Trichloroisocyanuric Acid as an Efficient Reagent for the Synthesis of Phosphoroamidates via Atherton-Todd Reaction under Base-Free Conditions

Article abstract of DOI:10.1055/s-0036-1589111

A simple, efficient, and novel method is developed for the synthesis of phosphoroamidates via an Atherton-Todd coupling reaction of amines with dialkyl H-phosphite using trichloroisocyanuric acid as an efficient and safe reagent. Treatment of amines with dialkyl H-phosphite and trichloroisocyanuric acid under base-free conditions gives phosphoroamidates in moderate to good yields. The reaction proceeded effectively to afford the corresponding phosphoroamidates via a dehydrogenative coupling of H-phosphonates with amines. This method is easy, rapid, and good-yielding for the synthesis of phosphoroamidates.

Full text of DOI:10.1055/s-0036-1589111

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–E
paper
A
en
B. Kaboudin et al.
Paper
Synthesis
Trichloroisocyanuric Acid as an Efficient Reagent for the Synthesis
of Phosphoroamidates via Atherton–Todd Reaction under Base-Free
Conditions
Babak Kaboudin*
Atousa Donyavi
O
O
TCCA (0.33 equiv)
MeCN, r.t., 1–6 h
R
NH2
+
H
P(OR')2
HN P(OR')2
R
Foad Kazemi
0
0
0
0
0-
0
0
1
8-
8
7
7
1-
1
7
3
13 examples
up to 92% yield
R = alkyl, aryl
R' = Et, i-Pr
O
Department of Chemistry, Institute for Advanced Studies
in Basic Sciences (IASBS), Zanjan 45137-66731, Iran
kaboudin@iasbs.ac.ir
Cl
Cl
N
N
TCCA =
O
N
O
Cl
Received: 04.07.2017
Accepted after revision: 29.08.2017
Published online: 12.09.2017
dialkyl chlorophosphate via the reaction of dialkyl phos-
phite with carbon tetrachloride in the presence of a base
followed by a nucleophilic addition of an amine to the re-
sulting dialkyl chlorophosphate. Other methods include the
coupling reaction of dialkyl phosphite with amines in the
presence of a transition metal copper salts with a base,7 or
the use of I2 as catalyst with stoichiometric amounts of
H2O2 as an oxidant.8 Recently, Rios et al. reported the use of
visible light in conjunction with an organic dye for the syn-
thesis of phosphoramidates via the cross dehydrogenative
coupling reactions between phosphites and amines.9 How-
ever, these methods have one or more drawback such as
long reaction time, harsh reaction conditions, low yields,
use of hazardous materials and transition metals, side reac-
tions,10 and also in some cases they are applicable to only
aromatic amines (Scheme 1).
DOI: 10.1055/s-0036-1589111; Art ID: ss-2017-z0440-op
Abstract A simple, efficient, and novel method is developed for the
synthesis of phosphoroamidates via an Atherton–Todd coupling reac-
tion of amines with dialkyl H-phosphite using trichloroisocyanuric acid
as an efficient and safe reagent. Treatment of amines with dialkyl H-
phosphite and trichloroisocyanuric acid under base-free conditions
gives phosphoroamidates in moderate to good yields. The reaction pro-
ceeded effectively to afford the corresponding phosphoroamidates via
a dehydrogenative coupling of H-phosphonates with amines. This
method is easy, rapid, and good-yielding for the synthesis of phospho-
roamidates.
