Asymmetric synthesis of functionalized tetrasubstituted α-aminophosphonates through enantioselective aza-Henry reaction of phosphorylated ketimines

Article abstract of DOI:10.1021/jo502233m

Bifunctional Cinchona alkaloid thioureas efficiently catalyze asymmetric nucleophilic addition of nitromethane to ketimines derived from α-aminophosphonic acids to afford tetrasubstituted α-amino-β-nitro-phosphonates. Catalytic hydrogenation of (S)-α-amin

Full text of DOI:10.1021/jo502233m

Article
pubs.acs.org/joc
Asymmetric Synthesis of Functionalized Tetrasubstituted
α‑Aminophosphonates through Enantioselective Aza-Henry Reaction
of Phosphorylated Ketimines
Javier Vicario, Pablo Ortiz, Jose M. Ezpeleta, and Francisco Palacios*
́
́ ́
Departamento de Química Organica I, Centro de Investigacion y Estudios Avanzados “Lucio Lascaray”- Facultad de Farmacia,
University of the Basque Country, UPV/EHU Paseo de la Universidad 7, 01006 Vitoria, Spain
S
* Supporting Information
ABSTRACT: Bifunctional Cinchona alkaloid thioureas efficiently catalyze asymmetric nucleophilic addition of nitromethane to
ketimines derived from α-aminophosphonic acids to afford tetrasubstituted α-amino-β-nitro-phosphonates. Catalytic
hydrogenation of (S)-α-amino-β-nitro-phosphonate 2d gives enantiopure (S)-α,β-diaminophosphonate 3.
the proximity of the cyano group to a tetrasubstituted carbon,
further derivatization of those substrates proved to be very
difficult. Although the hydrolysis of the nitrile to a carboxylic
acid group was feasible, those α-cyano α-aminophosphonates
failed to provide the corresponding α,β-diaminophosphonates
through reduction of the cyano group. The aza-Henry17
reaction, consisting in the addition of nitronate species to
imine electrophiles, is an alternative route to diamines
complementary to the cyanation of imine derivatives. Since
the first organocatalytic asymmetric aza-Henry reported by
Takemoto and co-workers,18 a number of organocatalysts that
are able to catalyze the highly stereoselective addition of
nitroalkanes to aldimines have been developed, including
Brønsted acids,19 phase-transfers catalysts,20 chiral ammonium
betaines,21 and chiral ureas or thioureas.22 Organocatalytic
enantioselective addition of nitroderivatives to cyclic ketimine
of heterocycles, such as quinazolin-2(1H)-ones23 and indol-3-
ones,24 have been already described using bifunctional
thioureas, and recently, a new bifunctional iminophosphorane
organocatalyst has been reported for the catalytic nucleophilic
addition of nitromethane to ketimines.25
Taking into account all the considerations mentioned above,
we thought that a catalytic asymmetric addition of nitro-
methane to functionalized ketimines derived from α-amino-
phosphonates would be an excellent method for the access to
enantiopure α-aminophosphonate units bearing an all-sub-
stituted α-carbon. This synthetic approach can be considered
globally as a route for the generation of tetrasubstituted α-
aminophosphonates by the substitution of hydrogen in a
trisubstituted α-aminophosphonate by a nucleophilic reagent
and the complementary process (“umpolung reaction”) of the
INTRODUCTION
■
The stereocontrolled formation of tetrasubstituted carbons is a
crucial challenge in chemical synthesis since they are known to
be present in many natural products and pharmaceutical
agents.1 The formation of tetrasubstituted centers from ketones
and ketimines was unachievable for a long time, due to the poor
electrophilic character of the carbonyl or ketimine groups and
the additional steric hindrance present on the substrate. In
addition, the enantiotopic faces of ketone derivatives are not as
easily discriminated as those of aldehyde derivatives when
asymmetric synthesis is sought.2
Because of their structural analogy to α-amino acids, α-
aminophosphonic acid derivatives have found numerous
applications3 in medicinal and pharmaceutical sciences as
haptens of catalytic antibodies,4a peptide mimetics,4b enzyme
inhibitors,4c antibacterial4d and anticancer agents,4e as well as
agrochemicals.5 The biological activity of aminophosphonic
acids is known to be strongly dependent on their absolute
configuration,6,7 and the stereoselective synthesis of amino-
phosphonic acid derivatives8 is a very important task in organic
chemistry. Catalytic asymmetric methodologies for the syn-
thesis of α-aminophosphonates9 have been developed, but
remarkably, only a few synthetic protocols are effective for the
enantioselective synthesis of tetrasubstituted α-aminophospho-
nates.10
During the past few years, our group has been involved in the
development of new strategies for the preparation of simple11
and vinylic12 α-aminophosphonates as well as of phosphadep-
sipeptides13 and β-aminophosphonates.14 Continuing with our
interest in aminophosphorus chemistry,7 we reported the
asymmetric preparation of α-aminophosphonic acid deriva-
tives,15 and the preparation of ketimines derived from α-
aminophosphonates10a,16 that have also been successfully
exploited as intermediates for the synthesis of enantiopure
tetrasubstituted α-cyano α-aminophosphonates.10a Because of
Received: September 29, 2014
© XXXX American Chemical Society
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electrophilic substitution of trisubstituted α-aminophosphonate
(Scheme 1).
target racemic α-amino-β-nitro-phosphonates 3a (R = Me,
Scheme 2).
Having demonstrated the effectiveness of our synthetic
protocol at a racemic stage, we proceeded to the study of
different chiral catalysts in the addition of nitromethane to α-
ketiminophosphonates 2. Bifunctional Bønsted base/H-bond
donor organocatalysts have demonstrated their huge potential
in the field of organocatalysis. Key features of those catalysts are
a basic tertiary amine and a hydrogen bond donor group, both
properly located in a chiral atmosphere. In the early 80s,
Wynberg and Hiemstra showed that those molecules are able to
catalyze organic reactions by activating both the nucleophile
and the electrophile substrates, making use of the basic
character of the molecule and, simultaneously, establishing
hydrogen bond interactions, respectively.28 Within this class of
compounds, the most widely used are Cinchona alkaloids I−II
(Figure 1).29
In our case, we would expect strong interaction of the H-
donor group with the iminic nitrogen and the phosphoryl
oxygen while the tertiary amine interacts with the nitromethane
nucleophile in a similar manner as in the case of the cyanation
reaction of these substrates.10a Our preliminary analysis of the
aza-Henry reaction of α-iminophosphonate 2a with nitro-
methane, without solvent, in the presence of a catalytic amount
of a Cinchona alkaloid I−II leads to a fast formation of α-
amino-β-nitro-phosphonates 3a but, unfortunately, with poor
enantioselectivity (Table 1, entries 1−6).
Scheme 1. General Strategies for the Synthesis of
Quaternary α-Aminophosphonates
Furthermore, the presence of a β-nitro moiety would confer
a great synthetic importance to the proposed methodology (Nu
= CH2NO2, Scheme 1). Because of the different possible
oxidation states of the vicinal nitrogen containing function-
alities, they are susceptible to a selective manipulation,26 most
commonly to vicinal diamines,27 by reduction of the nitro
group.
RESULTS AND DISCUSSION
■
Initially, the construction of the intermediate carbon−nitrogen
double bond from N-tosyl α-aminophosphonates 1 may be
performed by selective N-chlorination with an excess of
trichloroisocyanuric acid (TCCA) in CH2Cl2, followed by
treatment with an excess of base to give α-ketiminophospho-
nates 2 (Scheme 2).10a The electrophilic character to its iminic
Chiral thioureas have demonstrated their efficiency as
organocatalysts, particularly in aza-Henry reactions,22−25 and
for this reason, we tested the nucleophilic addition of
nitromethane to α-iminophosphonates 1a using (thio)ureas
III−VIII as organocatalysts. Although no reaction was observed
when (thio)ureas IIIa,b and IV were used as catalysts, which
may be attributable to the absence of the basic partner in the
catalytic system, the use of bifunctional thioureas V−VIII in the
aza-Henry reaction of nitromethane with α-iminophosphonate
2a in the absence of solvent afforded α-amino-β-nitro-
phosphonates 3a with increased enantioselectivities (Table 1,
entries 10−13)
Scheme 2. Synthesis of Quaternary α-Aminophosphonates
carbon makes them suitable substrates for nucleophilic addition
reactions. In a subsequent step, treatment of phosphonates 2a
(R = Me) with triethylamine in boiling nitromethane afforded
Encouraged by these results, we implemented the analysis of
the influence of the phosphorus substituent in α-iminophosph-
Figure 1. Organocatalysts tested in asymmetric aza-Henry reaction of α-ketiminophosphonates 2.
B
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Table 1. Screening of the Catalyst
a
b
entry
cat.
t (h)
% conv.
% ee
major (R/S)
1
2
Ia
3
3
75
100
100
95
95
60
0
10
4
S
Ib
S
3
Ic
3
6
S
4
IIa
IIb
IIc
IIIa
IIIb
IV
3
10
13
12
R
R
R
5
3
Figure 2. Correlation between the Winstein−Holness A-values of the
phosphonate substituents and the enantioselectivity of the aza-Henry
reaction.
6
22
22
22
22
3
7
8
0
9
0
for the phenyl group (APh = 2.80 kcal·mol−1), the best
enantiomeric excesses would be expected, but on the contrary,
a total lack of reactivity is observed in the addition reaction of
nitromethane, which may be due to an excessive steric
hindrance in the electrophilic imine carbon.
10
11
12
13
V
95
100
95
95
29
22
27
23
S
VI
6
R
R
R
VII
6
VIII
6
a
b
Determined by 31P NMR. Determined by chiral HPLC.
