Efficient Synthesis of Phosphonamidates through One-Pot Sequential Reactions of Phosphonites with Iodine and Amines

Article abstract of DOI:10.1002/chem.202002934

A one-pot sequential strategy to construct phosphonamidates has been developed by generating phosphonites in situ from arylmagnesium bromides and triethyl phosphite followed by treatment with iodine and amines. A variety of phosphonamidates were obtained with good to excellent yields at room temperature from easily available materials.

Full text of DOI:10.1002/chem.202002934

Accepted Article
Accepted Article
Title: Efficient Synthesis of Phosphonamidates via One-Pot Sequential
Reactions of Phosphonites with Iodine and Amines
Authors: Ai-Yun Peng, Xunwei Chen, Wenjun Luo, Yanlin Wang,
Zikang Li, and Xiaorui Ma
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To be cited as: Chem. Eur. J. 10.1002/chem.202002934
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10.1002/chem.202002934
Chemistry - A European Journal
FULL PAPER
Efficient Synthesis of Phosphonamidates via One-Pot Sequential
Reactions of Phosphonites with Iodine and Amines
Xunwei Chen, Wenjun Luo, Yanlin Wang, Zikang Li, Xiaorui Ma, and Ai-Yun Peng*
Dedication ((optional))
X. Chen, W. Luo, Y. Wang, Z. Li, X. Ma, Prof. Dr. A.-Y. Peng
School of Chemistry
Sun Yat-sen University
135 Xingangxi Lu, Guangzhou (China）
E-mail: cespay@mail.sysu.edu.cn
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: An one-pot sequential strategy to construct
phosphonamidates has been developed by generating phosphonites Several strategies have been developed for the synthesis of
in situ from aryl magnesium bromides and triethyl phosphite followed phosphonamidates, including (1) the classic aminolysis of
by treatment with iodine and amines. A variety of phosphonamidates phosphonochloridates from pre-generated phosphonic acid
were obtained with good to excellent yields at room temperature diesters or monoesters with chlorinating reagents1b-c,2a-b,3,7a,8
from easily available materials.
(Scheme 1a); (2) Atherton-Todd reaction between amines and
7b-c,9
H-phosphinates in the presence of CCl4 or Cl2
(Scheme 1b);
(3) direct coupling of amines and phosphonic acids or salts in
the presence of PPh3 and 2,2’-dithiodipyridine or other coupling
reagents1d-h,4,10 (Scheme 1c); (4) Staudinger-phosphonite
reaction of phosphonites and organic azides11 (Scheme 1d).
These methods have their own advantages as well as some
Introduction
Phosphonamidates, as prodrugs and transition-state analogues
of amide bond hydrolysis, have attracted significant attention in
medicinal chemistry. They show a wide range of biological
activities, such as antiviral,1 anticancer,2 enzyme inhibition,3 and
immune stimulant of T cell4 (Figure 1). In particular, Tenofovir
alafenamide (TAF), a phosphonoamidate prodrug of Tenofovir,
has been approved by FDA to treat human immunodefificiency
virus (HIV)5 in 2015 and hepatitis B virus (HBV)6 in 2016.
Moreover, some phosphonamidates have exhibited excellent
retardant efficacy and high thermal stability which makes them
have good application prospects as flame retardant additives in
polymer industry.7
major
disadvantages.
For
example,
the
classic
phosphonochloridate strategy is generally efficient and reliable,
but it involves lengthy steps, tedious workup and is incompatible
with some sensitive functional groups. The direct coupling
method avoids the use of chlorinating reagents and has been
successfully applied to the synthesis of phosphonamidate
peptides, but some special and expensive coupling reagents
and additives are needed and the yields are usually poor.
Atherton-Todd reaction and Staudinger-phosphonite reaction are
simple and efficient, while they both require hazardous reagents,
such as CCl4 or azides, and the starting materials are relatively
expensive and not easily available. In 2018, Moduni and
NH2
coworkers developed
a
novel approach to construct
N
phosphonamidates from the phosphonic acid diesters and
lithium amides,12 but it needs to use expensive and moisture-
sensitive triflic anhydride and the amines must be deprotonated
in advance. Very recently, Tan and coworkers reported a ZnI2-
triggered oxidative cross-coupling reaction of P(O)–H
compounds and amines and synthesized a series of phosphinic
N
H
N
H
N
OMe
N
N
N
O
P
N
PhO
O
O
O
P
HN
Br
N
OH
iPrO
F
amides
and
phosphoramidates
as
well
as
two
O
phosphonamidates.13 The biggest obstacle to using this method
for the synthesis of phosphonamidates is that the required H-
phosphinates are not easily available and very limited. Therefore,
it is still highly desirable to develop more practical, general,
antitumor agent targeting IDO1
TAF (Drug to treat HBV and HIV)
O
O
OAr
OR
P
P
OR
NH2
N
H
simple,
green
and
efficient
methods
to
prepare
OH
immune stimulant of T cell
O
phosphonamidates.
inhibitor of carbonic anhydrase
The combination of phosphites and iodine is an established
phosphorylation method, which has been successfully applied to
synthesize phosphoramidates and mixed phospates.14 Our
group has extensively reinvestigated this kind of iodine-mediated
phosphoramidation reaction15 and found it is a very powerful
and convenient way to access phosphoriamidates. We reasoned
Figure 1. Examples of biologically active phosphonamidates
1
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10.1002/chem.202002934
Chemistry - A European Journal
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that if we use phosphonites instead of phosphites in this reaction, increasing the ratio of PhMgBr/P(OMe)3 could improve the yield
phosphonoamidates with one C-P bond would be produced.
