Synthesis of fluorinated β-aminophosphonates and γ-lactams

Article abstract of DOI:10.1021/jo400281e

The functionalized polyfluorophosphorylated 1-azadienes I have been prepared by a Wittig reaction of ethyl glyoxalate and perfluorophosphorylated conjugated phosphoranes, obtained by reaction of phosphazenes and fluorinated acetylenic phosphonates. Subsequent reduction of both carbon-carbon and carbon-nitrogen double bonds of these 1-azadienes I affords the fluorine-containing β-aminophosphonates II, with the syn β-aminophosphonate being obtained as the major diastereoisomer. Base-mediated cyclocondensation of a diastereomeric mixture of aminophosphonates II leads exclusively to a new type of functionalized trans-γ-lactams III in a diastereoselective way. A computational study has also been used to explain the observed diastereoselectivity of these reactions.

Full text of DOI:10.1021/jo400281e

Article
pubs.acs.org/joc
Synthesis of Fluorinated β‑Aminophosphonates and γ‑Lactams
†
†
†
†
‡
́
́
́
Concepcion Alonso, Marıa Gonzalez, Marıa Fuertes, Gloria Rubiales, Jose Marıa Ezpeleta,
́
́
and Francisco Palacios*,†
†
‡
́
́
Departamento de Quımica Organica I and Centro de Investigacion Lascaray (Lascaray Research Center) and Departamento de
́
Fısica Aplicada, Facultad de Farmacia, Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Paseo de la
Universidad 7, 01006 Vitoria, Spain
S
* Supporting Information
ABSTRACT: The functionalized polyfluorophosphorylated
1-azadienes I have been prepared by a Wittig reaction of ethyl
glyoxalate and perfluorophosphorylated conjugated phosphor-
anes, obtained by reaction of phosphazenes and fluorinated
acetylenic phosphonates. Subsequent reduction of both carbon−
carbon and carbon−nitrogen double bonds of these 1-azadienes
I affords the fluorine-containing β-aminophosphonates II, with the syn β-aminophosphonate being obtained as the major
diastereoisomer. Base-mediated cyclocondensation of a diastereomeric mixture of aminophosphonates II leads exclusively to a
new type of functionalized trans-γ-lactams III in a diastereoselective way. A computational study has also been used to explain the
observed diastereoselectivity of these reactions.
N-protected haloamines12a or imines,15 or by ring opening of fluoro-
INTRODUCTION
■
alkyl aziridine-2-phosphonates.16
Organophosphorus compounds are important substrates in the
study of biochemical processes,1 and β-aminophosphonates, as they
are isosteres of β-amino acids, play an important role as enzyme
inhibitors, agrochemicals, and pharmaceuticals2 as well as reveal
diverse and interesting biological and biochemical properties. Some
β-aminophosphonic acids and their derivatives have been identified
as natural products.3a,b The parent acid was first isolated from
Celiata protozoa,3c and subsequently the compound along with its
different derivatives was obtained from microorganisms.3d,e
Other important uses of these compounds are as pesticides3f
and in the preparation of valuable metal complexes.3g,h
Furthermore, the introduction of a fluorine atom or a fluorinated
moiety can modulate the properties of a bioactive molecule, since
this may lead to changes in solubility, lipophilicity, metabolic stabi-
lity, conformation, hydrogen-bonding ability, or chemical
reactivity.4 Due to the unique properties of the fluorine atom,
fluorinated molecules occupy a significant place5 in pharmaceut-
ical/medicinal,6 agrochemical,7 and materials sciences.8 Fluorine
incorporation into a chemical structure has been used in
pharmaceutical development and drug design to prevent
molecules from being metabolized too quickly, thereby allowing
a drug to act before it is cleared from the body.9 In this respect,
particular interest has focused on developing synthetic methods
for the preparation of fluorinated building blocks,6,10 among them
fluorinated aminophosphonates.11 Efficient examples of amino-
phosphonates containing fluoroalkyl groups as ligands for phospho-
glycerate kinase12a or antibacterials,12b inhibitors of serine esterases,
alanine racemase, and pyrimidine phosphorylases,12c and also the
preparation of fluorinated peptidomimetics13 have been demon-
strated. However, the literature contains very few preparative
methods for the preparation of fluorinated β-aminophosphonates,
such as by the addition of amines to unsaturated phosphonates,12b,14
by the addition of fluorinated phosphonate carbanions to
On the other hand, γ-lactams have important applications in
the drug-discovery process, as key intermediates in the preparation
of biologically and pharmaceutically relevant molecules in the
treatment of cancer,17a fungal infections,17b epilepsy,17c,d HIV,17e,f
neurodegenerative diseases,17g and depression.17h The γ-lactam
core showed a better fit than the larger δ-lactam core into the
narrow hydrophobic pocket of histone deacetylase (HDAC) active
site and showed better inhibition profiles of HDACs and cancer
cell growth inhibitory activities.18a γ-Lactams are also viable
glycinamide replacements within a series of cyclohexane-based
CCR2 antagonists which could find additional use in the design
and development of future antagonists.18b
Continuing with our interest in the chemistry of fluorinated
aminophosphorus derivatives as well as of electron-rich,19 fluorinated,20
and functionalized 1-azadienes,21 here we report the diastereolective
preparation of novel fluoroalkyl- and phosphorus-substituted
γ-lactams I and fluorine-containing β-aminophosphonates II from
functionalized 1-azadienes III, easily prepared from phosphazenes
IV, polyfluoroacetylenephosphonates V, and ethyl glyoxalate VI
(Scheme 1).
RESULTS AND DISCUSSION
■
The formation of conjugated phosphoranes by the reaction of
phosphazenes and acetylenic esters has been reported.22
Therefore, a convenient method for the synthesis of some
diethoxyphosphinyl perfluoroalkylidene phosphoranes based on
a [2 + 2] cycloaddition reaction between phosphazenes 1 and
polyfluoroacetylenephosphonates 2 has been developed (Scheme 2).
Received: February 6, 2013
Published: March 13, 2013
© 2013 American Chemical Society
3858
dx.doi.org/10.1021/jo400281e | J. Org. Chem. 2013, 78, 3858−3866

The Journal of Organic Chemistry
Article
Scheme 1
Table 1. Polyfluorophosphorylated Ylides 4 Obtained
entry compd
PR3
RF
Ar
reaction conditions
1
2
3
4
4a
4b
4c
4d
PMe3
CF3
p-MeO-C6H4 CHCl3/30 min/room
temp
PMe3
PMe3
CF3
CF3
p-Me-C6H4
CHCl3/30 min/room
temp
p-NO2-C6H4 CHCl3/30 min/room
temp
PMe2Ph CF3
p-MeO-C6H4 CHCl3/30 min/room
temp
5
6
7
4e
4f
PMe2Ph CF3
PMe2Ph CF3
p-Me-C6H4
CHCl3/1 h/room temp
p-NO2-C6H4 CHCl3/15 h/room temp
a
4g
PPh3
CF3
p-Me-C6H4
CHCl3/21.5 h/Δ
toluene/17.5h/Δ
8
4h
4i
PMe3
PMe3
PMe3
C2F5
C2F5
p-MeO-C6H4 CHCl3/3 h/room temp
9
p-NO2-C6H4 CHCl3/30 h/Δ
10
4j
CF2H p-NO2-C6H4 toluene/4 h/Δ
Phosphazenes 1 were readily prepared by addition of the corres-
ponding phosphines to azides through the Staudinger reaction.23
Given the instability of P-alkylphosphazene species,24 they were
allowed to react in situ with polyfluoroacetylenephosphonates 2
prepared according to the established procedure.25 Reaction progress
for the formation of ylides 4 was monitored by 31P NMR
spectroscopy. Signals for the phosphazenes (δ 2−10 ppm) and the
yne phosphonates (δ −9 to −11 ppm)25 disappear, and resonances
corresponding to polyfluorophosphorylated ylides 4 appear in the
range δ 15−26 ppm. 19F NMR could be applied similarly, with the
loss of 2 (δ −53 to −112 ppm) and the appearance of 4 (δ −60 to
−70 ppm). The results are summarized in Table 1.
a
Isolated by recrystallization (68%).
phoshorus ylides were found to react with ethyl glyoxalate.
Treatment of a chloroform solution of ylide 4 with 1 equiv of
ethyl glyoxalate gave corresponding 1-azadienes 6 in moderate
to good yields (Scheme 2, Table 2). Formation of 1-azadienes 6
Table 2. Polyfluorophosphorylated Derivatives 6 Obtained
a
entry compd
RF
Ar
reaction conditions yield, %
1
2
3
4
5
6a
6b
6c
6d
6e
CF3
p-MeO-C6H4
p-Me-C6H4
15 h/room temp
12 h/room temp
20 h/room temp
24 h/reflux
76
65
80
68
76
The structure of isolated ylide 4g (R = Ph) was determined
by NMR spectroscopy and mass spectrometry. The 31P NMR
spectrum of ylide 4g presents two doublets for phosphonate
and phosphorane phosphorus atoms, observed respectively at
δ 24.2 and 25.7 ppm with the coupling constant 2JPP = 51.1 Hz.
The formation of phosphoranes 4 could be explained by [2 + 2]
cycloaddition between phosphazenes 1 and polyfluoroacetylene-
phosphonates 2, via intermediates 3 followed by ring opening,
affording polyfluoroalkylated diethoxyphosphinyl phosphoranes 4
(Scheme 2) in a way similar to that reported for phosphazenes and
phosphorus ylides with acetylenic esters.22 With the exception of
trifluoromethylphosphorylated ylide 4g (R = Ph), which could be
isolated and purified by recrystallization in hexane (68% yield,
Table 1, entry 7), in general polyfluorophosphorylated ylides 4
were unstable and were used in situ without purification in further
reactions. In fact, water-assisted hydrolysis of trifluoromethyl
diethoxyphosphorylated ylide 4a (RF = CF3, Ar = p-MeOC6H4)
rapidly yielded the corresponding hydrolyzed product as a mixture
of imine-enamine tautomers 5/5′ (Scheme 2).
