Organocatalytic Michael addition of 2-nitro methylene imidazolidines to α,β-unsaturated aldehydes: Concise synthesis of chiral insecticide Paichongding

Article abstract of DOI:10.1016/j.tet.2015.07.056

An organocatalytic Michael reaction of 2-nitro methylene imidazolidines to α,β-unsaturated aldehydes followed by acetal-amination affords hexahydroimidazo[1,2-a]pyridines in high yields and with moderate to excellent enantioselectivity. The utility of the reaction was illustrated by a one-step transformation to Paichongding, an insecticide of the neonicotinoid family.

Full text of DOI:10.1016/j.tet.2015.07.056

Tetrahedron xxx (2015) 1e8
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Organocatalytic Michael addition of 2-nitro methylene
imidazolidines to
a,b-unsaturated aldehydes: concise synthesis of
chiral insecticide Paichongding
Yanpeng Lou , Yin Xu , Zhuo Chai , Xusheng Shao , Gang Zhao ,*, Zhong Li
a
a
b
a
b
a,
*
a
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road,
Shanghai 200237, China
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
b
3
45 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An organocatalytic Michael reaction of 2-nitro methylene imidazolidines to a,b-unsaturated aldehydes
Received 11 June 2015
Received in revised form 16 July 2015
Accepted 21 July 2015
Available online xxx
followed by acetal-amination affords hexahydroimidazo[1,2-a]pyridines in high yields and with mod-
erate to excellent enantioselectivity. The utility of the reaction was illustrated by a one-step trans-
formation to Paichongding, an insecticide of the neonicotinoid family.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalytic
Michael addition
Nitroenamine
Chiral insecticide
1. Introduction
(Nephotettix bipunctatus). However, the construction of these
structures in catalytic enantioselective way is still unexplored.
5
Over the past decades, neonicotinoid insecticides have ranked
among the most important classes of insecticides mainly as major
insecticides against various sucking and biting insects, owing to the
advantages such as low mammalian toxicity, broad insecticidal
Recently, functionalized nitroenamines have been used as
a versatile building block for the synthesis of useful compounds in
asymmetric catalysis (Scheme 1). In their highly efficient asym-
metric synthesis of (ꢀ)-oseltamivir, Ma’s group developed an
organocatalytic Michael addition of aldehydes to N-acyl-2-amino-
1
scope and high potency. Several members of this family have been
commercialized.2 Due to the presence of resistance development
and the need to minimize detrimental effect on agricultural pro-
duction, the development of insecticides bearing new structures
1-nitroethenes by using diphenylprolinol silyl ether catalysts.
6
Yuan’s group reported the asymmetric Michael addition of 3-
substituted oxindoles to N-acyl-2-amino-1-nitroethenes catalyzed
3
7
and novel functioning modes is still highly desired. Different from
by chiral amino alcohols. In both cases, the N-protected nitroen-
the early generations of non-chiral neonicotinoid insecticides,
some of the newly developed members with the best efficacy have
several chiral centers such as Sulfoxaflor, Paichongding and
Cycloxaprid (Fig. 1).4 Similar to imidacloprid, Paichongding is
a nicotinic acetylcholine receptor (nAChR) agonist with low
mammalian toxicity and significant activity against imidacloprid-
resistant insects and is used for the control of a broad spectrum
of sucking and biting insects, such as cowpea aphids (Aphis crac-
civora), brown planthopper (Nilaparvata lugens), and fabricius
amine served as a Michael acceptor. More recently, Bode’s group
used a new substituted nitroenamine with a free primary amine
functionality as reaction partner in the NHC-catalyzed annulation
8
with
a
,b
-unsaturated aldehydes. Almost at the same time, Dai and
Hsung reported an asymmetric aza-[3þ3]-annulation of
pyrrolidine-based exo-cyclic vinylogous amides and urethanes with
9
chiral vinyl iminium salts. Inspired by these works and as part of
our continued interest in the application of asymmetric organo-
catalysis to the construction of useful structures, we have de-
veloped an organocatalytic [3þ3]-annulation way for the synthesis
of chiral neonicotinoids from substituted nitroenamine 1 and a,b-
*
Corresponding authors. E-mail addresses: zhaog@mail.sioc.ac.cn (G. Zhao),
unsaturated aldehydes.
lizhong@ecust.edu.cn (Z. Li).
http://dx.doi.org/10.1016/j.tet.2015.07.056
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
Y. Lou et al. / Tetrahedron xxx (2015) 1e8
Fig. 1. Structures of neonicotinoid pesticides; *Denotes chiral center.
Scheme 1. The application of nitroenamines in asymmetric catalysis.
2
. Results and discussion
prolonged reaction time (Table 1, entries 12e14). After a survey of
reaction temperature, the optimum reaction conditions were
ꢁ
Various chiral diarylprolinol catalysts derived from
L
-proline
established as that of entry 17 (ꢀ20 C), providing the desired
were first screened in the model reaction between 2-chloro-5-((2-
nitromethylene)imidazolidin-1-yl)methyl) pyridine 1a and (E)-
hex-2-enal 2a (Table 1, entries 1e5). Due to the poor solubility of
the compound 1a in CH Cl , one equivalent of acetic acid as addi-
product in 92% yield, 84% ee and 8:1 dr.
With the optimal conditions in hand, we then examined the
generality of the reaction with a variety of -unsaturated aldehydes
(
a,b
2
2
(Table 2). For different alkyl substituted a,b-unsaturated aldehydes 2
1
tive was necessary for the reaction to give satisfactory yields. To our
delight, when the TMS-protected diphenylprolinol silyl ether 4c
was employed as catalyst, the reaction was completed within 48 h
to provide the desired cyclic hemiaminal product 3a in 65% yield,
(R ¼alkyl), the reactions generally proceeded smoothly to deliver
the desired products 3 in high yields and moderate to good dia-
stereo- and enantioselectivities (Table 2, entries 1e5). Notably, both
the dr and ee value increased as the length of the carbon chains of
the unsaturated aldehydes increased (Table 2, entries 1e4). However,
when the longer (E)-dec-2-enal was used, a drop in the enantiose-
lectivity was observed, albeit with improved dr and comparable
yield (10:1 dr, 74% ee, entry 5). The reaction did not proceed to full
5
7% ee, and 2:1 dr. The use of other carboxylic acids as additive,
performing the reaction in toluene or reducing the amount of the
additive all failed to improve the yield (Table 1, entries 6e11). Al-
though a significant improvement on enantioselectivity was ob-
served when the basic NaOAc or DMAP was used as additive, the
reaction yield was low due to incomplete conversion even with
1
conversion even after an extended reaction time when R is a bulky
cyclohexyl group, but an excellent ee value was obtained (95% ee,
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Y. Lou et al. / Tetrahedron xxx (2015) 1e8
3
Table 1
a
Screening of reaction conditions
ꢁ
Yield (%)b
ee (%)d
Entry
cat.