Key words phosphoroamidate, amines, dialkyl H-phosphite, cou-
pling, Atherton–Todd reaction
Phosphorus–nitrogen bond formation is an active and
important research area for the preparation of valuable in-
termediates in organic synthesis.1 Among the various or-
ganophosphorus compounds including P–N bonds, phos-
phoroamidates are of interest as effective in biologically ac-
tive molecules, medicinal chemistry, and industrially
important products.2 A number of phosphoramidates have
become important chiral ligands for metal-catalyzed reac-
tions in organic transformations.3 A number of biologically
active natural products such as agrocin 84, thymectacin
(NB1011), stampidine, phosmidosine, and microcin C7 con-
tain phosphoramidate functional groups as a key structural
unit.4 Phosphoroamidates can be also used as a prodrug for
the preparation of 2′-C-methylcytidine, which is the first
nucleoside inhibitor of HCV NS5B polymerase with their re-
ducing activity on the viral load in patients infected with
HCV.5
Previously reported work
O
O
O
Et
N
H
N
CCl4
Et3N
R
NH2
+
H
P(OR')2
R
P(OR')2
+
H
P
O
R'
Et
OR'
Et
side product
Atherton–Todd reaction
O
O
H
CuCl2 (2 equiv)
R
NH2
+
H
P(OR')2
R
N P(OR')2
Cs2CO3 (2 equiv)
(1 equiv)
(2 equiv)
O
O
H
Rose Bengal (20 mol%)
green light, 70 °C
R
NH2
NH2
+
H
P(OR')2
R
N P(OR')2
O
O
H
N
I2, H2O2 (excess)
CH2Cl2, 36 h
R
+
H
P(OR')2
R
P(OR')2
This work
O
O
H
TCCA (0.33 equiv)
A more straightforward and common one-pot process
for the synthesis of phosphoroamidates is the Atherton–
Todd reaction.6 The process involves the in situ formation of
R
NH2
+
H
P(OR')2
R
N P(OR')2
MeCN, 1–6 h
Scheme 1 Previously reported work, and this work
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

B
B. Kaboudin et al.
Paper
Synthesis
Trihaloisocyanuric acids are safe and stable electrophilic
halogenating reagents, due to the large group of N-haloim-
ides in their structures. These reagents can transfer three
electrophilic halogens atoms to a substrate and at the end
of the halogenations process, cyanuric acid precipitates and
can be recovered from the reaction mixture. Trichloroisocy-
anuric acid (TCCA) is an inexpensive commercially available
solid mainly reported to use for oxidation, chlorination, and
dehydrogenation reactions.11–18 To the best of our knowl-
edge, there is no report on the synthesis of phosphoroami-
dates by the reaction of amines with dialkyl phosphates in
the presence of TCCA in a one-pot manner. Therefore, we
decided to study the feasibility of the TCCA as a safe reagent
for the synthesis of phosphoroamidates under base-free
conditions (Scheme 1).
ford the desired products 3b–d in moderate to good yields.
Benzylamine and 2-phenethylamine as aliphatic amines
also reacted with a mixture of diethyl phosphite and TCCA
to give compounds 3e and 3f in 88 and 92% yield, respec-
tively (Table 2, entries 5 and 6). As shown in Table 2, the re-
action proceeded very well in high yield with aliphatic
amines. This method was also applied to the coupling of α-
naphthylamine with diethyl phosphite in the presence of
TCCA (entry 7).
Table 2 Coupling Reaction of Dialkyl Phosphites with Aminesa
O
O
TCCA (0.33 equiv)
MeCN, r.t., 1–6 h
R
NH2
+
H
P(OR')2
HN P(OR')2
R
1
2
3
Initially, the coupling reaction of diethyl phosphite (2a)
with aniline (1a) was chosen as the model reaction and the
experimental data for screening conditions are listed in Ta-
ble 1. A mixture of 1.0 equivalent of diethyl phosphite (2a),
1 equivalent of aniline (1a), and 0.33 equivalent of TCCA
was stirred in MeCN (3 mL) at room temperature for 5
hours to give 3a in 70% yield (Table 1, entry 1). The yield of
the reaction did not change on further increase of the cata-
lyst, reaction temperature, and reaction time (entries 2–4).
As shown in Table 1 (entries 5–7), after 24 hours, the cou-
pling of 1a with 2a generally gave low yields in CHCl3, DMF,
and EtOAc compared to MeCN in the presence of TCCA (0.33
equiv).