CF3
CF3
p-NO2-C6H4
p-NO2-C6H4
p-NO2-C6H4
C2F5
CF2H
15 h/room temp
a
Isolated by flash chromatography.
could be explained by a Wittig reaction between the ylide and
the carbonyl group affording stereoselectively the correspond-
ing E isomer of 1-azadiene and the corresponding phosphine
oxide (Scheme 2).
Polyfluorophosphorylated 1-azadienes 6 were fully charac-
terized by 1D and 2D NMR spectroscopy and MS
spectrometry. One characteristic signal for azadiene 6a (RF =
1
CF3, Ar = p-MeOC6H4) in the H NMR spectrum is the
doublet at δ 6.96 ppm, with the coupling constant JHP = 22.7
3
Hz, corresponding to the vinylic CH proton of the azadiene.
The 13C NMR spectrum shows a characteristic doublet signal at
2
δ 139.7 ppm with the coupling constant JCP = 7.6 Hz for the
vinylic CH carbon and a doublet at δ 163.1 ppm with the coupling
constant JCP = 26.0 Hz for the carboxyl carbon. Coupling
Subsequently, the Wittig reaction of ylides 4 with carbonyl
compounds was explored. The perfluoroalkylated conjugated
3
Scheme 2. Formation of Fluorinated Phosphorus Ylides 4 and 1-Azadienes 6
3859
dx.doi.org/10.1021/jo400281e | J. Org. Chem. 2013, 78, 3858−3866

The Journal of Organic Chemistry
Article
constants in this range are consistent with an E configuration of
the vinylic double bond.
The potential conversion of functionalized azadienes 6 to
fluorinated β-aminophosphonates was explored. Treatment of 6
with NaBH4 at 0 °C afforded β-aminophosphonates 7/7′ in good
yields as syn/anti mixtures of diastereoisomers (Scheme 3, Table 3),
(the minor diastereoisomer has significantly higher solubility), its
structure being unequivocally determined by X-ray analysis (see
the Supporting Information).
Formation of β-aminophosphonates 7 could be explained by
reduction of both the carbon−carbon and the iminic carbon−
nitrogen double bonds to give both diastereoisomers of
saturated β-aminophosphonates. The mechanism of this
reaction could be explained as follows: first reduction of the
carbon−carbon double bond by means of an initial attack of
hydride at the most positive carbon of the heterodienic system
to afford the corresponding enamine 8 (Scheme 3, vide supra),
which is in tautomeric equilibrium with imine 9 and enamine
10, and subsequent reduction of the second double bond.
The relative energies of structures 8−10 (when RF = CF3,
C2F5, CF2H) were calculated using Gaussian 0926 within the
density functional theory (DFT) framework27 at the B3LYP-
(PCM)/6-31G* and M06-2X(PCM)//6-31G*//B3LYP/6-31G*
level using ethanol as solvent (for details see the Supporting
Information). Taking into account the results obtained, imines 9 are
more stable than enamines 8 or 10 in all cases (RF = CF3, C2F5,
CF2H; see the Supporting Information for details). Afterward, for
the subsequent reduction of the iminic double bond of derivatives
9, a second hydride entrance to the iminic intermediate could be
possible by a or b face approach (Scheme 4), affording the syn (7)
Scheme 3. Formation of Diastereomeric Mixture of
Fluorinated β-Aminophosphonates by 1-Azadiene Reduction
with NaBH4
Table 3. Polyfluorophosphorylated Derivatives 7 Obtained
Scheme 4. Hydride Attack onto Imine 9
a
entry compd
RF
Ar
reaction conditions yield, %
b
1
2
3
4
5
7a/7′a
7b/7′b
7c/7′c
7d/7′d
7e/7′e
CF3
p-MeO-C6H4
p-Me-C6H4
2 h/room temp
1 h/room temp
1 h/room temp
1 h/room temp
2 h/room temp
60
50
82
b
b
c
CF3
CF3
p-NO2-C6H4
p-NO2-C6H4
C2F5
CF2H
60
35
c
p-NO2-C6H4
a
b
Isolated by flash chromatography. Obtained as a diastereomeric
c
mixture 60/40. Obtained as a diastereomeric mixture 95/5.
in different proportions for the syn and anti isomers, determined by
NMR spectroscopy and mass spectrometry.
For example, the 31P NMR spectrum of β-aminophospho-
nates 7b/7′b (RF = CF3, Ar = p-Me-C6H4) shows two singlets
at δ 27.4 and 27.0 ppm, for the major and minor diastereomers
(ratio 60/40), respectively, and in the 19F NMR spectrum
two doublets appear at δ −75.6 ppm (3JFH = 6.1 Hz) and at δ
−72.4 ppm (3JFH = 7.6 Hz), for the major and minor diaster-
or anti (7′) diastereoisomer, respectively, of the corresponding
β-aminophosphonate.
Hydride approaches the face containing the smaller groups,
affording the corresponding syn β-aminophosphonate 7 as the
major diastereoisomer. Therefore, experimental and theoretical
results may explain that reduction of polyfluorophosphorylated
1-azadienes 6 with NaBH4 in ethanol affords the corresponding
syn β-aminophosphonates 7 as major diastereoisomers. It is
noteworthy that these compounds show an interesting
structure from a biological point of view,2,6 and no precedents
for the synthesis of this type of polyfluoro β-amino-
phosphonates can be found in the literature.
β-Aminophosphonates 7 were efficiently converted to highly
valuable γ-lactams17,18 by ring closure of these acyclic compounds.
Base treatment of diastereomeric mixture of fluorinated
β-aminophosphonates 7/7′ with NaH in THF afforded exclusively
the cyclic trans-γ-lactam 11 as a single diastereoisomer (Scheme 5,
Table 4).
The exclusive formation of trans-γ-lactam diastereoisomer 11
may be explained by deprotonation of the amine group with
NaH in THF and intramolecular attack of the resulting
nitrogen anion on the carbonyl group followed by the loss of
ethanol to afford γ-lactams 11/11′ as a mixture of trans and cis
diastereoisomers. However, due to the basic reaction
conditions, isomerization may occur in γ-lactams 11/11′, and
1
eomers, respectively. The H NMR spectrum shows as charac-
teristic signals two methyl singlets at δ 2.15 ppm (major) and δ
2.14 ppm (minor) and two differentiated multiplets at 4.46−
4.56 ppm (major) and 4.26−4.38 ppm (minor) for the proton α
to the CF3 group. The 13C NMR spectrum shows two
characteristic double quadruplets at δ 55.9 ppm with the two
coupling constants 2JCF = 29.5 Hz and 2JCP = 2.5 Hz for the major
isomer and at δ 56.2 ppm with the two coupling constants 2JCF
=
30.5 Hz and 2JCP = 4.3 Hz for the minor isomer, corresponding to
carbons bonded to the CF3 group. The anti or syn configuration
assignment for β-aminophosphonates 7 and 7′ was difficult to
determine by NMR spectroscopy. Small differences in chemical
shift, the overlap of signals, and complex splitting patterns due to
the presence of nuclei such as phosphorus and fluorine in the
structure precluded measurement of accurate coupling constants
for each diastereoisomer.
Fortunately, in the case of β-aminophosphonate 7b (RF = CF3,
Ar = p-Me-C6H4), the isolation of the major syn diastereoisomer
was possible in 46% yield by recrystallization from heptane
3860
dx.doi.org/10.1021/jo400281e | J. Org. Chem. 2013, 78, 3858−3866

The Journal of Organic Chemistry
Article
Scheme 5. Cyclization of Fluorinated β-Aminophosphonates
7 toward γ-Lactams
Scheme 6. Transformation of Compounds 11′ into 11 and
Their Calculated Free Energy Differences (in kcal/mol)
Computed at the B3LYP(PCM)/6-31G* + ZPVE Level
a
Using Tetrahydrofuran as Solvent
a
Numbers in parentheses correspond to calculated free energy
Table 4. Polyfluorophosphorylated γ-Lactams 11 Obtained
differences (in kcal/mol) computed at the M06-2X(PCM)/6-
31G*//B3LYP/6-31G* + ZPVE level using tetrahydrofuran as
solvent.
a
entry compd
RF
Ar
reaction conditions yield, %
1
2
3
4
5
11a
11b
11c
11d
11e
CF3
p-MeO-C6H4
p-Me-C6H4
15 h/room temp
3 h/room temp
24 h/room temp
36 h/room temp
5 h/room temp
90
80
90
90
70
CF3
CF3
p-NO2-C6H4
p-NO2-C6H4
p-NO2-C6H4
results are in agreement with the isomerization of the γ-lactam
under the basic reaction conditions.
C2F5
CF2H
a
CONCLUSION
Isolated by flash chromatography.
■
In summary, we report the synthesis of functionalized polyfluor-
ophosphorylated 1-azadienes by Wittig reactions from perfluor-
ophosphorylated conjugated phosphoranes, obtained by the
reaction of phosphazenes and fluorinated acetylenic phosphonates.
Subsequent reduction of both carbon−carbon and carbon−
nitrogen double bonds of 1-azadienes constitute a convenient
synthetic route leading to novel fluoroalkyl β-aminophosphonates
as a diastereomeric mixture, with the syn β-aminophosphonate
being obtained as the major diastereoisomer. It was shown that
base-mediated cyclocondensation of diastereomeric mixture of
aminophosphonates leads exclusively to a new type of function-
alized trans-γ-lactams. Fluoroalkyl β-aminophosphonates and
polyfluorophosphorylated γ-lactams could be interesting, because
these new phosphorus- and fluorine-containing compounds show
promise for the preparation of novel, biologically active compounds
useful in drug design.2,6,17,18 Theoretical calculations have been used
to explain the diastereoselectivity of the 1-azadiene reduction
mechanism, and computational studies also show a higher stability
for the trans γ-lactams than for the cis isomers, in concert with the
experimental observations.
only the most stable trans diastereomer of polyfluorophos-
phorylated-γ-lactam 11 (Scheme 5) is obtained. As far as we
know, this strategy appears to represent the first synthesis of
polyfluorophosphorylated γ-lactams.17,18
The structure of γ-lactams 11 was assigned on the basis of
1D and 2D NMR spectroscopy, including HMQC and HMBC
experiments, and mass spectrometric data. The 1H NMR
spectrum of compound 11c (RF = CF3, Ar = p-NO2-C6H4)
shows one double quadruplet at δ 4.90 ppm with the coupling
3
3
constants JHF = 6.4 and JHP = 18.4 Hz corresponding to the
proton 4-H bonded to the carbon with a CF3 substituent
(Figure 1); also the characteristic absence of carboxylic ethyl
EXPERIMENTAL SECTION
Figure 1. Labeled and numbered carbons for γ-lactam 11c.
