Benign synthesis of thiophosphates, thiophosphinates and selenophosphates in neat condition using N-chalcogenoimides as the source of electrophilic sulfur/selenium

Article abstract of DOI:10.1016/j.tetlet.2019.150965

A neat reaction protocol has been developed for synthesis of thiophosphate, thiophosphinate and selenophosphate compounds. N-chalcogenoimides have been used for chalcogenylation of P(O)H moieties of various H-phosphonates under solvent, catalyst and base free condition at room temperature in aerial atmosphere. Both S-aryl and S-alkyl phosphorothioate compounds were prepared by this method in good yields. Selenophosphates were also synthesized using N-(phenylseleno)phthalimide under solvent free condition.

Full text of DOI:10.1016/j.tetlet.2019.150965

Accepted Manuscript
Benign synthesis of thiophosphates, thiophosphinates and selenophosphates in
neat condition using N-chalcogenoimides as the source of electrophilic sulfur/
selenium
Manas Mondal, Amit Saha
PII:
S0040-4039(19)30716-6
https://doi.org/10.1016/j.tetlet.2019.150965
150965
DOI:
Article Number:
Reference:
TETL 150965
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 June 2019
18 July 2019
19 July 2019
Please cite this article as: Mondal, M., Saha, A., Benign synthesis of thiophosphates, thiophosphinates and
selenophosphates in neat condition using N-chalcogenoimides as the source of electrophilic sulfur/selenium,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.150965
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Benign synthesis of thiophosphates,
Leave this area blank for abstract info.
thiophosphinates and selenophosphates in
neat condition using N-chalcogenoimides as
the source of electrophilic sulfur/selenium
Manas Mondal and Amit Saha*
O
O
P
O
P
R1
R1
R1
R1
Neat
XR2
R2X
N
H
+
RT, air
Yield 83-91%
O
Solvent Free
Catalyst Free
Base Free
R1 = OEt, OiPr, Ph
X = S, Se

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Benign synthesis of thiophosphates, thiophosphinates and selenophosphates in neat
condition using N-chalcogenoimides as the source of electrophilic sulfur/selenium
Manas Mondala and Amit Sahaa, 
aDepartment of Chemistry, Jadavpur University, Kolkata 700032, India
———
ARTICLE INFO
ABSTRACT
 Corresponding author. e-mail: amit.saha@jadavpuruniversity.in (A. Saha)
Article history:
Received
A neat reaction protocol has been developed for synthesis of thiophosphate, thiophosphinate and
selenophosphate compounds. N-chalcogenoimides have been used for chalcogenylation of
Received in revised form
Accepted
Available online
P(O)H moieties of various H-phosphonates under solvent, catalyst and base free condition at
room temperature in aerial atmosphere. Both S-aryl and S-alkyl phosphorothioate compounds
were prepared by this method in good yields. Selenophosphates were also synthesized using N-
(phenylseleno)phthalimide under solvent free condition.
Keywords:
2009 Elsevier Ltd. All rights reserved.
Neat condition
Thiophosphate
Selenophosphate
N-thioimide
Introduction
Thiophosphates are having widespread applications as pesticides [1], insecticides [2], enzyme modifiers [3] and therapeutic agents
such as HIV-1, AChE inhibitors [4]. Thiophosphate and selenophosphate compounds also offer valuable reaction intermediates in
organic syntheses [5]. Various methodologies have been developed to prepare this important class of compounds. However, in most of
the cases the syntheses of thiophosphates [6, 7, 8b - 8e] and selenophosphates [8] were carried out using different organic solvents as
the reaction media. To minimize the chemical hazards of a synthetic procedure, it is essential to reduce the usage of toxic organic
solvents. Thus, it is now desirable to cultivate benign solvent free reaction conditions for synthesis of thiophosphate compounds. A
microwave assisted solvent free reaction was reported by Kaboudin et. al. for the synthesis of thiophosphates using elemental sulfur and
O
O
O
1
1
alkyl halides/tosylates [7d] in presence of triethylamine and acidic alumina. Iodine catalyzed, aqueous H2O mediated thioarylation of
2 Neat
R
R
R X N
2ditio
P
XR2
on n using diaryl disulfide and excess of H-
P
H
+
various H-phosphonates were carried out by Wu and coworkers [7b] under solvent free c
R1
R1
RT
phosphonates. Zhan et.al. [6c] recently reported a neat reaction protocol to produce thiophosphates by the reaction of organic disulfides
O
with silyl phosphites. However, a more generalized and benign protocol is needed to be developed for the synthesis of various
R1 = OEt, OiPr, Ph
phosphorothioate and phosphoroselenoate compounds. In our current study, we have accomplished the synthesis of
phosphorothioate/selenoate compounds in neat reaction medium at room temperature under open aerial atmosphere. Earlier we have
X = S, Se
used N-thioimides and N-selenoimide to prepare mixed disuldfide [9a] and diorganyl selenide [9b] compounds respectively. Here, we
have employed N-thioimides and N-selenoimide for chalcogenylation of phosphites under neat reaction condition. Thiophosphate,
thiophosphinate and selenophosphate compounds were prepared efficiently in an environmentally benign room temperature condition
without using any metal, catalyst, base, and solvent (scheme 1).
Scheme 1. Synthesis of chalcogenophosphates under neat reaction condition