However, to our surprise, such methodology has never been
used to synthesize phosphonamidates thus far. Herein, we
present a practical and efficient approach to synthesize
phosphonamidates by an one-pot sequential procedure from
of the desired product B, but the side product C would also be
gradually increased at the same time (entries 4–7). In contrast,
the disubstituted side reaction was not a problem for the
corresponding reaction of P(OEt)3 and the yield of the desired
phosphonite B could reach to 98% (entries 8–12, Table 1).
triethyl phosphite, aryl magnesium bromides, amines and iodine Based on these results, we chose P(OEt)3 as phosphorus
(Scheme 1e). This
available materials, needs no intermediate isolation and
proceeds under mild conditions.
strategy starts from cheap and easily
source and used the optimized conditions (ArMgBr/P(OEt)3
2.0/1, 0.2 M in THF, 25 oC, 36 h) for subsequent reactions.
=
Table 1 Optimization for the formation of phenyl phosphonite[a]
(a) Classical route:
O
P
O
P
O
P
R2R3NH
PCl5 or SOCl2
or (COCl)2
Cl
OR
R1
NR2R3
R1
OR'
OR
R1
OR'
R' = R or H
(b) Atherton-Todd reaction:
O
O
O
P
R2R3NH
CCl4
H
R1
P
NR2R3
NR2R3
R1
P
Cl
OR
R1
Entry
1
R
Ratio[b]
1.5:1
1.5:1
1.5:1
1.5:1
1.6:1
1.6:1
2.0:1
2.0:1
2.0:1
2.0:1
1.8:1
1.5:1
Temp.(oC)
Time (h)
5
A:B:C[c]
5:80:15
39:58:3
44:55:1
23:75:2
18:78:4
10:84:6
15:80:5
15:83:2
7:91:2
OR
OR'
Me
Me
Me
Me
Me
Me
Me
Et
70
50
25
25
25
25
25
25
25
25
25
25
(c) Direct coupling:
O
PPh3, 2,2'-dithiodipyridine or
other coupling reagents
O
P
2
5
R1
OR
OX
R1
P
R2R3NH
3
5
OR'
X = H, Na, SiMe3
4
10
10
32
10
10
24
36
24
24
(d) Staudinger-phosphonite:
O
5
OR
OR
R''N3
R'Li or R'MgBr
ClP(OR)2
R'
Ar
P
NHR''
NRR'
R'
P
P
6
OR
7
(e) This work:
O
P
OEt
RR'NH
I2
8
ArMgBr
Ar
P(OEt)3
9
Et
OEt
OEt
readily available materials
mild conditions
10
11
12
Et
0:98:2
one-pot process excellent functional tolerance
Et
19:79:2
21:77:2
Scheme 1. Synthetic routes toward phosphonamidates
Et
[a] Reaction conditions: P(OR)3 (2 mmol), PhMgBr in anhydrous THF, under
N2, final concentration with respect to P(OR)3 was 0.2 mmol/mL. [b] Molar ratio
of PhMgBr to P(OR)3. [c] The ratio of A:B:C was determined by 31P NMR on
the crude product (A: δP  138 ppm; B: δP  155 ppm; C: δP  110 ppm).
Results and Discussion
First of all, a high efficient method to generate phosphonites is
required. Nucleophilic substitution of chlorophosphite,
Next, we turned our attention to investigate the feasibility of the
iodine-mediated
phosphonamidation
reaction
of
the
bis(dialkylamino)chlorophosphine or triethyl phosphite with
organolithium reagents or Grignard reagents has been
employed to prepare phosphonites.11,16 Since trialkyl phosphite
is readily available, cheap and stable, we decided to choose it
as phosphorus source. In 2011, Volle et al.16 optimized the
reaction of triethyl phosphite and Grignard reagent to prepare
phosphonites. However, when using their optimal conditions
phosphonites. The addition order of iodine and amine was found
to be crucial for the success of this reaction. When adding iodine
(1 equiv) and n-butyl amine 2a (2 equiv) sequentially to the
above phenyl phosphonite solution (1 equiv), no desired product
3a was detected (entry 1, Table 2). We speculated this was
probably because the residual Garignard reagent in the system
could react with iodine, preventing the formation of
iodophosphonate and making the subsequent reaction difficult to
happen (see the proposed mechanism shown in Scheme 4).
Gratifyingly, when the addition order was reversed, i.e. the
amine 2a was added to the phenyl phosphonite solution first,
stirred for about 5 minutes and then added iodine, the reaction
proceeded smoothly and the desired product 3a (δP: 22 ppm)
was obtained in excellent yield within one hour (entry 2, Table 2).
This was likely the presence of amine prior to addition of iodine
could destroy the residual Garignard reagent and the formation
of iodophosphonate could be accomplished in this reaction
environment. We then examined the effect of the amount of
iodine and 2a (entries 2–5, Table 2). The results demonstrated
that one equivalent of iodine and two equivalents of 2a were
necessary and sufficient. When changing the molar ratio of
phosphonite B to 2a from 1:2 to 1:1, one equivalent of additional
o
(ArMgBr/P(OR)3 = 1.5/1, 0.2 M in THF, 70 C, 5 h), we observed
a considerable amount of byproduct diphenylphosphinite
C
except for the desired product B (entry 1, Table 1). Further
studies showed that compounds A, B and C in the reaction
mixture could all react with iodine and amines, which made it
very difficult to purify the final product phophonamidates. A
series of examinations were herein conducted to optimize the
reaction. 31P NMR spectroscopy and TLC were used to monitor
the reaction process and some typical results were summarized
in Table 1.
