Double hydrophosphorylation of nitriles catalyzed by rare-earth-metal lanthanum

Article abstract of DOI:10.1021/acs.joc.0c02016

A high-yielding and atom-efficient protocol for the double hydrophosphorylation of nitriles using a lanthanum-based N,N-dimethylbenzylamine complex (La(DMBA)₃) as a precatalyst is reported. This method provides a straightforward and convenient

Full text of DOI:10.1021/acs.joc.0c02016

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Double Hydrophosphorylation of Nitriles Catalyzed by Rare-Earth-
Metal Lanthanum
Yesmin Akter Rina and Joseph A. R. Schmidt*
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ABSTRACT: A high-yielding and atom-efficient protocol for the double
hydrophosphorylation of nitriles using a lanthanum-based N,N-dimethylben-
zylamine complex (La(DMBA)3) as a precatalyst is reported. This method
provides a straightforward and convenient approach for the synthesis of
biologically important organophosphorus compounds known as N-(α-
phosphoryl)amidophosphates in good to excellent yields. Nitriles with a
broad range of additional functionality were tolerated, including those with
halides, ethers, amines, and pyridyl groups.
applicable organophosphorus compounds catalytically, we
targeted the double hydrophosphorylation (addition of H−
P(O)(OR)2 to unsaturated systems) of nitriles as a means to
access N-(α-phosphoryl)amidophosphates. To date, there is
only one report detailing the double hydrophosphorylation of
nitriles, mediated by a ZnCl2/Et3N system. This system
requires environmentally unfriendly dichloromethane as
solvent and stoichiometric amounts of ZnCl2 and Et3N but
provides the 1,1-addition product (1-aminobisphosphonate) in
moderate yields with a somewhat limited substrate scope
(Scheme 1).17
With the limitations of this existing system in mind, we
explored the La(DMBA)3-catalyzed double hydrophosphor-
ylation of nitriles, either neat or in the more environmentally
friendly solvent toluene. We observed production of a new
regioisomer, the 1,2-addition product N-(α-phosphoryl)-
amidophosphate, where one phosphite is bound to the carbon
atom and another is bound to the nitrogen atom. Assuming
that this reaction behaved similarly to the addition reactions of
phosphine oxides with nitriles that we had previously
explored,14 then the 1,2-addition product observed here is
the thermodynamic product from this reaction, whereas
possible production of a 1,1-addition intermediate would be
representative of a kinetic reaction product. To our knowledge,
there are no previous reports of the catalytic double
hydrophosphorylation of nitriles to give N-(α-phosphoryl)-
amidophosphates.
INTRODUCTION
■
Since the turn of the century, there has been emerging interest
in organophosphorus compounds1 for use in medicinal
chemistry,2 agrochemistry,3 biological chemistry,4 materials
chemistry,5 organic synthesis,6 pharmaceuticals,7 and organo-
metallic catalysis.8 Effective synthesis and manipulation of
these compounds has become an indispensable part of the
global researcher’s toolbox, in both academic and industrial
laboratories. Amidophosphates, a class of organophosphorus
compounds, have attracted extensive attention from the
scientific community due to their utility as biologically active
compounds, chelating ligands for metal complex formation,
and as potential inhibitors of various cancer cell lines, including
HePG-2, MCF-7, HCT-116, and PC-3.9 Among amidophos-
phate derivatives, N-(α-phosphoryl)amidophosphates repre-
sent an area of increasing research interest.10 However,
efficient and convenient methods for preparation of these
compounds are still limited. Currently, the most general
method involves phosphorylation of aminophosphonates
through the Atherton−Todd reaction, which requires high
reaction temperature and prolonged heating to generate the
desired products in rather low yields due to the concurrent
formation of pyrophosphate byproducts.11 The key goal of our
current efforts has involved addressing the drawbacks of this
general method through the development of a straightforward
catalytic synthesis with high atom economy, cost efficiency,
and green chemistry aspects.
A lanthanum-based N,N-dimethylbenzylamine complex [La-
(DMBA)3],12 previously developed in our laboratory, has been
shown to be an excellent precatalyst for the hydrophosphina-
tion of heterocumulenes,13 hydrophosphinylation of nitriles14
and styrenes,15 and the hydrophosphination and hydro-
phosphinylation of alkynes.16 Encouraged by these La-
(DMBA)3-catalyzed organometallic transformations and in
connection with our ongoing interest in producing widely
Special Issue: The New Golden Age of Organo-
phosphorus Chemistry
Received: August 20, 2020
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© XXXX American Chemical Society
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A

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Scheme 1. Double Hydrophosphorylation of Nitriles
a
Table 1. Optimization of La(DMBA)3-Catalyzed Double Hydrophosphorylation of Nitriles
a
Optimized catalysis conditions: nitrile 1a (250 μL, 2.4 mmol, reaction solvent), phosphite 2a (1.0 mmol), La(DMBA)3 (2.5 mol %, 0.0125 mmol,
6.775 mg), 16 h, 50 °C. Yields were based on 2a using 31P{1H} NMR spectroscopy.
observed 22% of the 1,1-addition product 4a (Table 1, entries
3−5). After that, we increased the reaction temperature to 50
°C and returned to 1 mol % of La(DMBA)3, resulting in 95%
conversion to the 1,2-addition product 3a along with only trace
amounts of 1,1-addition product 4a and unreacted phosphite
2a (Table 1, entry 6). Finally, we achieved full conversion to
the desired 1,2-addition product at 50 °C with 2.5 mol % of
catalyst loading (Table 1, entry 7). In contrast, no 1,2- or 1,1-
addition product (3a or 4a) was detected when the reaction
was carried out in the absence of precatalyst La(DMBA)3 at
room temperature or 50 °C or even with higher temperature
(80 °C) or longer reaction times (Table 1, entries 1, 8, and 9).
Based on these optimization studies, we concluded that a
combination of benzonitrile (250 μL, 2.4 mmol, reaction
solvent), HP(O)(OEt)2 (1.0 mmol), and 2.5 mol % of
La(DMBA)3 at 50 °C provided the optimal conditions for this
catalysis.
RESULTS AND DISCUSSION
■
We set out to develop an atom-economic synthesis of N-(α-
phosphoryl)amidophosphates with good to excellent yields,
while employing mild conditions and green chemistry
principles, including green solvents, reduction in waste, and
reduced energy consumption. During the discovery and
optimization phase, we utilized the cheap and commercially
available starting materials benzonitrile 1a and diethylphos-
phite 2a. Using La(DMBA)3 (1 mol %) at room temperature
in neat benzonitrile with 1 mmol of diethylphosphite delivered
26% conversion to the thermodynamic 1,2-addition product 3a
along with 71% conversion to the kinetic 1,1-addition product
4a and 3% unreacted phosphite 2a (Table 1, entry 2). Inspired
by the overall conversion observed, but disappointed by the
formation of the mixture of both 1,2- and 1,1-addition
products 3a and 4a, we modified the reaction parameters in
an effort to obtain a higher yield of the 1,2-addition product,
essentially driving the reaction toward completion. We
increased the catalyst La(DMBA)3 loading from 1 mol % to
2.5, 5, and 10 mol %, resulting in successively increasing
conversion to the 1,2-addition product 3a 78%, but still
Having developed optimal reaction conditions, we next
investigated the scope of the nitrile substrate with respect to
diethylphosphite in order to validate the generality of this
method (see Table 2). The double hydrophosphorylation of a
B
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a
Table 2. Hydrophosphorylation of Nitriles
a
Reaction conditions: nitrile 1 (250 μL, 2.4 mmol, reaction solvent), diethylphosphite 2 (1.0 mmol), La(DMBA)3 (2.5 mol %, 0.0125 mmol, 6.78
b
mg), 16−20 h, 50 °C unless otherwise specified. Isolated yields reported. Symbols within the table are indicated as follows: *nitrile 1 (1.0 mmol),
diethylphosphite 2 (1.0 mmol), La(DMBA)3 (2.5 mol %, 0.0125 mmol, 6.78 mg), toluene (250 μL), 16−20 h, 50 °C; Ψnitrile 1 (2 mL),
diethylphosphite 2 (1.0 mmol), La(DMBA)3 (10 mol %, 0.05 mmol, 27.10 mg), 80 °C; 5 mol % La(DMBA)3; 10 mol % of La(DMBA)3; &15
#
$
η
mol % of La(DMBA)3; 48 h.
wide variety of nitriles with diethylphosphite proceeded very
efficiently in this catalysis, and the resulting N-(α-phosphoryl)-
amidophosphates were readily isolated in moderate to
excellent yields. Cross-coupling-ready functional groups such
as halogens (F, Cl, Br, I) at the ortho, meta, or para position of
aromatic nitriles were untouched under the reaction
conditions, giving the desired products 3b−3g efficiently.
