SiCl4-catalyzed/PR3-mediated β-C(sp3)?H functionalization of nitrones to α,β-unsaturated imines and aromatic heterocycles

Article abstract of DOI:10.1016/j.tet.2018.03.038

A novel method of SiCl₄-catalyzed/PR₃-mediated β-C(sp³)?H functionalization of nitrones with aldehydes/ketones to α,β-unsaturated imines was developed. The synthesis of α,β-unsaturated imines mainly invovles deoxygenation and aldol condensation, each proceeding under a cooperation effect between Lewis acid and Lewis base. In addition, both the acidity and hydrolytic stability of the weak SiCl₄ were supposed to be enhanced by coordination with phosphine oxide (R = Et) or phosphoric triamide (R = NMe₂) that originated from deoxygenation of nitrones by PR₃. In the case of 6-membered nitrone, a [1,3]-hydride shift within the resulted α,β-unsaturated imines renders the aromatization leading to 3,5-dialkylpyridines.

Full text of DOI:10.1016/j.tet.2018.03.038

Accepted Manuscript
3
SiCl -catalyzed/PR -mediated β-C(sp )−H functionalization of nitrones to α,β-
4
3
Unsaturated imines and aromatic heterocycles
De-Ping Zhu, Bao-Hua Xu, Yi-Ran Du, Suo-Jiang Zhang
PII:
S0040-4020(18)30303-X
10.1016/j.tet.2018.03.038
TET 29378
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 February 2018
Revised Date: 14 March 2018
Accepted Date: 19 March 2018
Please cite this article as: Zhu D-P, Xu B-H, Du Y-R, Zhang S-J, SiCl -catalyzed/PR -mediated
4
3
3
β-C(sp )−H functionalization of nitrones to α,β-Unsaturated imines and aromatic heterocycles,
Tetrahedron (2018), doi: 10.1016/j.tet.2018.03.038.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
SiCl4-Catalyzed/PR3-Mediated β-C(sp3)−H
Functionalization of Nitrones to α,β-
Unsaturated Imines and Aromatic
Heterocycles
Leave this area blank for abstract info.
De-Ping Zhua, b , Bao-Hua Xua, b , Yi-Ran Dua, b and Suo-Jiang Zhanga, b
a Key Laboratory of Green Process and Engineering, Beijing Key Laboratory of Ionic Liquids Clean Process,
State Key Laboratory of Multiphase Complex Systems, Institute of Process Engineering, Chinese Academy of
Sciences, Beijing 100190, PR China.
b School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049,
PR China.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
SiCl4-Catalyzed/PR3-Mediated β-C(sp3)−H Functionalization of Nitrones to α,β-
Unsaturated Imines and Aromatic Heterocycles
De-Ping Zhua, b , Bao-Hua Xua, b , Yi-Ran Dua, b and Suo-Jiang Zhanga, b
a Key Laboratory of Green Process and Engineering, Beijing Key Laboratory of Ionic Liquids Clean Process, State Key Laboratory of Multiphase Complex
Systems, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China.
b School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, PR China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel method of SiCl4-catalyzed/PR3-mediated β-C(sp3)−H functionalization of nitrones with
aldehydes/ketones to α,β-unsaturated imines was developed. The synthesis of α,β-unsaturated
imines mainly invovles deoxygenation and aldol condensation, each proceeding under a
cooperation effect between Lewis acid and Lewis base. In addition, both the acidity and
hydrolytic stability of the weak SiCl4 were supposed to be enhanced by coordination with
phosphine oxide (R = Et) or phosphoric triamide (R = NMe2) that originated from
deoxygenation of nitrones by PR3. In the case of 6-membered nitrone, a [1,3]-hydride shift
within the resulted α,β-unsaturated imines renders the aromatization leading to 3,5-
dialkylpyridines.
Available online
Keywords:
nitrone
β-C(sp3)−H functionalization
α,β-unsaturated imine
aldol condensation
deoxygenation
2018 Elsevier Ltd. All rights reserved
.
1. Introduction
such as high temperature and prolonged reaction time (without
the aid of microwave), are usually required under this protocol.
Alicyclic amines with varied functionalization play privileged
role as structural motifs of many bioactive materials and
synthetic origins.1 Different strategies are available for the
construction of such structural motifs, yet direct C−H bond
functionalization of proper amines has drawn unwavering
attentions. While the functionalization at α-C(sp3) of alicyclic
amines has been extensively explored,2 reports on those of more
challenging functionalization at β-C(sp3) were sporadic. Two
approaches were primarily employed to construct various C−C
bonds at β-C(sp3) so far. The first one involves transition metal-
catalyzed in-situ formation of electrophilic iminium ions from
tertiary/protected amines upon dehydrogenation in the
presence/absence of oxidants (Scheme 1A).3 The subsequent
isomerization of the iminium species leads to the formation of
nucleophilic enamines, which will undergo cross-coupling
reactions with the corresponding electrophiles at β-C(sp3). The
second one, denoted as redox-neutral method, operates via
intramolecular hydride transfer mechanism without the use of
external oxidant (Scheme 1B).4 Consequently, the generation of
aromatic heterocyclics or unsaturated imines accompanied with
β-functionalization from saturated cyclic amines and aldehydes
was attained in an uncatalyzed fashion or was mediated by a
carboxylic acid (> 0.5 equiv.).4b It is to note that harsh conditions,
Scheme 1. Summary of β-C(sp3)−H Functionalization of
Alicyclic Amines
The forementioned reactions on β-C(sp3)−H functionalization
of alicyclic amines necessitate the transiency imine or its
enamine tautomer function as nucleophile in the subsequent
cross-coupling. Specifically, the direct aldol condensation of
Corresponding author. E-mail: bhxu@ipe.ac.cn (B.-H. Xu), sjzhang@ipe.ac.cn (S.-J. Zhang).

2
Tetrahedron
o
cyclic imines (in a trimer form) with aldehydes at the β-C(sp3)
the reaction of 1a and 2a (2.0 equiv.) at 60 C for 24 h in the
presence of weak acid SiCl4 (10 mol%) and P(NMe2)3 (1.2
equiv.) in dichloroethane (DCE, 1 mL) under argon (entry 13).
The combination of active In(OTf)3 and P(NMe2)3 provides an
alternative choice to give 3aa in a satisfactory yield up to 85%,
but only being effective when the loading of 2a (3.0 equiv.) was
increased and the reaction was conducted in polar 1,4-dioxane (1
ACCEPTED MANUSCRIPT
position was once reported by Tomoda,5 which provided
unsaturated imines with moderate yields (10 ~ 77%) with a
prolonged reaction time (> 43 h). These unstable nucleophilic
species could also be obtained via reduction of inert chemical
bonds. For instance, reduction of quinoline substrate gives rise to
active intermediate which can undergo intramolecular hydrogen
transfer, thereby facilitating the direct reductive quinolyl β-
C(sp3)−H alkylation with aldehydes (Scheme 1C).6 By following
the reduction stratage, alicyclic imines can also be provided from
nitrones via deoxygenation, wherein halides,7 hydrides,8
heteroatom-based nucleophiles,9 Lewis acids,10 low-valent
transition metals11 were frequently utilized as the oxo-acceptor.
Some of these examples were promoted by reactive transition
metal complexes, but still lacking of efficiency.9d,e The
deoxygenated nitrones promise a subsequent coupling with
electrophiles, thereby affording alicyclic amines with β-C(sp3)
functionalized (Scheme 1D). However, development of novel
methodologies that operates under mild conditions still remains
challenging, wherein the high reactivity of nitrones towards the
upcoming electrophiles should be supressed.12 Herein, we report
an example of SiCl4-catalyzed/PR3-mediated β-C(sp3)−H
functionalization of cyclic nitrones. Upon reacting 5-membered
cyclic nitrones with SiCl4/PR3 followed by cross-couping with
aldehydes/ketones, alicyclic α,β-unsaturated imines were
obtained with mild to exellent yields. It was found both
deoxygenation and aldol condensation performed under a
cooperation effect between SiCl4 and PR3.The process is also
applicable for 6-membered nitrone which can be transformed into
dialkyl-substituted aromatic heterocycles.
o
mL) at 120 C (entry 12). This may be attributed to the intrinsic
instability of both 2a as a nitrone and the corresponding imine
intermediate upon deoxygenation as substantial decomposition
occurred when the temperature was raised up to 120 C. During
the condition optimization, the variety of Lewis acids and the
structure of PR3 were found to strongly influence the reactivity
(entries 7 11). As compared to triethylphosphine (PEt3), either
less nucleophilic triphenyl (PPh3) or more steric hindered
tricyclohexyl (PCy3) and tri-tert-butyl (P(t-Bu)3) phosphine led to
reduced selectivity, whereas the more basic phosphorous triamide
(P(NMe2)3) exhibited equally effective (entry 7 vs. 11 and entry
13 vs. 14).
o
Table 1. Condition Optimization for Generation of 3aa from
Reaction of 1a with 2aa
Conv.
(%)b
Yield
(%)b
Entry
LA
Base
Solvent
1c,d
2d
3d
4e
5
CoI2
CoI2
dppe
dppe
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1,4-dioxane
DCE
59
39
36
45
28
32
98
54
60
49
100
100
98
98
12
13
5
2. Results and discussion
dppe
−
Inspired by Yoo’s11a and previous studies13 on cobalt catalysis,
we envisioned the introduction of a combination of Co(II)
phosphine complex and metal powder might both promote the
deoxygenation of nitrones via the in-situ generated low-valent
cobalt and provide Lewis acidic environment for the subsequent
aldol condensation with aldehyde substrates. The model reaction
of 2-naphthaldehyde (1a) with 5,5-dimethyl-1-pyrroline-N-oxide
(DMPO, 2a) was thus carried out in the presence of CoI2 (10
mol%), 1,2-bis(diphenylphosphanyl)ethane (dppe) (15 mol%)
CoI2
dppe
25
15
32
69
9
InCl3
PEt3
6
InBr3
PEt3
7
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
SiCl4
PEt3
8
PPh3
o
9
PCy3
9
and stoichiometric In (1.2 equiv.) at 120 C for 24 h under argon
(Table 1, entry 1). The expected α,β-unsaturated imine 3aa was
obtained, but in a poor yield (12%). The isolated product was
found to have the C=C double bond exclusively with E-
configuration. The structural recognition of 3aa was
unambiguously confirmed by single crystal X-ray diffraction
analysis besides NMR and ESI-MS experiments. Surprisingly,
quantitative 1,2-bis(diphenylphosphino)ethane dioxide, which
features a typical 31P NMR signal at δ 33.2 ppm,14 was
simultaneously formed as a white solid precipitated in the
reaction solution. Moreover, the yield of 3aa is not affected
without In (entry 2), but remarkably reduced in the absence of
CoI2 reacting as a catalyst (entry 3). We can thus postulate that
the basic dppe reacts as an oxo-acceptor rather than ligand for the
low-valent cobalt complex generated in-situ. However, the
reactivity was not significantly improved by increasing the
amount of dppe to 0.5 molar equivalent, a theoretically
stochiometric amount (entry 4).