Bearing these results in mind, we thought that better results
could be obtained if the aza-Henry reaction was performed
under solvation conditions. For this reason, the nucleophilic
addition of nitromethane to di-iso-propyl α-iminophosphonate
onate substrates 2 on the enantioselectivity of the aza-Henry
reaction using thioureas V−VII. A correlation between the
Winstein−Holness A-values30 of the phosphonate substituents
and the enantioselectivity was explored. In the case of the
addition of nitromethane to dimethyl phosphonate 2a using
thioureas V−VII as catalysts (Table 2, entries 1−3, AMe = 1.74
i
2d (R = Pr) was performed in several solvents, using the
thiourea VII as a catalyst. To our surprise, the reaction did not
proceed at all when coordinating solvents were used (Table 3,
entries 1−4). This may be attributable to a stronger interaction
of the H-donor module of the thiourea catalyst with the solvent
molecules than with the imine substrates 2.
Table 2. Screening of the Phosphorus Substituent
Table 3. Screening of the Solvent and Temperature
b
c
entry comp
R
cat.
t (h) % conv.
% ee
major (R/S)
1
2
3a
3a
3a
3b
3b
3c
3c
3c
3d
3d
3d
Me
Me
Me
Bn
Bn
Et
V
3
6
95
100
95
29
22
27
10
10
35
31
30
37
42
45
R
S
S
R
S
R
S
S
R
S
S
a
b
VI
VII
entry
solvent
MeOH
T (°C) t (h) % conv.
% ee
major (R/S)
3
24
18
18
6
1
2
20
20
24
24
24
24
24
36
48
48
36
48
48
72
72
24
0
0
a
4
V
100
100
100
100
100
90
THF
a
5
VI
3
AcN
20
0
6
V
4
DMF
20
0
7
Et
VI
VII
V
6
5
CH2Cl2
CHCl3
CCl4
20
95
90
60
95
100
81
64
30
10
100
68
67
61
60
80
72
40
24
17
S
S
S
S
S
S
S
S
S
8
Et
6
6
20
9
iPr
iPr
iPr
24
6
7
20
10
11
VI
VII
95
8
Cl(CH2)2Cl
toluene
toluene
toluene
toluene
toluene
toluene
20
24
95
b
9
20
a
Catalyst loading was increased to 20%. Determined by 31P NMR.
Determined by chiral HPLC.
10
11
12
13
14
10
c
0
−10
−20
40
kcal·mol−1), a decreased enantiomeric excess was observed
toward dimethyl phosphonate 2a when α-dibenzyphosphonate
2b (Table 2, entries 4 and 5) with a smaller A-value (ABn = 1.68
kcal·mol−1) was used.
c
70
S
c
a
b
Determined by 31P NMR. Determined by chiral HPLC. β-
Elimination of H2NTs was also detected.
The enantioselectivity can be increased if diethyl phospho-
nate 2c is used (Table 2, entries 6−8), where a higher A-value
is found in the phosphonate substituents (AEt = 1.79 kcal·
mol−1). Finally, the best enantiomeric excesses were obtained
when di-iso-propyl phosphonate 2d was used as substrate
(Table 2, entries 9−11), where a notably higher A-value is
found (Ai‑Pr = 2.21 kcal·mol−1) (Figure 2). A special case is the
use of diphenylphosphonate derivatives. In view of the A-value
On the other hand, an inverse dependence of the
enantioselectivity into the polarity of the solvent is observed
if noncoordinating solvents are used (Table 3, entries 5−9).
This dependence probably arises from a diminution in the
difference of the energy of activation for the formation of the
two enantiomers due to a stabilization of both possible
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diastereomeric transition states in a polar solvent, rational for
reactions with ionic transition states.
major steric interaction can be observed between the
quinuclidine unity and the thiourea moiety in the transition
state proposed for the formation of the R isomer.
It is well-known that, in most cases, a drop in the
temperature of the reaction results in an increase in the
enantioselectivity, but in our case, substantial drops in
enantioselectivity and conversion were observed when the
aza-Henry reaction of α-iminophosphonate 2d was performed
at lower temperatures using toluene as solvent (Table 3, entries
10−13). Such effects may be related to a low solubility of the
substrate at low temperature. When the reaction was performed
at higher temperature, a drop in the enantioselectivity was
observed (Table 3, entry 14). Remarkably, in this case, the
formation of a substantial amount of a side product is observed
due to a subsequent β-elimination reaction of p-toluenesulfo-
namide. Other attempts at improving the enantioselectivity of
the process by increasing the catalyst loading were unsuccessful.
An optimal enantiomeric excess of 80% was obtained when the
reaction was performed at room temperature using 2 equiv of
nitromethane in the presence of a 10% of thiourea catalyst VII
and using toluene as solvent.
In order to determine the absolute configuration of the
stereogenic carbon of the major enantiomer, a pure isomer of
α-amino-β-nitro-phosphonate 3d was isolated by crystallization.
The X-ray diffraction spectrum showed an S absolute
configuration of the stereocenter (see the Supporting
Information).
It is interesting that neither Et3N, DABCO, pyridine, nor
phosphoric acids were able to catalyze the reaction, whereas
Cinchona alkaloids and thioureas were. It is also interesting that
addition of a donor molecule together with a basic reagent does
not catalyze the aza-Henry reaction at all. Both Cinchona
alkaloid derivatives and thioureas share a common structure,
having a basic nitrogen at a two carbon distance from a
functional group that is able to establish hydrogen bonding
(OH in Cinchona alkaloids derivatives, NH in thioureas). This
might indicate a crucial role for the OH and NH groups in the
transition state, which may activate the imino bond by
establishing hydrogen bonding.
The generalization of the asymmetric aza-Henry reaction of
di-iso-propyl α-ketiminophosphonates 2 catalyzed by thiourea
VII was put into effect using different aromatic α-substituents.
Very satisfactory enantioselectivities were obtained relative to
the model iminophosphonates 3d, with a phenyl substituent at
the α-carbon, (Table 4, entries 1−6). α-Arylimines with para-
or meta-alkyl substituted aromatic rings showed to be slightly
less reactive than the model substrate, but an increase of the
reaction times leads to the formation of α-amino-β-nitro-
phosphonates 3e−f in good yields and enantioselectivities
(Table 4, entries 2 and 3).
On the contrary, the addition of nitromethane to α-
arylimines 3g−i bearing electron withdrawing meta- or para-
substituents at the aromatic ring proceeded slightly faster than
in the case of the model substrate, most likely due to the
activation effect of the electron poor aromatic ring into the
imine system (Table 4, entries 4−6). Remarkably, when ortho-
substituted α-arylimines were used as substrates, no reaction at
all was observed, even at high temperatures. This fact could be
explained by the high steric crowding expected in the resulting
structure, especially taking into account that a tetrasubstituted
stereogenic carbon is being formed. Unfortunately, the scope of
the reaction is not applicable to electron rich aromatic
substituents, since imines bearing O- or N-substituted aromatic
rings proved to be totally unreactive in this reaction.
Finally, to show an example of the potential of substrates 3,
an enantiopure fraction of α-amino-β-nitro-phosphonate (S)-
3d was subjected to hydrogenation conditions, affording α,β-
diaminophosphonate (S)-4 in excellent yield (Scheme 3). The
1,2-amine moiety occurs in a wide number of natural products
and in pharmaceutical agents,27 while chiral 1,2-diamines are
also widely used in catalysis and asymmetric synthesis.27,31,32
To the best of our knowledge, enantiopure tetrasubstituted α-
amino-β-nitro-phosphonates 3 and α,β-diaminophosphonate 4
structures have not been reported so far.
On the basis of the models for similar processes proposed by
other authors,18,22a we suggest a tentative transition state where
each NH group of the thiourea catalyst establishes hydrogen
bonds with the imino nitrogen and phosphoryl oxygen,
respectively, while both coordinate with both oxygens of the
nitro group, as shown in Figure 3. According to this model, the
basic unity of the bifunctional catalyst would capture the acidic
proton from the hydroxyl group of the nitromethane tautomer
and its nucleophilic carbon would attack the imine carbon. A
CONCLUSIONS
■
The first organocatalytic enantioselective aza-Henry reaction
using iminophosphonates is reported. The fact that phosphory-
lated ketimine derivatives are used as substrates allows the
asymmetric synthesis of functionalized tetrasubstituted α-
aminophosphonates. These α-amino-β-nitrophosphonates are
susceptible to a further transformation into enantiopure α,β-
diaminophosphonates.
EXPERIMENTAL SECTION
■
General. Solvents for extraction and chromatography were
technical grade. All solvents used in reactions were freshly distilled
from appropriate drying agents before use. All other reagents were
recrystallized or distilled as necessary. All reactions were performed
under an atmosphere of dry nitrogen. Analytical TLC was performed
with silica gel 60 F254 plates. Visualization was accomplished by UV
light. 1H (300 MHz), 13C (75 MHz), and 31P NMR (120 MHz)
spectra were performed using CDCl3 solutions with TMS as an
internal reference (δ = 0.00 ppm) for H and 13C NMR spectra and
1
phosphoric acid (50%) as an external reference (δ = 0.0 ppm) for 31P
NMR spectra. Chemical shifts (δ) are reported in ppm. Coupling
constants (J) are reported in hertz. 1H and 13C NMR peak assignments
were supported by distortionless enhanced polarization transfer
(DEPT), correlation spectroscopy (COSY), or heteronuclear
correlation spectroscopy (HETCOR) experiments. Low-resolution
Figure 3. Tentative transition states for the formation of major (left)
and minor (right) enantiomers in thiourea (green) catalyzed addition
of nitromethane (red) to α-iminophosphonate 2d (blue).