Aromatic nitriles bearing the electron-withdrawing groups
−CF3 and −CN at the para positions also afforded the
corresponding products 3h and 3i. Furthermore, aromatic
nitriles with electron-rich groups, such as −CH3, t-Bu, −SCH3,
−OCH3, −NH2, and −N(CH3)2, were compatible with the
catalysis, generating products 3j−3p, although in some cases,
higher catalyst loading was required to reach full conversion to
the 1,2-addition products (N-(α-phosphoryl)-
amidophosphates) as observed via 31P{1H} NMR spectrosco-
py. Moreover, naphthyl- and alkene-substituted nitriles also
underwent hydrophosphorylation, producing the correspond-
ing products 3q and 3r. Additionally, the method also worked
for heteroaromatic nitriles 4-cyanopyridine and 2-cyanopyr-
idine to yield 3s and 3t. Aliphatic nitriles underwent
hydrophosphorylation, although the reaction proceeded quite
slowly and required a higher catalyst loading. For example,
phenylacetonitrile gave 3u in 79% yield after 48 h. Acetonitrile
underwent this double hydrophosphorylation reaction to
produce the corresponding product 3v in 62% yield, although
it required rather forcing conditions (80 °C, 48 h). In contrast,
cyclohexane carbonitrile resulted in a mixture of 1,2-addition
product, unreacted diethylphosphite, and 1,1-addition product
even at high temperature (80 °C), higher catalyst loadings (15
mol %), and longer reaction times (7 days). Attempted
hydrophosphorylation of o-toluinitrile, o-iodobenzonitrile, and
C
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1-cyanonapthalene with diethylphosphite failed to give either
the thermodynamic 1,2-addition product or the kinetic 1,1-
addition product, most likely due to steric hindrance; instead,
only the starting materials were observed in these reactions.
Having evaluated the scope of this reaction, we confirmed
the practical applicability of this catalytic system with a large-
scale reaction (Scheme 2). Scaling up the reaction by 20 times
(from 0.5 to 10 mmol) successfully provided a similar yield.
resonance for the 1,2-addition product increased, whereas that
of the 1,1-addition product decreased. Finally, after 18 h, the
1,1-addition product totally disappeared, leaving only the 1,2-
addition product. From these observations, we assert that the
1,1-addition product 1-aminobisphosphonate formed kineti-
cally but then ultimately furnished our desired thermodynami-
cally stable 1,2-addition product N-(α-phosphoryl)-
amidophosphate via lanthanum-catalyzed isomerization.
The mechanism for the double hydrophosphorylation of
nitriles is likely quite similar to our previously published
work,13−16 as depicted in Scheme 3. In the first step, the
stoichiometric protonolysis of precatalyst La(DMBA)3 with
HP(O)(OEt)2 leads to the formation of La(P(O)(OEt)2)3
(complex A), the active catalyst. Because of the strong
oxophilicity of the lanthanum center and the ability of
phosphite ligands to tautomerize, as we have previously
explored in-depth with phosphine oxides,16 these anionic
ligands are most likely bound to the lanthanum center via their
oxygen donor atoms. Additionally, it is unlikely that a three-
coordinate lanthanum ion exists, but rather additional
coordination is present at the metal center. Such donation
could be from the nitrile solvent, additional neutral phosphite
ligands, or chelation by additional oxygen atoms from the
deprotonated phosphite ligands. As we have no direct evidence
of this coordination, it is not depicted in Scheme 3. Insertion
of a nitrile generates intermediate B via a [3 + 2] cycloaddition
process (Scheme 4).14 Then protonolysis of intermediate B by
diethylphosphite yields intermediate C, which successively
undergoes a second insertion and protonolysis to yield the 1,1-
addition product 1-aminobisphosphonate (the kinetic prod-
uct) and regenerate the active catalyst A. In the final step,
isomerization of the 1,1-addition product 1-aminobisphosph-
onate produces the thermodynamically stable 1,2-addition
product N-(α-phosphoryl)amidophosphate.
a
Scheme 2. Scale-Up Experiment
a
Reaction conditions: benzonitrile (2500 μL, 24.0 mmol, reaction
solvent), diethylphosphite (20.0 mmol, 2.8 g), La(DMBA)3 (2.5 mol
%, 0.25 mmol, 136 mg), 20 h, 50 °C.
Based on our previous work, we hypothesized that 1,1-
addition products were initially formed but then isomerized
into 1,2-addition products before the starting material
diethylphosphite was completely consumed. In order to
monitor the reaction progress experimentally, we undertook
the catalytic hydrophosphorylation of benzonitrile in a J-Young
NMR tube in C7H8 monitored by time-resolved 31P{1H} NMR
spectroscopy (see the Supporting Information, Figure S71).
Within the first 30 min, a new singlet appeared at 20.97 ppm in
C7H8, assigned to the 1,1-addition product. The 31P{1H}
NMR resonance of this 1,1-addition product 1-aminobis-
phosphonate was previously reported at 19.14 ppm in
CDCl3.17 After 3 h, the 1,2-addition product appeared in the
spectrum as a pair of coupled doublets before the full
conversion of starting diethylphosphite to 1,1-addition
product. As time proceeded, the intensity of the 31P{1H}
The mechanism of the final isomerization step in this and in
our previous catalytic studies remains somewhat unclear.14,18 It
Scheme 3. Plausible Catalytic Cycle for the Double Hydrophosphorylation of Nitriles Using the La(DMBA)3 Precatalyst
D
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VXRS 400 (162 MHz) and were externally referenced to 0.00 ppm
with 85% H3PO4 in D2O. 19F NMR spectra were recorded on a
Varian VXRS 400 (376 MHz) and were externally referenced to
CFCl3 at 0.00 ppm. Infrared spectra were collected on a PerkinElmer
FT-IR spectrophotometer and are reported in terms of wavenumber
of absorption (cm−1). High-resolution mass spectra (HRMS) were
obtained on a Waters Synapt high-definition mass spectrometer by
electrospray ionization (ESI) with a TOF analyzer at the University of
Toledo, OH, USA. Melting points were determined in capillary tubes
using a capillary melting point apparatus.
Scheme 4. Tautomerization of the Phosphite Ligand Leads
to a [3 + 2] Cycloaddition Mechanism
General Procedure for the Catalytic Hydrophosphorylation
of Nitriles. Method 1: In a glovebox, an oven-dried 20 mL vial was
charged with α-La(DMBA)3 (6.78 mg, 0.0125 mmol) and
diethylphosphite (138.10 mg, 1.00 mmol). Then the nitrile (250
μL, 2.4 mmol, reaction solvent) was added to that mixture, and the
vial was taken out of the glovebox. The vial was placed in a 50 °C oil
bath, where the mixture was stirred for 16−20 h. Then the crude
compound was purified by flash chromatography on silica using ethyl
acetate/hexane (3:17) and methanol/ethyl acetate (3:17) as eluent.
Compounds 3a, 3e, 3f, 3j, 3k, 3l, 3t, 3u$η, and 3vψη were synthesized
is not readily catalyzed by general acids or bases but proceeds
well in the presence of the lanthanum catalysts. Based on
previous work by Onys’ko with a related system, we postulate
that the lanthanum center functions as a Lewis acid catalyst for
this isomerization reaction, as depicted in Scheme 5. Activation
of the PO bond by coordination to the lanthanum center
leads to intramolecular attack by the amine lone pair to form a
cyclic three-membered ring in the intermediate species.
Subsequent ring opening via cleavage of the P−C bond leads
to a net 1,2-shift of one of the phosphoryl groups, converting
the 1,1-kinetic product into the 1,2-thermodynamic product
and reducing the significant steric strain caused by the
quaternary carbon present in the kinetic product.
$
η
ψ
using this method: 10 mol % of La(DMBA)3, 48 h, and nitrile (2
mL), diethylphosphite (1.0 mmol), La(DMBA)3 (10 mol %), 80 °C.