10
11
12f
13g
14g
P(t-Bu)3
P(NMe2)3
P(NMe2)3
P(NMe2)3
PEt3
12
70
85
92
88
SiCl4
DCE
aReaction conditions: 1a (0.20 mmol), 2a (2.0 equiv.), LA (10 mol%),
base (1.2 equiv.), solvent (1 mL), 120 C, 24 h, under Ar; Determined by
1H NMR with CH2Br2 as internal standard; cIn (1.2 equiv.); dbase (15
mol%); ebase (0.5 equiv.); f2a (3.0 equiv.); g60 oC; LA: Lewis acid.
o
b
We next examined the limit and scope of carbonyl substrates
(1) under SiCl4 catalysis (Scheme 2), wherein the yield of each
product was determined after isolation. It was observed that
electronic variation of the substituents at the para-position of
benzaldehyde only slightly affected the reaction efficiency. The
corresponding α,β-unsaturated imine products substituted with a
methyl (3ha) and methoxyl (3ia) group were obtained in
relatively lower yields as compared with those bearing a halogen
(3ca, 3da and 3ea) or nitro-substituent (3fa). However, the
situation for benzaldehyde bearing cyano group (1g) is
complicated: a full conversion was detected by 1H NMR analysis
In an effort to address the problem of poor efficiency and to
understand the reaction mechanism in more details, a variety of
Lewis acids and PR3 (trisubstituted phosphine or phosphorous
triamide) reagents were investigated (Table 1). Reaction
conditions varing the solvents and temperatures were examined
(Table 1 and S1). The best yield of 3aa (92%) was obtained from

3
along with a multitude of unrecognizable products, which may be
attributed to the high reactivity of cyano group towards 2a via
[2+3] cycloaddition.12b,c In addition, the reaction proceeded
smoothly with meta-nitro-substituted benzaldehyde, delivering
3ja in a satifactory yield of 85%. Significant steric effect was
observed when introducing substituents to the ortho-position as
the performance of ortho-methyl-substituent (1l) was decreased
with the yield of 3la being 70%. Unexpectedly, no imine product
was detected in the case of ortho-nitro-substituted benzaldehyde
(1k), the reason of which will be discussed later in the paper.
Heteroaromatic aldehydes were successfully applied in cross-
coupling with 2a and yielding the α,β-unsaturated imine products
(3ma (81%), 3na (80%) and 3oa (76%)). The catalytic system
can also be expanded to polycyclic aromatic aldehydes, which
afforded 3pa (77%), 3qa (82%), 3ra (71%) and 3sa (79%),
respectively, by reacting with 2a. Not only aromatic aldehydes
but also aliphatic ones were tolerated. For instance, the reaction
of 1t with 2a under standard conditions provided 3ta in an
acceptable yield of 42%. 3ua originated from the reaction of α,β-
unsaturated aldehyde 1u with 2a was obtained, albeit with
moderate 45% yield. The supposed 1,3-dipolar cycloaddition
between the electron-deficient C=C bond of 1u and 2a as a
dipole was not observed.12b,c Besides various aldehydes, two
ketones (1v and 1w) were also employed as the carbonyl
substrate in the reaction with 2a, wherein only the electron-
deficient one afforded the desired imine (3va) with 59% yield.
With the success in functionalizing 2a with carbonyl
ACCEPTED MANUSCRIPT
electrophiles at β-C(sp3), we turned our attention to other cyclic
nitrones (2b, 2c and 2d) as the potential imine precursors for β-
C−H alkylation. We found that 5-membered cyclic nitrones (2b
and 2c) were well deoxygenated and underwent aldol
condensation with 1a and 1d, thus affording 3ab (65%), 3db
(66%), 3ac (56%) and 3dc (50%), respectively (Scheme 2). In
the case of reaction involving 2b, no regioisomeric-conjugated
imine with functionalization at the methyl position has been
observed. However, when 6-membered cyclic nitrone 2d is
applied, aromatization occurred forming 3,5-dialkylpyridines
under standard reaction conditions (Scheme 3). From the reaction
of 2d with 1a, 3,5-dialkylpyridine 4ad was obtained with 64%
yield, but without the desired α,β-unsaturated imine 3ad.
Sequential aldol condensation with aldehyde is proposed to
rationalize this observation.15 The functionalization of 2d at β-
methylene probably proceeded after deoxygenation as that for the
other nitrones to provide 3ad, which subsequently underwent
[1,3]-hydride shift forming 5-alkyl-2,3-dihydro-pyridine 5ad.
The allylic methylene in 5ad should be sufficiently active for
condensation with 1a. Therefore, the following sequence of
transformation is proposed to account for the second β-alkylation
to yield ultimately 4ad.
Scheme 3. Reactivity of 2,3,4,5-Tetrahydropyridine N-oxide (2d)
N
N
N
[1,3]-H shift
R
RCHO (1a)
deoxygenation
Scheme 2. Scope in Synthesis of α,β-Unsaturated Iminesa
R
R
aldol
N
O
condensation
R = 2-Naphth
3ad
5ad
H
H
2d, 2.0 equiv.
aldol
RCHO
condensation
RCHO (1a, 0.2 mmol)
(1a)
SiCl4 (10 mol%)
N
N
P(NMe2)3 (1.2 equiv.)
[1,3]-H shift
R
R
R
DCE (1 mL)
60 oC, 24 h
H
H
H
H
6ad
4ad, 64%
The best yield of 4ad (76%) was obtained under slightly
modified conditions (Scheme 4), which was also employed to
investigate the carbonyl substrate scope of the reaction. Several
aldehydes containing representative functional groups were
reacted with 2d providing structurally diverse pyridine
derivatives. Aldehydes with or without an electron-donating or
electron-withdrawing substituent in the aryl moiety were equally
efficient in providing the corresponding 3,5-dialkyl-substituted
pyridines. Moreover, the reaction performed well with
heteroaromatic aldehydes, thereby offering the desired pyridine
derivatives with satisfactory yields.
Scheme 4. Scope in Synthesis of 3,5-dialkylpyridines
SiCl4 (15 mol%)
N
O
P(NMe2)3 (1.2 equiv.)
+
N
O
R
R
R
H
DCE (1 mL), 60 oC, 24 h
1 (0.4 mol)
2d (1.0 equiv.)
4
On the basis of our results and literatures,16,17 a mechanistic
proposal for the SiCl4-catalyzed/PR3-mediated β-C(sp3)−H
functionalization of nitrone with aldehyde to α,β-unsaturated
imine is presented (Scheme 5). We believe the deoxygenation
was initiated by addition of the phosphorus atom to the iminyl
carbon rather than the oxygen, based on the same substituents
effect as observed in the study of Toy and Py.9f This step is

4
Tetrahedron
accelerated by SiCl4 since it renders the iminyl carbon more
aromatic heterocyclics accompanied with β-functionalization
ACCEPTED MANUSCRIPT
electrophilic, which is imposed by strong interaction between
electron-deficient silica atom and the nonbonding lone pair of
oxygen atom in nitrones. The formation of a trichlorosilyl cation
A was therefore rationally proposed, which may evolve to B
upon deoxygenation. According to the theory of Lewis base
activation of Lewis acid,17 ionic complex B should have an
enhanced acidity than neat SiCl4. Consequently, the coordination
of carbonyl substrates occured to give intermediate C. Imine
ligand in C is prone to tautomerize into enamine in D in the
presence of base. To clarify this point, independent experiments
on the aldol condensation between 1a and 5-methyl-3,4-dihydro-
2H-pyrrole (7) were conducted under SiCl4 catalysis (Scheme
6a). The extra addition of phosphine (PEt3, 1.2 equiv.) and imine
substrate (7, 1.2 equiv.) each resulted in α,β-unsaturated imine
3ab with nearly 20% increased yield, indicating both phosphine
and the released imine from nitrones can function as the base.19
In addition, the introduction of catalytic amount of phosphine
oxide (O=PEt3) was indeed found requisite to promote the aldol
condensation of 1a with 7. We suppose the next nucleophilic
addition of enamine to the carbonyl carbon at β-C(sp3) position
proceeded either intra- or inter-molecularly, leading to complex
E. In the case of In(OTf)3 catalysis, a stronger σ-bonding
between nitrogen and indium may impede such a step forward,
which therefore requires a higher temperature or solvent of weak
coordination to facilitate (Table S1). The desired α,β-unsaturated
imine (3) was formed upon dehydroxylation in the presence of
nitrones and phosphonium salts, coincidentally with the
intermediate A being regenerated. In principle, hydrolysis of
SiCl4 readily occurred to produce silicic acid (H2SiO3) and HCl in
the presence of moisture. However, the hydrolytic stability of
silane-species (A F) should be increased due to the coordination
by various Lewis base during the catalysis, such as R3PO, and the
steric hindrance thereby around the central silicon atom. As an
example, a trichlorosilane bearing a tetradentate ligand with three
coordinating arms has been reported to exhibit an unusual
stability towards moisture.18 On the other hand, independent
experiments under the catalysis of a combination of H2SiO3 (10
mol%) and HCl (40 mol%) were found not equally effective as
SiCl4 (10 mol%) (Scheme 6b and 6c). In the former case, tThe
reaction of 1a and 2b was completely suppressed and the
reactivity of aldol condensation between 1a and 7 was half
reduced as compared with that under SiCl4 catalysis. Besides,
complex C may be in equilibrium with the unreactive species F
depending on the nature of the bound carbonyl substrates. It did
present in the reaction of nonreactive 1k with 2a monitored by
the in-situ 1H NMR spectrum, wherein the aldehydic proton
disappeared and was replaced by a typical signal of α-chloro
trichlorosilyl ether at δ 4.9 ppm (Scheme S5).17d,20
from nitrones and carbonyl substrates was therefore attained with
satisfactory substrates tolerance.
