Asymmetric synthesis of piperidines using the nitro-Mannich reaction☆

Article abstract of DOI:10.1016/j.tet.2020.131821

A method for the synthesis of functionalized piperidines containing 3 contiguous stereocentres in the 2-,3- and 4- positions uses a diastereoselective nitro-Mannich to control stereochemistry. The nitro-Mannich reaction between a β-aryl/heteroaryl substituted nitroalkanes and glyoxylate imine provides β-nitro-amines with good selectivity (70:30 to >95:5) for the syn, anti-diastereoisomers. Reductive cyclisation with BF₃.OEt₂ and Et₃SiH gave, after purification, stereochemically pure piperidines in 19–57% yield for ten examples with different 4-aryl/heteroaryl substituents.

Full text of DOI:10.1016/j.tet.2020.131821

Tetrahedron 78 (2021) 131821
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of piperidines using the nitro-Mannich
*
reaction*
James C. Anderson*, Eva Bouvier-Israel, Christopher D. Rundell, Xiangyu Zhang
Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the synthesis of functionalized piperidines containing 3 contiguous stereocentres in the 2-
,3- and 4- positions uses a diastereoselective nitro-Mannich to control stereochemistry. The nitro-
Received 25 September 2020
Received in revised form
24 November 2020
Accepted 27 November 2020
Available online 2 December 2020
Mannich reaction between a
b-aryl/heteroaryl substituted nitroalkanes and glyoxylate imine provides
b
-nitro-amines with good selectivity (70:30 to >95:5) for the syn, anti-diastereoisomers. Reductive
cyclisation with BF3.OEt2 and Et3SiH gave, after purification, stereochemically pure piperidines in 19e57%
yield for ten examples with different 4-aryl/heteroaryl substituents.
© 2020 Elsevier Ltd. All rights reserved.
Keywords:
Piperidine
Nitro-Mannich reaction
Cyclisation
b
-nitroamine
Diastereoselective
1. Introduction
2. Results and discussion
Piperidines are present in numerous biologically active natural
products and are the most prevalent nitrogen ring system in FDA
approved drugs (for example Fig. 1) [1]. Paroxetine is a common
synthetic antidepressant drug and is the most potent, and one of
the most specific, selective serotonin reuptake inhibitors [2].
Around 35% of all medicines have originated from natural products
in some way [3]. Vincamine is a monoterpenoid indole alkaloid
found in the leaves of Vinca minor and is sold in Europe as a pre-
scription medicine for the treatment of primary degenerative and
vascular dementia [4]. Schizozygine was one of a small class of al-
kaloids first isolated by Renner and co-workers in 1963 from
Schizozygia caffaeoides (Boj.) Baill [5]. It demonstrated anti-fungal,
anti-bacterial [6] and anti-plasmodial activities [7]. Some mem-
bers of the family could not be assayed due to the scarcity of the
compound from natural resources. There is a definite need to
develop new methods to synthesis heterocycles that can deliver
ever more complex structures.
2.1. Development of a route to functionalized piperidines
We recently synthesized some of the Schizozygine alkaloids [8]
and in one of our discontinued routes we investigated the synthesis
of the core multi-functionalized piperidine 1 through a cyclisation
by reductive amination of a highly functionalized b-nitro amino
intermediate syn,anti-2 (Scheme 1). Other substituted piperidines
have been prepared by similar one pot multicomponent enantio-
selective strategies [9aef]. Stereodefined b-nitroamines are readily
synthesized using the nitro-Mannich reaction [10] and are useful
for heterocycle synthesis [11aej]. We have prepared similar syn,-
anti-intermediates 2 through a one pot conjugate addition nitro-
Mannich reaction sequence [12]. The diastereoselectivity of the
nitro-Mannich reaction is dictated by the chiral centre formed from
the conjugate addition of a nucleophile (such as 3) onto a nitro
alkene (such as 4). Initial attempts to use this one pot conjugate
addition nitro-Mannich reaction sequence with the dialkyl zinc
reagent 3 [13], formed in situ from the known Grignard reagent,
gave no reaction (Scheme 1, disconnection I). An alternative suc-
cessful disconnection which still allowed the same mechanism for
diastereocontrol involved a nitro-Mannich reaction between the
known nitro compound 6 and imine 5 (Scheme 1, disconnection II).
Enantiopure 6 can be prepared by an organo-catalyzed conjugate
*
Dedicated to the memory of Professor Jonathan M. J. Williams, a friend and
kind colleague who had the knack of asking me the simplest questions that I did not
know the answers to, but which always made me think.
* Corresponding author.
addition of nitromethane to the corresponding
a,b-unsaturated
E-mail address: j.c.anderson@ucl.ac.uk (J.C. Anderson).
https://doi.org/10.1016/j.tet.2020.131821
0040-4020/© 2020 Elsevier Ltd. All rights reserved.

J.C. Anderson, E. Bouvier-Israel, C.D. Rundell et al.
Tetrahedron 78 (2021) 131821
Fig. 1. Piperidine ring containing natural products.
Scheme 2. Stereoselective synthesis of piperidines using the nitro-Mannich/reductive
cyclisation sequence.
Scheme 3. Scope of the stereoselective synthesis of piperidines using the nitro-
Mannich/reductive cyclisation sequence.
Scheme 1. Disconnection of functionalized piperidine.
Table 1
Optimization of Base and Promoter for nitro-Mannich Reaction of 6a.a
aldehyde 7 using the Hayashi catalyst [14].
Entry
Base
Promoter
Conversion (%)b
drc
2.2. Optimization of nitro-Mannich/reductive cyclisation sequence
1
2
3
4
5
6
NaH
LDA
LDA
LDA
LiHMDS
LiHMDS
Zn(CF3CO2)2
TFA
Zn(CF3CO2)2
Cu(OTf)2
Zn(CF3CO2)2
Cu(OTf)2
100
100%
75%
65:35
70:30
65:35
>95:5
70:30
>95:5
To optimize the key nitro-Mannich reaction and cyclisation, use
was made of racemic b-substitued nitro compound 6a derived from
65%
100%d
81%
a tetramethylguanidine catalyzed Michael addition to give 8a
(Scheme 2) [15]. Reduction of the ester to the aldehyde and then
standard protection gave dimethyl acetal 6a in high overall yield.
Reaction with imine 5 under standard nitro-Mannich conditions
[nBuLi, then CF3CO2H (TFA)] [16a,b] gave a high yielding, but poorly
diastereoselective reaction (60:40, syn,anti-:syn,syn-) [17]. Our
original conjugate addition/nitro-Mannich methodology used a
catalytic amount (5 mol%) of Cu(OTf)2 and an excess of Zn(CF3CO2)2
was generated during the reaction, the presence of the latter had a
profound effect on the diastereoselectivity of the reaction [11aej]. A
screen of bases NaH, LDA and LiHMDS with excess TFA or Lewis
acids Cu(OTf)2 or Zn(CF3CO2)2 promoters was performed (Table 1)
to optimize this particular nitro-Mannich reaction (6a to 2a,
Scheme 2).
All the reactions gave the desired product in good conversion
and moderate to high diastereoselectivity in accord with our
transition state model (Table 1) [12]. Although a Brønsted acid
promoter (Entry 2) gave a similar diastereoselectivity to the Lewis
acid promoter Zn(CF3CO2) (Entry 3), it was found that Cu(OTf)2 was
superior (Entry 4). The Lewis acid Cu(OTf)2 was added as a solution
in THF, Zn(CF3CO2)2 was generated in situ from ZnEt2 and excess
TFA. Although the use of the promoter Cu(OTf)2 gave a more
a
6a (0.418 mmol) in THF (5 mL), NaH (1.1 equiv.) 0 ꢀC then 40 ꢀC 30 min
then ꢁ78 ꢀC, or LDA or LiHMDS both (1.1 equiv.), ꢁ40 ꢀCe0 ꢀC, 20 min then ꢁ78 ꢀC,
imine added (1.5 equiv.), 10 min at ꢁ78 ꢀC, then TFA (2 equiv.) or Zn(CF3CO2)2 (1.5
equiv.) with TFA (1.5 equiv.) or CuOTf (1.5 equiv.) added and then stirred for
1 h at ꢁ78 ꢀC before work up.
b
From 1H NMR.
From integration of CHNO2 signals.
Major 2a isolated in 67%yield.
c
d
diastereoselective reaction (Entries 4 and 6), the combination with
Zn(CF3CO2)2 gave a higher conversion (Entries 3 and 5). The com-
bination of LiHMDS with the Cu(OTf)2 promoter gave the highest
conversion to the desired syn,anti-2a so these conditions were used
to investigate the limitations of this particular reaction sequence.
The anti-nitro-Mannich products can be prone to retroadditon
and degradation on silica gel chromatography [12,16a,b]. Indeed
syn,anti-2a was not amenable to purification, so the reductive
cyclisation step was conducted on the crude material (2a to 1a,
Scheme 2). The reductive cyclisation was low yielding (<20%) using
Nyori’s Et3SiH, TMSOTf catalyzed reaction conditions [18]. Use of
2

J.C. Anderson, E. Bouvier-Israel, C.D. Rundell et al.
Tetrahedron 78 (2021) 131821
stoichiometric BF3.OEt2 and Et3SiH (2 equiv.) gave an improved
yield of 25% for 1a, but with substantial quantities of the reduced,
non-cyclized methyl ether product. To avoid the undesired reduc-
tion of the oxonium ion intermediate before cyclisation with the
amine, we investigated hydrolysis of the dimethyl acetal prior to
subsequent reduction of the ring closed iminium ion. After exten-
sive optimization we found that a one pot BF3.OEt2 mediated cyc-
lisation (CH2Cl2, -40C, 4 h), followed by reduction using Et3SiH
(ꢁ10C to rt, 1.5 h) gave an isolated yield of 1a in 48% yield over 2
steps as the desired single diastereoisomer. Proof that the stereo-
chemistry present in the
b-nitroamine 2a was reproduced in
piperidine 1a was provided by a NOESY experiment and corrobo-
rated by the multiplicity of the CHNO2 signal in the 1H NMR. The
result was also consistent with our total synthesis studies of
Schizozygine alkaloids [8]. The desired syn, anti-relative stereo-
chemistry of 1a would give rise to a favoured conformation dictated
by an equatorial aryl group (Scheme 2). Although this conformer
places the ester and nitro substituent in axial positions, the
hyperconjugation between the lone pair on nitrogen and the anti-
bonding orbital of the CeCO2Et bond provides additional stabili-
Scheme 4. Representative transformations of functionalized piperidines.
nitro-Mannich reaction sequence [5]. In a similar trend the o-
methoxy analogue gave a higher yield of product (1g, 30%)
compared to the o-bromo analogue (1h, 19%). The bromo-analogue
1h could be useful for further annulation to a dihdropyridine by
reduction of the nitro group and intramolecular transition metal
catalyzed amination [11c]. The disubstituted dioxolane analogue
gave a 41% yield of product (1i). Heterocyclic substituents were also
tolerated (1j, k).
zation (n-s* interaction) [19]. NOE contacts between CHNO2 its two
vicinal protons were observed, but that between ArCH and CHCO2Et
was not. This conformation would result in two small coupling
constants to CHNO2 and in the 1H NMR spectrum these were not
resolved, giving rise to a broad singlet instead.
2.3. Scope of the nitro-Mannich/reductive cyclisation sequence
To demonstrate the potential use of these functionalized pi-
peridines in target synthesis we investigated some transformations
of 1i as its 1,2-dioxolane motif is common in many natural products
and drug substances (Scheme 4). The PMP group could be easily
removed with CAN to give the crude amine 9 which could be
alternatively protected as its N-trifluoracetate 10 in 83% yield after
purification. The small loss of yield is due to some small oxidation
of 9 to a dihydroquinone derivative. The ester function of 1i could
be reduced to primary alcohol 11 in good yield with LiBH4 (90%).
Further CeC bond functionalization facilitated by the anion stabi-
lizing character of the nitro function was investigated, but was
found to be very difficult. Eventually it was found that stirring with
Triton-B in the presence of methyl acrylate gave the conjugate
addition product 12 in 35% yield. The formation of tertiary nitro
compounds are difficult due to the deprotonation event suffering
from steric inhibition of resonance and the product itself being very
congested.
A survey of the nitro-Mannich/reductive cyclisation procedure
for the synthesis of a series of 4-aryl piperidines was performed.
The required nitroalkanes 6 were uneventfully prepared as in
Scheme 1.
Moderate yields over two steps for the nitro-Mannich/reductive
cyclisation sequence to give functionalized piperidines were given
in most cases (Scheme 3,,Table 2). The relative stereochemistry of
the products were tentatively assigned based upon the assignment
of the major diastereoisomer of the b-nitroamine coupled with the
NMR characteristics of the corresponding piperidine being similar
to 1a (vide supra). Neutral or electron rich substituents in the para-
position of the aryl substituent were well tolerated (1b,c), but para-
electron withdrawing substituents gave decreased levels of dia-
stereoselectivity for the b-nitroamines and a correspondingly lower
yield of piperidine (1d,e), with the p-NO2 analogue giving no
cyclized product at all. Erosion of diastereoselectivity with
increasingly electron withdrawing substituents had been noted
before in our previous work on the one pot conjugate addition
3. Conclusion
Table 2
A method for the synthesis of stereochemically defined piperi-
dines was inspired from total synthesis studies of the Schizozygine
alkaloids. A homogeneous copper promoted nitro-Mannich reac-
tion between a suitably functionalized nitroalkane 6 and glyoxylate
Scope of nitro-Mannich/reductive cyclisation for piperidines.
6
Ar
dr 2a
Yield 1 (%)b
a
b
c
d
e
f
g
h
i
C6H5-
>95:5
90:10
90:10
80:20
75:25
70:30
95:5
48
51
57
24
34
p-CH3C6H5-
p-CH3OC6H5-
p-BrC6H5-
imine 5 gave stereochemically defined b-nitroamines 2 containing
3 contiguous chiral centres. In line with our previous studies [12]
the diastereoselectivity was controlled by the aryl stereocentre and
the inherent kinetic anti-selectivity of the nitro-Mannich reaction
to give the syn, anti-diastereoisomer 2 as the major compound.
Reductive cyclisation of the crude amino acetal gave, after purifi-
cation, moderate to good yields of the diastereochemically pure
pipreridines 1. Representative transformation of the functionalized
piperidines were briefly investigated. The methodology provides a
route to a rich source of functionalized piperidines and as the
enantioselective synthesis of 6 has been reported [14], enantio-
merically pure building blocks could be prepared.
p-FC6H5-
c
p-NO2C6H5-
o-CH3OC6H5-
o-BrC6H5-
m,p-(OCH2O)C6H5-
2-furyl
-
30
19
41
21
45
d
-
d
-
j
k
85:15
90:10
2-thiophenyl
a
b
c
From integration of CHNO2 signals.
Isolated yield of major diastereosiomer.
No product could be isolated.
d
Not possible to determine by 1H NMR.
3