Method 2: In a glovebox, an oven-dried 20 mL vial was charged
with α-La(DMBA)3 (6.78 mg, 0.0125 mmol), diethylphosphite
(138.10 mg, 1.00 mmol), and toluene (250 μL). Then the nitrile
(1.00 mmol) was added to that mixture, and the vial was taken out of
the glovebox. The vial was placed in a 50 °C oil bath, where the
mixture was stirred for 16−20 h. Then, the toluene was removed
under reduced pressure to afford crude N-(α-phosphoryl)-
amidophosphates. Compounds were then purified by flash chroma-
tography on silica using ethyl acetate/hexane (3:17) and methanol/
ethyl acetate (3:17) as eluent. Compounds 3b, 3c, 3d, 3g, 3h, 3i, 3m#,
3n#, 3o$, 3p&, 3q, 3r#, and 3s were synthesized using this method: #5
CONCLUSION
■
We have achieved a mild and convenient method for the
synthesis of N-(α-phosphoryl)amidophosphates via a rare-
earth-metal complex-catalyzed double hydrophosphorylation
of nitriles with diethylphosphite. This operationally simple and
efficient method proceeds with perfect atom-economy and
high efficiency using green solvents for a broad scope of nitrile
substrates with good to excellent isolated yields.
$
mol % of La(DMBA)3, 10 mol % of La(DMBA)3, &15 mol % of
La(DMBA)3.
Characterization of Products. Diethyl ((Diethoxyphosphoryl)-
(phenyl)methyl)phosphoramidate (3a):
EXPERIMENTAL SECTION
■
General Information. Lanthanum tris(N,N-dimethylbenzyl-
amine) (La(DMBA)3) was synthesized according to the procedure
previously published by our lab.12 Diethylphosphite was purchased
from Aldrich and dried over calcium hydride, filtered, freeze−pump−
thawed three times, transferred into a glovebox, and used without
further purification. Nitrile substrates for products (3a−3q and 3s−
3v) were purchased from Oakwood, Alfa, Aldrich, Acros, or AK
Scientific. The nitrile substrate for product 3r was synthesized
according to a literature report.19 All nitrile substrates were dried over
calcium hydride, filtered, freeze−pump−thawed three times, and
stored in a nitrogen-filled glovebox. Toluene was dried over sodium
metal, distilled under nitrogen, freeze−pump−thawed three times,
and stored in a nitrogen-filled glovebox.
1
Colorless liquid (185 mg, 98%); H NMR (600 MHz, CDCl3) δ =
7.38 (d, 3JH−H = 7.8 Hz, 2H), 7.30 (t, 3JH−H = 7.8 Hz, 2H), 7.27−7.23
(m, 1H), 4.51−4.40 (m, 1H), 4.14−4.06 (m, 2H), 4.00−3.82 (m,
5H), 3.66−3.55 (m, 2H), 1.28 (t, 3JH−H = 7.2 Hz, 3H), 1.21 (t, 3JH−H
= 7.2 Hz, 3H), 1.04 (t, 3JH−H = 7.2 Hz, 3H), 0.97 (t, 3JH−H = 7.2 Hz,
3H); 13C{1H} NMR (151 MHz, CDCl3) δ = 136.7, 128.3 (d, JP−C
=
2.3 Hz), 127.9 (d, JP−C = 2.9 Hz), 127.8 (d, JP−C = 5.7 Hz), 63.2 (d,
J
P−C = 6.9 Hz), 62.9 (d, JP−C = 6.9 Hz), 62.3 (d, JP−C = 5.1 Hz), 62.2
(d, JP−C = 4.7 Hz), 52.9 (d, JP−C = 154.5 Hz), 16.3 (d, JP−C = 5.7 Hz),
Characterization. All 1H NMR spectra were collected either on a
Varian Inova 600 MHz or a Bruker 600 MHz instrument and were
internally referenced to residual proton solvent signals for CDCl3 at δ
7.26 ppm. 13C NMR spectra were recorded either on a Varian Inova
600 (151 MHz) or a Bruker 600 (151 MHz) instrument and were
also internally referenced at 77.00 ppm to deuterated chloroform.
16.0 (d, JP−C = 5.7 Hz), 15.9 (d, JP−C = 7.6 Hz), 15.6 (d, JP−C = 7.6
3
Hz); 31P{1H} NMR (243 MHz, CDCl3) δ = 22.32 (d, JP−P = 39.4
3
Hz), 6.98 (d, JP−P = 39.4 Hz). This compound is known in the
literature.11,20
Diethyl ((4-Bromophenyl)(diethoxyphosphoryl)methyl)-
phosphoramidate (3b):
1
Data for H NMR are reported as follows: chemical shift (δ ppm),
multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet),
integration, and coupling constant (Hz). All 31P{1H} NMR spectra
were obtained from either a Varian Inova 600 (243 MHz) or a Varian
Scheme 5. Postulated Mechanism for Product Isomerization
E
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1
White solid (202 mg, 88%); H NMR (600 MHz, CDCl3) δ = 7.45
Diethyl ((Diethoxyphosphoryl)(3-fluorophenyl)methyl)-
phosphoramidate (3e):
3
3
4
(d, JH−H = 7.8 Hz, 2H), 7.29 (dd, JH−H = 7.8 Hz, JH−P = 1.8 Hz,
2H), 4.50−4.41 (m, 1H), 4.17−4.06 (m, 2H), 4.01−3.88 (m, 5H),
3.78−3.64 (m, 2H), 1.29 (t, 3JH−H = 7.2 Hz, 3H), 1.23 (t, 3JH−H = 7.2
Hz, 3H), 1.12 (t, 3JH−H = 7.2 Hz, 3H), 1.06 (t, 3JH−H = 7.2 Hz, 3H);
13C{1H} NMR (151 MHz, CDCl3) δ = 135.9, 131.4 (d, JP−C = 1.7
Hz), 129.5 (d, JP−C = 5.9 Hz), 122.0 (d, JP−C = 4.1 Hz), 63.3 (d, JP−C
= 6.9 Hz), 63.1 (d, JP−C = 6.9 Hz), 62.5 (d, JP−C = 2.9 Hz), 62.4 (d,
JP−C = 3.5 Hz), 52.4 (d, JP−C = 154.5 Hz), 16.3 (d, JP−C = 6.3 Hz),
16.1 (d, JP−C = 5.7 Hz), 16.0 (d, JP−C = 7.4 Hz), 15.8 (d, JP−C = 6.9
White solid (177 mg, 89%); 1H NMR (600 MHz, CDCl3) δ = 7.31−
3
7.25 (m, 1H), 7.20−7.14 (m, 2H), 6.96 (t, JH−H = 7.8 Hz, 1H),
4.54−4.44 (m, 1H), 4.24−4.17 (m, 1H), 4.17−4.06 (m, 2H), 4.01−
3.88 (m, 4H), 3.76−3.64 (m, 2H), 1.29 (t, 3JH−H = 7.2 Hz, 3H), 1.22
Hz); 31P{1H} NMR (243 MHz, CDCl3) δ = 21.61 (d, JP−P = 38.4
3
(t, 3JH−H = 7.2 Hz, 3H), 1.10 (t, 3JH−H = 7.2 Hz, 3H), 1.03 (t, 3JH−H
=
Hz), 6.68 (d, 3JP−P = 38.4 Hz); IR (cm−1) 3205.50 (br), 2983.40 (w),
2938.50 (w), 2908.60 (w), 1489.10 (w), 1461.70 (w), 1394.30 (w),
1369.40 (w), 1227.27 (s), 1025.35 (s), 962.27 (s), 862.71 (m),
835.97 (m), 797.87 (m), 740.48 (m), 705.99 (m), 551.92 (m); mp =
71−73 °C; HRMS (ESI) m/z calcd for C15H27BrNO6P2 [(M + H)+]
458.0497, found 458.0510.
7.2 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ = 162.5 (dd, 1JF−C
= 246.7 Hz, JP−C = 2.7 Hz), 139.5 (d, JP−C = 6.9 Hz), 129.8 (dd, 4JF−C
3
= 2.4 Hz, JP−C = 8.4 Hz), 123.6 (dd, JF−C = 2.9 Hz, JP−C = 5.7 Hz),
114.9−114.7 (m, 2C), 63.2 (d, JP−C = 6.9 Hz), 63.1 (d, JP−C = 6.9
Hz), 62.4 (d, JP−C = 5.7 Hz), 62.3 (d, JP−C = 5.9 Hz), 52.6 (d, JP−C
=
155.5 Hz), 16.3 (d, JP−C = 5.7 Hz), 16.1 (d, JP−C = 5.7 Hz), 16.0 (d,
JP−C = 7.6 Hz), 15.7 (d, JP−C = 7.6 Hz); 31P{1H} NMR (243 MHz,
Diethyl ((4-Chlorophenyl)(diethoxyphosphoryl)methyl)-
phosphoramidate (3c):
CDCl3) δ = 21.61 (d, 3JP−P = 38.4 Hz), 6.83 (d, 3JP−P = 38.4 Hz); 19
F
NMR (376 MHz, CDCl3) δ = −112.96; IR (cm−1) 3228.10 (br),
3058.30 (w), 2991.00 (w), 2933.50 (w), 2908.60 (w), 1613.00 (w),
1590.53 (w), 1464.31 (w), 1394.20 (w), 1260.70 (m), 1234.11 (s),
1152.98 (m), 1112.79 (m), 1023.35 (s), 939.76 (s), 914.97 (s),
791.14 (s), 735.05 (s), 693.81 (s), 597.91 (m), 521.90 (w); mp =
32−34 °C; HRMS (ESI) m/z calcd for C15H27FNO6P2 [(M + H)+]
398.1297, found 398.1295.