D
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Table 4. Generalization of Organocatalytic Aza-Henry Reaction of Iminophosphonates 2
a
b
entry
comp
Ar
t (h)
% yield
% ee
major (R/S)
c
c
1
2
3
4
5
6
3d
3e
3f
C6H5
36
48
48
24
24
24
85, 71
83
80, >99
81
S
S
S
S
S
S
p-CH3-C6H4
m-CH3-C6H4
p-CF3-C6H4
p-NO2-C6H4
m-NO2-C6H4
83
84
3g
3h
85
80
87
80
3i
82
81
a
b
c
Pure yield after column. Determined by chiral HPLC. After crystallization.
Diisopropyl (((4-Methylphenyl)sulfonamido)(m-tolyl)meth-
yl)phosphonate (1f). The procedure was followed, using (E)-4-
methyl-N-(3-methylbenzylidene)-benzenesulfonamide (6.83 g, 25
mmol) and diisopropyl phosphite (4.2 mL, 30 mmol), affording
9.22 g (84%) of 1f as a white solid. m.p.: 169−170 °C (Toluene). 1H
NMR (300 MHz, CDCl3): δ (ppm) 0.81 (d, 3JHH = 6.2 Hz, 3H, CH3),
Scheme 3. Synthesis of Enantiopure α,β-
Diaminophosphonate 4
3
3
1.23 (d, JHH = 6.2 Hz, 3H, CH3), 1.38 (d, JHH = 6.0 Hz, 3H, CH3),
3
1.39 (d, JHH = 6.1 Hz, 3H, CH3), 2.03 (s, 3H, CH3), 2.25 (s, 3H,
CH3), 4.35 (m, 1H, CH), 4.69 (dd, 3JHH = 9.4 Hz, 2JPH = 24.6 Hz, 1H,
CHP), 4.86 (m, 1H, CH), 6.74 (broad s, 1H, NH), 6.89−6.97 (m, 6H,
6 CHar), 7.42 (d, 3JHH = 8.2 Hz, 2H, 2 × CHar). 13C NMR (75 MHz,
CDCl3): δ 21.0 (CH3), 21.4 (CH3), 23.1 (d, 3JPC = 6.2 Hz, CH3), 24.0
mass spectra (MS) were obtained by electron impact (EI), and high-
resolution mass spectra (HRMS) were obtained by positive-ion
electrospray ionization (Supporting Information). Data are reported in
the form m/z (intensity relative to base = 100). Infrared spectra (IR)
were taken as neat solids. Peaks are reported in cm−1. N-Tosyl α-
ketiminophosphonates 2a−d and 2g−h,10a tertiary α-aminophospho-
nates 1a−d and 1g−h,10a and their tosylimine precursors33 were
synthesized following literature procedures.
Synthesis of N-Tosyl α-Aminophosphonates 1. Substrates 1
were synthesized by nucleophilic addition of phosphites to the
corresponding tosylimines using the following procedure: To a
suspension of the corresponding N-tosylimine33 (25 mmol) and the
corresponding dialkylphosphite (30 mmol) in toluene (50 mL) was
added triethylamine (0.35 mL, 2.5 mmol). The solution was stirred
and refluxed in toluene for 24−48 h until the disappearance of N-
tosylimine. The solution was allowed to cool to room temperature,
and upon cooling to −20 °C, crystals were obtained. The resulting
solid was collected by filtration, washed with cold toluene (30 mL) and
hexanes (30 mL), and dried under low pressure to afford pure N-tosyl
α-aminophosphonates. 1a−d and 1g−h are known compounds.10a
Diisopropyl (((4-Methylphenyl)sulfonamido)(p-tolyl)meth-
yl)phosphonate (1e). The procedure was followed, using (E)-4-
methyl-N-(4-methylbenzylidene)-benzenesulfonamide (6.83 g, 25
mmol) and diisopropyl phosphite (4.2 mL, 30 mmol), affording
8.77 g (80%) of 1e as a white solid. m.p.: 171−172 °C (Toluene). 1H
NMR (300 MHz, CDCl3): δ (ppm) 0.81 (d, 3JHH = 6.2 Hz, 3H, CH3),
3
(d, JPC = 5.6 Hz, CH3), 24.4 (d, 3JPC = 2.9 Hz, CH3), 24.7 (d, 3JPC
=
3.1 Hz, CH3), 53.6 (d, 1JPC = 160.6 Hz, CHP), 72.4 (d, 2JPC = 7.4 Hz,
CHO), 73.1 (d, 2JPC = 7.4 Hz, CHO), 126.1 (d, 3JPC = 5.8 Hz, CHar),
127.2 (2 × CHar), 127.8 (CHar), 128.1 (d, 4JPC = 1.9 Hz, CHar), 129.3
3
(d, JPC = 5.9 Hz, CHar), 133.6 (Cquat), 137.4 (Cquat), 138.6 (Cquat),
142.3 (Cquat). 31P NMR (120 MHz, CDCl3): δ (ppm) 19.2. FTIR
(KBr) νmax (cm−1): 3321 (NH st), 1333 (OSO st as), 1235 (P
O st), 1170 (OSO st sim). HRMS (Q-TOF) m/z calcd for
C21H30NO5PS [MH]+ 440.1661, found 440.1657.
Diisopropyl (((4-Methylphenyl)sulfonamido)(3-nitrophenyl)-
methyl)phosphonate (1i). The procedure was followed, using (E)-
4-methyl-N-(3-nitrobenzylidene)-benzenesulfonamide (7.65 g, 25
mmol) and diisopropyl phosphite (4.2 mL, 30 mmol), affording
10.34 g (88%) of 1i as a white solid. m.p.: 192−193 °C (Toluene). 1H
NMR (300 MHz, CDCl3): 0.98 (d, 3JHH = 6.2 Hz, 3H, CH3), 1.34 (d,
3
3JHH = 6.2 Hz, 3H, CH3), 1.47 (d, JHH = 6.1 Hz, 3H, CH3), 1.52 (d,
3JHH = 6.2 Hz, 3H, CH3), 2.13 (s, 3H, CH3), 4.58 (m, 1H, CH), 4.91
3
2
(dd, JHH = 10.3 Hz, JPH = 25.8 Hz, 1H, CHP), 5.06 (m, 1H, CH),
3
3
6.78 (d, JHH = 8.2 Hz, 2H, 2 × CHar), 7.22 (t, JHH = 7.8 Hz, 1H,
CHar), 7.39 (d, 3JHH = 8.2 Hz, 2H, 2 × CHar), 7.49 (d, 3JHH = 7.3 Hz,
1H, CHar), 7.84 (d, 3JHH = 8.2 Hz, 1H, CHar), 7.95 (d, 4JPH = 1.8 Hz,
1H, CHar), 8.19 (broad d, JPH = 9.3 Hz, 1H, NH),). 13C NMR (75
2
3
MHz, CDCl3): δ 21.3 (CH3), 23.4 (d, JPC = 6.2 Hz, CH3), 24.0 (d,
3JPC = 5.7 Hz, CH3), 24.4 (d, 3JPC = 3.0 Hz, CH3), 24.8 (d, 3JPC = 3.1
1
2
3
3
Hz, CH3), 55.8 (d, JPC = 161.9 Hz, CHP), 72.9 (d, JPC = 7.6 Hz,
CHO), 74.3 (d, 2JPC = 7.4 Hz, CHO), 122.3 (d, 3JPC = 2.8 Hz, CHar),
123.4 (d, 5JPC = 4.8 Hz, CHar), 127.1 (2 × CHar), 128.7 (d, 4JPC = 2.0
1.21 (d, JHH = 6.2 Hz, 3H, CH3), 1.35 (d, JHH = 6.2 Hz, 6H, 2 ×
CH3), 2.25 (s, 3H, CH3), 2.29 (s, 3H, CH3), 4.36 (m, 1H, CHO), 4.66
(dd, JHH = 9.2 Hz, JPH = 24.6 Hz, 1H, CHP), 4.78 (m, 1H, CHO),
3
2
2
3
Hz, CHar), 130.9 (2 × CHar), 135.1 (d, JPC = 5.7 Hz, Cquat), 135.9
6.28 (broad s, 1H, NH), 6.87 (d, JHH = 8.0 Hz, 2H, 2 × CHar), 6.97
(Cquat), 138.3 (d, JPC = 2.2 Hz, Cquat), 142.9 (Cquat). 31P NMR (120
2
3
3
(d, JHH = 8.2 Hz, 2H, 2 × CHar), 7.05 (d, JHH = 8.0 Hz, 2H, 2 ×
MHz, CDCl3): δ (ppm) 17.5. FTIR (KBr) νmax (cm−1): 3311 (NH st),
1331 (OSO st as), 1228 (PO st), 1160 (OSO st sim).
HRMS (Q-TOF) m/z calcd for C20H28N2O7PS [MH]+ 471.1355,
found 471.1358.
CHar), 7.44 (d, JHH = 8.2 Hz, 2H, 2 × CHar). 13C NMR (75 MHz,
3
CDCl3): δ 21.3 (CH3), 21.5 (CH3), 23.1 (d, 3JPC = 6.0 Hz, CH3), 24.1
(d, 3JPC = 5.7 Hz, CH3), 24.4 (d, 3JPC = 3.0 Hz, CH3), 24.7 (d, 3JPC
=
2.6 Hz, CH3), 56.1 (d, 1JPC = 160.0 Hz, CHP), 72.6 (d, 2JPC = 6.8 Hz,
2
Synthesis of N-Tosyl α-Ketiminophosphonates 2. Procedure:
To a solution of N-tosyl α-aminophosphonate 1 (10 mmol) in CH2Cl2
(30 mL) was added trichloroisocyanuric acid (30 mmol). The
resulting suspension was stirred until the disappearance of the starting
N-tosyl α-aminophosphonate, which was monitored by 31P NMR.