As shown in Table 1, when decreasing the temperature to room
o
temperature (about 25 C), the desired reaction could take place
smoothly though at slower rate and the side reaction could be
largely suppressed (entries 1–3, Table 1). For the reaction of
P(OMe)3 at room temperature, prolonging the reaction time and
2
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10.1002/chem.202002934
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base such as Et3N was required to scavenge the formed
hydroiodic acid (entries 2, 5, Table 2). Further studies revealed
that the reaction completed within 0.5 hour and the extension of
the reaction time to 2 hours gave the same results (entries 2, 6,
7, Table 2).
while the aryl phosphonites with one or two electron-withdrawing
fluoro substituents gave the corresponding products 3r and 3s in
only 77 % and 64 % yields.
We also made some preliminary attempts to synthesize alkyl
phosphonamidates using this method. Unfortunately, under the
same conditions, the reactions of ethylmagnesium bromide and
ethynylmagnesium bromide with triethyl phosphite, iodine and
aniline resulted in complex systems and did not lead to the
desired phosphonamidates. We speculated that such results
might be related to the fact that alkyl phosphonites oxidize
rapidly compared to aryl phosphonites.11f Therefore, in order to
synthesize alkyl phosphonamidates by the present strategy, the
reaction conditions need to be further adjusted and explored.
Table 2 Synthesis of phosphonamidate 3a[a]
Entry
I2 (equiv)
2a (equiv)
Et3N (equiv)
Time (h)
Yield of 3a[b]
1
2
3
4
5
6
7
1
2
2
2
2
1
2
2
0
0
0
0
1
0
0
1
0[c]
90
90
79
90
90
90
1
1
1.2
0.8
1
1
1
1
1
2
1
0.5
[a] Reaction conditions unless otherwise specified: phoshonite B (1.0 mmol)
and 2a in THF (2.5 mL), was added I2 in THF (1 mL), and stirred under N2 at rt.
[b] Determined by 31P NMR on the reaction mixture. [c] To the solution of
phoshonite B was added I2 first and then 2a.
With these conditions in hand, we subsequently explored the
scope and limitations of this sequential procedure with different
amines and the results were summarized in Scheme 2. The
reaction exhibited excellent generality and functional tolerance.
The in situ formed phenyl phosphonite could react with various
amines at room temperature, leading to
a
series of
phosphonamidates in good to excellent yields. Both aliphatic
primary amines (i.e. n-butylamine, benzyl amine) and secondary
amines (i.e. piperidine, morpholine, diethylamine) worked well to
give 3a–3e in 77%–84% yields. All examined aromatic amines
proceeded the reaction smoothly, while the yields of the desired
products were affected by the electron nature of the substituents.
For example, aniline could react with phenyl phosphonite rapidly
and cleanly to afford 3f in 94 % yield. When there is an electron-
withdrawing group such as chloride and fluoride in the para
position of aniline, the yields of the products 3g and 3h
decreased to 75 % and 54 %, respectively. The amines bearing
a 4-cyano and 4-ester group could be successfully converted
into 3i and 3j though in relatively lower yields. The presence of a
hindered methyl group in the ortho position of aniline had no
apparent negative effect on the reaction and the target product
3k could be obtained in 80% yield. Moreover, fused ring
aromatic amines performed well, giving products 3l and 3m in
good yields.
Scheme 2. Substrate scope of amines. Conditions: 1a (4.0 mmol), Mg (4.0
mmol), P(OEt)3 (2.0 mmol) in THF (10 mL) was added 2 (4.0 mmol), I2 (2.0
mmol) in THF (2 mL). Isolated yields are given in parentheses.
This method can be conveniently extended to other aryl
bromides, leading to 3n–3s in good to excellent yields (Scheme
3). Under the standard conditions, the aryl phosphonites from
ortho-, meta-, and para-methyl-substituted aryl magnesium
bromides and triethyl phosphite could all transformed to the
target products 3n–3p in good yields, indicating the reaction is
not sensitive to steric hindrance. However, the electronic effect
of the substituents has some impacts on the reaction. The
reaction of aryl phosphonite bearing an electron-donating
methoxy group produced the desired product 3q in 95% yield,
Scheme 3. Substrate scope of aryl bromides. Conditions: 1 (4.0 mmol), Mg
(4.0 mmol), P(OEt)3 (2.0 mmol) in THF (10 mL) was added 2 (4.0 mmol), I2
(2.0 mmol) in THF (2 mL). Isolated yields are given in parentheses.
3
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on 200–300 mesh silica gel. Thin-layer chromatography was conducted
on a Kieselgel 60 F254. Compounds 3a, 3c, 3e and 3f are known
compounds; their identities are confirmed by 1H/ 13C/ 31P NMR spectra
which are consistent with the related literature.17-19 Other products are
new compounds; their structures are identified by their 11H, 13C, 31P and
19F NMR, HRMS and IR data.
Based on the above results and the literatures about the
formation of iodophosphate from Arbuzov reaction of trialkyl
phosphite with iodine,14 a plausible mechanism was proposed in
Scheme 4A. The reaction of iodine with arylphosphonite would
produce intermediate I, which could be attacked by iodide to
form iodophosphonate II (Arbuzov reaction). Nucleophilic attack
of iodophosphonte II by amines, with the elimination of HI, would
lead to phosphonamidates 3. To justify this mechanism, we
attempted to use oxygen nucleophiles rather than amines to
catch the key intermediate II. When the phenyl phosphonite
solution (1 equiv) was treated with substituted phenols (2 equiv),
triethyl amine (1 equiv) and iodine (1 equiv), two mixed
phosphonates 4a and 4b were obtained albeit in lower yields
(Scheme 4B), indicating that the present strategy involves an
iodophosphonate intermediate and has the potential to access
various phosphonyl compounds.