■
All reagents from commercial suppliers were used without further
purification. All solvents were freshly distilled before use from appropriate
drying agents. THF was distilled from sodium/benzophenone and used
immediately. All other reagents were recrystallized or distilled when
necessary. Reactions were performed under a dry nitrogen atmosphere.
Analytical TLCs were performed with silica gel 60 F254 plates.
Visualization was accomplished by UV light. Column chromatography
was carried out using silica gel 60 (230−400 mesh ASTM). Melting
points were determined with an electrothermal digital melting point
apparatus without correction. NMR spectra were obtained on 300 MHz
and 400 MHz spectrometers and recorded at 25 °C. Chemical shifts for
1H NMR spectra are reported in ppm downfield from TMS, chemical
shifts for 13C NMR spectra are recorded in ppm relative to internal
chloroform (δ 77.2 ppm for 13C), chemical shifts for 19F NMR are
reported in ppm downfield from fluorotrichloromethane (CFCl3), and
chemical shifts for 31P NMR are reported in ppm from an aqueous
group signals is observed. Moreover, in the 31P NMR spectrum
a singlet at δ 26.4 ppm and in the 19F NMR spectrum a doublet at
4
δ −75.9 ppm with the coupling constant JPF = 6.1 Hz are
observed. The structure of compound 11c was also confirmed
unambiguously by X-ray analysis (see the Supporting Information).
To have a better understanding of factors controlling the
stereoselective formation of trans-γ-lactam 11, the relative stabilities
of cis-γ-lactam 11′ and trans-γ-lactam 11 were determined. Calc-
ulated free energy differences computed at the B3LYP(PCM)/
6-31G* and M06-2X(PCM)//6-31G*//B3LYP/6-31G* level
using tetrahydrofuran as solvent indicate that trans-γ-lactams
11a−e are about 3 kcal/mol more stable than cis-γ-lactams
11′a−e (Scheme 6 and the Supporting Information), and these
3861
dx.doi.org/10.1021/jo400281e | J. Org. Chem. 2013, 78, 3858−3866

The Journal of Organic Chemistry
Article
solution of H3PO4 (33%). Coupling constants (J) are reported in hertz.
The terms m, s, d, t, and q refer to multiplet, singlet, doublet, triplet, and
quartet, respectively; br refers to a broad signal. 13C NMR, 31P NMR, and
19F NMR were broad-band decoupled from hydrogen nuclei. Infrared
(d, 3JHH = 7.1 Hz, 2H, Harom), 6.92 (d, 3JHP = 8.8 Hz, 2H, Harom), 7.17 (d,
3JHP = 8.8 Hz, 2H, Harom), 8.78 (s, NH) ppm. 13C NMR (75 MHz,
CDCl3): δ 15.8 (CH3 imine), 16.1 (CH3 enamine), 28.4 (d, 1JCP = 136.2
1
Hz, CH2−P imine), 52.2 (d, JCP = 103.3 Hz, C−P enamine), 55.3
2
spectra (IR) were recorded with an infrared spectrometer; absorbance
frequencies are given at maximum intensity in cm−1. MS spectra were
obtained on a chromatographic spectrometer, and HRMS spectra were
obtained on an instrument at 70 eV with a ionization source.
(OCH3 enamine), 55.4 (OCH3 imine), 62.6 (d, JCP = 6.1 Hz, OCH2
2
enamine), 63.2 (d, JCP = 6.5 Hz, OCH2 imine), 113.9 (2HCarom
1
enamine), 114.3 (2HCarom imine), 118.2 (q, JCF = 279.4 Hz, CF3
enamine), 118.5 (q, 1JCF = 278.8 Hz, CF3 imine), 120.9 (2HCarom imine),
Perfluoroacetylene phosphonates26 and azides23 (caution! low-
molecular-weight carbon azides used in this study are potentially
explosive; appropriate protection measures should always be taken
when handling these compounds) were prepared according to
literature procedures.
128.1 (2HCarom enamine), 131.9 (d, JCP = 9.1 Hz, Carom−N enamine),
4
139.6 (Carom−N imine), 139.7150.9 (m, C−CF3 imine), 157.7 (Carom−O
imine), 158.1 (Carom−O enamine), 160.5 (N−C enamine) ppm. 31P
NMR (120 MHz, CDCl3): δ 19.6 (imine), 22.8 (enamine) ppm. 19F
NMR (282 MHz, CDCl3): δ −64.04 (enamine), −71.46 (imine) ppm.
HRMS for C14H19F3NO4P [M]+: calcd 353.1004, found 353.1009.
General Procedure for the Preparation of 1-Azadienes. To a
solution of ylide (10 mmol) in CHCl3 (25 mL) at 0 °C under a
nitrogen atmosphere was added dropwise a solution of ethyl glyoxalate
(10 mmol, 50% in toluene, 1.0 mL). The reaction mixture was stirred
General Procedure for the Preparation of Ylides. To a solution
of azide (10 mmol) in CHCl3 (25 mL) at 0 °C under nitrogen atmos-
phere was added dropwise a solution of phosphine (11 mmol).
(Caution! Low-molecular-weight carbon azides used in this study are
potentially explosive. Appropriate protection measures should always be
taken when handling these compounds.) The mixture was stirred at room
temperature until N2 release had finished. Afterward a solution of the
corresponding perfluoroacetylenephosphonate (10 mmol) in CHCl3
was added dropwise and stirred at the corresponding temperature until
the disappearance of starting materials was observed by 31P NMR
spectra.
at the corresponding temperature and monitored by 31P NMR and 19
F
NMR spectroscopy until consumption of starting materials. Evapo-
ration of the solvent gave a residue which was purified by column
chromatography, affording the corresponding 1-azadienes.
(2E)-Ethyl 3-Diethoxyphosphinyl-5,5,5-trifluoro-4-(4-methoxy-
phenylimino)pent-2-enoate (6a). The general procedure was
followed using ylide 4a and stirring at room temperature for 15 h.
Evaporation of the solvent gave a residue which was purified by
chromatography with hexane/ethyl acetate (5/1) as eluent, affording
3.32 g of a orange oil (76%), Rf = 0.43 (50/50, hexane/ethyl acetate).
[1-Diethoxyphosphinyl-2-(4-tolylimino)-3,3,3-trifluoropropylidene]-
triphenylphosphorane (4g). The general procedure was followed
using p-tolyl azide (1.33 g) and triphenylphosphine (2.62-g) stirred at
20 °C for 30 min followed by addition of trifluoromethylacetylene-
phosphonate 2a (2.31 g). (Caution! Low-molecular-weight carbon azides
used in this study are potentially explosive. Appropriate protection
measures should always be taken when handling these compounds.) The
mixture was then stirred with refluxing chloroform for 21.5 h. Evaporation
of the solvent gave a residue which was recrystallized in hexanes, affording
2.14 g of a yellowish solid (68%), mp 118−120 °C. 1H NMR (300 MHz,
CDCl3): δ 1.08 (t, 3JHH = 7.0 Hz, 6H, CH3), 2.15 (s, 3H, CH3), 3.76−3.83
3
1H NMR (300 MHz, CDCl3): δ 1.03 (t, JHH = 7.2 Hz, 3H, CH3),
1.21−1.42 (m, 6H, CH3), 3.74 (s, 3H, OCH3), 3.84−4.17 (m, 4H,
3
OCH2), 4.20−4.29 (m, 2H, OCH2), 6.80 (d, JHH = 8.8 Hz, 2H,
Harom), 6.93 (d, 3JHH = 8.8 Hz, 2H, Harom), 6.96 (d, 3JHP = 22.7 Hz, 1H,
CH) ppm. 13C NMR (75 MHz, CDCl3): δ 13.7 (2CH3), 15.7
(2CH3), 55.2 (OCH3), 62.1 (OCH2), 62.5 (d, 2JCP = 6.2 Hz, OCH2),
2
1
62.8 (d, JCP = 6.2 Hz, OCH2), 113.8 (2HCarom), 119.1 (q, JCF
=
3
3
2
(m, 4H, OCH2), 5.67 (d, JHH = 8.1 Hz, 2H, Harom), 6.77 (d, JHH = 8.1
279.4 Hz, CF3), 122.4 (2HCarom), 138.7 (Carom), 139.7 (d, JCP = 7.6
2
2
Hz, 2H, Harom), 7.43−7.55 (m, 10H, Harom), 7.83−7.89 (m, 5H, Harom
)
Hz, HC), 150.0 (dq, JCF = 35.9 Hz, JCP = 5.5 Hz, C−CF3), 159.0
ppm. 13C NMR (75 MHz, CDCl3): δ 16.2−16.4 (m, 2CH3), 20.6 (CH3),
(Carom), 163.1 (d, JCP = 26.0 Hz, CO) ppm. 31P NMR (120 MHz,
3
60.7 (m, 2OCH2), 118.2 (dq, 1JCF = 116.8 Hz, 3JCP = 14.1 Hz, CF3), 118.3
CDCl3): δ 9.6 ppm. 19F NMR (282 MHz, CDCl3): δ −68.9 ppm.
HRMS for C18H23F3NO6P [M]+: calcd 437.1215, found 437.1214.
