Conjugate addition nitro-Mannich reaction of carbon and heteroatom nucleophiles to nitroalkenes

Article abstract of DOI:10.1016/j.tet.2014.10.042

The conjugate addition nitro-Mannich reactions of ethyl-β-nitroacrylate (1) and β-nitrostyrene (2) with electron rich aromatic nucleophiles, stabilized carbanions, alcohols, amines, thiols, and diphenyl phosphine oxide were investigated. The one pot conju

Full text of DOI:10.1016/j.tet.2014.10.042

Tetrahedron xxx (2014) 1e15
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Conjugate addition nitro-Mannich reaction of carbon and
heteroatom nucleophiles to nitroalkenes
,
a
b,
y
James C. Anderson a , Andreas S. Kalogirou , Graham J. Tizzard
*
a Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
b National Crystallography Service, School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The conjugate addition nitro-Mannich reactions of ethyl-b-nitroacrylate (1) and b-nitrostyrene (2) with
Received 19 August 2014
Received in revised form 7 October 2014
Accepted 17 October 2014
Available online xxx
electron rich aromatic nucleophiles, stabilized carbanions, alcohols, amines, thiols, and diphenyl phos-
phine oxide were investigated. The one pot conjugate addition nitro-Mannich reaction was unsuccessful
except for the addition of alkoxides to 2 in alcohol as solvent. Isolation of the conjugate addition products
followed by deprotonation with nBuLi and treatment with a simple imine in the presence of TFA led to
b-
nitroamine derived products. Products derived from 1 spontaneously cyclised in only a few examples and
on the whole led to inherently unstable products. Products derived from 2 were isolated as their tri-
fluoroacetamides, gave good yields of single diastereoisomers for aromatic and alkoxide nucleophiles
and the structures were verified by single crystal X-ray crystallography. Products derived from amine
nucleophiles were isolated in low yields while sulfur nucleophiles gave poor diastereoselectivities.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Nitro-Mannich reaction
Nitroalkenes
Conjugate addition
Diastereoselective
Contiguous stereocentres
1. Introduction
Nitro-Mannich reaction
R3
N
NO2
The nitro-Mannich reaction has emerged as a powerful method
for the construction of CeC bonds with control of up to two con-
R2
O
O
R2
R3
NO2
base
N
R1
R1
R1
tiguous CeN stereocentres in the
b-nitroamine products
H
HN
R3
(Scheme 1).1 The product
b-nitroamines have emerged as flexible
Conjugate addition nitro-Mannich reaction
synthetic building blocks due to the complimentary oxidation
states of the two nitrogen atoms. They have been used in the
synthesis of many nitrogen containing functional groups including
R3
R2
N
Nu HN
NO2
Nu
R2
NO2
R1
R1
Nu
NO2
R1
Nu = H, R or
Heteroatom
a
-amino carbonyls,2,3 1,2-diamines,4e7 peptidomimetics,8 natural
products9e15 and many heterocyclic small molecules.16e28 To ad-
dress the paucity of structurally diverse nitroalkanes we have de-
veloped conjugate addition nitro-Mannich protocols (Scheme
1).29e31 The use of nitroalkenes (prepared via the Henry reaction)
provides easy access to more structurally complex nitro coupling
H
Scheme 1.
nitroamines.31 Enantioselective 1,4-addition of dialkylzincs to
nitroalkenes generated zinc nitronates, which when reacted with
partners, thereby generating b-nitroamines with higher levels of
functionality, which may be further manipulated to produce
a range of useful intermediates. The 1,4-addition of nucleophiles to
nitroalkenes generates a nitronate species, which can undergo
a subsequent nitro-Mannich reaction with a suitable imine. The use
of a Hantzsch ester as a hydride source and a simple chiral thiourea
organocatalyst to catalyse the reductive nitro-Mannich reaction,
an imine gave complex
b-nitroamines with excellent diaster-
eocontrol over three contiguous stereocentres.29 Two distinct ste-
reochemical outcomes were possible, dependent upon the choice
of solvent, which dictated whether the reaction was homogeneous
or heterogeneous. We extended this strategy to the addition of
diorganozinc nucleophiles to ethyl-b-nitroacrylate, the products of
gave access to enantio-enriched and structurally diverse
b-
which spontaneously lactamized in situ to give densely substituted
pyrrolidin-2-ones.26 Up to the present time, the conjugate addition
nitro-Mannich methodology has been limited to the use of dio-
rganozinc and hydride reagents. We thought that the use of more
* Corresponding author. Tel.: þ44(0)2076795585; e-mail address: j.c.anderson@
ucl.ac.uk (J.C. Anderson).
y
Corresponding author for crystallographic results. E-mail: gjt1@soton.ac.uk.
http://dx.doi.org/10.1016/j.tet.2014.10.042
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042

2
J.C. Anderson et al. / Tetrahedron xxx (2014) 1e15
readily available carbon nucleophiles and especially heteroatom
nucleophiles would greatly increase the versatility of the conjugate
addition nitro-Mannich reaction.
O
O
Conditions
ð3Þ
+
ROH
EtO
NO2
EtO
NO2
1
OR
2. Results and discussion
Table 1
1,4-addition of ROH to nitroacrylate 1
A number of heteroatom nucleophiles are known to add to
nitro-alkenes. Furthermore, possible modification of the Nu group
in the final products could enable further applications in target
synthesis. From the large number of possible nucleophiles, we
concentrated on a representative sample of carbon, oxygen, nitro-
gen, sulfur and phosphorus nucleophiles. The scope of nitroalkenes
that could be used is potentially large, so for this investigation we
Entry
ROH/conditions
Compound
Yield/%a
1
2
3
MeONa/MeOH added to 1, rt
1 added to MeONa/MeOH, rt
1 added to MeONa/MeOH, ꢀ78 ꢁC
MeOH, reflux
d
6
6
6
7
d
62
80
85
89
62
d
d
d
d
4
5
6
EtOH, reflux
BnOH, 100 ꢁC
8
selected to study the reactions of ethyl-b-nitroacrylate (1) and b-
7
PhOH/PhMe, rt
d
d
d
d
nitrostyrene (2), as we have used both of these extensively in
8
PhOH/PhMe, reflux
previous studies.26,29e31
9
10
PhOH/PhMe, K2CO3 (0.3 equiv), rt
PhOH, melt (70 ꢁC)
We investigated the 1,4-addition reactions to nitroacrylate 1
first. The addition of electron rich aromatics such as indole de-
rivatives to 1 is known to be promoted by CeCl3/NaI supported on
silica.32 There also exists an organocatalysed asymmetric pro-
tocol.33 Synthesis of the indole addition product 3 was straight-
forward (91%) and the literature conditions could also be used with
trimethoxybenzene to give 4 in 87% yield (Eq. 1).
a
Isolated yields.
The 1,4-addition of nitrogen nucleophiles was subsequently
investigated. Simply mixing nitroacrylate 1 with simple substituted
amines in most cases gave fast and clean reactions (Eq. 4, Table 2).
Reactions with hydrazine and ammonia were unsuccessful, as was
reaction with oxazolidin-2-one, which was surprising as it is
known to add to simple nitroalkenes quite readily.36
O
O
EtO
NO2 EtO
MeO
NO2
CeCl3/NaI/SiO2
MeCN
O
O
O
OMe
ð1Þ
CH2Cl2
ð4Þ
EtO
NO2
R1R2NH
+
EtO
NO2
EtO
NO2
NR1R2
NH
1
1
+ ArH
3, 91%
4, 87% OMe
Table 2
1,4-addition of substituted amines to nitroacrylate 1
The attempted addition of some stabilized nucleophiles derived
from Meldrum’s acid, malononitrile and diethyl malonate under
neutral conditions, with a variety of amines and NaH were all un-
successful. By analogy to an example in the literature though 1,3-
cyclohexanedione in the presence of Et3N led to the addition
product 5 in nearly quantitative yield (Eq. 2).34
Entry
R1R2NH (equivs.)
T/ꢁC
t/h
Compound
Yield/%a
1
2
3
p-MeOPhNH2 (1.8)
Morpholine (1.2)
BnNH2 (1.1)
rt
rt
0
24
1
1
9
10
11
98
98
81
a
Isolated yields.
O
In a similar manner the 1,4-addition of 1H-benzotriazole (12)
was attempted, but gave no reaction. In the presence of catalytic
Et3N (0.1 equiv) product 13, derived from elimination of HNO2 from
the desired addition product, was isolated in 47% yield (Eq. 5).
Elimination of HNO2 from nitroalkanes under basic or acidic con-
ditions has been reported and in this case is exacerbated by the
acidifying effect of the ester group.37
O
O
EtO
O
NO2
OH
Et3N (1 equiv.)
MeOH, 0 oC
+
NO2
ð2Þ
EtO
1
O
5, 99%
The 1,4-addition of oxygen nucleophiles to nitroalkenes is well
documented,35 so the corresponding additions of alcohols to
nitroacrylate 1 were investigated (Eq. 3). Addition of a solution of
MeONa in MeOH (0.10 M) to a solution of nitroacrylate at rt, gave
only degradation of the starting material (baseline on TLC). This
result was attributed to base-catalysed polymerization. Reversing
the addition mode led to the formation of the 1,4-addition product
6 in 62% yield, after quenching with AcOH and aqueous workup
(entry 2, Table 1). Performing the same reaction at ꢀ78 ꢁC gave 6 in
an improved 80% yield (entry 3). Furthermore, when nitroacrylate 1
was refluxed in MeOH for 24 h, 6 was isolated in 85% yield (entry 4).
It was found that activation of the nitroacrylate 1 under acidic
conditions was ineffective in promoting the conjugate addition of
alcohols. Other simple alcohols EtOH and BnOH when refluxed
with 1 gave the corresponding addition products 7 and 8 in 89% and
62% yield, respectively (entries 5 and 6). Reaction with phenol was
unsuccessful (entries 7e10) as was attempts at the 1,4-addition of
H2O/hydroxide ion.
O
O
N
EtO
CH2Cl2
N
+
NO2
EtO
N
ð5Þ
Et3N (0.1 equiv)
N
H
N
1
N
12
13, 47%
The conjugate addition of a sulfur and a phosphorus nucleo-
phile was also investigated. Despite following the literature pre-
cedent with 1-propanethiol,38 treatment of nitroacrylate 1 with 1-
butanethiol in the presence of catalytic Et3N led to consumption of
starting material over 24 h, but again gave elimination of HNO2 to
give 14 in 38% yield (Eq. 6). Repeating the reaction in the absence
of base, with 1-butanethiol (1.00 equiv), in EtOH, at rt, was much
faster (consumption of starting material in 10 min), but again
failed to provide the desired product. Only a baseline spot was
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042

J.C. Anderson et al. / Tetrahedron xxx (2014) 1e15
3
Table 3
observed on TLC indicating degradation, presumably due to
polymerisation.
1,4-additions of carbon nucleophiles to
b
-nitrostyrene (2)
Compound
Entry
NuH/conditions
Yield/%a
O
O
HN
THF
EtO
+
NO2
EtO
ð6Þ
SH
Et3N (0.4 equiv)
S
1
32
1
Indole, CeCl3/NaI/SiO2
92
NO2
14, 38%
16
Simple addition of diphenylphosphine (1.10 equiv) to a solution
OMe
of 1 in THF, at rt, led to complete consumption of the starting
material in 20 min. It was not possible to isolate any product, due to
instability to purification. As phosphines are prone to oxidation we
repeated the reaction with diphenylphosphine oxide. The reaction
was slower (completed in 17 h), but unfortunately the only product
isolated was the eliminated product 15 in 56% yield (Eq. 7).
32
2
2,4,6-(MeO)3Ph, CeCl3/NaI/SiO2
71
MeO
OMe
NO2
17
O
MeO2C
CO2Me
NO2
O
O
P
EtO
Ph
THF, rt
3
4
5
6
7
CH2(CO2Et)2, NaH, THF39
96
d
89
d
34
ð7Þ
+
NO2
Ph
EtO
H
P
Ph
O
1
Ph
18
15, 56%
CH2(CN)2, NaH, 15-crown-5, THF
CH2(CN)2, proline, DMF40
d
Investigations into the 1,4-addition of a similar series of nucle-
ophiles to -nitrostyrene (2) were generally more successful. Re-
action with electron rich aromatics and stabilized carbon
nucleophiles worked well in most cases to give the desired prod-
ucts (Eq. 8, Table 3).
NC
CN
NO2
b
19
1,3-cyclohexadione, Et3N, THF
d
Nu
NO2
Conditions
NO2
+
Nu-H
ð8Þ
O
O
NO2
2
1,3-cyclohexadione,
MeONa, MeOH41
2
20
Incontrasttothe 1,4-additionofsimplealcoholsto nitroacrylate1,
refluxof -nitrostyrene (2) in methanol gave no reaction (Eq. 9, Table
b
4, entry 1). Attempts at an acid catalysed 1,4-addition of MeOH were
also ineffective (entries 2,3). Addition of MeONa was much more
successful with treatment in MeOH giving the highest yield of 22
(entries 4e6).44 The optimized conditions were then applied to
O
O
O
42
O
8
Meldrum’s acid, Et3N, CH2Cl2
96
NO2
t
a range of other simple alcohols (entries 7e9). The use of BuOH
21
(mp¼23e26 ꢁC) as the solvent required warming to 30 ꢁC, which led
to a poor yield of 1,4-addition product 26 (entry 10). Using THF as
a cosolventwasmuch moreeffectivegiving 26in40%yield(entry14).
9
1-phenylvinyl trimethylsilyl ether,
d
d
TBAF, THF ꢀ45 ꢁC43
a
Isolated yields.
OR
NO2
Conditions
NO2
ð9Þ
+
ROH
2
Table 4
1,4-addition of ROH to
b
-nitrostyrene (2)a
Entry
ROH/conditions
Compound
Yield/%b
For entry 13 (Table 4) although TLC indicated complete con-
sumption of starting material to the 1,4-addition product 26, after
work up with saturated aqueous NH4Cl only a trace of 26 was ob-
served. Instead there was a complex mixture of degradation
1
2
3
4
5
6
7
8
MeOH, reflux, 22 h
MeOH, TFA (10 equiv)
MeOH, H2SO4 (2 equiv)
MeONa, 15-crown-5, THF
MeONa, MeOH, Et2O
MeONa, MeOH
d
d
d
d
53
62
73
66
66
58
9
d
d
22
22
22
23
24
25
26
products among, which we could identify benzaldehyde and
b-
nitrostyrene (2). While the formation of 2 can be readily explained
EtONa, EtOH
t
by base catalysed elimination of BuOH, the presence of benzalde-
BnONa, BnOH
iPrONa, iPrOH
hyde can be explained by elimination of 2-methylpropene and ni-
tromethane (Eq. 10).
9
10
11
12
13
14
tBuONa, tBuOH
tBuONa, tBuOH, DMF
tBuONa, 18-crown-6, THF
Degradationc
Degradationc
2 and PhCHO
26
d
d
d
40
tBuONa, (0.53 M in BuOH), THFd
t
tBuONa, (0.53 M in BuOH), THF
t
O
O
O
a
H
O
ð10Þ
Alkoxide (1 equiv) and reactions quenched with AcOH (6 equiv).
Isolated yields.
Baseline by TLC.
b
c
+
+
NO2
N
d
Reaction quenched with satd. aq. NH4Cl.
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042