1
White solid (180 mg, 87%); H NMR (600 MHz, CDCl3) δ = 7.35
3
4
3
(dd, JH−H = 8.4 Hz, JH−P = 1.8 Hz, 2H), 7.29 (d, JH−H = 8.4 Hz,
2H), 4.52−4.42 (m, 1H), 4.16−4.06 (m, 2H), 4.05−3.87 (m, 5H),
3.77−3.63 (m, 2H), 1.29 (t, 3JH−H = 7.2 Hz, 3H), 1.23 (t, 3JH−H = 7.2
Hz, 3H), 1.11 (t, 3JH−H = 7.2 Hz, 3H), 1.05 (t, 3JH−H = 7.2 Hz, 3H);
13C{1H} NMR (151 MHz, CDCl3) δ = 135.4, 133.8 (d, JP−C = 2.9
Hz), 129.2 (d, JP−C = 5.7 Hz), 128.5 (d, JP−C = 1.7 Hz), 63.2 (d, JP−C
= 7.6 Hz), 63.1 (d, JP−C = 7.4 Hz), 62.4 (d, JP−C = 4.7 Hz), 62.39 (d,
JP−C = 4.5 Hz), 52.4 (d, JP−C = 154.5 Hz), 16.3 (d, JP−C = 6.3 Hz),
16.1 (d, JP−C = 5.1 Hz), 16.0 (d, JP−C = 7.4 Hz), 15.8 (d, JP−C = 7.6
Diethyl ((Diethoxyphosphoryl)(2-fluorophenyl)methyl)-
phosphoramidate (3f):
White solid (175 mg, 88%); 1H NMR (600 MHz, CDCl3) δ = 7.48 (t,
3JH−H = 7.2 Hz, 1H), 7.28−7.22 (m, 1H), 7.15−7.10 (m, 1H), 7.02 (t,
3JH−H = 9.0 Hz, 1H), 4.89−4.79 (m, 1H), 4.16 (m, 2H), 4.01 (m,
3H), 3.96−3.83 (m, 2H), 3.78−3.69 (m, 1H), 3.65−3.56 (m, 1H),
Hz); 31P{1H} NMR (243 MHz, CDCl3) δ = 21.73 (d, JP−P = 38.4
3
Hz), 6.79 (d, 3JP−P = 38.4 Hz); IR (cm−1) 3210.70 (br), 2982.05 (w),
2935.50 (w), 2910.50 (w), 1492.05 (m), 1459.40 (w), 1394.40 (w),
1229.53 (s), 1024.46 (s), 961.77 (s), 863.18 (m), 838.09 (m), 797.53
(m), 740.25 (m), 708.76 (m), 551.37 (m); mp = 48−50 °C; HRMS
(ESI) m/z calcd for C15H27ClNO6P2 [(M + H)+] 414.1002, found
414.0981.
3
3
1.31 (t, JH−H = 7.2 Hz, 3H), 1.25 (t, JH−H = 7.2 Hz, 3H), 1.07 (t,
3JH−H = 7.2 Hz, 3H), 0.98 (t, JH−H = 7.2 Hz, 3H); 13C{1H} NMR
3
(151 MHz, CDCl3) δ = 159.9 (dd, 1JF−C = 247.3 Hz, JP−C = 6.3 Hz),
4
129.6 (dd, JF−C = 2.3 Hz, JP−C = 8.3 Hz), 129.1 (m, 1C), 124.4 (d,
JP−C = 13.7 Hz), 124.2 (m, 1C), 115.2 (dd, JF−C = 1.7 Hz, JP−C
5
=
Diethyl ((Diethoxyphosphoryl)(4-fluorophenyl)methyl)-
phosphoramidate (3d):
22.0 Hz), 63.2 (d, JP−C = 7.6 Hz), 63.15 (d, JP−C = 6.8 Hz), 62.4 (d,
JP−C = 5.1 Hz), 62.3 (d, JP−C = 5.1 Hz), 46.0 (d, JP−C = 157.9 Hz),
16.3 (d, JP−C = 6.3 Hz), 16.0 (d, JP−C = 5.1 Hz), 15.97 (d, JP−C = 6.9
Hz), 15.6 (d, JP−C = 7.4 Hz); 31P{1H} NMR (243 MHz, CDCl3) δ =
21.39 (dd, 3JP−P = 37.7 Hz, JP−F = 4.3 Hz), 6.52 (d, 3JP−P = 37.7 Hz);
19F NMR (376 MHz, CDCl3) δ = −117.91; IR (cm−1) 3241.82 (br,
m), 2986.50 (m), 2909.40 (w), 1616.20 (w), 1588.50 (w), 1493.42
(m), 1456.88 (m), 1263.21 (s), 1229.36 (s), 1161.87 (m), 1124.25
(m), 1024.28 (s), 966.54 (s), 907.58 (s), 799.72 (s), 747.13 (s),
648.69 (m), 614.58 (m), 570.46 (m); mp = 61−63 °C; HRMS (ESI)
m/z calcd for C15H27FNO6P2 [(M + H)+] 398.1297, found 398.1299.
Diethyl ((Diethoxyphosphoryl)(3-iodophenyl)methyl)-
phosphoramidate (3g):
White solid (192 mg, 97%); 1H NMR (600 MHz, CDCl3) δ = 7.41−
3
7.35 (m, 2H), 7.01 (t, JH−H = 8.4 Hz, 2H), 4.52−4.42 (m, 1H),
4.16−4.05 (m, 2H), 4.00−3.86 (m, 5H), 3.74−3.61 (m, 2H), 1.29 (t,
3JH−H = 7.2 Hz, 3H), 1.22 (t, 3JH−H = 7.2 Hz, 3H), 1.09 (t, 3JH−H = 7.2
Hz, 3H), 1.04 (t, JH−H = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz,
3
1
CDCl3) δ = 162.4 (dd, JF−C = 247.3 Hz, JP−C = 2.9 Hz), 132.7 (d,
J
P−C = 3.3 Hz), 129.5 (dd, 3JF−C = 9.1 Hz, JP−C = 5.7 Hz), 115.2 (dd,
2JF−C = 21.3 Hz, JP−C = 2.3 Hz), 63.2 (d, JP−C = 7.6 Hz), 63.0 (d, JP−C
= 7.6 Hz), 62.4 (d, JP−C = 5.7 Hz), 62.3 (d, JP−C = 5.7 Hz), 52.2 (d,
JP−C = 155.1 Hz), 16.3 (d, JP−C = 6.3 Hz), 16.1 (d, JP−C = 5.9 Hz),
16.0 (d, JP−C = 7.6 Hz), 15.7 (d, JP−C = 7.6 Hz); 31P{1H} NMR (243
MHz, CDCl3) δ = 22.06 (dd, 3JP−P = 39.1 Hz, JP−F = 4.4 Hz), 6.84 (d,
3JP−P = 39.1 Hz); 19F NMR (376 MHz, CDCl3) δ = −114.31; IR
(cm−1) 3222.21 (br), 2986.60 (w), 2932.80 (w), 2902.00 (w),
2876.50 (w), 1605.38 (m), 1513.02 (s), 1456.51 (m), 1392.52 (w),
1260.71 (m), 1229.68 (s), 1117.31 (m), 1092.52 (m), 1021.24 (s),
955.50 (s), 912.12 (s), 846.25 (m), 802.20 (m), 743.65 (m), 585.70
(m), 551.01 (m); mp = 53−55 °C; HRMS (ESI) m/z calcd for
C15H27FNO6P2 [(M + H)+] 398.1297, found 398.1304.