Additive
T (days)
T ( C)
1
2
3
4
5
6
7
8
4a
4a
4b
4c
4d
4c
4c
4c
4c
4c
4c
4c
4c
4c
4c
4c
4c
/
5
5
5
2
5
4
4
4
3
2
5
5
5
5
3
4
4
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
0
13
61
73
65
67
48
9
19
60
78
44
54
44
Trace
69
92
92
ND
19
15
57
0
29
ND
ND
51
48
57
71
69
ND
73
79
84
AcOH
AcOH
AcOH
AcOH
PhCOOH
o-NO
p-CH
n-PrCOOH
AcOH
2
-PhCOOH
O-PhCOOH
3
9
e
10
11
12
13
14
15
16
17
f
AcOH
NaOAc
DMAP
NaOAc
AcOH
AcOH
AcOH
g
h
i
0
ꢀ10
ꢀ20
c
The diastereomeric ratio was determined by 1H NMR spectroscopic analysis of the crude product.
a
Reactions were carried out with 1a (0.1 mmol), 2a (0.15 mmol), and additive (0.1 mmol) in the presence of catalyst 4 in the solvent (1 mL) at the specified temperature.
Isolated yields of diastereoisomers mixture.
b
d
e
f
The ee value was determined by chiral HPLC analysis. ND¼not determined.
Toluene was used as a solvent.
The reaction was carried out with 0.05 mmol of acetic acid.
g
h
i
dr¼3:1.
dr¼5:1.
dr¼8:1.
entry 6). Moreover, two other nitroenamines 1b and 1c were also
well-tolerated in the reaction to provide comparable results (Table 2,
entries 7e8). When the reactions were performed with substituted
resulting intermediate I will undergo isomerization to II, which will
undergo hydrolysis to furnish the desired product while regener-
ating the catalyst.
1
cinnamaldehydes (R was an aryl group), the corresponding hemi-
aminal products were etherificated to facilitate the determination of
ee values by chiral HPLC (better solubility in hexanes-isopropyl al-
cohol mixture). In general, the reactions were less successful with
substituted cinnamaldehydes derivatives in that both lower enan-
tioselectivities and diastereoselectivities were obtained, irrespective
of the electronic nature or position of the substituents on the ben-
3. Conclusion
In summary, we have developed an asymmetric organocatalytic
Michael addition/acetal-amination sequence to synthesize chiral
neonicotinoid analogs. The reaction is featured with simple and
readily available starting materials and L-proline-derived organo-
catalysts, easy scalability and mild reaction conditions.
1
zene ring of R (Table 2, entries 9e16).
To test the scalability of the reaction, the reaction between 1a
and 2a was performed on gram scale (Scheme 2). To our delight, in
the presence of 10 mol % of 4c, the desired product was obtained in
4. Experimental
9
0% yield, 8:1 dr and 84% ee, which are almost the same as those of
4.1. General information
the small scale reaction. The utility of the reaction was illustrated by
a one-step conversion of the product 3b to Paichongding 5 by
refluxing with n-propanol in the presence of 10 mol % of p-TsOH in
1
The H NMR spectra were recorded on a Bruker (400 MHz). All
chemical shifts (d) were given in ppm. Data were reported as fol-
8
5% yield and 1:1 dr, without loss of enantioselectivity.
The absolute configuration of the product 3a (trans isomer) was
lows: chemical shift, integration, multiplicity (s¼single, d¼doublet,
t¼triplet, q¼quartet, br¼broad, m¼multiplet, cm¼complex multi-
1
0
13
determined to be (5R, 7R) by X-ray crystallographic analysis, and
the others were assigned by analogy (Fig. 2).
plet) and coupling constants (Hz). C NMR spectra were recorded
on a DPX-400 (400 MHz). Flash column chromatography was per-
formed using H silica gel. For thin-layer chromatography (TLC),
silica gel plates (HSGF 254) were used and compounds were visu-
alized by irradiation with UV light. Analytical high performance
liquid chromatography (HPLC) was carried out on SHIMADZU
equipment using chiral columns. Melting points were determined
A plausible reaction mechanism was proposed to explain the
stereochemical result of the reaction (Fig. 2). The
a
,b
-unsaturated
0
aldehyde is firstly activated by catalyst 4c to form iminium 2 . The
Michael donor 1 then will attack the iminium from the Re face to
minimize steric hindrance from the diarylsilyl ether moiety. The
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4
Y. Lou et al. / Tetrahedron xxx (2015) 1e8
Table 2
Scope of the tandem reactiona
Entry
1
R1
R2
3
Yield (%)b
dr (%)c
ee (%)d
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1a
1a
1a
1a
1a
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
CH
3
H
H
H
H
H
H
H
H
CH
CH
CH
CH
CH
CH
CH
CH
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
88
85
78
85
80
40
83
85
77
80
80
72
67
91
90
85
3:1
3:1
7:1
7:1
10:1
5:1
7:1
6:1
6:1
1:1
3:1
4:1
4:1
4:1
6:1
3:1
60
73
79
91
74
95
66
88
78
26
51
47
36
43
46
43
2
C H
5
n-C
n-C
n-C
Cyclohexyl
n-C
n-C
4
H
H
H
7
5
7
11
15
3
H
H
7
3
7
6
C H
5
3
3
3
3
3
3
3
3
0
1
2
3
4
5
6
4-ClC
3-ClC
2-ClC
4-FC
4-MeOC
6
H
H
H
4
4
4
6
6
6 4
H
6
H
4
2-MeC
4-MeC
6
H
H
4
4
6
a
(1 mL) at ꢀ20 ꢁC. For entries 8e16, the
2 2
Reactions were carried out with 1 (0.1 mmol), 2 (0.15 mmol), and acetic acid (0.1 mmol) in the presence of catalyst 4c in CH Cl
alcohol products were converted to methyl ethers by treatment with p-TsOH in methanol at reflux.
b
Isolated yields of diastereoisomers mixture.
c
The diastereomeric ratio was determined by 1H NMR spectroscopic analysis of the crude product.
d
The ee value was determined by chiral HPLC analysis.
Scheme 2. Gram-scale synthesis of 3a and conversion of 3b to Paichongding 5.
on a SGW X-4 melting point and were uncorrected. Optical rota-
tions were measured on a JASCO P-1010 Polarimeter at
IR spectra were recorded on a PerkineElmer 983G instrument.
unsaturated aldehyde 2 (0.15 mmol) and acetic acid (0.1 mmol,
l
¼589 nm.