Scheme 5. Mechanistic Proposal for β-C(sp3)−H Function-
alization of nitrones to α,β-Unsaturated Imines
2a
DMPO ( ) + PR3
SiCl4
R
Cl
Cl
+ R3PO + base
+ H2O
N
O
Si Cl
Cl
3
N
deoxygenation
P
2a
DMPO ( ) + R3P
R3
A
+ base•HCl
R3P
Cl
Si
Cl
R3P
Cl
O
O
O
R
N
Si
Cl
B
N
Cl
Cl
Cl
E
+ base
O
HCl
base•HCl
R
H
1
R3P
Cl
R3P
Cl
R3P
Cl
O
N
O
O
N
O
+ base
O
N
O
Si
Cl
Si
Cl
Si
Cl
Cl
Cl
Cl
Cl
- base•HCl
Cl
R
R
F
D
C
R
Scheme 6. Control Experiments
O
SiCl4 (10 mol%)
H
N
a
+
N
DCE (1 mL)
60 oC, 24 h
1a (0.2 mmol)
7 (2.0 equiv.)
3ab
(1) blank
(2) O=PEt3 (0.2 equiv.)
(3) O=PEt3 (0.2 equiv.) + PEt3 (1.2 equiv.) 50%
10%
31%
(4) O=PEt3 (0.2 equiv.) + 7 (1.2 equiv.)
43%
O
PEt3 (1.2 equiv.)
H
N
b
+
N
O
DCE (1 mL)
60 oC, 24 h
3ab
1a (0.2 mmol)
2b (2.0 equiv.)
(5) SiCl4 (10 mol%)
(6) H2SiO3 (10 mol%)
65%
N.R.
N.R.
(7) H2SiO3 (10 mol%) + HCl (40 mol%)
O
O=PEt3 (1.2 equiv.)
H
N
c
+
N
DCE (1 mL)
60 oC, 24 h
1a (0.2 mmol)
7 (1.2 equiv.)
3ab
(8) SiCl4 (10 mol%)
(9) H2SiO3 (10 mol%)
26%
15%
(10) H2SiO3 (10 mol%) + HCl (40 mol%) 14%
4. Experimental section
3. Conclusions
All reactions were prepared and sealed using a glass tube in a
glove box filled with argon. Then the reactions were carried out
on a multi-zone reaction platform, which was purchased from
Tokyo Rikakikai Co., LTD (CCX-1102). All chemicals were
purchased from commercial suppliers, Sigma Aldrich, Alfa Aesar
or Adamas. All the solvents were dried and distilled under argon
prior to use. 5,5-Dimethyl-1-pyrroline-N-oxide (2a) was
purchased from Adamas. Other nitrones were prepared according
to reported methods.21 NMR spectra were recorded on a bruker
ASCEND spectrometer (1H, 600 MHz; 13C, 151 MHz) and a
JEOL JNM-ECA600 spectrometer (1H, 600 MHz; 13C, 151
In summary, we demonstrated a novel approach of β-
C(sp3)−H functionalization of nitrones catalyzed by weak Lewis
acid SiCl4 in the presence of Lewis base PR3 (R = Et or NMe2).
The synthesis of α,β-unsaturated imines mainly invovles
deoxygenation and aldol condensation, each proceeding under a
cooperation effect between Lewis acid and Lewis base. In
addition, both the acidity and hydrolytic stability of weak SiCl4
were supposed to be enhanced by coordination with the
phosphine oxide/phosphoric triamide that originated from
deoxygenation of nitrones by phosphine/phosphorous triamide,
thereby rendering a mild and efficient transformation. In the case
of 6-membered nitrone, a [1,3]-hydride shift within the resulted
α,β-unsaturated imines renders the aromatization leading to 3,5-
dialkylpyridines. The generation of unsaturated imines or
1
MHz). H NMR and 13C NMR, chemical shift δ is given relative
to TMS and referenced to the solvent signal. Column
chromatography was performed using silica gel or neutral
alumina. Analytical TLC was done using precoated silica gel 60
F254 plates. ESI-MS analysis was performed on a Bruker time of

5
flight mass spectrometer microTOF-Q II using an electro spray
ionization (ESI) source. FT/IR spectra was recorded on Thermo
Fisher Nicolet 380 Instrument at normal temperature making KBr
pellet grinding the sample with KBr (IR Grade).
(CH=N), 144.0 (=Cquat), 134.4 (i-Nap), 133.5 (i-Nap), 133.0 (i-
ACCEPTED MANUSCRIPT
Nap), 128.6 (=CH), 128.4 (2C, =CHNap), 128.3 (=CHNap), 127.8
(=CHNap), 126.7 (=CHNap), 126.6 (=CHNap), 126.4 (=CHNap), 74.6
(Cquat(CH3)2), 42.7 (CH2), 29.7 (CH3). HRMS (ESI) m/z Calcd
for [C17H18N, M+H]+: 236.1434; Found: 236.1427. FT/IR (KBr):
ῦ = 3354, 3058, 2964, 2924, 2863, 2184, 1595, 1576, 1463, 1375,
1362, 1337, 1274, 1251, 1178, 1135, 940, 908, 818, 750, 733,
723, 597, 474 cm-1.
4.1. General procedure for the synthesis of nitrones (2b, 2c and
2d).21
To a stirred suspension of urea hydrogen peroxide (UHP)
(1.411 g, 15 mmol) in MeOH (10 mL), methyltrioxorhenium
(MTO) (6.2 mg, 0.5 mol%) was added. Within 15 min the yellow
color appeared, the reaction mixture was cooled in an ice bath at
−2 °C and the imine 7 or amine 8, 9 (5 mmol) was then added
dropwise via syringe over 30 min. After completion of the
addition, the reaction was warmed up to 20 °C. Another three
portions of MTO (6.2 mg, 0.5 mol%) were added at 30 min
intervals. After each addition, the reaction mixture developed a
yellow color, which then disappeared. The resulting solution was
stirred at 20°C until disappearance of the starting material (TLC
control). After removal of the solvent under reduced pressure, the
residue was diluted with CH2Cl2 and the undissolved urea filtered
off. Removal of the solvent afforded the crude product, which
was purified by flash column chromatography on neutral
alumina. The product was found to be unstable, but it could be
stored for several days at −30°C under Ar atmosphere.
Scheme 2. 3ba. Yield: 31 mg (84%), n-hexane/ethyl acetate
1:5 (Rf = 0.50), pale yellow oil. H NMR (600 MHz, CDCl3,
298K): δ = 7.70 (s, 1H, CH=N), 7.44 (dm, JHH = 7.2 Hz, 2H, o-
Ph), 7.39 (m, 2H, m-Ph), 7.30 (m, 1H, p-Ph), 6.78 (t, JHH = 3.0
1
3
4
4
Hz, 1H, =CH), 2.68 (d, JHH = 3.0 Hz, 2H, CH2), 1.36 (s, 6H,
2×CH3). 13C NMR (151 MHz, CDCl3, 298K): δ = 164.5 (CH=N),
143.7 (=Cquat), 136.8 (i-Ph), 129.0 (Ph), 128.8 (Ph), 128.3 (=CH),
128.2 (p-Ph), 74.5 (Cquat(CH3)2), 42.5 (CH2), 29.7 (CH3). HRMS
(ESI) m/z Calcd for [C13H16N, M+H]+: 186.1277; Found:
186.1263. FT/IR (KBr): ῦ = 3343, 3041, 2965, 2923, 2862,
2184, 1572, 1489, 1446, 1375, 1303, 1150, 977, 940, 921, 753,
690, 515 cm-1.
Scheme 2. 3ca. Yield: 36 mg (88%), n-hexane/ethyl acetate
1:5 (Rf = 0.65), pale yellow solid. H NMR (600 MHz, CDCl3,
1
298K): δ = 7.66 (s, 1H, CH=N), 7.40 (m, 2H, Ph), 7.07 (m, 2H,
Ph), 6.71 (t, 4JHH = 3.0 Hz, 1H, =CH), 2.61 (d, 4JHH = 3.0 Hz, 2H,
CH2), 1.34 (s, 6H, 2×CH3). 13C NMR (151 MHz, CDCl3, 298K):
δ = 164.2 (C=N), 162.4 (d, 1JCF = 249.6 Hz, p-Ph), 143.5 (=Cquat),
133.1 (d, JCF = 4.0 Hz, i-Ph), 130.6 (d, JCF = 8.3 Hz, o-Ph),
126.5 (=CH), 115.8 (d, 2JCF = 21.6 Hz, m-Ph), 74.5 (Cquat(CH3)2),
42.4 (CH2), 29.7 (CH3). 19F NMR (564 MHz, CDCl3, 298K): δ =
−112.5 (p-C6H4F). HRMS (ESI) m/z Calcd for [C13H15FN,
M+H]+: 204.1183; Found: 204.1179. FT/IR (KBr): ῦ = 3325,
3023, 2963, 2922, 2847, 1736, 1576, 1492, 1456, 1413, 1360,
1308, 1281, 1266, 1250, 1179, 1136, 1087, 1009, 933, 874, 593,
516 cm-1.
4.1.1. 2-Methyl-1-pyrroline N-oxide (2b).
Yield: 0.43g, 87%. CH2Cl2-MeOH 200:1. 1H NMR (600
MHz, CDCl3, 298K): δ = 3.96 (m, 2H, N-CH2), 2.69 (m, 2H,
CH2), 2.06 (m, 2H, CH2), 1.99 (s, 3H, CH3). 13C NMR (151
MHz, CDCl3, 298K): δ = 144.8 (C=N), 62.0 (N-CH2), 33.0
(CH2), 16.6 (CH2), 12.6 (CH3).
4
3
4.1.2. 1-pyrroline N-oxide (2c).