General procedure for the synthesis of 3: A solution of aryl bromide
(20 mmol) in THF (10 mL) was added dropwise to a suspension of Mg
turnings (20 mmol) in THF (10 mL) under nitrogen atmosphere. The
reaction mixture was stirred vigorously at reflux temperature at first until
the color of the mixture became gray-black, and then cooled to room
temperature with addition of the remaining aryl bromide slowly. The aryl
magnesium bromide solution in THF was herein obtained when the Mg
turnings disappeared and stored under nitrogen for further use. To a
solution of P(OEt)3 (2 mmol) in THF (6 mL) was added dropwise the
above aryl magnesium bromide solution (4 mL, about 4 mmol) at room
temperature over 5 to 10 min. The reaction mixture was stirred at room
temperature for 36 h and then was added the solutions of amine (2 mmol)
in THF (8 mL) and iodine (2 mmol) in THF (2 mL) successively. After
stirring at room temperature under nitrogen atmosphere for 60 min, the
reaction mixture was then evaporated in vacuo and the residue was
dissolved in CH2Cl2 (50 mL), washed with saturated with saturated NH4Cl,
brine, and then dried over anhydrous NaSO4. After removal of the solvent
in vacuo, the residue was purified by column chromatography on silica
gel with petroleum ether /EtOAc (10:1–1:1) as eluent to give the
corresponding product 3.
A. Proposed mechanism
I-
O
P
O
I
RR'NH
-HI
OEt
P
Ar
O
Et
Ar
EtO
Ar
P
NRR'
I
I
I
P
-EtI
OEt
-I-
Ar
OEt
OEt
3
I
II
B. Reactions of phenols with iodophosphonate intermediate
O
P
ROH
P(OEt)3
Mg
Ph
OR
ArMgBr
Ethyl N-butyl-P-phenylphosphonamidate (3a)17
PhBr
THF
r.t. 36 h
I2, THF
rt, 2 h
THF
OEt
4
Compound 3a was isolated (405 mg, 84% yield) as pale-yellow oil. 1H
NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 12.7, 7.4 Hz, 2H), 7.55–7.44 (m,
3H), 4.20–4.06 (m, 2H), 2.91–2.85 (m, 2H), 2.68 (br s, 1H), 1.51–1.41 (m,
2H), 1.37 (t, J = 7.0 Hz, 3H), 1.34–1.27 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H);
31P NMR (162 MHz, CDCl3) δ 22.67; 13C NMR (101 MHz, CDCl3) δ
131.71 (d, J = 2.9 Hz), 131.40 (d, J = 9.7 Hz), 131.06 (d, J = 173.1 Hz),
128.37 (d, J = 14.2 Hz), 60.49 (d, J = 5.6 Hz), 40.61, 33.88 (d, J = 6.2
Hz), 19.75, 16.43 (d, J = 6.7 Hz), 13.67.
1a
MeO
OMe
O
O
O
P
O
P
OEt
OEt
4a (42%)
4b (54%)
Ethyl N-benzyl-P-phenylphosphonamidate (3b)
Scheme 4. (A) Proposed mechanism. (B) Reactions of oxygen nucleophiles
Compound 3b was isolated (518 mg, 94% yield) as pale-yellow oil. IR
(KBr) 3210, 2981, 2929, 2902, 1439, 1204, 1130, 1039, 955 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.89–7.78 (m, 2H), 7.56–7.51 (m, 1H), 7.49–
7.44 (m, 2H), 7.33–7.24 (m, 5H), 4.16–4.04 (m, 4H), 3.20 (br s, 1H), 1.34
(td, J = 7.0, 2.8 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 22.32; 13C NMR
(101 MHz, CDCl3) δ 139.61 (d, J = 6.5 Hz), 131.86 (d, J = 2.8 Hz),
131.48 (d, J = 9.7 Hz), 130.79 (d, J = 172.8 Hz), 128.53 (d, J = 2.4 Hz),
128.37, 127.38, 127.30, 60.77 (d, J = 5.6 Hz), 44.88, 16.39 (d, J = 6.8
Hz). HRMS (ESI) m/z calculated for C15H18NO2P [M+H]+: 276.1153,
found: 276.1152.
with iodophosphonate intermediate.
Conclusions
In conclusion, we developed a simple and efficient method for
the synthesis of phosphonamidates via an one-pot sequential
procedure from readily available materials. Compared with
existing literature methods to phosphonamidates, the present
approach demonstrates several attractive features, including
cheap and easily available materials, mild conditions, high
efficiency, excellent functional tolerance and simple operation.
As the involving iodophosphonate intermediate has the potential
to react with various nucleophiles, this method will have wide
applications in the synthesis of not only phosphonamidates but
also other phosphonyl compounds.
Ethyl N,N-diethyl-P-phenylphosphonamidate(3c)17
Compound 3c was isolated (396 mg, 82% yield) as pale-yellow oil. 1H
NMR (400 MHz, CDCl3) δ 7.78–7.72 (m 2H), 7.54–7.35 (m, 3H), 4.22–
4.11 (m, 1H), 4.1–3.99 (m, 1H), 3.30–2.81 (m, 4H), 1.38 (t, J = 7.1 Hz,
3H), 1.07 (t, J = 7.1 Hz, 6H); 31P NMR (162 MHz, CDCl3) δ 23.03; 13C
NMR (101 MHz, CDCl3) δ 131.80 (d, J = 175.7 Hz), 131.31, 131.22,
128.25 (d, J = 14.1 Hz), 59.91 (d, J = 5.8 Hz), 38.86 (d, J = 4.9 Hz),
16.37 (d, J = 6.9 Hz), 14.16.