2
Tetrahedron Letters
Results and discussion
The reaction is easy to handle and proceeds under mild condition. A mixture of dialkyl phosphite and N-thioimide was stirred at
room temperature in neat condition under aerial atmosphere until completion of the reaction (monitored by TLC).
o
In our first attempt, the thiophenylation of diethyl phosphite was tried using N-thiophenyl phthalimide in DMF solvent at 80 C
(entry 1, Table 1). However, the reaction was not very clean and desired product was formed along with some unidentified side
products. The reaction in DMF solvent produced the thiophosphate product in improved yield (63%) at room temperature (RT) (entry 2,
Table 1). The reactions in other solvents like THF, DMSO, MeCN and toluene (entries 3 - 6, Table 1) also did not produce the product
in satisfactory yield.
Table 1
Optimization of the reaction condition
O
O
P
O
P
EtO
EtO
solvent
EtO
EtO
SPh
PhS
N
+
H
O
entry solvent
temp. (oC) time
yield (%)
48
DMF
1
4 h
4 h
80
2
DMF
RT
63
3
4
THF
RT
RT
RT
4 h
4 h
4 h
57
69
DMSO
MeCN
5
6
60
45
Toluene
RT
RT
4 h
7
neat
40 min
86
8
9
neat
H2O
30 min
4 h
RT
RT
72
-
Reaction condition: A mixture of N-(phenylthio)phthalimide (1 mmol) and diethyl phosphite (1 mmol) in 4 ml of solvent was stirred
in aerial atmosphere for certain time period. Yields reported are the isolated yields.
The reaction did not proceed at all in water medium (entry 9, Table 1). Surprisingly, when the reaction was carried out in neat condition
the desired thiophosphate was obtained in good yield (86%) within 40 min of time period at room temperature (entry 7, Table 1).
Increasing the reaction time period beyond 40 min did not improve the yield of the product.
The optimized reaction condition was then explored to prepare a series of phosphorothioate/thiophosphinate compounds using N-
thioimides (2) as the source of sulfur. Various S-aryl thiophosphates (3a - 3c, 3g, 3j, 3n, 3o) and S-aryl thiophosphinate (3k) were
prepared using N-(phenylthio)phthalimide (entries 1 and 10, Table 2), N-(p-methoxyphenylthio)phthalimide (entries 2, 7 and 11, Table
2), N-(p-chlorophenylthio)phthalimide (entry 3, Table 2), N-(p-fluorophenylthio)phthalimide (entry 14, Table 2) and N-(p-t-
butylphenylthio)phthalimide (entry 15, Table 2) in good yields under the neat reaction condition. Thioalkylations were also carried out
under the similar reaction condition using N-(ethythio)succinimide (entry 4, Table 2), N-(octylthio)succinimide (entries 5, 8 and 12,
Table 2) and N-(benzylmercapto)succinimide (entries 6, 9 and 13, Table 2) to produce desired S-alkyl thiophosphates (3d - 3f, 3h, 3i)
and S-alkyl thiophosphinates (3l, 3m). Diethyl phosphite, diisopropyl phosphite and diphenylphosphine oxide were successfully
employed in the synthesis of phosphorothioate/thiophosphinate compounds.
We also tried the synthesis of selenophosphate compounds under the similar reaction condition. Phenylselenylations of diethyl
phosphite and diisopropyl phosphite were carried out
Table 2
Synthesis of various thiophosphate and thiophosphinate compounds
O
1O
P
R1
O
P
R
R1
R1
Neat
RT
R2S
N
SR2
+
H
O
3
1
2
R1
time (min)
yield (%)
N-thioimide
product
entry
O
N
O
OEt
40
86
1
PhS
PhS P(OEt)2
3a
O
O
O