Yield: 0.34g, 80%. CH2Cl2-MeOH 200:1. 1H NMR (600 MHz,
CDCl3, 298K): δ = 6.90 (m, 1H, =CH), 3.98 (m, 2H, N-CH2),
2.75 (m, 2H, CH2), 2.26 (m, 2H, CH2). 13C NMR (151 MHz,
CDCl3, 298K): δ = 134.2 (=CH), 61.1 (N-CH2), 27.7 (CH2), 18.1
(CH2).
Scheme 2. 3da. Yield: 38 mg (86%), n-hexane/ethyl acetate
1:5 (Rf = 0.65), pale yellow oil. H NMR (600 MHz, CDCl3,
1
4
298K): δ = 7.68 (s, 1H, CH=N), 7.35 (s, 4H, Ph), 6.71 (t, JHH
=
3.0 Hz, 1H, =CH), 2.62 (d, 4JHH = 3.0 Hz, 2H, CH2), 1.35 (s, 6H,
2×CH3). 13C NMR (151 MHz, CDCl3, 298K): δ = 164.2 (C=N),
143.7 (=Cquat), 135.0 (p-Ph), 134.0 (i-Ph), 130.0 (Ph), 128.9 (Ph),
127.4 (=CH), 74.4 (Cquat(CH3)2), 42.4 (CH2), 29.5 (CH3). HRMS
(ESI) m/z Calcd for [C13H15ClN, M+H]+: 220.0888; Found:
220.0897. FT/IR (KBr): ῦ = 3289, 3004, 2964, 2924, 2850,
1735, 1575, 1491, 1464, 1409, 1361, 1308, 1282, 1251, 1181,
1138, 1091, 1011, 935, 874, 817, 596, 518, 462 cm-1.
4.1.3. 2,3,4,5-Tetrahydropyridine N-oxide (2d).
Yield: 0.41g, 82%. CH2Cl2-MeOH 200:1. 1H NMR (600 MHz,
CDCl3, 298K): δ = 7.15 (m, 1H, =CH), 3.75 (m, 2H, N-CH2),
2.39 (m, 2H, CH2), 1.92 (m, 2H, CH2), 1.68 (m, 2H, CH2). 13C
NMR (151 MHz, CDCl3, 298K): δ = 137.3 (N=CH), 57.8 (N-
CH2), 25.5 (CH2), 22.8 (CH2), 17.4 (CH2).
4.2. General procedure for synthesis of α,β-unsaturated imine
(3).
Scheme 2. 3ea. Yield: 44 mg (83%), n-hexane/ethyl acetate
1
1:5 (Rf = 0.60), pale yellow solid. H NMR (600 MHz, CDCl3,
To a dry tube containing a dichloroethane (1 mL) solution of
nitrone (0.40 mmol, 2.0 equiv.), SiCl4 (0.02 mmol, 10 mol%),
P(NMe2)3 (0.24 mmol, 1.2 equiv.) and aldehyde (0.20 mmol)
were added in a glove box. Then, the tube was sealed by
polytetrafluoroethylene bottle stopper with rubber ring and
thread. The mixture was then stirred and heated at 60°C. After
reaction for 24 h, the mixture was cooled to room temperature.
Removal of the solvent afforded the crude product, which was
purified by thin layer chromatography on silica gel.
298K): δ = 7.68 (s, 1H, CH=N), 7.50 (dm, 3JHH4 = 9.0 Hz, 2H, Ph),
3
7.29 (dm, JHH = 9.0 Hz, 2H, Ph), 6.70 (t, JHH = 3.0 Hz, 1H,
=CH), 2.61 (d, 4JHH = 3.0 Hz, 2H, CH2), 1.35 (s, 6H, 2×CH3). 13
C
NMR (151 MHz, CDCl3, 298K): δ = 164.0 (CH=N), 144.2
(=Cquat), 135.6 (p-Ph), 131.8 (Ph), 130.0 (Ph), 126.7 (=CH), 122.0
(i-Ph), 74.5 (Cquat(CH3)2), 42.4 (CH2), 29.5 (CH3). HRMS (ESI)
m/z Calcd for [C13H15BrN, M+H]+: 264.0382; Found: 264.0340.
FT/IR (KBr): ῦ = 3137, 3004, 2963, 2923, 2849, 1735, 1576,
1488, 1463, 1428, 1406, 1361, 1308, 1280, 1251, 1211, 1181,
1138, 1103, 1076, 1008, 935, 906, 874, 836, 814, 790, 734, 596,
515 cm-1.
4.2.1 Characterization of α,β-unsaturated imine (3).
Scheme 2. 3aa. Yield: 42 mg (89%), n-hexane/ethyl acetate
1
1:5 (Rf = 0.65), white solid. H NMR (600 MHz, CDCl3, 298K):
Scheme 2. 3fa. Yield: 42 mg (91%), n-hexane/ethyl acetate
1:5 (Rf = 0.60), yellow solid. 1H NMR (600 MHz, CDCl3,
δ = 7.88 (s, 1H, =CHNap), 7.84 (m, 3H, =CHNap), 7.74 (s, 1H,
CH=N), 7.57 (m, 1H, =CHNap), 7.49 (m, 2H, =CHNap), 6.92 (t,
3
298K): δ = 8.24 (dm, JHH = 8.4 Hz, 2H, Ph), 7.74 (s, 1H,
4
4JHH = 3.0 Hz, 1H, =CH), 2.78 (d, JHH = 3.0 Hz, 2H, CH2), 1.39
CH=N), 7.56 (dm, 3JHH = 8.4 Hz, 2H, Ph), 6.81 (t, 4JHH = 2.4 Hz,
1H, =CH), 2.69 (d, 4JHH = 2.4 Hz, 2H, CH2), 1.37 (s, 6H, 2×CH3).
(s, 6H, 2×CH3). 13C NMR (151 MHz, CDCl3, 298K): δ = 164.5

6
Tetrahedron
ACCEPTED MANUSCRIPT
13C NMR (151 MHz, CDCl3, 298K): δ = 163.7 (CH=N), 147.9
MHz, CDCl3, 298K): δ = 163.6 (CH=N), 150.2 (Py), 148.5
(p-Ph), 146.9 (=Cquat), 143.4 (i-Ph), 129.3 (Ph), 125.4 (=CH),
124.1 (Ph), 75.2 (Cquat(CH3)2), 42.9 (CH2), 29.6 (CH3). HRMS
(ESI) m/z Calcd for [C13H15N2O2, M+H]+: 231.1128; Found:
231.1142. FT/IR (KBr): ῦ = 3140, 3020, 2921, 2849, 1740,
1646, 1600, 1579, 1522, 1448, 1352, 1314, 1156, 1097, 1418,
1070, 972, 895, 821, 787, 733, 672, 513, 474 cm-1.
(=Cquat), 144.2 (i-Py), 124.9 (=CH), 122.9 (Py), 75.1
(Cquat(CH3)2), 42.8 (CH2), 29.6 (CH3). HRMS (ESI) m/z Calcd
for [C12H15N2, M+H]+: 187.1230; Found: 187.1240. FT/IR
(KBr): ῦ = 3142, 3022, 2966, 2928, 2212, 1723, 1683, 1627,
1597, 1547, 1489, 1464, 1416, 1379, 1363, 1329, 1277, 1209,
1138, 1070, 993, 907, 812, 791, 732, 677, 644, 625, 600, 536 cm-
1
.
Scheme 2. 3ha. Yield: 31 mg (78%), n-hexane/ethyl acetate
2:5 (Rf = 0.60), brown oil. 1H NMR (600 MHz, CDCl3, 298K): δ
= 7.66 (s, 1H, CH=N), 7.33 (m, 2H, Ph), 7.19 (m, 2H, Ph), 6.72
Scheme 2. 3na. Yield: 28 mg (80%), n-hexane/ethyl acetate
1:5 (Rf = 0.50), brown oil. 1H NMR (600 MHz, CDCl3, 298K): δ
= 7.68 (s, 1H, CH=N), 7.48 (d, 3JHH = 1.2 Hz, 1H, =CHFu), 6.62
4
2
(t, JHH = 2.4 Hz, 1H, =CH), 2.64 (d, JHH = 2.4 Hz, 2H, CH2),
2.37 (s, 3H, CH3Ph), 1.34 (s, 6H, 2×CH3). 13C NMR (151 MHz,
CDCl3, 298K): δ = 164.4 (CH=N), 143.0 (=Cquat), 138.2 (i-Ph),
134.1 (p-Ph), 129.5 (Ph), 128.9 (Ph), 127.6 (=CH), 74.4
(Cquat(CH3)2), 42.5 (CH2), 29.7 (CH3), 21.4 (CH3Ph). HRMS
(ESI) m/z Calcd for [C14H18N, M+H]+: 200.1434; Found:
200.1430. FT/IR (KBr): ῦ = 3355, 3189, 2920, 2849, 1647,
1632, 1599, 1469, 1415, 1069, 995, 911, 799, 737, 557, 478 cm-1.
4
3
3
(t, JHH = 3.0 Hz, 1H, =CH), 6.47 (dd, JHH = 3.6 Hz, JHH = 1.2
Hz, 1H, =CHFu), 6.45 (d, 3JHH = 3.6 Hz, 1H, =CHFu), 2.64 (d, 4JHH
= 3.0 Hz, 2H, CH2), 1.35 (s, 6H, 2×CH3). 13C NMR (151 MHz,
CDCl3, 298K): δ = 163.1 (CH=N), 152.7 (=Cquat), 143.2 (=CHFu),
141.1 (i-Fu), 115.1 (=CH), 112.0 (=CHFu), 111.6 (=CHFu), 74.0
(Cquat(CH3)2), 42.4 (CH2), 29.5 (CH3). HRMS (ESI) m/z Calcd
for [C11H14NO, M+H]+: 176.1070; Found: 176.1084. FT/IR
(KBr): ῦ = 3114, 2962, 2919, 2849, 1724, 1634, 1577, 1463,
1361, 1261, 1226, 1129, 1073, 1017, 931, 885, 799, 736, 593 cm-
Scheme 2. 3ia. Yield: 34 mg (79%), n-hexane/ethyl acetate
1:5 (Rf = 0.60), yellow oil. 1H NMR (600 MHz, CDCl3, 298K): δ
= 7.64 (s, 1H, CH=N), 7.38 (m, 2H, Ph), 6.91 (m, 2H, Ph), 6.70
1
.