(2E)-Ethyl 3-Diethoxyphosphinyl-5,5,5-trifluoro-4-(4-tolylimino)-
pent-2-enoate (6b). The general procedure was followed using ylide
4b and stirring at room temperature for 15 h. Evaporation of the
solvent gave a residue which was purified by chromatography with
hexane/ethyl acetate (5/1) as eluent, affording 3.06 g of a yellowish oil
3
(HCarom), 118.5 (HCarom), 123.0 (d, JCP = 17.1 Hz, Carom), 126.2 (dd,
1
1JCP = 91.7 Hz, JCP = 2.5 Hz, Carom), 128.1 (HCarom), 128.2 (HCarom),
128.3 (HCarom), 128.4 (HCarom), 128.6 (HCarom), 129.1 (HCarom), 130.8
(HCarom), 131.5 (HCarom), 131.6 (HCarom), 131.8 (HCarom), 131.8
1
(HCarom), 131.9 (HCarom), 132.5 (d, JCP = 9.6 Hz, HCarom), 133.8 (d,
1JCP = 9.6 Hz, HCarom), 147.3 (Carom), 146.6 (Carom), 153.4 (dq, 2JCF = 28.4
Hz, 2JCP= 9.2 Hz, CN) ppm. 31P NMR (120 MHz, CDCl3): δ 24.2 (d,
1
(65%), Rf = 0.43 (50/50, hexane/ethyl acetate). H NMR (300 MHz,
CDCl3): δ 1.05 (t, 3JHH = 7.2 Hz, 3H, CH3), 1.21−1.32 (m, 6H, CH3),
2.27 (s, 3H, CH3), 3.92−4.10 (m, 4H, OCH2), 4.23−4.29 (m, 2H,
2
2JPP = 51.1 Hz), 25.7 (d, JPP = 51.1 Hz) ppm. 19F NMR (282 MHz,
CDCl3): δ −59.3 ppm. MS (EI, 70 eV): m/z (%) 597 (10) [M]+. HRMS
3
3
for C32H32F3NO3P2 [M]+: calcd 597.1810, found 597.1815.
OCH2), 6.80 (d, JHH = 6.5 Hz, 2H, Harom), 6.90 (d, JHH = 22.2 Hz,
1H, CH), 7.07 (d, JHH = 6.5 Hz, 2H, Harom) ppm. 13C NMR (75
3
Hydrolysis of Ylides. Diethyl (3,3,3-Trifluoro-2-((4-methoxy-
phenyl)imino)propyl)phosphonate (5) and Diethyl (3,3,3-Trifluoro-2-
((4-methoxyphenyl)amino)prop-1-en-1-yl)phosphonate (5′). To a
solution of 4-methoxyphenyl azide (10 mmol, 1.49 g) in CHCl3 (25 mL)
at 0 °C under a nitrogen atmosphere was added dropwise a solution of
trimethylphosphine (11 mmol, 2.62 g). (Caution! Low-molecular-weight
carbon azides used in this study are potentially explosive. Appropriate
protection measures should always be taken when handling these
compounds.) The mixture was then stirred in chloroform at room
temperature for 30 min. Afterward a solution of trifluoromethylacetylene-
phosphonate 2a (10 mmol, 2.31 g) in CHCl3 was added dropwise and the
mixture was stirred at room temperature for 30 min. To the resulting
solution was added 1.5 mL of water, and the reaction mixture was stirred at
room temperature for 1.5 h until consumption of starting ylide, as
monitored by 31P NMR and 19F NMR spectroscopy. Evaporation of the
solvent gave a residue which was purified by column chromatography,
affording the corresponding mixture of imine 5 and enamine 5′ as a
colorless oil (70%), Rf = 0.48 (50/50, hexane/ethyl acetate). 1H NMR (300
MHz, CDCl3): δ 1.29−1.41 (m, 12H, CH3), 3.14 (d, 2JHP = 23.8 Hz, CH2−
P), 3.80 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 4.08−4.21 (m, 8H, OCH2),
4.68 (d, 2JHP = 6.0 Hz, CH-P), 6.61 (d, 3JHH = 7.1 Hz, 2H, Harom), 6.79
MHz, CDCl3): δ 13.7 (CH3), 15.8 (CH3), 15.9 (CH3), 20.7 (CH3),
2
2
62.1 (OCH2), 63.0 (d, JCP = 6.5 Hz, OCH2), 63.2 (d, JCP = 6.0 Hz,
1
OCH2), 118.4 (q, JCF = 279.5 Hz, CF3), 120.0 (2HCarom), 129.1
(2HCarom), 135.8 (Carom), 136.2 (d, 1JCP = 156.1 Hz, C−P), 139.6 (d, 3JCP
= 7.5 Hz, HC), 144.3 (Carom), 151.6 (dq, 2JCF = 36.6 Hz, 2JCp = 5.5 Hz,
C−CF3), 163.2 (d, JCP = 25.7 Hz, CO) ppm. 31P NMR (120 MHz,
3
CDCl3): δ 9.4 ppm. 19F NMR (282 MHz, CDCl3): δ −69.1 ppm. HRMS
for C18H23F3NO5P [M]+: calcd 421.1266, found 421.1268.
(2E)-Ethyl 3-Diethoxyphosphinyl-5,5,5-trifluoro-4-(4-nitrophenyl-
imino)pent-2-enoate (6c). The general procedure was followed using
ylide 4c and stirring at room temperature for 20 h. Evaporation of the
solvent gave a residue which was purified by chromatography with
ether as eluent, affording 1.82 g of a yellowish oil (80%).
The general procedure was followed using ylide 4f and stirring at room
temperature for 6 days. Evaporation of the solvent gave a residue which
was purified by chromatography with ether as eluent, affording 0.68 g of a
1
yellowish oil (30%), Rf = 0.27 (50/50, hexane/ethyl acetate). H NMR
(300 MHz, CDCl3): δ 1.19−1.38 (m, 9H, CH3), 4.02−4.14 (m, 4H,
OCH2), 4.31−4.38 (m, 2H, OCH2), 6.80 (d, 3JHP = 21.7 Hz, 1H, CH),
3
3
7.03 (d, JHH = 8.9 Hz, 2H, Harom), 8.22 (d, JHH = 8.8 Hz, 2H, Harom
)
3862
dx.doi.org/10.1021/jo400281e | J. Org. Chem. 2013, 78, 3858−3866

The Journal of Organic Chemistry
Article
ppm. 13C NMR (75 MHz, CDCl3): δ 13.9 (2CH3), 16.1 (CH3), 62.6
HRMS for C18H27F3NO6P [M]+: calcd 441.1532, found 441.1528. Data
for the minor isomer 7′a are as follows. 1H NMR (300 MHz, CDCl3): δ
1.12−1.29 (m, 9H, CH3), 2.59−2.93 (m, 3H, CH2, P−CH), 3.69 (s, 3H,
2
2
(OCH2), 63.5 (d, JCP = 17.1 Hz, OCH2), 63.7 (d, JCP = 17.1 Hz,
1
OCH2), 119.9 (2HCarom), 124.7 (2HCarom), 130.1 (q, JCF = 224.8 Hz,
3
1
2
OCH3), 3.91−4.52 (m, 7H, OCH2, CH), 4.76 (d, JHH = 10.3 Hz, 1H,
CF3), 138.8 (d, JCP = 174.5 Hz, C−P), 139.5 (d, JCP = 7.1 Hz,
3
2
2
NH), 6.57 (d, JHH = 9.0 Hz, 2H, CHarom), 6.67−6.73 (m, 2H, CHarom
)
HC), 145.5 (Carom), 152.7 (Carom), 155.2 (dq, JCF = 37.4 Hz, JCP
=
ppm. 13C NMR (75 MHz, CDCl3): δ 14.1 (CH3), 16.1 (CH3), 16.3
8.9 Hz, C−CF3), 163.5 (d, 3JCP = 25.2 Hz, CO) ppm. 31P NMR (120
MHz, CDCl3): δ 9.2 ppm. 19F NMR (282 MHz, CDCl3): δ −69.7 ppm.
HRMS for C17H20F3N2O7P [M]+: calcd 452.0960, found 452.0980.
(2E)-Ethyl 3-Diethoxyphosphinyl-3,3,4,4,4-pentafluoro-4-(4-nitro-
phenylimino)pent-2-enoate (6d). The general procedure was followed
using ylide 4i and stirring in refluxing chloroform for 24 h. Evaporation
of the solvent gave a residue which was purified by chromatography
with hexane/ethyl acetate (5/1) as eluent, affording 3.41 g of an
(CH3), 30.5 (CH2), 33.5 (d, 1JCP = 143.6 Hz, CH−P), 55.6 (OCH3), 57.1
2
2
(dq, JCF = 30.3 Hz, JCP = 3.9 Hz, CH−CF31), 61.3 (OCH2), 62.4−62.8
3
(2OCH2), 114.5−116 (4HCarom), 125.8 (dq, JCF = 284.2 Hz, JCP = 4.7
Hz, CF3), 126.5 (2HCarom), 140.5 (Carom), 153.0 (Carom), 171.6 (d, 3JCP
=
12.8 Hz, CO) ppm. 31P NMR (120 MHz, CDCl3): δ 27.0 ppm. 19F
3
NMR (282 MHz, CDCl3): δ −72.5 (d, JFH = 6.1 Hz) ppm. HRMS for
C18H27F3NO6P [M]+: calcd 441.1532, found 441.1528.
1
orange oil (68%), Rf = 0.72 (50/50, hexane/ethyl acetate). H NMR
(3S,4R),(3R,4S)- and (3S,4S),(3R,4R)-Ethyl 3-Diethoxyphosphinyl-
5,5,5-trifluoro-4-(4-tolylamino)pentanoate (7b/7′b). The general
procedure was followed using the 1-azadiene 6b (5 mmol) and
2 equiv of sodium borohydride (0.38 g, 10 mmol). The reaction mixture
was stirred at room temperature for 1 h. Evaporation of the solvent
gave a residue which was purified by chromatography with hexane/
ethyl acetate (50/50) as eluent, affording 1.06 g of a yellow oil (50%)
as a 60/40 diastereomeric mixture: Rf = 0.54 (50/50, hexane/ethyl
(300 MHz, CDCl3): δ 1.21−1.74 (m, 9H, CH3), 3.82−4.21 (m, 4H,
CH2), 4.21−4.43 (m, 2H, CH2), 6.82 (d, 3JHP = 21.7 Hz, 1H, CH),
7.07 (d, 3JHH = 8.9 Hz, 2H, Harom), 8.21 (d, 3JHH = 8.8 Hz, 2H, Harom
)
ppm. 13C NMR (75 MHz, CDCl3): δ13.9 (2CH3), 16.1 (CH3), 62.6
2
2
(OCH2), 63.5 (d, JCP = 17.1 Hz, OCH2), 63.7 (d, JCP = 17.1 Hz,
OCH2), 114.0−120.5 (m, C2F5), 119.6(2HCarom), 125.6 (2HCarom),
1
2
137.6(d, JCP = 174.7 Hz, C−P), 139.6(d, JCP = 6.5 Hz, HC),
145.3 (Carom), 152.4 (Carom), 154.0 (m, C−C2F5), 163.1(d, 3JCP = 24.7
Hz, CO) ppm. 31P NMR (120 MHz, CDCl3): δ 8.2 ppm. 19F NMR
(282 MHz, CDCl3): δ −80.8 (CF3), −118.3 (CF2) ppm. HRMS for
C18H20F5N2O7P [M]+: calcd 502.0926, found 502.0928.