White solid (223 mg, 88%); 1H NMR (600 MHz, CDCl3) δ = 7.73 (s,
1H), 7.58 (d, 3JH-H = 7.8 Hz, 1H), 7.37 (d, 3JH-H = 7.8 Hz, 1H), 7.03
(t, 3JH-H = 7.8 Hz, 1H), 4.45 - 4.36 (m, 1H), 4.18 - 4.06 (m, 3H), 3.98
- 3.86 (m, 4H), 3.76 - 3.63 (m, 2H), 1.27 (t, 3JH-H = 7.2 Hz, 3H), 1.21
3
3
3
(t, JH-H = 7.2 Hz, 3H), 1.10 (t, JH-H = 7.2 Hz, 3H), 1.02 (t, JH-H
=
7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ = 139.2, 136.9 (d,
JP-C = 2.9 Hz), 136.7 (d, JP-C = 5.7 Hz), 129.9, 127.1 (d, JP-C = 5.1
Hz), 93.9 (d, JP-C = 2.3 Hz), 63.3 (d, JP-C = 6.9 Hz), 63.1 (d, JP-C = 7.4
F
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Article
Hz), 62.4 (d, JP-C = 5.7 Hz), 62.35 (d, JP-C = 6.3 Hz), 52.4 (d, JP-C
=
MHz, CDCl3) δ = 137.6 (d, JP−C = 2.9 Hz), 133.5, 129.0 (d, JP−C
1.8 Hz), 127.6 (d, JP−C = 5.7 Hz), 63.1 (d, JP−C = 6.8 Hz), 62.8 (d,
P−C = 6.9 Hz), 62.3 (d, JP−C = 5.1 Hz), 62.2 (d, JP−C = 5.9 Hz), 52.6
=
154.5 Hz), 16.3 (d, JP-C = 5.7 Hz), 16.1 (d, JP-C = 5.7 Hz), 16.0 (d, JP-C
= 7.6 Hz), 15.7 (d, JP-C = 8.0 Hz). 31P{1H} NMR (243 MHz, CDCl3)
J
3
3
δ = 21.49 (d, JP-P = 38.4 Hz), 6.75 (d, JP-P = 38.4 Hz). IR (cm-1):
3227.21 (br, m), 3046.50 (w), 2980.35 (m), 2934.70 (w), 2906.00
(w), 1589.70 (w), 1564.82 (w), 1456.09 (m), 1393.10 (m), 1367.50
(m), 1234.73 (s), 1162.28 (m), 1026.04 (s), 968.73 (s), 949.54 (s),
909.02 (s), 798.23 (s), 733.40 (s), 695.20 (s), 656.90 (m), 568.41
(m), 518.24 (w); mp = 52−54 °C; HRMS (ESI) m/z calcd for
C15H27INO6P2 [(M + H)+] 506.0358, found 506.0338.
(d, JP−C = 155.1 Hz), 21.0, 16.3 (d, JP−C = 5.7 Hz), 16.1 (d, JP−C = 6.3
Hz), 16.0 (d, JP−C = 7.6 Hz), 15.6 (d, JP−C = 8.0 Hz); 31P{1H} NMR
3
3
(243 MHz, CDCl3) δ = 22.53 (d, JP−P = 38.4 Hz), 6.89 (d, JP−P
=
38.4 Hz). This compound is known in the literature.11
Diethyl ((Diethoxyphosphoryl)(m-tolyl)methyl)-
phosphoramidate (3k):
Diethyl ((Diethoxyphosphoryl)(4-(trifluoromethyl)phenyl)-
methyl)phosphoramidate (3h):
White solid (191 mg, 97%); 1H NMR (600 MHz, CDCl3) δ = 7.21−
3
7.15 (m, 3H), 7.07 (d, JH−H = 6.6 Hz, 1H), 4.47−4.37 (m, 1H),
4.14−4.06 (m, 2H), 3.99−3.81 (m, 5H), 3.67−3.56 (m, 2H), 2.31 (s,
3H), 1.29 (t, 3JH−H = 7.2 Hz, 3H), 1.22 (t, 3JH−H = 7.2 Hz, 3H), 1.07
(t, 3JH−H = 7.2 Hz, 3H), 0.99 (t, 3JH−H = 7.2 Hz, 3H); 13C{1H} NMR
(151 MHz, CDCl3) δ = 137.9 (d, JP−C = 2.3 Hz), 136.5, 128.7 (d,
JP−C = 2.9 Hz), 128.4 (d, JP−C = 5.7 Hz), 128.2 (d, JP−C = 1.7 Hz),
124.8 (d, JP−C = 5.7 Hz), 63.2 (d, JP−C = 6.9 Hz), 62.9 (d, JP−C = 6.9
White solid (215 mg, 96%); 1H NMR (600 MHz, CDCl3) δ = 7.57−
7.52 (m, 4H), 4.62−4.51 (m, 1H), 4.35−4.25 (m, 1H), 4.14−4.06
(m, 2H), 3.96−3.87 (m, 4H), 3.79−3.63 (m, 2H), 1.27 (t, 3JH−H = 7.2
3
3
Hz, 3H), 1.20 (t, JH−H = 7.2 Hz, 3H), 1.10 (t, JH−H = 7.2 Hz, 3H),
1.00 (t, 3JH−H = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ =
141.0, 130.2 (qd, 2JF−C = 32.6 Hz, JP−C = 2.8 Hz), 128.2 (d, JP−C = 5.4
Hz), 62.3 (d, JP−C = 5.3 Hz), 62.2 (d, JP−C = 5.1 Hz), 52.9 (d, JP−C
=
1
Hz), 125.3 (m, 1C), 123.9 (q, JF−C = 272.3 Hz), 63.4 (d, JP−C = 2.4
154.5 Hz), 21.3, 16.3 (d, JP−C = 5.7 Hz), 16.0 (d, JP−C = 6.3 Hz),
Hz), 63.35 (d, JP−C = 2.6 Hz), 62.6 (d, JP−C = 6.0 Hz), 62.61 (d, JP−C
= 5.7 Hz), 52.8 (d, JP−C = 153.11 Hz), 16.4 (d, JP−C = 6.0 Hz), 16.2
(d, JP−C = 5.9 Hz), 16.0 (d, JP−C = 7.4 Hz), 15.8 (d, JP−C = 7.6 Hz);
15.97 (d, JP−C = 7.4 Hz), 15.6 (d, JP−C = 8.0 Hz); 31P{1H} NMR (243
3
3
MHz, CDCl3) δ = 22.45 (d, JP−P = 39.4 Hz), 6.87 (d, JP−P = 39.4
Hz); IR (cm−1) 3228.96 (br), 3045.30 (w), 2978.52 (m), 2931.61
(m), 2869.50 (w), 1610.30 (w), 1456.82 (m), 1393.33 (m), 1369.10
(w), 1297.00 (w), 1261.61 (m), 1235.85 (s), 1160.14 (m), 1100.93
(m), 1025.72 (s), 969.35 (s), 949.46 (s), 910.32 (s), 836.30 (m),
800.42 (s), 732.32 (s), 702.50 (s), 672.96 (m), 573.56 (m), 516.80
(w); mp = 38−40 °C; HRMS (ESI) m/z calcd for C16H30NO6P2 [(M
+ H)+] 394.1548, found 394.1539.
3
31P{1H} NMR (243 MHz, CDCl3) δ = 21.36 (d, JP−P = 37.6 Hz),
6.58 (d, 3JP−P = 37.6 Hz); 19F NMR (376 MHz, CDCl3) δ = −62.88;
IR (cm−1) 3202.92 (br), 2985.05 (m), 2938.60 (w), 2908.20 (w),
1618.50 (m), 1460.00 (w), 1393.70 (w), 1327.41 (s), 1228.49 (s),
1159.11 (s), 1120.06 (s), 1027.23 (s), 966.05 (s), 869.91 (s), 846.48
(m), 801.38 (s), 748.77 (s), 653.28 (m), 604.87 (s); mp = 113−115
°C; HRMS (ESI) m/z calcd for C16H27F3NO6P2 [(M + H)+]
448.1265, found 448.1264.