4
4
(t, JHH = 3.0 Hz, 1H, =CH), 3.83 (s, 3H, OCH3), 2.62 (d, JHH
=
Scheme 2. 3oa. Yield: 29 mg (76%), n-hexane/ethyl acetate
1:5 (Rf = 0.50), brown oil. 1H NMR (600 MHz, CDCl3, 298K): δ
= 7.67 (s, 1H, CH=N), 7.38 (d, 3JHH = 4.2 Hz, 1H, =CHThio), 7.16
3.0 Hz, 2H, CH2), 1.33 (s, 6H, 2×CH3). 13C NMR (151 MHz,
CDCl3, 298K): δ = 164.5 (CH=N), 159.6 (p-Ph), 141.7 (=Cquat),
130.3 (Ph), 129.7 (i-Ph), 127.4 (=CH), 114.3 (Ph), 74.4
(Cquat(CH3)2), 55.5 (OCH3), 42.5 (CH2), 29.8 (CH3). HRMS
(ESI) m/z Calcd for [C14H18NO, M+H]+: 216.1383; Found:
216.1387. FT/IR (KBr): ῦ = 3389, 3001, 2963, 2926, 2862,
2837, 1639, 1605, 1576, 1512, 1463, 1375, 1361, 1303, 1253,
1207, 1176, 1139, 1112, 1033, 939, 896, 875, 825, 762, 596, 556,
531 cm-1.
3
3
3
(d, JHH = 3.6 Hz, 1H, =CHThio), 7.08 (dd, JHH = 4.2 Hz, JHH
=
3.6 Hz, 1H, =CHThio), 6.99 (t, JHH = 3.0 Hz, 1H, =CH), 2.64 (d,
4JHH = 3.0 Hz, 2H, CH2), 1.35 (s, 6H, 2×CH3). 13C NMR (151
MHz, CDCl3, 298K): δ = 163.2 (CH=N), 141.8 (i-Thio), 141.5
(=Cquat), 129.0 (=CHThio), 127.7 (=CHThio), 127.1 (=CHThio), 120.3
(=CH), 74.6 (Cquat(CH3)2), 42.7 (CH2), 29.8 (CH3). HRMS (ESI)
m/z Calcd for [C11H14NS, M+H]+: 192.0841; Found: 192.0866.
FT/IR (KBr): ῦ = 3186, 3072, 2965, 2923, 2850, 2208, 1578,
1463, 1421, 1364, 1258, 1177, 1048, 910, 854, 800, 731, 644,
601, 510 cm-1.
4
Scheme 2. 3ja. Yield: 39 mg (85%), n-hexane/ethyl acetate
1
1:5 (Rf = 0.60), pale yellow solid. H NMR (600 MHz, CDCl3,
298K): δ = 8.29 (s, 1H, CH=N), 8.13 (d, 3JHH = 7.8 Hz, 1H, o-
Ph), 7.72 (s, 1H, o-PhNO2), 7.71 (d, 3JHH = 9.0 Hz, 1H, p-Ph), 7.56
Scheme 2. 3pa. Yield: 36 mg (77%), n-hexane/ethyl acetate
3
3
4
1
(dd, JHH = 9.0 Hz, JHH = 7.8 Hz, 1H, m-Ph), 6.80 (t, JHH = 2.4
Hz, 1H, =CH), 2.70 (d, JHH = 2.4 Hz, 2H, CH2), 1.37 (s, 6H,
1:5 (Rf = 0.65), pale yellow solid. H NMR (600 MHz, CDCl3,
298K): δ = 8.10 (d, JHH = 7.8 Hz, 1H, =CHNap), 7.88 (d, JHH
=
4
3
3
2×CH3). 13C NMR (151 MHz, CDCl3, 298K): δ = 163.5 (CH=N),
148.6 (m-PhNO2), 146.5 (=Cquat), 138.4 (i-Ph), 134.5 (Ph), 129.6
(Ph), 125.1 (=CH), 122.8 (Ph), 122.5 (Ph), 74.9 (Cquat(CH3)2),
42.4 (CH2), 29.5 (CH3). HRMS (ESI) m/z Calcd for
[C13H15N2O2, M+H]+: 231.1128; Found: 231.1132. FT/IR (KBr):
ῦ = 3359, 3086, 2965, 2925, 2864, 1724, 1579, 1530, 1465, 1429,
1351, 1309, 1274, 1208, 1185, 1138, 1099, 1081, 937, 897, 822,
792, 734, 677, 599 cm-1.
7.8 Hz, 1H, =CHNap), 7.84 (s, 1H, CH=N), 7.82 (d, 3JHH = 7.8 Hz,
1H, =CHNap), 7.60 (d, 3JHH = 7.2 Hz, 1H, =CHNap), 7.56 (dd, 3JHH
= 7.8 Hz, JHH = 7.8 Hz, 1H, =CHNap), 7.53 (dd, JHH = 7.8 Hz,
3
3
3JHH = 7.2 Hz, 1H, =CHNap)，7.49 (dd, JHH = 7.8 Hz, JHH = 7.8
3
3
Hz, 1H, =CHNap), 7.47 (br s, 1H, =CH), 2.64 (d, JHH = 1.8 Hz,
4
2H, CH2), 1.34 (s, 6H, 2×CH3). 13C NMR (151 MHz, CDCl3,
298K): δ = 164.3 (CH=N), 145.3 (=Cquat), 133.8 (i-Nap), 133.2 (i-
Nap), 131.7 (i-Nap), 129.00 (=CH), 128.95 (Nap), 126.7 (Nap),
126.2 (Nap), 125.6 (Nap), 125.4 (Nap), 123.7 (Nap), 73.6
(Cquat(CH3)2), 42.3 (CH2), 29.4 (CH3). HRMS (ESI) m/z Calcd
for [C17H18N, M+H]+: 236.1434; Found: 236.1426. FT/IR (KBr):
ῦ = 3433, 3050, 2917, 2849, 1735, 1686, 1654, 1582, 1508, 1463,
1360, 1336, 1240, 1052, 1019, 989, 896, 778, 731, 595, 465 cm-1.
Scheme 2. 3la. Yield: 28 mg (70%), n-hexane/ethyl acetate
1
1:5 (Rf = 0.50), pale yellow oil. H NMR (600 MHz, CDCl3,
298K): δ = 7.72 (s, 1H, C-H, imine), 7.44 (d, 4JHH = 7.8 Hz, 1H,
4
o-Ph), 7.21 (m, 3H, m-/p-Ph), 6.92 (dd, JHH = 2.4 Hz, 1H, C-H,
olefin), 2.61 (d, JHH = 3.0 Hz, 2H, CH2), 2.38 (s, 3H, o-CH3),
2
1.33 (s, 6H, 2CH3). 13C NMR (151 MHz, CDCl3, 298K): δ =
164.4 (C=N), 144.3 (=Cquat), 137.2 (Ph), 135.4 (Ph), 130.6 (Ph),
128.1 (Ph), 127.3 (Ph), 126.0 (Ph), 125.2 (=CH), 73.9 (C2Me),
42.2 (CH2), 29.6 (CH3), 20.1 (o-CH3). HRMS (ESI) m/z Calcd
for [C14H18N, M+H]+: 200.1434; Found: 200.1436. FT/IR (KBr):
ῦ = 3358, 3018, 2963, 2925, 2860, 1733, 1600, 1577, 1482, 1462,
1378, 1361, 1304, 1274, 1251, 1198, 1140, 1103, 937, 793, 757,
741, 597, 519, 461 cm-1.
Scheme 2. 3qa. Yield: 47 mg (82%), n-hexane/ethyl acetate
1:5 (Rf = 0.65), yellow solid. 1H NMR (600 MHz, CDCl3,
298K): δ = 8.44 (s, 1H, CH=N), 8.04 (m, 4H, Anthra), 8.01 (s,
1H, p-Anthra), 7.52 (t, 4JHH = 3.0 Hz, 1H, =CH), 7.50 (m, 4H,
4
Anthra), 2.01 (d, JHH = 3.0 Hz, 2H, CH2), 1.24 (s, 6H, 2×CH3).
13C NMR (151 MHz, CDCl3, 298K): δ = 162.8 (CH=N), 149.3
(=Cquat), 131.5 (=CH), 130.8 (i-Anthra), 129.1 (Anthra), 128.8
(Anthraquat), 127.3 (Anthraquat), 126.1 (Anthra), 125.7 (Anthra),
125.5 (Anthra), 73.3 (Cquat(CH3)2), 41.3 (CH2), 29.5 (CH3).
HRMS (ESI) m/z Calcd for [C21H20N, M+H]+: 286.1590; Found:
286.1630. FT/IR (KBr): ῦ = 3394, 2920, 2849, 1686, 1654,
1618, 1577, 1561, 1468, 1421, 1082, 913, 745, 674, 664, 629,
602, 577, 565, 541, 518, 478 cm-1.