11.4 mg) were added. The resulting mixture was vigorously stirred
ꢁ
at ꢀ20 C. When the reaction was finished (determined by TLC
Mass spectra analysis was performed on API 200 LC/MS system
analysis), the crude mixture was warmed to the room temperature.
(
Applied Biosystems Co. Ltd.).
All reagents purchased from commercial sources were purified
Saturated NaHCO
the reaction. And the resulting mixture was extracted with CH
(15 mLꢂ3) and the combined organic layer was washed by brine
(10 mL). The combined organic extracts were dried over Na SO
and filtered and concentrated in vacuo. The crude product was
purified by column chromatography to afford the products 3.
For entries 8e16, the alcohol product was diluted in the meth-
anol (2.0 mL), p-TsOH (0.01 mmol, 1.7 mg) was added and reflux
3
aqueous solution (10 mL) was added to quench
2
Cl
2
by standard techniques prior to use. b-Nitro enamines were pre-
pared according to literature procedures. Preparation and charac-
terization of the catalysts 4ae4d were reported in the published
literatures.11
2
4
,
4
.2. General procedure for asymmetric Michael reactions and
further etherification
until the reaction completed. Saturated NaHCO
10 mL) was added to quench the reaction. And the resulting
mixture was extracted with CH Cl
(15 mLꢂ3) and the combined
organic layer was washed by brine (10 mL). The combined organic
extracts were dried over Na SO , and filtered and concentrated in
3
aqueous solution
(
To a solution of the catalyst 4c (10 mol %, 0.01 mmol, 6.5 mg) in
2
2
CH
2
Cl
2
(1.0 mL) was added nitro-methylene imidazole
1
ꢁ
(
0.1 mmol), and the mixture was cooled to ꢀ20 C, and then the
a
,
b
-
2
4
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Y. Lou et al. / Tetrahedron xxx (2015) 1e8
5
Fig. 2. The X-ray crystal structure of 3a and a tentative mechanism.
ꢁ
26
ꢀ78.5 (c 0.5, MeOH). 1H NMR
vacuo. The crude product was purified by column chromatography
to afford the methyl ethers product.
mp 213e215 C. 78% yield. [
a
]
D
(400 MHz, DMSO-d
6
):
d
8.39 (d, J¼0.8 Hz, 1H), 7.85 (dd, J ¼1.6 Hz,
1
J
2
¼8.4 Hz, 1H), 7.53 (d, J¼8.0 Hz, 1H), 6.32 (d, J¼5.6 Hz, 1H),
4
.3. Characterization data for the Michael adducts
4.84e4.88 (m, 1H), 4.73e4.81 (m, 2H), 3.65e3.82 (m, 4H), 3.16 (t,
J¼6.4, 1H), 1.90e1.92 (m, 2H), 1.41e1.47 (m, 1H), 1.23e1.29 (m, 3H),
13
4
.3.1. (5R,7R)-1-((6-chloropyridin-3-yl)methyl)-8-nitro-7-propyl-
1.16e1.19 (m, 1H), 1.07e1.08 (m, 1H) 0.89 (t, J¼7.2 Hz, 3H); C NMR
4
a
1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridin-5-ol 3a. Yellow solid,
(100 MHz, DMSO-d
76.4 51.4, 49.9, 45.0, 36.2, 33.8, 33.4, 29.2, 22.7, 14.4. Enantiometric
excess: 79%. HPLC analysis; PC-2, MeOH/H
O¼90/10, 0.7 mL/min,
254 nm, t ¼11.8 min (minor). IR (Neat): 3226,
¼8.7 min (major), t
2955, 2925, 2857, 1546, 1501, 1460, 1426, 1357, 1259, 1124 cm
6
): d 158.2,149.7, 149.5, 139.6,132.6,124.4, 108.2,
ꢁ
26
1
mp 180e181 C. 77% yield. [
400 MHz, DMSO-d ):
a]
D
ꢀ48.3 (c 0.5, MeOH). H NMR
(
6
d
8.32 (d, J¼2.4 Hz, 1H), 7.79 (dd, J
1
¼2.4 Hz,
2
J
1
¼8.4 Hz, 1H), 7.48 (d, J¼8.4 Hz, 1H), 6.27 (d, J¼6.8 Hz, 1H),
R
R
ꢀ
1
4
.66e4.82 (m, 2H), 4.70 (d, J¼4.8 Hz, 1H), 3.57e3.77 (m, 4H), 3.12 (t,
.
J¼6.4 Hz, 1H), 1.83e1.87 (m, 2H), 1.30e1.36 (m, 1H), 1.12e1.23 (m,
13
2
H), 0.97e1.03 (m, 1H), 0.81 (t, J¼7.2 Hz, 3H); C NMR (100 MHz,
DMSO-d ): 158.2, 149.6, 149.5, 139.6, 132.6, 124.4, 108.1, 76.3, 51.3,
9.9, 45.0, 36.2, 36.0, 33.6, 20.2, 14.5. Enantiometric excess: 84%.
HPLC analysis; PC-2, MeCN/H
O¼90/10, 0.5 mL/min, 230 nm,
¼11.5 min (major), t ¼14.9 min (minor).