Diethyl ((4-(tert-Butyl)phenyl)(diethoxyphosphoryl)methyl)-
phosphoramidate (3l):
Diethyl ((4-Cyanophenyl)(diethoxyphosphoryl)methyl)-
phosphoramidate (3i):
1
White solid (208 mg, 96%); H NMR (600 MHz, CDCl3) δ = 7.34
(d, 3JH−H = 8.4 Hz, 2H), 7.30 (d, 3JH−H = 8.4 Hz, 2H), 4.50−4.39 (m,
1H), 4.16−4.09 (m, 2H), 4.00−3.86 (m, 4H), 3.80−3.72 (m, 1H),
3.70−3.64 (m, 1H), 3.63−3.57 (m, 1H), 1.31 (t, 3JH−H = 7.2 Hz, 3H),
1
White solid (175 mg, 87%); H NMR (600 MHz, CDCl3) δ = 7.61
(d, 3JH−H = 7.8 Hz, 2H), 7.53 (d, 3JH−H = 7.8 Hz, 2H), 4.60−4.51 (m,
1H), 4.22−4.15 (m, 1H), 4.13−4.07 (m, 2H), 3.98−3.89 (m, 4H),
3.82−3.75 (m, 1H), 3.73−3.66 (m, 1H), 1.27 (t, 3JH−H = 7.2 Hz, 3H),
1.21 (t, JH−H = 7.2 Hz, 3H), 1.12 (t, JH−H = 7.2 Hz, 3H), 1.04 (t,
3JH−H = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ = 142.4,
132.0 (d, JP−C = 2.3 Hz), 128.6 (d, JP−C = 5.1 Hz), 118.4, 111.7 (d,
3
3
1.28 (s, 9H), 1.23 (t, JH−H = 7.2 Hz, 3H), 1.07 (t, JH−H = 7.2 Hz,
3
3H), 0.96 (t, JH−H = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz,
3
3
CDCl3) δ = 151.0 (d, JP−C = 2.9 Hz), 133.5, 127.4 (d, JP−C = 5.7 Hz),
125.2 (d, JP−C = 2.3 Hz), 63.2 (d, JP−C = 6.9 Hz), 62.9 (d, JP−C = 6.9
Hz), 62.3 (d, JP−C = 5.3 Hz), 62.2 (d, JP−C = 4.7 Hz), 52.6 (d, JP−C
=
J
P−C = 2.9 Hz), 63.4 (d, JP−C = 6.8 Hz), 63.3 (d, JP−C = 7.6 Hz), 62.6
154.9 Hz), 34.5, 31.2, 16.3 (d, JP−C = 6.3 Hz), 16.0 (d, JP−C = 4.7 Hz),
(d, JP−C = 5.3 Hz), 62.5 (d, JP−C = 5.1 Hz), 52.9 (d, JP−C = 152.7 Hz),
16.3 (d, JP−C = 5.7 Hz), 16.1 (d, JP−C = 5.7 Hz), 16.0 (d, JP−C = 7.6
Hz), 15.8 (d, JP−C = 6.8 Hz); 31P{1H} NMR (243 MHz, CDCl3) δ =
15.99 (d, JP−C = 7.4 Hz), 15.6 (d, JP−C = 8.0 Hz); 31P{1H} NMR (243
3
3
MHz, CDCl3) δ = 22.62 (d, JP−P = 40.1 Hz), 6.88 (d, JP−P = 40.1
Hz); IR (cm−1) 3231.03 (br), 2967.65 (m), 2935.00 (w), 2906.30
(m), 2869.70 (m), 1513.80 (w), 1461.09 (m), 1392.92 (m), 1366.77
(m), 1264.17 (m), 1234.87 (s), 1163.09 (m), 1100.97 (m), 1024.97
(s), 965.51 (s), 916.55 (s), 850.13 (m), 835.32 (m), 796.08 (s),
748.41 (s), 574.34 (s); mp = 36−38 °C; HRMS (ESI) m/z calcd for
C19H36NO6P2 [(M + H)+] 436.2017, found 436.2016.
20.86 (d, JP−P = 37.2 Hz), 6.46 (d, JP−P = 37.2 Hz); IR (cm−1)
3213.19 (br), 2983.98 (m), 2940.50 (w), 2910.40 (w), 2226.46 (s),
1608.14 (w), 1511.40 (w), 1466.44 (m), 1393.75 (m), 1370.90 (w),
1231.53 (s), 1163.03 (w), 1099.14 (m), 1019.42 (s), 957.24 (s),
910.53 (s), 875.15 (s), 853.47 (s), 796.66 (s), 751.34 (s), 676.14 (m),
585.81 (s); mp = 106−108 °C; HRMS (ESI) m/z calcd for
C16H27N2O6P2 [(M + H)+] 405.1344, found 405.1328.
Diethyl ((Diethoxyphosphoryl)(p-tolyl)methyl)phosphoramidate
(3j):
3
3
Diethyl ((Diethoxyphosphoryl)(4-(methylthio)phenyl)methyl)-
phosphoramidate (3m):
1
White solid (202 mg, 95%); H NMR (600 MHz, CDCl3) δ = 7.30
(d, 3JH−H = 8.4 Hz, 2H), 7.16 (d, 3JH−H = 8.4 Hz, 2H), 4.47−4.37 (m,
1H), 4.13−4.04 (m, 2H), 3.98−3.84 (m, 5H), 3.71−3.59 (m, 2H),
1
White solid (172 mg, 88%); H NMR (600 MHz, CDCl3) δ = 7.26
(d, 3JH−H = 7.8 Hz, 2H), 7.12 (d, 3JH−H = 7.8 Hz, 2H), 4.47−4.38 (m,
1H), 4.15−4.06 (m, 2H), 4.00−3.84 (m, 4H), 3.81−3.73 (m, 1H),
3.69−3.56 (m, 2H), 2.31 (s, 3H), 1.31−1.27 (m, 3H), 1.26−1.21 (m,
3H), 1.11−1.05 (m, 3H), 1.03−0.97 (m, 3H); 13C{1H} NMR (151
3
3
2.42 (s, 3H), 1.27 (t, JH−H = 7.2 Hz, 3H), 1.20 (t, JH−H = 7.2 Hz,
3
3
3H), 1.08 (t, JH−H = 7.2 Hz, 3H), 1.01 (t, JH−H = 7.2 Hz, 3H);
13C{1H} NMR (151 MHz, CDCl3) δ = 138.3 (d, JP−C = 3.5 Hz),
G
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Article
133.4, 128.2 (d, JP−C = 6.3 Hz), 126.1, 63.2 (d, JP−C = 7.4 Hz), 62.9
(d, JP−C = 7.6 Hz), 62.3 (d, JP−C = 4.1 Hz), 62.27 (d, JP−C = 4.9 Hz),
52.4 (d, JP−C = 154.9 Hz), 16.3 (d, JP−C = 6.3 Hz), 16.1 (d, JP−C = 5.7
Hz), 16.0 (d, JP−C = 7.6 Hz), 15.7 (d, JP−C = 7.4 Hz), 15.5; 31P{1H}
Hz), 62.23 (d, JP−C = 2.3 Hz), 62.2 (d, JP−C = 2.3 Hz), 52.2 (d, JP−C =
156.9 Hz), 40.4, 16.4 (d, JP−C = 6.3 Hz), 16.2 (d, JP−C = 5.7 Hz), 16.0
(d, JP−C = 7.6 Hz), 15.8 (d, JP−C = 8.2 Hz); 31P{1H} NMR (243 MHz,
3
3
CDCl3) δ = 23.03 (d, JP−P = 40.1 Hz), 7.11 (d, JP−P = 40.1 Hz).
3
This compound is known in the literature.11
NMR (243 MHz, CDCl3) δ = 22.14 (d, JP−P = 38.6 Hz), 6.89 (d,
3JP−P = 38.6 Hz); IR (cm−1) 3198.12 (br), 2979.15 (m), 2931.00 (w),
Diethyl ((Diethoxyphosphoryl)(naphthalen-2-yl)methyl)-
phosphoramidate (3q):
2906.00 (w), 1599.20 (m), 1495.30 (m), 1459.40 (m), 1440.30 (m),
1390.48 (m), 1228.68 (s), 1161.84 (m), 1098.19 (m), 1025.30 (s),
960.15 (s), 913.50 (s), 832.75 (s), 797.48 (s), 713.61 (m), 546.63
(m); mp = 44−47 °C; HRMS (ESI) m/z calcd for C16H30NO6P2S
[(M + H)+] 426.1269, found 426.1261.