Entry 1 R
2 R′
Product 3
Time Yield
(h) (%)b
H
OEt
N
P
1
2
Ph
Et
Et
3a
3b
5
4
70
78
OEt
O
H
OEt
N
P
4-MeC6H4
OEt
O
Me
H
O
N
O2N
P
3
4
3-O2NC6H4
Et
3c
5
6
62
40
OEt
EtO
EtO
EtO
O
P
Table 1 Reaction of Aniline (1a) with Diethyl Phosphite (2a) in the
NH
Presence of TCCAa
3-Cl-2-MeC6H3 Et
3d
Me
Cl
O
O
H
N
TCCA
NH2
+
H
P(OEt)2
P(OEt)2
H
N
O
3a
1a
2a
P
5
6
PhCH2
Et
Et
3e
3f
2
1
88
92
EtO
O
OEt
Cl
Cl
N
N
H
TCCA =
N
O
P
O
N
O
PhCH2CH2
EtO
OEt
Cl
OEt
Entry TCCA (equiv) Solvent
Temp (°C)
Time (h)
3a; Yield (%)b
EtO
P
HN
O
1
2
3
4
5
6
7
0.33
1
MeCN
MeCN
MeCN
MeCN
CHCl3
DMF
r.t.
5
5
70
71
70
66
42
36
50
7
α-naphthyl
Et
3g
4
50
r.t.
0.33
0.33
0.33
0.33
0.33
r.t.
24
5
H
N
O
P
reflux
r.t.
Oi-Pr
8
9
Ph
i-Pr
i-Pr
3h
3i
5
3
63
69
24
24
24
Oi-Pr
r.t.
H
N
Oi-Pr
EtOAc
r.t.
P
4-MeC6H4
Oi-Pr
a Equimolar amounts of 1a and 2a were used.
O
b Isolated yield.
Me
This process was applied successfully to other amines as
summarized in Table 2. Substituted anilines reacted with a
mixture of diethyl phosphite and TCCA (0.33 equiv) to af-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

C
B. Kaboudin et al.
Paper
Synthesis
Table 2 (continued)
O
O
P
Cl
Cl
O
Entry 1 R
2 R′
i-Pr
Product 3
Time Yield
(h) (%)b
N
N
H
OR'
OR'
3
O
N
i-PrO
R
N
O
Cl
P
O
i-PrO
NH
3
H
H
R'O
R'O
P
H
10
3-O2NC6H4
3j
5
47
1
3
N
R
NO2
3
O
P
O
HCl
R'O
R'O
O
3
HO
O
OH
O
Cl
N
N
11
12
PhCH2
i-Pr
i-Pr
3k
3l
2
1
68
70
HN
P
Oi-Pr
5
Oi-Pr
N
OH
H
O
P
N
Oi-Pr
PhCH2CH2
Scheme 3 Proposed mechanism for the synthesis of phosphoroami-
dates 3
Oi-Pr
Oi-Pr
i-PrO
In conclusion, we have reported here the synthesis of
phosphoroamidates via a coupling reaction of an amine
with dialkyl phosphite in MeCN at room temperature in the
presence of TCCA. It was found that TCCA is an effective re-
agent for this transformation. A simple workup, mild and
base-free reaction conditions, moderate to good yields, and
clean reaction mixtures make this method an attractive and
a useful contribution to present methodologies.
P
HN
O
13
α-naphthyl
i-Pr
3m
4
22
a Conversions were monitored by TLC.
b Yields refer to the isolated pure products.
The coupling reaction of amines with a mixture diiso-
propyl phosphite and TCCA was also studied (Table 2, en-
tries 8–13). The reaction of aromatic and aliphatic amines
with a mixture of diisopropyl phosphite and TCCA at ambi-
ent temperature, gave the desired products 3h–m in mod-
erate to good yields.
It was also possible to carry out this reaction with N-
methylaniline and the corresponding phosphoroamidate 4
was obtained in 29% yield (Scheme 2).
All chemicals were commercial products. NMR spectra were obtained
with a 400 MHz Bruker Avance instrument with the chemical shifts
being reported as δ ppm and couplings expressed in hertz (Hz). Silica
gel column chromatography was carried out with silica gel 100 (Merck
No. 10184). Merck Silica gel 60 F254 plates (No. 5744) were used for
the preparative TLC. Melting points are uncorrected.