Scheme 2. 3ma. Yield: 30 mg (81%), n-hexane/ethyl acetate
1:5 (Rf = 0.65), brown oil. 1H NMR (600 MHz, CDCl3, 298K): δ
3
= 8.61 (d, JHH = 6.0 Hz, 2H, Py), 7.71 (s, 1H, CH=N), 7.27 (d,
3JHH = 6.0 Hz, 2H, Py), 6.67 (t, 4JHH = 2.4 Hz, 1H, =CH), 2.67 (d,
4JHH = 2.4 Hz, 2H, CH2), 1.36 (s, 6H, 2×CH3). 13C NMR (151

7
Scheme 2. 3ra. Yield: 44 mg (71%), n-hexane/ethyl acetate
1:5 (Rf = 0.65), orange solid. 1H NMR (600 MHz, CDCl3,
(CH=N), 147.8 (=Cquat), 132.6 (i-Ph), 130.0 (Ph), 129.3 (CCF3),
ACCEPTED MANUSCRIPT
128.9 (=CH), 128.7 (p-Ph), 128.7 (Ph), 74.6 (Cquat(CH3)2), 41.8
3
3
298K): δ = 8.34 (d, JHH = 9.0 Hz, 1H, Pyr), 8.20 (d, JHH = 4.2
Hz, 1H, Pyr), 8.19 (d, 3JHH = 3.6 Hz, 1H, Pyr), 8.15 (d, 3JHH = 3.6
Hz, 1H, Pyr), 8.14 (d, 3JHH = 4.2 Hz, 1H, Pyr), 8.11 (d, 3JHH = 7.8
Hz, 1H, Pyr), 8.08 (d, 3JHH = 8.4 Hz, 1H, Pyr), 8.04 (d, 3JHH = 9.0
(CH2), 29.3 (CH3). 19F NMR (564 MHz, CDCl3, 298K): δ = -
1
61.5 (CF3). For 3va′: H NMR (600 MHz, CDCl3, 298K): δ =
8.19 (s, 1H, CH=N), 7.40 (m, 3H, Ph), 7.25 (m, 2H, Ph), 2.26 (q,
4JFH = 3.0 Hz, 2H, CH2), 1.26 (s, 6H, 2×CH3). 19F NMR (564
MHz, CDCl3, 298K): δ = -57.9 (CF3). HRMS (ESI) m/z Calcd
for [C14H15F3N, M+H]+: 254.1151; Found: 254.1151. FT/IR
(KBr): ῦ = 3060, 2969, 2930, 1726, 1585, 1445, 1428, 1365,
1342, 1305, 1218, 1156, 1124, 942, 921, 888, 844, 765, 718, 702,
659, 608, 439 cm-1.
3
3
Hz, 1H, Pyr), 8.02 (dd, JHH = 8.4 Hz, JHH = 7.8 Hz, 1H, Pyr),
7.90 (s, 1H, CH=N), 7.75 (t, 4JHH = 2.0 Hz, 1H, =CH), 2.75 (d,
2JHH = 2.0 Hz, 2H, CH2), 1.38 (s, 6H, 2×CH3). 13C NMR (151
MHz, CDCl3, 298K): δ = 164.2 (CH=N), 145.9 (=Cquat), 131.5
(Pyrquat), 131.2 (Pyrquat), 130.9 (Pyrquat), 130.7 (Pyrquat), 129.2
(Pyrquat), 128.0 (=CH), 127.9 (=CH), 127.5 (=CH), 126.3 (=CH),
125.7 (=CH), 125.5 (=CH), 125.3 (=CH), 125.0 (Pyrquat), 124.9
(Pyrquat), 124.7 (=CH), 124.5 (=CH), 123.1 (=CH), 74.0
(Cquat(CH3)2), 42.4 (CH2), 29.6 (CH3). HRMS (ESI) m/z Calcd
for [C23H20N, M+H]+: 310.1590; Found: 310.1582. FT/IR (KBr):
ῦ = 3041, 3003, 2964, 2926, 2862, 2202, 1677, 1577, 1487, 1463,
1429, 1379, 1360, 1307, 1275, 1252, 1206, 1185, 1139, 1105,
935, 908, 842, 818, 798, 761, 732, 714, 680, 642, 592, 538, 515
cm-1.
Scheme 2. 3ab. Yield: 29 mg (65%), n-hexane/ethyl acetate
1:5 (Rf = 0.50), pale yellow solid. H NMR (600 MHz, CDCl3,
298K): δ = 7.93 (s, 1H, Nap), 7.84 (m, 3H, Nap), 7.61 (m, 1H,
Nap), 7.49 (m, 2H, Nap), 6.89 (t, JHH = 3.0 Hz, 1H, =CH), 4.26
1
4
5
(m, 2H, N-CH2), 2.98 (m, 2H, CH2), 2.29 (t, JHH = 1.8 Hz, 3H,
CH3). 13C NMR (151 MHz, CDCl3, 298K): δ = 173.1 (C=N),
143.3 (=Cquat), 134.6 (i-Nap), 133.6 (i-Nap), 132.9(i-Nap), 128.37
(=CH), 128.32 (2C, =CHNap), 127.8 (=CHNap), 126.57 (=CHNap),
126.55 (2C, =CHNap), 125.1 (=CHNap), 59.0 (N-CH2), 30.0 (CH2),
16.4 (CH3). HRMS (ESI) m/z Calcd for [C16H16N, M+H]+:
222.1277; Found: 222.1279. FT/IR (KBr): ῦ = 3051, 2921, 2857,
1735, 1629, 1600, 1504, 1430, 1372, 1338, 1307, 1264, 1176,
1125, 1018, 922, 893, 813, 745, 475 cm-1.
Scheme 2. 3sa. Yield: 41 mg (79%), n-hexane/ethyl acetate
1
1:5 (Rf = 0.65), pale yellow solid. H NMR (600 MHz, CDCl3,
298K): δ = 7.71 (s, 1H, CH=N), 7.63 (dm, 3JHH = 7.7 Hz, 2H, o-
3
Ph), 7.63 (dm, 3JHH = 8.3 Hz, 2H, PhC=C), 7.51 (dm, JHH = 8.4
Hz, 2H, PhC=C), 7.46 (m, 2H, m-Ph), 7.37 (m, 1H, p-Ph), 6.80 (t,
Scheme 2. 3db. Yield: 27 mg (66%), n-hexane/ethyl acetate
1:5 (Rf = 0.50), pale yellow solid. H NMR (600 MHz, CDCl3,
4
4JHH = 3.0 Hz, 1H, =CH), 2.70 (d, JHH = 3.0 Hz, 2H, CH2), 1.37
1
(s, 6H, 2×CH3). 13C NMR (151 MHz, CDCl3, 298K): δ = 164.3
(CH=N), 143.9 (=Cquat), 140.9 (i-Ph), 140.5 (i-Ph), 135.9 (i-Ph),
129.4 (Ph), 129.0 (Ph), 127.7(=CH), 127.41 (Ph), 27.36 (i-Ph),
127.1 (Ph), 74.6 (Cquat(CH3)2), 42.7 (CH2), 29.7 (CH3). HRMS
(ESI) m/z Calcd for [C19H20N, M+H]+: 262.1590; Found:
262.1592. FT/IR (KBr): ῦ = 3086, 3030, 2999, 2972, 2929,
2885, 1574, 1485, 1460, 1427, 1410, 1363, 1317, 1276, 1181,
944, 909, 891, 879, 829, 767, 731, 697, 601, 594, 553, 501 cm-1.
298K): δ = 7.40 (m, 2H, Ph), 7.35 (m, 2H, Ph), 6.70 (t, 4JHH = 3.0
Hz, 1H, =CH), 4.03 (m, 2H, N-CH2), 2.84 (m, 2H, CH2), 2.23 (t,
5JHH = 1.8 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3, 298K): δ
= 172.8 (C=N), 143.6 (=Cquat), 135.6 (i-Ph), 133.6 (i-Ph), 130.0
(2C, Ph), 129.0 (2C, Ph), 123.6 (=CH), 59.1 (N-CH2), 29.9
(CH2), 16.3 (CH3). HRMS (ESI) m/z Calcd for [C12H13ClN,
M+H]+: 206.0731; Found: 206.0726. FT/IR (KBr): ῦ = 3360,
2921, 2852, 1724, 1660, 1632, 1601, 1589, 1491, 1427, 1409,
1385, 1314, 1287, 1270, 1094, 924, 889, 834, 514 cm-1.
Scheme 2. 3ta. Yield: 16 mg (42%), n-hexane/ethyl acetate
1
1:5 (Rf = 0.65), colourless liquid. H NMR (600 MHz, CDCl3,
Scheme 2. 3ac. Yield: 23 mg (56%), n-hexane/ethyl acetate
1:5 (Rf = 0.65), red brown solid. H NMR (600 MHz, CDCl3,
298K): δ = 7.97 (s, 1H, Nap), 7.92 (s, 1H, CH=N), 7.85 (m, 3H,
Nap), 7.60 (m, 1H, Nap), 7.50 (m, 2H, Nap), 7.03 (t, JHH = 3.0
4
298K): δ = 7.55 (s, 1H, CH=N), 5.77 (dm, JHH = 9.0 Hz, 1H,
1
4
=CH), 2.32 (d, JHH = 3.0 Hz, 2H, (CH2)quat), 2.07 (m, 1H, i-Cy),
1.73 (m, 2H, Cy), 1.66 (m, 2H, Cy), 1.30 (s, 6H, 2×CH3), 1.25
(m, 2H, Cy), 1.13 (m, 2H, Cy). 13C NMR (151 MHz, CDCl3,
298K): δ = 164.8 (CH=N), 140.4 (=Cquat), 136.1 (=CH), 72.1
(Cquat(CH3)2), 40.1 (CH2), 39.3 (i-Cy), 32.0 (Cy), 29.2 (CH3),
25.9 (Cy), 25.7 (Cy). HRMS (ESI) m/z Calcd for [C13H22N,
M+H]+: 192.1747; Found: 192.1753. FT/IR (KBr): ῦ = 3207,
2926, 2852, 1676, 1618, 1448, 1367, 1317, 1085, 818, 734, 674,
557, 463 cm-1.
4
Hz, 1H, =CH), 4.26 (m, 2H, N-CH2), 2.98 (m, 2H, CH2). 13C
NMR (151 MHz, CDCl3, 298K): δ = 168.8 (CH=N), 143.8
(=Cquat), 134.4 (i-Nap), 133.5 (i-Nap), 133.0 (i-Nap), 128.7
(=CH), 128.43 (=CHNap), 128.38 (=CHNap), 127.9 (=CHNap),
127.8 (=CHNap), 126.72 (=CHNap), 126.65 (=CHNap), 126.4
(=CHNap), 62.2 (N-CH2), 28.5 (CH2). HRMS (ESI) m/z Calcd for
[C15H14N, M+H]+: 208.1121; Found: 208.1123. FT/IR (KBr): ῦ =
3054, 2925, 2853, 1679, 1591, 1573, 1506, 1464, 1374, 1338,
1291, 1274, 1261, 1153, 1124, 1017, 978, 953, 936, 921, 903,
874, 819, 751, 733, 646, 518, 481 cm-1.