Then, the solid residue was removed by filtration to afford a clear
solution of the intermediate N-chloro α-aminophosphonate and
CHO), 72.9 (d, JPC = 7.2 Hz, CHO), 121.3 (2 × CHar), 128.4 (2 ×
CHar), 128.6 (2 × CHar), 128.8 (2 × CHar), 137.2 (Cquat), 138.0
(Cquat), 138.7 (d, JPC = 2.1 Hz, Cquat), 142.3 (Cquat). 31P NMR (120
2
MHz, CDCl3): δ (ppm) 19.2. FTIR (KBr) νmax (cm−1): 3318 (NH st),
1336 (OSO st as), 1229 (PO st), 1165 (OSO st sim).
HRMS (Q-TOF) m/z calcd for C21H30NO5PS [MH]+ 440.1661,
found 440.1658.
E
dx.doi.org/10.1021/jo502233m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
poly(4-vinylpyridine) (3 g), previously dried at 100 °C overnight, was
added. The resulting suspension was stirred under reflux overnight,
and the reaction was then filtered and concentrated under reduced
pressure. The resulting yellow oily crude was purified by crystallization
from diethyl ether.
under vacuum, and the crude residue was purified by column
chromatography (AcOEt/Hexanes).
Procedure B. A solution of α-ketiminophosphonate 2d−i (0.5
mmol), nitromethane (1 mmol), and thiourea VII (10%) in toluene (2
mL) was stirred at rt for 24−48 h. (see Table 4). The resulting
solution was concentrated under vacuum, and the crude residue was
purified by column chromatography (AcOEt/Hexanes).
Diisopropyl (p-Tolyl(tosylimino)methyl)phosphonate (2e).
The procedure was followed, using diisopropyl (p-tolyl(tosylamino)-
methyl)phosphonate 1e (4.39 g, 10 mmol), affording 3.19 g (73%) of
2e as a white solid. The formation of the intermediate N-chloro α-
aminophosphonate was ensured by 31P NMR (δ = 16.1 ppm). m.p.:
114−115 °C (Et2O). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.08 (d,
3JHH = 6.1 Hz, 6H, 2 × CH3), 1.25 (d, 3JHH = 6.1 Hz, 6H, 2 × CH3),
2.41 (s, 3H, CH3), 2.42 (s, 3H, CH3), 4.66 (m, 2H, 2 × CHO), 7.26
Dimethyl (1-((4-Methylphenyl)sulfonamido)-2-nitro-1-phen-
ylethyl)phosphonate (3a). Procedure A was followed, using (E)-
diethyl(phenyl(tosylimino)methyl)phosphonate 2a (184 mg, 0.5
mmol), affording 139 mg (76%) of 3a as a white solid (ee = 27%).
1
m.p.: 167−168 °C (Et2O). H NMR (300 MHz, CDCl3): δ 2.42 (s,
3
3
3H, CH3), 3.44 (d, JPH = 11.1 Hz, 3H, CH3O), 3.48 (d, JPH = 11.1
3
3
3
Hz, 3H, CH3O), 5.58 (d, JPH = 8.6 Hz, 1H, CH2NO2), 5.62 (s, 1H,
(d, JHH = 8.2 Hz, 2H, 2 × CHar),.7.29 (d, JHH = 8.2 Hz, 2H, 2 ×
CH2NO2), 5.82 (d, 3JPH = 11.6 Hz, 1H, NH), 7.19 (d, 3JHH = 8.3 Hz, 2
CHar),.7.73 (d, JHH = 8.2 Hz, 2H, 2 × CHar),.7.80 (d, 3JHH = 8.2 Hz,
3
3
× CHar), 7.20 (d, JHH = 6.6 Hz, 2 × CHar), 7.26−7.30 (m, 3H, 3 ×
2H, 2 × CHar). 13C NMR (75 MHz, CDCl3): δ 21.8 (CH3), 21.9
CHar), 7.52 (d, JHH = 8.3 Hz, 2 × CHar). 13C NMR (75 MHz,
3
3
3
(CH3), 23.5 (d, JPC = 5.7 Hz, 2 × CH3), 24.2 (d, JPC = 3.4 Hz, 2 ×
CH3), 73.9 (d, 2JPC = 7.3 Hz, 2 × CHO), 127.8 (d, 3JPC = 1.9 Hz 2 ×
CHar), 128.9 (2 × CHar), 129.0 (2 × CHar), 129.7 (2 × CHar), 131.5
(d, 2JPC = 24.1 Hz, Cquat), 137.5(d, 5JPC = 1.4 Hz Cquat), 142.7 (Cquat),
144.4 (Cquat), 178.9 (d, 1JPC = 197.4 Hz, CN). 31P NMR (120 MHz,
CDCl3): δ (ppm) 3.4. FTIR (KBr) νmax (cm−1): 1609 (CN st),
1335 (OSO st as), 1261 (PO st), 1168 (OSO st sim).
HRMS (Q-TOF) m/z calcd for C21H28NO5PS [MH]+ 438.1504,
found 438.1599.
CDCl3): δ 21.7 (CH3), 54.7 (d, 2JPC = 7.8 Hz, CH3O), 55.0 (d, 2JPC
=
7.5 Hz, CH3O), 62.8 (d, 1JPC = 152.2 Hz, Cquat), 76.0 (CH2), 127.4 (2
× CHar) 127.6 (d, 3JPC = 4.8 Hz, 2 × CHar), 128.6 (d, 4JPC = 2.6 Hz, 2
5
× CHar), 129.1 (d, JPC = 2.6 Hz, CHar), 129.4 (2 × CHar), 132.0 (d,
2JPC = 7.8 Hz, Cquat) 138.7 (Cquat),143.8 (Cquat). 31P NMR (120 MHz,
CDCl3): δ (ppm) 20.1. FTIR (neat) νmax (cm−1): 3313(NH st), 1559
(NO st as), 1369 (NO st sim), 1321(OSO st sim), 1150
(OSO st as), 1022 (PO st), HRMS (Q-TOF) m/z calcd for
C17H21N2O7PS [MH]+ 429.0885, found 429.0882. [α]2D0 = −9.5° (c =
0.41, CH2Cl2). ee was determined by HPLC analysis (Chiracel-IA,
Heptane/Ethanol 90:10, 1 mL/min). Retention time (min): 25.90
(minor) and 34.37 (major).
Diisopropyl (m-Tolyl(tosylimino)methyl)phosphonate (2f).
The procedure was followed, using diisopropyl (m-tolyl(tosylamino)-
methyl)phosphonate 1f (4.39 g, 10 mmol), affording 3.10 g (71%) of
2f as a white solid. The formation of the intermediate N-chloro α-
aminophosphonate was ensured by 31P NMR (δ = 16.2 ppm). m.p.:
118−119 °C (Et2O). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.09 (d,
3JHH = 6.2 Hz, 6H, 2 × CH3), 1.26 (d, 3JHH = 6.2 Hz, 6H, 2 × CH3),
2.39 (s, 3H, CH3), 2.42 (s, 3H, CH3), 4.74 (m, 2H, 2 × CHO), 7.25−
Dibenzyl (1-((4-Methylphenyl)sulfonamido)-2-nitro-1-phen-
ylethyl)phosphonate (3b). Procedure A was followed (in this case,
20% catalyst loading was used), using α-dibenzyl(phenyl(tosylimino)-
methyl)phosphonate 2b (260 mg, 0.5 mmol), affording 185 mg (71%)
of 3b as a white solid (ee = 10%). m.p.: 128−129 °C (Et2O). 1H NMR
(300 MHz, CDCl32): δ 2.29 (s, 3H, CH3), 4.35−4.70 (m, 4H, 2 ×
3
7.33 (m, 5H, 5 × CHar), 7.75 (m, 1H, CHar), 7.76 (d, JHH = 8.3 Hz,
2H, 2 × CHar). 13C NMR (75 MHz, CDCl3): δ 21.6 (CH3), 21.8
3
CH2O), 5.46 (dd, JHH = 10.2, JPH = 41.8 Hz, 1H, CH2NO2), 5.52
3
3
2
3
3
(CH3), 23.3 (d, JPC = 5.8 Hz, 2 × CH3), 23.4 (d, JPC = 3.5 Hz, 2 ×
(dd, JHH = 10.3, JPH = 24.6 Hz, 1H, CH2NO2), 5.96 (d, JPH = 11.6
2
3
3
CH3), 74.0 (d, JPC = 7.2 Hz, 2 × CHO), 125.7 (d, JPC = 4.4 Hz
CHar), 127.9 (2 × CHar), 128.1 (CHar), 128.7 (d, 3JPC = 3.8 Hz CHar),
129.7 (2 × CHar), 132.4 (d, 4JPC = 1.1 Hz CHar), 134.2 (d, 2JPC = 24.5
Hz, Cquat), 137.3 (d, 4JPC = 2.3 Hz, Cquat), 137.9 (Cquat), 144.0 (Cquat),
Hz, 1H, NH), 6.96 (d, JHH = 7.0 Hz, 2H, 2 × CHar), 7.01−7.07 (m,
6H, 6 × CHar), 7.13−7.22 (m, 9H, 9 × CHar), 7.38 (d, 3JHH = 8.2 Hz,
2H, 2 × CHar). 13C NMR (75 MHz, CDCl3): δ 21.3 (CH3), 62.7 (d,
1JPC = 151.9 Hz, Cquat), 69.8 (d, 2JPC = 7.9 Hz, CH2O), 69.9 (d, 2JPC
=
179.3 (d, JPC = 197.8 Hz, CN). 31P NMR (120 MHz, CDCl3): δ
1
8.0 Hz, CH2O), 75.7 (CH2NO2), 126.4 (CHar), 127.3 (2 ×
(ppm) 3.2. FTIR (KBr) νmax (cm−1): 1611 (CN st), 1331 (OS
O st as), 1267 (PO st), 1163 (OSO st sim). HRMS (Q-TOF)
m/z calcd for C21H28NO5PS [MH]+ 438.1504, found 438.1598.