4
J.C. Anderson et al. / Tetrahedron xxx (2014) 1e15
The 1,4-addition of amines required some investigation, but
anisidine added directly to 1 (Eq. 4, Table 2) and we repeated this
reaction in the presence of imine 37 to explore whether the in-
termediate nitronate species 38 would undergo a nitro-Mannich
reaction to give 39 and whether this would cyclise spontaneously
or otherwise to 40 (Scheme 3). We hoped that the acidic proton in
38 would be able to protonate imine 37 to facilitate the nitro-
Mannich reaction.4
a number of different substrates could be synthesized (Eq. 11,
Table 5). While stirring with electron rich 2,4-dimethoxyaniline
gave a good yield of 1,4-addition product 27 (70%, Entry 1), the
less nucleophilic parent aniline was unreactive (Entry 2). By anal-
ogy to the literature, performing the reaction in water worked well
(68%, Entry 3).45 The electron withdrawn para-nitroaniline was
unreactive under both sets of conditions, but deprotonation with
nBuLi and subsequent addition to nitroalkene 2 gave the desired
1,4-addition product 29 in 45% yield (entry 4). Reaction with mor-
pholine in CH2Cl2 at rt gave complete consumption of starting
material, but only a small yield (22%) of 1,4-addition product 30 was
isolated (entry 5). Performing the reaction in the presence of cat-
alytic Sm(OTf)3 (0.2 equiv)46 was much more successful leading to
a 94% yield of the addition product 30 (entry 6). The reaction of 2
with hydrazine in MeOH led to degradation. A solution of ammonia
in THF gave no addition product, while saturating a solution of 2
with ammonia gas caused degradation. Reaction with benzo-
triazole (12) in CH2Cl2 at rt gave isolation of the 1,4-addition
product in good 83% yield (entry 7). Reaction with 2-
NH
2
PMP
N
O
O
37
OMe
Ph
EtO
NO2
PMP
conjugate
addition
EtO
NO2
EtO
nitro-Mannich
H2N
38
1
H
N
O
O
NO2
lactam
formation
PMP
Ph
N
PMP
NH HN
O2N
PMP
PMP
Ph
39
40
t
Scheme 3. Investigation of desired reaction (PMP¼p-methoxyphenyl).
oxazolidinone required deprotonation with BuOK and 18-crown-
6 (entry 8).36
Mixing of the reactants in PhMe only led to isolation of the 1,4-
addition product 9 (tautomer of 38) in 86% yield. Repeating the
reaction in CH2Cl2 at rt or reflux led to quantitative conversion to 9.
The addition of acid was investigated by mixing the reactants in
THF and adding TFA (3 equiv to 1), but this again gave 9 in 93% yield
after 24 h. The use of the more electrophilic p-tosylimine and other
nucleophiles: morpholine, phenol and 1-butanethiol were all sur-
veyed under a variety of different conditions, but were all
unsuccessful.
NR1R2
NO2
Conditions
NO2
R1R2NH
ð11Þ
+
2
Table 5
1,4-addition of amines to
b
-nitrostyrene (2)
Entry
R1R2NH/conditions
Compound
Yield/%a
1
2
3
4
5
6
7
8
2,4-diMeOPhNH2/CH2Cl2
PhNH2/CH2Cl2
PhNH2/H2O
27
d
70
d
In light of these results we decided to investigate a two step
process where the 1,4-addition product was deprotonated with
nBuLi to form a nitronate species, and then imine and acid added.
We were pessimistic of this strategy due to perceived problems
28
29
30
30
31
32
67
45
22
94
83
90
4-NO2PhNH2/nBuLi/THF
HN(CH2CH2)2O/CH2Cl2
HN(CH2CH2)2O/Sm(OTf)3/CH2Cl2
12/CH2Cl2
with
b
-elimination of the 1,4-addition products. However reaction
carbon nucleophiles gave
of 3 and 4 derived from electron rich
p
2-Oxazolidinone/tBuOK/18-C-6/THF
highly functionalized pyrrolidinones in moderate yields, but as
single diastereoisomers (Eq. 12).
a
Isolated yields.
H
N
O
The conjugate addition of thiols proceeded by analogy to the
literature and gave the sulfides 33 and 34 by the smooth addition of
1-butanethiol and thiophenol, respectively (Scheme 2). Sulfide 34
was also oxidized to its corresponding sulfone by OxoneÒ in MeOH/
H2O37 to give 35 in 97% yield. Treatment of 2 with diphenylphos-
phine oxide gave the 1,4 addition product 36 in 89% yield.
O
N
PMP
i) nBuLi (1 equiv)
41, 53%
O2N
EtO
NO2
ii) 37, (2 equiv)
iii) TFA (3.5 equiv) MeO
Ph
ð12Þ
R
OMe
3, R = 3-indolyl
4, R = 2,4,6-(MeO)3Ph
O
SR
RSH, EtOH
NO2
33 R = nBu, 95%
34 R = Ph, 97%
35 SO2Ph, 97%
N
PMP
MeO
O2N
Et3N
(0.05 equiv.)
42, 53%
NO2
Ph
Oxone
O
2
Ph2P
It would be highly unlikely for the aromatic side chains in 3 and
(Ph)2P(O)H, THF
NO2
36, 89%
4 to b-eliminate. Nitroalkane 5 could eliminate a stabilized anion,
but reacted under similar conditions (2.1 equiv nBuLi to sequester
the enolic proton) to give the 6-membered octahydroquinoline 43
as opposed to the 5-membered lactam (Eq. 13).
Et3N
(0.05 equiv.)
Scheme 2.
With a variety of 1,4-addition reactions with ethyl-
b-nitro-
acrylate (1) and -nitrostyrene (2) characterized for a range of non
b
O
O
NO2
N
diorganozinc nucleophiles, we first investigated whether it was
feasible to conduct a conjugate addition nitro-Mannich reaction
with 1. Our previous work with diorganozinc nucleophiles to 1 gave
products, which had spontaneously lactamized in situ to give
densely substituted pyrrolidin-2-ones.26 We had shown that p-
Ph
i) nBuLi (2 equiv)
EtO
O
EtO
HO
NO2
O
ð13Þ
ii) 37, (2 equiv)
iii) TFA (3.5 equiv)
PMP
5
43, 38%
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042

J.C. Anderson et al. / Tetrahedron xxx (2014) 1e15
5
relevant internuclear distances gave us confidence in assigning the
stereochemistry of 43 as drawn (Table 6).48 The cis/trans stereo-
chemistry of 43 was the closest fit to the spectroscopic data.
The stereochemical outcome of the five products formed in this
reaction are all tentatively derived from a syn, anti-diastereoisomer
Investigation of the nitro-Mannich reaction of the remaining
1,4-addition products to ethyl- -nitroacrylate (1) derived from O, N,
b
S or P nucleophiles were not encouraging. The only products iso-
lated were 44 (42%) and 45 (7%), with the other substrates giving
a complex mixture of products. Both 44 and 45 were unstable, both
degrading afterw30 min at rt, probably because of the electron
donating substituent at C-3 of the pyrrolidinone (Scheme 4).
of the precursor b-nitroamine. As we determined in our previous
study of dialkyl zinc additions to 1,26 although the other di-
astereoisomers may form in the nitro-Mannich reaction they are in
equilibrium through a retro-re-addition reaction and it is only the
syn, anti-diastereoisomer that seems to cyclise in a rate de-
termining and irreversible lactamisation.
O
R
i) nBuLi (1 equiv)
O
N
PMP
EtO
6, R = OMe
NO2
ii) 37, (2 equiv)
iii) TFA (3.5 equiv)
We then surveyed the use of the 1,4-addition products derived
from b-nitrostyrene (2) in nitro-Mannich reactions. The 1,4-addition
O2N
R
Ph
44, R = OMe, 42%
reactions had required many different reaction protocols and each
protocol was tested with a representative nucleophile for in situ
nitro-Mannich addition reactivity by adding imine 37 and TFA to the
reaction mixtures. All except one example of the addition of NaOMe
were unsuccessful (vide infra). As above we then investigated the
two pot procedure for all of the 1,4-additionproducts derived from 2.
10, R = N(CH2CH2)2O
45, R = N(CH2CH2)2O, 7%
O
X
possible
degradation
pathway
PMP
O
X
N
N
PMP
O2N
O2N
Ph
Ph
The derivatives derived from electron rich
p carbon nucleo-
Scheme 4. Investigation of desired reaction (PMP¼p-methoxyphenyl).
philes 16 and 17 were reacted under standard nitro-Mannich
conditions with nBuli, imine 37 and TFA. Upon workup 1H NMR
showed good conversion and excellent diastereoselectivity (95:5).
Like the pyrrolidinones synthesised in our previous work, the
lactams here were all isolated as single diastereoisomers. Although
we could not obtain a single crystal X-ray structure determination,
the J3 coupling constants between the ring protons are in range with
those observed previously. This suggests that the major di-
astereoisomer formed from the nitro-Mannich reaction is the usual
syn, anti-diastereoisomer and that this is disposed towards favour-
able cyclisation to a pyrrolidinone product. This tentative stereo-
chemical assignment is supported by the relative stereochemistry of
piperidine 43. One dimensional nOe experiments and analysis of the
J3 coupling constants around the piperidine ring were not definitive
(Fig. 1). Coupling constant JH2-H3 is large, suggesting a trans re-
lationship, while JH3-H4 is of a medium value suggesting a cis re-
lationship. This concurs with the large nOe enhancement of 3.2% for
H3 upon irradiation of H4. However the small nOe observed at H2
upon irradiation of H4 is ambiguous. Although if H2 and H4 were cis,
we would expect a JH3-H4 to be similar to JH2-H3, and a strong nOe
enhancement to exist between them. Molecular modelling of each
diastereoisomer and calculation of their coupling constants and
These sensitive b-nitroamine products were isolated as their tri-
fluoroacetamides 46 and 47 as single diastereoisomers in 50% and
83% yields, respectively (Scheme 5). A single crystal X-ray structure
determination of 47 verified the anti, anti relative stereochemis-
try.49 The indole derivative 46 was not crystalline, but the coupling
constants between the alkane CeH protons were similar, so we also
assigned that as the anti, anti-diastereoisomer.
H
N
O
PMP
N
CF3
PMP
Ph
R
NO2
R
HN
ii
i
NO2
46, 50%
Ph
MeO
MeO
NO2
16, R = 3-indolyl
17, R = 2,4,6-(MeO)3Ph
R = 3-indolyl,
conv. 63%, dr 95:5
R = 2,4,6-(MeO)3Ph,
conv. 84%, dr >95:5
O
OMe
PMPN
CF3
NO2
+0.6%
+3.2%
47, 83%
H
NO2
Scheme 5. Reagents and conditions (i) nBuLi, THF -78 ꢁC; 37, TFA; (ii) TFAA, Py, CH2Cl2, rt.
H
H
Ph
JH2-H3 = 8.7 Hz
JH2-H4 = 5.3 Hz
EtO2C
O
3
4
2
N
PMP
In contrast the other 1,4-addition products derived from stabi-
lised carbon nucleophiles did not undergo the nitro-Mannich re-
action. Reaction of malonate 18 and the malononitrile 19 gave only
recovered starting materials. Cyclohexanedione 20 and Meldrums
Fig. 1. Values of nOe enhancements and coupling constants for 43.
Table 6
Calculated selected coupling constants and internuclear distances for all diastereoisomers of 43
NO2
NO2
NO2
N
NO2
N
EtO2C
O
Ph
3
EtO2C
O
Ph
EtO2C
O
Ph
EtO2C
O
Ph
4
2
N
N
PMP
PMP
PMP
PMP
43
cis/trans
cis/cis
trans/trans
trans/cis
JH2-H3 (Hz)
JH3-H4 (Hz)
10.6
4.5
3.84
3.06
3.4
12.1
3.84
3.08
2.0
3.9
2.45
2.41
10.6
11.8
2.64
3.09
ꢀ
H2eH4 (A)
ꢀ
H3eH4 (A)
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042

6
J.C. Anderson et al. / Tetrahedron xxx (2014) 1e15
acid 21 gave only a complicated mixture of degradation products. In
these experiments 2 equiv of nBuLi were used as 18e21 all possess
a more or comparably acidic proton to the O2NC-H proton.
The nitro-Mannich reactions of the alcohol addition products
yield of recovered starting material 31 was also isolated. A single
crystal X-ray structure determination of 53 and 54 confirmed the
anti, anti relative stereochemistry.49 We have tentatively assigned
the p-nitro-aniline derivative 52 as the anti, anti-diastereoisomer,
although the alkane coupling constants for 52 are significantly
different from those of 53 and 54. This could be due to the fact that
52 possesses a relatively acidic NeH proton capable of hydrogen
bonding internally to the other vicinal amino group, which could
substantially alter the conformation compared to 53 and 54.
22e25 under the standard conditions gave the desired
b-nitro-
amines in good conversions and diastereoselectivities. After pro-
tection, the resultant trifluoroacetamides were isolated in good
yields and as single diastereoisomers (Scheme 6). A single crystal X-
ray structure determination of 48 confirmed the anti, anti relative
stereochemistry.49 All of the ether analogues 48e51 exhibited
a tight range of coupling constants for the alkane protons; JROCH-
R = p-NO2Ph,
conv. 65%, dr 90:10
PMP
Ph
R
6.7e8.5 Hz and JO2NCH-NCH 10.7e11.0 Hz. Due to these close
R
HN
O2NCH
i
NO2
values we assigned 49e51 also as the anti, anti-diastereoisomers.
R = benzotriazole,
conv. 10%, dr >95:5
Ph
ii
t
The BuO derivative 26 led to onlyw5% of nitro-Mannich product
NO2
O
t
R = 2-oxazolidinone,
conv. 45%, dr 75:25
amongst starting materials,
b
-nitrostyrene (2) and BuOH from
b
-
29, R = p-NO2Ph
31, R = benzotriazole
32, R = 2-oxazolidinone
elimination of 26 (w65%). Possible steric compression from the
large tert-butyl group could account for the propensity of this
substrate towards elimination.
PMP
R
N
CF3
52, R = p-NO2Ph, 17%
53, R = benzotriazole, 10%
54, R = 2-oxazolidinone, 33%
Ph
Ph
NO2
Scheme 7. Reagentsand conditions (i) nBuLi, THF ꢀ78 ꢁC;37, TFA; (ii)TFAA, Py, CH2Cl2, rt.
PMP
Ph
R
R = OMe, conv. 78%, dr 90:10
R = OEt, conv. 80%, dr >95:5
R = OBn, conv. 88%, dr 90:10
R = OiPr, conv. 82%, dr >95:5
R
HN
i
NO2
Ph
ii
Finally, the nitro-Mannich reactions of the sulphur and phos-
phorus 1,4-addition products were investigated. Nitro-Mannich
reaction of both nbutyl sulfide 33 and phenyl sulfide 34 de-
rivatives gave reasonable conversions (73% and 57%), but were
poorly diastereoselective. Subsequent trifluoroacetamide pro-
22, R = OMe
23, R = OEt
24, R = OBn
25, R = OiPr
NO2
O
PMP
R
48, R = OMe, 71%
49, R = OEt, 78%
50, R = OBn, 64%
51, R = OiPr, 80%
N
CF3
tection led to the protected b-nitroamines 55 and 56 in moderate
Ph
Ph
isolated yields and similarly disappointing diastereoselectivites
(Scheme 8). Despite 56 being isolated as a solid, suitable crystals for
X-ray analysis could not be obtained and coupled with the fact that
each diastereomeric pair of products 55 and 56 possessed very
similar alkane coupling constants, we could not substantiate any
relative stereochemistry with confidence.
NO2
Scheme 6. Reagents and conditions (i) nBuLi, THF ꢀ78 ꢁC; 37, TFA; (ii) TFAA, Py, CH2Cl2, rt.
A one pot conjugate addition nitro-Mannich was attempted
with NaOMe in MeOH. The solvent MeOH was needed for a high
yielding 1,4-addition to 2, but we had not used this solvent in nitro-
Mannich reactions before. Reaction of
MeONa in MeOH, followed by addition of solutions of imine 37 and
TFA in MeOH and trifluoroacetamide protection of the resultant
PMP
SR
SR HN
NO2
i
NO2
b-nitrostyrene (2) with
R = nBu, conv. 73%, dr 55:45
Ph
ii
Ph
R = pH, conv. 57%, dr >65:35
33, R = nBu
34, R = Ph
crude b-nitroamine product, trifluoroacetamide 48 was isolated in
O
43% yield as a single diastereoisomer. When imine 37 was present
from the beginning of the reaction with the nitroalkene, 48 was
isolated in 49% yield, which was very close to the overall yield of the
two pot procedure (52%). Although other alcohols could be used in
this multicomponent procedure, a limitation is the liquidity of the
alcohol solvent at the initial temperature of the nitro-Mannich
reaction of ꢀ78 ꢁC.
PMP
RS
55, R = nBu, 56%, dr 60:40
56, R = Ph, 47%, dr 65:35
N
CF3
Ph
Ph
NO2
Scheme 8. Reagentsand conditions (i) nBuLi, THF ꢀ78 ꢁC; 37, TFA; (ii)TFAA, Py, CH2Cl2, rt.
The nitro-Mannich reactions of N-substituted nitroalkanes were
not as successful as those of the ether series. Electron rich amines
Reactions of sulfone 35 and phosphine oxide 36 1,4-addition
products were unsuccessful, in both cases returning unreacted
starting materials. As the O2NC-H proton is expected to be the most
acidic based on the pKa of simple compounds (pKa’s in DMSO
NO2w17, to P(O)R2w25 and
to SO2Phw24)50 and there is at
-nitrophopshonate51 and
least one example each of -nitro-
sulfone52 reacting
to NO2 (all be it in a conjugate addition re-
action), this result was unexpected. Perhaps the electron
withdrawing nature of both the -substituents renders the nitro-
27, 28 and 30 gave none of the desired
stead yielding only parent -nitrostyrene (2) and the free amine,
which indicated -elimination. We attribute this to the acid (TFA)
b-nitroamine products, in-
b
b
a to
added to promote the nitro-Mannich reaction. Quenching of the
nitro-Mannich reaction without TFA led to recovery of starting
materials. Reduction of the amount of TFA from 3.5 to 1.0 equiv did
not change the result. Nitro-Mannich reaction of the p-nitro-aniline
derivative 29 gave 65% conversion (dr 90:10, Scheme 7), but only
led to a 17% yield of protected product 52. A substantial amount of
material degraded during the trifluoroacetamide protection by
elimination of the PMP amine trifluoroacetamide under the basic
reaction conditions. Quite why this particular substrate is so sen-
sitive to this elimination remains unanswered. The substrates de-
rived from benzotriazole 31 and oxazolidinone 32 gave protected
nitro-Mannich products 53 and 54 in similarly modest yields
(10% and 33%). In the case of the benzotriazole product 53 a 79%
a
a
b
b
a
b
nate species too unreactive for the nitro-Mannich reaction.
The sense of diastereoselectivity for the aryl, alkoxy and amino
conjugate addition derivatives are all profoundly anti, anti as
drawn. This is in direct contrast to our previous work were dia-
lkylzinc addition to 1 or a variety of nitro styrenes led to pre-
dominantly the syn, anti-diastereoisomer or for the latter case in
certain solvents the syn, syn-diastereoisomer.26,29 The anti-dia-
stereoselectivity for the nitro-Mannich reaction is by far the most
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042