Ethyl phenyl(piperidin-1-yl)phosphinate (3d)
Experimental Section
Compound 3d was isolated (390 mg, 77% yield) as pale-yellow oil. IR
(KBr) 3408, 2977, 2738, 2537, 2437, 1632, 1441, 1196, 1136, 1045, 946
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.79–7.69 (m, 2H), 7.53–7.41 (m, 3H),
4.24–4.05 (m, 2H), 3.11–3.05 (m, 4H), 1.59–1.54 (m, 2H), 1.51–1.48 (m,
4H).1.39 (t, J = 7.1 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 21.69; 13C
NMR (101 MHz, CDCl3) δ 131.41 (d, J = 2.8 Hz), 131.18 (d, J = 9.5 Hz),
130.50 (d, J = 174.5 Hz), 128.29 (d, J = 14.1 Hz), 60.15 (d, J = 6.0 Hz),
44.92 (d, J = 2.5 Hz), 26.03 (d, J = 4.7 Hz), 24.56, 16.41 (d, J = 6.7 Hz);
General: The 1H, 13C, 31P and 19F NMR spectra were recorded on a
Varian INOVA 400 NMR instrument. All melting points were measured on
a
WRS-3 Melting Point Meter and were uncorrected. HRMS were
determined using an Agilent Technologies 6230 TOF LC/MS mass
spectrometer. IR spectra were recorded using KBr pellets on a Bruker
Equinox 55 FT/IR spectrometer. Column chromatography was performed
4
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10.1002/chem.202002934
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HRMS (ESI) m/z calculated for C13H20NO2P [M+H]+: 254.1310, found:
254.1313.
= 6.4 Hz); HRMS (ESI) m/z calculated for C15H15N2O2P [M+H]+: 287.0949,
found: 287.0952.
Ethyl morpholino(phenyl)phosphinate (3e)18
Ethyl P-phenyl-N-(o-tolyl)phosphonamidate (3k)
Compound 3e was isolated (398 mg, 78% yield) as pale-yellow oil. 1H
NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 12.7, 7.3 Hz, 2H), 7.58–7.45 (m,
3H), 4.35–4.03 (m, 2H), 3.69–3.62 (m, 4H), 3.15–3.11 (m, 4H), 1.42 (t, J
= 7.1 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 21.09; 13C NMR (101 MHz,
CDCl3) δ 132.10 (d, J = 9.8 Hz), 131.83 (d, J = 2.9 Hz), 131.28 (d, J = 9.4
Hz), 129.99 (d, J = 173.3 Hz), 128.50 (d, J = 14.1 Hz), 67.06 (d, J = 5.8
Hz), 60.63 (d, J = 5.9 Hz), 44.15, 16.44 (d, J = 6.6 Hz).
Compound 3k was isolated (440 mg, 80% yield) as white solid. Mp: 143–
145 °C. IR (KBr) 3154, 3080, 2984, 2897, 1583, 1501, 1217, 1131, 1026
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.87–7.81 (m, 2H), 7.55–7.41 (m, 3H),
7.11 (d, J = 7.5 Hz, 1H), 7.08–6.97 (m, 2H), 6.88–6.83 (m, 1H), 5.12 (s,
1H), 4.37–4.13 (m, 2H), 2.27 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H); 31P NMR
(162 MHz, CDCl3) δ 17.33; 13C NMR (101 MHz, CDCl3) δ 138.06, 132.22
(d, J = 2.9 Hz), 131.41 (d, J = 10.2 Hz), 130.63, 130.09 (d, J = 176.7 Hz),
128.56 (d, J = 14.8 Hz), 126.98, 125.35 (d, J = 9.2 Hz), 121.82, 117.25,
61.11 (d, J = 5.9 Hz), 17.82, 16.29 (d, J = 6.8 Hz); HRMS (ESI) m/z
calculated for C15H18NO2P [M+H]+:276.1153, found: 276.1159.
Ethyl N,P-diphenylphosphonamidate(3f)19
Compound 3f was isolated (491 mg, 94% yield) as white solid. Mp: 124–
3
125 °C (lit. 119−120 °C). 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J =
13.5, 8.0 Hz, 2H), 7.57–7.41 (m, 3H), 7.16 (t, J = 7.7 Hz, 2H), 6.95–6.87
(m, 3H), 6.50 (br s, 1H), 4.40–4.13 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H); 31P
NMR (162 MHz, CDCl3) δ 17.27; 13C NMR (101 MHz, CDCl3) δ 140.20,
132.17 (d, J = 3.0 Hz), 131.53 (d, J = 104.7 Hz), 131.41 (d, J = 10.3 Hz),
129.22, 128.55 (d, J = 14.8 Hz), 121.39, 117.48 (d, J = 6.5 Hz), 60.99 (d,
J = 6.2 Hz), 16.29 (d, J = 6.8 Hz).
Ethyl N-naphthalen-1-yl-P-phenylphosphonamidate(3l)
Compound 3l was isolated (442 mg, 71% yield) as white solid. Mp: 138–
139 °C. IR (KBr) 3151, 3056, 2980, 2929, 1576, 1518, 1469, 1210, 1131,
1037 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.3 Hz, 1H), 7.93–
7.81 (m, 3H), 7.58–7.47 (m, 4H), 7.46–7.39 (m, 2H), 7.29–7.20 (m, 2H),
5.87 (d, J = 5.1 Hz, 1H), 4.39–4.18 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H); 31P
NMR (162 MHz, CDCl3) δ 17.89; 13C NMR (101 MHz, CDCl3) δ 134.85,
134.29, 132.29 (d, J = 3.0 Hz), 131.57, 131.47, 129.87 (d, J = 177.2 Hz),
128.83, 128.64, 128.50, 126.06 (d, J = 3.5 Hz), 125.84, 122.66, 120.12,
114.38 (d, J = 2.7 Hz), 61.32 (d, J = 5.9 Hz), 16.33 (d, J = 6.7 Hz); HRMS
(ESI) m/z calculated for C18H18NO2P [M+H]+: 312.1153, found: 312.1166.
