An efficient synthesis of phosphoramidates from halides in aqueous ethanol

Article abstract of DOI:10.1016/j.tetlet.2016.05.003

An environment friendly and efficient synthesis of primary phosphoramidates has been developed from benzyl/allyl/alkyl/propargyl halides in aqueous ethanol as a green reaction medium via in-situ formation of azide. The method is simple, metal free and high yielding at room temperature with wide substrate scope and functional group compatibility. The optimized protocol can be used for synthesis of phosphoramidate intermediates used as prodrug moieties to improve therapeutic potential of the parent drug.

Full text of DOI:10.1016/j.tetlet.2016.05.003

Accepted Manuscript
An efficient synthesis of phosphoramidates from halides in aqueous ethanol
N.A. Dangroo, A.A. Dar, R. Shankar, M.A. Khuroo, P.L. Sangwan
PII:
S0040-4039(16)30500-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.003
TETL 47617
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 March 2016
30 April 2016
2 May 2016
Please cite this article as: Dangroo, N.A., Dar, A.A., Shankar, R., Khuroo, M.A., Sangwan, P.L., An efficient
synthesis of phosphoramidates from halides in aqueous ethanol, Tetrahedron Letters (2016), doi: http://dx.doi.org/
10.1016/j.tetlet.2016.05.003
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N. A. Dangroo, A. A. Dar, R. Shankar, M. A. Khuroo, P. L. Sangwan

1
Tetrahedron Letters
An efficient synthesis of phosphoramidates from halides in aqueous ethanol
N. A. Dangroo,a A. A. Dar,a R. Shankar,a M. A. Khuroo, b and P. L. Sangwana,*
a Bio-organic Chemistry Division, CSIR-Indian Institute of Integrative Medicine Jammu Tawi-180001, India
b Department of Chemistry, University of Kashmir, Srinagar-190006, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An environment friendly and efficient synthesis of primary phosphoramidates has been
developed from benzyl/allyl/alkyl/propargyl halides in aqueous ethanol as a green reaction
medium via in-situ formation of azide. The method is simple, metal free and high yielding at
room temperature with wide substrate scope and functional group compatibility. The optimized
protocol can be used for synthesis of phosphoramidate intermediates used as prodrug moieties to
improve therapeutic potential of the parent drug.
Available online
Keywords:
Phosphoramidates
Menthol
2009 Elsevier Ltd. All rights reserved.
Aqueous ethanol
1. Introduction
phosmidosine,5 and GS-6620.10 They also form important
pharmacophore of many biologically potent compounds e.g.
Phosphoramidates have gained considerable interest from last
few decades as they have various applications in different area of
medicinal chemistry. They have been used in enantioselective
Lewis base activated catalytic conversion such as Aldol and
allylation reactions.1 In addition to catalytic applications, N-
arylphosphoramidates have been used as precursors for the
synthesis of various heterocycles such as azetidines, aziridines,
quinazolinediones and imines.2,3 Beside this, they are also used to
synthesize phosphate esters in nucleotides chemistry.4 In
analytical chemistry, phosphor-ramidates improve ionization
efficiency and suppress matrix related ion effects in MALDI-
TOF mass spectrometry.5 McGuigan et al. (1992) reported that
phosphoramidates can be used as prodrug moieties to improve
therapeutic potential of the parent drug.6 Phosphoramidates serve
as surrogates for amide bond in the synthesis of peptide based
protease inhibitors7 as well as represents some key structure in a
number of biologically active natural products like agrocin 84,8
sofosbuvir (FDA approved drug) used for the treatment of
hepatitis C virus (HCV),11 evofosfamidum (TH-302) which is in
clinical trials for cancer treatment (Fig. 1).12 Recently,
phosphoramidates have also been used in the field of plant
hormone as abscisic acid agonists that play role in plant growth
regulators.13
Owing to their great utility and potential applications in
different area of chemistry particularly in pharmaceutical arena,
spectacular interest has been paid for the development of new
and efficient method for the synthesis of phosphoramidates. A
number of classical strategies employed for the synthesis of
phosphoramidates, including (i) the reaction of amines with
suitable phosphoryl halide,10 (ii) reaction of amines with
phosphoryl chloride generated in situ by halogenation of H-
phosphonate with carbon tetrachloride,14 (iii) iodine catalyzed
oxidation of phosphite triesters in the presence of excess butyl
amine (250 equiv).15 In addition to above, phosphoramidates
were also synthesized through oxidative coupling of amines and
H-phosphonates using Cu(I), Ir(III) and I2 recently16 (Scheme 1).
Figure 1. Some representative bioactive phosphoramidates
Corresponding author
Scheme 1. Synthesis of phosphoramidates
E-mail address: plsangwan@iiim.ac.in (PL Sangwan)