Phosphoroamidates 3; General Procedure
O
O
TCCA (0.33 equiv)
MeCN, r.t., 4 h
The required dialkyl phosphite (1.5 mmol) was added to a stirred
solution of trichloroisocyanuric acid (0.116 g, 0.5 mmol) in MeCN (3
mL) and the reaction mixture was stirred for 15 min at r.t. The respec-
tive amine (1.5 mmol) was added and the mixture was stirred for 1–6
h (Table 2) at r.t. The resulting solution was diluted with aq 5% NaOH
(10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic
layers were washed with brine and dried (Na2SO4). The pure product
was obtained by column chromatography on silica gel with n-hex-
ane–EtOAc (9:1 to 6:4) as eluent (Table 2).
NH
+
H
P(OEt)2
N
P(OEt)2
Me
Me
2a
4
29% isolated yield
Scheme 2 Reaction of N-methylaniline with a mixture of diethyl phos-
phite and TCCA
A proposed mechanism is outlined in Scheme 3 for the
synthesis of phosphoroamidates via the coupling of amines
with dialkyl phosphite in the presence of TCCA under base-
free conditions. The present process is thought to proceed
via the reaction of dialkyl phosphite with TCCA to give dial-
kyl chlorophosphate 5, a known intermediate, followed by
nucleophilic substitution of amine with the intermediate to
give the phosphoroamidate 3. The generation of HCl gas
was detected by wet pH paper test.
All products gave satisfactory spectral data in accord with the as-
signed structures and literature reports.
Diethyl Phenylphosphoramidate (3a)
Yield: 0.240 g (70%); white solid; mp 93–95 °C (Lit.6 mp 93 °C).
1H NMR (CDCl3, 400 MHz): δ = 1.3 (6 H, t, JHH = 6.8 Hz), 4.0–4.24 (4 H,
m), 6.94 (1 H, t, JHH = 7.6 Hz), 7.09 (2 H, d, JHH = 5.6 Hz), 7.25 (2 H, t,
JHH = 7.6 Hz), 7.5 (1 H, NH).
13C NMR (CDCl3, 100 MHz): δ = 16.6 (d, JCP = 7.0 Hz), 62.6 (d, JCP = 5.0
Hz), 117.2 (d, JCP = 8.0 Hz), 121.2, 129.1, 140.2.
31P NMR (CDCl3, H3PO4): δ = 3.05.
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D
B. Kaboudin et al.
Paper
Synthesis
Diethyl p-Tolylphosphoramidate (3b)
31P NMR (CDCl3, H3PO4): δ = 2.88.
Yield: 0.283 g (78%); white solid; mp 90–92 °C (Lit.9 mp 89–91 °C).
Diisopropyl Phenylphosphoramidate (3h)
Yield: 0.243 g (63%); white solid; mp 121–123 °C (Lit.19 mp 122–
124 °C).
1H NMR (CDCl3, 400 MHz): δ = 1.32 (6 H, t, JHH = 6.4 Hz), 2.29 (3 H, s),
4.06–4.22 (4 H, m), 6.98 (2 H, d, JHH = 8.4 Hz), 7.07 (2 H, d, JHH = 8.4
Hz), 7.29 (1 H, NH).
1H NMR (CDCl3, 400 MHz): δ = 1.23 (6 H, d, JHH = 6.4 Hz), 1.41 (6 H, d,
JHH = 6.4 Hz), 4.654–4.767 (2 H, m), 6.79 (1 H, NH, br, exch. D2O), 6.94
(1 H, t, JHH = 7.6 Hz), 7.05 (2 H, d, JHH = 7.6 Hz), 7.25 (2 H, m),
13C NMR (CDCl3, 100 MHz): δ = 23.7 (d, JCP = 5.0 Hz), 71.5 (d, JCP = 5.0
Hz), 117.3 (d, JCP = 7.0 Hz), 121.0, 129.0, 140.3.
13C NMR (CDCl3, 100 MHz): δ = 16.1 (d, JCP = 7.0 Hz), 20.5, 62.5 (d, JCP
5.0 Hz), 117.2 (d, JCP = 7.0 Hz), 129.7, 130.6, 137.4.
31P NMR (CDCl3, H3PO4): δ = 3.15.
=
Diethyl (3-Nitrophenyl)phosphoramidate (3c)
Yield: 0.255 g (62%); white solid; mp 118–120 °C (Lit.9 mp 120 °C).
31P NMR (CDCl3, H3PO4): δ = 0.36.