Diethyl ((Diethoxyphosphoryl)(4-methoxyphenyl)methyl)-
phosphoramidate (3n):
White solid (173 mg, 81%); 1H NMR (600 MHz, CDCl3) δ = 7.86 (s,
3
1H), 7.84−7.80 (m, 3H), 7.54 (d, JH−H = 9.0 Hz, 1H), 7.49−7.46
(m, 2H), 4.72−4.62 (m, 1H), 4.18−4.10 (m, 2H), 4.03−3.85 (m,
5H), 3.68−3.57 (m, 2H), 1.32 (t, 3JH−H = 7.2 Hz, 3H), 1.23 (t, 3JH−H
= 7.2 Hz, 3H), 1.06 (t, 3JH−H = 7.2 Hz, 3H), 0.95 (t, 3JH−H = 7.2 Hz,
3H); 13C{1H} NMR (151 MHz, CDCl3) δ = 134.1, 133.0 (d, JP−C
=
1
1.7 Hz), 132.9 (d, JP−C = 2.3 Hz), 128.1 (d, JP−C = 1.2 Hz), 127.9,
127.6, 126.9 (d, JP−C = 7.4 Hz), 126.2, 126.16, 125.5 (d, JP−C = 4.1
White solid (180 mg, 88%); H NMR (600 MHz, CDCl3) δ = 7.29
(d, 3JH−H = 8.4 Hz, 2H), 6.83 (d, 3JH−H = 8.4 Hz, 2H), 4.44−4.35 (m,
1H), 4.13−4.05 (m, 2H), 3.97−3.81 (m, 5H), 3.75 (s, 3H), 3.67−
3.56 (m, 2H), 1.27 (t, JH−H = 7.2 Hz, 3H), 1.21 (t, JH−H = 7.2 Hz,
3H), 1.07 (t, JH−H = 7.2 Hz, 3H), 1.01 (t, JH−H = 7.2 Hz, 3H);
13C{1H} NMR (151 MHz, CDCl3) δ = 159.3 (d, JP−C = 2.9 Hz),
128.9 (d, JP−C = 5.7 Hz), 128.7, 113.7 (d, JP−C = 1.8 Hz), 63.1 (d, JP−C
= 6.9 Hz), 62.8 (d, JP−C = 7.6 Hz), 62.3 (d, JP−C = 4.5 Hz), 62.2 (d,
JP−C = 4.7 Hz), 55.2, 52.2 (d, JP−C = 155.7 Hz), 16.3 (d, JP−C = 6.3
Hz), 63.3 (d, JP−C = 6.9 Hz), 63.1 (d, JP−C = 6.9 Hz), 62.4 (d, JP−C
=
3
3
5.3 Hz), 62.37 (d, JP−C = 5.1 Hz), 53.1 (d, JP−C = 153.9 Hz), 16.4 (d,
3
3
J
P−C = 5.9 Hz), 16.1 (d, JP−C = 5.7 Hz), 16.0 (d, JP−C = 7.4 Hz), 15.7
(d, JP−C = 8.3 Hz); 31P{1H} NMR (243 MHz, CDCl3) δ = 22.24 (d,
3JP−P = 38.6 Hz), 6.89 (d, 3JP−P = 38.6 Hz); IR (cm−1) 3201.60 (br),
2983.25 (m), 2930.40 (w), 2903.60 (w), 1598.70 (w), 1509.30 (w),
1457.40 (w), 1392.10 (w), 1269.90 (w), 1232.47 (s), 1164.10 (m),
1027.16 (s), 957.73 (s), 866.84 (m), 796.35 (m), 749.75 (s), 648.61
(m); mp = 73−76 °C; HRMS (ESI) m/z calcd for C19H30NO6P2 [(M
+ H)+] 430.1548, found 430.1545.
Hz), 16.1 (d, JP−C = 5.7 Hz), 16.0 (d, JP−C = 7.6 Hz), 15.7 (d, JP−C
=
7.6 Hz); 31P{1H} NMR (243 MHz, CDCl3) δ = 22.57 (d, 3JP−P = 40.1
3
Hz), 6.96 (d, JP−P = 40.1 Hz). This compound is known in the
literature.11
Diethyl ((Diethoxyphosphoryl)(4-(prop-1-en-2-yl)phenyl)-
methyl)phosphoramidate (3r):
Diethyl ((4-Aminophenyl)(diethoxyphosphoryl)methyl)-
phosphoramidate (3o):
1
Colorless liquid (178 mg, 85%); H NMR (600 MHz, CDCl3) δ =
1
White solid (140 mg, 71%); H NMR (600 MHz, CDCl3) δ = 7.14
3
3
7.43 (d, JH−H = 7.8 Hz, 2H), 7.34 (d, JH−H = 7.8 Hz, 2H), 5.37 (s,
1H), 5.07 (s, 1H), 4.53−4.43 (m, 1H), 4.15−4.08 (m, 2H), 4.02−
3
4
3
(dd, JH−H = 8.4 Hz, JP−H = 1.8 Hz, 2H), 6.61 (d, JH−H = 8.4 Hz,
2H), 4.38−4.27 (m, 1H), 4.13−4.06 (m, 2H), 3.99−3.91 (m, 2H),
3.91−3.83 (m, 2H), 3.80−3.72 (m, 1H), 3.66−3.57 (m, 2H), 1.28 (t,
3JH−H = 7.2 Hz, 3H), 1.22 (t, 3JH−H = 7.2 Hz, 3H), 1.07 (t, 3JH−H = 7.2
3
3.86 (m, 5H), 3.73−3.60 (m, 2H), 2.12 (s, 3H), 1.30 (t, JH−H = 7.2
Hz, 3H), 1.24 (t, 3JH−H = 7.2 Hz, 3H), 1.10 (t, JH−H = 7.2 Hz, 3H),
3
1.02 (t, 3JH−H = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ =
142.5, 140.7 (d, JP−C = 2.9 Hz), 135.7, 127.6 (d, JP−C = 5.7 Hz), 125.3
(d, JP−C = 2.3 Hz), 112.6, 63.2 (d, JP−C = 6.8 Hz), 63.0 (d, JP−C = 6.8
Hz, 3H), 1.03 (t, JH−H = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz,
3
CDCl3) δ = 146.3 (d, JP−C = 2.7 Hz), 128.8 (d, JP−C = 5.7 Hz), 126.2,
114.9 (d, JP−C = 1.8 Hz), 63.2 (d, JP−C = 6.9 Hz), 62.8 (d, JP−C = 7.6
Hz), 62.3 (d, JP−C = 2.4 Hz), 62.2 (d, JP−C = 1.7 Hz), 52.3 (d, JP−C
Hz), 62.3 (d, JP−C = 5.3 Hz), 62.29 (d, JP−C = 5.1 Hz), 52.6 (d, JP−C
=
=
154.5 Hz), 21.6, 16.3 (d, JP−C = 6.3 Hz), 16.1 (d, JP−C = 5.7 Hz), 16.0
(d, JP−C = 7.4 Hz), 15.7 (d, JP−C = 7.6 Hz); 31P{1H} NMR (243 MHz,
CDCl3) δ = 22.26 (d, 3JP−P = 38.6 Hz), 6.86 (d, 3JP−P = 38.6 Hz); IR
(cm−1) 3227.45 (br, s), 2979.90 (m), 2936.00 (m), 2905.70 (m),
1597.69 (s), 1455.25 (m), 1392.47 (m), 1259.94 (m), 1229.00 (s),
1158.61 (m), 1121.31 (m), 1019.69 (s), 970.89 (s), 951.70 (s),
910.65 (s), 869.81 (m), 844.66 (s), 801.17 (s), 751.41 (s), 725.48
(m), 564.55 (s); HRMS (ESI) m/z calcd for C18H32NO6P2 [(M +
H)+] 420.1704, found 420.1706.
156.3 Hz), 16.3 (d, JP−C = 6.3 Hz), 16.2 (d, JP−C = 5.7 Hz), 16.0 (d,
JP−C = 7.4 Hz), 15.7 (d, JP−C = 8.0 Hz); 31P{1H} NMR (243 MHz,
CDCl3) δ = 22.89 (d, 3JP−P = 39.9 Hz), 7.06 (d, 3JP−P = 39.9 Hz); IR
(cm−1) 3459.80 (m), 3341.56 (m), 3204.59 (br), 2983.68 (m),
2936.90 (w), 2906.30 (w), 1642.20 (m), 1613.78 (s), 1520.48 (s),
1452.98 (m), 1392.35 (m), 1231.03 (s), 1181.98 (m), 1019.84 (s),
959.94 (s), 917.39 (s), 843.80 (s), 797.52 (s), 755.05 (s), 564.73
(m); mp = 103−105 °C; HRMS (ESI) m/z calcd for C15H29N2O6P2
[(M + H)+] 395.1500, found 395.1494.