3
Reaction condition: A mixture of N-thioimide (2) (1 mmol) and R1 P(O)H (1) (1 mmol) was stirred at room temperature in aerial
2
atmosphere for certain time period. Yields reported are the isolated yields.
efficiently using N-(phenylseleno)phthalimide under the solvent free condition (Scheme 2). N-(phenylseleno)phthalimide plays the role
of electrophilic selenium donor in presence of phosphorous nucleophiles like dialkyl phosphites at room temperature under the neat
reaction condition in aerial atmosphere.
Scheme 2. Phenylselenylation of dialkyl phosphites
Conclusions
In conclusion, this is a convenient and general method to prepare structurally variable thiophosphate/thiophosphinate compounds.
The neat reaction protocol also works satisfactorily for synthesis of selenophosphates. All the reactions were performed at room
temperature under solvent free condition without using any catalyst, base or additive. The reactions do not require any sophisticated
inert reaction set up. Thus, the described method offers an environmentally friendly route to prepare phosphorothioate/thiophosphinate
and phosphoroselenoate compounds.

O
O
OEt
OEt
H
P(OEt)2
, 45 min
, 40 min
PhSe
P
O
4a
, 85%
Neat
4
Tetrahedron Letters
PhSe
N
O
RT, air
Acknowledgments
O
H
P(OiPr)2
OiPr
OiPr
O
PhSe
P
We are pleased to acknowledge the financial support from UGC-
BSR Start-up-grant (FD Diary No.4855; Dated: 24.09.2018). UGC-
4b
, 87%
CAS program in Chemistry, Jadavpur University and the DST-PURSE Program at Jadavpur University are also acknowledged.
Supplementary data
Supplementary data to this article can be found online
References
[1] (a) C. Fest and K.-J. Schmidt, The chemistry of organophosphorus pesticides, Springer Science & Business Media, 2012;
(b) N. N. Melnilkov, Chemistry of Pesitcides, Springer-Verlag, New York, 1971;
(c) D. P. Braithwaite, Nature 200 (1963) 1011;
(d) W. R. Morton, S. M. Drance, M. Fairclough, Am. J. Ophthalmol. 68 (1969) 1003;
(e) L. D. Quin, A Guide to Organophosphorus Chemistry, Wiley, New York, 2000.
[2] (a) D. K. Myers, B. Mendel, H. R. Gersmann, J. A. A. Ketelaar, Nature 170 (1952) 805;
(b) C. W. Berger, Jr., L. G. Sultatos, Fundam Appl Toxicol. 37 (1997) 150;
(c) M. C. Dutt, P. H. Seow, J. Agric. Food Chem. 11 (1963) 467.
[3] (a) K. A. Hassall, The Biochemistry and Uses of Pesticides, 2nd ed.; VCH: Weinheim, 1990, 269–275.
(b) M. Fukuoka, S. Shuto, N. Minakawa, Y. Ueno, A. Matsuda, J. Org. Chem. 65 (2000) 5238.
[4] (a) A. Kaboudin, S. Emadi, A. Hadizadeh, Bioorg. Chem. 37 (2009) 101;
(b) L. L. Murdock, T. L. Hopkins, J. Agric. Food Chem., 16 (1968) 954;
(c) B. T. Gabelt, E. A. Hennes, J. L. Seeman, B. Tian, P. L. Kaufman, Invest. Ophthalmol. Vis. Sci. 45 (2004) 2732;
(d) T. Kalebic, P. S. Schein, AIDS Res. Hum. Retroviruses. 10 (1994) 727;
(e) J. A. Fraietta, Y. M. Mueller, D. H. Do, V. M. Holmes, M. K. Howett, M. G. Lewis, A. C. Boesteanu, S. S. Alkan, P. D. Katsikis, Antimicrob.
Agent Chemother. 54 (2010) 4064.
[5] (a) M. Piekutowska, Z. Pakulski, Carbohydr. Res. 343 (2008) 785;
(b) C. Lopin, G. Gouhier, A. Gautier, S.R. Piettre, J. Org. Chem. 68 (2003) 9916;
(c) M. Piekutowska, Z. Pakulski, Tetrahedron Lett. 48 (2007) 8482;
(d) L.-B. Han, N. Choi, M. Tanaka, J. Am. Chem. Soc. 118 (1996) 7000;
(e) A. Toy, E. N. Walsh, Phosphorus Chemistry in Everyday Living, 2nd ed.; American Chemical Society: Washington DC, 1987, Chap. 18;
(f) L. D. Quin, A Guide to Organophosphorus Chemistry; Wiley: New York, 2000.
[6] (a) Y.-J. Ouyang, Y.-Y. Li, N.-B. Li, X.-H. Xu, Chin. Chem. Lett. 24 (2013) 1103;
(b) S. Torii, N. Sayo, H. Tanaka, Chem. Lett. 9 (1980) 695;
(c) Z. Zhan, Z. Yang, D. Ma, H. Zhang, Y. Shi, Q. Wang, Y. Deng, L. Hai, Y. Wu, ChemSusChem 11 (2018) 1426;
(d) L. Zhang, P. Zhang, X. Li, J. Xu, G. Tang, Y. Zhao, J. Org. Chem. 81 (2016) 5588;
(e) Y.-C. Liu, C.-F. Lee, Green Chem. 16 (2014) 357;
(f) S. Song, Y. Zhang, A. Yeerlan, B. Zhu, J. Liu, N. Jiao, Angew. Chem. Int. Ed. 56 (2017) 2487;
(g) B. Kaboudin, Y. Abedi, J.-y. Kato, T. Yokomatsu, Synthesis 45 (2013) 2323;
(h) Y. Moon, Y. Moon, H. Choia, S. Hong, Green Chem. 19 (2017) 1005;
(i) J. Bai, X. Cui, H. Wanga, Y. Wu, Chem. Commun. 50 (2014) 8860;
(j) J. Wang, X. Huang, Z. Ni, S. Wang, Y. Pan, J. Wu, Tetrahedron 71 (2015) 7853;
(k) J. Wang, X. Huang, Z. Ni, S. Wang, J. Wu, Y. Pan, Green Chem. 17 (2015) 314;
(l) S. Li, T. Chen, Y. Saga, L.-B. Han, RSC Adv. 5 (2015) 71544;
(m) C. Min, R. Zhang, Q. Liu, S. Lin, Z. Yan, Synlett 29 (2018) 2027;
(n) J. Xu, L. Zhang, X. Li, Y. Gao, G. Tang, Y. Zhao, Org. Lett. 18 (2016) 1266;
(o) Y. Zhu, T. Chen, S. Li, S. Shimada, L.-B. Han, J. Am. Chem. Soc. 138 (2016) 5825;