Scheme 2. 3ua. Yield: 19 mg (45%), n-hexane/ethyl acetate
1:5 (Rf = 0.56), yellow oil. 1H NMR (600 MHz, CDCl3, 298K): δ
= 7.65 (s, 1H, CH=N), 7.44 (d, 3JHH = 7.8 Hz, 2H, o-Ph), 7.34 (t,
3JHH = 7.5 Hz, 2H, m-Ph), 7.27 (dt, 3JHH = 7.2 Hz, 1H, p-Ph), 6.80
(d, 3JHH = 10.8 Hz, 1H, =CH), 6.73 (d, 3JHH = 15.6 Hz, 1H, =CH),
6.53 (dt, 3JHH = 10.8 Hz, 4JHH = 2.4 Hz, 1H, =CHquat) 2.53 (d, 4JHH
= 2.4 Hz, 2H, CH2), 1.34 (s, 6H, 2×CH3). 13C NMR (151 MHz,
CDCl3, 298K): δ = 163.0 (CH=N), 144.8 (=Cquat), 137.0, 136.6,
128.9 (Ph), 128.8, 128.4, 126.8(Ph), 126.2, 73.2 (Cquat(CH3)2),
40.4 (CH2), 29.7 (CH3). HRMS (ESI) m/z Calcd for [C15H18N,
M+H]+: 212.1434; Found: 212.1392. FT/IR (KBr): ῦ = 3354,
3190, 2957, 2923, 2851, 2255, 1659, 1631, 1589, 1467, 1371,
1260, 1182, 1098, 885, 843, 801, 734, 690, 661, 476 cm-1.
Scheme 2. 3dc. Yield: 19 mg (50%), n-hexane/ethyl acetate
1:5 (Rf = 0.50), brown oil. H NMR (600 MHz, CDCl3, 298K) δ
1
4
= 7.87 (s, 1H, CH=N), 7.37 (m, 4H, Ph), 6.77 (t, JHH = 3.0 Hz,
1H, =CH), 4.21 (m, 2H, CH2), 2.79 (m, 2H, CH2). 13C NMR (151
MHz, CDCl3, 298K): δ = 168.3 (C=N), 144.3 (=Cquat), 135.4 (i-
Ph), 133.8 (i-Ph), 130.0 (2C, Ph), 129.0 (2C, Ph), 125.8 (=CH),
62.5 (N-CH2), 28.4 (CH2). HRMS (ESI) m/z Calcd for
[C11H11ClN, M+H]+: 192.0575; Found: 192.0570. FT/IR (KBr):
ῦ = 3357, 3009, 2922, 2852, 1726, 1659, 1633, 1576, 1491, 1470,
1450, 1409, 1308, 1292, 1157, 1090, 1011, 973, 923, 868, 840,
816, 681, 512, 416 cm-1.
Scheme 2. 3va. Yield: 30 mg (59%), n-hexane/ethyl acetate
1
2:5 (Rf = 0.65), yellow oil. 3va: 3va′ = 11:3. For 3va: H NMR
4.3. General procedure for synthesis of 3,5-dialkylsubstituted
(600 MHz, CDCl3, 298K): δ = 7.45 (s, 1H, CH=N), 7.42 (m, 3H,
pyridine (4).
4
Ph), 7.28 (m, 2H, Ph), 2.71 (q, JFH = 3.6 Hz, 2H, CH2), 1.35 (s,
6H, 2×CH3). 13C NMR (151 MHz, CDCl3, 298K): δ = 160.2

8
Tetrahedron
3
3
To a dry tube containing a dichloroethane (1 mL) solution of
3JHH = 5.4 Hz, 2H, =CHThio), 6.94 (dd, JHH = 4.2 Hz, JHH = 3.6
ACCEPTED MANUSCRIPT
3
nitrone (0.40 mmol, 1.0 equiv.), SiCl4 (0.06 mmol, 15 mol%),
P(NMe2)3 (0.48 mmol, 1.2 equiv.) and aldehyde (0.40 mmol)
were added in a glove box. Then, the tube was sealed by
polytetrafluoroethylene bottle stopper with rubber ring and
thread. The mixture was then stirred and heated at 60°C. After
reaction for 24 h, the mixture was cooled to room temperature.
Removal of the solvent afforded the crude product, which was
purified by thin layer chromatography on silica gel.
Hz, 2H, =CHThio), 6.79 (d, JHH = 3.6 Hz, 2H, =CHThio), 4.15 (s,
4H, CH2). 13C NMR (151 MHz, CDCl3, 298K): δ = 147.6
(=CHPyr), 142.3 (i-Pyr), 137.0 (=CHPyr), 136.1 (i-Thio), 127.2
(=CHThio), 125.8 (=CHThio), 124.6 (=CHThio), 33.2 (CH2). HRMS
(ESI) m/z Calcd for [C15H14NS2, M+H]+: 272.0562; Found:
272.0566.
Scheme 4 4xd. Yield: 31 mg (60%), n-hexane/ethyl acetate 5:1
1
(Rf = 0.40), yellow solid. H NMR (600 MHz, CDCl3, 298K): δ
4.3.1. Characterization of 3,5-dialkylsubstituted pyridine (4).
Scheme 4 4ad. Yield: 55 mg (76%), n-hexane/ethyl acetate
= 8.49 (m, 4H, =CHPyr), 8.38 (s, 2H, =CHPyr), 7.42 (dt, 3JHH = 7.8
Hz, 2H, =CHPyr), 7.24 (t, JHH = 1.8 Hz, 1H, =CHPyr), 7.22 (dd,
3
3JHH = 7.8 Hz, 3JHH = 4.8 Hz, 2H, =CHPyr), 3.94 (s, 4H, CH2). 13
C
1
5:1 (Rf = 0.23), pale yellow solid. H NMR (600 MHz, CDCl3,
NMR (151 MHz, CDCl3, 298K): δ = 150.2 (=CHPyr), 148.5
(=CHPyr), 148.3 (i-Pyr), 136.7 (=CHPyr), 136.3 (i-Pyr), 135.4
(=CHPyr), 135.2 (=CHPyr), 123.7 (=CHPyr), 36.2 (CH2). HRMS
(ESI) m/z Calcd for [C17H16N3, M+H]+: 262.1339; Found:
262.1341.
298K): δ = 8.42 (s, 2H, =CHPyr), 7.80 (m, 2H, =CHNap), 7.76 (d,
3JHH = 8.4 Hz, 2H, =CHNap), 7.74 (m, 1H, =CHNap), 7.58 (s, 1H,
=CHNap), 7.45 (m, 4H, =CHNap), 7.37 (s, 1H, =CHPyr), 7.27 (d,
3JHH = 1.8 Hz, 1H, =CHNap), 7.25 (d, 3JHH = 1.8 Hz, 1H, =CHNap),
4.09 (s, 4H, CH2). 13C NMR (151 MHz, CDCl3, 298K): δ =
148.1 (=CHPyr), 137.4 (i-Nap), 137.3 (=CHPyr), 136.5 (i-Nap),
133.7 (i-Nap), 132.3 (i-Nap), 128.5 (=CHNap), 127.8 (=CHNap),
127.7 (=CHNap), 127.4 (=CHNap), 127.3 (=CHNap), 126.3
(=CHNap), 125.8 (=CHNap), 39.2 (CH2). HRMS (ESI) m/z Calcd
for [C27H22N, M+H]+: 360.1747; Found: 360.1727.
Acknowledgments
Financial supports by National Natural Science Foundation of
China (Petrochemical Joint Fund U1662133 and No. 21476240),
Instrument Developing Project of the Chinese Academy of
Sciences (No. YZ201521) and CAS 100-Talent Program (2014),
are gratefully acknowledged.
Scheme 4 4bd. Yield: 34 mg (66%), n-hexane/ethyl acetate
1
5:1 (Rf = 0.40), pale yellow solid. H NMR (600 MHz, CDCl3,
298K): δ = 8.35 (d, JHH = 1.8 Hz, 2H, =CHPyr), 7.31 (s, 1H,
4
Appendix A. Supplementary data
=CHPyr), 7.29 (d, JHH = 7.5 Hz, 4H, Ph), 7.22 (t, JHH = 7.5 Hz,
3
3
2H, p-Ph), 7.15 (d, 3JHH = 7.5 Hz, 4H, Ph), 3.94 (s, 4H, CH2). 13
C
General information, general procedure, procedures for control
NMR (151 MHz, CDCl3, 298K): δ = 148.1 (=CHPyr), 139.9 (i-
Pyr), 137.0 (=CHPyr), 136.4 (i-Ph), 128.9 (4C, Ph), 128.8 (4C,
Ph), 126.6 (2C, Ph), 39.1 (CH2). HRMS (ESI) m/z Calcd for
[C19H18N, M+H]+: 260.1434; Found: 260.1448.
experiments, characterization data, and H NMR, 13C NMR and
1
2D NMR spectroscopic data (PDF); and X-ray of 3aa (cif).
References and notes
Scheme 4 4fd. Yield: 43 mg (62%), n-hexane/ethyl acetate 5:1
(Rf = 0.40), pale yellow solid. 1H NMR (600 MHz, CDCl3,
1. (a) Mahato S, Jana CK. Chem Rec. 2016;16:1477-1488;
(b) Seidel D. Acc Chem Res. 2015;48:317-328;
4
3
298K): δ = 8.39 (d, JHH = 1.8 Hz, 2H, =CHPyr), 8.16 (dt, JHH
=
(c) Bolleddula J, DeMent K, Driscoll JP,Worboys P, Brassil PJ,
Bourdet DL. Drug Metab Rev. 2014;46:379-419;
(d) Schumperli MT, Hammond C, Hermans I. ACS Catal.
2012;2:1108-1117;
(e) Felpin FX, Lebreton J. Tetrahedron. 2004;60:10127-10153;
(f) Sampedro D, Migani A, Pepi A, Busi E, Basosi R, Latterini L,
Elisei F, Fusi S, Ponticelli F, Zanirato V, Olivucci M. J Am Chem
Soc. 2004;126:9349-9359;
3
8.4 Hz, 4JHH = 1.8 Hz, 4H, o-Ph), 7.31 (d, JHH = 9.0 Hz, 4H, m-
Ph), 7.24 (t, JHH = 1.8 Hz, 1H, =CHPyr), 3.94 (s, 4H, CH2). 13C
4
NMR (151 MHz, CDCl3, 298K): δ = 148.8 (=CHPyr), 147.2 (i-
Pyr), 147.0 (=CHPyr), 136.8 (2C, Ph), 135.0 (i-Ph), 129.7 (4C,
Ph), 124.2 (4C, Ph), 36.2 (CH2). HRMS (ESI) m/z Calcd for
[C19H16N3O4, M+H]+: 350.1135; Found: 350.1115.