Ethyl N-(4-chlorophenyl)-P-phenylphosphonamidate(3g)
Compound 3g was isolated (319 mg, 54% yield) as pale-yellow oil. IR
(KBr) 3150, 3057, 2946, 2867, 1598, 1495, 1438, 1218, 1130, 1025, 750
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.90–7.81 (m, 2H), 7.56–7.42 (m, 3H),
7.13–7.09 (m, 2H), 6.90–6.86 (m, 2H), 6.70 (br s, 1H), 4.35–4.13 (m, 2H),
1.40 (t, J = 7.1 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 17.12; 13C NMR
(101 MHz, CDCl3) δ 138.91, 132.37 (d, J = 2.9 Hz), 131.36 (d, J = 10.3
Hz), 129.92 (d, J = 139.9 Hz), 129.17, 128.64 (d, J = 14.9 Hz), 126.47,
118.72 (d, J = 6.6 Hz), 61.13 (d, J = 6.1 Hz), 16.29 (d, J = 6.8 Hz); HRMS
Ethyl N-9H-fluoren-1-yl-P-phenylphosphonamidate(3m)
Compound 3m was isolated (440 mg, 63% yield) as white solid. Mp:
191–193 °C. IR (KBr) 3145, 3096, 2985, 2897, 1620, 1585, 1487, 1457,
1207, 1127, 1024 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.95–7.86 (m, 2H),
7.65 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.53–7.43 (m, 4H),
7.35–7.17 (m, 3H), 6.96 (dd, J = 8.2, 2.0 Hz, 1H), 6.16 (d, J = 5.9 Hz, 1H),
4.39–4.19 (m, 2H), 3.79 (s, 2H), 1.42 (t, J = 7.1 Hz, 3H); 31P NMR (162
MHz, CDCl3) δ 17.33; 13C NMR (101 MHz, CDCl3) δ 144.78, 142.60,
141.44, 139.07, 135.70, 132.24 (d, J = 3.0 Hz), 131.51, 131.41, 130.15 (d,
J = 176.9 Hz), 128.59 (d, J = 14.8 Hz), 126.71, 125.83, 124.83, 120.47,
119.08, 116.47 (d, J = 6.4 Hz), 114.52 (d, J = 6.5 Hz), 61.16 (d, J = 6.1
Hz), 36.93, 16.34 (d, J = 6.8 Hz); HRMS (ESI) m/z calculated for
(ESI) m/z calculated for
296.0614.
C
14H15ClNO2P [M+H]+: 296.0607, found:
Ethyl N-(4-fluorophenyl)-P-phenylphosphonamidate (3h)
Compound 3h was isolated (419 mg, 75% yield) as white solid. Mp: 123–
124 °C. IR (KBr) 3165, 3090, 2962, 2873, 1511, 1211, 1131, 1030 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.87–7.81(m, 2H), 7.56–7.51 (m, 1H), 7.47–
7.42 (m, 2H), 6.92–6.82 (m, 4H), 6.21 (d, J = 5.7 Hz, 1H), 4.36–4.14 (m,
2H), 1.40 (t, J = 7.1 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 17.47. 19F
NMR (376 MHz, CDCl3) δ -122.42; 13C NMR (101 MHz, CDCl3) δ 159.23,
136.09, 132.29 (d, J = 3.0 Hz), 131.41 (d, J = 10.2 Hz), 129.91 (d, J =
177.2 Hz). 128.60 (d, J = 14.7 Hz), 119.08, 115.83 (d, J = 22.6 Hz),
61.10 (d, J = 5.9 Hz), 16.29 (d, J = 6.7 Hz); HRMS (ESI) m/z calculated
for C14H15FNO2P [M+H]+: 280.0903, found: 280.0907.
C
21H20NO2P [M+H]+: 350.1310, found: 350.1319.
Ethyl N-benzyl-P-(p-tolyl)phosphonamidate (3n)
Compound 3n was isolated (469 mg, 81% yield) as pale-yellow oil. IR
(KBr) 3217, 3029, 2981, 2926, 1605, 1452, 1203, 1126, 1038, 958 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 12.7, 8.0 Hz, 2H), 7.40–7.19
(m, 7H), 4.18–4.00 (m, 4H), 3.08–3.02 (m, 1H), 2.42 (s, 3H), 1.33 (t, J =
7.1 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 22.96; 13C NMR (101 MHz,
CDCl3) δ 142.37 (d, J = 2.9 Hz), 139.66 (d, J = 6.8 Hz), 131.58 (d, J =
10.2 Hz), 129.20 (d, J = 14.7 Hz), 128.54, 127.36 (d, J = 175.6 Hz),
127.34 (d, J = 8.5 Hz), 60.72 (d, J = 5.5 Hz), 44.87, 21.62, 16.39 (d, J =
6.7 Hz); HRMS (ESI) m/z calculated for C16H20NO2P [M+H]+: 290.1310,
found: 290.1304.
Methyl 4-((ethoxy(phenyl)phosphoryl)amino)benzoate (3i)
Compound 3i was isolated (262 mg, 41% yield) as pale-yellow oil. IR
(KBr) 3151, 3055, 2955, 2881, 1712, 1609, 1516, 1258, 1032 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.90–7.83 (m, 4H), 7.54–7.42 (m, 3H), 7.08 (d,
J = 5.9 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 4.41–4.14 (m, 2H), 3.85 (s, 3H),
1.41 (t, J = 7.1 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 17.02; 13C NMR
(101 MHz, CDCl3) δ 166.78, 144.87, 132.52 (d, J = 3.0 Hz), 131.33 (d, J
= 10.4 Hz), 131.16, 129.47 (d, J = 179.6 Hz), 128.71 (d, J = 14.9 Hz),
122.96, 116.66 (d, J = 6.8 Hz), 61.34 (d, J = 6.2 Hz), 51.83, 16.26 (d, J =
6.6 Hz); HRMS (ESI) m/z calculated for C16H18NO4P [M+H]+: 320.1052,
found: 320.1049.