1
acetate). Data for the major isomer 7b are as follows. H NMR (300
MHz, CDCl3): δ 1.10−1.26 (m, 9H, CH3), 2.15 (s, 3H, CH3), 2.55−
2.92 (m, 3H, CH−P, CH2), 3.88−4.13 (m, 6H, OCH2), 4.38 (d,
3JHH = 10.7 Hz, 1H, NH), 4.46−4.56 (m, 1H, CH−CF3), 6.62 (d,
3JHH = 8.5 Hz, 2H, Harom), 6.88−6.92 (m, 2H, Harom) ppm. 13C NMR
(75 MHz, CDCl3): δ 14.0 (CH3), 16.0 (CH3), 16.2 (CH3), 20.2
(2E)-Ethyl 3-Diethoxyphosphinyl-5,5-difluoro-4-(4-nitrophenyl-
imino)pent-2-enoate (6e). The general procedure was followed using
ylide 4j and stirring at room temperature for 15 h. Evaporation of the
solvent gave a residue which was purified by chromatography with hexane/
ethyl acetate (5/1) as eluent, affording 1.65 g of a dark orange oil (76%),
(CH3), 31.8 (CH2), 33.4 (d, 1JCP = 143.4 Hz, CH-P), 55.9 (dq, 2JCF
=
29.5 Hz, 2JCP = 2.5 Hz, CH−CF3), 61.0 (d, 2JCP = 3.8 Hz, OCH2), 62.4
2
1
(d, JCP = 6.9 Hz, OCH2), 114.0 (2CHarom), 125.5 (dq, JCF = 284.8
3
1
Hz, JCP = 15.5 Hz, CF3), 128.3 (Carom), 129.6 (2CHarom), 143.4
Rf = 0.61 (50/50, hexane/ethyl acetate). H NMR (300 MHz, CDCl3):
(Carom), 171.1 (d, JCP = 15.3 Hz, CO) ppm. 31P NMR (120 MHz,
3
δ 1.19−1.38 (m, 9H, CH3), 3.87−4.38 (m, 6H, CH2), 6.32 (t, 3JHH = 52.5
CDCl3): δ 27.4 ppm. 19F NMR (282 MHz, CDCl3): δ −75.6 (d,
Hz, 1H, CHF2), 6.78 (d, 3JHP = 24.7 Hz, 1H, CH), 7.03 (d, 3JHH = 8.9
3JFH = 6.1 Hz) ppm. HRMS for C18H27F3NO5P [M]+: calcd 425.1579,
3
Hz, 2H, Harom), 8.20 (d, JHH = 8.9 Hz, 2H, Harom) ppm. 13C NMR (75
1
MHz, CDCl3): δ 14.2 (CH3), 16.3 (2CH3), 62.6 (OCH2), 63.7 (d, 2JCP
=
found 425.1590. Data for the minor isomer 7′b are as follows. H
1
NMR (300 MHz, CDCl3): δ 1.10−1.26 (m, 9H, CH3), 2.14 (s, 3H,
CH3), 2.55−2.92 (m, 3H, CH−P, CH2), 3.88−4.13 (m, 6H, OCH2),
4.26−4.38 (m, 1H, CH−CF3), 4.90 (d, 3JHH = 10.4 Hz, 1H, NH), 6.50
5.5 Hz, 2OCH2), 111.9 (t, JCF = 247.3 Hz, CF2H), 120.0 (2HCarom),
124.6 (2HCarom), 136.7 (Carom), 138.2 (d, 1JCP = 26.2 Hz, C−P), 145.2
(d, 2JCP = 7.1 Hz, CH), 153.7 (Carom), 159.8−162.0 (m, C−CF2H), 163.8
3
(d, JHH = 8.4 Hz, 2H, Harom), 7.00−7.17 (m, 2H, Harom) ppm. 13C
3
(d, JCP = 25.7 Hz, CO) ppm. 31P NMR (120 MHz, CDCl3): δ 8.9
ppm. 19F NMR (282 MHz, CDCl3): δ −120.2 (dq, 2JFF = 306.7 Hz, 2JFH
=
NMR (75 MHz, CDCl3): δ 14.1 (CH3), 16.1 (2CH3), 20.1 (CH3),
1
2
27.6 Hz) ppm. HRMS for C17H21F2N2O7P [M]+: calcd 434.1054, found
434.1073.
29.9 (CH2), 33.3 (d, JCP = 143.5 Hz, CH−P), 56.2 (dq, JCF = 30.5
2
2
Hz, JCP = 4.3 Hz, CH−CF3), 61.2 (d, JCP = 6.3 Hz, OCH2), 62.5
2
1
(d, JCP = 6.9 Hz, OCH2), 113.3 (2CHarom), 125.1 (dq, JCF = 284.3
General Procedure for the Preparation of β-Aminophosph-
onates. To a solution of the 1-azadiene (5 mmol) in ethanol (15 mL)
cooled to 0 °C under a nitrogen atmosphere was added sodium
borohydride portionwise. The reaction mixture was stirred at the
corresponding temperature and monitored by 31P NMR and 19F NMR
spectroscopy until consumption of starting materials. Then the reaction
mixture was diluted with a water/HCl (2 M)/methylene chloride mixture
(1/1/3) (3 × 50 mL); the aqueous phase was extracted with methylene
chloride and dried over MgSO4, and the crude product was purified by
column chromatography to afford the corresponding β-aminophospho-
nate.
3
Hz, JCP = 4.3 Hz, CF3), 127.8 (Carom), 129.6 (2CHarom), 143.9
(Carom), 170.9 (d, JCP = 12.5 Hz, CO) ppm. 31P NMR (120 MHz,
3
CDCl3): δ 27.0 ppm. 19F NMR (282 MHz, CDCl3): δ −72.4 (d,
3JFH = 7.6 Hz) ppm. HRMS for C18H27F3NO5P [M]+: calcd 425.1579,
found 425.1590.
(3S,4R),(3R,4S)- and (3S,4S),(3R,4R)-Ethyl 3-Diethoxyphosphinyl-
5,5,5-trifluoro-4-(4-nitrophenylamino)pentanoate (7c/7′c). The
general procedure was followed using the 1-azadiene 6c (5 mmol) and
1 equiv of sodium borohydride (0.19 g, 5 mmol). The reaction mixture
was stirred at room temperature for 1 h. Evaporation of the solvent gave a
residue which was purified by chromatography with ether as eluent,
affording 1.87 g of an orange oil (82%) as a 60/40 diastereomeric
mixture: Rf = 0.76 (50/50, hexane/ethyl acetate). Data for the major
isomer 7c are as follows. 1H NMR (300 MHz, CDCl3): δ 1.21−1.24 (m,
9H, CH3), 2.57−3.02 (m, 3H, CH2, P−CH), 4.04−4.26 (m, 6H, OCH2),
(3S,4R),(3R,4S)- and (3S,4S),(3R,4R)-Ethyl 3-Diethoxyphosphinyl-
5,5,5-trifluoro-4-(4-methoxyphenylamino)pentanoate (7a/7′a).
The general procedure was followed using 1-azadiene 6a and 2 equiv of
sodium borohydride (0.38 g, 10 mmol). The reaction mixture was stirred at
room temperature for 2 h. Evaporation of the solvent gave a residue which
was purified by chromatography with ether as eluent, affording 1.27 g of an
orange oil (60%) as a 60/40 diastereomeric mixture, Rf = 0.52 (50/50,
3
4.53−4.85 (m, 1H, CH), 6.13 (d, JHH = 10.1 Hz, 1H, NH), 6.77 (d,
3JHH = 9.2 Hz, 2H, Harom), 8.09−8.14 (m, 2H, Harom) ppm. 13C NMR (75
MHz, CDCl3): δ 14.3 (CH3), 16.5 (CH3), 16.6 (CH3), 30.5 (CH2), 33.5
(d, 1JCP = 143.6 Hz, HC-P), 53.4 (dq, 2JCF = 30.5 Hz, 2JCP = 3.3 Hz, HC−
CF3), 61.9 (OCH2), 61.2−62.5 (m, 2OCH2), 112.6 (2HCarom), 124.5
1
hexane/ethyl acetate). Data for the major isomer 7a are as follows. H
NMR (300 MHz, CDCl3): δ 1.12−1.29 (m, 9H, CH3), 2.59−2.93 (m, 3H,
CH2, P−CH), 3.66 (s, 3H, OCH3), 3.91−4.52 (m, 8H, OCH2, CH, NH),
6.67−6.73 (m, 4H, CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ 14.0
1
3
(dq, JCF = 284.9 Hz, JCP = 13.1 Hz, CF3), 126.5 (2HCarom), 139.7
(Carom), 151.6 (Carom), 171.4 (d, 3JCP = 15.6 Hz, CO) ppm. 31P NMR
(120 MHz, CDCl3): δ 27.0 ppm. 19F NMR (282 MHz, CDCl3): δ −72.5
1
(CH3), 16.1 (CH3), 16.2 (CH3), 31.9 (CH2), 33.0 (d, JCP = 143.7 Hz,
CH−P), 55.6 (OCH3), 55.7 (dq, 2JCF = 30.9 Hz, 2JCP = 4.0 Hz, CH−CF3),
61.2 (OCH2), 62.2−62.6 (2OCH2), 114.5−116 (4HCarom), 125.2 (dq,
1JCF = 284.8 Hz, 3JCP = 15.6 Hz, CF3), 139.9 (Carom), 154.0 (Carom), 171.4
4
(d, JFH = 7.6 Hz) ppm. HRMS for C17H21F2N2O7P [M]+: calcd
434.1054, found 434.1061. Data for the minor isomer 7′c are as follows.