(g) Liddell JR. Nat Prod Rep. 2002;19:773-781.
2. (a) Chen WJ, Ma LL, Paul A, Seidel D. Nat Chem. 2018;10:165-169;
(b) Zhu ZB, Seidel D. Org Lett. 2016;18:631-633;
(c) Chen WJ, Wilde RG, Seidel D. Org Lett. 2014;16:730-732;
(d) Das D, Sun AX, Seidel D. Angew Chem Int Ed. 2013;52:3765-
3769;
(e) Mitchell EA, Peschiulli A, Lefevre N, Meerpoel L, Maes Bert
UW. Chem Eur J. 2012;18:10092-10142.
3. (a) He Y, Wang F, Zhang XY, Fan XS. Chem Commun.
2017;53:4002-4005;
Scheme 4 4id. Yield: 38 mg (59%), n-hexane/ethyl acetate 5:1
(Rf = 0.23), pale yellow solid. 1H NMR (600 MHz, CDCl3,
298K): δ = 8.30 (d, JHH = 1.8 Hz, 2H, =CHPyr), 7.29 (t, 3JHH = 2.4
3
Hz, 1H, =CHPyr), 7.06 (dt, JHH = 9.0 Hz, JHH = 1.8 Hz, 4H, Ph),
6.83 (dt, 3JHH = 9.0 Hz 3JHH = 3.0 Hz, 4H, Ph), 3.88 (s, 4H, CH2),
3.79 (s, 6H, OCH3). 13C NMR (151 MHz, CDCl3, 298K): δ =
158.4 (2C, Ph), 147.4 (=CHPyr), 137.3 (i-Pyr), 137.1 (=CHPyr),
131.8 (i-Ph), 129.9 (4C, Ph), 114.2 (4C, Ph), 55.4 (CH2), 38.2
(OCH3). HRMS (ESI) m/z Calcd for [C21H22NO2, M+H]+:
320.1645; Found: 320.1625.
(b) Takasu N, Oisaki K, Kanai M. Org Lett. 2013;15:1918-1921;
(c) Sundararaju B, Achard M, Sharma G V M, Bruneau C. J Am
Chem Soc. 2011;133:10340-10343;
(d) Xia XF, Shu XZ, Ji KG, Yang YF, Shaukat A, Liu XY, Liang
YM. J Org Chem. 2010;75:2893-2902;
Scheme 4 4nd. Yield: 22 mg (45%), n-hexane/ethyl acetate
5:1 (Rf = 0.50), orange solid. 1H NMR (600 MHz, CDCl3,
298K): δ = 8.41 (s, 2H, =CHPyr), 7.55 (s, 1H, =CHPyr), 7.34 (d,
3
3
3JHH = 1.2 Hz, 2H, =CHFu), 6.31 (dd, JHH = 3.0 Hz, JHH = 1.8
Hz, 2H, =CHFu), 6.05 (d, 3JHH = 3.0 Hz, 2H, =CHFu), 3.99 (s, 4H,
CH2). 13C NMR (151 MHz, CDCl3, 298K): δ = 148.8 (=CHPyr),
147.2 (i-Pyr), 147.0 (=CHPyr), 136.8 (i-Fu), 135.0 (=CHFu), 129.7
(=CHFu), 124.2 (=CHFu), 33.2 (CH2). HRMS (ESI) m/z Calcd for
[C15H14NO2, M+H]+: 240.1019; Found: 240.1023.
(e) Zhou JD, Zhao HL, Li Y, Jin C, Su WK. Tetrahedron Lett.
2017;58:3174-3177.
4. (a) Ma LL, Paul A, Breugst M, Seidel D. Chem Eur J.
2016;22:18179-18189;
(b) Mandal S, Mahato S, Jana CK. Org Lett. 2015;17:3762-3765;
(c) Chen WJ, Kang YK, Wilde RG, Seidel D. Angew Chem Int Ed.
2014;53:5179-5182.
5. Norris JF, Rubinstein D. Bull Chem Soc Jpn. 1983;56:3199-3120.
6. (a) Tan ZD, Jiang HF, Zhang M. Org Lett. 2016;18:3174-3177;
(b) Xie F, Xie R, Zhang JX, Jiang HF, Du L, Zhang M. ACS Catal.
2017;7:4780-4785.
Scheme 4 4od. Yield: 29 mg (54%), n-hexane/ethyl acetate
5:1 (Rf = 0.40), yellow solid. 1H NMR (600 MHz, CDCl3,
298K): δ = 8.41 (s , 2H, =CHPyr), 7.47 (s, 1H, =CHPyr), 7.17 (d,

9
7. (a) Hortmann AG, Koo J, Yu CC. J Org Chem. 1978;43:2289-2291;
ACCEPTED MANUSCRIPT
(b) Balicki R, Kaczmarek L, Malinowski M. Synth Commun.
1989;19:897-900;
(c) Balicki R. Chem Ber. 1990;123:647-648;
(d) Yadav JS, Reddy BVS, Reddy M.M. Tetrahedron Lett.
2000;41:2663-2665;
(e) Ilias M, Barman DC, Prajapati D, Sandhu JS. Tetrahedron Lett.
2002;43:1877-1879.
8. Balicki R, Cybulski M, Maciejewski G. Synth Commun.
2003;33:4137-4141.
9. (a) Horner L, Hoffmann H. Angew Chem Int Ed. 1956;68:437-485;
(b) Agolini F, Bonnett R. Can. J Chem Rev Can Chim. 1962;40:181-
183;
(c) Milliet P, Lusinchi X. Tetrahedron. 1979;35:43-49;
(d) Sanz R, Escribano J, Fernandez Y, Aguado R, Pedrosa MR,
Arnaiz FJ. Synlett. 2005;9:1389-1392;
(e) Fuentes JA, Clarke ML. Synlett. 2008;17:2579-2582;
(f) Cividino P, Dheu AML, Ou J, Milet A, Py S, Toy PH.
Tetrahedron Lett. 2009;50:7038-7042.
10. (a) Saini A, Kumar S, Sandhu JS. Synlett. 2006;3:395-398;
(b) Oh K, Knabe WE. Tetrahedron. 2009;65:2966-2974.
11. (a) Han JH, Choi KI, Kim JH, Yoon CM, Yoo BW. Synth Commun.
2006;36:415-419;
(b) Singh SK, Reddy AS, Mangle M, Ganesh KR. Tetrahedron.
2007;63:126-130;
(c) Ma R, Liu AH, Huang CB, Li XD, He LN. Green Chem.
2013;15:1274-1279;
(d) Jeong J, Lee D, Chang S. Chem Commun. 2015;51:7035-7038.
12. (a) Ye CX, Melcamu YY, Li HH, Cheng JT, Zhang TT, Ruan YP,
Zheng X, Lu X, Huang PQ. Nat Commun. 2018;9:410-418;
(b) Merino P, Tejero T, Delso I, Matute R. Org Biomol Chem.
2017;15:3364-3375;
(c) Rios-Gutierrez M, Daru A, Tejero T, Domingo LR, Merino P.
Org Biomol Chem. 2017;15:1618-1627;
13. (a) Yang JF, Seto YW, Yoshikai N. ACS Catal. 2015;5:3054-3057;
(b) Moselage M, Li J, Ackermann L. ACS Catal. 2015;5: 498-525;
(c) Lenges CP, Brookhart M, White PS. Angew Chem Int Ed.
1999;38:552-555;
(d) Lenges CP, White PS, Brookhart M.
1998;120:6965-6979;
J Am Chem Soc.
(e) Lenges CP, Brookhart M. J Am Chem Soc. 1997;119:3165-3166.
14. Petersson MJ, Loughlin WA, Jenkins ID. Chem Commun.
2008;37:4493-4494.
15. (a) Platonova AY, Seidel D. Tetrahedron Lett. 2015;56:3147-3150;
(b) Oda M, Fukuchi Y, Ito S, Thanh NC, Kuroda S. Tetrahedron Lett.
2007;48:9159-9162;
(c) Burrows WD, Burrows EP. J Org Chem.1963;28:1180-1182;
(d) Burrows EP, Burrows WD, Hutton RF. J Org Chem.1962;27:316-
317;
(e) Poirier RH, Morin RD, McKim Arveta M, Bearse AE. J Org
Chem. 1961;26:4275-4278;
(f) Rügheimer L, Ber Dtsch Chem Ges. 1892;25:2421-2429.
16. Fujiwara Y, Oda M, Shoji T, Abe T, Kuroda S. Heterocycles.
2012;85:1187-1195.
17. (a) Liu XD, Verkade JG. Inorg Chem. 1998;37:5189-5197;
(b) Denmark SE, Wynn T. J Am Chem Soc. 2001;123:6199-6200;
(c) Denmark SE, Wynn T, Beutner GL.
2002;124:13405-13407;
J Am Chem Soc.
(d) Denmark SE, Beutner GL, Wynn T, Eastgate MD. J Am Chem
Soc. 2005;127:3774-3789.
18. Kobayashi J, Ishida K, Kawashima T. Silicon Chem. 2002;1:351-354.
19. (a) Kramer GM, Maas ET Jr, Dines MB. Inorg Chem. 1981;20:1415-
1418;
(b) Maji B, Baidya M, Ammer J, Kobayashi S, Mayer P, Ofial AR.
Eur J Org Chem. 2013;16:3369-3377.
20. (a) Lokensgard JP, Fisher JW, Bartz WJ, Meinwald J. J Org Chem.
1985;50:5609-5611;
(b) Gundersen LL, Benneche T. Acta Chem. Scand. 1991;45:975-
977.
21. (a) Goti A, Nannelli L. Tetrahedron Lett. 1996;37:6025-6028;
(b) Goti A, Cardona F, Soldaini G. Org Synth. 2005;81:204-212;
(c) Soldaini G, Cardona F, Goti A. Org Lett. 2007;9:473-476;
(d) Burchak ON, Philouze C, Chavant PY, Py S. Org Lett.
2008;10:3021-3023.