Diisopropyl ((3-Nitrophenyl)(tosylimino)methyl)phos-
phonate (2i). The procedure was followed, using diisopropyl (m-
nitrophenyl(tosylamino)methyl)-phosphonate 1i (4.70 g, 10 mmol),
affording 3.65 g (78%) of 2i as a white solid. The formation of
intermediate N-chloro α-aminophosphonate was ensured by 31P NMR
4
CHar),127.6 (d, JPC = 4.8 Hz, 2 × CHar), 128.2(2 × CHar), 128.3(2
× CHar), 128.4 (d, 4JPC = 2.6 Hz, 2 × CHar),128.6 (d, 4JPC = 4.6 Hz, 2
× CHar), 128.8 (d, 3JPC = 7.0 Hz, 2 × CHar), 128.9 (CHar), 129.3 (2 ×
2
2
CHar), 129.6 (CHar), 132.1 (d, JPC = 7.6 Hz, Cquat) 135.1 (d, JPC
=
2
5.5 Hz, Cquat), 135.1 (d, JPC = 5.3 Hz, Cquat), 138.7 (Cquat),143.6
(Cquat). 31P NMR (120 MHz, CDCl3): δ (ppm) 18.7. FTIR (KBr) νmax
(cm−1): 3297 (NH st), 1557 (NO st as), 1330 (NO st sim), 1370
(OSO st sim), 1156 (OSO st as), 987 (PO st). HRMS
(Q-TOF) m/z calcd for C29H29N2O7PS [MH]+ 581.1511, found
581.1525. [α]2D0 = −3.2° (c = 0.26, CH2Cl2). ee was determined by
HPLC analysis (Chiracel-IA, Heptane/Ethanol 90:10, 1 mL/min).
Retention time (min): 29.67 (minor) and 32.11 (major).
1
(δ = 15.1 ppm). m.p.: 121−122 °C (Et2O). H NMR (300 MHz,
CDCl3): δ (ppm) 1.14 (d, 3JHH = 6.2 Hz, 6H, 2 × CH3), 1.30 (d, 3JHH
= 6.2 Hz, 6H, 2 × CH3), 2.43 (s, 3H, CH3), 4.72 (m, 2H, 2 × CHO),
3
3
7.31 (d, JHH = 8.4 Hz, 2H, 2 × CHar), 7.66 (t, JHH = 8.0 Hz, 1H,
CHar), 7.77 (d, 3JHH = 8.4 Hz, 2H, 2 × CHar), 8.01 (dd, 3JHH = 8.0 Hz,
Diethyl (1-((4-Methylphenyl)sulfonamido)-2-nitro-1-phenyl-
ethyl)phosphonate (3c). Procedure A was followed, using diethyl-
(phenyl(tosylimino)methyl)phosphonate 2c (198 mg, 0.5 mmol),
affording 166 mg (73%) of 3c as a white solid (ee = 30%). m.p.: 143−
4JHH = 1.6 Hz, H, CHar), 8.35 (m, 1H, CHar), 8.48 (s, 1H, CHar). 13
C
3
NMR (75 MHz, CDCl3): δ 21.7 (CH3), 23.4 (d, JPC = 5.7 Hz, 2 ×
CH3), 24.1 (d, JPC = 3.6 Hz, 2 × CH3), 74.7 (d, JPC = 7.2 Hz, 2 ×
3
2
1
3
3
144 °C (Et2O). H NMR (300 MHz, CDCl3): δ 1.02 (t, JHH = 7.1
CHO), 123.0 (d, JPC = 3.2 Hz CHar), 125.7 (CHar), 127.9 (2 ×
3
CHar), 129.7 (2 × CHar), 129.9 (CHar), 134.0 (d, 3JPC = 3.8 Hz CHar),
Hz, 3H, CH3), 1.14 (d, JHH = 7.0 Hz, 3H, CH3), 2.33 (s, 3H, CH3),
3.51−3.93 (m, 4H, 2 × CH2O), 5.51 (s, 1H, CH2NO2), 5.55 (d, 3JPH
=
135.4 (d, 2JPC = 25.3 Hz, Cquat), 136.2 (d, JPC = 2.2 Hz, Cquat), 145.3
4
3.5 Hz, 1H, CH2NO2), 5.83 (broad d, 3JPH = 10.5 Hz, 1H, NH), 7.08
(Cquat), 147.6 (Cquat), 176.2 (d, JPC = 202.0 Hz, CN). 31P NMR
1
3
(120 MHz, CDCl3): δ (ppm) 2.4. FTIR (KBr) νmax (cm−1): 1608
(CN st), 1327 (OSO st as), 1261 (PO st), 1160 (OSO
st sim). HRMS (Q-TOF) m/z calcd for C29H25N2O7PS [MH]+
469.1198, found 469.1111.
(d, JHH = 8.2 Hz, 4 × CHar), 7.14−7.21 (m, 3H, 3 × CHar), 7.40 (d,
3JHH = 8.2 Hz, 2 × CHar). 13C NMR (75 MHz, CDCl3): δ 16.1 (d, 3JPC
= 5.7 Hz, 2 × CH3), 21.6 (CH3), 62.5 (d, 2JPC = 151.5 Hz, Cquat), 64.5
2
2
(d, JPC = 7.8 Hz, CH2O), 64.9 (d, JPC3 = 7.5 Hz, CH2O), 76.1
(CH2NO24), 127.4 (2 × CHar) 127.7 (d, JPC = 4.8 Hz, 2 × CHar),
Asymmetric Aza-Henry of N-Tosyl α-Ketiminophosphonates
2. Procedure A. A solution of α-ketiminophosphonate 2a−c (0.5
mmol) and thiourea VII (10%) in nitromethane (2 mLwas stirred at rt
for 3−24 h. (see Table 2). The resulting solution was concentrated
5
128.3 (d, JPC = 2.5 Hz, 2 × CHar), 128.9 (d, JPC = 2.7 Hz, CHar),
2
129.3 (2 × CHar), 132.0 (d, JPC = 7.4 Hz, Cquat) 138.8 (Cquat),143.6
(Cquat). 31P NMR (120 MHz, CDCl3): δ (ppm) 17.9. FTIR (KBr) νmax
F
dx.doi.org/10.1021/jo502233m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(cm−1): 3298 (NH st), 1556 (NO st as), 1331 (N O st sim),
1245 (OSO st sim), 1152 (OSO st as), 1023 (PO st).
HRMS (Q-TOF) m/z calcd for C29H25N2O7PS [MH]+ 457,1198,
found 457.1201. [α]2D0 = −8.3° (c = 0.29, CH2Cl2). ee was determined
by HPLC analysis (Chiracel-IA, Heptane/Ethanol 90:10, 1 mL/min).
Retention time (min): 16.69 (minor) and 19.31 (major).
1H, CHa3r). 13C NMR (75 MHz, CDCl3): δ 21.2 (CH3), 21.6 (CH3),
3
22.9 (d, JPC = 6.2 Hz, CH3), 23.5 (d, JPC = 5.7 Hz, CH3), 23.8 (d,
3
1
3JPC = 3.0 Hz, CH3), 24.2 (d, JPC = 2.5 Hz, CH3), 62.2 (d, JPC
=
153.7 Hz, Cquat), 74.3 (d, 2JPC = 8.0 Hz, CHO), 74.5 (d, 2JPC = 7.7 Hz,
CHO), 76.3 (CH2), 125.1 (d, 3JPC = 5.1 Hz, CHar), 127.3 (2 × CHar),
128.1 (d, 4JPC = 2.0 Hz, CHar), 128.8 (d, 3JPC = 2.2 Hz, CHar), 129.2 (2
× CHar), 131.3 (d, 3JPC = 5.9 Hz, CHar), 135.6 (Cquat), 137.4 (d, 2JPC
=
Diisopropyl (1-((4-Methylphenyl)sulfonamido)-2-nitro-1-
phenylethyl)phosphonate (3d). Procedure B was followed, using
diisopropyl(phenyl(tosylimino)methyl)phosphonate 2d (212 mg, 0.5
mmol), affording 205 mg (85%) of 3d as a white solid (ee = 80%,
2.6 Hz, Cquat), 139.2 (d, 5JPC = 1.4 Hz, Cquat), 140.3 (Cquat). 31P NMR
(120 MHz, CDCl3): δ (ppm) 16.1. FTIR (KBr) νmax (cm−1): 3289
(NH st), 1562 (NO st as), 1335 (NO st sim), 1362 (OSO
st sim), 1160 (OSO st as), 988 (PO st). HRMS (Q-TOF) m/z
1
>99% after crystallization from Et2O). m.p.: 161−162 °C (Et2O). H
3
calcd for C22H31N2O7PS [MH]+ 499.1668, found 499,1672. [α]2D0
=
NMR (300 MHz, CDCl3): δ 0.76 (d, JHH = 6.2 Hz, 3H, CH3), 1.16
3
3
(d, JHH = 6.2 Hz, 3H, CH3), 1.19 (d, JHH = 6.2 Hz, 3H, CH3), 1.20
−26.7° (c = 0.31, CH2Cl2). ee was determined by HPLC analysis
(Chiracel-IA, Heptane/Ethanol 99:1, 1 mL/min). Retention time
(min): 22.66 (minor) and 49.15 (major).