1H NMR (300 MHz, CDCl3): δ 1.21−1.24 (m, 9H, CH3), 2.57−3.02 (m,
3H, CH2, CH), 4.04−4.26 (m, 6H, OCH2), 4.53−4.85 (m, 1H, CH),
3
(d, JCP = 15.3 Hz, CO) ppm. 31P NMR (120 MHz, CDCl3): δ 27.4
4
ppm. 19F NMR (282 MHz, CDCl3): δ −72.6 (d, JFH = 7.6 Hz) ppm.
3863
dx.doi.org/10.1021/jo400281e | J. Org. Chem. 2013, 78, 3858−3866

The Journal of Organic Chemistry
Article
3
3
6.22 (d, JHH = 10.2 Hz, 1H, NH), 6.67 (d, JHH = 9.2 Hz, 2H, Harom),
8.09−8.14 (m, 2H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ 14.3
4-Diethoxyphosphinyl-5-trifluoromethyl-1-(4-methoxyphenyl)-
pyrrolidin-2-one (11a). The general procedure was followed using a
diastereomeric mixture of β-aminophosphonates 7a/7′a (0.44 g). The
reaction mixture was stirred at room temperature for 15 h. Evaporation
of the solvent gave a residue which was purified by chromatography
with hexane/ethyl acetate (1/10) as eluent, affording 0.36 g of an
1
(CH3), 16.3 (CH3), 16.4 (CH3), 31.9 (CH2), 33.0 (d, JCP = 143.7 Hz,
2
2
HC−P), 55.0 (dq, JCF = 31.6 Hz, JCP = 4.3 Hz, HC−CF3), 61.8
1
(OCH2), 61.2−62.5 (m, 2OCH2), 112.2 (2HCarom), 124.5 (dq, JCF
=
3
288.5 Hz, JCP = 4.3 Hz, CF3), 126.5 (2HCarom), 139.7 (Carom), 152.0
1
(Carom), 171.6 (d, JCP = 13.2 Hz, CO) ppm. 31P NMR (120 MHz,
3
orange oil (90%): Rf = 0.24 (50/50, hexane/ethyl acetate). H NMR
CDCl3): δ 26.9 ppm. 19F NMR (282 MHz, CDCl3): δ −72.1 (d, 4JFH
=
(300 MHz, CDCl3): δ 1.25−1.35 (m, 6H, CH3), 2.66−3.08 (m, 3H,
7.6 Hz) ppm. HRMS for C17H21F2N2O7P [M]+: calcd 434.1054, found
434.1063.
CH, CH2), 3.56 (s, 3H, OMe), 4.11−4.22 (m, 4H, OCH2), 4.55−4.65
(m, 1H, CH−CF3), 6.87 (d, 3JHH = 8.9 Hz, 2H, Harom), 7.16 (d, 3JHH
=
8.9 Hz, 2H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ 16.4 (CH3),
(3S,4R),(3R,4S)- and (3S,4S),(3R,4R)-Ethyl 3-Diethoxyphosphinyl-
5,5,6,6,6-pentafluoro-4-(4-nitrophenylamino)hexanoate (7d/7′d).
The general procedure was followed using the 1-azadiene 6d
(5 mmol) and 2 equiv of sodium borohydride (0.38 g, 10 mmol).
The reaction mixture was stirred at room temperature for 1 h.
Evaporation of the solvent gave a residue which was purified by
chromatography with ether as eluent, affording 1.52 g of a yellow oil
(60%) as a 95/5 diastereomeric mixture: Rf = 0.52 (50/50, hexane/
1
2
16.4 (CH3), 29.4 (d, JCP = 107 Hz, CH), 30.6 (d, JCP = 4.7 Hz,
2
CH2), 55.4 (OCH3), 61.0 (q, JCF = 28.8 Hz, HC−CF3), 63.3 (d,
2JCP = 6.8 Hz, 2OCH2), 114.6 (2HCarom), 124.7 (dq, 1JCF = 268.3 Hz,
3JCP = 15.7 Hz, CF3), 127.1 (2HCarom), 129.5 (Carom), 158.9 (Carom),
172.6 (CO) ppm. 31P NMR (120 MHz, CDCl3): δ 26.5 ppm. 19F
NMR (282 MHz, CDCl3): δ −76.0 (d, 4JFH = 6.1 Hz) ppm. HRMS for
C16H21F3NO5P [M]+: calcd 395.1126, found 395.1109.
1
ethyl acetate). Data for the major isomer 7d are as follows. H NMR
4-Diethoxyphosphinyl-5-trifluoromethyl-1-(4-tolyl)pyrrolidin-2-
one (11b). The general procedure was followed using a diastereomeric
mixture of β-aminophosphonates 7b/7′b (0.46 g). The reaction
mixture was stirred at room temperature for 3 h. Evaporation of the
solvent gave a residue which was purified by chromatography with
hexane/ethyl acetate (10/1) as eluent, affording 0.37 g of an orange oil
(80%): Rf = 0.29 (50/50, hexane/ethyl acetate). 1H NMR (300 MHz,
CDCl3): δ 1.20−1.24 (m, 6H, CH3), 2.29 (s, 3H, CH3), 2.70−3.10
(m, 3H, CH, CH2), 4.11−4.18 (m, 4H, OCH2), 4.87−4.93 (m, 1H,
(300 MHz, CDCl3): δ 1.20−1.37 (m, 9H, CH3), 2.67−2.86 (m, 3H,
CH2, CH), 3.92−4.27 (m, 6H, OCH2), 4.86−5.01 (m, 1H, CH), 5.71
(d, 3JHH = 11.1 Hz, 1H, NH), 6.74 (d, 3JHH = 9.2 Hz, 2H, Harom), 8.07
(d, JHH = 9.2 Hz, 2H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ
3
1
14.1 (CH3), 16.2 (CH3), 16.3 (CH3), 30.3 (CH2), 33.8 (d, JCP
=
143.3 Hz, HC−P), 50.4−50.9 (m, HC−C2F5), 61.6 (OCH2), 62.1−
62.8 (m, 2OCH2), 112.4 (HCarom), 121.1−126.3 (m, C2F5), 126.2
(HCarom), 139.7 (Carom), 150.7 (Carom), 171.4 (d, 3JCP = 13.6 Hz, C
O) ppm. 31P NMR (120 MHz, CDCl3): δ 26.3 ppm. 19F NMR (282
3
3
CH−CF3), 7.12 (d, JHH = 8.7 Hz, 2H, HCarom), 7.16 (d, JHH = 8.7
Hz, 2H, HCarom) ppm. 13C NMR (75 MHz, CDCl3): δ 16.4 (CH3),
2
MHz, CDCl3): δ −82.4 (CF3), −116.4 (d, Fa, JFF = 274.4 Hz),
2
3
1
2
−126.3 (dd, Fb, JFF = 274.4 Hz, JFH = 24.0 Hz) ppm. HRMS for
C18H24F5N2O7P [M]+: calcd 506.1239, found 506.1241. Data for
minor isomer 7′d are as follows. 31P NMR (120 MHz, CDCl3): δ 26.1
ppm. 19F NMR (282 MHz, CDCl32): δ −82.7 (CF3), −118.0 (d, Fa,
16.4 (CH3), 29.2 (d, JCP = 150.6 Hz, CH), 31.0 (d, JCP = 4.7 Hz,
2
2
CH2), 61.0 (q, JCF = 34.2 Hz, C−CF3), 63.3 (d, JCP = 6.6 Hz,
2OCH2), 124.1 (2HCarom), 124.5 (dq, 1JCF = 284.3 Hz, 3JCP = 16.0 Hz,
CF3), 124.8 (2HCarom), 142.5 (Carom), 145.7 (Carom), 172.0 (CO)
ppm. 31P NMR (120 MHz, CDCl3): δ 26.4 ppm. 19F NMR (282 MHz,
2JFF = 273.8 Hz), −124.2 (dd, Fb, JFF = 273.8 Hz, JFH = 22.0 Hz)
3
ppm. HRMS for C18H24F5N2O7P [M]+: calcd 506.1239, found
506.1241.
CDCl3): δ −76.0 (d, JFH = 6.1 Hz) ppm. MS (EI, 70 eV): m/z (%)
4
379 (3) [M+]. HRMS for C16H21F3NO4P [M]+: calcd 379.1171, found
379.1160.