4.3.5. (5R,7R)-1-((6-chloropyridin-3-yl)methyl)-8-nitro-7-pentyl-
6
d
1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridin-5-ol 3e. Yellow solid,
ꢁ
22
1
4
mp 217e218 C. 85% yield. [
(400 MHz, DMSO-d ):
a
]
D
ꢀ43.6 (c 0.4, MeOH). H NMR
2
6
d
8.34 (d, J¼2.0 Hz, 1H), 7.80 (dd, J ¼2.0 Hz,
1
t
R
R
J
2
¼8.4 Hz, 1H), 7.49 (d, J¼8.4 Hz, 1H), 6.30 (d, J¼6.4 Hz, 1H),
4
.79e4.84 (m, 1H), 4.73e4.81 (m, 2H), 3.74e3.78 (m, 2H),
4
.3.2. (5R,7R)-1-((6-chloropyridin-3-yl)methyl)-7-methyl-8-nitro-
3.60e3.72 (m, 2H), 3.11 (t, J¼6.0, 1H), 1.86e1.89 (m, 2H), 1.36e1.39
4
a
1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridin-5-ol 3b. Yellow solid,
(m, 1H), 1.19e1.25 (m, 6H), 0.98e1.11 (m, 1H), 0.86 (t, J¼6.4 Hz, 3H);
ꢁ
26
1
13
mp 170e172 C. 88% yield. [
400 MHz, DMSO-d ):
a
]
D
ꢀ44.0 (c 0.5, MeOH). H NMR
6
C NMR (100 MHz, DMSO-d ): d 158.2, 149.7, 149.5, 139.6, 132.6,
(
6
d
8.34 (d, J¼2.0 Hz, 1H), 7.80 (dd, J
1
¼2.4 Hz,
124.4, 108.2, 76.4, 51.4, 49.9, 45.1, 36.2, 33.8, 33.6, 31.9, 26.7, 22.5,
3
5
J
1
¼8.4 Hz, 1H), 7.49 (d, J¼8.0 Hz, 1H), 6.29 (d, J¼6.4 Hz, 1H),
14.4. HRMS-ESI (m/z): calcd for C18
found: 381.1683. Enantiometric excess: 91%. HPLC analysis; PC-2,
MeOH/H ¼13.3 min (major),
O¼90/10, 0.5 mL/min, 254 nm, t
¼18.2 min (minor). IR (Neat): 3154, 1955, 1923, 2856, 1538, 1505,
H
25
N
4
O
3
Cl (Mþ): 381.1688;
4
.80e4.84 (m,1H), 4.58e4.75 (m, 3H), 3.57e3.75 (m, 4H), 3.12e3.15
(
m, 1H), 1.89e1.96 (m, 1H), 1.67e1.76 (m, 1H), 1.04 (d, J¼6.4 Hz, 3H).
2
R
13
C NMR (100 MHz, DMSO-d
24.3, 109.2, 75.9, 51.9, 49.8, 45.2, 38.5, 28.2, 19.8. Enantiometric
excess: 60%. HPLC analysis; PC-2, MeOH/H
O¼90/10, 0.5 mL/min,
¼11.8 min (minor).
6
):
d
158.5, 149.6, 149.5, 139.7, 132.6,
t
R
ꢀ
1
1
1427, 1367, 1296, 1218, 1144 cm .
2
2
30 nm, t
R
¼9.8 min (major), t
R
4.3.6. (5R,7R)-1-((6-chloropyridin-3-yl)methyl)-7-heptyl-8-nitro-
1
,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridin-5-ol 3f. Yellow solid, mp
ꢁ
27
1
4
.3.3. (5R,7R)-1-((6-chloropyridin-3-yl)methyl)-7-ethyl-8-nitro-
234e236 C. 80% yield. [
(400 MHz, DMSO-d ):
a
]
D
ꢀ32.6 (c 0.5, MeOH). H NMR
4
a
1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridin-5-ol 3c. Yellow solid,
6
d
8.32 (br s,1H), 7.48 (d, J¼7.2 Hz,1H), 7.46 (d,
ꢁ
26
1
mp 195e197 C. 85% yield. [
400 MHz, DMSO-d ):
a]
D
ꢀ72.8 (c 0.5, MeOH). H NMR
J¼8.0 Hz, 1H), 6.29 (d, J¼4.8 Hz, 1H), 4.80 (d, J¼4.0 Hz, 1H), 4.71 (br
s, 2H), 3.59e3.76 (m, 4H), 3.11 (t, J¼5.2 Hz, 1H), 1.85 (br s, 2H), 1.36
(
6
d
8.36 (d, J¼1.8 Hz, 1H), 7.82 (dd, J ¼2.0 Hz,
1
13
J
2
¼8.2 Hz, 1H), 7.51 (d, J¼8.2 Hz, 1H), 6.32 (d, J¼5.6 Hz, 1H),
(br, 1H), 1.20 (br, 10H), 1.02 (br, 1H), 0.85 (t, J¼6.8 Hz, 3H); C NMR
4
.63e4.84 (m, 3H), 3.49e3.93 (m, 4H), 3.06 (t, J¼6.4, 1H), 1.82e1.88
(100 MHz, DMSO-d
6
): d 157.7, 149.2, 149.0, 139.0, 132.1, 123.8, 107.7,
(
m, 2H), 1.41e1.51 (m, 1H), 1.13e1.32 (m, 1H), 0.75 (t, J¼7.2 Hz, 3H);
75.8, 50.8, 49.4, 44.5, 35.6, 33.3, 33.1, 31.3, 29.1, 28.6, 26.5, 22.0, 13.9.
13
35
C NMR (100 MHz, DMSO-d
24.4, 107.9, 76.3, 51.6, 49.8, 45.1, 35.7, 35.1, 26.4, 11.7. Enantiometric
excess: 73%. HPLC analysis; PC-2, MeCN/H
O¼90/10, 0.7 mL/min,
¼9.8 min (minor). IR (Neat): 3226,
6
):
d
158.5, 149.7, 149.6, 139.7, 132.6,
HRMS-ESI (m/z): calcd for C20
H
29
N
4
O
3
Cl (Mþ): 409.2001; found:
1
409.1994. Enantiometric excess: 74%. HPLC analysis; PC-2, MeOH/
2
H
2
O¼90/10, 0.5 mL/min, 254 nm, t
R
¼16.2 min (major), t ¼23.8 min
R
2
2
54 nm, t
R
¼8.1 min (major), t
R
(minor). IR (Neat): 3215, 2956, 2923, 2853, 1561, 1524, 1360, 1303,
1145, 1068 cm
ꢀ
1
ꢀ1
960, 2928, 1461, 1203, 1125, 1024 cm
.
.