1H NMR (CDCl3, 400 MHz): δ = 1.38 (6 H, t, JHH = 7.2 Hz), 4.13–4.28 (4
H, m), 7.37–7.44 (3 H, m), 7.81 (1 H, NH), 7.93 (1 H, s).
13C NMR (CDCl3, 100 MHz): δ = 16.1 (d, JCP = 6.0 Hz), 63.3 (d, JCP = 5.0
Hz), 111.9 (d, JCP = 7.0 Hz), 116.1, 123.3 (d, JCP = 8.0 Hz), 129.9, 141.6,
149.0.
Diisopropyl p-Tolylphosphoramidate (3i)
Yield: 0.280 g (69%); white solid; mp 156–157 °C (Lit.19 white solid).
1H NMR (CDCl3, 400 MHz): δ = 1.24 (6 H, d, JHH = 6.0 Hz), 1.40 (6 H, d,
JHH = 6.0 Hz), 2.29 (3 H, s), 4.66–4.74 (2 H, m), 5.91 (1 H, NH, br, exch.
D2O), 6.91 (2 H, d, JHH = 8.4 Hz), 7.06 (2 H, d, JHH = 8.4 Hz).
13C NMR (CDCl3, 100 MHz): δ = 20.5, 23.7 (d, JCP = 5.0 Hz), 71.6 (d, JCP
5.0 Hz), 117.3 (d, JCP = 7.0 Hz), 129.6, 130.6, 137.4.
31P NMR (CDCl3, H3PO4): δ = 1.58.
=
Diethyl (3-Chloro-2-methylphenyl)phosphoramidate (3d)
31P NMR (CDCl3, H3PO4): δ = 0.21.
Yield: 0.165 g (40%); purple solid; mp 63–65 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.33 (6 H, t, JHH = 4 Hz), 2.343 (3 H, s),
4.05–4.20 (4 H, m), 5.38 (1 H, NH), 7.02–7.29 (3 H, m).
Diisopropyl (3-Nitrophenyl)phosphoramidate (3j)
Yield: 0.215 g (47%); white solid; mp 105–108 °C.
13C NMR (CDCl3, 100 MHz): δ = 14.2, 13.0 (d, JCP = 7.0 Hz), 63.0 (d, JCP
5.0 Hz), 116.0, 122.9, 123.8 (d, JCP = 11 Hz), 127.1, 134.9, 139.2.
31P NMR (CDCl3, H3PO4): δ = 1.85.
=
1H NMR (CDCl3, 400 MHz): δ = 1.28 (6 H, d, JHH = 6.4 Hz), 1.44 (6 H, d,
JHH = 6.4 Hz), 4.50–4.81 (2 H, m), 7.35–7.43 (2 H, m), 7.7 (1 H, NH, br,
exch. D2O), 7.80–7.93 (2 H, m).
13C NMR (CDCl3, 100 MHz): δ = 23.7 (d, JCP = 5.0 Hz), 72.4 (d, JCP = 6.0
Hz), 111.8 (d, JCP = 7.0 Hz), 115.8, 123.1 (d, JCP = 8.0 Hz), 129.7, 141.8,
148.9.
Anal. Calcd for C11H17ClNO3P: C, 47.57; H, 6.17; N, 5.04. Found: C,
48.01; H, 6.35; N, 4.96.
Diethyl Benzylphosphoramidate (3e)9
31P NMR (CDCl3, H3PO4): δ = –0.98.
Yield: 0.320 g (88%); yellow oil.
1H NMR (CDCl3, 400 MHz): δ = 1.24 (6 H, t, JHH = 7.2 Hz), 3.69 (1 H,
NH), 3.93–4.06 (6 H, m), 7.20–7.32 (5 H, m).
Anal. Calcd for C12H19N2O5P: C, 47.68; H, 6.33; N, 9.26. Found: C,
47.59; H, 6.04; N, 9.02.
13C NMR (CDCl3, 100 MHz): δ = 16.1 (d, JCP = 7.0 Hz), 45.1, 62.2 (d, JCP
5.0 Hz), 127.2 (d, JCP = 14 Hz), 128.4, 139.0 (d, JCP = 6.0 Hz).
31P NMR (CDCl3, H3PO4): δ = 8.87.