(d, 3JHH = 6.0 Hz, 3H, CH3), 2.31 (s, 3H, CH3), 4.21 (m, 1H, CHO),
4.50 (m, 1H, CHO), 5.44 (dd, JHH = 13.8, JPH = 7.8 Hz, 1H,
CH2NO2), 5.56 (dd, 2JHH = 13.8, 3JPH = 20.3 Hz, 1H, CH2NO2), 5.83
2
3
Diisopropyl (1-((4-Methylphenyl)sulfonamido)-2-nitro-1-(4-
(trifluoromethyl)phenyl)ethyl)phosphonate (3g). The procedure
was followed, using diisopropyl ((tosylimino)(4-(trifluoromethyl)-
phenyl)methyl)phosphonate 2g (246 mg, 0.5 mmol), affording 325
mg (85%) of 3g as a white solid (ee = 80%). m.p.: 177−178 °C
3
3
(broad d, JPH = 8.3 Hz, 1H, NH), 7.01 (d, JHH = 7.6 Hz, 2H, 2 ×
3
CHar),7.02 (d, JHH = 8.4 Hz, 2H, 2 × CHar), 7.10−7.20 (m, 3H, 3 ×
CHar), 7.31 (d, JHH = 8.4 Hz, 2H, 2 × CHar). 13C NMR (75 MHz,
3
3
3
CDCl3): δ 21.5 (CH3), 22.9 (d, JPC = 6.3 Hz, CH3), 23.6 (d, JPC
=
3
3
1
3
5.5 Hz, CH3), 23.7 (d, JPC = 3.8 Hz, CH3), 24.2 (d, JPC = 2.7 Hz,
CH3), 62.1 (d, 1JPC = 153.4 Hz, Cquat), 74.1 (d, 2JPC = 8.2 Hz, CHO),
74.5 (d, 2JPC = 7.8 Hz, CHO), 76.3 (d, 2JPC = 1.4 Hz CH2), 127.2 (2 ×
CHar), 127.8 (2 × CHar), 127.9 (d, 4JPC = 3.3 Hz, 2 × CHar), 128.6 (d,
(Et2O). H NMR (300 MHz, CDCl3): δ 0.85 (d, JHH = 6.2 Hz, 3H,
3
3
CH3), 1.23 (d, JHH = 6.2 Hz, 3H, CH3), 1.27 (d, JHH = 2.2 Hz, 3H,
CH3), 1.29 (d, 3JHH = 2.2 Hz, 3H, CH3), 2.37 (s, 3H, CH3), 4.38 (m,
2
3
1H, CH), 4.66 (m, 1H, CH), 5.57 (dd, JHH = 13.9, JPH = 21.6 Hz,
5JPC = 3.3 Hz, CHar), 129.0 (2 × CHar),, 131.6 (d, 2JPC = 6.8 Hz, Cquat
)
2
3
1H, CH2NO2), 5.61 (dd, JHH = 13.9, JPH = 30.6 Hz, 1H, CH2NO2),
6.10 (broad d, 3JPH = 8.9 Hz, 1H, NH), 7.08 (d, 3JHH = 8.2 Hz, 2H, 2 ×
CHar), 7.27−7.35 (m, 4H, 4 × CHar), 7.40 (d, 3JHH = 8.2 Hz, 2H, 2 ×
CHar). 13C NMR (75 MHz, CDCl3): δ 21.2 (CH3), 22.7 (d, 3JPC = 6.0
Hz, CH3), 23.3 (d, 3JPC = 5.5 Hz, CH3), 23.5 (d, 3JPC = 3.7 Hz, CH3),
23.9 (d, 3JPC = 2.9 Hz, CH3), 61.7 (d, 1JPC = 151.7 Hz, Cquat), 74.5 (d,
2JPC = 5.8 Hz, CHO), 74.6 (d, 2JPC = 6.1 Hz, CHO), 75.1 (d, 2JPC = 1.8
138.9 (Cquat),143.4 (Cquat). 31P NMR (120 MHz, CDCl3): δ (ppm)
16.3. FTIR (KBr) νmax (cm−1): 3266 (NH st), 1548 (NO st as),
1370 (NO st sim), 1321 (OSO st sim), 1156 (OSO st
as), 979 (P O st) HRMS (Q-TOF) m/z calcd for C21H30N2O7PS
[MH]+ 485,1511, found 485.1518. [α]D20 = −33.0° (c = 0.91, CH2Cl2).
ee was determined by HPLC analysis (Chiracel-IA, Heptane/Ethanol
90:10, 1 mL/min). Retention time (min): 49.51 (minor) and 51.23
(major).
1
3
Hz, CH2NO2), 123.5 (d, JFC = 271.9 Hz, CF3), 124.4 (d, JFC = 3.2
Hz, 2 × CHar), 126.2 (2 × CHar), 128.4 (d, 3JPH = 5.0 Hz, 2 × CHar),
129.4 (2 × CHar), 135.8 (dq, 2JPC = 5.2 Hz, 5JFC = 1.8 Hz, Cquat), 138.3
(Cquat), 139.5 (Cquat), 143.1 (Cquat). 31P NMR (120 MHz, CDCl3): δ
Diisopropyl (1-((4-Methylphenyl)sulfonamido)-2-nitro-1-(p-
tolyl)ethyl)phosphonate 3e. Procedure B was followed, using
diisopropyl (p-tolyl(tosylimino)methyl)phosphonate 2e (219 mg, 0.5
mmol), affording 207 mg (83%) of 3e as a white solid (ee = 81%).
7
(ppm) 14.8 (q, JPF = 1.8 Hz). FTIR (KBr) νmax (cm−1): 3301 (NH
st), 1560 (NO st as), 1334 (NO st sim), 1366 (OSO st
1
m.p.: 131−132 °C (Et2O). H NMR (300 MHz, CDCl3): δ 0.82 (d,
sim), 1151 (OSO st as), 995 (PO st). HRMS (Q-TOF) m/z
3
3JHH = 6.0 Hz, 3H, CH3), 1.20 (d, JHH = 6.1 Hz, 3H, CH3), 1.22 (d,
calcd for C22H28F32O7PS [MH]+ 553,1385, found 553,1382. [α]2D0
=
3JHH = 6.1 Hz, 6H, 2 × CH3), 2.23 (s, 3H, CH3), 2.37 (s, 3H, CH3),
−28.2° (c = 0.33, CH2Cl2). ee was determined by HPLC analysis
(Chiracel-IA, Heptane/Ethanol 90:10, 1 mL/min). Retention time
(min): 25.62 (minor) and 28.12 (major).
4.26 (m, 1H, CHO), 4.58 (m, 1H, CHO), 5.46 (dd, 2JHH = 13.7, 3JPH
=
2
3
7.6 Hz, 1H, CH2NO2), 5.59 (dd, JHH = 13.7, JPH = 20.5 Hz, 1H,
CH2NO2), 6.82 (d, 3JHH = 8.2 Hz, 2H, 2 × CHar), 7.06 (d, 3JHH = 8.3
Hz, 1H, CHar), 7.09 (dd, 3JHH = 8.2 Hz, 3JPH = 2.1 Hz, 2H, 2 × CHar),
7.35 (d, 3JHH = 8.3 Hz, 2H, 2 × CHar). 13C NMR (75 MHz, CDCl3): δ
Diisopropyl (1-((4-Methylphenyl)sulfonamido)-2-nitro-1-(4-
nitrophenyl)ethyl)phosphonate (3h). The procedure was fol-
lowed, using diisopropyl ((4-nitrophenyl)(tosylimino)methyl)-
phosphonate 2h (234 mg, 0.5 mmol), affording 230 mg (87%) of
20.5 (CH3), 21.0 (CH3), 22.4 (d, 3JPC = 6.2 Hz, CH3), 23.0 (d, 3JPC
=
3
3
1
5.4 Hz, CH3), 23.2 (d, JPC = 3.0 Hz, CH3), 24.0 (d, JPC = 2.4 Hz,
CH3), 61.4 (d, 1JPC = 154.7 Hz, Cquat), 73.5 (d, 2JPC = 8.2 Hz, CHO),
73.9 (d, 2JPC = 7.3 Hz, CHO), 75.5 (CH2), 126.7 (2 × CHar), 128.1 (2
× CHar), 128.5 (2 × CHar), 128.9 (2 × CHar),, 138.0 (d, 2JPC = 2.8 Hz,
Cquat) 138.3 (Cquat), 138.4 (Cquat), 142.7 (Cquat). 31P NMR (120 MHz,
CDCl3): δ (ppm) 16.1. FTIR (KBr) νmax (cm−1): 3285 (NH st), 1561
(NO st as), 1323 (NO st sim), 1367 (OSO st sim), 1158
(OSO st as), 988 (PO st). [α]2D0 = −21.2° (c = 0.21, CH2Cl2).
HRMS (Q-TOF) m/z calcd for C22H31N2O7PS [MH]+ 499.1668,
found 499.1671. ee was determined by HPLC analysis (Chiracel-IA,
Heptane/Ethanol 99:1, 1 mL/min). Retention time (min): 21.84
(minor) and 55.53 (major).