Diethyl ((Diethoxyphosphoryl)(pyridin-4-yl)methyl)-
phosphoramidate (3s):
Diethyl ((Diethoxyphosphoryl)(4-(dimethylamino)phenyl)-
methyl)phosphoramidate (3p):
1
White solid (163 mg, 86%); H NMR (600 MHz, CDCl3) δ = 8.56
(d, 3JH−H = 4.8 Hz, 2H), 7.35 (d, 3JH−H = 4.8 Hz, 2H), 4.56−4.46 (m,
1H), 4.26−4.18 (m, 1H), 4.15−4.06 (m, 2H), 4.00−3.89 (m, 4H),
3.85−3.77 (m, 1H), 3.76−3.65 (m, 1H), 1.27 (t, 3JH−H = 7.2 Hz, 3H),
1
White solid (140 mg, 66%); H NMR (600 MHz, CDCl3) δ = 7.21
(d, 3JH−H = 7.2 Hz, 2H), 6.64 (d, 3JH−H = 7.2 Hz, 2H), 4.39−4.30 (m,
1H), 4.13−4.06 (m, 2H), 3.99−3.91 (m, 2H), 3.90−3.83 (m, 2H),
3
3
3
1.23 (t, JH−H = 7.2 Hz, 3H), 1.14 (t, JH−H = 7.2 Hz, 3H), 1.04 (t,
3JH−H = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ = 149.7
(d, JP−C = 2.3 Hz), 145.9, 122.7 (d, JP−C = 4.5 Hz), 63.4 (d, JP−C = 6.9
Hz), 63.37 (d, JP−C = 6.9 Hz), 62.6 (d, JP−C = 4.1 Hz), 62.55 (d, JP−C
= 5.1 Hz), 52.4 (d, JP−C = 152.1 Hz), 16.3 (d, JP−C = 5.9 Hz), 16.1 (d,
3.74−3.66 (m, 1H), 3.65−3.56 (m, 2H), 2.90 (s, 6H), 1.29 (t, JH−H
= 7.2 Hz, 3H), 1.23 (t, 3JH−H = 7.2 Hz, 3H), 1.08 (t, 3JH−H = 7.2 Hz,
3H), 1.03 (t, JH−H = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz,
3
CDCl3) δ = 150.2 (d, JP−C = 1.7 Hz), 128.5 (d, JP−C = 5.7 Hz), 123.9,
112.2 (d, JP−C = 1.7 Hz), 63.1 (d, JP−C = 6.9 Hz), 62.7 (d, JP−C = 7.4
H
https://dx.doi.org/10.1021/acs.joc.0c02016
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
JP−C = 5.7 Hz), 16.0 (d, JP−C = 7.6 Hz), 15.8 (d, JP−C = 7.6 Hz);
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02016.
■
3
31P{1H} NMR (243 MHz, CDCl3) δ = 20.66 (d, JP−P = 36.5 Hz),
sı
3
6.64 (d, JP−P = 36.5 Hz); IR (cm−1) 3227.53 (br, s), 3061.00 (w),
2980.32 (m), 2936.30 (m), 2908.00 (w), 1598.03 (s), 1562.30 (w),
1455.45 (m), 1392.60 (m), 1260.26 (m), 1228.77 (s), 1157.83 (m),
1122.14 (m), 1021.00 (s), 972.89 (s), 952.11 (s), 911.10 (s), 870.12
(m), 845.03 (s), 801.81 (s), 751.69 (s), 565.43 (s); mp = 67−69 °C;
HRMS (ESI) m/z calcd for C14H27N2O6P2 [(M + H)+] 381.1344,
found 381.1350.
Experimental procedures and NMR spectra for all
hydrophosphorylation products (3a−3v); detailed spec-
tra showing the production and subsequent isomer-
ization of the 1,1- to 1,2-addition products (PDF)
Diethyl ((Diethoxyphosphoryl)(pyridin-2-yl)methyl)-
phosphoramidate (3t):
AUTHOR INFORMATION
Corresponding Author
■
Joseph A. R. Schmidt − Department of Chemistry &
Biochemistry, School of Green Chemistry and Engineering,
College of Natural Sciences and Mathematics, The University of
Toledo, Toledo, Ohio 43606-3390, United States;
orcid.org/0000-0003-3019-0055; Phone: 419-530-1512;
Email: Joseph.Schmidt@utoledo.edu; Fax: 419-530-4033
1
Colorless liquid (173 mg, 91%); H NMR (600 MHz, CDCl3) δ =
3
3
8.57 (d, JH−H = 4.8 Hz, 1H), 7.67 (t, JH−H = 7.8 Hz, 1H), 7.40 (d,
3JH−H = 7.8 Hz, 1H), 7.22 (t, JH−H = 6.0 Hz, 1H), 4.80−4.70 (m,
3
1H), 4.39−4.31 (m, 1H), 4.12−3.93 (m, 7H), 3.85−3.74 (m, 1H),
1.28−1.21 (m, 9H), 1.09 (t, JH−H = 7.2 Hz, 3H); 13C{1H} NMR
3
(151 MHz, CDCl3) δ = 154.9, 149.0 (d, JP−C = 2.7 Hz), 136.4 (d,
JP−C = 1.7 Hz), 123.2 (d, JP−C = 5.3 Hz), 122.8 (d, JP−C = 2.9 Hz),
63.3 (d, JP−C = 6.8 Hz), 63.0 (d, JP−C = 6.9 Hz), 62.5 (d, JP−C = 5.1
Hz), 62.4 (d, JP−C = 5.1 Hz), 54.3 (d, JP−C = 154.5 Hz), 16.3 (d, JP−C
= 5.7 Hz), 16.2 (d, JP−C = 5.7 Hz), 16.0 (d, JP−C = 7.4 Hz), 15.8 (d,
Author
Yesmin Akter Rina − Department of Chemistry & Biochemistry,
School of Green Chemistry and Engineering, College of Natural
Sciences and Mathematics, The University of Toledo, Toledo,
Ohio 43606-3390, United States
J
P−C = 7.6 Hz); 31P{1H} NMR (243 MHz, CDCl3) δ = 20.91 (d, 3JP−P
3
= 35.0 Hz), 7.40 (d, JP−P = 35.0 Hz); IR (cm−1) 3215.40 (br),
2982.80 (m), 2933.80 (w), 2909.40 (w), 1590.80 (m) 1572.00 (w),
1434.98 (m), 1393.11 (m), 1239.63 (s), 1163.74 (m), 1017.93 (s),
961.93 (s), 791.33 (m), 751.72 (s), 567.82 (m); HRMS (ESI) m/z
calcd for C14H27N2O6P2 [(M + H)+] 381.1344, found 381.1350.
Diethyl (1-(Diethoxyphosphoryl)-2-phenylethyl)-
phosphoramidate (3u):
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02016
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Acknowledgement is made to the Donors of the American
Chemical Society Petroleum Research Fund for support of this
research.
1
Colorless liquid (155 mg, 79%); H NMR (600 MHz, CDCl3) δ =
7.29−7.26 (m, 4H), 7.23−7.18 (m, 1H), 4.17−4.00 (m, 5H), 3.98−
3.91 (m, 1H), 3.89−3.78 (m, 2H), 3.76−3.66 (m, 1H), 3.64−3.53
(m, 1H), 3.25−3.16 (m, 1H), 2.88−2.81 (m, 1H), 1.30 (t, 3JH−H = 7.2
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Hz, 3H), 1.25 (t, JH−H = 7.2 Hz, 3H), 1.21 (t, JH−H = 7.2 Hz, 3H),
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1
Colorless liquid (98 mg, 62%); H NMR (600 MHz, CDCl3) δ =
4.19−3.99 (m, 8H), 3.55−3.43 (m, 1H), 2.94−2.84 (m, 1H), 1.39−
1.26 (m, 15H); 13C{1H} NMR (151 MHz, CDCl3) δ = 62.6 (d, JP−C
= 6.8 Hz), 62.5 (d, JP−C = 5.7 Hz), 62.45 (d, JP−C = 5.3 Hz), 62.3 (d,
JP−C = 6.9 Hz), 44.5 (d, JP−C = 159.8 Hz), 18.0, 16.4 (d, JP−C = 6.9
Hz), 16.36 (d, JP−C = 6.3 Hz), 16.1 (d, JP−C = 3.5 Hz), 16.06 (d, JP−C
= 4.1 Hz); 31P{1H} NMR (243 MHz, CDCl3) δ = 26.40 (d, JP−P
=
3
34.7 Hz), 7.58 (d, 3JP−P = 34.7 Hz); IR (cm−1) 3319.70 (br), 2987.33
(w), 2907.98 (w), 2879.00 (w), 1643.80 (w), 1443.93 (w), 1393.83
(w), 1222.56 (s), 1163.44 (m), 1022.19 (s), 953.74 (s), 865.43 (m),
796.15 (m), 566.76 (m); HRMS (ESI) m/z calcd for C10H26NO6P2
[(M + H)+] 318.1235, found 318.1236.
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