J.C. Anderson, E. Bouvier-Israel, C.D. Rundell et al.
Tetrahedron 78 (2021) 131821
4. Experimental section
with CH2Cl2 (2 ꢂ 80 mL). The combined organic layers were washed
with brine (100 mL), dried (MgSO4) and concentrated. The resulting
yellow oil was purified by flash column chromatography (20%
EtOAc/Hexane) to give 4a (7.64 g, 92%) as a colourless oil. Rf 0.65
4.1. General information
All non-aqueous reactions were carried out in oven-dried
glassware under an inert atmosphere unless otherwise indicated.
All reaction temperatures refer to the values of the external heating
element and not that of the reaction mixture. Room temperature
implies a temperature range of 20e25 ꢀC. A temperature of 0 ꢀC was
achieved using an ice-water bath whereas cryogenic conditions
(ꢁ78 ꢀC or ꢁ40 ꢀC) were achieved using a dry ice and acetone or
acetonitrile bath respectively. All additions of reagent occurred as a
single portion or fast unless otherwise stated. Column chroma-
tography was carried out using Merk Geduran® silica gel 60 and
analytical thin layer chromatography was carried out using Merck
Keiselgel aluminium-backed plates coated with silica gel. Compo-
nents were visualised using ultra-violet light (254 nm) and a basic
potassium permanganate dip. Removal of solvent in vacuo was
achieved using Büchi rotary evaporators and either the house
vacuum or a Büchi Vac® V-500 pump.
(25% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3)
d 7.69 (1H, d,
J ¼ 16.1), 7.53 (2H, dd, J ¼ 7.0, 2.8), 7.43e7.36 (3H, m), 6.44 (1H, d,
J ¼ 16.1), 4.27 (2H, q, J ¼ 7.3), 1.34 (3H, t, J ¼ 7.2). This data was
consistent with literature [20].
4.3. Nitroalkane esters (8)
4.3.1. Ethyl 4-nitro-3-phenylbutanoate (8a)
To a stirred solution of 4a (5.00 g, 28.3 mmol) in nitromethane
(26 mL) was added tetramethylguanidine (0.88 mL, 7.1 mmol). The
resulting mixture was heated to 70 ꢀC and the stirring was
continued for 21 h. The reaction mixture was cooled to room
temperature, quenched with aqueous HCl solution (1.0 M, 75 mL)
and then extracted with EtOAc (2 ꢂ 60 mL). The combined organic
layers were dried (Na2SO4) and concentrated. The residue was
purified by flash column chromatography (20% EtOAc/Hexane) to
give the desired product 8a (3.76 g, 56%) as a yellow oil. Rf (20%
All commercial chemicals and solvents were used as supplied
unless otherwise stated. The dry solvents THF and CH2Cl2 were
obtained from a solvent tower, where degassed solvents were
EtOAc in hexane) 0.24; 1H NMR (400 MHz, CDCl3)
d 7.37e7.31 (2H,
m), 7.31e7.27 (1H, m), 7.25e7.21 (2H, m), 4.73 (1H, dd, J ¼ 12.5, 7.0),
4.64 (1H, dd, J ¼ 12.5, 7.8), 4.11e4.05 (2H, q, J ¼ 7.0), 3.99 (1H, quin,
J ¼ 7.5), 2.76 (2H, dd, J ¼ 7.4, 1.6), 1.17 (3H, t, J ¼ 7.2). Data consistent
with literature [23].
passed through two columns of activated alumina and a 7 mm filter
under 4 bar pressure. Other anhydrous solvents were purchased
bottled from the Aldrich chemical company and used as provided.
Activation of 4 Å molecular sieves was achieved by heating under a
high vacuum.
Melting points are uncorrected and were obtained using a
Reichert Melting Point Apparatus. Infrared (IR) spectra were
recorded on a PerkinElmer spectrum 100 FT-IR (ATR mode). All 1H
and 13C NMR data were recorded using Bruker AVANCE III 300 MHz,
Bruker AVANCE III 400 MHz, Bruker AVANCE III 600 MHz at 300,
400 and 600 MHz for 1H and 150 MHz for 13C. Samples were made
as dilute solutions of CDCl3 and spectra recorded at 298 K. Data
were analyzed using ACD/NMR processor academic edition. All
4.3.2. Ethyl 4-nitro-3-(p-tolyl)butanoate (8b)
The a,b-unsaturated ester 4b (1.24 g, 4.86 mmol) was converted
to the crude product 8b as described for the synthesis of compound
8a. The residue was purified by flash column chromatography (14%
EtOAc/Hexane) to give the desired product 8b (1.09 g, 54%) as a
yellow oil. Rf (14% EtOAc/Hexane): 0.18; 1H NMR (600 MHz, CDCl3)
d
7.18e7.05 (4H, m), 4.79 (2H, m), 4.08 (2H, qd, J ¼ 7.1, 1.5), 3.94 (1H,
quin, J ¼ 7.4), 2.74 (2H, dd, J ¼ 7.4, 1.9), 2.32 (3H, s), 1.18 (3H, t,
chemical shifts (
d
) are reported in parts per million (ppm), relative
J ¼ 7.0); 13C NMR (151 MHz, CDCl3)
d 170.8 (C]O), 137.9 (C), 135.4
to residual solvent peaks of CDCl3 d ¼ 7.26 for 1H NMR and
d
¼ 77.1
(C), 129.8 (CH), 127.3 (CH), 79.7 (CH2), 61.0 (CH2), 40.0 (CH), 38
(CH2), 21.2 (CH3),14.2 (CH3); FTIR (neat, film) 2984,1730,1551,1376;
HRMS (ESI) [C13H17NO4þNa]þ calcd 274.1050, found 274.1050.
for 13C NMR. Multiplicities for 1H coupled signals are designated as
s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, quin ¼ quintet,
m ¼ multiplet. Coupling constants (J) are reported in Hertz (Hz).
Mass spectroscopy data were collected on Thermo Finnigan
Mat900xp (EI/CI) and Waters LCT Premier XE (ES) instruments.
Mass spectrometry data was collected on Thermo Finnigan
Mat900xp (EI/CI) VG-70se (FAB) and Waters LCT Premier XE (ES)
instruments.
4.3.3. Ethyl 3-(4-methoxyphenyl)-4-nitrobutanoate (8c)
To a stirred solution of 4c (1.40 g, 6.79 mmol) in nitromethane
(15 mL), was added tetramethylguanidine (0.21 mL, 1.7 mmol). The
resulting mixture was heated to 70 ꢀC and the stirring was
continued overnight. The temperature was then raised to 90 ꢀC and
the mixture stirred for another 2 days. Workup and purification
were as for 8b to give the desired product 8c (695 mg, 38%, 96%
brsm) as a yellow oil. Rf (40% EtOAc/Hexane): 0.51; 1H NMR
4.2. Synthesis of a,b-unsaturated esters (4)
The known conjugate esters 4a [20], b [20], c [20], d [20], e [20],
f [20], g [21], h [21], i [22], j [20], k [20], were obtained by reaction
of the commercially available aldehydes with triethyl- or trime-
thylphosphonoacetate according to the representative procedure
below and characterisation data (1H and 13C NMR) were in agree-
ment with the literature.
(600 MHz, CDCl3)
d
7.16e7.12 (2H, d, J ¼ 8.7), 6.88e6.84 (2H, d,
J ¼ 8.7), 4.70 (1H, dd, J ¼ 12.4, 8.1), 4.59 (1H, dd, J ¼ 12.4, 8.1), 4.08
(2H, dq, J ¼ 7.1, 3.1), 3.93 (2H, quin, J ¼ 7.5), 3.78 (3H, s), 2.77e2.69
(2H, m), 1.18 (3H, t, J ¼ 7.2). Data are consistent with literature [24].
4.3.4. Ethyl 3-(4-bromophenyl)-4-nitrobutanoate (8d)
4.2.1. Ethyl cinnamate (4a)
The a,b-unsaturated ester 4d (1.24 g, 4.86 mmol) was converted
To a stirred solution of triethylphosphonoacetate (9.40 mL,
47.1 mmol) in THF (200 mL) was added potassium tert-butoxide
(5.28 g, 47.1 mmol) portionwise at 0 ꢀC. The cooling bath was
removed, and the resulting mixture was stirred for 1 h. A solution of
benzaldehyde (5.00 g, 47.1 mmol) in THF (50 mL) was added
through an addition funnel dropwise and the stirring was
continued for 2 h. The reaction mixture was concentrated then satd.
Aq. NH4Cl (100 mL) was added and the reaction mixture extracted
to the crude product 8d as described for the synthesis of compound
8a. The residue was purified by flash column chromatography (14%
EtOAc/Hexane) to give the desired product 8d (1.08 g, 70%) as a
yellow oil. Rf (11% EtOAc/Hexane): 0.1; 1H NMR (400 MHz, CDCl3)
d
7.52e7.39 (2H, m), 7.13e7.04 (2H, m), 4.72 (1H, dd, J ¼ 12.7, 7.5),
4.60 (1H, dd, J ¼ 12.7, 7.5), 4.09 (2H, qd, J ¼ 7.1, 1.3), 4.00e3.92 (1H,
m), 2.78e2.67 (2H, m), 1.19 (3H, t, J ¼ 7.1). Data consistent with
literature [24].
4