=
Diisopropyl Benzylphosphoramidate (3k)
Yield: 0.275 g (68%); white solid; mp 48–50 °C (Lit.19 mp 48–50 °C).
1H NMR (CDCl3, 400 MHz): δ = 1.31 (6 H, d, JHH = 6.4 Hz), 1.38 (6 H, d,
JHH = 6.4 Hz), 2.95 (1 H, NH), 4.11 (2 H, d, JHH = 8.4 Hz), 4.61–4.69 (2 H,
m), 7.27–7.34 (5 H, m).
13C NMR (CDCl3, 100 MHz): δ = 23.8 (t, JCP = 4.0 Hz), 45.4, 70.9 (d, JCP
5.0 Hz), 127.3, 127.9, 128.7, 139.7 (d, JCP = 7.0 Hz).
Diethyl Phenethylphosphoramidate (3f)8
Yield: 0.355 g (92%); yellow oil.
=
1H NMR (CDCl3, 400 MHz): δ = 1.23 (6 H, t, JHH = 6.8 Hz), 2.73 (2 H, t,
JHH = 6.8 Hz), 3.06–3.12 (2 H, m), 3.36 (1 H, NH), 3.85–3.97 (4 H, m),
7.13–7.21 (3 H, m), 7.23–7.25 (2 H, m).
31P NMR (CDCl3, H3PO4): δ = 6.59.
13C NMR (CDCl3, 100 MHz): δ = 16.1 (d, JCP = 7.0 Hz), 37.9 (d, JCP = 6.0
Hz), 42.7, 62.0 (d, JCP = 5.0 Hz), 126.3, 128.4, 128.8, 138.9.
31P NMR (CDCl3, H3PO4): δ = 9.25.
Diisopropyl Phenethylphosphoramidate (3l)
Yield: 0.300 g (70%); yellow oil.
1H NMR (CDCl3, 400 MHz): δ = 1.30–1.45 (12 H, m), 2.80 (2 H, t, JHH
=
1.8 Hz), 2.96 (1 H, NH), 3.15–3.21 (2 H, m), 4.53–4.65 (2 H, m), 7.21–
7.35 (5 H, m).
13C NMR (CDCl3, 100 MHz): δ = 23.8 (d, JCP = 5.0 Hz), 37.8 (d, JCP = 6.0
Hz), 42.7, 70.7 (d, JCP = 5.0 Hz), 126.3, 128.6, 128.9, 138.7.
Diethyl Naphthalen-1-ylphosphoramidate (3g)
Yield: 0.210 g (50%); white solid; mp 106–108 °C (Lit.9 mp 103–
105 °C).
1H NMR (CDCl3, 400 MHz): δ = 1.35 (6 H, t, JHH = 6.4 Hz), 4.112–4.289
(4 H, m), 6.38 (1 H, NH, br, exch. D2O), 7.41–7.58 (5 H, m), 7.87 (1 H,
dd, J1 = 1.6 Hz, J2 = 7.2 Hz), 8.12 (1 H, dd, J1 = 1.2 Hz, J2 = 8 Hz).
13C NMR (CDCl3, 100 MHz): δ = 16.1 (d, JCP = 7.0 Hz), 62.9 (d, JCP = 5.0
Hz), 114.2 (d, JCP = 2.0 Hz), 120.6, 122.7, 125.5, 125.6, 125.9 (d, JCP = 3.0
Hz), 126.0, 128.7, 134.3, 134.9.
31P NMR (CDCl3, H3PO4): δ = 7.13.
Anal. Calcd for C14H24NO3P: C, 58.93; H, 8.47; N, 4.91. Found: C, 59.10;
H, 8.16; N, 4.84
Diisopropyl Naphthalen-1-ylphosphoramidate (3m)
Yield: 0.104 g (22%); white solid; mp 148–152 °C (Lit.19 white solid).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

E
B. Kaboudin et al.
Paper
Synthesis
1H NMR (CDCl3, 400 MHz): δ = 1.22 (6 H, d, JHH = 6 Hz), 1.43 (6 H, d,
JHH = 6 Hz), 4.71–4.82 (2 H, m), 5.91 (1 H, NH), 7.39–7.57 (5 H, m),
7.87–7.98 (2 H, m).