4
.3.4. (5R,7R)-7-butyl-1-((6-chloropyridin-3-yl)methyl)-8-nitro-
4.3.7. (5R,7S)-1-((6-chloropyridin-3-yl)methyl)-7-cyclohexyl-8-
nitro-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridin-5-ol 3g. Yellow
4
a
1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridin-5-ol 3d. Yellow solid,
Please cite this article in press as: Lou, Y.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.07.056

6
Y. Lou et al. / Tetrahedron xxx (2015) 1e8
ꢁ
27
1
solid, mp 95e98 C. 40% yield. [
400 MHz, CDCl ):
a]
D
ꢀ57.8 (c 0.5, MeOH). H NMR
1H), 3.83e3.89 (m, 2H), 3.69e3.77 (m, 2H), 3.37 (s, 3H), 2.14e2.31
(m, 1H), 1.69e1.84 (m, 1H); C NMR (100 MHz, DMSO-d ): d 158.1,
6
149.2, 144.6, 139.4, 132.0, 131.8, 129.8,128.4,127.7, 124.0, 106.2, 83.4,
55.6, 51.5, 49.9, 47.1, 38.1, 37.8. HRMS-ESI (m/z): calcd for
13
(
3
d
8.54 (br s, 1H), 7.62 (d, J¼7.2 Hz, 1H), 7.29 (d,
J¼8.0 Hz, 1H), 6.14 (br, 1H), 5.08 (d, J¼15.6 Hz, 1H), 4.80 (br s, 1H),
4
3
0
1
3
.55 (d, J¼15.6 Hz, 1H), 4.21e4.28 (m, 1H), 3.92e3.99 (m, 1H),
3
5
.44e3.60 (m, 2H), 3.29 (t, J¼4.4 Hz, 1H), 1.47e1.73 (m, 7H),
C
20
H
20
N
4
O
3
Cl
excess: 26% for major diastereoisomer, 30% for minor di-
astereoisomer. HPLC analysis; PC-2, MeOH/H
O¼90/10, 0.7 mL/
min, 254 nm, major diastereoisomer,
¼11.7 min (major),
¼12.7 min (minor); minor diastereoisomer, t ¼22.1 min (major),
¼36.7 min (minor). IR (Neat):2930, 1557, 1490, 1459, 1323, 1272,
2
(Mþ): 435.0985; found: 435.0975. Enantiometric
.87e1.25 (m, 6H); 13C NMR (100 MHz, CDCl
): d 158.8, 151.0, 149.6,
3
38.6, 130.6, 124.1, 107.7, 77.5, 51.8, 48.7, 44.5, 40.7, 39.4, 33.0, 31.5,
2
3
5
0.2, 26.3, 26.2. HRMS-ESI (m/z): calcd for C19
15.1507; found: 415.1509. Enantiometric excess: 95%. HPLC anal-
ysis; PC-2, MeCN/H ¼11.2 min
O¼90/10, 0.7 mL/min, 214 nm, t
major), t
¼16.3 min (minor). IR (Neat):3218, 2925, 2851, 1553,
H
25
N
4
O
3
Cl (Mþ):
t
R
4
t
t
R
R
2
R
R
ꢀ
1
(
R
1148, 1082, 1023 cm
.
ꢀ
1
1
462, 1393, 1281, 1209, 1132, 1025 cm
.
4
.3.12. (5R,7S)-7-(3-chlorophenyl)-1-((6-chloropyridin-3-yl)
4
. 3. 8. (5R, 7R)-1-benzyl-8-nitro-7-propyl-1, 2, 3, 5, 6, 7-
3h. Yellow solid, mp
20.1 (c 0.5, MeOH). H NMR (400 MHz,
7.32e7.35 (m, 2H), 7.26e7.28 (m, 3H), 6.26 (d,
J¼6.4 Hz, 1H), 4.65e4.81 (m, 3H), 3.67e3.76 (m, 2H), 3.50e3.59 (m,
H), 3.17 (t, J¼6.4 Hz, 1H), 1.86e1.89 (m, 2H), 1.40e1.44 (m, 1H),
methyl)-5-methoxy-8-nitro-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyri-
ꢁ
25
hexahydroimidazo[1,2-a]pyridin-5-ol
dine 3l. Yellow solid, mp 84e86 C. 80% yield. [
a
]
D
13.0 (c 0.5,
ꢁ
27
1
1
130e131 C. 83% yield. [
a
]
D
MeOH). H NMR (400 MHz, CDCl
3
):
d
8.37 (br s, 1H), 7.84 (d,
DMSO-d ):
6
d
J¼8.4 Hz, 1H), 7.31 (d, J¼8.4 Hz, 1H), 7.16e7.20 (m, 1H), 7.11e7.14 (m,
2H), 6.94 (d, J¼7.2 Hz, 1H), 5.06 (d, J¼14.8 Hz, 1H), 4.63 (d,
2
J¼15.2 Hz, 1H), 4.38e4.43 (m, 1H), 4.33 (dd, J
1
¼7.2 Hz, J ¼9.6 Hz,
2
13
1
(
5
C
.19e1.28 (m, 2H), 1.09e1.11 (m, 1H), 0.82 (t, J¼6.8 Hz, 1H); C NMR
100 MHz, DMSO-d ): 157.9, 136.7, 128.3, 127.6, 127.3, 107.4, 75.9,
3.3, 48.5, 44.4, 35.8, 35.5, 33.3,19.7, 14.0. HRMS-ESI (m/z): calcd for
(Mþ): 318.1812; found: 318.1809. Enantiometric ex-
O¼90/10, 0.5 mL/min,
¼13.6 min (minor). IR (Neat): 3213,
956, 2928, 2871, 1665, 1557, 1545, 1393, 1287, 1208, 1123, 1099,
1H), 3.72e3.93 (m, 2H), 3.49e3.61 (m, 2H), 3.38 (s, 3H), 2.28e2.41
13
6
d
3
(m, 1H), 1.86e1.92 (m, 1H); C NMR (100 MHz, CDCl ): d 158.5,
151.3, 149.2, 146.5, 139.4, 134.3, 130.5, 129.8, 126.6, 126.5, 124.9,
124.6, 107.4, 83.9, 55.9, 52.8, 49.7, 46.0, 38.8, 36.9. HRMS-ESI (m/z):
17
23
H N
3
O
3
3
5
cess: 66%. HPLC analysis; PC-4, MeCN/H
2
2
2
calcd for C20
tiometric excess: 51% for major diastereoisomer, 92% for minor
diastereoisomer. HPLC analysis; PC-2, MeOH/H
O¼90/10, 0.7 mL/
min, 254 nm, major diastereoisomer,
¼10.6 min (major),
¼12.1 min (minor); minor diastereoisomer, t ¼18.7 min (major),
¼39.3 min (minor). IR (Neat): 2931, 1557, 1515, 1462, 1324, 1272,
H
20
N
4
O
3
Cl
2
(Mþ): 435.0985; found: 435.0976. Enan-
30 nm, t
R
¼11.3 min (major), t
R
2
ꢀ
1
1029 cm
.
t
R
t
t
R
R
4
.3.9. (5R,7R)-1-((2-chlorothiazol-5-yl)methyl)-8-nitro-7-propyl-
R
ꢀ
1
1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridin-5-ol 3i. Yellow solid, mp
1150, 1080, 1022 cm .