J.C. Anderson, E. Bouvier-Israel, C.D. Rundell et al.
Tetrahedron 78 (2021) 131821
4.3.5. Ethyl 3-(4-fluorophenyl)-4-nitrobutanoate (8e)
C
12H13NO6 [M].þ 267.0737, found 267.0738.
The a,b-unsaturated ester 4e (1.50 g, 8.30 mmol) was converted
to the crude product 8e as described for the synthesis of compound
8a. The residue was purified by flash column chromatography (30%
EtOAc/Hexane) to give the desired product 8 (1.63 g, 81%) as a
yellow oil. Rf (30% EtOAc in hexane): 0.53; 1H NMR (700 MHz,
4.3.10. Ethyl 3-(furan-2-yl)-4-nitrobutanoate (8j)
The -unsaturated ester 4j (1.11 g, 6.71 mmol) was converted
to the crude product 8j as described for the synthesis of compound
8a. The residue was purified by flash column chromatography (14%
EtOAc/Hexane) to give the desired product 8j (1.08 g, 71%) as a
yellow oil. Rf 0.44 (17% EtOAc/Hexane); 1H NMR (600 MHz, CDCl3)
a,b
CDCl3)
d
7.23e7.17 (2H, m), 7.08e6.97 (2H, m), 4.72 (1H, dd, J ¼ 12.6,
6.8), 4.61 (1H, dd, J ¼ 12.7 8.1), 3.98 (1H, p, J ¼ 7.4), 3.64 (3H, s), 2.77
(1H, dd, J ¼ 16.3, 7.2), 2.73 (1H, dd, J ¼ 16.3, 7.6); 13C NMR (176 MHz,
d
7.35 (1H, dd, J ¼ 1.8, 0.8), 6.30 (1H, dd, J ¼ 3.3, 1.9), 6.17 (1H, d,
CDCl3)
d
171.04 (C), 162.48 (d, J ¼ 247.1 Hz, CeF), 134.12 (d,
J ¼ 3.3), 4.72 (2H, d, J ¼ 6.9), 4.14 (1H, q, J ¼ 7.1), 4.08 (2H, q, J ¼ 7.0),
J ¼ 3.4 Hz, C), 129.13 (d, J ¼ 8.2 Hz, CH), 116.22 (d, J ¼ 21.6 Hz, CH),
79.49 (CH2), 52.16 (CH3), 39.61 (CH), 37.69 (CH2). Data consistent
with literature [25].
2.78 (2H, qd, J ¼ 16.4, 7.1), 1.23 (3H, t, J ¼ 7.1); 13C NMR (151 MHz,
CDCl3)
d 170.57 (C]O), 151.4 (C), 142.6 (CH), 110.6 (CH), 107.3 (CH),
77.2 (CH2) 61.2 (CH2), 35.5 (CH), 34.2 (CH2), 14.2 (CH3); FTIR (neat,
film) 2984, 1729, 1553, 1375 cmꢁ1; HRMS (EI) [C10H13NO5þNH4]
calcd 245.1132, found 245.1131.
4.3.6. Ethyl 4-nitro-3-(4-nitrophenyl)butanoate (8f)
The a,b-unsaturated ester 4f (1.55 g, 7.01 mmol) was converted
to the crude product 8f as described for the synthesis of compound
8a using 0.5 eq of tetramethylguanidine. The residue was purified
by flash column chromatography (20% EtOAc/Hexane) to give the
desired product 8f (777 mg, 39%) as a yellow oil. Rf 0.12 (20% EtOAc/
4.3.11. Ethyl 4-nitro-3-(thiophen-2-yl)butanoate (8k)
The a,b-unsaturated ester 4k (1.09 g, 5.98 mmol) was converted
to the crude product 8k as described for the synthesis of compound
8a. The residue was purified by flash column chromatography (11%
EtOAc/Hexane) to give the desired product 8k (972 mg, 67%) as a
yellow oil. Rf 0.22 (11% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3)
Hexane); 1H NMR (400 MHz, CDCl3)
d
8.22 (2H, d, J ¼ 8.8), 7.44 (2H,
d, J ¼ 8.5), 4.79 (1H, dd, J ¼ 12.9, 6.4), 4.69 (1H, dd, J ¼ 12.9, 8.4),
4.13e4.07 (3H, m), 2.79 (2H, dd, J ¼ 7.4, 6.1), 1.19 (3H, t, J ¼ 7.2). Data
are consistent with literature [26].
d
7.22 (1H, dd, J ¼ 4.9, 1.4), 6.96e6.91 (2H, m), 4.77 (1H, dd, J ¼ 12.7,
7.1) 4.67 (1H, dd, J ¼ 12.7, 7.1), 4.31 (1H, q, J ¼ 7.2), 4.13 (2H, q,
J ¼ 7.1), 2.81 (2H, d, J ¼ 7.2), 1.22 (3H, t, J ¼ 7.1). Data consistent with
literature [24].
4.3.7. Ethyl 3-(2-methoxyphenyl)-4-nitrobutanoate (8g)
The a,b-unsaturated ester 4g (5.00 g, 24,2 mmol) was converted
to the crude product 8g as described for the synthesis of compound
8a. The residue was purified by flash column chromatography (17%
EtOAc/Hexane) to give the desired product 8g (4.12 g, 64%) as a
yellow oil. Rf 0.32 (20% EtOAc/Hexane); 1H NMR (600 MHz, CDCl3)
4.4. Nitroalkane acetals (6)
d
7.28e7.24 (1H, m), 7.16 (1H, d, J ¼ 7.2), 6.93e6.87 (2H, m),
4.4.1. (4,4-Dimethoxy-1-nitrobutan-2-yl)benzene (6a)
4.82e4.75 (2H, m), 4.18 (1H, quin, J ¼ 7.5), 4.11e4.05 (2H, m), 3.86
To a cooled (ꢁ78 ꢀC) and stirred solution of 4a (2.00 g,
8.43 mmol) in CH2Cl2 (50 mL), was added DIBAL-H (1.0 M in hex-
ane, 16.9 mL) dropwise. The resulting mixture was stirred at ꢁ78 ꢀC
for 1 h. The mixture was quenched with MeOH (20 mL) and slowly
warmed up to 0 ꢀC. Aqueous HCl (2.0 M, 30 mL) was added and the
resulting mixture stirred for 10 min. The layers were separated, the
aqueous layer was extracted with CH2Cl2 (2 ꢂ 40 mL). The com-
bined organic layers were dried (Na2SO4) and concentrated. Puri-
fication of the residue by flash column chromatography (25%
EtOAc/Hexane) gave 4-nitro-3-phenylbutanal (1.38 g, 86%) as a
yellow oil. Rf (25% EtOAc/Hexane): 0.13; 1H NMR (400 MHz, CDCl3)
(3H, s) 2.90e2.82 (2H, m), 1.18 (3H, t, J ¼ 7.1); 13C NMR (151 MHz,
CDCl3)
d 171.4 (C]O), 157.3 (C), 129.5 (CH), 129.3 (CH), 126.1 (CH),
120.1 (CH), 111.1 (C), 78.0 (CH2), 60.9 (CH2), 55.5 (CH3), 37.0 (CH),
36.0 (CH2), 14.2 (CH3); FTIR (neat, film) 2981, 1730, 1550, 1376,
1245 cmꢁ1; HRMS (ESI) [C13H17NO5þNH4]þ calcd 285.14445, found
285.14445.
4.3.8. Ethyl 3-(2-bromophenyl)-4-nitrobutanoate (8h)
The a,b-unsaturated ester 4h (1.96 g, 7.70 mmol) was converted
to the crude product 8h as described for the synthesis of compound
8a. The residue was purified by flash column chromatography (17%
EtOAc/Hexane) to give the desired product 8h (1.66 g, 68%) as a
yellow oil. Rf 0.30 (20% EtOAc/Hexane); 1H NMR (600 MHz, CDCl3)
d
9.71 (1H, s), 7.38e7.32 (2H, m), 7.32e7.28 (1H, m), 7.25e7.20 (2H,
m), 4.65 (2H, dq, J ¼ 12.7, 7.4), 4.11e4.04 (1H, m), 3.02e2.89 (2H, m,
2H). Data consistent with literature [27].
d
7.60 (1H, dd, J ¼ 8.1,1.1), 7.32e7.28 (1H, m), 7.22 (1H, d, J ¼ 7.8, 1.6),
To a stirred solution of the aldehyde (1.00 g, 5.18 mmol) in
MeOH (15 mL), TsOH.H2O (493 mg, 2.59 mmol) and HC(OMe)3
(1.13 mL, 10.4 mmol) were added and the resulting mixture was
refluxed for 1 h. The reaction mixture was cooled to room tem-
perature and concentrated. The residue was then dissolved in
CH2Cl2 (20 mL) and washed with saturated NaHCO3 aqueous so-
lution (20 mL). The organic layers were separated, the aqueous
layer was extracted with CH2Cl2 (2 ꢂ 20 mL) and the combined
organic layers were dried (MgSO4) then concentrated. The residue
was purified by flash column chromatography (20% EtOAc/Hexane)
to afford the desired product 6a (1.12 g, 90%) as a colourless oil. Rf
7.15 (1H, dt, J ¼ 7.7, 1.6), 4.80e4.73 (2H, m), 4.48 (1H, quin, J ¼ 7.1),
4.09 (2H, dq, J ¼ 7.2, 1.3), 2.90e2.82 (2H, m), 1.18 (3H, t, J ¼ 7.1); 13
C
NMR (151 MHz, CDCl3)
d 170.6 (C]O), 137.3 (C), 133.9 (CH), 129.5
(C), 128.1 (CH), 128.0 (CH), 124.7 (CH), 77.8 (CH2), 61.1 (CH2), 39.0
(CH), 36.4 (CH2), 14.2 (CH3); FTIR (neat, film) 2979, 1726, 1548, 1375;
HRMS (ESI) [C12H14NO4Br þ H]þ calcd 316.0179, found 316.0173.
4.3.9. Methyl 3-(benzo[1,3]dioxol-5-yl)-4-nitrobutanoate (8i)
The a,b-unsaturated ester 4i (343 mg,1.66 mmol) was converted
to the crude product 8i as described for the synthesis of compound
8a. The residue was purified by flash column chromatography (30%
EtOAc/Hexane) to give the desired product 8i (408 mg, 92%) as a
yellow oil. Rf (30% EtOAc in hexane): 0.63; 1H NMR (400 MHz,
(25% EtOAc/Hexane): 0.39; 1H NMR (600 MHz, CDCl3)
d 7.36e7.32
(2H, m), 7.30e7.27 (1H, m), 7.23e7.20 (2H, m), 4.66 (1H, dd, J ¼ 12.6,
7.2), 4.56 (1H, dd, J ¼ 12.5, 8.4), 4.14 (1H, dd, J ¼ 7.8, 3.7), 3.68e3.62
(1H, m), 3.29 (3H, s), 3.24 (3H, s), 2.06e2.01 (1H, m), 1.95e1.90 (1H,
CDCl3)
d
6.76e6.67 (3H, m), 5.95 (2H, s), 3.91 (1H, m), 3.65 (3H, s),
171.1 (C), 148.2 (C),
2.76e2.67 (2H, m); 13C NMR (150 MHz, CDCl3)
d
m); 13C NMR (151 MHz, CDCl3)
d 129.2 (C), 127.9 CH), 127.6 (CH),
147.4 (C), 131.9 (C), 120.8 (CH), 108.8 (CH), 107.6 (CH), 101.4 (CH2),
79.7 (CH2), 52.1 (CH3), 40.1 (CH), 37.8 (CH2); FTIR (neat, cmꢁ1) 2950,
1728, 1547, 1501, 1486, 1241, 1169, 1035; HRMS (EI) calcd. for
102.2 (CH), 80.9 (CH2), 53.2 (CH3), 53.1 (CH3), 40.4 (CH), 36.2 (CH2);
FTIR (neat, film) 2938, 1551, 1379, 1127 cmꢁ1
[C12H16NO4þNa]þ calcd 262.1055, found 262.1051.
; HRMS (EI)
5