2
Tetrahedron
2. Result and Discussion
A series of solvents were screened for the model reaction and
interestingly, it was observed that rate of conversion completely
depends on the nature of solvents (Table 1). In non polar solvents
like benzene, toluene and xylene, poor yields were obtained with
incomplete substrate conversion even after a long reaction time
(48 h or more) at room temperature (Table 1, entries 1-3). In
polar solvents like DMF, DMSO, THF, acetonitrile and methanol
moderate yields were obtained (60-67%) with incomplete
substrate conversion even if reaction time was extended at room
temperature (Table 1, entries 4-8). In case of DMF and DMSO
side products were formed due to prolonged reaction time as
reported in the litrature.19 Further these solvents require higher
temperature for complete substrate conversion because of poor
solubility of sodium azide, but at high temperature alkyl
bromides are known to undergo an Arbuzov type reaction20 to
form phosphonates without forming our desired product. The
literature supports various reactions involving NaN3 can be
performed in water as a reaction medium,21 so we contemplate
that mixture of water miscible solvents could be a better reaction
medium and at the same time perform the reaction in two
steps/one pot manner to avoid the side reactions. In view of this,
various combinations of miscible polar solvents (1:1) like DMF-
H2O, DMSO-H2O, THF-H2O, CH3CN-H2O, MeOH-H2O, EtOH-
H2O, acetone-H2O, and t-BuOH-H2O (Table 1, entries 9-16) were
examined and interestingly, the reaction proceed smoothly with
complete substrate conversion to give the desired product in
excellent yields in each solvent mixture with much shorter
reaction time at room temperature. Fascinatingly, the aqueous
solvents proved better for compensation of high temperature and
prolonged reaction time. Among the 50% aqueous alcohols,
EtOH: water was chosen as better reaction medium because of
lesser reaction time (4.5 h), better yield (94%) and ecofriendly.
The solvent effect was further confirmed by executing the
reaction using different proportion of ethanol: water i.e. EtOH:
water (1:3), EtOH: water (3:1) as well as only EtOH and water
separately (Table 1, entries 17-20). The use of water alone as
reaction medium produced poor yield even after employing a
prolonged reaction time due to very poor solubility of benzyl
halide (Table 1, entry 20) while in case of ethanol yield
comparatively equal to methanol with reduction in reaction
duration. Both the reaction rate and the yield were increased
gradually as the proportion of water increased upto the ratio of
ethanol : water (1:1). Therefore aqueous ethanol (1:1) was chosen
as the effective composition involving minimum use of organic
solvent with 94% overall yield of the desired product 1a in 4.5 h
of reaction time at room temperature (entry 14). By this
methodology desired products were obtained with clean and
complete conversion without any side product.
The major limitations associated with existing protocols
involve the use and handling of hazardous phosphoryl halides,
environmentally harmful organic solvents, toxic metal catalysts,
excessive use of reagents, harsh reaction conditions, expensive