3h as a white solid (ee = 80%). m.p.: 166−167 °C (Et2O). H NMR
(300 MHz, CDCl3): δ 0.88 (d, 3JHH = 6.1 Hz, 3H, CH3), 1.19 (d, 3JHH
3
= 6.1 Hz, 3H, CH3), 1.24 (d, JHH = 6.1 Hz, 6H, 2 × CH3), 2.34 (s,
3
3H, CH3), 4.39 (m, 1H, CH), 4.63 (m, 1H, CH), 5.51 (d, JPH = 2.5
3
Hz, 1H, CH2NO2), 5.55 (s, 1H, CH2NO2), 6.06 (broad d, JPH = 9.1
3
Hz, 1H, NH), 7.05 (d, JHH = 8.4 Hz, 2H, 2 × CHar), 7.33 (d, 3JHH
=
3
4
8.4 Hz, 2H, 2 × CHar), 7.40 (dd, JHH = 9.0, JPH = 2.2 Hz, 2H, 2 ×
CHar), 7.83 (d, JHH = 9.0 Hz, 2H, 2 × CHar). 13C NMR (75 MHz,
3
3
3
CDCl3): δ 21.8 (CH3), 23.3 (d, JPC = 5.9 Hz, CH3), 23.8 (d, JPC
=
3
3
5.4 Hz, CH3), 24.0 (d, JPC = 3.7 Hz, CH3), 24.2 (d, JPC = 3.2 Hz,
CH3), 62.4 (d, 1JPC = 149.9 Hz, Cquat), 75.1 (d, 2JPC = 7.9 Hz, CHO),
75.2 (d, 2JPC = 8.2 Hz, CHO), 76.1 (d, 2JPC = 2.2 Hz CH2NO2), 122.9
(d, 4JPC = 2.3 Hz, 2 × CHar), 127.3 (2 × CHar) 129.3 (d, 3JPC = 4.8 Hz,
2 × CHar), 129.6 (2 × CHar), 138.5 d, 5JPC = 1.4 Hz, Cquat), 139.7 (d,
Diisopropyl (1-((4-Methylphenyl)sulfonamido)-2-nitro-1-(m-
tolyl)ethyl)phosphonate (3f). Procedure B was followed, using
diisopropyl (m-tolyl(tosylimino)methyl)phosphonate 2f (219 mg, 0.5
mmol), affording 207 mg (83%) of 3f as a white solid (ee = 84%).
2JPC = 6.1 Hz, Cquat), 144.5 (Cquat), 147.7 (d, 4JPC = 3.0 Hz, Cquat). 31
P
NMR (120 MHz, CDCl3): δ (ppm) 15.3. FTIR (KBr) νmax (cm−1):
3324 (NH st), 1552 (NO st as), 1352 (NO st sim), 1348 (O
SO st sim), 1152 (OSO st as), 969 (P O st). HRMS (Q-
TOF) m/z calcd for C21H28N3O9PS [MH]+ 530.1362, found
530.1359. [α]2D0 = −27.3° (c = 0.34, CH2Cl2). ee was determined by
HPLC analysis (Chiracel-IB, Heptane/Ethanol 99:1, 1 mL/min).
Retention time (min): 45.72 (minor) and 50.88 (major).
1
m.p.: 133−134 °C (Et2O). H NMR (300 MHz, CDCl3): δ 0.82 (d,
3
3JHH = 6.2 Hz, 3H, CH3), 1.20 (d, JHH = 6.2 Hz, 3H, CH3), 1.22 (d,
3
3JHH = 6.1 Hz, 3H, CH3), 1.24 (d, JHH = 6.0 Hz, 3H, CH3), 2.36 (s,
3H, CH3), 2.39 (s, 3H, CH3), 4.28 (m, 1H, CHO), 4.53 (m, 1H,
CHO), 5.48 (dd, 2JHH = 13.6, 3JPH = 7.3 Hz, 1H, CH2NO2), 5.63 (dd,
2JHH = 13.6, 3JPH = 21.6 Hz, 1H, CH2NO2), 7.00 (d, 3JHH = 8.2 Hz, 2H,
2 × CHar),7.08 (d, 3JHH = 8.2 Hz, 1H, CHar), 7.22−7.28 (m, 3H, 3 ×
CHar), 7.35 (d, 3JHH = 8.2 Hz, 2H, 2 × CHar), 7.80 (d, 3JHH = 8.2 Hz,
Diisopropyl (1-((4-Methylphenyl)sulfonamido)-2-nitro-1-(3-
nitrophenyl)ethyl)phosphonate (3i). Procedure B was followed,
G
dx.doi.org/10.1021/jo502233m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
using diisopropyl ((3-nitrophenyl)(tosylimino)methyl)phosphonate 2i
(230 mg, 0.5 mmol), affording 217 mg (82%) of 3i as a white solid (ee
= 81%). m.p.: 161−162 °C (Et2O). H NMR (300 MHz, CDCl3): δ
ACKNOWLEDGMENTS
■
1
The present work has been supported by the Direccion
de Investigacion
(MICINN, Madrid DGI, CTQ2012-34323) and by the
Departamento de Educacion, Universidades e Investigacion
́
General
3
3
́
del Ministerio de Ciencia e Innovacion
́
1.25 (d, JHH = 6.1 Hz, 3H, CH3), 1.30 (d, JHH = 6.1 Hz, 3H, CH3),
1.31 (d, 3JHH = 6.1 Hz, 6H, 2 × CH3), 2.41 (s, 3H, CH3), 4.69 (m, 1H,
CHO), 4.78 (m, 1H, CHO), 5.01 (dd, 2JHH = 13.0, 3JPH = 5.2 Hz, 1H,
́
́
2
3
CH2NO2), 5.63 (dd, JHH = 13.0, JPH = 5.0 Hz, 1H, CH2NO2), 5.58
́
del Gobierno Vasco and Universidad del Paıs Vasco (GV, IT
3
(broad s, 1H, NH), 7.03 (d, JHH = 8.4 Hz, 2H, 2 × CHar), 7.56 (t,
422-10; UPV/EHU-UFI 11/22).
3JHH = 8.0 Hz, 1H, CHar), 7.80 (d, 3JHH = 8.0 Hz, 1H, CHar), 7.95 (d,
3JHH = 8.4 Hz, 2H, 2 × CHar), 8.20 (d, 3JHH = 8.0 Hz, 1H, CHar), 8.52
(d, JPH = 1.9 Hz, 1H, CHar) 13C NMR (75 MHz, CDCl3): δ 21.6
4
REFERENCES
■
3
3
(CH3), 23.6 (d, JPC = 5.5 Hz, CH3), 23.9 (d, JPC = 5.0 Hz, CH3),
(1) (a) Morken, J. P. Nature 2014, 508, 324. (b) Shimizu, M. Angew.
Chem., Int. Ed. 2011, 50, 5988. (c) Hawner, C.; Alexakis, A. Chem.
Commun. 2010, 46, 7295. (d) Baro, A., Christoffers, J., Eds. Quaternary
Stereocenters: Challenges, Solutions for Organic Synthesis; Wiley-VCH:
Weinhein, 2005. (e) Bella, M.; Gasperi, T. Synthesis 2009, 1583.
(2) Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873.
(3) (a) Van der Jeught, K.; Stevens, C. V. Chem. Rev. 2009, 109,
2672. (b) Berlicki, L.; Kafarski, P. Curr. Org. Chem. 2005, 9, 1829.
(c) Kafarski, P.; Lejczak, B. Curr. Med. Chem.: Anti-Cancer Agents 2001,
1, 301.
3
3
24.1 (d, JPC = 3.5 Hz, CH3), 24.2 (d, JPC = 3.0 Hz, CH3), 64.4 (d,
1JPC = 157.9 Hz, Cquat), 74.4 (d, 2JPC = 8.1 Hz, CHO), 74.7 (d, JPC
=
2
7.5 Hz, CHO), 76.0 (CH2NO2), 122.0 (d, 3JPC = 3.9 Hz, CHar), 123.9
(CHar), 126.5 (2 × CHar), 129.3 (d, 4JPC = 3.0 Hz, CHar), 129.8 (2 ×
2
2
CHar), 132.7 (d, JPC = 4.0 Hz, Cquat), 135.7 (Cquat), 138.7 (d, JPC
=
1.2 Hz, Cquat), 143.5 (Cquat). 31P NMR (120 MHz, CDCl3): δ (ppm)
15.5. FTIR (KBr) νmax (cm−1): 3287 (NH st), 1560 (NO st as),
1336 (NO st sim), 1367 (OSO st sim), 1157 (OSO st
as), 991 (PO st). HRMS (Q-TOF) m/z calcd for C21H28N3O9PS
[MH]+ 530.1362, found 530.1360. [α]D20 = −27.8° (c = 0.35, CH2Cl2).
ee was determined by HPLC analysis (Chiracel-IB, Heptane/Ethanol
99:1, 1 mL/min). Retention time (min): 28.99 (minor) and 33.56
(major).
(4) (a) Hirschmann, R.; Smith, A. B., III; Taylor, C. M.; Benkovic, P.
A.; Taylor, S. D.; Yager, K. M.; Sprengeler, P. A.; Venkovic, S. J. Science
1994, 265, 234. (b) Macchiarulo, A. R.; Pellicciari. J. Mol. Graphics
́
Modell. 2007, 26, 728. (c) Sienczyk, M.; Winiarski, L.; Kasperkiewicz,
Synthesis of Diisopropyl (2-Amino-1-((4-methylphenyl)-
sulfonamido)-1-(3-nitrophenyl)ethyl)phosphonate ((S)-4). Pro-
cedure: A solution of diisopropyl (1-((4-methylphenyl)sulfonamido)-
2-nitro-1-phenylethyl)phosphonate (S)-3d (97 mg, 0.2 mmol) in
methanol (1 mL) was stirred for 3 days in the presence of Pd-C (10%)
under a hydrogen atmosphere (80 psi). The resulting suspension was
filtered through Celite in order to remove Pd-C, and the resulting clear
solution was evaporated under reduced pressure. The crude residue
was purified by column chromatography (AcOEt/MeOH 3:1),
affording 88 mg (95%) of (S)-4 as a white solid. m.p.: 133−134 °C
P.; Psurski, M.; Wietrzyk, J.; Oleksyszyn, J. Bioorg. Med. Chem. Lett.
2011, 21, 7224. (d) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J.
Med. Chem. 1986, 29, 29. (e) Yao, G.; Ye, M.; Huang, R.; Li, Y.; Pan,
Y.; Xu, Q.; Liao, Z.; Wang, H. Bioorg. Med. Chem. Lett. 2014, 24, 501.