J.C. Anderson, E. Bouvier-Israel, C.D. Rundell et al.
Tetrahedron 78 (2021) 131821
4.4.2. 1-(4,4-Dimethoxy-1-nitrobutan-2-yl)-4-methylbenzene (6b)
To a cooled (ꢁ78 ꢀC) and stirred solution of 4b (820 mg,
3.26 mmol) in CH2Cl2 (20 mL), was added dropwise DIBAL-H (1.0 M
in hexane, 6.52 mL). The resulting mixture was stirred at ꢁ78 ꢀC for
4 h. Additional DIBAL-H (1.0 M in hexane, 2.7 mL) was added and
the mixture stirred at ꢁ78 ꢀC for 2 h. No further conversion was
observed and the mixture was quenched and worked up as for the
aldehyde for 6a. Purification of the residue by flash column chro-
matography (20% EtOAc/Hexane) gave 4-nitro-3-(p-tolyl)butanal
(320 mg, 47%) as a pale yellow oil and some recovered starting
material (274 mg, 33%) as a yellow oil; Rf (25% EtOAc/Hexane): 0.19;
product 6d in 2 h, as described for the synthesis of compound 6a.
The residue was purified by flash column chromatography (12%
EtOAc/Hexane) to afford the desired product 6d (628 mg, 62%) as a
colourless oil. Rf 0.62 (17% EtOAc/Hexane); 1H NMR (600 MHz,
CDCl3)
d
7.49e7.45 (2H, m), 7.11e7.08 (2H, m), 4.60 (1H, dd, J ¼ 12.7,
7.7), 4.52 (1H, dd, J ¼ 12.7, 7.7), 4,13 (1H, dd, J ¼ 7.6, 3.7), 3.63 (1H, tt,
J ¼ 8.9, 6.3), 3.29 (3H, s), 3.25 (3H, s), 2.02 (1H, ddd, J ¼ 13.6, 7.6,
5.9), 1.88 (1H, ddd, J ¼ 14.0, 9.1, 3.7); 13C NMR (151 MHz, CDCl3)
d
138.3 (C), 132.4 (C), 129.3 (CH), 121.9 (CH), 102.2 (CH), 80.1 (CH2),
53.3 (CH3), 39.9 (CH), 36.15 (CH2); FTIR (neat, film) 2937, 1552, 1378,
1127 cmꢁ1; HRMS (ESI) [C14H13N3O2þNa]þ calcd 340.0155, found
340.0159.
1H NMR (600 MHz, CDCl3)
(2H, d, J ¼ 8.1), 4.67e4.57 (2H, m), 4.04 (1H, quin, J ¼ 7.3), 2.96e2.88
(2H, m), 2.32 (3H, s); 13C NMR (151 MHz, CDCl3)
199.0 (CHO),138.1
d
9.70 (1H, s), 7.15 (2H, d, J ¼ 8.1), 7.12
d
4.4.5. 1-(4,4-Dimethoxy-1-nitrobutan-2-yl)-4-fluorobenzene (6e)
The ester 4e (1.11 g, 4.60 mmol) was converted to the desired
product 3-(2-fluorophenyl)-4-nitrobutanal (1.36 g, 81%) as a dark
pink oil, as described for the synthesis of compound 6a. Rf 0.1 (25%
(C), 135.1 (C), 130.0 (CH), 127.4 (CH), 79.7 (CH2), 46.6 (CH2), 37.8
(CH), 21.2 (CH3); FTIR (neat, film) 2921, 1722, 1548, 1379; HRMS
(ESI) [C11H13NO3þNa]þ calcd 230.0788, found 230.0788.
The aldehyde (308 mg, 1.49 mmol) was converted to the crude
product 6b in 2 h, as described for the synthesis of compound 6a.
The residue was purified by flash column chromatography (20%
EtOAc/Hexane) to afford the desired product 6b (262 mg, 70%) as a
colourless oil. Rf 0.30 (25% EtOAc/Hexane); 1H NMR (600 MHz,
EtOAc/Hexane); 1H NMR (300 MHz, CDCl3)
d 9.71 (1H, s), 7.21 (2H,
dd, J ¼ 8.6, 5.2), 7.04 (2H, t, J ¼ 8.7), 4.71e4.54 (2H, m), 4.08 (1H,
quin, J ¼ 7.3), 2.94 (2H, d, J ¼ 7.2). Data consistent with literature
[28].
The aldehyde (788 mg, 3.73 mmol) was converted to the crude
product 6e, as described for the synthesis of compound 6a. The
residue was purified by flash column chromatography (33% EtOAc/
Hexane) to afford the desired product 6e (644 mg, 67%) as an or-
ange oil. Rf 0.30 (33% EtOAc/Hexane); 1H NMR (600 MHz, CDCl3)
CDCl3)
d
7.15 (2H, d, J ¼ 8.1), 7.10 (2H, d, J ¼ 7.9), 4.63 (1H, dd,
J ¼ 12.4, 7.2), 4,53 (1H, dd, J ¼ 12.4, 8.3), 4.15 (1H, dd, J ¼ 7.7, 3.6),
3.63e3.58 (1H, m), 3.29 (3H, s), 3.24 (3H, s), 2.33 (3H, s), 2.05e1.99
(1H, m), 1.93e1.88 (1H, m); 13C NMR (151 MHz, CDCl3)
d 137.6 (C),
136.0 (C), 129.8 (CH), 127.4 (CH), 102.3 (CH), 80.6 (CH2), 53.2 (CH3),
53.0 (CH3), 40.1 (CH), 36.2 (CH2), 21.2 (CH3); FTIR (neat, film) 2950,
d 7.20e7.17 (2H, m), 7.05e7.02 (2H, m), 4.63 (1H, m), 4.52 (1H, dd,
J ¼ 12.5, 8.8), 4.14 (1H, d, J ¼ 3.8), 3.67e3.62 (1H, m), 3.29 (3H, s),
1550, 1377, 1126 cmꢁ1
;
HRMS (ESI) [C13H19NO4þNa]þ calcd
3.25 (3H, s), 2.03 (1H, ddd, J ¼ 13.9, 7.8, 5.8), 1.91e1.86 (1H, m); 13
C
276.1206, found 276.1206.
NMR (151 MHz, CDCl3)
d
162.31 (d, J ¼ 246.6 Hz), 134.90 (d,
J ¼ 3.3 Hz), 129.17 (d, J ¼ 8.2 Hz), 116.13 (d, J ¼ 21.5 Hz), 102.19 (CH),
4.4.3. 1-(4,4-Dimethoxy-1-nitrobutan-2-yl)-4-methoxybenzene
(6c)
80.43 (CH2), 53.3 (CH3), 53.2 (CH3), 39.7 (CH), 36.3 (CH2); FTIR (neat,
film) 2930, 1551, 1510, 1377, 1225, 1126 cmꢁ1
[C12H15FNO4þNa] calcd 280.0961, found 280.0970.
; HRMS (EI)
The ester 4c (685 mg, 2.56 mmol) was converted to the crude
aldehyde in 3 h, as described for the synthesis of 6a. Purification of
the residue by flash column chromatography (20% EtOAc/Hexane)
gave 3-(4-methoxyphenyl)-4-nitrobutanal (414 mg, 72%) as a pale-
yellow oil. Rf 0.23 (25% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3)
4.4.6. 1-(4,4-Dimethoxy-1-nitrobutan-2-yl)-4-nitrobenzene (6f)
The ester 4f (770 mg, 2.70 mmol) was converted to the crude
aldehyde, as described for the synthesis of compound 6a. Purifi-
cation of the residue by flash column chromatography (30% EtOAc/
Hexane) gave 4-nitro-3-(4-nitrophenyl)butanal (256 mg, 40%) as an
orange oil and some recovered starting material 4f (183 mg, 24%) as
a yellow oil. Rf 0.19 (25% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3)
d
9.70 (1H, s), 7.15 (2H, d, J ¼ 8.8), 6.86 (2H, d, J ¼ 8.8), 4.60 (2H, m),
4.03 (1H, quin, J ¼ 7.2), 3.79 (3H, s), 2.92 (2H, d, J ¼ 6.5). Data
consistent with literature [26].
The aldehyde (404 mg, 1.81 mmol) was converted to the crude
product 6c in 1.5 h, as described for the synthesis of compound 6a.
The residue was purified by flash column chromatography (20%
EtOAc/Hexane) to afford the desired product 6c (236 mg, 48%) as a
yellow oil. Rf (20% EtOAc/Hexane): 0.15; 1H NMR (600 MHz, CDCl3)
d
9.74 (1H, s), 8.22 (2H, d, J ¼ 8.8), 7.45 (2H, d, J ¼ 8.8), 4.79e4.63
(2H, m), 4.25e4.17 (1H, m), 3.03 (2H, d, J ¼ 7.0). Data consistent
with literature [28].
The aldehyde (243 mg, 1.02 mmol) was converted to the crude
product 6f in 2 h, as described for the synthesis of compound 6a.
The residue was purified by flash column chromatography (40%
EtOAc/Hexane) to afford the desired product 6f (179 mg, 63%) as a
colourless oil. Rf 0.29 (50% EtOAc/Hexane); 1H NMR (600 MHz,
d
7.15e7.11 (2H, m), 6.89e6.85 (2H, m), 4.62 (1H, dd, J ¼ 12.3, 7.1),
4.52 (1H, dd, J ¼ 12.4, 8.5), 4.14 (1H, dd, J ¼ 7.9, 3.6), 3.79 (3H, s),
3.63e3.57 (1H, m), 3.29 (3H, s), 3.24 (3H, s), 2.01 (1H, ddd, J ¼ 13.8,
8.0, 5.6), 1.89 (1H, ddd, J ¼ 13.7, 9.6, 3.6); 13C NMR (151 MHz, CDCl3)
d
159.2 (C), 131.5 (C), 128.6 (CH), 114.5 (CH), 102.3 (CH), 80.7 (CH2),
CDCl3)
d
8.22 (2H, d, J ¼ 8.8), 7.42 (2H, d, J ¼ 8.7), 4.76 (1H, dd,
55.4 (CH3), 53.2 (CH3), 53.1 (CH3), 39.7 (CH), 36.3 (CH2); FTIR (neat,
J ¼ 13.0, 6.2), 4,61 (1H, dd, J ¼ 13.0, 9.2), 4.17 (1H, dd, J ¼ 7.2, 4.0),
3.89e3.75 (1H, m), 3.31 (3H, s), 3.27 (3H, s), 2.08 (1H, td, J ¼ 14.0,
6.7), 1.95 (1H, ddd, J ¼ 14.1, 8.6, 3.9); 13C NMR (151 MHz, CDCl3)
film) 2957, 1549, 1378, 1250, 1124 cmꢁ1
[C13H19NO5þNa]þ calcd 292.1155, found 292.1156.
;
HRMS (ESI)
d
147.6 (C), 147.0 (C), 128.6 (CH), 124.4 (CH), 102.1 (CH), 79.6 (CH2),
4.4.4. 1-Bromo-4-(4,4-dimethoxy-1-nitrobutan-2-yl)benzene (6d)
The ester 4d (1.04 g, 3.30 mmol) was converted to the product 3-
(4-bromophenyl)-4-nitrobutanal (884 mg, 98%) in 5 h as described
for the synthesis of compound 6a. The product was obtained
without purification as a yellow oil. Rf 0.26 (20% EtOAc/Hexane); 1H
53.5 (CH3 x 2), 40.1 (CH), 36.1 (CH2); FTIR (neat, film) 2937, 1551,
1519, 1346, 1377, 1126 cmꢁ1; HRMS (ESI) [C12H16N2O6þNa]þ calcd
307.0901, found 307.0901.
4.4.7. 1-(4,4-Dimethoxy-1-nitrobutan-2-yl)-2-methoxybenzene
(6g)
NMR (400 MHz, CDCl3)
d 9.71 (1H, s), 7.51e7.44 (2H, m), 7.15e7.09
(2H, m), 4.67 (1H, dd, J ¼ 12.6, 7.4), 4.63 (1H, dd, J ¼ 12.6, 7.4), 4.05
(1H, q, J ¼ 7.1), 2.94 (2H, d, J ¼ 7.1). Data consistent with literature
[23].
The ester 4g (2.00 g, 7.48 mmol) was converted to the crude
aldehyde as described for the synthesis of compound 6a. Purifica-
tion of the residue by flash column chromatography (25% EtOAc/
Hexane) gave 3-(2-methoxyphenyl)-4-nitrobutanal (1.36 g, 81%) as
The aldehyde (868 mg, 3.19 mmol) was converted to the crude
6