Ethyl N-benzyl-P-(m-tolyl)phosphonamidate (3o)
Compound 3o was isolated (434 mg, 75% yield) as pale-yellow oil. IR
(KBr) 3220, 2981, 2926, 1704, 1454, 1201, 1122, 1040, 958 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.70–7.58 (m, 2H), 7.41–7.23 (m, 7H), 4.18–
4.03 (m, 4H), 3.12–3.06 (m, 1H), 2.40 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H);
31P NMR (162 MHz, CDCl3) δ 23.03; 13C NMR (101 MHz, CDCl3) δ
142.37 (d, J = 3.0 Hz), 139.67 (d, J = 6.9 Hz), 131.63, 131.53, 129.28,
129.13, 128.54, 127.38, 127.35(d, J=176.14 Hz), 127.29, 60.72 (d, J =
5.5 Hz), 44.87, 21.62, 16.39 (d, J = 6.8 Hz); HRMS (ESI) m/z calculated
for C16H20NO2P [M+H]+:290.1310, found: 290.1313.
Ethyl N-(4-cyanophenyl)-P-phenylphosphonamidate (3j)
Compound 3j was isolated (218 mg, 38% yield) as pale-yellow oil. IR
(KBr) 3132, 3034, 2935, 2870, 2218, 1725, 1608, 1513, 1294, 1037 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J = 13.4, 7.6 Hz, 2H), 7.58 (t, J =
7.0 Hz, 1H), 7.53–7.40 (m, 5H), 7.01 (d, J = 7.2 Hz, 2H), 4.40–4.13 (m,
2H), 1.42 (t, J = 6.8 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 16.71; 13C
NMR (101 MHz, CDCl3) δ 144.81, 133.53, 132.79 (d, J = 2.4 Hz), 131.28
(d, J = 10.4 Hz), 129.12 (d, J = 179.4 Hz), 128.86 (d, J = 14.9 Hz),
119.17, 117.42 (d, J = 6.8 Hz), 104.22, 61.55 (d, J = 6.0 Hz), 16.27 (d, J
Ethyl N-benzyl-P-(o-tolyl)phosphonamidate(3p)
Compound 3p was isolated (446 mg, 77% yield) as pale-yellow oil. IR
(KBr) 3229, 3029, 2979, 2929, 1597, 1453, 1204, 1141, 1034, 955 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 13.8, 7.7 Hz, 1H), 7.43 (t, J =
5
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10.1002/chem.202002934
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FULL PAPER
7.5 Hz, 1H), 7.35–7.22 (m, 7H), 4.26–3.96 (m, 4H), 3.13–3.06 (m, 1H),
128.53 (d, J = 15.5 Hz), 99.17 (d, J = 4.6 Hz), 97.32, 62.95 (d, J = 5.8
2.64 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 22.17; Hz), 55.44, 16.34 (d, J = 6.5 Hz); HRMS (ESI) m/z calculated for
13C NMR (101 MHz, CDCl3) δ 141.70 (d, J = 10.6 Hz), 139.67 (d, J = 6.6
Hz), 133.22 (d, J = 9.5 Hz), 131.96 (d, J = 2.6 Hz), 131.40 (d, J = 14.1
Hz), 128.97 (d, J = 170.7 Hz), 128.56, 127.44, 127.31, 125.37 (d, J =
13.9 Hz), 60.52 (d, J = 5.7 Hz), 44.92, 21.31 (d, J = 3.9 Hz), 16.36 (d, J =
6.7 Hz); HRMS (ESI) m/z calculated for C16H20NO2P [M+H]+:290.1310,
found: 290.1306.
C16H19O5P [M+H]+: 323.1048, found: 323.1052.
Ethyl (2-isopropyl-5-methylphenyl) phenylphosphonate (4b)
Compound 4b was isolated (348 mg, 54% yield) as pale-yellow oil. IR
(KBr) 3483, 2965, 2930, 2871, 1507, 1441, 1259, 1131, 1090, 1038, 967
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.97–7.84 (m, 2H), 7.60–7.45 (m, 3H),
7.19–7.11 (m, 2H), 6.93 (d, J = 7.8 Hz, 1H), 4.37–4.10 (m, 2H), 3.33–
3.15 (m, 1H), 2.29 (s, 13H), 1.35 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 6.9 Hz,
3H), 1.12 (d, J = 6.9 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 14.90; 13C
NMR (101 MHz, CDCl3) δ 147.85 (d, J = 8.0 Hz), 136.57, 136.29 (d, J =
6.0 Hz), 132.64 (d, J = 2.9 Hz), 131.82 (d, J = 10.1 Hz), 128.58 (d, J =
13.4 Hz), 128.21 (d, J = 191.8 Hz), 126.38, 125.72, 120.84 (d, J = 2.5
Hz), 62.88 (d, J = 5.9 Hz), 26.55, 22.98 (d, J = 2.1 Hz), 20.91, 16.31 (d, J
= 6.5 Hz); HRMS (ESI) m/z calculated for C18H23O3P [M+H]+:319.1463,
Ethyl N-benzyl-P-(4-methoxyphenyl)phosphonamidate(3q)
Compound 3q was isolated (580 mg, 95% yield) as white solid. Mp: 59–
61 °C. IR (KBr) 3178, 2976, 2905, 2838, 1599, 1505, 1253, 1199, 1030
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 12.4, 8.7 Hz, 2H), 7.35–
7.25 (m, 5H), 7.01–6.94 (m, 2H), 4.19–4.01 (m, 4H), 3.87 (s, 1H), 3.02–
2.95 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ
23.09; 13C NMR (101 MHz, CDCl3) δ 162.49 (d, J = 3.3 Hz), 139.68 (d, J
= 6.7 Hz), 133.53 (d, J = 11.1 Hz), 128.56, 127.34 (d, J = 7.7 Hz), 127.03, found: 319.1464.