ꢁ
27
1
146e147 C. 85% yield. [
a]
D
ꢀ248.1 (c 0.5, MeOH). H NMR
(
400 MHz, DMSO-d ):
6
d
7.62 (s, 1H), 6.29 (d, J¼6.8 Hz, 1H),
4.3.13. (5R,7S)-7-(2-chlorophenyl)-1-((6-chloropyridin-3-yl)
methyl)-5-methoxy-8-nitro-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyri-
4
.72e4.83 (m, 3H), 3.57e3.73 (m, 4H), 3.15 (t, J¼6.0 Hz, 1H), 1.87 (t,
ꢁ
27
J¼5.6 Hz, 1H), 1.51e1.55 (m, 1H), 1.23e1.31 (m, 2H), 1.17e1.20 (m,
dine 3m. Yellow solid, mp 103e104 C. 72% yield. [
MeOH). H NMR (400 MHz, CDCl
a
]
D
ꢀ23.5 (c 0.5,
13
1
1
H), 0.86 (t, J¼7.2 Hz, 3H); C NMR (100 MHz, DMSO-d
6
):
d
157.4,
3
):
¼8.0 Hz, 1H), 7.31 (d, J¼8.4 Hz, 1H), 7.11e7.20 (m, 3H),
6.95 (d, J¼7.2 Hz, 1H), 6.94 (d, J¼7.2 Hz, 1H), 5.06 (d, J¼15.2 Hz, 1H),
4.62 (d, J¼15.2 Hz, 1H), 4.39e4.43 (m, 1H), 4.33 (dd, J ¼7.2 Hz,
¼9.6 Hz, 1H), 3.72e3.85 (m, 2H), 3.57e3.70 (m, 2H), 3.38 (s, 3H),
d 8.37 (br s, 1H), 7.85 (dd,
151.4, 141.0, 136.2, 107.7, 75.7, 48.4, 47.2, 44.4, 35.5, 35.4, 32.8, 19.7,
J
1
¼2.0 Hz, J
1
3
5
1
4.0. HRMS-ESI (m/z): calcd for C14
found: 359.0934. Enantiometric excess: 88%. HPLC analysis; PC-4,
MeCN/H ¼10.0 min (major),
O¼90/10, 0.5 mL/min, 254 nm, t
¼10.5 min (minor). IR (Neat): 3207, 2955, 2926, 2871, 1557, 1531,
H
19
N
4
O
3
S
Cl (Mþ): 359.0939;
1
2
R
J
2
13
t
R
2.27e2.42 (m, 1H), 1.86e1.92 (m, 1H); C NMR (100 MHz, CDCl
3
):
ꢀ
1
1372, 1289, 1139, 1052 cm
.
d
158.5, 151.3, 149.2, 146.5, 139.4, 134.3, 130.5, 129.8, 126.6, 126.5,
1
24.9, 124.6, 107.4, 83.9, 55.9, 52.8, 49.7, 46.0, 38.8, 36.9. HRMS-ESI
3
5
4
7
.3.10. (5R,7S)-1-((6-chloropyridin-3-yl)methyl)-5-methoxy-8-nitro-
(m/z): calcd for C20
20
H N
4
O
3
Cl
2
(Mþ): 435.0985; found: 435.0977.
4
a
-phenyl-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridine 3j. Yellow
Enantiometric excess: 47% for major diastereoisomer, 88% for minor
diastereoisomer. HPLC analysis; PC-2, MeOH/H
O¼90/10, 0.7 mL/
min, 254 nm, major diastereoisomer,
¼10.6 min (major),
¼12.1 min (minor); minor diastereoisomer, t ¼17.7 min (major),
¼28.2 min (minor). IR (Neat): 2927, 1557, 1462, 1269, 1143, 1078,
ꢁ
27
1
solid, mp 94e96 C. 77% yield. [
400 MHz, CDCl ):
8.36 (d, J¼1.6 Hz, 1H), 7.84 (dd, J
¼8.0 Hz, 1H), 7.28 (d, J¼8.0 Hz, 1H), 7.23 (d, J¼7.6 Hz, 2H),
.14e7.18 (m, 1H), 7.04 (d, J¼7.2 Hz, 2H), 5.01 (d, J¼15.2 Hz, 1H), 4.65
d, J¼15.2 Hz,1H), 4.36e4.42 (m, 2H), 3.72e3.85 (m, 2H), 3.54e3.64
a
]
D
2.9 (c 0.5, MeOH). H NMR
2
(
3
d
1
¼2.0 Hz,
t
R
J
2
t
t
R
R
7
R
ꢀ
1
(
(
(
1021 cm
.
13
m, 2H), 3.36 (s, 3H), 2.34e2.40 (m,1H),1.95e2.02 (m,1H); C NMR
100 MHz, CDCl ): 158.4, 151.2, 149.2, 143.8, 139.4, 130.7, 128.1,
26.5, 126.3, 124.5, 107.9, 84.1, 55.6, 52.6, 49.8, 45.8, 39.0, 36.5.
3
d
4.3.14. (5R,7S)-1-((6-chloropyridin-3-yl)methyl)-7-(4-fluorophenyl)-
5-methoxy-8-nitro-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridine
1
3
5
ꢁ
27
HRMS-EI (m/z): calcd for C20
4
5
H
21
N
4
O
3
Cl (Mþ): 400.1302; found:
3n. Yellow solid, mp 160e163 C. 67% yield. [
a]
D
23.5 (c 0.5,
1
00.1329. Enantiometric excess: 78% for major diastereoisomer,
8% for minor diastereoisomer. HPLC analysis; PC-2, MeOH/
MeOH). H NMR (400 MHz, DMSO-d
6
):
¼8.0 Hz, 1H), 7.53 (d, J¼8.4 Hz, 1H), 6.98e7.02 (m,
4H), 4.90 (d, J¼15.6 Hz, 1H), 4.71 (d, J¼15.6 Hz, 1H), 4.60 (m, 1H),
4.01 (dd, J ¼11.6 Hz, 1H), 3.76e4.04 (m, 4H), 3.37 (s, 3H),
¼6.8 Hz, J
2.18e2.32 (m, 1H), 1.71e1.78 (m, 1H); C NMR (100 MHz, DMSO-
):
160.7 (d, JCeF¼239.4 Hz), 158.7, 149.7, 142.0 (d, JCeF¼2.5 Hz),
39.8, 132.3, 128.7 (d, JCeF¼7.6 Hz), 124.5, 114.9 (d, JCeF¼21.0 Hz),
106.9, 83.9, 56.0, 52.0, 50.3, 47.6, 38.5, 38.4. HRMS-ESI (m/z): calcd
d
8.42 (d, J¼1.6 Hz, 1H), 7.89
(dd, J
1
¼2.0 Hz, J
2
H
2
O¼90/10, 0.5 mL/min, 254 nm, major diastereoisomer,
¼15.74 min (major), t ¼17.7 min (minor); minor diastereoisomer,
¼30.3 min (major), t ¼51.8 min (minor). IR (Neat): 2931, 2891,
t
t
R
R
1
2
13
R
R
ꢀ
1
1561, 1460, 1249, 1145, 1080, 1022 cm
.
d
6
d
1
4
5
.3.11. (5R,7S)-7-(4-chlorophenyl)-1-((6-chloropyridin-3-yl)methyl)-
-methoxy-8-nitro-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridine
3
5
for C20
metric excess: 36% for major diastereoisomer, 37% for minor di-
astereoisomer. HPLC analysis; PC-2, MeOH/H
O¼90/10, 0.7 mL/
min, 254 nm, major diastereoisomer,
¼9.6 min (major),
¼10.4 min (minor); minor diastereoisomer, t ¼17.2 min (major),
H
20
N
4
O
3
ClF (Mþ): 419.1281; found: 419.1274. Enantio-
ꢁ
27
3
k. Yellow solid, mp 192e195 C. 77% yield. [
a
]
D
3.2 (c 0.5, MeOH).