J.C. Anderson et al. / Tetrahedron xxx (2014) 1e15
7
common diastereoselectivity exhibited by this reaction and most
probably arises through a closed Zimmerman-Traxler like transi-
tion state.4,7 In this work it is of interest that we obtained the anti-
diastereoselectivity between the stereocentre derived from the 1,4-
addition and the nitro stereocentre from the nitro-Mannich re-
action. To explain our earlier results we accepted that the control of
the diastereoselectivity from the initial conjugate addition step was
a subsequent in situ nitro-Mannich addition reaction was the
compatibility of reagents and conditions. The one pot conjugate
addition nitro-Mannich reaction with 1 was unsuccessful for all
nucleophiles investigated. The one pot procedure with 2 was found
to work with MeONa in MeOH and then adding imine 37 and TFA,
which gave after protection, the desired
b-nitroamine tri-
fluoroacetamide as a single diastereoisomer. This reaction could
also be performed by adding NaOMe to a mixture of 2 and 37 and
then adding TFA. The b-nitroamine was again isolated as its tri-
dictated by the energetics of electrophilic addition adjacent to an
stereocentre. Houk had calculated that the trajectory of an elec-
trophilic addition adjacent to an -stereocentre, ignoring any
a-
a
fluoroacetamide as a single diastereoisomer in a yield comparable
to the 2 step procedure also investigated (w50%). A limitation to
this method is that the alcohol solvent has to remain liquid at the
initial temperature of the nitro-Mannich reaction of ꢀ78 ꢁC. Other
types of nucleophiles were unsuccessful with the one pot conjugate
addition nitro-Mannich reaction with 2.
More success was found with the two-pot procedures. The 1,4-
addition products from nitroacrylate 1 were isolated in good yields
(81e99%). Subsequent deprotonation with nBuLi and reaction with
imine 37 and TFA, gave stable pyrrolidine products with only the
indole and 2,4,6-trimethoxyphenyl derivatives. The methoxide and
morpholine pyrrolidine derivatives, although isolable, were un-
stable over time. The 1,3-cyclohexanedione derivative gave a piper-
idine product in 38% yield. These few highly functionalized products
were all isolated as single diastereoisomers. The conjugate addition
stereoelectronic effects that normally arise from polar substituents
on the directing centre, is energetically most favourable from
a FelkineAnh like reactive conformation.53 If we assume for the
cases of 46 and 47 that the indole substituent and especially the
trimethoxyphenyl substituent are the largest substituents of that
chiral centre, then the most reactive conformation (A, Fig. 2) will
have those groups perpendicular to the nitronate anion. This model
would correctly predict the major anti-diastereoselectivity ob-
served in both additions.
†
Ar
Ar
O2N
Ph
E
E
NO2
Ar
Ph
Ph
Ar = 3-indolyl or
2,4,6-(MeO)3Ph
electrophile
NO2
E
H H
A
of the same range of nucleophiles to
yields of 1,4-addition products (45e97%). After deprotonation and
nitro-Mannich reaction, the isolated -nitroamines were protected
b-nitrostyrene (2) gave variable
†
O2N H
Ph
b
as their trifluoroacetamides sotheycould be purified. Thereaction of
the aromatic derivatives was successful, whereas the derivatives of
nucleophilic methylene nucleophiles were mostly ineffective. Nitro-
Mannich reactions of alcohol derivatives gave good yields of tri-
X
E
E
H X
or
X
B
E
E
NO2
Ph
Ph
electrophile
†
NO2
O2N X
X = OR or NR2
fluoroacetamide protected b-nitroamines, except for the tert-buta-
H
nol derivative. Reaction of amine derivatives was mostly ineffective,
with only small yields of products being isolated in limited cases.
Thiol derivatives gave the desired trifluoroacetamides in medium
yields, but uncharacteristically poor diastereoselectivities, while
adducts of phosphines were unreactive.
H Ph
C
Fig. 2. Houk-type analysis of electrophilic attack adjacent to an a-stereocentre.
A complication arises when we consider the more polar alkoxy
and amino substituents, which also gave anti-diastereoselectivity.
In the Felkin-Anh model for nucleophilic addition to carbonyl
groups, a more polar substituent favours the perpendicular position
Limitations do exist for the conjugate addition nitro-Mannich
methodology presented here. Problems with b-elimination of the
nucleophile from the 1,4-addition product on formation of the
nitronate species may account for the failure of the stabilized car-
bon nucleophile derivatives in the nitro-Mannich reaction. The
stabilized nucleophiles also make relatively good leaving groups.
The 1,4-addition products derived from amines participated poorly
in the nitro-Mannich reaction. This is probably due to the basic
amine being protonated by the acid required to promote the nitro-
so that it can lower the LUMO of the carbonyl
with its low lying orbital. By contrast electrophilic addition
favours an electron donor perpendicular to the
mize the energy of the HOMO. To account for the same sense of
facial addition the Ph or H groups, as electron donors, would have to
be placed perpendicular to the nitronate -orbital leading to con-
p* orbital by overlap
s*
C-X
p-orbital to maxi-
p
p
Mannich reaction, leading to b-elimination. Less basic, but more
former B or C (Fig. 2). Houk carried out further calculations, which
suggested that the most reactive conformation for a chiral centre
containing an electron withdrawing group (O substituent) adjacent
to an alkene reacting with an electrophile, would be the inside
conformer C. However in this case there would be severe but-
tressing between the developing C-electrophile bond and the
phenyl group, which suggests conformer B would be more favour-
able. The sulfur derivatives are neither very electron withdrawing or
sterically bulky, so their corresponding diastereoselectivity is low.
electron withdrawn amines while less likely to be protonated are
themselves better leaving groups and again performed poorly.
Certain nucleophiles, particularly the electron rich aromatics or
alcohols, on the whole did not suffer from this degradation and
gave good yields of products as single diastereoisomers. The high
levels of anti, anti-diastereoselectivity with nitro-Mannich re-
actions of derivatives from 2 is in contrast to the addition of dialkyl
zinc nucleophiles, which routinely gives syn, anti- or syn, syn-dia-
stereoselectivity. These densely functionalized diastereomerically
pure products could potentially serve as useful building blocks for
target synthesis.
3. Conclusion
The investigation of the conjugate addition nitro-Mannich re-
action of non-zinc nucleophiles to ethyl-b-nitroacrylate (1) and b-
4. Experimental section
4.1. General
nitrostyrene (2) was described. A diverse range of nucleophiles
including electron rich aromatic nucleophiles, stabilized carban-
ions, alcohols, amines, thiols, and phosphines were surveyed. Each
set of nucleophiles had their own particular reaction protocols for
a successful 1,4-addition reaction and the main complication with
Melting points are uncorrected and were recorded on a Reichert
Melting Point Apparatus. All 1H and 13C NMR data were recorded
using Bruker AVANCE III 400 MHz and Bruker AVANCE III 600 MHz
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042

8
J.C. Anderson et al. / Tetrahedron xxx (2014) 1e15
machines at 400 and 600 MHz for 1H and 100 and 150 MHz for 13C,
respectively. 19F NMR data were recorded on a Bruker AMX
300 MHz machine at 282 MHz. Samples were made as dilute so-
lutions of CDCl3 and spectra recorded at 298 K, unless otherwise
stated. Data were manipulated directly using Bruker XwinNMR
61.1 (CH2), 74.3 (CH2), 90.6 (CH), 103.8 (Cq), 158.6 (Cq), 161.3 (Cq),
171.6 (Cq); m/z (CIþ) 314 (MþHþ, 73%), 267 (MþHþ-NO2, 100%), 240
(40%); HRMS: found 314.12450, C14H20NO7 requires 314.12398.
4.2.3. Ethyl 3-nitro-2-(2,6-dioxocyclohexyl)propanoate (5).34 To
(version 2.6) or Top Spin (version 2.1). All chemical shifts (
d
) are
a solution of 1,3-cyclohexanedione (62 mg, 0.55 mmol) in MeOH
reported in parts per million (ppm), relative to residual solvent
(3 mL) was added Et3N (77 m
L, 0.55 mmol) at 0 ꢁC, followed by a so-
peaks
d
¼7.26 for 1H NMR and
d
¼77.1 for 13C NMR. Multiplicities for
lution of nitroacrylate 1 (80 mg, 0.55 mmol) in MeOH (2 mL). The
mixture was warmed to rt and stirred until complete consumption of
the nitroacrylate (TLC, 2 h). A solution of HCl 0.5 M (10 mL) was then
added and the mixture extracted with CH2Cl2 (3ꢂ10 mL), dried
(MgSO4), filtered and evaporated in vacuo. Purification by flash col-
1H coupled signals are denoted as s¼singlet, d¼doublet, t¼triplet,
q¼quartet, quint¼quintet, m¼multiplet. Coupling constants (J) are
reported in Hertz (Hz). 13C multiplicities were assigned using
a DEPT sequence. Where appropriate, HMQC, COSY, HMBC, NOE
experiments were carried out to aid assignment. Mass spectroscopy
data were collected on Thermo Finnigan Mat900xp (EI/CI) VG-70se
(FAB) and Waters LCT Premier XE (ES) instruments. Infrared data
were collected using PerkineElmer 100 FTIR spectrometer as a thin
film. Elemental analysis was performed on an Exeter Analytical Inc.
EA440 horizontal load analyser. Optical rotations were obtained
using a PerkineElmer 343 model polarimeter. X-ray crystallogra-
phy was carried out using a AFC12 goniometer, equipped with an
enhanced sensitivity (HG) Saturn724þ detector mounted at the
window of an FR-Eþ SuperBright molybdenum rotating anode
umn chromatography (Petrol:Me2CO 1:1) gave nitroalkane
5
(140 mg, 99%) as a white solid, mp. 91e92 ꢁC; Rf 0.47 (Petrol:Me2CO
1:1); IR ymax (thin film) 3420, 2981,1710,1584,1557,1382,1282,1248,
1192, 1031, 1012, 678 cmꢀ1; 1H NMR (600 MHz)
d 1.23 (m, 3H), 2.01
(m, 2H), 2.52(m, 4H), 4.16 (m, 2H), 4.36(m,1H), 4.72 (m,1H), 5.02(dd,
J¼13.7, 8.4,1H), 8.62 (br s,1H); 13C NMR (150 MHz)
d 13.9 (CH3), 20.3
(CH2), 32.5 (CH2), 37.5 (CH), 61.9 (CH2), 73.7 (CH2), 110.1 (Cq), 171.8
(Cq),188.6 (Cq); m/z (CIþ) 178 (MþHþ, 30%), 211 (20%),180 (27%),165
(100%); HRMS: found 258.09712, C11H16NO6 requires 258.09776.
generator with HF Varimax optics (100
mm focus).
4.2.4. Ethyl 2-methoxy-3-nitropropanoate 6. A solution of nitro-
acrylate 1 (80 mg, 0.55 mmol) in MeOH (5 mL) was stirred at reflux
until complete consumption of the starting material (24 h). The sol-
vent was then evaporated in vacuo and the residue purification by
flash column chromatography (Petrol:EtOAc 4:1) gave nitroalkane 6
(83mg, 85%)asacolourlessoil;Rf 0.44(Petrol:EtOAc4:1);IRymax (thin
film)2984,1937,1751,1736,1557,1379,1193,1129,1038,1017cmꢀ1;1H
For all non-aqueous chemistry, glassware was rigorously flame-
dried and an inert (N2) atmosphere maintained throughout. All
solvents and chemicals were used as received unless stated. Chro-
matographic separations were performed using Merck GeduranÒ
silica gel 60. Petroleum ether with a boiling range 40e60 ꢁC was
used. Commercial solvents and reagents were used as supplied or
purified in accordance to standard procedures. The dry solvents
Diethyl Ether (Et2O), Tetrahydrofuran (THF), Dichloromethane
(DCM), Toluene and Hexane were obtained from a solvent tower,
where degassed solvents were passed through two columns of
activated alumina and a 7 micron filter under 4 bar pressure.
Benzaldehyde was distilled from calcium hydride under an atmo-
sphere of nitrogen, and stored at 5 ꢁC. All solutions of organo-
lithium reagents were kept under a Nitrogen atmosphere at 5 ꢁC
and standardised with Salicylaldehyde Phenylhydrazone.54
NMR (600 MHz)
d
1.31 (t, J¼7.2, 3H), 3.53(s, 3H), 4.27(m, 2H), 4.45(dd,
J¼8.1, 3.5,1H), 4.65 (dd, J¼13.9, 8.2, 1H), 4.72 (dd, J¼13.9, 3.6, 1H); 13
C
NMR (150 MHz) d 14.0 (CH3), 59.5 (CH3), 62.1 (CH2), 75.8 (CH2), 76.6
(CH), 168.4 (Cq); m/z (EIþ) 178 (Mþ, 100%); HRMS: found 178.07170,
C6H11NO5 requires 178.07155; Anal. Cald. For C6H11NO5: C, 40.68, H,
6.26, N, 7.91. Found C, 40.38, H, 6.29, N, 7.57%.
4.2.5. Ethyl 2-ethoxy-3-nitropropanoate (7). In an identical pro-
cedure as to the preparation of 6, nitroacrylate 1 (100 mg,
0.69 mmol) in EtOH (7 mL) after purification by flash column
chromatography (Petrol:Et2O 9:1) gave nitroalkane 7 (117 mg, 89%)
as a colourless oil; Rf 0.33 (Petrol:Et2O 9:1); IR ymax (thin film) 2923,
4.2. 1,4-Additions to nitroacrylate 1
4.2.1. Ethyl 2-(1H-indol-3-yl)-3-nitropropanoate (3).32 To a pre-
formed mixture of CeCl3$NaI$SiO2 (11:2.5:1, 339 mg) was added
MeCN (4 mL) followed by indole (69 mg, 0.59 mmol) and nitro-
acrylate 1 (85 mg, 0.59 mmol). The mixture was stirred for 30 min,
the solvent removed in vacuo and the residue stirred for 24 h. Ad-
dition of Et2O (30 mL), filtration through celite,Ò evaporation in
vacuo and purification by flash column chromatography (Petrol:E-
tOAc 4:1) gave nitroalkane 3 (140 mg, 89%) as a yellow oil; Rf 0.23
1753, 1736, 1559, 1379, 1200, 1130, 1052, 1019, 559 cmꢀ1
;
1H NMR
1.21 (t, J¼7.1, 3H), 1.31 (t, J¼7.2, 3H), 3.56 (m, 1H), 3.84
(600 MHz)
d
(m, 1H), 4.26 (m, 2H), 4.57 (dd, J¼3.5, 8.4, 1H), 4.64 (dd, J¼8.5, 13.6,
1H), 4.71 (dd, J¼8.5, 13.5, 1H); 13C NMR (150 MHz)
d 14.1 (CH3), 14.9
(CH3), 62.0 (CH2), 67.7 (CH2), 75.1 (CH), 76.1 (CH2), 168.8 (Cq); no
Mþ peak on mass spec; Anal. Cald. For C7H13NO5: C, 43.98, H, 6.85,
N, 7.33. Found C, 44.24, H, 6.86, N, 7.58%.
(Petrol:EtOAc 4:1); 1H NMR (600 MHz)
d
1.24 (t, J¼7.1, 3H), 4.20 (m,
4.2.6. Ethyl 2-(benzyloxy)-3-nitropropanoate (8). A solution of
nitroacrylate 1 (73 mg, 0.50 mmol) in BnOH (1 mL) was stirred at
100 ꢁC until complete consumption of the starting material (24 h).
The solvent was then evaporated in vacuo and the residue purified
by flash column chromatography (Petrol:CH2Cl2 1:1) gave nitro-
alkane 8 (79 mg, 62%) as a colourless oil; Rf 0.46 (Petrol: CH2Cl2
1:1); IR ymax (thin film) 2922, 2852, 1745, 1559, 1456, 1378, 1274,
2H), 4.65 (dd, J¼14.5, 5.0, 1H), 4.76 (dd, J¼9.8, 4.9, 1H), 5.22 (dd,
J¼14.4, 9.9, 1H), 7.12 (app. d, J¼2.6, 1H), 7.19 (m, 1H), 7.26 (m, 1H),
7.39 (app. d, J¼8.2, 1H), 7.68 (app. d, J¼8.0, 1H), 8.34 (br s, 1H), in
agreement with that reported.33
4.2.2. Ethyl 2-(2,4,6-trimethoxyphenyl)-3-nitropropanoate
(4).32 Procedure identical to above, 1,3,5-trimethoxybenzene
(84 mg, 0.50 mmol) and nitroacrylate 1 (73 mg, 0.50 mmol) gave
after purification by flash column chromatography (Petrol:Et2O
1:1) 4 (140 mg, 89%) as white crystals, mp. 107e108 ꢁC; Rf 0.27
(Petrol:Et2O 1:1); IR ymax (thin film) 2952, 2843, 1732, 1609, 1594,
1554, 1500, 1459, 1420, 1378, 1344, 1329, 1226, 1203, 1152, 1119,
1203, 1131, 1020 cmꢀ1; 1H NMR (600 MHz)
(m, 2H), 4.60 (d, J¼11.2, 1H), 4.68 (m, 3H), 4.87 (d, J¼11.2, 1H),
7.30e7.38 (m, 5H); 13C NMR (150 MHz)
14.1(CH3), 62.1 (CH2), 73.7
d
1.32 (t, J¼7.1, 3H), 4.28
d
(CH2), 74.2 (CH), 76.0 (CH2), 128.3 (CH), 128.4 (CH), 128.5 (CH), 136.2
(Cq), 168.6 (Cq); m/z (CIþ) 254 (MþHþ, 13%) (HRMS analysis failed),
181 (MþHþ-COOEt, 100%).
1058, 1029, 951, 815 cmꢀ1; 1H NMR (600 MHz)
d
1.18 (t, J¼7.1, 3H),
3.79 (s, 6H), 3.82 (s, 3H), 4.10e4.21 (m, 2H), 4.29 (dd, J¼13.5, 5.2,
4.2.7. Ethyl 2-((4-methoxyphenyl)amino)-3-nitropropanoate (9). To
a stirred solution of nitroacrylate 1 (201 mg, 1.39 mmol) in CH2Cl2
(14 mL) was added at rt para-anisidine (307 mg, 2.50 mmol) and the
1H), 5.05 (dd, J¼8.8, 5.2, 1H), 5.12 (dd, J¼13.5, 8.8, 1H), 6.12 (s, 2H);
13C NMR (150 MHz)
d 14.1(CH3), 38.0 (CH), 55.3 (CH3), 55.7 (CH3),
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042