J.C. Anderson, E. Bouvier-Israel, C.D. Rundell et al.
Tetrahedron 78 (2021) 131821
a colourless oil. Rf 0.30 (25% EtOAc/Hexane); 1H NMR (400 MHz,
4.4.10. 2-(4,4-Dimethoxy-1-nitrobutan-2-yl)furan (6j)
CDCl3)
d
9.70 (1H, s), 7.30e7.26 (1H, m), 7.15 (1H, dd, J ¼ 7.7, 1.6),
The ester 4j (991 mg, 4.36 mmol) was converted to the crude
aldehyde in 2 h as described for the synthesis of compound 6a.
Purification of the residue by flash column chromatography (20%
EtOAc/Hexane) gave 3-(furan-2-yl)-4-nitrobutanal (550 mg, 69%)
as a yellow oil. Rf 0.33 (20% EtOAc/Hexane); 1H NMR (400 MHz,
6.95e6.88 (2H, m), 4.78e4.68 (2H, m), 4.29 (1H, quin, J ¼ 7.1), 3.87
(3H, s), 3.07e2.94 (2H, m). Data are consistent with literature [28].
The aldehyde (1.00 g, 4.48 mmol) was converted to the crude
product 6g in 1.5 h, as described for the synthesis of compound 6a.
The residue was purified by flash column chromatography (20%
EtOAc/Hexane) to afford the desired product 6g (424 mg, 35%) as a
yellow oil and some recovered starting aldehyde (197 mg, 20%) as a
colourless oil. Rf 0.40 (25% EtOAc/Hexane); 1H NMR
CDCl3)
d
9.76 (1H, s), 7.39e7.22 (1H, m), 6.31 (1H, dd, J ¼ 3.3, 1.9),
6.18 (1H, dt, J ¼ 3.3, 0.7), 4.73e4.60 (2H, m), 4.18 (1H, q, J ¼ 7.0),
3.08e2.84 (2H, m). Data are consistent with literature [24].
The aldehyde (515 mg, 2.81 mmol) was converted to the crude
product 6j (613 mg, 95%) in 2 h, as described for the synthesis of
compound 6a. The product was obtained with no purification as a
pale brown oil. Rf 0.58 (20% EtOAc/Hexane); 1H NMR (600 MHz,
(600 MHz,CDCl3)
d
7.24 (1H, d, J ¼ 1.5), 7.13 (1H, dd, J ¼ 7.5, 1.3),
6.93e6.87 (2H, m), 4.79e4.71 (2H, m), 4.18 (1H, dd, J ¼ 7.7, 3.8), 3.85
(4H, m), 3.28 (3H, s), 3.24 (3H, s), 2.13e2.01 (2H, m); 13C NMR
(151 MHz, CDCl3)
d
157.5 (C), 129.8 (CH), 129.0 (CH), 126.8 (C), 121.0
CDCl3)
d
7.36 (dd, J ¼ 1.9, 0.8 Hz, 1H), 6.30 (dd, J ¼ 3.2, 1.9 Hz, 1H),
(CH), 111.2 (CH), 102.7 (CH), 78.9 (CH2), 55.4 (CH3), 52.7 (CH3), 37.2
(CH), 34.2 (CH2); FTIR (neat, film) 2925, 1549, 1378, 1244,
1124 cmꢁ1; HRMS (ESI) [C13H18NO5þNa]þ calcd 292.1161, found
292.1164.
6.16 (d, J ¼ 3.2 Hz, 1H), 4.65e4.59 (m, 2H), 4.26 (dd, J ¼ 7.1, 4.2 Hz,
1H), 3.79 (dt, J ¼ 14.7, 7.3 Hz,1H), 3.30 (d, J ¼ 16.0 Hz, 6H), 2.06e1.95
(m, 2H); 13C NMR (151 MHz, CDCl3)
d 152.2, 142.5, 110.5, 107.4,
102.4, 78.2, 53.5, 53.3, 34.2 (d, J ¼ 12.4 Hz); FTIR (neat, film) 2936,
1551, 1436, 1125, 1051, 739 cmꢁ1; HRMS (ESI) [C10H15NO5þH]þ
calcd 229.0950, found 229.0952.
4.4.8. 1-Bromo-2-(4,4-dimethoxy-1-nitrobutan-2-yl)benzene (6h)
The ester 4h (1.63 g, 5.15 mmol) was converted to the crude
aldehyde in 2.5 h, as described for the synthesis of compound 6a.
Purification of the residue by flash column chromatography (25%
EtOAc/Hexane) 3-(2-bromophenyl)-4-nitrobutanal (912 mg, 65%)
4.4.11. 2-(4,4-Dimethoxy-1-nitrobutan-2-yl)thiophene (6k)
The ester 4k (941 mg, 3.87 mmol) was converted to the crude
aldehyde (771 mg, 95%) in 3 h, as described for the synthesis of
compound 6a. The product 4-nitro-3-(thiophen-2-yl)butanal was
obtained with no purification as a brown oil. Rf 0.12 (11% EtOAc/
as
(600 MHz,CDCl3)
a
colourless oil. Rf 0.25 (40% EtOAc/Hexane); 1H NMR
d
9.73 (1H, s), 7.62 (1H, dd, J ¼ 1.1, 8.1), 7.35e7.27
(1H, m), 7.22e7.13 (2H, m), 4.81e4.65 (2H, m), 4.56 (1H, quin,
Hexane); 1H NMR (600 MHz, CDCl3)
d
9.73 (1H, t, J ¼ 0.9), 7.23 (1H,
J ¼ 6.9), 3.11e2.93 (2H, m); 13C NMR (151 MHz, CDCl3)
d
198.6
dd, J ¼ 5.0, 1.2), 6.97e6.91 (2H, m), 4.68(1H, dd, J ¼ 12.7, 7.1), 4.63
(CHO), 137.1 (C), 134.0 (CH), 129.7 (CH), 128.3 (CH), 124.5 (C), 77.6
(CH2), 45.4 (CH2), 37.0 (CH); FTIR (neat, film) 2920,1722, 1549,1378;
HRMS (ESI) [C10H10NO3Br þ NH4]þ calcd 289.0182, found 289.0182.
The aldehyde (887 mg, 3.26 mmol) was converted in 2.5 h to the
desired product 6h (943 g, 91%) as a pale yellow oil, as described for
the synthesis of compound 6a. Rf 0.23 (25% EtOAc/Hexane); 1H
(1H, dd, J ¼ 12.7, 7.1), 4.39 (1H, quin, J ¼ 7.0), 3.05e2.95 (2H, m); 13
C
NMR (151 MHz, CDCl3)
d 198.5 (CHO), 141.0 (C), 127.4 (CH), 125.9
(CH), 125.2 (CH), 79.8 (CH2), 47.2 (CH2), 33.6 (CH); FTIR (neat, film)
2840, 1720, 1548, 1378; HRMS (ESI) [C10H15NO4S þ H]þ calcd
246.0800, found 246.0805.
The aldehyde (703 mg, 3.53 mmol) was converted to the crude
product 6k in 2 h, as described for the synthesis of compound 6a.
The residue was purified by flash column chromatography (14%
EtOAc/Hexane) to afford the desired product 6k (710 mg, 82%) as a
yellow oil. Rf 0.58 (20% EtOAc/Hexane); 1H NMR (600 MHz, CDCl3)
NMR (600 MHz, CDCl3)
d
7.60 (1H, dd, J ¼ 8.0, 1.2), 7.31 (1H, t,
J ¼ 7.5), 7.22 (1H, dd, J ¼ 7.8, 1.6), 7.14 (1H, dt, J ¼ 7.6, 1.7), 4.71e4.63
(2H, m), 4.24 (2H, dd, J ¼ 6.6, 4.7), 3.31 (3H, s), 3.26 (3H, s),
2.11e2.00 (2H m); 13C NMR (151 MHz, CDCl3)
d 138.4 (C),133.9 (CH),
129.2 (C) 128.1 (CH), 102.5 (CH), 78.9 (CH2), 53.7 (CH3), 52.9 (CH3),
d
7.23 (1H,dd, J ¼ 5.1, 0.9), 6.95 (1H, dd, J ¼ 5.1, 3.5), 6.91 (1H, ddd,
38.9 (CH), 35.5 (CH2); FTIR (neat, film) 2931, 1547, 1376, 1122 cmꢁ1
HRMS (ESI) [C12H16BrNO4þNa]þ calcd 340.0155, found 340.0154.
;
J ¼ 3.5, 1.1, 0.5), 4.66 (1H, dd, J ¼ 12.7, 7.5), 4.55 (1H, dd, J ¼ 12.7, 7.5),
4.26 (1H, dd, J ¼ 7.6, 3.7), 4.02e3.97 (1H, m), 3.31 (3H, s), 3.28 (3H,
s), 2.09e1.94 (2H, m); 13C NMR (151 MHz, CDCl3)
d 142.1 (C), 127.3
4.4.9. 5-(4,4-Dimethoxy-1-nitrobutan-2-yl)benzo[1,3]dioxole (6i)
(CH), 125.7 (CH), 124.9 (CH), 102.3 (CH), 80.9 (CH2), 53.5 (CH3), 53.3
(CH3), 37.4 (CH), 35.9 (CH2); FTIR (neat, film) 2936, 1549, 1377,
1123 cmꢁ1; HRMS (ESI) [C10H15NO4S þ H]þ calcd 268.0614, found
268.0616.
The ester 4i (2.50 g, 9.36 mmol) was converted to the crude
aldehyde in 2.5 h, as described for the synthesis of compound 6a.
Purification of the residue by flash column chromatography (30%
EtOAc/Hexane) 3-(benzo[1,3]dioxol-5-yl)-4-nitrobutanal (1.75 g,
80%) as a colourless oil. Rf (30% EtOAc in Hexane) 0.16; 1H NMR
4.5. Ethyl (E)-2-((4-methoxyphenyl)imino)acetate (5)
(600 MHz, CDCl3)
d 9.70 (1H, s), 7.27e6.68 (3H, m), 5.96 (2H, s),
4.65e4.62 (1H, dd, J ¼ 12.0, 6.6), 4.57e4.54 (1H, dd, J ¼ 12.0, 7.8),
To a solution of p-anisidine in dry CH2Cl2 (40 mL), was added
Na2SO4 (5.00 g, 40.6 mmol), then ethylglyoxylate and left to stir for
60 h. The reaction mixture was filtered and concentrated to afford
the imine 5 (9.30 g, 100%) contains residual toluene. The crude
product was used without further purification. Rf 0.44 (50% EtOAc/
4.01e3.99 (1H, m), 2.91e2.89 (2H, m); 13C NMR (151 MHz, CDCl3)
d
198.9 (CHO), 148.4 (C), 147.5 (C), 131.8 (C), 120.9 (CH), 108.9 (CH),
107.7 (CH), 101.4 (CH2), 79.7 (CH2), 46.6 (CH2), 37.9 (CH); Data
consistent with literature [14].
The aldehyde (146 mg, 0.62 mmol) was converted in 2.5 h to the
desired product 6i (178 mg, 100%) as a pale-yellow oil, as described
for the synthesis of compound 6a. Rf (20% EtOAc in hexnae) 0.34; 1H
Hexane); 1H NMR (400 MHz, CDCl3)
d 7.94 (1H, s), 7.39e7.33 (2H,
m), 6.96e6.91 (2H, m), 4.41 (2H, q, J ¼ 7.3), 3.84 (3H, s), 1.40 (3H, t,
J ¼ 7.2). Data consistent with literature [29].
NMR (500 MHz, CDCl3)
d 6.77e6.66 (3H, m), 5.95 (2H, s), 4.60 (1H,
dd, J ¼ 12.5, 7.0), 4.49 (1H, dd, J ¼ 8.5,12.5), 4.16 (1H, dd, J ¼ 7.5, 3.5),
4.6. Optimization of base and promoter for nitro-Mannich reaction
of ethyl 6,6-dimethoxy-2-((4-methoxyphenyl)amino)-3-nitro-4-
phenylhexanoate (6a, Table 1)
3.58e3.54 (1H, m), 3.29 (3H, s), 3.25 (3H, s), 2.01e1.96 (1H, m),
1.88e1.83 (1H, m); 13C NMR (126 MHz, CDCl3)
d 148.2 (C), 147.2 (C),
132.7 (C), 120.9 (CH), 108.8 (CH), 107.6 (CH), 102.1 (CH), 101.3 (CH2),
80.6 (CH2), 53.2 (CH3), 53.0 (CH3), 40.2 (CH2), 36.2 (CH); FTIR (neat,
cmꢁ1) 2937, 2834, 1743, 1550, 1443, 1247 cmꢁ1; HRMS (ESI) calcd
for C13H18NO6 [MþH]þ 483.1050, found 283.1051.
4.6.1. Entry 1
To a cooled (0 ꢀC) and stirred solution of nitroalkane 6a (100 mg,
0.418 mmol) in dry THF (5 mL) under N2 atmosphere, was added
7

J.C. Anderson, E. Bouvier-Israel, C.D. Rundell et al.
Tetrahedron 78 (2021) 131821
NaH (15.1 mg, 0.450 mmol). The reaction mixture was slowly
warmed up to room temperature then heated at 40 ꢀC for 30 min.
The mixture was cooled to room temperature then ꢁ78 ꢀC and a
solution of imine 5 (127 mg, 0.615 mmol) in THF (1 mL) was added
dropwise. The mixture was stirred for 10 min. In another flask TFA
(0.10 mL) was added dropwise to a solution of ZnEt2 (1.0 M in
hexane, 0.62 mL) in THF (0.30 mL) at ꢁ40 ꢀC, under N2. The
resulting solution was stirred for 10 min and transferred to the
nitronate solution dropwise. The reaction mixture was stirred
at ꢁ78 ꢀC for 1 h. The reaction mixture was quenched with TFA
(0.1 mL), diluted with EtOAc (20 mL) and washed with saturated
NaHCO3 (2 ꢂ 15 mL). The aqueous layer was extracted with EtOAc
(2 ꢂ 20 mL) and the combined organic layers were dried (Na2SO4)
and concentrated to give the crude nitroamine (dr 65:35, syn-anti
major) as a brown oil. Rf 0.26 (20% EtOAc/Hexane).
J ¼ 7.2); 13C NMR (151 MHz, CDCl3)
d
168.7 (C]O), 153.4 (C), 137.6
(C), 129.3 (CH), 129.0 (CH), 128.5 (CH), 115.8 (CH), 114.9 (CH), 101.2
(CH), 93.8 (CH), 62.6 (CH2), 58.2 (CH), 55.8 (CH3), 53.1 (CH3), 51.4
(CH3), 41.6 (CH), 35.3 (CH2), 14.3 (CH3); FTIR (neat, film) 3376, 2938,
1741, 1553, 1514, 1370, 1239, 1127 cmꢁ1; HRMS (EI) [C23H30N2O7]þ.
calcd 447.2131, found 447.2110.
4.6.6. Entry 6
Identical to method 4 with LiHDMS (1.0 M in THF) as a base to
give the crude nitroamine 2a (dr > 95:5, syn-anti major) as a brown
oil. Purification by flash column chromatography was attempted
but degradation of the product was observed. Rf 0.26 (20% EtOAc/
Hexane).
4.7. General procedure for the synthesis of piperidines using the
nitro-Mannich/reductive cyclisation sequence (1, Table 2)
4.6.2. Entry 2
To a cooled (ꢁ40 ꢀC, MeCN/dry ice bath) and stirred solution of
nitroalkane 6a (100 mg, 0.418 mmol) in dry THF (5 mL) under N2
atmosphere, was added dropwise LDA (0.23 mL, 0.45 mmol). After
10 min the reaction was warmed up to (0 ꢀC) and stirred for 20 min.
The mixture was cooled to ꢁ78 ꢀC and a solution of imine 5
(127 mg, 0.615 mmol) in THF (1 mL) was added dropwise. The
mixture was stirred for 10 min. The reaction mixture was quenched
with TFA (0.1 mL) and worked up identical to Method 1 to give the
crude nitroamine (dr 70:30, syn-anti major) as a brown oil. Rf 0.26
(20% EtOAc/Hexane.
Identical to entry 6, Table 1, except for the work up procedure.
The reaction was quenched with MeOH (5 mL), concentrated, then
dissolved in CH2Cl2 (10 mL), filtered through Celite and concen-
trated to give the crude b-nitroamine which was then subjected to
the cyclisation conditions described for 1a above.
4.7.1. Ethyl 1-(4-methoxyphenyl)-3-nitro-4-phenylpiperidine-2-
carboxylate (1a)
To a cooled (ꢁ40 ꢀC) solution of crude nitroamine from above
(1.16 g, 2.60 mmol) in CH2Cl2 (40 mL) under N2 atmosphere, was
added BF3.OEt2 (2.37 mL, 7.80 mmol) dropwise and the reaction
mixture stirred for 4 h. The cooling bath was left but not recharged
and the temperature was kept below 0 ꢀC. TLC (20% EtOAc/Hexane)
showed complete consumption of starting material. Then Et3SiH
(0.62 mL, 3.9 mmol) was added, the mixture was warmed up to
room temperature and stirred for 1.5 h. The reaction was quenched
with saturated NaHCO3 (50 mL) and the mixture extracted with
CH2Cl2 (2 ꢂ 50 mL). The combined organic layers were dried
(Na2SO4) and concentrated. The residue was purified flash column
chromatography (14% EtOAc/Hexane) to give the desired product
1a (290 mg, 48%) as a yellow solid; mp 105e112 ꢀC; Rf 0.25 (20%
4.6.3. Entry 3
To a cooled (ꢁ40 ꢀC, MeCN/dry ice bath) and stirred solution of
nitroalkane 6a (100 mg, 0.418 mmol) in dry THF (5 mL) under N2
atmosphere, was added dropwise LDA (0.23 mL, 0.45 mmol). After
10 min the reaction was warmed up to (0 ꢀC) and stirred for 20 min.
The mixture was cooled to ꢁ78 ꢀC and a solution of imine 5
(127 mg, 0.615 mmol) in THF (1 mL) was added dropwise. The
remainder of the reaction was performed identical to Method 1 to
give the crude nitroamine (dr 65:35, syn-anti major) as a brown oil.
Rf 0.26 (20% EtOAc/Hexane).
EtOAc/Hexane); 1H NMR (600 MHz, CDCl3)
d 7.39e7.35 (2H, m),
4.6.4. Entry 4
7.35e7.31 (2H, m), 7.29 (1H, d, J ¼ 7.0), 6.92 (1H, d, J ¼ 9.0), 6.83 (1H,
d, J ¼ 8.8), 5.45 (1H, s, br), 5.17 (1H, s), 4.31e4.18 (2H, m), 3.77 (3H,
s), 3.64e3.59 (1H, m), 3.49 (1H, td, J ¼ 12.2, 3.0), 3.23 (1H, dt,
J ¼ 13.1, 3.3), 2.82 (1H, qd, J ¼ 12.8, 5.3), 1.99 (1H, d, J ¼ 12.2), 1.29
To a cooled (ꢁ40 ꢀC, MeCN/dry ice bath) and stirred solution of
nitroalkane 6a (100 mg, 0.418 mmol) in dry THF (5 mL) under N2
atmosphere, was added dropwise LDA (0.23 mL, 0.45 mmol). After
10 min the reaction was warmed up to (0 ꢀC) and stirred for 20 min.
The mixture was cooled to ꢁ78 ꢀC and a solution of imine 5
(127 mg, 0.615 mmol) in THF (1 mL) was added dropwise. The
mixture was stirred for 10 min. A solution of Cu(OTf)2 (222 mg,
0.615 mmol) in THF (2 mL) was added dropwise and the reaction
mixture was stirred at ꢁ78 ꢀC for 1 h. The reaction mixture was
quenched with EtOH (5 mL), diluted with EtOAc (15 mL) and
washed with EDTA (15 mL). The aqueous layer was extracted with
EtOAc (2 ꢂ 15 mL) and the combined organic layers were dried
(Na2SO4) and concentrated to give the crude nitroamine (dr > 95:5,
syn-anti major) as a brown oil. Rf 0.26 (20% EtOAc/Hexane).
(3H, t, J ¼ 7.2); 13C NMR (151 MHz, CDCl3)
d 169.3 (C]O), 154.4 (C),
144.2 (C). 139.6 (C), 128.7 (CH), 127.5 (CH), 119.9 (CH), 114.5 (CH),
86.2 (CH), 65.6 (CH), 61.9 (CH2), 55.7 (CH3), 45.2 (CH2), 40.1 (CH),
24.1 (CH2), 14.4 (CH3); FTIR (neat, film) 2955, 1713, 1545, 1507,1366,
1228 cmꢁ1; HRMS (ESI) [C21H24N2O5þH]þ calcd 385.1758, found
385.1756.
4.7.2. Ethyl 1-(4-methoxyphenyl)-3-nitro-4-(p-tolyl)piperidine-2-
carboxylate (1b)
The nitroalkane 6b (73.0 mg, 0.288 mmol) was converted to the
crude nitroamine (dr 90:10, syn-anti major) as a yellow oil ac-
cording to the general method. Rf 0.22 (25% EtOAc/Hexane); 1H
4.6.5. Entry 5
NMR (400 MHz, CDCl3) d 7.27e7.22 (4H, m), 6.70e6.67 (2H, m),
Identical to method 3 with LiHMDS (1.0 M in THF) as a base to
give the crude nitroamine (dr 70:30, syn-anti major) as a brown oil.
The residue was purified by flash column chromatography (20%
EtOAc/Hexane) to afford the desired nitroamine 2a (122 mg, 67%).
6.25e6.22 (2H, m), 5.03 (1H, dd, J ¼ 11.7, 2.6, CHNO2), 4.39e4.32
(1H), 4.28e4.20 (2H, m), 4.06 (1H, dd, J ¼ 8.7, 2.6), 3.97e3.93 (1H,
m), 3.88e3.80 (1H, m), 3.73 (3H, s), 3.21 (3H, s), 3.14 (3H, s), 2.40
(3H, s) 1.95e1.79 (2H, m) 1.41 (3H, t, J ¼ 7.2).
Rf 0.26 (20% EtOAc/Hexane); 1H NMR (600 MHz, CDCl3)
d
7.47e7.33
The crude nitroamine (134 mg, 0.288 mmol) was converted to
the crude piperidine 1b according to the general method. The
residue was purified flash column chromatography (11% EtOAc/
Hexane) to give the desired product 1b (59.0 mg, 51%) as a yellow
(5H, m), 6.69e6.64 (2H, m), 6.26e6.20 (2H, m), 5.04 (1H, dd,
J ¼ 11.7, 2.6, CHNO2), 4.40e4.33 (1H, m), 4.30e4.21 (2H, m), 4.04
(1H, dd, J ¼ 8.7, 2.6), 3.94 (1H, dd, J ¼ 8.8, 3.2), 3.89 (1H, dt, J ¼ 11.6,
3.8), 3.72 (3H, s), 3.22e3.17 (6H, m), 1.97e1.84 (2H, m) 1.42 (3H, t,
gum. Rf 0.42 (25% EtOAc/Hexane); 1H NMR (600 MHz, CDCl3)
d 7.22
8