8.42 (br, 1H), 7.88e7.90 (m, 1H),
.53 (d, J¼8.4 Hz, 1H), 7.21e7.25 (m, 2H), 6.98e7.01 (m, 2H), 4.89 (d,
J¼15.6 Hz, 1H), 4.60e4.74 (m, 2H), 4.00 (dd, J ¼6.8 Hz, J ¼11.2 Hz,
1
H NMR (400 MHz, DMSO-d
6
):
d
2
7
t
R
1
2
t
R
R
Please cite this article in press as: Lou, Y.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.07.056

Y. Lou et al. / Tetrahedron xxx (2015) 1e8
7
t
1
R
¼27.1 min (minor). IR (Neat): 2935, 1893, 1556, 1506, 1480, 1392,
dried over Na
2
SO
4
, and filtered and concentrated in vacuo. The
ꢀ
1
270, 11467, 1080, 1023 cm
.
crude product was purified by column chromatography
CH Cl
(
2
2
eMeOH: v/v¼80/1) to afford the methyl ethers product 5
4
.3.15. (5R,7S)-1-((6-chloropyridin-3-yl)methyl)-5-methoxy-7-(4-
(60.0 mg, 85%yield).
methoxyphenyl)-8-nitro-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridine
ꢁ
27
3
o. Yellow solid, mp 159e162 C. 91% yield. [
a
]
D
ꢀ2.9 (c 0.5,
4.4.1. (5R,7R)-1-((6-chloropyridin-3-yl)methyl)-7-methyl-8-nitro-5-
1
MeOH). H NMR (400 MHz, DMSO-d
6
):
¼8.0 Hz, 1H), 7.52 (d, J¼8.4 Hz, 1H), 6.83e6.85 (m,
H), 6.73e6.75 (m, 2H), 4.88 (d, J¼15.2 Hz, 1H), 4.75 (d, J¼15.6 Hz,
H), 4.56e4.57 (m, 1H), 3.98 (dd, J ¼10.8 Hz, 1H),
¼6.8 Hz, J
.75e3.90 (m, 4H), 3.70 (s, 3H), 3.35 (s, 3H), 2.18e2.29 (m, 1H),
.72e1.79 (m, 1H); 13C NMR (100 MHz, DMSO-d
): 158.6, 157.7,
49.8, 149.7, 139.8, 137.6, 132.4, 127.9, 124.5, 113.8, 107.3, 84.0, 55.9,
d
8.41 (d, J¼2.4 Hz, 1H), 7.88
propoxy-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridine
5.. Yellow
ꢁ
27
1
(
dd, J
1
¼2.4 Hz, J
2
solid, mp 129e132 C. 95% yield. [
(400 MHz, CDCl ):
a
]
D
14.7 (c 0.5, MeOH). H NMR
2
1
3
1
1
3
d
8.31e8.33 (m, 1H), 7.86 (dd, J
1
¼2.4 Hz,
1
2
J
2
¼8.4 Hz, 0.5H), 7.82 (dd, J
1
¼2.4 Hz, J ¼8.2 Hz, 0.5H), 7.33 (s, 0.5H),
2
7.31 (s, 0.5H), 4.88 (d, J¼15.2 Hz, 0.5H), 4.82 (d, J¼15.2 Hz, 0.5H),
4.65 (d, J¼10.4 Hz, 0.5H), 4.62 (d, J¼10.4 Hz, 0.5H), 4.55 (dd,
6
d
J
1
¼2.0 Hz, J ¼4.0 Hz, 0.5H), 4.50 (t, J¼3.2 Hz, 0.5H), 3.95e4.02 (m,
2
5
C
5.4, 51.8, 50.3, 47.4, 38.5, 38.3. HRMS-ESI (m/z): calcd for
0.5H), 3.81e3.87 (m, 0.5H), 3.65e3.73 (m, 1H), 3.34e3.60 (m, 5H),
2.14e2.21 (m, 0.5H), 1.99e2.00 (m, 1H), 1.75e1.81 (m, 0.5H),
1.54e1.64 (m, 2H), 1.26 (d, J¼6.8 Hz, 1.5H), 1.22 (d, J¼6.8 Hz, 1.5H),
3
5
21
23
H N
4
O
4
Cl (Mþ): 431.1481; found: 431.1472. Enantiometric
excess: 43% for major diastereoisomer, 45% for minor di-
astereoisomer. HPLC analysis; PC-2, MeOH/H
O¼90/10, 0.7 mL/
min, 254 nm, major diastereoisomer,
¼13.8 min (major),
¼15.2 min (minor); minor diastereoisomer, t ¼25.6 min (major),
¼43.5 min (minor). IR (Neat): 2936, 1558, 1524, 1465, 1339, 1217,
13
2
0.95 (t, J¼7.6 Hz, 1.5H), 0.91 (t, J¼6.2 Hz, 1.5H); C NMR (100 MHz,
t
R
3
CDCl ): d 158.5, 157.1, 150.9, 150.9, 149.1, 149.1, 139.3, 139.1, 130.9,
t
t
R
R
130.8, 124.3, 124.3, 110.1, 84.9, 83.2, 70.2, 70.1, 52.5, 52.3, 49.4, 49.1,
45.7, 45.6, 35.9, 33.0, 28.3, 27.8, 23.0, 22.9, 19.7, 19.2, 10.6, 10.5.