J.C. Anderson et al. / Tetrahedron xxx (2014) 1e15
9
mixture was stirred until complete consumption of the nitroacrylate
butanethiol (180
mL, 1.24 mmol) and triethylamine (24
mL,
(TLC, 24 h). The mixture was then evaporated and purification by
flash column chromatography (Petrol:EtOAc 4:1) gave nitroalkane 9
(364 mg, 98%) as an orange solid; mp. 74e75 ꢁC; Rf 0.40 (Petrol:EtOAc
4:1);IR ymax (thin film) 3387, 3010, 2956, 2917, 2836,1732,1546,1515,
0.17 mmol), and the mixture was stirred overnight until complete
consumption of 1 (TLC, 22 h). The mixture was then evaporated in
vacuo and purification of the residue by flash column chromatog-
raphy (Petrol: Et2O 9:1) gave acrylate 14 (29 mg, 38%) as a colour-
less oil, which was found to be unstable and could not be
completely characterised, Rf 0.38 (Petrol:Et2O 9:1); IR ymax (thin
1317, 1250, 1233, 1210, 1186, 1152, 1031, 829, 806 cmꢀ1 1H NMR
;
(600 MHz)
d
1.29 (t, J¼7.1, 3H), 3.75 (s, 3H), 4.26 (br s, 1H), 4.27 (m,
2H), 4.55 (t, J¼5.0,1H), 4.76 (dd, J¼13.7, 4.8,1H), 4.82 (dd, J¼13.7, 5.1,
film) 2959, 1719, 1583, 1465, 1385, 1277, 1248, 1117, 1025 cmꢀ1
NMR (600 MHz) 1.33 (m, 3H), 1.47 (m, 2H), 1.66 (m, 2H), 2.72 (m,
2H), 4.27 (m, 2H), 5.40 (s, 1H), 6.35 (s, 1H); 13C NMR (150 MHz)
;
1H
1H), 6.68 (app d, J¼8.9, 2H), 6.80 (app. d, J¼8.9, 2H); 13C NMR
d
(150 MHz) d 14.0 (CH3), 55.6 (CH3), 56.3 (CH), 62.5 (CH2), 75.8 (CH2),
114.9 (CH),115.9 (CH),139.2 (Cq),153.6 (Cq),169.7 (Cq); m/z (EIþ) 268
d 13.6 (CH3),14.1 (CH3), 22.2 (CH2), 29.7 (CH2), 31.1 (CH2), 61.7 (CH2),
(Mþ, 20%), 149 (100%), 134 (46%); HRMS: found 268.10592,
118.5 (CH2), 137.9 (Cq), 164.6 (Cq); m/z (EIþ) 188 (M þ, 30%), 107
C12H16N2O5 requires 268.10686; Anal. Cald. For C12H16N2O5: C, 53.73,
(100%); HRMS: found 188.08600, C9H16O2S requires 188.08655.
H, 6.01, N, 10.44. Found C, 53.74, H, 6.00, N, 10.15%.
4.2.12. Ethyl 2-(diphenylphosphoryl)acrylate (15). To a stirred so-
lution of the nitroacrylate 1 (65 mg, 0.45 mmol) in dry THF (5 mL) at
rt was added diphenylphosphine oxide (100 mg, 0.500 mmol) and
the mixture was stirred at rt overnight, until complete consump-
tion of 1 (TLC, 16 h). After completion, the mixture was evaporated
and purification of the residue by flash column chromatography
gave acrylate 15 (75 mg, 56%) as a yellow oil; Rf 0.29 (Petrol:Me2CO
3:2); IR ymax (thin film) 3058, 2981, 1721, 1438, 1250, 1184, 1118,
4.2.8. Ethyl 2-morpholino-3-nitropropanoate (10). In an identical
procedure as to the preparation of 9, nitroacrylate 1 (80 mg,
0.55 mmol) in wet CH2Cl2 (5 mL) and morpholine (54
mL,
0.66 mmol) gave after purification by flash column chromatogra-
phy (Petrol:EtOAc 4:1) nitroalkane 10 (125 mg, 98%) as an orange
oil; Rf 0.33 (Petrol:EtOAc 4:1); IR ymax (thin film) 2965, 2858, 1729,
1557, 1383, 1187, 1116, 1023, 855 cmꢀ1; 1H NMR (600 MHz)
d 1.31 (t,
J¼7.2, 3H), 2.50 (m, 2H), 2.80 (m, 2H), 3.62 (m, 4H), 4.03 (dd, J¼8.9,
1098, 1019, 728, 695 cmꢀ1; 1H NMR (600 MHz)
d
1.05 (t, J¼7.1, 3H),
6.4,1H), 4.23 (m, 2H), 4.61 (dd, J¼13.5, 9.0,1H), 4.67 (dd, J¼13.6, 6.4,
4.10 (q, J¼7.1, 2H), 6.30 (dd, PꢀHJ ¼ 17.4, 2J¼1.4, 1H), 7.25 (dd, PꢀHJ ¼
1H); 13C NMR (150 MHz)
d 14.3 (CH3), 49.9 (CH2), 61.4 (CH2), 64.5
33.6, 2J¼1.4, 1H), 7.40e7.60 (m, 6H), 7.85 (m, 4H); 13C NMR
(CH), 67.1 (CH2), 73.3 (CH2), 168.1 (Cq); m/z (EIþ) 232 (Mþ, 7%), 159
(Mþ-COOEt, 53%), 113 (Mþ-NO2-COOEt, 100%); HRMS: found
232.10474, C9H16N2O5 requires 232.10537.
(150 MHz)
d
13.7 (CH3), 61.4 (CH2), 128.4 (d, J¼12.6, CH), 131.2 (d,
J¼108.6, Cq), 131.8 (d, J¼10.1, CH), 132.0 (d, J¼2.8, CH), 137.3 (d,
J¼95.5, Cq), 144.6 (d, J¼4.9, CH2), 164.3 (d, J¼14.1, Cq); 31P NMR
(300 MHz)
d
26.0; m/z (ESIþ) 301 (MþHþ, 100%), 243 (55%), 215
4.2.9. Ethyl 2-(benzylamino)-3-nitropropanoate (11). To a stirred
solution of nitroacrylate 1 (80 mg, 0.55 mmol) in CH2Cl2 (5 mL) was
(40%); HRMS: found 301.0996, C17H18O3P requires 301.0994.
added at 0 ꢁC benzylamine (72
mL, 0.66 mmol) and the mixture was
4.3. 1,4-Additions to
b-nitrostyrene 2
stirred at this temperature until complete consumption of 1 (TLC,
1 h). The mixture was then evaporated and purification by flash
column chromatography (Petrol:EtOAc 4:1) gave nitroalkane 11
(112 mg, 81%) as an orange oil; Rf 0.59 (Petrol:EtOAc 4:1); IR ymax
(thin film) 3340, 3030, 2982, 2931, 1735, 1557, 1379, 1196, 1020, 739,
4.3.1. 3-(2-Nitro-1-phenylethyl)-1H-indole (16).32 In
a
manner
identical to the preparation of 3 indole (59 mg, 0.50 mmol) was
added to -nitrostyrene (2, 74 mg, 0.50 mmol) and purification by
b
flash column chromatography (Petrol:EtOAc 4:1) gave nitroalkane
699 cmꢀ1
;
1H NMR (600 MHz)
d
1.31 (t, J¼7.1, 3H), 2.27 (br s, 1H),
16 (123 mg, 92%) as a colourless oil; Rf 0.43 (Petrol:EtOAc 4:1); 1H
3.81 (d, J¼13.3, 1H), 3.85 (dd, J¼6.1, 5.0, 1H), 3.96 (d, J¼13.3, 1H),
NMR (600 MHz)
d
4.96 (dd, J¼12.4, 8.4, 1H), 5.09 (dd, J¼12.4, 7.7,
4.26 (m, 2H), 4.63 (dd, J¼13.5, 4.9, 1H), 4.67 (dd, J¼13.5, 6.0, 1H),
1H), 5.21 (t, J¼8.1, 1H), 7.04 (d, J¼2.3, 1H), 7.10 (app. t, J¼7.5, 1H),
7.22 (app. t, J¼7.5, 1H), 7.29 (m, 1H), 7.35 (m, 5H), 7.47 (d, J¼7.9, 1H),
7.28 (m, 1H), 7.31e7.36 (m, 4H); 13C NMR (150 MHz)
d 14.0 (CH3),
52.0 (CH2), 57.7 (CH), 62.0 (CH2), 76.7 (CH2), 127.4 (CH), 128.2 (CH),
128.5 (CH), 138.8 (Cq), 170.8 (Cq); m/z (CIþ) 253 (MþHþ, 4%), 179
(9%), 133 (Mþ-NO2-COOEt, 17%), 106 (PhCH¼NH2þ, 20%), 91 (PhCH3þ,
100%); HRMS: found 253.11934, C12H17N2O4 requires 253.11883.
8.09 (br s, 1H); 13C NMR (150 MHz)
d 41.5 (CH), 79.5 (CH2), 111.4
(CH), 114.4 (Cq), 118.9 (CH), 119.9 (CH), 121.6 (CH), 122.7 (CH), 126.0
(Cq), 127.5 (CH), 127.7 (CH), 128.9 (CH), 136.4 (Cq), 139.1 (Cq). Data
in agreement with that reported.55
4.2.10. Ethyl 2-(1H-benzo[d][1,2,3]triazol-1-yl)acrylate (13). To a so-
lution of nitroacrylate 1 (72 mg, 0.50 mmol) in CH2Cl2 (5 mL) was
added 1H-benzo[d][1,2,3]triazole (12, 65 mg, 0.55 mmol) and the
mixture was stirred at rt until complete consumption of 1 (TLC, 2
days). The mixture was then evaporated in vacuo and purification of
the residue by flash column chromatography (Petrol:Et2O 7:3) gave
acrylate 13 (62 mg, 47%) as a colourless oil; Rf 0.38 (Petrol:Et2O 7:3);
IR ymax (thin film) 2984, 1729, 1635, 1455, 1378, 1276, 1240, 1178,
4.3.2. 1,3,5-Trimethoxy-2-(2-nitro-1-phenylethyl)benzene (17).32 In
a manner identical to the preparation of 3 1,3,5-trimethoxybenzene
(84 mg, 0.50 mmol) was added to
b-nitrostyrene (2, 74 mg,
0.50 mmol) and purification by flash column chromatography
(Petrol:EtOAc 4:1) gave nitroalkane 17 (113 mg, 71%) as a colourless
oil, Rf 0.43 (Petrol:EtOAc 4:1); 1H NMR (600 MHz)
d 3.80 (s, 3H),
3.81 (s, 6H), 5.14 (dd, J¼12.8, 7.6, 1H), 5.26 (dd, J¼12.7, 8.1, 1H), 5.51
(t, J¼7.9, 1H), 6.14 (s, 2H), 7.19 (t, J¼7.3, 1H), 7.27 (t, J¼7.4, 2H), 7.33
1074, 1055, 1018, 785, 747 cmꢀ1; 1H NMR (600 MHz)
d
1.32 (t, J¼7.2,
(d, J¼7.6, 2H); 13C NMR (150 MHz)
d 38.5 (CH), 55.2 (CH3), 55.7
3H), 4.36 (q, J¼7.2, 2H), 6.30 (s, 1H), 6.74 (s, 1H), 7.41 (app. t, J¼7.8,
1H), 7.44 (app. d, J¼8.4, 1H), 7.52 (app. t, J¼7.4, 1H), 8.10 (d, J¼8.3,
(CH3), 78.3 (CH2), 91.0 (CH), 108.5 (Cq), 126.5 (CH), 127.5 (CH), 128.2
(CH), 140.4 (Cq), 158.9 (Cq), 160.5 (Cq). Data in agreement with that
reported.56
1H); 13C NMR (150 MHz)
d 14.0 (CH3), 62.5 (CH2), 110.6 (CH), 120.1
(CH), 124.2 (CH), 125.2 (CH2), 128.2 (Cq),133.1 (Cq),134.4 (Cq),145.8
(Cq), 161.6 (Cq); m/z (CIþ) 218 (MþHþ, 100%), 161 (26%), 133 (98%);
HRMS: found 218.09295, C11H12N3O2 requires 218.09247; Anal.
Cald. For C11H11N3O2: C, 60.82, H, 5.10, N, 19.34. Found C, 60.53, H,
5.21, N, 19.63%.
4.3.3. Diethyl 2-(2-nitro-1-phenylethyl)malonate (18).39 To a solu-
tion of diethyl malonate (0.15 mL, 1.0 mmol) in THF (3 mL) was
added NaH (24 mg, 1.0 mmol, 95%) and the mixture stirred at rt for
15 min. A solution of b-nitrostyrene (2, 74 mg, 0.50 mmol) in THF
(2 mL) was then added and the mixture stirred at rt until complete
consumption of the nitroalkene (TLC, 15 min). The mixture was
then quenched with addition of saturated aqueous NH4Cl (10 mL)
4.2.11. Ethyl 2-(butylthio)acrylate (14). To a stirred solution of
nitroacrylate 1 (60 mg, 0.41 mmol) in THF (2 mL) at rt was added 1-
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042

10
J.C. Anderson et al. / Tetrahedron xxx (2014) 1e15
and extracted with CH2Cl2 (3ꢂ10 mL), the combined organics were
then washed with brine (10 mL), dried (MgSO4), evaporated in
vacuo and purification of the crude residue by flash column chro-
matography (Hexane:Et2O 7:3) gave nitroalkane 18 (148 mg, 96%)
as a colourless oil; Rf 0.30 (Hexane:Et2O 7:3); 1H NMR (600 MHz)
organics washed with brine (10 mL), dried (MgSO4) and purifica-
tion of the crude residue by flash column chromatography (Petro-
l:Et2O 9:1) gave nitroalkane 22 (133 mg, 73%, lit.44 60%) as
a colourless oil, Rf 0.63 (Petrol:Et2O 9:1); 1H NMR (600 MHz)
d 3.28
(s, 3H), 4.41 (dd, J¼12.8, 3.3, 1H), 4.62 (dd, J¼12.7, 10.1, 1H), 4.97 (dd,
d
1.05 (t, J¼7.1, 3H), 1.27 (t, J¼7.1, 3H), 3.83 (d, J¼9.4, 1H), 4.02 (q,
J¼7.2, 2H), 4.27 (m, 3H), 4.85 (dd, J¼13.1, 9.4, 1H), 4.95 (dd, J¼13.1,
4.8, 1H), 7.23e7.34 (m, 5H); 13C NMR (150 MHz)
13.7 (CH3), 14.0
J¼10.2, 3.4, 1H), 7.36e7.45 (m, 5H); 13C NMR (150 MHz)
d 57.1 (CH3),
80.0 (CH), 80.4 (CH2), 126.8 (CH), 129.0 (CH), 129.1 (CH), 135.9 (Cq).
d
Data in agreement with that reported.44
(CH3), 42.9 (CH), 54.9 (CH), 61.9 (CH2), 62.2 (CH2), 77.6 (CH2), 128.0
(CH), 128.4 (CH), 128.9 (CH), 136.1 (Cq), 166.8 (Cq), 167.5 (Cq). Data
in agreement with that reported.57
4.3.8. (1-Ethoxy-2-nitroethyl)benzene (23).44 In an identical man-
ner as for the preparation of 22, but with EtONa in EtOH gave
nitroalkane 23 (129 mg, 66%, lit.44 6%) as a colourless oil; Rf 0.49
4.3.4. 2-(2-Nitro-1-phenylethyl)malononitrile (19).40 To a solution
(Petrol:Et2O 9:1); 1H NMR (600 MHz)
d
1.16 (t, J¼7.3, 3H), 3.39 (m,
of
L
-Proline (11.5 mg, 10 mol %) in DMF (1 mL) was added malo-
-nitrostyrene (149 mg,
2H), 4.39 (dd, J¼12.8, 3.4, 1H), 4.61 (dd, J¼12.8, 10.3, 1H), 5.06 (dd,
nonitrile (66 mg, 1.0 mmol) followed by
b
J¼10.0, 3.3,1H), 7.35e7.42 (m, 5H); 13C NMR (150 MHz)
d 14.9 (CH3),
1.00 mmol) and the mixture was stirred at rt until complete con-
sumption of the nitroalkene (TLC, 20 h). Water (10 mL) was then
added, the mixture extracted with Et2O (3ꢂ10 mL), dried (MgSO4),
evaporated in vacuo and purified by flash column chromatography
(CH2Cl2) gave nitroalkane 19 (192 mg, 89%) as a yellow oil; Rf 0.49
62.9 (CH2), 78.2 (CH), 80.5 (CH2), 126.7 (CH), 128.9 (CH), 129.0 (CH),
136.7 (Cq). Data in agreement with that reported.44
4.3.9. (1-(Benzyloxy)-2-nitroethyl)benzene (24).44 In an identical
manner as for the preparation of 22, but with BnONa in BnOH gave
nitroalkane 24 (171 mg, 66%, lit.44 30%) as a colourless oil; Rf 0.39
(DCM); 1H NMR (600 MHz)
d
4.09 (m, 1H), 4.43 (d, J¼6.0, 1H), 4.90
(dd, J¼14.2, 6.2, 1H), 4.97 (dd, J¼14.3, 7.9, 1H), 7.30e7.48 (m, 5H);
13C NMR (150 MHz)
27.6 (CH), 43.7 (CH), 74.9 (CH2), 110.3 (Cq),
(Petrol:Et2O 9:1); 1H NMR (600 MHz)
d
4.34 (d, J¼11.6, 1H), 4.42
d
(dd, J¼12.8, 3.4, 1H), 4.52 (d, J¼11.5, 1H), 4.70 (dd, J¼12.8, 10.1, 1H),
110.4 (Cq), 127.7 (CH), 129.9 (CH), 130.4 (CH), 131.8 (Cq). Data in
agreement with that reported.40
5.16 (dd, J¼10.2, 3.4, 1H), 7.23e7.41 (m, 9H); 13C NMR (150 MHz)
d
70.9 (CH2), 77.5 (CH), 80.3 (CH2), 127.0 (CH),127.9 (CH),128.0 (CH),
128.4 (CH), 129.2 (CH), 129.2 (CH), 136.0 (Cq), 136.9 (Cq). Data in
agreement with that reported.44
4.3.5. 3-Hydroxy-2-(2-nitro-1-phenylethyl)cyclohex-2-enone
(20).41 To a solution of 1,3-cyclohexanedione (560 mg, 5.00 mmol)
in methanol (1 mL) was added a solution of sodium (25 mg,
1.1 mmol) in methanol (2 mL) and the mixture stirred for 1 min at
4.3.10. (1-Isopropoxy-2-nitroethyl)benzene (25).44 In an identical
manner as for the preparation of 22, but with iPrONa in iPrOH gave
nitroalkane 25 (121 mg, 58%) as a colourless oil; Rf 0.51 (Petrol:Et2O
9:1); IR ymax (thin film) 2974, 1553, 1494, 1454, 1418, 1379, 1336,
1224, 1143, 1122, 1095, 1062, 1029, 976, 762, 717, 699 cmꢀ1; 1H NMR
rt. The mixture was then cooled to 0 ꢁC, a solution of
b-nitrostyrene
(745 mg, 5.00 mmol) in methanol (2 mL) was added and the mix-
ture stirred at this temperature for 30 min, then at rt until complete
consumption of the starting material (TLC, 5 h). The mixture was
poured into iceewater, neutralised with 10% HCl, filtered and
recrystallised from methanol to give pure nitroalkane 20 (440 mg,
34%, lit.41 68%) as a white solid; mp. 142e143 ꢁC (lit. 144e146 ꢁC); Rf
(600 MHz)
d
1.07 (d, J¼6.2, 3H), 1.13 (d, J¼6.2, 3H), 3.56 (sept, J¼6.1,
1H), 4.36 (dd, J¼12.7, 3.3, 1H), 4.57 (dd, J¼12.6, 10.3, 1H), 5.17 (dd,
J¼10.2, 3.2, 1H), 7.35 (m, 1H), 7.40 (m, 4H); 13C NMR (150 MHz)
d
20.8 (CH3), 23.2 (CH3), 70.4 (CH), 75.8 (CH), 80.8 (CH2), 126.7 (CH),
0.35 (Petrol:Me2CO 1:1); 1H NMR (600 MHz)
(m, 4H), 5.08 (m, 2H), 5.19 (m, 1H), 7.19e7.34 (m, 5H), 9.91 (br s,
1H); 13C NMR (150 MHz)
20.4 (CH2), 33.0 (CH2), 35.2 (CH2), 38.2
d
1.86 (m, 2H), 2.37
128.8 (CH), 128.9 (CH), 137.5 (Cq); m/z (CIþ) 210 (MþHþ, 6%), 162
(Mþ-HNO2, 24%), 149 (Mþ-CH2NO2, 61%), 107 (PhCHOþHþ, 100%),
104 (PhCH¼CHþ2 , 72%); HRMS: found 210.11276, C11H16NO3 requires
210.11302.
d
(CH), 77.3 (CH2), 114.4 (Cq), 126.9 (CH), 127.8 (CH), 128.4 (CH), 138.8
(Cq), 139.7 (Cq), 197.4 (Cq). Data in agreement with that reported.41
4.3.11. (1-(tert-Butoxy)-2-nitroethyl)benzene (26). A 0.53 M solu-
t
t
4.3.6. 2,2-Dimethyl-5-(2-nitro-1-phenylethyl)-1,3-dioxane-4,6-dione
tion of BuONa in BuOH (1.90 mL, 1.00 mmol) was added to a so-
lution of -nitrostyrene (2, 149 mg, 1.00 mmol) in THF (10 mL) at rt.
The mixture was stirred at this temperature for 5 min and then
acetic acid (4.00 L, 6.00 mmol) was added, the mixture stirred for
(21).42 To a solution of Meldrum’s acid (144 mg, 1.00 mmol) in
b
CH2Cl2 (7 mL) was added Et3N (130
mL, 1.00 mmol) and the mixture
stirred at rt for 30 min before -nitrostyrene (2, 149 mg, 1.00 mmol)
b
m
was added in one batch and the mixture stirred at rt until complete
consumption of the starting material (TLC, 1 h). The mixture was
acidified to pH¼2 with addition of 10% HCl, extracted with CH2Cl2
(3ꢂ10 mL), dried (MgSO4) and evaporated in vacuo to give pure
nitroalkane 21 (280 mg, 96%, lit.42 88%) as a white solid; mp.
92e94 ꢁC (lit.42 93e95 ꢁC); Rf 0.49 (DCM:MeOH 10:1); 1H NMR
5 min and then poured into H2O (20 mL). The mixture was
extracted with CH2Cl2 (3ꢂ10 mL), the combined organics washed
with brine (10 mL), dried (MgSO4), evaporated in vacuo and puri-
fication of the crude residue by flash column chromatography
(Petrol:Et2O 9:1) gave nitroalkane 26 (89 mg, 40%) as a white solid;
mp. 45e46 ꢁC; Rf 0.57 (Petrol:Et2O 9:1); IR ymax (thin film) 2977,
1555,1455,1379,1190,1092,1066, 963, 765, 722, 701 cmꢀ1; 1H NMR
(600 MHz)
1H), 5.02 (dd, J¼14.0, 6.5, 1H), 5.40 (dd, J¼14.0, 9.0, 1H), 7.30e7.35
(m, 5H); 13C NMR (150 MHz)
27.6 (CH3), 28.1 (CH3), 41.8 (CH), 48.5
d
1.39 (s, 3H), 1.71 (s, 3H), 4.04 (d, J¼3.2, 1H), 4.64 (m,
(600 MHz)
d
1.10 (s, 9H), 4.32 (dd, J¼12.0, 3.3, 1H), 4.49 (dd, J¼12.0,
d
10.2, 1H), 5.27 (dd, J¼10.1, 3.2, 1H), 7.31e7.41 (m, 5H); 13C NMR
(CH), 75.9 (CH2), 105.9 (Cq), 128.8 (CH), 128.9 (CH), 129.2 (CH), 135.1
(Cq), 164.0 (Cq), 164.4 (Cq). Data in agreement with that reported.42
(150 MHz) d 28.3 (CH3), 72.0 (OCH), 75.5 (Cq), 81.9 (CH2), 126.2
(CH), 128.3 (CH), 128.7 (CH), 140.2 (Cq); m/z (CIþ) 224 (MþHþ, 6%),
163 (MþHþ-CH3NO2, 65%), 150 (MþHþ-tBuOH, 26%), 107
(PhCHOþHþ, 100%); HRMS: found 224.12912, C12H18NO3 requires
224.12867; Anal. Cald. For C12H17NO3: C, 64.55, H, 7.67, N, 6.27.
Found C, 64.76, H, 7.79, N, 6.07%.
4.3.7. (1-Methoxy-2-nitroethyl)benzene (22).44 A 1.5 M solution of
MeONa in MeOH (670
of -nitrostyrene (2, 149 mg, 1.00 mmol) in MeOH (10 mL). The
mixture was stirred at rt until no more nitroalkene was observed on
TLC (15 min). Acetic acid (400 L, 6.00 mmol) was then added and
mL, 1.00 mmol) was added at rt to a solution
b
m
4.3.12. 2,4-Dimethoxy-N-(2-nitro-1-phenylethyl)aniline
a solution of -nitrostyrene (2, 149 mg, 1.00 mmol) in dry CH2Cl2
(5 mL) was added 2,3-dimethoxyaniline (184 mg, 1.20 mmol) at rt
(27). To
the mixture stirred for 5 min and then poured into H2O (20 mL).
The mixture was extracted with CH2Cl2 (3ꢂ10 mL), the combined
b
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042