anhydrous conditions and prolonged reaction time. In an
alternative approach, phosphoramidates could be synthesized by
coupling trialkyl phosphites and organic azides, which
circumvent the above said limitations and environmentally
benign nitrogen gas is the only by-product in the reaction.
However, this method relies on the preparation and use of
unstable and explosive organic azides in health hazardous
reaction medium.17 For economic and environmental concerns,
eco-compatible organic methodologies are being developed by
avoiding the use of toxic reagents and solvents in excess. Thus, it
would be highly desirable to synthesize primary phosphor-
ramidates in one pot under environmental friendly conditions, so
that isolation and reaction steps in process can be avoided.
Keeping in view the limitations of the earlier methods and our
interest in developing new, green and time shorting synthetic
methodologies,18 herein we report a green, mild, metal free and
efficient synthesis of primary phosphoramidates from alkyl
halides and trialkylphosphites. The method involves in situ
generation of organic azides and does not require excess and
toxic reagents.
At the onset of this work, the model reaction was performed
with benzyl bromide (1 eq), sodium azide (1.5 eq) and
triethylphosphite (1 eq) in DMF at room temperature produced
the desired product 1a with 67% yield in 20 h (Table 1, entry 4).
Encouraged by the catalyst free formation of desired product,
reaction conditions were optimized to improve yield in minimum
reaction time.
Table 1. Screening of various solvents for synthesis of
phosphoramidatesa
Entry Solvent/s
Yield (%)b
43
Time(h)
48
1
2
3
4
5
6
7
Benzene
Toluene
51
48
Xylene
54
48
DMF
67
20
DMSO
60
12
THF
67
12
MeCN
61
24
After optimization, scope of the developed protocol was
investigated for regioselective phosphoramidate synthesis of
various benzyl halides. First, the influence of the substitution
pattern at the benzyl bromide was studied. It was noticed that all
performed reactions were neat and clean affording the desired
products in excellent yields within reaction time limit (Table 2,
entries 1-7). The developed protocol was found compatible with
various substituted benzyl halide (Cl and Br) functionalities such
as Cl, Br, F, OCH3 and NO2. Benzyl bromides with electron
withdrawing substituents were found more reactive than electron
donating substituents (Table 2, entries 1-15). Reaction was also
carried out with bromo methyl substituted triazoles (Table 2,
entries 15-17) and afforded desired products in excellent yield. o-
Substituted benzyl halides (Table 2, entries 3, 4 and 6) were
found to react sluggishly and slightly lowered the yield in
contrast to p- and m- substituted benzyl halides. Beside this, it
8
9
MeOH
67
89
93
92
87
91
94
94
93
90
94
67
12
DMF - H2O (1:1)
DMSO - H2O (1:1)
THF - H2O (1:1)
MeCN - H2O(1:1)
MeOH - H2O (1:1)
EtOH - H2O (1:1)
Acetone - H2O (1:1)
t-BuOH - H2O (1:1)
EtOH - H2O (1:3)
EtOH - H2O (3:1)
EtOH
4.5
4.5
4.5
6
10
11
12
13
14
15
16
17
18
19
20
5
4.5
4.5
5
4.5
4.5
4.5
24
H2O
57
aAll the reactions were carried out using 1 eq of benzyl
bromide, 1.5 eq of NaN3 and 1 eq of triethylphosphite in 10 mL
of solvent/s.
bIsolated yield of the product.