Enantiometric excess: 60% for major diastereoisomer, 60% for mi-
R
ꢀ
1
1155, 1060, 1024 cm
.
nor diastereoisomer. HPLC analysis; PC-2, MeOH/H
2
O¼90/10,
¼14.4 min (major),
¼30.5 min (major),
4
7
.3.16. (5R,7S)-1-((6-chloropyridin-3-yl)methyl)-5-methoxy-8-nitro-
0.5 mL/min, 254 nm, major diastereoisomer, t
R
-o-tolyl-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridine
3p. Yellow
t
t
R
¼15.6 min (minor); minor diastereoisomer, t
R
ꢁ
27
1
solid, mp 244e245 C. 90% yield. [
a
]
D
15.2 (c 0.5, MeOH). H NMR
R
¼37.9 min (minor).
(
400 MHz, CDCl ):
3
d
8.37 (br s, 1H), 7.85 (dd, J
1
¼1.6 Hz, J ¼8.4 Hz,
1
1
6
1
3
H), 7.29 (d, J¼8.4 Hz, 1H), 7.10e7.12 (m, 1H), 7.03e7.05 (m, 2H),
Acknowledgements
.71 (d, J¼6.4 Hz, 1H), 5.02 (d, J¼14.8 Hz, 1H), 4.64 (d, J¼15.2 Hz,
H), 4.52e4.57 (m, 1H), 4.38 (m, 1H), 3.59e3.83 (m, 4H), 3.36 (s,
Financial support from the National High Technology Research
and Development Program of China (863 Program, 2011AA10A207),
and the National Natural Science Foundation of China (Nos.
21472046, 21272247, 21290184) is gratefully acknowledged.
13
H), 2.44 (s, 3H), 2.32e2.38 (m, 1H), 1.72e1.78 (m, 1H); C NMR
): 158.7, 151.2, 149.3, 142.5, 139.6, 135.5, 130.8,
30.6, 126.2, 126.1, 124.7, 124.6, 108.7, 84.2, 55.9, 52.8, 49.9, 46.2,
(
100 MHz, CDCl
3
d
1
3
4
3
5
5.4, 35.0, 19.3. HRMS-ESI (m/z): calcd for C21
15.1531; found: 415.1526. Enantiometric excess: 46% for major
diastereoisomer, 25% for minor diastereoisomer. HPLC analysis; PC-
, MeOH/H
¼10.7 min (major), t
¼19.3 min (major), t
512, 1448, 1239, 1141, 1060, 1016 cm
23
H N
4
O
3
Cl (Mþ):
Supplementary data
2
2
O¼90/10, 0.7 mL/min, 254 nm, major diastereoisomer,
¼12.0 min (minor); minor diastereoisomer,
¼30.5 min (minor). IR (Neat): 2919, 1560,
Supplementary data (Copies of NMR spectra and HPLC for the
isolated products and Crystal data and structure of 3a. Supple-
mentary data associated with this article can be found in the online
version.) related to this article can be found at http://dx.doi.org/
t
t
R
R
R
R
ꢀ
1
1
.
1
0.1016/j.tet.2015.07.056.
4
7
.3.17. (5R,7S)-1-((6-chloropyridin-3-yl)methyl)-5-methoxy-8-nitro-
-p-tolyl-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridine
3q. Yellow
References and notes
ꢁ
27
1
solid, mp 104e106 C. 85% yield. [
a
]
D
8.5 (c 0.5, MeOH). H NMR
(
400 MHz, CDCl ):
3
d
8.37 (br s, 1H), 7.85 (dd, J
1
¼1.6 Hz, J
1
¼8.4 Hz,
1. For recent reviews, see: (a) Nauen, F.; Michael, E. B. Angew. Chem., Int. Ed. 2013,
52, 9464; (b) Elbert, A.; Schindler, M.; Nauen, R.; Jeschke, P. J. Agric. Food Chem.
1
6
1
3
H), 7.29 (d, J¼8.4 Hz, 1H), 7.10e7.12 (m, 1H), 7.03e7.05 (m, 2H),
2011, 59, 2897; (c) Kagabu, S. J. Agric. Food Chem. 2011, 59, 2887; (d) Schneider,
.71 (d, J¼6.4 Hz, 1H), 5.02 (d, J¼14.8 Hz, 1H), 4.64 (d, J¼15.2 Hz,
H), 4.52e4.57 (m, 1H), 4.38 (m, 1H), 3.59e3.83 (m, 4H), 3.36 (s,
C. Angew. Chem., Int. Ed. 2009, 48, 2082; (e) Tomizawa, M.; Casida, J. E. Acc.
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suda, K.; Buckingham, S. D.; Kleier, D.; Rauh, J. J.; Grauso, M.; Sattelle, D. B.
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Nichols, R. Pest Manag. Sci. 2008, 64, 1082.
13
H), 2.44 (s, 3H), 2.32e2.38 (m, 1H), 1.72e1.78 (m, 1H); C NMR
): 158.7, 151.2, 149.3, 142.5, 139.6, 135.5, 130.8,
30.6, 126.2, 126.1, 124.7, 124.6, 108.7, 84.2, 55.9, 52.8, 49.9, 46.2,
(
100 MHz, CDCl
3
d
1
3
4
35
5.4, 35.0, 19.3. HRMS-ESI (m/z): calcd for C21
15.1531; found: 415.1524. Enantiometric excess: 43% for major
diastereoisomer, 29% for minor diastereoisomer. HPLC analysis; PC-
, MeOH/H
¼12.9 min (major), t
¼25.5 min (major), t
512, 1456, 1393, 1271, 1221, 1080, 1022 cm
23
H N
4
O
3
Cl (Mþ):
2
3
4
. Commercial agonists. (a) Jeschke, P. Modern Crop Protection Compounds; Wiley-
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2
2
O¼90/10, 0.7 mL/min, 254 nm, major diastereoisomer,
¼14.7 min (minor); minor diastereoisomer,
¼46.8 min (minor). IR (Neat): 2925, 1557,
t
t
R
R
R
R
ꢀ
1
1
.
4
.4. Conversion of 3b to Paichongding 5
2012, 51, 4627; (d) Nauen, R.; Denholm, I. Arch. Insect Biochem. Physiol. 2005, 58,
To a solution of 3b (64.8 mg, 0.2 mmol) in 1-Propanol (4 mL), p-
TsOH (0.02 mmol, 3.4 mg) was added and reflux until the reaction
completed. Saturated NaHCO
to quench the reaction. And the resulting mixture was extracted
with CH Cl
(30 mLꢂ3) and the combined organic layer was
washed by brine (20 mL). The combined organic extracts were
200.
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3
aqueous solution (20 mL) was added
2
2
Please cite this article in press as: Lou, Y.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.07.056

8
Y. Lou et al. / Tetrahedron xxx (2015) 1e8
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Please cite this article in press as: Lou, Y.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.07.056