J.C. Anderson et al. / Tetrahedron xxx (2014) 1e15
11
and the mixture was stirred overnight until no more nitroalkene
was observed (TLC, 19 h). The mixture was then evaporated in vacuo
and purification by flash column chromatography (Petrol:EtOAc
4:1) gave the nitroalkane 27 (212 mg, 70%) as a yellow oil; Rf 0.38
column chromatography (Petrol:Et2O 7:3) gave nitroalkane 31
(111 mg, 83%) as a colourless oil; Rf 0.45 (Petrol:Et2O 7:3); 1H NMR
(600 MHz)
d
5.16 (dd, J¼14.8, 4.8,1H), 5.95 (dd, J¼14.6, 9.8,1H), 6.60
(dd, J¼9.8, 4.8,1H), 7.36 (m, 2H), 7.43 (m, 3H), 8.07 (d, J¼8.4,1H); 13
C
(Petrol:EtOAc 4:1); 1H NMR (600 MHz)
d
3.72 (s, 3H), 3.85 (s, 3H),
NMR (150 MHz) d 59.7 (CH), 76.5 (CH2), 109.3 (CH),120.1 (CH),124.5
4.66 (br s, 1H), 4.70 (dd, J¼12.3, 5.5, 1H), 4.73 (dd, J¼12.2, 8.3, 1H),
(CH), 126.8 (CH), 128.0 (CH), 129.5 (CH), 129.7 (CH), 132.6 (Cq), 133.9
5.13 (dd, J¼8.0, 5.9, 1H), 6.31 (dd, J¼8.8, 2.6, 1H), 6.45 (d, J¼2.5, 2H),
(Cq), 146.1 (Cq). Data in agreement with that reported.60
7.32 (m, 1H), 7.39 (m, 4H); 13C NMR (150 MHz)
d 55.6 (CH3), 55.6
(CH3), 57.2 (CH3), 80.1 (CH2), 99.2 (CH), 103.5 (CH), 111.9 (CH), 126.5
(CH), 128.5 (CH), 129.2 (CH), 129.6 (Cq), 138.1 (Cq), 148.3 (Cq), 152.8
(Cq). Data in agreement with that reported.58
4.3.17. 3-(2-Nitro-1-phenylethyl)oxazolidin-2-one (32).36 To a mix-
ture of 2-oxazolidinone (87 mg, 1 mmol), tBuOK (112 mg, 1 mmol)
and 18-crown-6 (264 mg, 1.00 mmol) was added dry THF (5 mL)
and the mixture was stirred at rt for 1 h. The mixture was then
4.3.13. N-(2-Nitro-1-phenylethyl)aniline (28).45 A mixture of
nitrostyrene (2,149 mg, 1.00 mmol), aniline (110 L,1.20 mmol) and
b
-
cooled to ꢀ78 ꢁC and a solution of
b-nitrostyrene (2, 149 mg,
m
1.00 mmol) in THF (5 mL) was added and the mixture stirred at this
temperature until complete consumption of the starting material
(TLC, 30 min). A saturated aqueous solution of NH4Cl (20 mL) was
then added and the mixture warmed to rt and extracted with Et2O
(3ꢂ20 mL), dried (MgSO4), evaporated in vacuo and purification of
the residue by flash column chromatography (Petrol:Me2CO 7:3)
gave nitroalkane 32 (213 mg, 90%) as a colourless oil, Rf 0.50 (Pet-
rol:Me2CO 3:2); IR ymax (thin film) 2976, 2925, 1740, 1553, 1482,
H2O (4 mL) was stirred vigorously for 2 h. The mixture was then
extracted with CH2Cl2 (3ꢂ10 mL), dried (MgSO4) and evaporated in
vacuo. Purification by flash column chromatography (Petrol:Et2O
9:1) gave nitroalkane 28 (163 mg, 67%) as a yellow oil, Rf 0.28
(Petrol:Et2O 9:1); 1H NMR (600 MHz)
d
4.44 (d, J¼6.6, 1H), 4.73 (d,
J¼6.7, 2H), 5.21 (q, J¼6.9, 1H), 6.65 (d, J¼8.0, 2H), 6.78 (t, J¼7.4, 1H),
7.18 (t, J¼7.9, 2H), 7.36 (m, 1H), 7.42 (m, 4H); 13C NMR (150 MHz)
d
56.5 (CH), 79.9 (CH2),113.8 (CH),118.8 (CH),126.4 (CH),128.6 (CH),
1419, 1380, 1248, 1111, 1076, 1047, 761, 733, 699 cmꢀ1
(600 MHz)
;
1H NMR
129.2 (CH), 129.3 (CH), 137.6 (Cq), 145.6 (Cq). Data in agreement to
d
3.36 (dt, J¼8.0, 8.8, 1H), 3.61 (m, 1H), 4.29 (m, 2H), 4.86
that reported.59
(dd, J¼5.4, 13.0, 1H), 5.28 (dd, J¼10.3, 13.0, 1H), 5.58 (dd, J¼5.4, 10.3,
1H), 7.31e7.35 (m, 2H), 7.37e7.43 (m, 3H); 13C NMR (150 MHz)
4.3.14. 4-Nitro-N-(2-nitro-1-phenylethyl)aniline (29). A solution of
d 42.0 (CH2), 55.7 (CH), 62.2 (CH2), 74.5 (CH2), 127.3 (CH), 129.3
nBuLi (400
m
L, 2.5 M, 1.00 mmol) in hexane was added to a solution
(CH), 133.6 (Cq), 157.6 (Cq), one CH peak missing; m/z (CIþ) 237
(MþHþ, 100%), 176 (Mþ-CH3NO2, 67%); HRMS: found 237.08724,
of para-nitroaniline (138 mg, 1.00 mmol) in dry THF (10 mL) at
ꢀ78 ꢁC and the mixture stirred for 10 min before a solution of
b
-
C11H13N2O4 requires 237.08753; Anal. Cald. For C11H12N2O4: C,
55.93, H, 5.12, N, 11.86. Found C, 56.19, H, 5.23, N, 11.60%.
nitrostyrene (2, 149 mg, 1.00 mmol) in dry THF (2 mL) was added
dropwise. The mixture was stirred at this temperature for 10 min
and then warmed to rt and stirred until complete consumption of
the starting nitroalkene (TLC, 1.5 h). Saturated aqueous NaHCO3
solution (10 mL) was then added and the mixture extracted with
CH2Cl2 (3ꢂ10 mL), dried (MgSO4) and evaporated in vacuo. Purifi-
cation by flash column chromatography (Petrol:EtOAc 4:1) gave
nitroalkane 29 (129 mg, 45%) as a yellow oil; Rf 0.21 (Petrol:EtOAc
4:1); IR ymax (thin film) 3365, 3065, 2922, 1596, 1551, 1503, 1476,
4.3.18. Butyl(2-nitro-1-phenylethyl)sulfane (33).38 To a stirred so-
lution of
added 1-butanethiol (53
b
-nitrostyrene (2, 74 mg, 0.50 mmol) in EtOH (1 mL) was
L, 0.50 mmol) at rt followed by Et3N (4 L,
m
m
5 mol %) when the mixture was instantly decolorized and after
5 min of stirring the mixture was evaporated to give pure nitro-
alkane 33 (114 mg, 95%) as a colourless oil, which was used without
further purification; Rf 0.63 (Petrol:Et2O 9:1); IR ymax (thin film)
1378, 1302, 1277, 1184, 1110, 833, 752, 698 cmꢀ1
;
1H NMR
2959, 2930, 2873, 1555, 1455, 1376, 747, 699 cmꢀ1 1H NMR
;
(600 MHz)
d
4.79 (m, 2H), 5.28 (m, 1H), 5.40 (d, J¼6.5, 1H), 6.59
(600 MHz)
2.45 (t, J¼7.4, 2H), 4.56 (t, J¼7.9, 1H), 4.76 (d, J¼7.8, 2H), 7.30e7.38
(m, 5H); 13C NMR (150 MHz)
13.5 (CH3), 21.8 (CH2), 31.1 (CH2), 31.3
d
0.87 (t, J¼7.4, 3H), 1.35 (m, 2H), 1.53 (quint., J¼7.6, 2H),
(app. d, J¼8.9, 2H), 7.36e7.44 (m, 5H), 8.05 (app. d, J¼8.9, 2H); 13C
NMR (150 MHz)
d
56.0 (CH), 79.6 (CH2),112.5 (CH),126.2 (CH),126.2
d
(CH), 129.2 (CH), 129.2 (CH), 129.6 (CH), 135.9 (Cq), 139.3 (Cq), 151.0
(Cq); m/z (EIþ) 287 (Mþ, 25%), 227 (85%), 181 (17%), 138 (24%), 104
(100%); HRMS: found 287.09031, C14H13N3O4 requires 287.09005.
(CH2), 46.5 (CH), 79.3 (CH2), 127.6 (CH), 128.4 (CH), 129.0 (CH), 137.4
(Cq); m/z (CIþ) 240 (MþHþ, 100%), 193 (MþꢀNO2, 56%), 179 (69%),
150 (Mþ-BuS, 67%); HRMS: found 240.10582, C12H18NO2S requires
240.10617; Anal. Cald. For C12H17NO2S: C, 60.22, H, 7.16, N, 5.85.
Found C, 60.32, H, 7.21, N, 5.92%.
4.3.15. N-(2-Nitro-1-phenylethyl)morpholine (30).46 To a solution of
b
-nitrostyrene (2, 149 mg, 1.00 mmol) in CH2Cl2 (5 mL) was added
morpholine (87 L,1.0 mmol) followed bySm(OTf)3 (1 mg, 0.2 mol %)
m
4.3.19. (2-Nitro-1-phenylethyl) (phenyl)sulfane (34).38 In an identi-
and the mixture was stirred at rt overnight until the nitroalkene was
consumed (TLC, 24 h). CH2Cl2 (10 mL) was then added, the mixture
washed with H2O (10 mL) and brine (10 mL), dried (MgSO4) and
evaporated in vacuo to give nitroalkane 30 (222 mg, 94%) as a red oil,
which was used without further purification; Rf 0.46 (Petrol:EtOAc
cal manner as for the preparation of 33, thiophenol (51 mL,
0.50 mmol) gave nitroalkane 34 (125 mg, 97%) as a colourless oil,
used without further purification; Rf 0.67 (Petrol:Et2O 9:1); 1H NMR
(600 MHz)
d
4.73 (dd, J¼12.8, 6.0, 1H), 4.86 (m, 1H), 4.91 (m, 1H),
49.7 (CH), 78.4 (CH2),
7.27e7.44 (m, 10H); 13C NMR (150 MHz)
d
4:1); 1H NMR (600 MHz)
d
2.36 (m, 2H), 2.52 (m, 2H), 3.64 (m, 4H),
4.34 (dd, J¼9.5, 5.8, 1H), 4.57 (dd, J¼12.3, 5.8, 1H), 4.99 (dd, J¼12.3,
9.5,1H), 7.20 (m, 2H), 7.37 (m, 3H); 13C NMR (150 MHz)
49.8 (CH2),
127.6 (CH), 128.5 (CH), 128.7 (CH), 128.9 (CH), 129.3 (CH), 131.7 (Cq),
133.7 (CH), 136.2 (Cq). Data in agreement with that reported.61
d
66.9 (CH2), 66.9 (CH), 79.6 (CH2), 128.3 (CH), 128.6 (CH), 129.3 (CH),
4.3.20. (2-Nitro-1-(phenylsulfonyl)ethyl)benzene (35).47 To a solu-
tion of sulfide 34 (259 mg, 1.00 mmol) in MeOH (5 mL), cooled to
133.6 (Cq). Data in agreement to that reported.46
0
ꢁC, was added OxoneÒ (923 mg, 1.50 mmol) in H2O (10 mL) and
4.3.16. 1-(2-Nitro-1-phenylethyl)-1H-benzo[d][1,2,3]triazole (31). To
the resulting suspension was stirred for 1 h, then left to warm to rt
and stirred overnight (22 h). After completion H2O (10 mL) was
added and the mixture extracted with CH2Cl2 (3ꢂ10 mL). The
combined organics were then washed with brine (10 mL), dried
(MgSO4) and evaporated in vacuo to give pure sulfone 35 (301 mg,
97%) as a white solid, which was used without further purification;
a solution of
was added 1H-benzo[d][1,2,3]triazole (12, 65 mg, 0.55 mmol) fol-
lowed by Et3N (6 L,10 mol %) and the mixture was stirred at rt until
b-nitrostyrene (2, 74 mg, 0.50 mmol) in CH2Cl2 (5 mL)
m
complete consumption of the nitroalkene (TLC, 19 h). The mixture
was then evaporated in vacuo and purification of the residue by flash
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042

