between cyclopropanols and oxime acetates. In this
way, cyclopropanols and oxime acetates were converted to
enones and imines, respectively, which then undergo cascade
annulation and oxidative aromatization to yield pyridine
derivatives. This tactic not only represents the first example
for TEMPO-catalyzed redox reaction, where both TEMPOH
and TEMPO are active catalysts, but also has the merits of
excellent functional group tolerance, high chemoselectivity,
broad substrate scope and good compatibility for the
frameworks of natural products and pharmaceutical molecules.
By using 4-HO-TEMPOH as the catalyst, the annulation
between enones and oxime esters can take place as well to
give pyridine products. Further studies on TEMPO-catalyzed
redox reaction for the synthetic purpose are ongoing in our
laboratory.
ASSOCIATED CONTENT
Supporting Information.
Detailed experimental procedures and spectral data for all
products are provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: hanb@lzu.edu.cn
ORCID
Wei Yu: 0000-0002-3131-3080
Bing Han: 0000-0003-0507-9742
Author Contributions
†J.-L. Zhan and M.-W. Wu contributed equally.
Notes
The authors declare no competing financial interest.
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TOC
R2
O
cat. 4-HO-TEMPO
R2
R2
R1
[3+3]
annulation
HO
R3
R1
R3
4-HO-
TEMPO
4-HO-
TEMPOH
in-situ generated
NH2
+
oxidative
aromatization
R1
N
R4
NH
R4
NOAc
R4
R4
48 examples
up to 88% yield
redox
R3
R3
TEMPO catalyzed redox reaction
both TEMPOH and TEMPO as active catalysts




in-situ generated enones and imines metal-free, additive-free broad substrate scope


pyridine synthesis in one pot
good functional group tolerance
high chemoselectivity


ACS Paragon Plus Environment