3
was also observed that benzyl bromides reacted faster than the
corresponding chlorides since bromide is a good leaving group.
14
85
Table 2. Synthesis of various phosphoramidate (1a-1o)
15
16
92
90
93
Entry
1
Substrate
Product
Yield
(%)a
94
96
87
91
17
2
3
4
aIsolated yield of the product.
Efforts were made for further extension of the developed
protocol using allyl and propargyl halides (Table 3). In case of
allyl and propargyl halides the reaction proceeded smoothly and
the desired products were formed in excellent yields (Table 3,
entries 1-7), but required slightly longer reaction time. However,
in case of alkyl bromides the desired phosphoramidates were
formed at higher temperature with relatively lower yields (Table
2, entries 6 & 7). Triethylphosphite showed slightly better
reactivity than the corresponding trimethylphosphite.
5
6
89
91
Table 3. Synthesis of various phosphoramidate of aliphatic
halides (1p-1u)
Entry
Substrate
Product
Yield (%)a
71
7
92
87
90
93
1
8
73
70
63
2
3
4
9
10
11
12
89
88
60
55
5
6
52
7
13
86
aIsolated yield of the product.

4
Tetrahedron
4. General experimental procedure:
Keeping in mind the applications of phosphoramidates in
In a typical procedure, the substrate benzyl halide (1
mmol) and NaN3 (1.5 mmol) were taken in round bottom
flask containing ethanol-water (1:1) (10 mL). The resulting
solution was stirred at room temperature till the starting
material was completely consumed (monitored by TLC).
Trialkyl phosphite (1 mmol) was added to the flask and
further stirred till the completion of reaction as monitored by
TLC. After completion of reaction, Ethanol was evaporated
in the reaction mixture and diluted with water. Aqueous
reaction mixture was extracted with EtOAc. Combined
organic layer was concentrated on rotavapour under reduced
pressure, crude reaction mixture was purified on silica gel
(60-120) column chromatography using chloroform and
methanol as eluting solvents. The purified compounds were
various fields like pharmaceuticals and agro-pharmaceuticals, the
developed methodology was applied on natural products for
being our area of interest to carry out structural modification of
bioactive natural products for better potency with least toxicity. 22
Natural product (NP) (−)-menthol was taken as a model substrate
for preparation of its phosphoramidate 3 through formation of
intermediate 2 of the parent molecule (Scheme 2).23 In view of
this, the reaction of intermediate 2 under optimized conditions
afforded the desired phosphoramidate 3 with excellent yield
(90%). The result of this reaction recommends that the present
methodology can be used for preparation of biological active
natural product derived phosphoramidates.
1
characterised by spectroscopic techniques i.e. H NMR, 13C
NMR, IR and HRMS. Spectroscopic data of all the
1
synthesised products along with H NMR, 13C NMR spectra
are provided in supporting information while the data of
compound
3 is given below.
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-2-
((dimethoxy phosphoryl)amino) acetate (3); Colour less
oil; IR (cm-1, CHCl3 soln): 3384, 2955, 2927, 1746, 1458,
1255, 1035 and 834; 1HNMR (400 MHz, CDCl3) δ 4.66 (m,
1H), 3.57-3.66 (m, 8H), 3.35 (m, 1H), 1.90 (d, J = 11.2 Hz, 1H),
1.80 – 1.69 (m, 1H), 1.60 (d, J = 11.3 Hz, 2H), 1.40 (bs, 1H),
1.30 (t, J = 11.3 Hz, 1H), 0.94 (dt, J = 38.7, 13.4 Hz, 2H), 0.84
(d, J = 16.4 Hz, 6H), 0.67 (m, 3H). 13C NMR (100 MHz, CDCl3)
δ 169.41 (d, J = 6.4 Hz), 74.02, 51.83 (2x OCH3), 45.74, 41.72,
39.58, 32.91, 30.15, 24.99, 22.20, 20.72, 19.45, 15.06. 31PNMR
Scheme 2. Synthesis of Phosphoramidate of (-)-menthol
A comparison with existing methodologies, the developed
method offers a better alternative for the synthesis of benzyl,
allyl, alkyl, and propargyl phosphoramidates in terms of yield,
reaction time and eco-compatibility.24 Additionally, various
allylic phosphoramidates synthesized by this route could be
subjected to thermal [3, 3]-sigmatropic intra-molecular
rearrangement, leading to the selective N–C bond formation to
synthesize different types of products depending upon the proper
choice of substituents on the substrates.25 Further, the
standardized procedure offers significant green advantages,
avoiding purification and handling of hazardous organic azides
involving their in-situ formation. Use of eco-friendly and
biodegradable aqueous as a reaction medium makes the protocol
more attractive by avoiding the use of toxic organic solvents.
(160 MHz, CDCl3)
δ 10.57; HRESIMS m/z calcd for
C14H28NO5P [M+H]+ 322.0147, found 322.0154.
Acknowledgments
Authors (NAD) thank to Council of Scientific and Industrial
Research (CSIR-UGC), New Delhi for the award of senior
research fellowship. Staff of instrumentation division of our
institute is well acknowledged for recording the spectroscopic
data. This research was supported by a grant from the CSIR 12th
five-year project BSC0108.
Based on the previous mechanistic reports and controlled
experiment,26 the first step may involve the nucleophilic attack of
(-N3) on halide to form azide 4 which upon reaction with trialkyl
phosphite losses N2 to form phosphorimidate 5 which finally
rearranges to final products 1a-u (Scheme 3).
Supplementary Material
Complete experimental details and characterization data for all
products. This material is available free of charge via the Internet
References and notes
Scheme 3. Plausible mechanism for the synthesis of
phosphoramidates
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An eco-friendly and efficient synthesis has been developed for
the synthesis of primary phosphoramidates using simple azide
precursors like benzyl, allyl, alkyl and propargyl halides in
EtOH-H2O (1:1) as a green reaction medium. Operational
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6
Tetrahedron
Research highlights
Efficient synthesis of primary
phosphoramidates.
Aqueous ethanol as a green reaction
medium
The methodology was applied on natural
products to carry out structural .