(3S,4R),(3R,4S)- and (3S,4S),(3R,4R)-Ethyl 3-Diethoxyphosphinyl-
5,5-difluoro-4-(4-nitrophenylamino)pentanoate (7e/7′e). The gen-
eral procedure was followed using the 1-azadiene 6e (5 mmol) and
2 equiv of sodium borohydride (0.38 g, 10 mmol). The reaction mixture
was stirred at room temperature for 2 h. Evaporation of the solvent
gave a residue which was purified by chromatography with ether as
eluent, affording 0.77 g of a yellow oil (35%) as a 95/5 diastereomeric
mixture,: Rf = 0.24 (50/50, hexane/ethyl acetate). Data for major
4-Diethoxyphosphinyl-5-trifluoromethyl-1-(4-nitrophenyl)-
pyrrolidin-2-one (11c). The general procedure was followed using a
diastereomeric mixture of β-aminophosphonates 7c/7′c (0.46 g). The
reaction mixture was stirred at room temperature for 24 h. Evaporation
of the solvent gave a residue which was purified by chromatography
with hexane/ethyl acetate (10/1) as eluent, affording 0.36 g of a yellow
solid (90%): mp 115−117 °C (methylene chloride/hexane). 1H NMR
(300 MHz, CDCl3): δ 1.24 (m, 6H, CH3), 2.70−3.20 (m, 3H, CH,
1
isomer 7e are as follows. H NMR (300 MHz, CDCl3): δ 1.17−1.57
CH2), 4.11−4.18 (m, 4H, OCH2), 4.90 (dq, 1H, 3JHF = 6.4 Hz, 3JHP
=
(m, 9H, CH3), 2.45−2.98 (m, 3H, CH2, CH), 4.10−4.20 (m, 6H,
3
3
OCH2), 4.20−4.39 (m, 1H, CH), 5.81 (d, JHH = 10.0 Hz, 1H, NH),
18.4 Hz, CH−CF3), 7.55 (d, JHH = 8.7 Hz, 2H, HCarom), 8.23 (d,
3JHH = 8.8 Hz, 2H, HCarom) ppm. 13C NMR (75 MHz, CDCl3): δ 16.4
(CH3), 16.4 (CH3), 29.2 (d, 1JCP = 150.6 Hz, CH), 31.0 (d, 2JCP = 4.7
2
3
3
6.05 (dt, JHF = 57.7 Hz, JHH = 6.1 Hz, 1H, CF2H), 6.45 (d, JHH
=
10.3 Hz, 2H, CHarom), 8.08 (d, 3JHH = 10.3 Hz, 2H, CHarom) ppm. 13
C
2
2
NMR (75 MHz, CDCl3): δ 14.7 (CH3), 16.4−16.2 (m, 2CH3), 31.0
(CH2), 32.8 (d, 1JCP = 136.1 Hz, HC−P), 54.7−55.4 (m, HC−CF2H),
61.5 (OCH2), 62.9−63.2 (m, 2OCH2), 111.9 (HCarom), 115.4 (t,
1JCF = 277.0 Hz, CF2H), 126.2(HCarom), 139.0 (Carom), 152.4(Carom),
Hz, CH2), 61.0 (q, JCF = 34.2 Hz, C−CF3), 63.3 (d, JCP = 6.6 Hz,
2OCH2), 124.1 (2HCarom), 124.5 (dq, 1JCF = 284.3 Hz, 3JCP = 16.0 Hz,
CF3), 124.8 (2HCarom), 142.5 (Carom), 145.7 (Carom), 172.0 (CO)
ppm. 31P NMR (120 MHz, CDCl3): δ 26.4 ppm. 19F NMR (282 MHz,
CDCl3): δ −75.9 (d, 4JFH = 6.1 Hz) ppm. HRMS for C15H18F3N2O6P
[M]+: calcd 410.0855, found 410.0859.
170.8 (d, 3JCP = 16.6 Hz, CO) ppm. 31P NMR (120 MHz, CDCl3):
δ 27.5 ppm. 19F NMR (282 MHz, CDCl3): δ −121.0 (ddd, Fa, JFF
=
2
285.0 Hz, 2JFH = 55.6 Hz, 3JFH = 6.1 Hz), −124.1 (ddd, Fb, 2JFF = 285.0
Hz, 2JFH = 56.4 Hz, 3JFH = 12.2 Hz) ppm. HRMS for C17H25F2N2O7P
[M]+: calcd 438.1367, found 438.1384. Data for minor isomer 7′e are as
follows. 31P NMR (120 MHz, CDCl3): δ 27.4 ppm. 19F NMR (282 MHz,
CDCl3): δ −121.2 (dd, Fa, 2JFF = 284.5 Hz, 3JFH = 6.2 Hz), −124.4 (ddd,
4-Diethoxyphosphinyl-5-perfluoroethyl-1-(4-nitrophenyl)-
pyrrolidin-2-one (11d). The general procedure was followed using a
diastereomeric mixture of β-aminophosphonates 7d/7′d (0.46 g). The
reaction mixture was stirred at room temperature for 36 h. Evaporation
of the solvent gave a residue which was purified by chromatography
with hexane/ethyl acetate (10/1) as eluent, affording 0.37 g of an
2
2
3
Fb, JFF = 284.5 Hz, JFH = 56.4 Hz, JFH = 12.9 Hz) ppm. HRMS for
1
C17H25F2N2O7P [M]+: calcd 438.1367, found 438.1384.
orange oil (90%): Rf = 0.36 (50/50, hexane/ethyl acetate). H NMR
(300 MHz, CDCl3): δ 1.22−1.34 (m, 6H, CH3), 2.74−3.21 (m, 3H,
General Procedure for the Preparation of γ-Lactams. To a
sodium hydride suspension (0.04 g, 1.5 mmol) in THF (5 mL) cooled to
0 °C under a nitrogen atmosphere was added dropwise a solution of the
β-aminophosphonate (1 mmol) in THF. The reaction mixture was stirred
at the corresponding temperature and monitored by 31P NMR and 19F
NMR spectroscopy until consumption of the starting β-aminophosphonate.
Evaporation of the solvent gave a residue which was purified by column
chromatography, affording the corresponding γ-lactam.
CH, CH23), 4.12−4.25 (m, 4H, CH2), 4.97−5.17 (m, 1H, CH−CF2),
3
7.60 (d, JHH = 9.0 Hz, 2H, HCarom), 8.29(d, JHH = 9.0 Hz, 2H,
HCarom) ppm. 13C NMR (75 MHz, CDCl3): δ 16.2 (CH3), 16.4
1
2
(CH3), 29.2 (d, JCP = 143.9 Hz, CH), 31.0 (d, JCP = 6.8 Hz, CH2),
2
59.5 (m, HC−CF2), 63.3 (d, JCP = 2.0 Hz, 2OCH2), 111.2−116.7 (m,
CF3), 118.3 (qt, 1JCF = 305.9 Hz, 2JCF = 35.1 Hz, CF2), 124.1 (2HCarom),
124.6 (2HCarom), 143.1 (Carom), 145.6 (Carom), 172.0 (CO) ppm.
3864
dx.doi.org/10.1021/jo400281e | J. Org. Chem. 2013, 78, 3858−3866

The Journal of Organic Chemistry
Article
31P NMR (120 MHz, CDCl3): δ 25.6 ppm. 19F NMR (282 MHz,
CDCl3): δ −81.9 (CF3), −123.4 (d, 2JFF = 280.0 Hz, CF3) ppm. HRMS
for C16H18F5N2O6P [M]+: calcd 460.0834, found 460.0823.
901, 1−19. (g) Cabeza, A.; Ouyang, X.; Sharma, C. V. K.; Aranda, M.
A. G.; Bruque, S.; Clearfield, A. Inorg. Chem. 2002, 41, 2325−2333.
(h) Caseiola, M.; Castantino, W.; Peraio, A.; Rega, T. Solid State Ionics
1995, 77, 229−233.
4-Diethoxyphosphinyl-5-difluoromethyl-1-(4-nitrophenyl)-
pyrrolidin-2-one (11e). The general procedure was followed using a
diastereomeric mixture of β-aminophosphonates 7e/7′e (0.44 g). The
reaction mixture was stirred at room temperature for 5 h. Evaporation
of the solvent gave a residue which was purified by chromatography
with hexane/ethyl acetate (10/1) as eluent, affording 0.27 g of an
(4) (a) Ojima, I. In Fluorine in Medicinal Chemistry and Chemical
́
Biology; Wiley-Blackwell: Chichester, U.K., 2009. (b) Begue, J. P.;
Bonnet-Delpon, D. In Bioorganic and Medicinal Chemistry of Fluorine;
Wiley: Chichester, U.K., 2008. (c) Kirsch, P. In Modern Fluoroorganic
Chemistry. Synthesis, Reactivity, Application; Wiley-VCH: Weinheim,
Germany, 2004.
1
orange oil (70%): Rf = 0.39 (50/50, hexane/ethyl acetate). H NMR
(300 MHz, CDCl3): δ 1.25−1.74 (m, 6H, CH3), 2.66−3.12 (m, 3H,
CH,CH2), 4.12−4.19 (m, 4H, 2OCH2), 4.78−4.98 (m, 1H, CH-
CF2H), 5.97 (t, 2JHF =54.5 Hz, 1H, CF2H), 7.13 (d, 3JHH = 8.9 Hz, 2H,
(5) As many as 25−30% of agrochemicals and 20% of
pharmaceuticals on the market are estimated to contain fluorine.
(6) For reviews see: (a) Vulpetti, A.; Dalvit, C. Drug Discovery Today
3
HCarom), 7.21(d, JHH = 8.9 Hz, 2H, HCarom) ppm. 13C NMR (75
2012, 17, 890−897. (b) Muller, K.; Bohm, H.-J. Chem. Biol. 2009, 16,
̈
̈
2
MHz, CDCl3): δ 16.4 (CH3), 16.4 (CH3), 29.9 (d, JCP = 5.5 Hz,
1130−1131. (c) Filler, R.; Saha, R. Fut. Med. Chem. 2009, 1, 777−791.
(d) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359−4369. (e) Purser,
S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320−330. (f) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305−321.
(g) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013−1029. (h) Dolbier,
1
CH2), 31.3 (d, JCP = 160.8 Hz, CH), 60.8−61.0 (m, HC−CF2H),
63.3 (2OCH2), 100.8−116.1 (m, CF2H), 123.3 (HCarom), 125.0
(HCarom), 142.5 (Carom), 145.8 (Carom), 172.3 (CO) ppm. 31P NMR
(120 MHz, CDCl3): δ 26.8 ppm. 19F NMR (282 MHz, CDCl3) δ
2
2
−129.2 (dd, JFH = 7.6 Hz, JFH = 55.0 Hz) ppm. HRMS for
W. R. J. Fluorine Chem. 2006, 126, 157−163. (i) Bohm, H.-J.; Banner,
̈
C15H19F2N2O6P [M]+: calcd 392.0961, found 392.0949.
D.; Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.; Obst-Sander, U.;
̈
Stahl, M. l. ChemBioChem 2004, 5, 637−643. (j) Strunecka, A.;
Patocka, J.; Connett, P. J. Appl. Biomed. 2004, 2, 141−150.
(7) (a) Modern Crop Protection Compounds, 2nd ed.; Kraemer, W.,
Schirmer, U., Jeschke, P., Witschel, M., Eds.; Wiley: Chichester, U.K.,
2011; Vols. 1−3. (b) Jeschke, P. Pest Manage. Sci. 2010, 66, 10−27.
(c) Theodoridis, G. Adv. Fluorine Sci. 2006, 2, 121−175. (d) Thayer,
A. M. Chem. Eng. News 2006, 84, 15−17. (e) Jeschke, P. ChemBioChem
2004, 5, 570−589.