121.90 (d, J = 179.7 Hz), 113.98 (d, J = 15.3 Hz), 60.71 (d, J = 5.5 Hz),
55.32, 44.87, 16.40 (d, J = 6.8 Hz); HRMS (ESI) m/z calculated for
C16H20NO3P [M+H]+: 306.1259, found: 306.1259.
Acknowledgements
Ethyl N-benzyl-P-(4-fluorophenyl)phosphonamidate (3r)
This work was supported by Key Laboratory of Synthetic
Chemistry of Natural Substances, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences.
Compound 3r was isolated (452 mg, 77% yield) as pale-yellow oil. IR
(KBr) 3206, 2982, 2928, 2903, 1594, 1500, 1453, 1212, 1162, 1036, 957
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.88–7.77 (m, 2H), 7.38–7.21 (m, 5H),
7.17–7.10 (m, 2H), 4.19–3.99 (m, 4H), 3.32–3.25 (m, 1H), 1.33 (t, J = 7.0
Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 21.36; 19F NMR (376 MHz, CDCl3)
δ -107.02; 13C NMR (101 MHz, CDCl3) δ 166.25 (d, J = 3.7 Hz), 163.74
(d, J = 3.7 Hz), 139.44 (d, J = 6.4 Hz), 134.03 (dd, J = 11.1, 8.7 Hz),
128.57, 127.36 (d, J = 2.1 Hz), 126.92 (dd, J = 176.9, 3.4 Hz), 115.70 (dd,
J = 20.7, 15.4 Hz), 60.83 (d, J = 5.6 Hz), 44.87, 16.37 (d, J = 6.7 Hz);
HRMS (ESI) m/z calculated for C15H17FNO2P [M+H]+: 294.1059, found:
294.1064.
Keywords: Arbuzov reaction• iodine• phosphonamidates•
phosphonites • phosphonates
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Ethyl N,P-bis(4-fluorophenyl)phosphonamidate (3s)
Compound 3s was isolated (380 mg, 64% yield) as white solid. Mp: 85–
87 °C. IR (KBr) 3172, 2987, 2962, 2871, 1594, 1511, 1392, 1258, 1128,
1036 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.90–7.78 (m, 2H), 7.17–7.11 (m,
2H), 6.89–6.87 (m, 4H), 4.35–4.13 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H); 31P
NMR (162 MHz, CDCl3) δ 16.12; 19F NMR (376 MHz, CDCl3) δ -105.84, -
121.83; 13C NMR (101 MHz, CDCl3) δ 166.47 (d, J = 3.9 Hz), 163.95 (d, J
= 4.0 Hz), 159.33, 156.94, 134.02 (dd, J = 11.7, 8.9 Hz), 125.93 (dd, J =
181.2, 3.0 Hz), 119.13, 116.00 (dd, J = 22.0, 15.3 Hz), 61.23 (d, J = 5.9
Hz), 16.28 (d, J = 6.7 Hz); HRMS (ESI) m/z calculated for C14H14F2NO2P
[M+H]+: 298.0808, found: 298.0811.
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General procedure for the synthesis of 4: The procedure is similar to
the synthesis of compounds 3 except that the starting material amine
was replaced by the phenols. To a solution of the in situ prepared phenyl
phosphonite (2 mmol) in THF (6 mL) was added the solutions of the
corresponding substituted phenol (4 mmol) in THF (8 mL), triethyl amine
(2 mmol) and iodine (2 mmol) in THF (2 mL) successively. After stirring at
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CH2Cl2 (50 mL), washed with saturated with saturated NH4Cl, brine, and
then dried over anhydrous NaSO4. After removal of the solvent in vacuo,
the residue was purified by column chromatography on silica gel with
petroleum ether /EtOAc (10:1–1:1) as eluent to give the corresponding
product 4.
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3,5-Dimethoxyphenyl ethyl phenylphosphonate (4a)
Compound 4a was isolated (267 mg, 42% yield) as pale-yellow oil. IR
(KBr) 3448, 2962, 2932, 2844, 1599, 1475, 1438, 1261, 1204, 1155,
1135, 1058, 1037 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.99–7.82 (m, 2H),
7.63–7.56 (m, 1H), 7.53–7.47 (m, 2H), 6.37–6.35 (m, 2H), 6.26–6.24 (m,
1H), 4.38–4.19 (m, 2H), 3.74 (s, 6H), 1.39 (t, J = 7.1 Hz, 3H); 31P NMR
(162 MHz, CDCl3) δ 15.35; 13C NMR (101 MHz, CDCl3) δ 161.16, 152.09,
135.93 (d, J = 192.7 Hz), 132.79 (d, J = 3.0 Hz), 131.98 (d, J = 10.2 Hz),
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10.1002/chem.202002934
Chemistry - A European Journal
FULL PAPER
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10.1002/chem.202002934
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An iodine-mediated one-pot sequential phosphonoamidation of phosphonites with amines is developed. A variety of
phosphonamidates were obtained from easily available starting materials with good to excellent yields under mild conditions.
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