12
J.C. Anderson et al. / Tetrahedron xxx (2014) 1e15
mp. 180e181 ꢁC; Rf 0.49 (Petrol:Et2O 4:1); IR ymax (thin film) 3068,
procedure A. Nitroalkane 4
(126 mg, 0.400 mmol), nBuLi
3009, 2956, 1553, 1496, 1447, 1417, 1374, 1360, 1298, 1280, 1143,
(0.40 mmol), imine 37 (170 mg, 0.800 mmol) and TFA (1.40 mmol)
after purification by flash column chromatography (Petrol:Me2CO
7:3) gave pyrrolidinone 42 (102 mg, 53%) as a white solid; mp.
96e97 ꢁC; Rf 0.28 (Petrol:Me2CO 7:3); IR ymax (thin film) 3003,
2940, 2839, 1713, 1611, 1595, 1553, 1512, 1457, 1364, 1249, 1205,
1080, 852, 760, 727, 700, 688 cmꢀ1; 1H NMR (600 MHz)
d 4.99 (dd,
J¼10.1, 4.7, 1H), 5.10 (dd, J¼14.0, 10.0, 1H), 5.37 (dd, J¼14.0, 4.6, 1H),
7.14 (m, 2H), 7.29 (m, 2H), 7.36 (m, 1H), 7.45 (m, 2H), 7.55 (m, 2H),
7.63 (m, 1H); 13C NMR (150 MHz)
d 67.9 (CH), 72.7 (CH2), 128.7 (Cq),
129.0 (CH),129.1 (CH),129.1 (CH),129.4 (CH),130.0 (CH),134.5 (CH),
135.8 (Cq); m/z (CIþ) 292 (Mþ, 30%), 251 (11%), 186 (13%), 150
(100%); HRMS: found 292.06466, C14H13NO4S requires 292.06435;
Anal. Cald. For C14H13NO4S: C, 57.72, H, 4.50, N, 4.81. Found C, 57.71,
H, 4.40, N, 4.72%.
1152, 1118, 1033, 835, 817, 701 cmꢀ1; 1H NMR (600 MHz)
d 3.72 (s,
3H), 3.77 (br s, 3H), 3.82 (s, 3H), 3.95 (br s, 3H), 5.12 (d, J¼9.5, 1H),
5.26 (dd, J¼9.6, 7.5, 1H), 5.70 (d, J¼7.5, 1H), 6.18 (m, 2H), 6.78 (app.
d, J¼9.1, 2H), 7.24 (app. d, J¼9.1, 1H), 7.26e7.32 (m, 5H); 13C NMR
(150 MHz)
d 44.2 (CH), 55.3, 55.4, 55.8 and 56.0 (CH3), 65.0 (CH),
90.9 and 91.4 (CH), 92.2 (CH), 104.1 (Cq), 114.0 (CH), 125.0 (CH),
127.1 (CH), 128.9 (CH), 129.0 (CH), 129.7 (Cq), 137.4 (Cq), 157.1 (Cq),
158.6 (Cq), 159.7 (Cq), 161.6 (Cq), 170.0 (Cq); m/z (EIþ) 479 (MþHþ,
100%), 432 (MþHþ-NO2, 70%), 264 (30%); HRMS: found 479.1808,
4.3.21. (2-Nitro-1-phenylethyl)diphenylphosphine oxide (36). To
a solution of
rt was added diphenylphosphine oxide (101 mg, 0.50 mmol) fol-
lowed by Et3N (4 L, 5 mol %) and the mixture was stirred at rt until
b-nitrostyrene (2, 74 mg, 0.50 mmol) in THF (2 mL) at
m
C18H20N3O4 requires 479.1818; Anal. Cald. For C26H27N2O7: C, 65.26,
the nitroalkene was consumed (TLC, 24 h). After completion, the
mixture was evaporated and purification by flash column chro-
matography (Petrol:Me2CO 1:1) gave phosphine oxide 36 (157 mg,
89%) as a white solid; mp. 206e207 ꢁC (lit.61 208e209 ꢁC); Rf 0.61
H, 5.48, N, 5.85. Found C, 65.39, H, 5.78, N, 5.59%.
4.4.1.3. (2S*,3R*,4R*)-Ethyl 1-(4-methoxyphenyl)-3-nitro-5-oxo-
2-phenyl-1,2,3,4,5,6,7,8-octahydroquinoline-4-carboxylate
(43). Prepared by general procedure A, except 2.1 equiv of nBuLi
was used. Nitroalkane 5 (36 mg, 0.14 mmol), nBuLi (0.28 mmol),
imine 37 (59 mg, 0.28 mmol) and TFA (0.49 mmol) after purification
by flash column chromatography (Petrol:Me2CO 7:3) gave quino-
line 43 (24 mg, 38%) as a yellow oil; Rf 0.17 (Petrol:Me2CO 7:3); IR
ymax (thin film) 2932, 1730, 1557, 1508, 1396, 1247, 1181, 1027, 841,
(Petrol:Me2CO 1:1); 1H NMR (600 MHz)
d
4.42 (m,1H), 4.76 (m,1H),
5.12 (m, 1H), 7.21e7.28 (m, 7H), 7.39e7.44 (m, 3H), 7.62 (m, 3H),
7.99 (m, 2H); 13C NMR (150 MHz)
d
45.8 (d, J¼64.0, CH), 72.7 (d,
J¼5.9, CH2), 128.2 (d, J¼2.5, CH), 128.3 (d, J¼12.3, CH), 128.7 (d,
J¼1.7, CH), 129.3 (d, J¼11.6, CH), 129.4 (d, J¼5.1, CH), 129.6 (d, J¼8.6,
Cq), 130.3 (Cq), 130.9 (d, J¼9.2, CH), 131.1 (d, J¼8.8, CH), 131.6 (d,
J¼5.6, Cq), 132.0 (d, J¼2.8, CH), 132.7 (d, J¼2.8, CH). Data in agree-
ment to that reported.62
733, 702 cmꢀ1; 1H NMR (600 MHz)
d
1.28 (t, J¼7.2, 3H),1.92 (m, 2H),
2.22 (m, 2H), 2.40 (m, 2H), 3.74 (s, 3H), 4.22 (m, 2H), 4.43 (d, J¼5.3,
1H), 5.19 (dd, J¼8.7, 5.3, 1H), 5.24 (d, J¼8.8, 1H), 6.40e6.90 (br, 4H),
4.4. Nitro-Mannich reaction of nitroacrylate adducts
7.15 (m, 2H), 7.26 (m, 3H); 13C NMR (150 MHz, at 60 ꢁC)
d 14.0 (CH3),
21.3 (CH2), 28.9 (CH2), 35.8 (CH2), 39.6 (CH), 55.3 (CH3), 61.8 (CH2),
63.7 (CH), 85.5 (CH), 104.2 (Cq), 114.6 (CH), 128.2 (CH), 28.9 (CH),
129.1 (CH), 130.1 (CH), 134.7 (Cq), 135.3 (Cq), 158.9 (Cq), 161.3 (Cq),
171.0 (Cq), 193.8 (Cq); m/z (EIþ) 450 (Mþ, 32%), 404 (MþꢀNO2, 86%),
330 (Mþ-HNO2-COOEt, 100%), 254 (Mþ-NO2-COOEt -Ph, 35%);
HRMS: found 450.17902, C25H26N2O6 requires 450.17854.
4.4.1. General procedure A for the synthesis of pyrrolidin-2-ones. A
solution of nitroalkane (0.50 mmol) in THF (5 mL), was cooled to
ꢀ78 ꢁC and nBuLi (0.55 mmol, of a 2.5 M solution in hexanes,
1.1 equiv) was added dropwise. The orange mixture was stirred at
this temperature for 10 min before the imine 37 (1.00 mmol,
2.0 equiv) in THF (2 mL) was added via cannula. The mixture was
stirred for 20 min, before TFA (1.75 mmol, 3.5 equiv) in THF (0.5 mL)
was added via cannula. The mixture was stirred at this temperature
for a further 1 h before being warmed to rt for 16 h. Saturated
aqueous NaHCO3 (20 mL) and Et2O (20 mL) were then added and
the layers separated. The aqueous phase was extracted with Et2O
(3ꢂ20 mL), and the combined organics washed with brine (20 mL),
dried (MgSO4) and concentrated in vacuo to leave the crude pyr-
rolidinone. which was purified by column chromatography.
4.4.1.4. (3S*,4R*,5R*)-3-Methoxy-1-(4-methoxyphenyl)-4-nitro-
5-phenylpyrrolidin-2-one (44). Prepared by general procedure A.
Nitroalkane 6 (75 mg, 0.42 mmol), nBuLi (0.460 mmol), imine 37
(134 mg, 0.640 mmol) and TFA (0.850 mmol) after purification by
flash column chromatography (Petrol:EtOAc 7:3) gave pyrrolidi-
none 44 (60 mg, 42%) as an orange oil that was unstable (degra-
dation was observed after 30 min at rt); Rf 0.35 (Petrol:EtOAc 7:3);
IR ymax (thin film) 2958, 2925, 1713, 1555, 1511, 1367, 1248, 1106,
1030, 834, 700 cmꢀ1; 1H NMR (600 MHz)
d 3.72 (s, 1H), 3.75 (s, 1H),
4.4.1.1. (3S*,4S*,5R*)-3-(1H-Indol-3-yl)-1-(4-methoxyphenyl)-4-
nitro-5-phenylpyrrolidin-2-one (41). Prepared by general procedure
A. Nitroalkane 3 (153 mg, 0.620 mmol), nBuLi (0.680 mmol), imine
37 (260 mg, 1.24 mmol) and TFA (2.17 mmol) after purification by
flash column chromatography (Petrol:EtOAc 3:2) gave pyrrolidi-
none 41 (140 mg, 53%, 79% based on recovered starting material) as
an orange solid; mp. 196e197 ꢁC; Rf 0.34 (Petrol:EtOAc 3:2); IR ymax
4.74 (d, J¼6.0, 1H), 5.02 (t, J¼5.8, 1H), 5.48 (d, J¼5.7,1H), 6.78 (app d,
J¼9.1, 2H), 7.20 (app d, J¼9.1, 2H), 7.21e7.40 (m, 5H); 13C NMR
(150 MHz)
d 55.3 (CH3), 59.6 (CH3), 64.1 (CH), 81.2 (CH), 91.1 (CH),
114.2 (CH), 125.3 (CH), 127.1 (CH), 128.4 (Cq), 129.3 (CH), 129.4 (CH),
135.9 (Cq), 157.9 (Cq), 167.2 (Cq); m/z (EIþ) 342 (Mþ, 100%), 266
(Mþ-PhþH, 23%), 147 (17%); HRMS: found 342.12084, C18H18N2O5
requires 342.12102.
(thin film) 3329, 2960, 1701, 1555, 1512, 1364, 1250, 743 cmꢀ1
NMR (600 MHz)
3.74 (s, 1H), 4.92 (d, J¼7.9, 1H), 5.27 (dd, J¼7.8,
6.5,1H), 5.73 (d, J¼6.3,1H), 6.85 (m, 3H), 7.21 (m, 2H), 7.23e7.36 (m,
7H), 7.64 (m, 1H), 8.70 (br s, 1H); 13C NMR (150 MHz)
46.5 (CH),
;
1H
d
4.4.1.5. (3S*,4R*,5R*)-1-(4-Methoxyphenyl)-3-morpholino-4-
nitro-5-phenylpyrrolidin-2-one (45). Prepared by general pro-
cedure A. Nitroalkane 10 (105 mg, 0.450 mmol), nBuLi
(0.500 mmol), imine 37 (143 mg, 0.680 mmol) and TFA
(0.990 mmol) after purification by flash column chromatography
(Petrol:EtOAc 3:2) gave pyrrolidinone 45 (12 mg, 7%) as an orange
oil that was unstable (degradation was observed after 30 min at rt);
Rf 0.31 (Petrol:EtOAc 3:2); IR ymax (thin film) 2961, 2853, 1709, 1557,
d
55.3 (CH3), 65.9 (CH), 92.4 (CH), 108.5 (Cq), 112.0 (CH), 114.2 (CH),
118.1 (CH), 120.2 (CH), 122.5 (CH), 124.3 (CH), 125.4 (CH), 125.4 (Cq),
126.9 (CH), 129.2 (CH), 129.2 (Cq), 129.3 (CH), 136.2 (Cq), 136.6 (Cq),
157.7 (Cq), 170.8 (Cq); m/z (EIþ) 427 (Mþ, 20%), 380 (Mþ-HNO2,
100%), 351 (MþHþ-Ph, 17%), 230 (10%), 210 (17%); HRMS: found
427.15312, C18H20N3O4 requires 427.15266.
1512, 1249, 1115,1031, 835 cmꢀ1; 1H NMR (600 MHz)
d 2.87 (m, 4H),
3.73 (s, 3H), 3.78 (m, 4H), 4.46 (d, J¼7.4, 1H), 5.10 (dd, J¼7.4, 6.2,1H),
4.4.1.2. (3S*,4S*,5R*)-1-(4-methoxyphenyl)-4-nitro-5-phenyl-3-
(2,4,6-trimethoxyphenyl)pyrrolidin-2-one (42). Prepared by general
5.50 (d, J¼6.2, 1H), 6.79 (app d, J¼8.9, 2H), 7.15e7.35 (m, 7H); 13C
NMR (150 MHz) d 49.3 (CH2), 55.3 (CH3), 64.2 (CH), 66.8 (CH2), 70.4
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042