(5) Bonarska, D.; Kleszczynska, H.; Sarapuk, J. Cell Mol. Biol. Lett.
́
2002, 7, 929.
(6) For reviews, see: (a) Mucha, A.; Kafarski, P.; Berlicki, L. J. Med.
Chem. 2011, 54, 5955. (b) Orsini, F.; Sello, G.; Sisti, M. Curr. Med.
Chem. 2010, 17, 264.
(7) For reviews, see: Palacios, F.; Alonso, C.; de Los Santos, J. M.
Chem. Rev. 2005, 105, 899.
1
3
(Hexanes/CH2Cl2). H NMR (300 MHz, CDCl3): δ: 0.79 (d, JHH
=
=
3
3
6.1 Hz, 3H, CH3), 1.12 (d, JHH = 6.1 Hz, 3H, CH3), 1.15 (d, JHH
́
(8) (a) Ordonez, M.; Viveros-Ceballos, J. L.; Cativiela, C.; Azerpe, A.
̃
3
6.1 Hz, 3H, CH3), 1.16 (d, JHH = 6.1 Hz, 3H, CH3), 2.29 (s, 3H,
CH3), 3.24 (broad s, 3H, NH + NH2), 3.63 (s, 1H, CH2NH2), 3.70 (d,
3JPH = 13.8, 1H, CH2NH2), 4.23 (m, 1H, CH), 4.50 (m, 1H, CH),
7.00 (d, 3JHH = 8.2 Hz, 4H, 4 × CHar),7.06 (dd, 3JHH = 6.9, 4JHH = 1.4
Hz, 1H, CHar), 7.19−7.22 (m, 2H, 2 × CHar), 7.37 (d, 3JHH = 8.2 Hz,
2H, 2 × CHar). 13C NMR (75 MHz, CDCl3): δ 21.6 (CH3), 23.1 (d,
3JPC = 6.3 Hz, CH3), 23.8 (d, 3JPC = 5.4 Hz, CH3), 24.2 (d, 3JPC = 3.4
Hz, CH3), 24.3 (d, 3JPC = 2.5 Hz, CH3), 45.3 (d, 2JPC = 3.9 Hz, CH2),
65.1 (d, 1JPC = 149.3 Hz, Cquat), 73.2 (d, 2JPC = 8.0 Hz, CHO), 73.5 (d,
́
Curr. Org. Synth. 2012, 9, 310. (b) Ordonez, M.; Rojas-Cabrera, H.;
̃
Cativiela, C. Tetrahedron 2009, 65, 17.
(9) Merino, P.; Marques-Lopez, E.; Herrera, R. P. Adv. Synth. Catal.
2008, 350, 1195.
(10) (a) Vicario, J.; Ezpeleta, J. M.; Palacios, F. Adv. Synth. Catal.
2012, 354, 2641. (b) Bera, K.; Namboothiri, I. N. N. Org. Lett. 2012,
14, 980. (c) Nakamura, S.; Hayashi, M.; Hiramatsu, Y.; Shibata, N.;
Funahashi, Y.; Toru, T. J. Am. Chem. Soc. 2009, 131, 18240. (d) Wilt, J.
C.; Pink, M.; Johnston, J. N. Chem. Commun. 2008, 4177. (e) Kim, S.
M.; Kim, H. R.; Kim, D. Y. Org. Lett. 2005, 7, 2309. (f) Bernardi, L.;
Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 5772.
(g) Kuwano, R.; Nishio, R.; Ito, Y. Org. Lett. 1999, 1, 837.
(11) (a) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Alonso, J. M.
Tetrahedron 2004, 60, 8937. (b) Vicario, J.; Alonso, C.; de Los Santos,
J. M.; Palacios, F. Curr. Org. Synth. 2010, 7, 628.
(12) (a) Palacios, F.; Vicario, J.; Maliszewska, A.; Aparicio, D. J. Org.
Chem. 2007, 72, 2682. (b) Palacios, F.; Ochoa de Retana, A. M.; Velez
del Burgo, A. J. Org. Chem. 2011, 76, 9472.
(13) de los Santos, J. M.; Ignacio, R.; Aparicio, D.; Palacios, F. J. Org.
Chem. 2007, 72, 5202.
5
2JPC = 7.8 Hz, CHO), 127.2 (2 × CHar), 127.7 (d, JPC = 2.9 Hz,
CHar), 127.9 (d, 4JPC = 2.5 Hz, 2 × CHar), 128.3 (d, 3JPC = 5.0 Hz, 2 ×
2
CHar), 129.2 (2 × CHar), 134.7 (d, JPC = 4.4 Hz, Cquat) 139.0
(Cquat),143.3 (Cquat). 31P NMR (120 MHz, CDCl3): δ (ppm) 21.6.
FTIR (KBr) νmax (cm−1): 3399 (NH st), 3132 (NH st), 1321 (O
SO st sim), 1156 (OSO st as), 969 (PO st). HRMS (Q-
TOF) m/z calcd for C21H31N2O5PS [MH]+ 455.1770, found
455.1776. [α]2D0 = −19.2° (c = 0.88, CH2Cl2).
ASSOCIATED CONTENT
■
S
* Supporting Information
́
(14) Alonso, C.; Gonzalez, M.; Fuertes, M.; Rubiales, G.; Ezpeleta, J.
CIF file and thermal ellipsoid plot for 3d and copies of 1H and
13C NMR spectra for compounds 2−4. This material is
available free of charge via the Internet at http://pubs.acs.org.
M.; Palacios, F. J. Org. Chem. 2013, 78, 3858 and references therein.
(15) Palacios, F.; Olszewski, T. K.; Vicario, J. Org. Biomol. Chem.
2010, 8, 4255.
(16) Vicario, J.; Ortiz, P.; Palacios, F. Eur. J. Org. Chem. 2013, 7095.
(17) Noble, A.; Anderson, J. C. Chem. Rev. 2013, 113, 2887.
(18) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett.
2004, 6, 625.
(19) (a) Singh, A.; Yoder, R. A.; Shen, B.; Johnston, J. N. J. Am.
Chem. Soc. 2007, 129, 3466. (b) Rueping, M.; Antonchick, A. P. Org.
Lett. 2008, 10, 1731. (c) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45,
3909.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: francisco.palacios@ehu.es.
Notes
The authors declare no competing financial interest.
H
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Article
(20) (a) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi,
L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 7975. (b) Gomez-Bengoa,
E.; Linden, A.; Lopez, R.; Mugica-Mendiola, I.; Oiarbide, M.; Palomo,
́
́
C. J. Am. Chem. Soc. 2008, 130, 7955.
(21) Uraguchi, D.; Koshimoto, K.; Ooi, T. J. Am. Chem. Soc. 2008,
130, 10878.
(22) (a) Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44,
466. (b) Jiang, X.; Zhang, Y.; Wu, L.; Zhang, G.; Liu, X.; Zhang, H.;
Fu, D.; Wang, R. Adv. Synth. Catal. 2009, 351, 2096. (c) He, H.-X.;
Yang, W.; Du, D.-M Adv. Synth. Catal. 2013, 355, 1137.
(23) Xie, H.; Zhang, Y.; Zhang, S.; Chen, X.; Wang, W. Angew. Chem.,
Int. Ed. 2011, 50, 11773.
(24) (a) Arai, T.; Matsumura, E.; Masu, H. Org. Lett. 2014, 16, 2768.
(b) Parra, A.; Alfaro, R.; Marzo, L.; Moreno-Carrasco, A.; García
Ruano, J. L.; Aleman
́
, J. Chem. Commun. 2012, 48, 9759.
(25) Nunez, M. G.; Alistair, J. M.; Dixon, D. J. J. Am. Chem. Soc.
́
̃
2013, 135, 16348.
(26) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New
York, 2001.
(27) For reviews, see: (a) Cardona, F.; Goti, A. Nat. Chem. 2009, 1,
269. (b) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des.
2006, 67, 101. (c) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew.
Chem., Int. Ed. 1998, 37, 2580.
(28) (a) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417.
(b) Wynberg, H. Top. Stereochem. 1986, 16, 8.
́
(29) (a) Kacprzak, K.; Gawronski, J. Synthesis 2001, 961. (b) Yoon,
T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
(30) The A-value for a particular substituent corresponds to the
difference in Gibbs free energy between the higher energy
conformation (axial substitution) and the lower energy conformation
(equatorial substitution) in a cyclohexane ring. For references, see:
(a) Eliel, E. L., Wilen, S. H., Mander, L. N., Eds. Stereochemistry of
Organic Compounds; Wiley: New York, 1994. (b) Hirsch, J. A. Top.
Stereochem. 1967, 199.
(31) For an excellent review: Kizirian, J. C. Chem. Rev. 2008, 108,
140.
́
(32) For recent contributions, see: (a) Avila, A.; Chinchilla, R.;
Gomez Bengoa, E.; Najera, C. Tetrahedron: Asymmetry 2013, 24, 1531.
́
́
(b) MacDonald, M. J.; Hesp, C. R.; Schipper, D. J.; Pesant, M.;
Beauchemin, A. M. Chem.Eur. J. 2013, 19, 2597. (c) Schuettler, C.;
Li-Boehmer, Z.; Harms, K.; von Zezschwitz, P. Org. Lett. 2013, 15,
800. (d) Olson, D. E.; Roberts, D. A.; Du Bois, J. Org. Lett. 2012, 14,
6174. (e) Anderson, J. C.; Noble, A.; Tocher, D. A. J. Org. Chem. 2012,
77, 6703. (f) Wixey, J. S.; Ward, B. D. Chem. Commun. 2011, 47, 5449.
(33) McKay, W. R.; Proctor, G. R. J. Chem. Soc., Perkin Trans. 1 1981,
2435.
I
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