J.C. Anderson, E. Bouvier-Israel, C.D. Rundell et al.
Tetrahedron 78 (2021) 131821
(2H, d, J ¼ 8.1), 7.18 (2H, d, J ¼ 7.9), 6.94e6.90 (2H, m), 6.86e6.80
(2H, m), 5.43 (1H, t, J ¼ 2.5), 5.15 (1H, s), 4.20e4.18 (2H, m), 3.78
(3H, s), 3.61 (1H, dd, J ¼ 12.2, 4.7), 3.49 (1H, td, J ¼ 12.2, 3.2), 3.20
(1H, dt, J ¼ 13.2, 3.7), 2.80 (1H, qd, J ¼ 12.8, 5.3), 2.35 (3H, s),
1.98e1.93 (1H, m), 1.29 (3H, t, J ¼ 7.2); 13C NMR (151 MHz, CDCl3)
4.7.5. Ethyl 4-(4-fluorophenyl)-1-(4-methoxyphenyl)-3-
nitropiperidine-2-carboxylate (1e)
The nitroalkane 6e (300 mg, 1.17 mmol) to the crude nitroamine
(dr 75:25, syn-anti major) as a brown oil according to the general
method. Rf 0.30 (20% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3)
d
169.3 (C]O),154.3 (C),144.3 (C),137.0 (CH),136.5 (CH),129.4 (CH),
d
7.33 (2H, dd, J ¼ 8.8, 5.3), 7.17e7.10 (2H, m), 6.69 (2H, d, J ¼ 8.8),
127.3 (CH), 119.9 (CH), 114.5 (CH) 86.2 (CH), 65.5 (CH), 61.9 (CH2),
55.7 (CH3), 45.2 (CH2), 39.8 (CH), 24.3 (CH2), 21.16 (CH3), 14.4 (CH3);
FTIR (neat, film) 2931, 1721, 1549, 1509, 1387, 1241 cmꢁ1; HRMS
(ESI) [C22H26N2O5þH]þ calcd 399.19150, found 399.19145.
6.24 (2H, d, J ¼ 8.8), 5.00 (1H, dd, J ¼ 11.5, 2.8, CHNO2), 4.38e4.31
(1H, m), 4.26e4.15 (2H, m), 4.07e4.00 (1H, m), 3.94e3.86 (2H, m),
3.72 (3H, s), 3.19 (3H, s), 3.14 (3H, s), 1.98e1.78 (2H, m) 1.40 (3H, t,
J ¼ 7.2).
The crude nitroamine (295 mg, 0.64 mmol) was converted to the
crude piperidine 1e according to the general method. The residue
was purified flash column chromatography (20% EtOAc/Hexane) to
give the desired product 1e (110 mg, 34%) as a yellow gum. Rf 0.27
4.7.3. Ethyl 1,4-bis(4-methoxyphenyl)-3-nitropiperidine-2-
carboxylate (1c)
The nitroalkane 6c (30.0 mg, 0.110 mmol) was converted to the
crude nitroamine (dr 90:10, syn-anti major) as a yellow oil ac-
cording to the general method. Rf 0.15 (20% EtOAc/Hexane); 1H
(20% EtOAc/Hexane); 1H NMR (600 MHz, CDCl3)
d 7.29 (2H, dd,
J ¼ 8.5, 5.3), 7.05 (2H, t, J ¼ 8.7), 6.92e6.88 (2H, m), 6.84e6.80 (2H,
m), 5.38 (1H, s, br), 5.15 (1H, s), 4.23 (2H, q, J ¼ 7.2), 3.77 (3H, s), 3.60
(1H, dd, J ¼ 12.1, 5.0), 3.46 (1H, dt, J ¼ 12.2, 3.1), 3.20 (1H, td, J ¼ 13.1,
3.6), 2.77 (1H, dq, J ¼ 12.8, 5.3), 1.94 (1H, d, J ¼ 13.7), 1.27 (3H, t,
NMR (400 MHz, CDCl3)
d 7.29e7.26 (2H, m), 7.00e6.94 (2H, m),
6.72e6.66 (2H, m), 6.26e6.22 (2H, m), 5.00 (1H, dd, J ¼ 11.7, 2.6,
CHNO2), 4.40e4.32 (1H, m), 4.28e4.20 (2H, m), 4.08 (1H, dd, J ¼ 8.8,
2.8), 3.95 (1H, dd, J ¼ 8.8, 3.3), 3.83e3.80 (1H, m), 3.73 (3H, s), 3.20
(3H, s), 3.15 (3H, s), 1.96e1.77 (2H, m) 1.41 (3H, t, J ¼ 7.2).
J ¼ 7.2); 13C NMR (151 MHz, CDCl3)
d 169.3 (C]O), 154.4 (C), 144.1
(C), 129.1 (CH), 120.0 (CH), 115.7 (CH), 115.5 (CH), 114.4 (CH), 86.1
(CH), 65.6 (CH), 62.0 (CH2), 55.7 (CH3), 45.1 (CH2), 39.5 (CH), 24.3
(CH2), 14.4 (CH3); FTIR (neat, film) 2924, 1708, 1549, 1365,
1225 cmꢁ1; HRMS (ESI) [C21H23FN2O5þH]þ calcd 403.1669, found
403.1657.
The crude nitroamine (52.4 mg, 0.110 mmol) was converted to
the crude piperidine 1c according to the general method. The res-
idue was purified flash column chromatography (14% EtOAc/Hex-
ane) to give the desired product 1c (26 mg, 57%) as a brown gum. Rf
4.7.6. Ethyl 1-(4-methoxyphenyl)-3-nitro-4-(4-nitrophenyl)
piperidine-2-carboxylate (1f)
The nitroalkane 6f (62 mg, 0.22 mmol) was converted to the
crude nitroamine (dr 70:30, syn-anti major) as a yellow oil ac-
cording to the general method. Rf 0.12 (25% EtOAc/Hexane); 1H
0.36 (20% EtOAc/Hexane); 1H NMR (600 MHz,CDCl3)
d 7.23 (2H, d,
J ¼ 8.7), 6.91e6.87 (4H, m), 6.82 (2H, d, J ¼ 9.0), 5.38 (1H, s, br), 5.12
(1H, s), 4.23 (2H, qd, J ¼ 7.2, 1.7), 3.80 (3H, s), 3.76 (3H, s), 3.62e3.58
(1H, m), 3.47 (1H, dt, J ¼ 12.2, 3.2), 3.17 (1H, td, J ¼ 13.3, 3.7), 2.79
(1H, qd, J ¼ 12.8, 5.1), 1.93 (1H, d, J ¼ 13.0), 1.27 (3H, t, J ¼ 7.2); 13
C
NMR (400 MHz, CDCl3)
d 8.29e8.24 (2H, m), 7.68e7.63 (2H, m),
NMR (151 MHz, CDCl3)
d 169.3 (C]O), 158.8 (C), 154.3 (C), 144.2
7.38e7.32 (2H, m), 6.92 (2H, dd, J ¼ 8.9, 1.9), 5.08 (1H, dd, J ¼ 10.8,
3.3, CHNO2), 4.40 (2H, q, J ¼ 7.0), 4.19e4.14 (1H, m), 4.02 (1H, dd,
J ¼ 10.8, 3.5), 3.97 (1H, dd, J ¼ 9.0, 3.5), 3.90 (1H, dd, J ¼ 8.2, 3.4),
3.83 (3H, s), 3.31 (6H, m), 1.96e1.85 (2H, m) 1.42e1.36 (3H, m).
The crude nitroamine (108 mg, 0.218 mmol) was converted to
the crude piperidine 1f as described for the synthesis of compound
2a. The residue was purified flash column chromatography (25%
EtOAc/Hexane), desired product 1f was not isolated. Rf 0.27 (25%
EtOAc/Hexane).
(CH), 131.5 (CH), 128.6 (CH), 119.9 (CH), 114.4 (CH), 114.1 (CH) 83.4
(CH), 64.8 (CH), 61.9 (CH2), 55.7 (CH3), 45.1 (CH2), 40.3 (CH), 24.8
(CH2), 14.4 (CH3); FTIR (neat, film) 2934, 1742, 1550, 1365,
1244 cmꢁ1; HRMS (ESI) [C22H26N2O6þH]þ calcd 415.1864, found
415.1864.
4.7.4. Ethyl 4-(4-bromophenyl)-1-(4-methoxyphenyl)-3-
nitropiperidine-2-carboxylate (1d)
The nitroalkane 6d (100 mg, 0.31 mmol) was converted to the
crude nitroamine (dr 80:20, syn-anti major) as a yellow oil ac-
cording to the general method. Rf 0.49 (20% EtOAc/Hexane); 1H
4.7.7. Ethyl 4-(2-methoxyphenyl)-1-(4-methoxyphenyl)-3-
nitropiperidine-2-carboxylate (1g)
Nitroalkane 6g (110 mg, 0.408 mmol) was converted to the
crude nitroamine (dr 95:5, syn-anti major) as a brown oil according
to the general method. Rf 0.22 (20% EtOAc/Hexane). Rf 0.22 (20%
NMR (300 MHz, CDCl3)
d
7.57 (2H, d, J ¼ 8.4), 7.29e7.18 (2H, m), 6.71
(2H, d, J ¼ 8.9), 6.26 (2H, d, J ¼ 8.9), 5.01 (1H, dd, J ¼ 11.4, 2.9,
CHNO2), 4.36 (1H, m), 4.20 (2H, m), 4.06e3.97 (1H, m), 3.96e3.88
(1H, m), 3.73 (3H, s), 3.19 (3H, s), 3.14 (3H, s), 2.40 (3H, s) 1.98e1.76
(2H, m) 1.39 (3H, t, J ¼ 7.2).
EtOAc/Hexane); 1H NMR (400 MHz, CDCl3)
d 7.37e7.27 (2H, m),
7.01e6.92 (2H, m), 6.71e6.66 (2H, m), 6.36e6.34 (2H, m), 5.56 (1H,
d, J ¼ 10.0), 4.30e4.15 (2H, m), 4.13e4.09 (1H, m), 4.07e4.01 (1H,
m), 3.96 (1H, dd, J ¼ 8.5, 3.3), 3.71 (3H, s), 3.19 (3H, s), 3.12 (3H, s),
2.27e2.14 (1H, m), 1.86e1.79 (1H, m) 1.37e1.32 (3H, m).
The crude nitroamine (163 mg, 0.310 mmol) was converted to
the crude piperidine 1d according to the general method. The
residue was purified flash column chromatography (11% EtOAc/
Hexane) to give the desired product 1d (35.0 mg, 24%) as a yellow
The crude nitroamine (212 mg, 0.445 mmol) was converted to
the crude piperidine 1g according to the general method. The
residue was purified flash column chromatography (11% EtOAc/
Hexane) to give the desired product 1g (56 mg, 30%) as a yellow
gum. Rf 0.68 (20% EtOAc/Hexane); 1H NMR (600 MHz, CDCl3)
d 7.48
(2H, d, J ¼ 8.5), 7.20 (2H, d, J ¼ 8.2), 6.89 (2H, d, J ¼ 9.1), 6.82 (2H, d,
J ¼ 9.1), 5.38 (1H, t, J ¼ 2.5), 5.16 (1H, s), 4.26e4.19 (2H, m), 3.76 (3H,
s), 3.61e3.57 (1H, m), 3.45 (1H, td, J ¼ 12.2, 3.2), 3.18 (1H, dt,
J ¼ 13.2, 3.7), 2.75 (1H, qd, J ¼ 12.9, 5.2), 1.94 (1H, d, J ¼ 11.8), 1.26
gum. Rf 0.56 (20% EtOAc/Hexane); 1H NMR (700 MHz,CDCl3)
d 7.35
(1H, d, J ¼ 7.0), 7.28e7.26 (1H, m), 6.99 (1H, t, J ¼ 7.5), 6.95e6.90
(2H, m), 6.88 (1H, d, J ¼ 8.2), 6.86e6.78 (2H, m), 5.64 (1H, t, J ¼ 2.2),
5.16 (1H, s), 4.29e4.19 (2H, m), 3.86 (3H, s), 3.77 (3H, s), 3.67 (1H, td,
J ¼ 12.1, 3.1), 3.59 (1H, dd, J ¼ 11.9, 4.6), 3.51 (1H, dt, J ¼ 13.5, 3.5),
2.80 (1H, qd, J ¼ 12.8, 5.1), 1.84 (1H, dd, J ¼ 12.8, 2.5), 1.31 (3H, t,
(3H, t, J ¼ 7.1); 13C NMR (151 MHz, CDCl3)
d 169.3 (C]O), 154.5 (C),
144.1 (C), 138.7 (CH), 131.8 (CH), 129.3 (CH), 121.4 (CH), 120.0 (CH),
114.5 (CH), 85.9 (CH), 65.6 (CH), 62.0 (CH2), 55.7 (OCH3), 45.1 (CH2),
39.6 (CH), 24.1 (CH2), 14.4 (CH3); FTIR (neat, film) 2925, 1722, 1549,
1510, 1242 cmꢁ1; HRMS (ESI) [C21H23N2O5Br þ H]þ calcd 463.0863,
found 463.0862.
J ¼ 7.1); 13C NMR (176 MHz, CDCl3)
d 169.3 (C]O), 156.7 (C), 154.2
(C), 144.4 (C), 128.8 (CH), 128.5 (CH), 127.3 (CH), 120.9 (CH), 119.8
(CH), 114.5 (CH), 110.0 (CH), 83.7 (CH), 65.1 (CH), 61.7 (CH2), 55.7
9