J.C. Anderson et al. / Tetrahedron xxx (2014) 1e15
13
(CH), 87.3 (CH), 114.2 (CH), 125.0 (CH), 126.6 (CH), 128.8 (Cq), 129.3
(CH), 129.4 (CH), 136.4 (Cq), 157.7 (Cq), 167.0 (Cq); m/z (CIþ) 398
(MþHþ, 7%), 310 (Mþ-C4H5NO, 11%), 266 (MþHþ- C4H5NOeNO2,
18%), 227 (72%), 105 (100%); HRMS: found 398.17131, C21H24N3O5
requires 398.17160.
(CH), 90.0 (CH), 107.3 (Cq), 112.9 (CH), 113.4 (CH), 116.1 (CF3, q,
J¼288.7), 126.7 and 127.4 (CH), 127.7 (Cq), 127.9, 128.2, 128.3 and
131.6 (CH), 131.6 (Cq), 131.7 and 132.7 (CH), 140.1 (Cq), 157.5 (O]
CCF3, q, J¼35.6), 159.5 and 160.6 (Cq); 19F NMR (282 MHz)
ꢀ67.74
d
(3F, s, CF3); m/z (ESþ) 647 (MþNaþ, 20%), 625 (MþHþ, 15%), 578
(MþꢀNO2,15%), 457 (25%), 378 (15%), 359 (Mþ-NO2-PMPeNHeTFA,
70%), 257 ((OMe)3C6H3CHþPh, 100%); HRMS: found 647.2003,
4.5. Nitro-Mannich reaction to
b-nitrostyrene adducts
C33H31F3N2O7Na requires 647.1981; Anal. Cald. For C33H31F3N2O7: C,
4.5.1. General procedure B for the synthesis of
b
-nitroamides. A so-
63.46, H, 5.00, N, 4.48. Found C, 63.36, H, 4.96, N, 4.44%.
lution of nitroalkane (0.500 mmol) in THF (5 mL), was cooled to
ꢀ78 ꢁC and nBuLi (0.550 mmol, of a 2.5 M solution in hexanes,
1.1 equiv) was added dropwise. The orange mixture was stirred at
this temperature for 10 min, before the imine 37 (1.00 mmol,
2.0 equiv) in THF (2 mL) was added via cannula. The mixture was
stirred for 10 min before a 1:1 vol. mixture of TFA:THF (TFA
1.75 mmol, 3.5 equiv) was added dropwise. The mixture was stirred
at this temperature for a further 1 h, then warmed to rt over 5 min
and quenched with saturated aqueous NaHCO3 (10 mL) extracted
with Et2O (3ꢂ10 mL), dried (MgSO4), concentrated in vacuo to give
4.5.1.3. 2,2,2-Trifluoro-N-((1R*,2R*,3S*)-3-methoxy-2-nitro-1,3-
diphenylpropyl)-N-(4-methoxyphenyl)acetamide (48). Prepared by
general procedure B. Nitroalkane 22 (44 mg, 0.24 mmol), nBuLi
(96
(64
m
m
L, 2.5 M, 0.24 mmol), imine 37 (101 mg, 0.480 mmol) and TFA
L, 0.840 mmol) gave after TFA-protection and purification by
flash column chromatography (Petrol:Et2O 4:1) 48 (83 mg, 71%) as
a white solid; mp. 69e70 ꢁC; Rf 0.32 (Petrol:Et2O 4:1); IR ymax (thin
film) 2937, 2837, 1692,1557, 1509,1254,1203,1182, 1151,1096,1026,
842, 754, 733, 699, 659 cmꢀ1 1H NMR (600 MHz)
; d 3.24 (s, 3H),
crude
b
-nitroamine. A sample was taken for 1H NMR analysis and
3.82 (s, 3H), 5.06 (d, J¼8.4, 1H), 5.38 (dd, J¼10.9, 8.5, 1H), 6.01 (dd,
J¼8.8, 2.6, 1H), 6.54 (dd, J¼8.8, 3.0, 1H), 6.89 (d, J¼11.0, 1H), 6.92 (m,
2H), 7.00 (dd, J¼8.7, 3.0, 1H), 7.16 (app t, J¼7.7, 2H), 7.25 (m, 1H),
7.36e7.44 (m, 5H), 7.73 (dd, J¼8.8, 2.6, 1H); 13C NMR (150 MHz)
the rest of the crude product was dissolved in CH2Cl2 (6 mL), cooled
to ꢀ78 ꢁC and pyridine (140
mL, 1.50 mmol) and trifluoroacetic
anhydride (240 mL, 1.50 mmol) were added. The mixture was then
warmed to rt and stirred for a further 3 h. The mixture was then
washed with aqueous HCl 2 M (3ꢂ10 mL) and brine (10 mL), dried
(MgSO4), concentrated in vacuo and purified by flash column
d 55.4 (CH3), 57.0 (CH3), 61.7 (CH), 84.7 (CH), 89.5 (CH), 113.5 (CH),
113.6 (CH), 116.6 (q, J¼290.1, CF3), 126.8 (Cq), 127.7 (CH), 128.4 (CH),
128.7 (CH), 129.3 (CH), 129.3 (CH), 129.5 (CH), 131.4 (CH), 132.9 (Cq),
133.5 (CH), 135.6 (CH), 157.9 (q, J¼35.7, C]OCF3), 160.1 (Cq); 19F
chromatography to give the trifluoroacetamide protected
b-
nitroamine.
NMR (282 MHz)
d
ꢀ67.82 (3F, s, CF3); m/z (EIþ) 488 (Mþ, 5%), 219
(PMPNHTFAþ, 8%), 149 (14%), 121 (PhCH-OMeþ, 100%); HRMS:
found 488.15642, C25H23F3NO5 requires 488.15535; Anal. Cald. For
4.5.1.1. N-((1R*,2S*,3R*)-3-(1H-Indol-3-yl)-2-nitro-1,3-
diphenylpropyl)-2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide
(46). Prepared by general procedure B. Nitroalkane 16 (123 mg,
C25H23F3NO5: C, 61.47, H, 4.75, N, 5.74. Found C, 61.60, H, 5.05, N,
5.63%.
0.460 mmol), nBuLi (184
0.920 mmol) and TFA (123
m
L, 2.5 M, 0.460 mmol), imine 37 (194 mg,
mL, 1.61 mmol) gave after TFA-protection
4.5.1.4. N-((1R*,2R*,3S*)-3-Ethoxy-2-nitro-1,3-diphenylpropyl)-
and purification by flash column chromatography (Petrol:Et2O 1:1)
46 (133 mg, 50%) as a colourless oil; Rf 0.34 (Petrol:Et2O 1:1); IR
ymax (thin film) 3420, 3063, 3034, 2927, 2840, 1691, 1606, 1555,
1510, 1497, 1456, 1414, 1367, 1301, 1255, 1206, 1180, 1157, 1033, 840,
2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide (49). Prepared by
general procedure B. Nitroalkane 23 (110 mg, 0.560 mmol), nBuLi
(224
(150
m
m
L, 2.5 M, 0.560 mmol), imine 37 (236 mg, 1.12 mmol) and TFA
L, 1.96 mmol) gave after TFA-protection and purification by
756, 734, 699 cmꢀ1; 1H NMR (600 MHz)
d
3.74 (s, 3H), 4.91 (d, J¼6.7,
flash column chromatography (Petrol:Et2O 4:1) 49 (219 mg, 78%) as
a yellow oil; Rf 0.36 (Petrol:Et2O 4:1); IR ymax (thin film) 2977, 1694,
1556, 1510, 1457, 1300, 1254, 1203, 1182, 1152, 1092, 1075, 1032, 843,
1H), 5.92 (dd, J¼8.9, 2.8, 1H), 6.25 (d, J¼9.2, 1H), 6.40 (dd, J¼6.6, 9.2,
1H), 6.49 (dd, J¼8.8, 3.0, 1H), 6.63 (dd, J¼8.8, 3.0, 1H), 6.79 (dd,
J¼8.7, 2.7, 1H), 6.92 (dd, J¼8.2, 1.1, 2H), 7.01e7.34 (m, 9H), 7.41 (m,
783, 755, 733, 699 cmꢀ1
;
1H NMR (600 MHz)
d
1.17 (t, J¼7.1, 3H),
3H), 6.92 (d, J¼2.5, 1H), 8.25 (br s, 1H); 13C NMR (150 MHz)
d
43.9
3.40 (m, 2H), 3.82 (s, 3H), 5.13 (d, J¼8.4, 1H), 5.38 (dd, J¼10.9, 8.5,
1H), 6.01 (dd, J¼9.1, 2.4, 1H), 6.55 (dd, J¼8.9, 3.1, 1H), 6.83 (d, J¼10.9,
1H), 6.92 (m, 2H), 7.00 (dd, J¼8.8, 3.0,1H), 7.16 (m, 2H), 7.25 (m, 2H),
(CH), 55.3 (CH3), 62.8 (CH), 89.1 (CH), 111.2 (CH), 113.4 (CH), 113.6
(CH), 114.7 (Cq), 116.1 (q, J¼289.0), 118.8, 120.0, 122.3, 122.6, 127.7,
128.4, 128.6, 128.7, 129.3, 129.6, 131.1 and 132.5 (CH), 126.4, 126.9,
132.8, 136.0 and 138.3 (Cq), 158.3 (q, J¼35.5, Cq), 160.1 (Cq); 19F
7.38 (m, 5H), 7.74 (dd, J¼8.7, 2.5, 1H); 13C NMR (150 MHz)
d 14.6
(CH3), 55.4 (CH3), 61.7 (CH), 65.2 (CH2), 83.2 (CH), 89.9 (CH), 113.5
(CH), 113.6 (CH), 116.4 (q, J¼288.5, CF3), 126.8 (Cq), 127.6 (CH), 128.4
(CH), 128.7 (CH), 129.2 (CH), 129.3 (CH), 131.7 (CH), 133.4 (Cq), 133.5
(CH), 136.4 (Cq), 157.7 (q, J¼35.0, Cq), 160.2 (Cq); 19F NMR
NMR (282 MHz)
d
ꢀ67.60 (3F, s, CF3); m/z (EIþ) 573 (Mþ, 27%), 308
(Mþ-NO2-PMPeNHeTFA,100%), 206 (PhCHþ-(Indole), 32%); HRMS:
found 573.18730, C32H26F3N3O4 requires 573.18699.
(282 MHz)
d
ꢀ67.31 (3F, s, CF3); m/z (CIþ) 502 (Mþ, 27%), 410 (Mþ-
4.5.1.2. 2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-((1R*,2S*,3R*)-2-
nitro-1,3-diphenyl-3-(2,4,6-trimethoxyphenyl)propyl)acetamide
(47). Prepared by general procedure B. Nitroalkane 17 (113 mg,
EtOH-NO2, 24%), 135 (100%); HRMS: found 502.17064,
C26H25F3N2O5 requires 502.17101.
0.360 mmol), nBuLi (144
0.720 mmol) and TFA (96
m
L, 2.5 M, 0.360 mmol), imine 37 (150 mg,
4.5.1.5. N-((1R*,2R*,3S*)-3-(Benzyloxy)-2-nitro-1,3-
mL, 1.26 mmol) gave after TFA-protection
diphenylpropyl)-2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide
(50). Prepared by general procedure B. Nitroalkane 24 (160 mg,
and purification by flash column chromatography (Petrol:Et2O 4:1)
47 (185 mg, 83%) as a white solid, mp. 185e186 ꢁC; Rf 0.13 (Petro-
l:Et2O 4:1); IR ymax (thin film) 3031, 2939, 2841, 1696, 1605, 1590,
1550, 1510, 1495, 1455, 1203, 1180, 1150, 1122, 1059, 1035, 814, 735,
0.620 mmol), nBuLi (248
m
L, 2.5 M, 0.620 mmol), imine 37 (262 mg,
1.24 mmol) and TFA (166
mL, 2.17 mmol) gave after TFA-protection
and purification by flash column chromatography (Petrol:Et2O 9:1)
50 (224 mg, 64%) as a yellow oil; Rf 0.26 (Petrol:Et2O 9:1); IR ymax
(thin film) 3035, 1696, 1557, 1510, 1254, 1206, 1183, 1169, 1156, 1069,
699 cmꢀ1; 1H NMR (600 MHz)
d 3.30 (br s, 3H), 3.72 (s, 3H), 3.77 (s,
3H), 4.05 (br s, 3H), 5.14 (d, J¼11.5, 1H), 5.70e6.20 (br s, 2H), 5.78 (d,
J¼6.8, 1H), 6.01 (dd, J¼9.0, 2.9, 1H), 6.35 (dd, J¼9.0, 3.1, 1H), 6.73 (d,
J¼7.6, 2H), 6.76 (dd, J¼8.8, 2.9, 1H), 7.01 (app. t, J¼7.6, 2H), 7.04 (m,
1H), 7.13 (dd, J¼11.5, 6.8, 1H), 7.15e7.19 (m, 4H), 7.46 (app. d, J¼7.6,
912, 734, 700 cmꢀ1 1H NMR (600 MHz)
; d 3.78 (s, 3H), 4.33 (d,
J¼10.9, 1H), 4.53 (d, J¼10.9, 1H), 5.22 (d, J¼6.7, 1H), 5.50 (dd, J¼11.0,
6.8, 1H), 5.96 (dd, J¼8.8, 2.5, 1H), 6.50 (dd, J¼8.8, 3.0, 1H), 6.70 (d,
J¼11.0, 1H), 6.82 (dd, J¼8.8, 3.0, 1H), 6.94 (d, J¼7.4, 2H), 7.17 (m, 2H),
2H); 13C NMR (150 MHz)
d 41.2 (CH), 55.3 (CH3), 65.2 (CH), 87.0
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042

14
J.C. Anderson et al. / Tetrahedron xxx (2014) 1e15
7.25 (m, 2H), 7.30 (m, 5H), 7.47 (m, 3H), 7.52 (m, 2H); 13C NMR
(150 MHz) 55.3 (CH3), 61.0 (CH), 71.5 (CH2), 81.7 (CH), 90.0 (CH),
8.01 (d, J¼8.3, 1H); 13C NMR (150 MHz)
d 55.3 (CH3), 63.0 (CH), 63.9
d
(CH), 86.0 (CH), 109.1 (CH), 113.2 (CH), 113.8 (CH), 115.9 (q, J¼288.6,
CF3), 120.2 (CH), 124.4 (CH), 126.9 (CH), 127.2 (Cq), 127.9 (CH), 128.4
(CH),129.0 (CH), 129.2 (CH),129.6 (CH), 129.8 (Cq),129.9 (CH), 130.2
(CH), 131.4 (CH), 131.7 (CH), 132.2 (Cq), 132.6 (CH), 132.5 (Cq), 145.8
(Cq), 158.2 (q, J¼35.9, O]CCF3), 159.9 (Cq); 19F NMR (282 MHz)
113.3 and 113.6 (CH), 116.1 (q, J¼288.7, CF3), 126.4 (Cq), 127.9, 128.2,
128.4, 128.4, 128.7, 128.9, 129.0, 129.3, 129.6, 131.4 and 133.2 (CH),
133.4,135.4 and 136.3 (Cq),157.8 (q, J¼35.2, Cq),160.1 (Cq); 19F NMR
(282 MHz)
d
ꢀ67.47 (3F, s, CF3); m/z (CIþ) 564 (Mþ, 100%), 410 (Mþ-
BnOH-NO2, 57%), 197 (28%); HRMS: found 564.18742, C31H27F3N2O5
requires 564.18666.
d
ꢀ67.86 (3F, s, CF3); m/z (EIþ) 575 (Mþ, 18%), 410 (Mþ-
C6H4N3eHNO2, 25%), 357 (Mþ-PMP-N-TFA, 100%), 282 (39%), 180
(65%); HRMS: found 575.17786, C30H24F3N5O4 requires 575.17749.
4.5.1.6. 2,2,2-Trifluoro-N-((1R*,2R*,3S*)-3-isopropoxy-2-nitro-
1,3-diphenylpropyl)-N-(4-methoxyphenyl)acetamide (51). Prepared
by general procedure B. Nitroalkane 25 (95 mg, 0.45 mmol), nBuLi
4.5.1.9. 2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-((1R*,2R*,3S*)-2-
nitro-3-(2-oxooxazolidin-3-yl)-1,3-diphenylpropyl)acetamide
(54). Prepared by general procedure B. Nitroalkane 32 (134 mg,
(180
TFA (121
m
L, 2.5 M, 0.450 mmol), imine 37 (190 mg, 0.900 mmol) and
L, 1.58 mmol) gave after TFA-protection and purification
m
0.570 mmol), nBuLi (248
1.14 mmol) and TFA (153
mL, 2.5 M, 0.620 mmol), imine 37 (240 mg,
by flash column chromatography (Petrol:Et2O 4:1) 51 (186 mg, 80%)
as a yellow oil; Rf 0.36 (Petrol:Et2O 4:1); IR ymax (thin film) 2976,
1695, 1556, 1510, 1254, 1203, 1168, 1153, 1120, 1090, 1067, 1034, 843,
mL, 2.00 mmol) gave after TFA-protection
and purification by flash column chromatography (Petrol:EtOAc
4:1) 54 (101 mg, 33%) as a white solid; mp. 202e203 ꢁC; Rf 0.21
(Petrol:EtOAc 4:1); IR ymax (thin film) 2926, 1748, 1695, 1557, 1511,
757, 733, 700 cmꢀ1
;
1H NMR (600 MHz)
d
1.16 (d, J¼6.2, 6H), 3.53
(m, 2H), 3.83 (s, 3H), 5.24 (d, J¼7.7, 1H), 5.43 (dd, J¼10.7, 7.7, 1H),
6.07 (d, J¼8.7, 1H), 6.58 (dd, J¼8.9, 3.0, 1H), 6.75 (d, J¼10.8, 1H), 6.95
(m, 2H), 6.99 (dd, J¼8.8, 3.0, 1H), 7.17 (m, 2H), 7.26 (m, 2H), 7.38 (m,
1412, 1252, 1207, 1181, 1034, 734, 703 cmꢀ1 1H NMR (600 MHz,
;
60 ꢁC)
d
3.22 (dt, J¼8.2, 7.3, 1H), 3.78 (s, 3H), 3.82 (ddd, J¼12.2, 8.3,
3.9, 1H), 4.25 (ddd, J¼12.8, 9.1, 4.0, 1H), 4.32 (dt, J¼9.5, 8.6, 1H), 5.56
(d, J¼10.3, 1H), 5.77 (d, J¼7.8, 1H), 6.55 (dd, J¼9.9, 7.9, 1H), 6.66 (dd,
J¼8.9, 2.8, 1H), 6.71 (m, 1H), 6.80 (dd, J¼8.9, 2.9, 1H), 7.04 (app. d,
J¼7.6, 2H), 7.09 (app. d, J¼8.1, 1H), 7.21 (app. t, J¼7.7, 2H), 7.31 (m,
5H), 7.70 (m, 1H); 13C NMR (150 MHz)
d 19.6 (CH3), 23.0 (CH3), 55.4
(CH3), 61.1 (CH), 69.3 (CH), 80.2 (CH), 90.4 (CH), 113.5 (CH), 113.6
(CH), 116.3 (q, J¼288.7, CF3), 126.8 (Cq), 127.6 (CH), 128.4 (CH), 128.8
(CH), 129.1 (CH), 129.3 (CH), 129.3 (CH), 131.7 (CH), 133.5 (CH), 133.7
(Cq),136.5 (Cq),157.5 (q, J¼35.4, Cq),160.2 (Cq); 19F NMR (282 MHz)
1H), 7.37 (m, 5H); 13C NMR (150 MHz)
d 42.5 (CH2), 55.4 (CH3), 59.1
(CH), 62.4 (CH2), 67.2 (CH), 85.8 (CH),113.4 (CH),114.4 (CH),116.0 (q,
J¼288.9, CF3), 128.3 (CH), 128.5 (CH), 128.5 (Cq), 129.1 (CH), 129.5
(CH), 129.8 (CH), 130.3 (CH), 131.5 (CH), 131.7 (Cq), 131.9 (CH), 132.5
(Cq), 158.2 (Cq), 158.6 (q, J¼35.9, O]CCF3), 160.1 (Cq); 19F NMR
d
ꢀ67.24 (3F, s, CF3); m/z (CIþ) 516 (Mþ, 32%), 410 (Mþ-IPA-NO2,
100%), 308 (24%); HRMS: found 516.18577, C27H27F3N2O5 requires
516.18666.
(282 MHz)
d
ꢀ67.63 (3F, s, CF3); m/z (ESIþ) 544 (MþHþ, 55%), 497
4.5.1.7. 2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-((1R*,2S*,3S*)-2-
nitro-3-((4-nitrophenyl)amino)-1,3-diphenylpropyl)acetamide
(52). Prepared by general procedure B. Nitroalkane 29 (114 mg,
(MþꢀNO2, 100%), 325 (Mþ-PMPNTFA, 40%), 308 (PhCHN(TFA)PMP,
40%); HRMS: found 544.1682, C27H25F3N3O6 requires 544.1695;
Anal. Cald. For C27H24F3N3O6: C, 59.67, H, 4.45, N, 7.73. Found C,
59.43, H, 4.51, N, 7.44%.
0.400 mmol), nBuLi (160
0.800 mmol) and TFA (31
m
m
L, 2.5 M, 0.400 mmol), imine 37 (169 mg,
L, 0.400 mmol) gave after TFA-protection
and purification by flash column chromatography (Petrol:Me2CO
4:1) 52 (40 mg, 17%) as a yellow solid; mp. 141e142 ꢁC, Rf 0.30
(Petrol:Me2CO 4:1); IR ymax (thin film) 3332, 1693, 1595, 1558, 1510,
1287,1258,1209,1180,1160,1109,1038, 838, 754, 733, 698 cmꢀ1; 1H
4.5.1.10. N-((1R*,2R*)-3-(Butylthio)-2-nitro-1,3-diphenylpropyl)-
2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide (55). Prepared by
general procedure B. Nitroalkane 33 (92 mg, 0.39 mmol), nBuLi
(156
mL, 2.5 M, 0.390 mmol), imine 37 (163 mg, 0.780 mmol) and
NMR (600 MHz)
d
3.77 (s, 3H), 5.33 (dd, J¼9.4, 3.1, 1H), 5.75 (dd,
TFA (105 m
L, 1.37 mmol) gave after TFA-protection and purification
J¼10.8, 3.1, 1H), 5.97 (app d, J¼8.8, 1H), 6.18 (d, J¼9.4, 1H), 6.34 (app
d, J¼8.8, 1H), 6.37 (d, J¼10.8, 1H), 6.54 (dd, J¼8.8, 3.0, 1H), 6.67 (app
d, J¼9.1, 1H), 6.72 (dd, J¼8.8, 3.1, 1H), 7.00 (m, 2H), 7.24 (app t, J¼7.3,
2H), 7.33 (app t, J¼7.5, 1H), 7.40e7.48 (m, 5H), 8.09 (app d, J¼9.1,
by flash column chromatography (Petrol:Et2O 9:1) 55 (118 mg, 56%)
as a yellow oil, Rf 0.44 (Petrol:Et2O 9:1); diastereoisomer ratio
(60:40) calculated by CHS signal,
ymax (thin film) 2960, 1697, 1557, 1510, 1255, 1208, 1181, 1165, 1035,
840, 734, 700 cmꢀ1 1H NMR (600 MHz)
d
major¼4.49,
d
minor¼4.44; IR
2H); 13C NMR (150 MHz)
d
55.5 (CH3), 58.0 (CH), 60.4 (CH), 90.0
;
d
0.86 (t, J¼7.4, 3H),
(CH), 112.5 (CH), 113.4 (CH), 113.7 (CH), 116.0 (q, J¼288.3, CF3), 126.3,
127.0, 128.7, 128.9, 129.6, 129.6, 129.8, 130.1 and 132.5 (CH), 133.2
(Cq), 135.0 (Cq),139.6 (Cq), 150.8 (Cq), 158.8 (q, J¼35.8, C]OCF3),
1.31e1.57 (m, 4H), 2.32 (t, J¼7.4, 2H), 3.82 (s, 3H), 4.49 (d, J¼6.2,1H),
5.64 (dd, J¼10.4, 6.2, 1H), 6.04 (dd, J¼8.8, 2.7, 1H), 6.40 (d, J¼10.3,
1H), 6.56 (dd, J¼8.8, 2.9, 1H), 6.93e7.44 (m, 10H); 13C NMR
160.4 (Cq); 19F NMR (282 MHz)
d
ꢀ67.41 (3F, s, CF3); m/z (EIꢀ) 593
(150 MHz) d 13.5 (CH3), 21.8, 30.5, 31.7 (CH2), 49.5 (CH), 55.4 (CH3),
(M-Hþ, 75%), 547 (M-HNOþ2 , 100%); HRMS: found 593.1653,
62.0 (CH), 89.8 (CH), 113.7, 113.8 (CH), 116.4 (q, J¼288.4, CF3), 126.7
(Cq), 128.1, 128.5, 128.7, 128.8, 128.9, 128.9, 129.3, 129.6, 131.2, 132.9
(CH), 133.0, 136.0, 137.4 (Cq), 158.3 (q, J¼35.6, O]CCF3), 160.2 (Cq);
C
30H24F3N4O6 requires 593.1648; Anal. Cald. For C30H25F3N4O6: C,
60.61, H, 4.24, N, 9.42. Found C, 60.33, H, 4.21, N, 9.39%.
19F NMR (282 MHz)
d
ꢀ67.71 (3F, s, CF3); m/z (EIþ) 547 (MþHþ, 4%),
4.5.1.8. N-((1R*,2R*,3S*)-3-(1H-Benzo[d][1,2,3]triazol-1-yl)-2-
nitro-1,3-diphenylpropyl)-2,2,2-trifluoro-N-(4-methoxyphenyl)acet-
amide (53). Prepared by general procedure B. Nitroalkane 31
500 (MþꢀNO2, 52%), 457 (Mþ-BuS, 100%), 193 (38%); HRMS: found
547.18784, C28H30F3N2O4S requires 547.18833; Anal. Cald. For
C
28H29F3N2O4S: C, 61.53, H, 5.35, N, 5.13. Found C, 61.14, H, 5.48, N,
5.33%.
Minor diastereomer: 1H NMR (600 MHz)
(111 mg, 0.410 mmol), nBuLi (164
mL, 2.5 M, 0.410 mmol), imine 37
(173 mg, 0.820 mmol) and TFA (110 L, 1.44 mmol) gave after TFA-
m
d
0.84 (t, J¼7.4, 3H),
protection and purification by flash column chromatography (Pet-
rol:Et2O 9:1) 53 (23 mg, 10%, 47% based on recovered starting
material) as a colourless oil; Rf 0.13 (Petrol:Et2O 9:1); IR ymax (thin
film) 2958, 2926, 2856, 1694, 1557, 1510, 1455, 1300, 1254, 1207,
1180, 1163, 1036, 841, 775, 744, 734, 701 cmꢀ1; 1H NMR (600 MHz)
1.31e1.57 (m, 4H), 2.45 (td, J¼7.1, 2.5, 2H), 3.82 (s, 3H), 4.44 (d,
J¼4.6, 1H), 5.59 (br. d, J¼9.6, 1H), 6.24 (dd, J¼10.4, 4.6, 1H), 6.63 (d,
J¼8.6, 1H), 6.74 (dd, J¼8.8, 2.9, 1H), 6.83 (dd, J¼8.8, 3.0, 1H),
6.93e7.44 (m, 9H); 13C NMR (150 MHz)
d 13.5 (CH3), 22.0, 31.0, 32.4
(CH2), 49.9 (CH), 55.4 (CH3), 67.9 (CH), 92.4 (CH), 113.3, 114.6 (CH),
116.2 (q, J¼288.4, CF3), 128.5, 128.7, 129.3, 129.6, 130.6, 130.7 (CH),
133.5 (Cq), 158.3 (q, J¼35.6, O]CCF3), 160.1 (Cq), 6 CH and three Cq
d
3.74 (s, 3H), 5.87 (d, J¼6.3, 1H), 6.02 (dd, J¼8.8, 2.4, 1H), 6.08 (d,
J¼10.7, 1H), 6.39 (dd, J¼8.8, 2.9, 1H), 6.75 (d, J¼7.7, 2H), 6.80 (dd,
J¼8.8, 2.9, 1H), 7.16 (m, 3H), 7.32 (m, 1H), 7.39 (m, 7H), 7.52 (s, 2H),
peaks missing; 19F NMR (282 MHz)
d
ꢀ67.73 (3F, s, CF3).
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042