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures, tables, and CIF files giving H NMR and 13C NMR
1
spectra of compounds 4g, 5/5′, 6a−e, 7/7′a−e, 7b, and 11a−e,
2D spectra of compounds 6a and 11c, ORTEP and X-ray
crystallographic data of compounds 7b and 11c, and Cartesian
coordinates, harmonic analysis data, and energies for all the
stationary points discussed in the computational studies. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(8) Pagliaro, M.; Ciriminna, R. J. Mater. Chem. 2005, 15, 4981−4991.
(9) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881−1886.
̈
(10) (a) Prabhakaran, J.; Underwood, M. D.; Parsey, R. V.; Arango,
V.; Majo, V. J.; Simpson, N. R.; Heertum, R. V.; Mann, J. J.; Kumar, J.
S. D. Bioorg. Med. Chem. 2007, 15, 1802. (b) Uneyama, K. In
Organofluorine Chemistry; Blackwell: Oxford, U.K., 2006. (c) Solo-
shonok, V. A. In Fluorine-Containing Synthons; American Chemical
Society: Washington, DC, 2005.
AUTHOR INFORMATION
Corresponding Author
*E-mail for F.P.: francisco.palacios@ehu.es.
Notes
■
(11) Romanenko, V. D.; Kukhar, V. P. Chem. Rev. 2006, 106, 3868−
3935.
(12) (a) Jakeman, D. L.; Ivory, A. J.; Wiliamson, M. P.; Blackburn, G.
M. J. Med. Chem. 1998, 41, 4439−4452. (b) Herczegh, P.; Buxton, T.
́
B.; McPherson, J. C.; Kovacs-Kulyassa, A.; Brewer, P. D.; Sztaricskai,
F.; Stroebel, G. G.; Plowman, K. M.; Farcasiu, D.; Hartmann, J. F. J.
Med. Chem. 2002, 45, 2338−2341. (c) Makhaeva, G. F.; Aksinenko, A.
Y.; Sokolov, V. B.; Baskin, I. I.; Palyulin, V. A.; Zefirov, N. S.; Hein, N.
D.; Kampf, J. W.; Wijeyesakere, S. J.; Richardson, R. J. Chem. Biol.
Interact. 2010, 187, 177−184.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Direccion
del Ministerio de Ciencia e Innovacion
by Gobierno Vasco and Universidad del Pais Vasco (GV, IT
422-10; UPV, UFI-QOSYC 11/12) is gratefully acknowledged.
UPV/EHU-SGIker technical support (MICINN, GV/EJ,
European Social Fund) is also gratefully acknowledged.
■
́
General de Investigacion
́
(CTQ2009-12156) and
́
́
(13) (a) Piras, H.; Fleming, I. N.; Harrison, W. T. A.; Zanda, M.
Synlett 2012, 44, 2899−2902. (b) Binkert, C.; Frigerio, M.; Jones, A.;
Meyer, S.; Pesenti, C.; Prade, L.; Viani, F.; Zanda, M. ChemBioChem
2006, 7, 181−186. (c) Lazzaro, F.; Crucianelli, M.; De Angelis, F.;
Frigerio, M.; Malpezzi, L.; Volonterio, A.; Zanda, M. Tetrahedron:
Asymmetry 2004, 15, 889−893. (d) Volonterio, A.; Bellosta, S.; Bravin,
F.; Bellucci, M. C.; Bruche, L.; Colombo, G.; Malpezzi, L.; Mazzini, S.;
Meille, S. V.; Meli, M.; Ramirez de Arellano, C.; Zanda, M. Chem. Eur.
J. 2003, 9, 4510−4522. (e) Molteni, M.; Volonterio, A.; Zanda, M.
Org. Lett. 2003, 5, 3887−3890.
REFERENCES
■
(1) For reviews see: (a) Mucha, A.; Kafarski, P.; Berlicki, L. J. Med.
Chem. 2011, 54, 5955−5980. (b) Palacios, F.; de los Santos, J. M.;
Vicario, J.; Alonso, C., The Chemistry of Hydroxylamines, Oximes and
Hydroxamic Acids - Patai’s Chemistry of Functional Groups; Wiley:
Chichester, U.K., 2011; Vol. 2, pp 351−439. (c) Ordonez, M.; Rojas-
́
̃
Cabrera, H.; Cativiela, C. Tetrahedron 2009, 65, 17−49. (d) Amino-
phosphonic and Amino-phosphinic Acids. Chemistry and Biological
Activity; Kukhar, V. P., Hudson, H. R., Eds.; Wiley: Chichester, U.K.,
2000.
(14) Cal, D. Tetrahedron Lett. 2012, 53, 3774−3776.
(15) (a) Roschenthaler, G.-V.; Kukhar, V. P.; Kulik, I. B.;
̈
Sorochinsky, A. E.; Soloshonok, V. A. J. Fluorine Chem. 2011, 132,
834−837. (b) Roschenthaler, G. V.; Kukhar, V.; Barten, N.;
̈
(2) For reviews see: (a) Van der Jeught, S.; Stevens, Ch. V. Chem.
Rev. 2009, 109, 2672−2702. (b) Palacios, F.; Alonso, C.; de los Santos,
J. M. Chem. Rev. 2005, 105, 899−931.
(3) (a) Metcaft, W. W.; van der Donk, W. A. Annu. Rev. Biochem.
2009, 78, 65−94. (b) Fields, S. C. Tetrahedron 1999, 55, 12237−
12273. (c) Horiguchi, M.; Kandatsu, M. Nature 1959, 184, 901−902.
(d) Hammerschmidt, F. Liebigs Ann. Chem. 1988, 531−535.
(e) Hammerschmidt, F.; Vollenkle, H. Liebigs Ann. Chem. 1989,
577−583. (f) Stalikas, C. D.; Konidani, C. N. J. Chromatogr. A 2001,
Gvozdovska, N.; Belik, M.; Sorochinsky, A. Tetrahedron Lett. 2004,
45, 6665−6667. (c) Sergeeva, N. N.; Golubev, A. S.; Henning, L.;
Burger, K. Synthesis 2003, 915−919. (d) Nieschalk, J.; Batsanov, A. S.;
O’Hagan, D.; Howard, J. Tetrahedron 1996, 52, 165−176.
(16) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org. Chem.
2006, 71, 6141−6148.
(17) (a) Das Sarma, K.; Zhang, J.; Huang, Y.; Davidson, J. G. Eur. J.
Org. Chem. 2006, 3730−3737. (b) Rose, G. M.; Hopper, A.; De Vivo,
3865
dx.doi.org/10.1021/jo400281e | J. Org. Chem. 2013, 78, 3858−3866

The Journal of Organic Chemistry
Article
M.; Tehim, A. Curr. Pharm. Des. 2005, 11, 3329−3334. (c) Shorvon, S.
Lancet 2001, 358, 1885−1892. (d) Reddy, P. A.; Hsiang, B. C. H.;
Latifi, T. N.; Hill, M. W.; Woodward, K. E.; Rothman, S. M.;
Ferrendelli, J. A.; Covey, D. F. J. Med. Chem. 1996, 39, 1898−1906.
(e) Kazmierski, W. M.; Andrews, W.; Furfine, E.; Spaltenstein, A.;
Wright, L. Bioorg. Med. Chem. Lett. 2004, 14, 5689−5692.
(f) Spaltenstein, A.; Almond, M. R.; Bock, W. J.; Cleary, D. G.;
Furfine, E. S.; Hazen, R. J.; Kazmierski, W. M.; Salituro, F. G.; Tung, R.
D.; Wright, L. L. Bioorg. Med. Chem. Lett. 2000, 10, 1159−1162.
(g) Tang, K.; Zhang, J. T. Neurol. Res. 2002, 24, 473−478. (h) Rose,
G. M.; Hopper, A.; De Vivo, M.; Tehim, A. Curr. Pharm. Des. 2005, 11,
3329−3334.
(18) (a) Lee, C.; Choi, E.; Cho, M.; Lee, B.; Oh, S. J.; Park, S.-K.;
Lee, K.; Kim, H. M.; Han, G. Bioorg. Med. Chem. Lett. 2012, 22, 4189−
4192. (b) Cherney, R. J.; Mo, R.; Meyer, D. T.; Voss, M. E.; Yang, M.
G.; Santella, J. B.; Duncia, J. V.; Lo, Y. C.; Yang, G.; Miller, P. B.;
Scherle, P. A.; Zhao, Q.; Mandlekar, S.; Cvijic, M. E.; Barrish, J. C.;
Decicco, C. P.; Carter, P. H. Bioorg. Med. Chem. Lett. 2010, 20, 2425−
2430.
(19) de los Santos, J. M .; Lopez, Y.; Aparicio, D.; Palacios, F. J. Org.
Chem. 2008, 73, 550−557.
(20) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Oyarzabal, J. J.
Org. Chem. 2004, 69, 8767−8774.
(21) Vicario, J.; Aparicio, D.; Palacios, F. J. Org. Chem. 2009, 74,
452−455.
(22) (a) Palacios, F.; Alonso, C.; Pagalday, J.; Ochoa de Retana, A.
M.; Rubiales, G. Org, Bioorg. Chem 2003, 1, 1112−1118. (b) Barluenga,
́
J.; Lopez, F.; Palacios, F. J. Organomet. Chem. 1990, 382, 61−67.
(23) Palacios, F.; Perez de Heredia, I.; Rubiales, G. J. Org. Chem.
1995, 60, 2384−2390. Formation of the phosphazenes 1 was detected
by nitrogen gas formation during the addition of phosphine and was
monitored by 31P NMR. The spectra showed the disappearance of the
phosphine signal and appearance of a new signal in the range of δ 2−
10 ppm of the corresponding phosphazenes 1.
(24) Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.; De los
Santos. Tetrahedron 2007, 63, 523−575.
(25) Tverdomed, S. N.; Kolanowski, J.; Lork, E.; Roschenthaler, G.-
̈
V. Tetrahedron 2011, 67, 3887−3903.
(26) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.;
Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador,
P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,
Revision B.01; Gaussian, Inc., Wallingford, CT, 2010.
(27) (a) Parr, R. G.; Yang, W. In Density-Functional Theory of Atoms
and Molecules; Oxford University Press: Oxford, U.K., 1989.
(b) Ziegler, T. Chem. Rev. 1991, 91, 651−667.
3866
dx.doi.org/10.1021/jo400281e | J. Org. Chem. 2013, 78, 3858−3866