J.C. Anderson, E. Bouvier-Israel, C.D. Rundell et al.
Tetrahedron 78 (2021) 131821
(CH3), 55.4 (CH3), 45.2 (CH2), 34.7 (CH), 24.0 (CH2), 14.4 (CH3); FTIR
(neat, film) 2935, 1727, 1552, 1377, 1265 cmꢁ1; HRMS (ESI)
[C22H26N2O6þH]þ calcd 415.1864, found 415.1870.
The crude nitroamine (192 mg, 0.44 mmol) was converted to the
crude piperidine 1j according to the general method. The residue
was purified flash column chromatography (11% EtOAc/Hexane) to
give the desired product 1j (34.0 mg, 21%) as a yellow gum. Rf 0.67
4.7.8. Ethyl 4-(2-bromophenyl)-1-(4-methoxyphenyl)-3-
nitropiperidine-2-carboxylate (1 h)
(20% EtOAc/Hexane); 1H NMR (600 MHz, CDCl3)
d 7.35e7.33 (1H,
m), 6.92 (2H, d, J ¼ 9.0), 6.81 (2H, d, J ¼ 9.0), 6.35 (1H, dd, J ¼ 3.3,
1.9), 6.19e6.17 (1H, m), 5.53 (1H, t, J ¼ 3.2), 5.13 (1H, d, J ¼ 3.0),
4.20e4.14 (2H, m), 3.76 (3H, s), 3.49 (1H, d, J ¼ 3.2), 3.48 (1H, t,
J ¼ 3.5), 3.34 (1H, dt, J ¼ 12.2, 3.8), 2.52 (1H, tdd, J ¼ 12.8, 10.1, 6.9),
2.07 (1H, dd, J ¼ 13.2, 3.5), 1.22 (3H, t, J ¼ 7.1); 13C NMR (151 MHz,
The nitroalkane 6 h (60.0 mg, 0.189 mmol) was converted to the
crude nitroamine as a yellow oil according to the general method.
Rf 0.15 (20% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3)
d 7.37 (2H,
dd, J ¼ 9.0, 2.8), 6.94 (2H, m), 6.83e6.78 (2H, m), 6.76e6.69 (2H, m),
5.30 (1H, dd, J ¼ 10.2, 4.4, CHNO2), 4.42 (2H, m), 4.35e4.27 (1H, m),
4.17e4.10 (1H, m), 4.09e4.00 (2H, m), 3.20 (3H, s), 3.15 (3H, s),
2.15e2.03 (2H, m) 1.41 (3H, t, J ¼ 7.7).
CDCl3) d 169.0 (C]O), 154.7 (C), 153.3 (C), 144.1 (C), 141.6 (CH), 120.5
(CH), 114.4 (CH), 110.7 (CH), 106.1 (CH), 82.9 (CH), 64.9 (CH), 61.9
(CH2), 55.7 (CH3), 44.9 (CH2), 35.0 (CH), 24.0 (CH2), 14.3 (CH3); FTIR
(neat, film) 2932, 1725, 1553, 1511, 1267 cmꢁ1; HRMS (ESI)
[C19H22N2O6þH]þ calcd 375.1551, found 375.1550.
The crude nitroamine (89.0 mg, 0.170 mmol) was converted to
the crude piperidine 1 h according to the general method. The
residue was purified flash column chromatography (14% EtOAc/
Hexane) to give the desired product 1 h (15 mg, 19%) as a yellow
solid; mp 117e122 ꢀC; Rf 0.32 (20% EtOAc/Hexane); 1H NMR
4.7.11. Ethyl 1-(4-methoxyphenyl)-3-nitro-4-(thiophen-2-yl)
piperidine-2-carboxylate (1k)
(600 MHz, CDCl3)
d
7.58 (1H, dd, J ¼ 8.0, 1.0), 7.49e7.45 (1H, m),
The nitroalkane 6k (100 mg, 0.44 mmol) was converted to the
crude nitroamine (dr 90:10, syn-anti major) as a brown oil ac-
cording to the general method. Rf 0.15 (20% EtOAc/Hexane); 1H
7.37e7.33 (1H, m), 7.19e7.15 (1H, m), 6.96e6.91 (1H, m), 6.86e6.81
(1H, m), 5.62 (1H, br.s), 5.17 (1H, s), 4.26 (1H, qd, J ¼ 10.7, 7.2), 4.18
(1H, qd, J ¼ 10.7, 7.2) 3.77 (3H, s), 3.76e3.73 (1H, m), 3.63e3.54 (2H,
m), 2.85 (1H, dq, J ¼ 12.8, 5.3),1.91e1.86 (1H, m), 1.29 (3H, t, J ¼ 7.2);
NMR (300 MHz, CDCl3)
d
7.36 (1H, dd, J ¼ 4.9, 1.3), 7.09 (2H, dd,
J ¼ 5.1, 2.0), 6.71 (2H, d, J ¼ 8.9), 6.33 (2H, J ¼ 8.9), 5.03 (1H, dd,
J ¼ 11.3, 2.7, CHNO2), 4.29e4.18 (4H, m), 4.09 (1H, dd, J ¼ 8.6, 3.2),
3.72 (3H, s), 3.23 (3H, s), 3.19 (3H, s), 2.40 (3H, s) 2.02e1.81 (2H, m)
1.41 (3H, t, J ¼ 7.2). The dr was calculated using the crude proton
NMR of the subsequent piperidine 1k.
13C NMR (151 MHz, CDCl3)
d 168.9 (C]O), 154.4 (C), 144.0 (C). 137.9
(C), 130.5 (CH), 129.3 (CH), 127.8 (CH), 124.5 (CH), 119.9 (CH), 114.5
(CH), 86.2 (CH), 65.6 (CH), 61.9 (CH2), 55.7 (CH3), 45.2 (CH2), 40.1
(CH), 24.1 (CH2), 14.4 (CH3); FTIR (neat, film) 2955, 1713, 1545,
1507,1366, 1228 cmꢁ1; HRMS (ESI) [C21H23N2O5Br þ H]þ calcd
463.0863, found 463.0864.
The crude nitroamine (368 mg, 0.815 mmol) was converted to
the crude piperidine 1k according to the general method. The
residue was purified flash column chromatography (11% EtOAc/
Hexane) to give the desired product 1k (143 mg, 45%) as a yellow
4.7.9. Ethyl 4-(benzo[1,3]dioxol-5-yl)-1-(4-methoxyphenyl)-3-
nitropiperidine-2-carboxylate (1i)
oil. Rf 0.35 (14% EtOAc/Hexane); 1H NMR (600 MHz, CDCl3)
d 7.22
The nitroalkane 6i (263 mg, 0.93 mmol) was converted to the
crude nitroamine as a yellow oil according to the general method.
Rf (20% EtOAc in hexane) 0.26; 1H NMR (600 MHz, CDCl3)
(1H, dd, J ¼ 4.9, 1.4), 6.99e6.96 (2H, m), 6.91e6.87 (2H, m),
6.83e6.80 (2H, m), 5.43 (1H, t, J ¼ 2.9), 5.07 (1H, d, J ¼ 2.1), 4.20 (2H,
q, J ¼ 7.1), 3.76 (3H, s), 3.57e3.44 (3H, m), 2.78 (1H, ddd, J ¼ 24.7,
12.6, 5.3), 2.09 (1H, dd, J ¼ 13.1, 2.7), 1.24 (3H, t, J ¼ 7.1); 13C NMR
d
6.88e6.82 (3H, m), 6.72e6.70 (2H, m), 6.30e6.29 (2H, m), 6.03
(2H, dd, J ¼ 6.8, 1.5), 4.98 (1H, dd, J ¼ 11.5, 2.7), 4.39e4.33 (1H, m),
4.28e4.21 (2H, m), 4.15e4.10 (1H, m), 4.01 (1H, dd, J ¼ 8.8, 3.0),
3.83e3.77 (1H, m), 3.74 (3H, s), 3.22 (3H, s), 3.18 (3H, s), 1.93e1.88
(1H, m), 1.82e1.76 (1H, m), 1.41 (3H, t, J ¼ 7.1).
(151 MHz, CDCl3) d 169.0 (C]O), 154.7 (C), 144.0 (C), 143.0 (C), 127.1
(CH), 124.9 (CH), 124.4 (CH), 120.3 (CH), 114.5 (CH), 85.9 (CH), 65.4
(CH), 62.0 (CH2), 55.7 (CH3), 45.3 (CH2), 36.6 (CH), 26.4 (CH2), 14.3
(CH3); FTIR (neat, film) 2929, 1723, 1550, 1509, 1240, 700 cmꢁ1
HRMS (EI) [C19H22N2O5S þ H] calcd 391.1322, found 391.1318.
;
The crude nitroamine was converted to the crude piperidine 1i
according to the general method. The residue was purified flash
column chromatography (14% EtOAc/Hexane) to give the desired
product 1i (134 mg, 41%). Rf (30% EtOAc in hexane): 0.38; 1H NMR
4.8. Ethyl 4-(benzo[d][1,3]dioxol-5-yl)-3-nitropiperidine-2-
carboxylate (9)
(600 MHz, CDCl3)
d 6.90e6.76 (7H, m), 5.96 (2H, s), 5.37e5.35 (1H,
m), 5.11 (1H, brs), 4.22 (2H, q, J ¼ 7.2), 3.76 (3H, s), 3.61e3.57 (1H,
m), 3.45 (1H, dt, J ¼ 12.0, 3.2), 3.14 (1H, td, J ¼ 13.2, 4.0), 2.74 (1H,
dq, J ¼ 12.8, 5.2), 1.91 (1H, d, J ¼ 13.1), 1.27 (3H, t, J ¼ 7.2); 13C NMR
To a cooled (0 ꢀC) and stirred solution of 1i (25.0 mg,
0.058 mmol) in MeCN (1.00 mL) under N2 was added a solution of
CAN (80.0 mg, 0.146 mmol) in H2O (1.00 mL) dropwise. The
resulting mixture was stirred at 0 ꢀC for 30 min during which time
the colour of mixture changed from wine red to orange. The reac-
tion mixture was diluted with EtOAc (10 mL) and quenched with
10% Na2S2O3 aq. solution (10 mL). Aqueous layer was extracted with
another portion of EtOAc (10 mL) and combined organic layers
were dried (Na2SO4) and concentrated to the free piperidine 9
(16.8 mg, quant, contain small amount of hydroquinone) as a brown
oil which was used directly into next step. Rf (70% EtOAc in hexane)
0.47; FTIR (neat, cmꢁ1) 3358, 2957, 2923, 1730, 1549, 1504, 1490,
(151 MHz, CDCl3)
d 169.2 (CO2Et), 154.3 (C), 148.0 (C), 146.8 (C),
144.2 (C), 133.4 (C), 120.7 (CH), 119.9 (CH), 114.4 (CH), 108.4 (CH),
108.1 (CH), 101.2 (CH2), 86.3 (CH), 65.4 (CH), 61.9 (CH2), 55.7 (CH3),
45.2 (CH2), 39.9 (CH), 24.4 (CH2), 14.4 (CH3); FTIR (neat, film) 2904,
1731, 1551, 1511, 1487, 1238, 1037 cmꢁ1; HRMS (ESI) C22H25N2O7
[MþH]þ calcd for 429.1662, found 429.1660.
4.7.10. Ethyl 4-(furan-2-yl)-1-(4-methoxyphenyl)-3-
nitropiperidine-2-carboxylate (1j)
The nitroalkane 6j (100 mg, 0.44 mmol) was converted to the
crude nitroamine (dr 85:15, syn-anti major) as a yellow oil ac-
cording to the general method. Rf 0.40 (20% EtOAc/Hexane); 1H
1442, 1256, 1237, 1037; 1H NMR (600 MHz, CDCl3)
d 6.77 (1H, d,
J ¼ 8.0), 6.75 (1H, d, J ¼ 1.8), 6.72e6.67 (1H, m), 5.95 (2H, q, J ¼ 1.5),
5.29 (1H, dd, J ¼ 4.2, 2.1), 4.36 (1H, dq, J ¼ 10.8, 7.2, ABX3 system),
4.33 (1H, dq, J ¼ 10.8, 7.1, ABX3 system), 4.27 (1H, d, J ¼ 2.2),
3.26e3.15 (2H, m), 2.86 (1H, ddd, J ¼ 13.4, 12.1, 3.2), 2.48 (1H, qd,
J ¼ 12.7, 4.5), 1.71 (1H, dq, J ¼ 13.2, 3.3), 1.38 (3H, t, J ¼ 7.1); 13C NMR
NMR (300 MHz, CDCl3)
d
7.48 (1H, d, J ¼ 1.3), 7.39e7.33 (1H, m),
6.95e6.90 (1H, m), 6.75e6.70 (2H, m), 6.39e6.34 (2H, m), 5.14 (1H,
dd, J ¼ 11.0, 2.9, CHNO2), 4.35e4.13 (4H, m), 4.09e4.01 (1H, m), 3.72
(3H, s), 3.22 (3H, s), 3.19 (3H, s), 2.03e1.82 (2H, m) 1.36 (3H, t,
J ¼ 7.2).
(151 MHz, CDCl3)
d 170.1 (C), 148.0 (C), 147.0 (C), 133.3 (C), 120.7
(CH), 108.5 (CH), 108.0 (CH), 101.3 (CH2), 85.7 (CH), 62.4 (CH2), 59.5
10