13C NMR (CDCl3, 100 MHz): δ = 23.7 (d, JCP = 5.0 Hz), 71.9 (d, JCP = 4.0
Hz), 113.9, 120.1, 122.2, 125.0, 125.1, 125.8 (d, JCP = 5.0 Hz), 125.9 (d,
JCP = 5.0 Hz), 128.8, 134.2, 135.0.
(4) (a) Roberts, W. P.; Tate, M. E.; Kerr, A. Nature 1977, 265, 379.
(b) Tate, M. E.; Murphy, P. J.; Roberts, W. P.; Kerr, A. Nature
1979, 265, 697. (c) Phillips, D. R.; Uramoto, M.; Isono, K.;
McCloskey, A. J. Org. Chem. 1993, 58, 854. (d) Guijarro, J. I.;
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D.; Dean, B. J.; McGowan, E. M.; Feeney, W. P.; Chiu, S. H. L.;
Cascieri, M. A.; Chicchi, G. G.; Kurtz, M. M.; Sadowski, S.; Ber, E.;
Tattersall, F. D.; Rupniak, N. M. J.; Williams, A. R.; Rycroft, W.;
Hargreaves, R.; Metzger, J. M.; MacIntyre, D. E. J. Med. Chem.
2000, 43, 1234. (f) Serpi, M.; Bibbo, R.; Rat, S.; Roberts, H.;
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31P NMR (CDCl3, H3PO4): δ = 0.31.
Diethyl N-Methyl-N-phenylphosphoramidate (4)8
Yield: 0.105 g (29%); yellow oil.
1H NMR (CDCl3, 400 MHz): δ = 1.28 (6 H, t, JHH = 6.4 Hz), 3.21 (3 H, d,
JHH = 8.4 Hz), 3.98–4.17 (4 H, m), 7.05–7.09 (1 H, m), 7.27–7.33 (4 H,
m).
13C NMR (CDCl3, 100 MHz): δ = 16.0 (d, JCP = 7.0 Hz), 36.8 (d, JCP = 5.0
Hz), 62.5 (d, JCP = 5.0 Hz), 121.8 (d, JCP = 4.0 Hz), 123.5, 128.9, 144.1 (d,
JCP = 4.0 Hz).
(5) Meppan, M.; Pacini, B.; Bazzo, R.; Koch, U.; Leone, J. F.;
Koeplinger, K. A.; Rowley, M.; Altamura, S. Eur. J. Med. Chem.
2009, 44, 3765.
31P NMR (CDCl3, H3PO4): δ = 5.90.
(6) (a) Atherton, F. R.; Openshaw, H. T.; Todd, A. R. J. Chem. Soc.
1945, 660. (b) Atherton, F. R.; Todd, A. R. J. Chem. Soc. 1947, 674.
(c) Le Corre, S. S.; Berchel, M.; Gorves, H. C.; Haelters, J.-P.;
Jaffres, P.-A. Beilstein J. Org. Chem. 2014, 10, 1166. (d) Steinberg,
G. M. J. Org. Chem. 1950, 15, 637. (e) Dar, B. A.; Dangroo, N. A.;
Gupta, A.; Wali, A.; Khuroo, M. A.; Vishwakarma, R. A.; Singh, B.
Tetrahedron Lett. 2014, 55, 1544. (f) Kaboudin, B.; Kazemi, F.;
Habibi, F. Tetrahedron Lett. 2015, 56, 6364. (g) Trofimov, B. A.;
Gusarova, N. K.; Volkov, P. A.; Ivanova, N. I.; Khrapova, K. O. Het-
eroat. Chem. 2016, 27, 44.
(7) (a) Purohit, A. K.; Pardasani, D.; Kumar, A.; Goud, D. R.; Jain, R.;
Dubey, D. K. Tetrahedron Lett. 2016, 57, 3754. (b) Fraser, J.;
Wilson, L. J.; Blundell, R. K.; Hayes, C. J. Chem. Commun. 2013, 49,
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418.
Funding Information
The authors gratefully acknowledge support from the Institute for
Advanced Studies in Basic Sciences (IASBS) Research Council under
grant No. G2016IASBS31101.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E