J.C. Anderson et al. / Tetrahedron xxx (2014) 1e15
15
17. Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, Y. Chem. Eur. J. 2006, 12,
466.
18. Hynes, P. S.; Stupple, P. A.; Dixon, D. J. Org. Lett. 2008, 10, 1389.
19. Jensen, K. L.; Poulsen, P. H.; Donslund, B. S.; Morana, F.; Jørgensen, K. A. Org. Lett.
2012, 14, 1516.
20. Handa, S.; Gnanadesikan, V.; Matsunga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010,
132, 4925.
21. Weng, J.; Li, Y.-B.; Wang, R.-B.; Li, F.-Q.; Liu, C.; Chan, A. S. C.; Lu, G. J. Org. Chem.
4.5.1.11. 2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-((1R*,2R*)-2-
nitro-1,3-diphenyl-3-(phenylthio)propyl)acetamide (56). Prepared
by general procedure B. Nitroalkane 34 (125 mg, 0.480 mmol),
nBuLi (192
and TFA (129
mL, 2.5 M, 0.480 mmol), imine 37 (203 mg, 0.920 mmol)
mL, 1.68 mmol) gave after TFA-protection and purifi-
cation by flash column chromatography (Petrol:Et2O 4:1) 56
(129 mg, 47%) as an orange solid, mp. 51e52 ꢁC; Rf 0.25 (Petrol:Et2O
9:1); diastereoisomer ratio (65:35) calculated by CHS signal,
2010, 75, 3125.
22. Kumaraswarmy, G.; Pitchaiah, A. Tetrahedron 2011, 67, 2536.
23. Davis, T. A.; Johnston, J. N. Chem. Sci. 2011, 2, 1076.
24. Davis, T. A.; Danneman, M. W.; Johnston, J. N. Chem. Commun. 2012, 5578.
25. Xie, H.; Zhang, Y.; Zhang, S.; Chen, X.; Wang, W. Angew. Chem. Int. Ed. 2011, 50,
11773.
d
major¼4.76,
d
minor¼4.70; IR ymax (thin film) 3063, 3032, 2964,
2840, 1695, 1557, 1509, 1301, 1254, 1208, 1180, 1166, 1033, 840, 733,
699 cmꢀ1; 1H NMR (600 MHz)
d
3.79 (s, 3H), 4.76 (d, J¼5.1, 1H), 5.69
26. Anderson, J. C.; Horsfall, L. R.; Kalogirou, A. S.; Mills, M. R.; Stepney, G. J.; Tiz-
(d, J¼9.8, 1H), 6.35 (dd, J¼9.8, 5.1, 1H), 6.65e7.40 (m, 19H); 13C NMR
zard, G. J. J. Org. Chem. 2012, 77, 6186.
(150 MHz)
d 54.0 (CH), 55.4 (CH3), 67.9 (CH), 92.2 (CH), 113.4 and
27. Anderson, J. C.; Noble, A.; Tocher, D. A. J. Org. Chem. 2012, 77, 6703.
28. Anderson, J. C.; Noble, A.; Ribelles Torres, P. Tetrahedron Lett. 2012, 53, 5707.
29. Anderson, J. C.; Stepney, G. J.; Mills, M. R.; Horsfall, L. R.; Blake, A. J.; Lewis, W. J.
Org. Chem. 2011, 76, 1961.
30. Anderson, J. C.; Blake, A. J.; Koovits, P. J.; Stepney, G. J. J. Org. Chem. 2012, 77,
4711.
31. Anderson, J. C.; Koovits, P. J. Chem. Sci. 2013, 4, 2897.
32. Bartoli, G.; Bosco, M.; Giuli, S.; Giuliani, A.; Lucarelli, L.; Marcantoni, E.; Sambri,
L.; Torregiani, E. J. Org. Chem. 2005, 70, 1941.
114.5 (CH), 116.1 (q, J¼288.6 and 288.3, CF3), 126.7 (Cq), 127.7, 128.0,
128.5, 128.7, 128.8, 128.8, 128.9, 129.2, 129.4, 129.5, 129.7, 129.8,
130.5, 130.8, 130.9, 131.2, 132.9 and 134.2 (CH), 132.0, 133.1, 133.8,
135.5, 135.6 and 137.0 (Cq), 158.4 (q, J¼35.6 and 35.8, O]CCF3),
160.1 (Cq); 19F NMR (282 MHz)
d
ꢀ67.84 (3F, s, CF3); m/z (EIþ) 566
(Mþ, 10%), 457 (Mþ-PhS, 38%), 308 (64%), 301 (Mþ-NO2-
33. Ganesh, M.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 16464.
34. Austin, R. E.; Maplestone, R. A.; Sefler, A. M.; Liu, K.; Hruzewicz, W. N.; Liu, C.
W.; Cho, H. S.; Wemmer, D. E.; Bartlett, P. A. J. Am. Chem. Soc. 1997, 119, 6461.
35. Perealkin, V. V.; Lipina, E. S.; Berestovitskaya, V. M.; Efremov, D. A. Nitroalkenes;
Wiley: Chichester, 1994; p 67.
36. Lucet, D.; Sabelle, S.; Kostelitz, O.; Le Gall, T.; Mioskowski, C. Eur. J. Org. Chem.
1999, 2583.
37. Tamura, R.; Kamimura, A.; Ono, N. Synthesis 1991, 423.
38. Lewandowska, E. Tetrahedron 2006, 62, 4879.
PMPeNHeTFA, 100%), 199 (44%); HRMS: found 566.14870,
C
30H25F3N2O4S requires 566.14816.
Minor diastereomer: 1H NMR (600 MHz)
d 3.80 (s, 3H), 4.70 (d,
J¼6.1,1H), 5.79 (dd, J¼10.0, 6.0,1H), 6.01 (dd, J¼8.8, 2.0,1H), 6.43 (d,
J¼10.0, 1H), 6.53 (dd, J¼8.8, 2.9, 1H), 6.65e7.40 (m, 17H); 13C NMR
(150 MHz)
d 52.9 (CH), 55.4 (CH3), 62.0 (CH), 88.8 (CH), 113.7 and
113.8 (CH), 116.3 (q, J¼288.6 and 288.3, CF3), 158.4 (q, J¼35.6 and
35.8, O]CCF3), 160.2 (Cq), the rest of the 13C peaks could not be
distinguished between the two diastereomers; 19F NMR (282 MHz)
39. Kao, K.-H.; Yang, C.-S.; Liu, J.-T.; Lin, W.-W.; Fang, H.-Y.; Yao, C.-F.; Chen, K.
Tetrahedron 1998, 54, 13997.
40. Kotrusz, P.; Toma, S.; Schmalz, H.-G.; Adler, A. Eur. J. Org. Chem. 2004, 1577.
ꢃ
d
ꢀ67.58 (3F, s, CF3).
ꢃ
ꢁ
41. Hrnciar, P.; Culak, I. Collect. Czech. Chem. Commun. 1984, 49, 1421.
42. Kleczkowska, E.; Sas, W. Pol. J. Chem. 2007, 81, 1457.
43. Ballini, R.; Bosica, G.; Gabrielli, S.; Palmieri, A. Tetrahedron 2009, 65, 2916.
44. Katerinopoulos, H. E.; Tagmatarchis, N.; Zaponakis, G.; Kefalakis, I.; Kordatos,
K.; Spyrakis, M.; Thermos, K. Eur. J. Med. Chem. 1995, 30, 949.
45. Ziyaei-Halimehjani, A.; Saidi, M. R. Tetrahedron Lett. 2008, 49, 1244.
46. Yadav, J. S.; Reddy, A. R.; Rao, Y. G.; Narsaiah, A. V.; Reddy, B. V. Synthesis 2007,
22, 3447.
Acknowledgements
We thank the Cyprus State Scholarship Foundation for funding,
Dr. L. Haigh and Mr. J. Hill for providing mass spectra and Ms. J.
Maxwell for microanalytical data.
47. Bourrain, S.; Hunt, P. A.; Huscroft, I. T.; Kulagowski, J. J.; London, C.; Naylor, E.
M.; Raubo, P. A.; Seward, E. M.. 229864 A1, US 2004.
48. Schlecht, M. F. Molecular Modeling on the PC; Wiley-VCH: New York, 1998;
Software used: PCMODEL, version 8.5; Serena Software: Redwood City, CA,
2003.
References and notes
49. Crystallographic data (excluding structure factors) for the structures 47, 48, 53
and 54 in this paper have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication nos. CCDC 1019665, 1019666,
1019667 and 1019668 respectively. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:
þ44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.Uk).
1. Noble, A.; Anderson, J. C. Chem. Rev. 2013, 113, 2887.
2. Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017.
3. Palomo, C.; Oiarbibe, M.; Halder, R.; Laso, A.; Lopez, R. Angew. Chem. Int. Ed.
ꢁ
2006, 45, 117.
4. Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. J. Org. Chem. 1998, 63,
9932.
50. Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
ꢂ
5. Bernardi, L.; Bonini, B. F.; Capito, E.; Dessole, G.; Comes-Franchini, M.; Fochi, M.;
51. Bigge, C. F.; Wu, J.-P.; Drummond, J. R. Tetrahedron Lett. 1991, 32, 7659.
Ricci, A. J. Org. Chem. 2004, 69, 8168.
52. Lopez, R.; Zalacain, M.; Palomo, C. Chem. Eur. J. 2011, 17, 2450.
6. Sturgess, A. M.; Yarberry, D. J. Tetrahedron Lett. 1993, 34, 4743.
7. Anderson, J. C.; Howell, G. P. J. Org. Chem. 2005, 70, 549.
8. Bursavich, M. G.; Rich, D. H. J. Med. Chem. 2002, 45, 541.
9. Jakubec, P.; Cockfield, D. M.; Dixon, D. J. Am. Chem. Soc. 2009, 131, 16632.
10. Jakubec, P.; Kyle, A. F.; Calleja, J.; Dixon, D. J. Tetrahedron Lett. 2011, 52, 6094.
11. Kyle, A. F.; akubec, P.; Cockfield, D. M.; Cleator, E.; Skidmore, J.; Dixon, D. J. Chem.
Commun. 2011, 10037.
12. Shen, B.; Johnston, J. N. Org. Lett. 2008, 10, 4397.
13. Kumaraswarmy, G.; Pitchaiah, A. Helv. Chim. Act. 2011, 94, 1543.
14. Jakubec, P.; Hawkins, A.; Felzmann, W.; Dixon, D. J. J. Am. Chem. Soc. 2012, 134,
17482.
€
53. Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; Jager, V.; Schohe, R.;
Fronczek, F. R. J. Am. Chem. Soc. 1984, 106, 3880.
54. Love, B. E.; Jones, E. G. J. Org. Chem. 1999, 64, 3755.
55. Jia, Y.-X.; Zhu, S.-F.; Yang, Y.; Zhou, Q.-L. J. Org. Chem. 2006, 71, 75.
56. Carmona, D.; Lamata, M. P.; Sanchez, A.; Viguri, F.; Oro, L. A. Tetrahedron:
Asymmetry 2011, 22, 893.
57. Liu, J.-M.; Wang, X.; Ge, Z. M.; Sun, Q.; Cheng, T. M.; Li, R.-T. Tetrahedron 2011, 67,
636.
58. Uraguchi, D.; Nakashima, D.; Ooi, T. J. Am. Chem. Soc. 2009, 131, 7242.
59. Choudhary, G.; Peddinti, R. K. Green. Chem. 2011, 13, 276.
60. Katritzky, A. R.; Pernak, J.; Fan, W.-Q.; Saczewski, F. J. Org. Chem. 1991, 56, 443.
61. Kotrusz, P.; Toma, S. Molecules 2006, 11, 197.
15. Anderson, J. C.; Kalogirou, A. S.; Porter, M. J.; Tizzard, G. J. Beil. J. Org. Chem. 2013,
9, 1737.
16. Tsuritani, N.; Yamada, K.-I.; Yoshikawa, N.; Shibasaki, M. Chem. Lett. 2002, 276.
62. Yamada, M.; Yamashita, M. Synthesis 1982, 1026.
Please cite this article in press as: Anderson, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.042