J.C. Anderson, E. Bouvier-Israel, C.D. Rundell et al.
Tetrahedron 78 (2021) 131821
(CH), 42.4 (CH2), 40.8 (CH), 24.8 (CH2), 14.4 (CH3). HRMS not
recorded.
(600 MHz, CDCl3)
d
6.94 (2H, d, J ¼ 9.0 Hz), 6.84 (2H, d, J ¼ 9.0 Hz),
6.75 (1H, d, J ¼ 8.0 Hz), 6.71 (1H, d, J ¼ 1.8 Hz), 6.64 (1H, dd, J ¼ 8.0,
1.9 Hz), 6.02e5.91 (2H, m), 4.45 (1H, s), 4.31 (1H, dd, J ¼ 13.3,
4.1 Hz), 4.07 (2H, qd, J ¼ 7.2, 0.9 Hz), 3.89 (1H, td, J ¼ 12.2, 3.9 Hz),
3.78 (3H, s), 3.67 (3H, s), 3.28 (1H, ddd, J ¼ 11.9, 5.7, 1.8 Hz),
2.86e2.75 (1H, m), 2.53e2.28 (4H, m), 2.04e1.98 (m, 1H); 13C NMR
4.9. Ethyl 4-(benzo[d][1,3]dioxol-5-yl)-3-nitro-1-(2,2,2-
trifluoroacetyl)piperidine-2-carboxylate (10)
To a cooled (ꢁ10 ꢀC) and stirred solution of above free piperidine
(151 MHz, CDCl3) d 172.7 (CO2), 168.8 (CO2), 155.2 (ArC), 147.7 (ArC),
9 in CH2Cl2 (1.00 mL) under N2 was added TFAA (10
mL, 0.070 mmol)
147.3 (ArC), 143.1 (ArC), 131.4 (ArC), 122.9 (ArCH), 120.5 (ArCH),
114.6 (ArCH), 109.6 (ArCH), 108.3 (ArCH), 101.3 (CH2), 94.8 (C), 64.2
(CH), 60.9 (CH2), 55.7 (CH3), 52.1 (CH3), 44.3 (CH2), 43.7 (CH), 28.8
(CH2), 28.5 (CH2), 24.81 (CH2), 14.1 (CH3). HRMS (ESI-TOF, m/z)
calcd. For C26H31N2O9 [MþH]þ 515.2029, found 515.2023.
and pyridine (5.5 mL, 0.070 mmol) and the resulting mixture was
stirred at this temperature for 10 min. The reaction was quenched
with 1 M HCl aq (5.0 mL) and extracted with CH2Cl2 (10 mL).
Combined organic layers were dried (Na2SO4) and concentrated.
Chromatography of reside on silica gel, using 30% EtOAc in hexane,
gave 10 (20.0 mg, 83% overall) as a colourless oil. Rf (30% EtOAc in
hexane) 0.32; FTIR (neat, cmꢁ1) 2984, 2908, 1742, 1697, 1554, 1506,
1491, 1446, 1235, 1205, 1170, 1147; HRMS (ESI-TOF); 1H NMR
(400 MHz, CDCl3) a mixture of diastereomers, dr 85:15; major
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
isomer:
d
6.77 (1H, d, J ¼ 7.8), 6.70e6.59 (2H, m), 5.96 (2H, s), 5.89
(1H, t, J ¼ 1.7), 5.49e5.42 (1H, m), 4.47e4.17 (3H, m), 3.39 (1H, ddd,
J ¼ 14.3, 13.0, 2.9), 3.19 (1H, dt, J ¼ 13.3, 3.4), 2.67 (1H, qd, J ¼ 13.3,
4.4), 1.92e1.78 (1H, m), 1.36 (3H, t, J ¼ 7.1); 13C NMR (101 MHz,
Acknowledgments
CDCl3)
d
166.0 (C), 157.2 (q, J ¼ 37.2, C(O)CF3), 148.3 (C), 147.6 (C),
This work was supported by the Engineering and Physical Sci-
ences Research Council (CDR), the China Scholarship Council (XZ),
Erasmus scheme (EI) and University College London.
130.9 (C), 120.5 (CH), 116.3 (q, J ¼ 287.4, CF3), 108.8 (CH), 107.5 (CH),
101.4 (CH2), 84.5 (CH), 63.5 (CH2), 55.5 (CH), 43.4 (CH2), 41.2 (CH),
23.8 (CH2), 14.2 (CH3); 19F NMR (282 MHz, CDCl3)
d
ꢁ67.90 (minor
isomer), ꢁ68.97 (major isomer). HRMS (ESI-TOF, m/z) calcd. For
Appendix A. Supplementary data
C
17H18N2O7F3 [MþH]þ 419.1066, found 419.1047.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131821.
4.10. 4-(benzo[d][1,3]dioxol-5-yl)-1-(4-methoxyphenyl)-3-
nitropiperidin-2-yl)-methanol (11)
References
To a cooled (0 ꢀC) and stirred solution of ester 1i (130 mg,
0.30 mmol) in THF (5.00 mL) was added LiBH4 (20.0 mg, 0.91 mmol)
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10 min and then at room temperature until full consumption of
starting material. The reaction mixture was cooled to 0 ꢀC and
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were dried (Na2SO4) and concentrated to give alcohol 11 (104 mg,
90%) as a white foam. Rf (33% EtOAc in hexane) 0.25; FTIR (neat,
cmꢁ1) 3385, 2894, 1545, 1501, 1238, 1037; 1H NMR (600 MHz,
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Org. Chem. 8 (2012) 567;
4.45e4.40 (1H, m), 3.92e3.89 (2H, m), 3.77 (3H, s), 3.63e3.60 (1H,
m), 3.33 (1H, q, J ¼ 4.2 Hz), 3.31e3.29 (1H, m), 2.86 (1H, dq, J ¼ 12.6,
4.8 Hz), 1.91e1.89 (1H, m), 1.67 (1H, t, J ¼ 5.4 Hz); 13C NMR
(f) P. Jakubec, A. Hawkins, W. Felzmann, D.J. Dixon, J. Am. Chem. Soc. 133
(2012) 17482.
(151 MHz, CDCl3) d 154.0 (ArC), 148.0 (ArC), 146.9 (ArC), 144.0 (ArC),
133.2 (ArC), 120.8 (ArCH), 119.1 (ArCH), 114.7 (ArCH), 108.5 (ArCH),
108.1 (ArCH), 101.2 (CH2), 85.7 (CH), 63.3 (CH), 58.4 (CH2), 55.7
(CH3), 43.7 (CH2), 38.8 (CH), 24.2 (CH2). HRMS (ESI, m/z) calcd. for
[10] A. Noble, J.C. Anderson, Chem. Rev. 113 (2013) 2887.
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(b) J.C. Anderson, L.R. Horsfall, A.S. Kalogirou, M.R. Mills, G.J. Stepney,
G.J. Tizzard, J. Org. Chem. 77 (2012) 6186;
C
20H23N2O6 [MþH]þ 387.1566, found 387.1567.
(c) J.C. Anderson, A. Noble, D.A. Tocher, J. Org. Chem. 77 (2012) 6703;
(d) J.C. Anderson, A. Noble, P. Ribelles Torres, Tetrahedron Lett. 53 (2012)
5707;
(e) J.C. Anderson, A.S. Kalogirou, M.J. Porter, G.J. Tizzard, Beilstein J. Org. Chem.
9 (2013) 1737;
(f) J.C. Anderson, J.P. Barham, C.D. Rundell, Org. Lett. 17 (2015) 4090;
(g) J.C. Anderson, I.B. Campbell, S. Campos, J. Shannon, D.A. Tocher, Org. Bio-
mol. Chem. I (2015) 170;
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G.J. Tizzard, Org. Biomol. Chem. 14 (2016) 8270;
4.11. Ethyl -4-(benzo[d][1,3]dioxol-5-yl)-3-(3-methoxy-3-
oxopropyl)-1-(4-methoxy-phenyl)-3-nitropiperidine-2-carboxylate
(12)
To a stirred solution of 1i (50.0 mg, 0.117 mmol) in MeCN
(1.00 mL) was added methyl acrylate (0.03 mL, 0.035 mmol) and
Triton-B (40% w/w in MeOH, 2 drops) and the resulting solution
was stirred at room temperature overnight. The reaction mixture
was quenched with sat. NH4Cl aqueous solution (10.0 mL) and
extracted with EtOAc (10.0 mL x 2). The combined organic layers
were dried (Na2SO4) and concentrated. Chromatography of the
residue on silica gel, using 20% EtOAc in hexane, gave 12 (21.0 mg,
35%) as a yellow solid. Rf (20% EtOAc in hexane) 0.14; FTIR (neat,
cmꢁ1) 2958, 1731, 1542, 1508, 1487, 1440, 1239, 1191, 1037; 1H NMR
(i) J.C. Anderson, C.D. Rundell, Synlett 27 (2016) 41;
(j) A. Abil, J.C. Anderson, M. Corpinot, E.S. Gascoigne, J. Tetrahedron 74 (2018)
5458.
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Chem. 76 (2011) 1961.
[13] Attempted preparations of the novel dialkyl zinc reagent 3 were by trans-
metallation with ZnCl2 (related to Nitz, T. J.; Montalbetti, C.; Mears, R.; Gai, X.;
Glen, E. WO Patent 57420, 2008) of the known Grignard (Gallen, C. M.; Wil-
liams, C. M. Org. Lett. 2008, 10, 713) and metathesis with diethylzinc (Rozema,
M. J.; Sidduri, A.; Knochel, P. J. Org. Chem. 1992, 57, 1956) of the parent iodo
11

J.C. Anderson, E. Bouvier-Israel, C.D. Rundell et al.
Tetrahedron 78 (2021) 131821
compound.
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[14] H. Gotoh, H. Ishikawa, Y. Hayashi, Org. Lett. 9 (2007) 5307. We repeated the
preparation of 6 from this paper and achieved identical results (80% yield, 93%
ee).
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9932;
(b) J.C. Anderson, G.P. Howell, J. Org. Chem. 70 (2005) 549.
[17] Ordinarily these two diastereoisomers make up >90% of the product mixture.
The stereochemical assignment of the two diastereoisomers was by exami-
nation of the magnitude of the coupling constants for the CHNO2 proton.
These can be correlated to single crystal X-ray structure determinations of
analogous syn,anti- and syn,syn- sructures (see reference 11)
[18] T. Tsunoda, M. Suzuki, R. Noyoro, Tetrahedron Lett. 20 (1979) 4679.
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(2012) 1516.
[26] R. Menicagli, S. Samaritani, Tetrahedron 52 (1996) 1425.
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12