5
(p) H. Grounds, K. Ermanis, S. A. Newgas, M. J. Porter, J. Org. Chem. 82 (2017) 12735;
(q) L. Wang, S. Yang, L. Chen, S. Yuan, Q. Chen, M.-Y. He, Z.-H. Zhang, Catal. Sci. Technol. 7 (2017) 2356;
(r) R. D. Crocker, M. A. Hussein, J. Ho, T. V. Nguyen, Chem. Eur. J. 23 (2017) 6259;
(s) T. Liu, X. Cui, Z. Yu, C. Li, Phosphorus, Sulfur, and Silicon and the Related Elements 187 (2012) 606;
(t) S. Kovacs, B. Bayarmagnai, A. Aillerie, L. J. Gooßen, Adv. Synth. Catal. 360 (2018) 1913.
[7] (a) S. Torii, H. Tanaka, N. Sayo, J. Org. Chem. 44 (1979) 2938;
(b) X. –M. Wu, Y. –X. Hong, Lett. Org. Chem. 14 (2017) 49;
(c) C. E. Müller, H. J. Roth, Tetrahedron Lett. 31 (1990) 501;
(d) B. Kaboudin, F. Farjadian, Beilstein J. Org. Chem. 2 (2006) 4;
(e) J. Ash, H. Huang, J. Y. Kang, Org. Biomol. Chem. 17 (2019) 3812;
(f) W. He, X. Hou, X. Li, L. Song, Q. Yu, Z. Wang, Tetrahedron 73 (2017) 3133;
(g) X. Zhang, D. Wang, D. An, B. Han, X. Song, L. Li, G. Zhang, L. Wang, J. Org. Chem. 83 (2018) 1532.
[8] (a) S. Chen, J. Chen, X. Xu, Y. He, R. Yi, R. Qiu, J. Organomet. Chem. 818 (2016) 123;
(b) S. Mitra, S. Mukherjee, S. K. Sen, A. Hajra, Bioorg. Med. Chem. Lett. 24 (2014) 2198;
(c) Q. Xu , C.-G. Liang, X. Huang, Synth. Commun. 33 (2003) 2777;
(d) J. Wang, X. Wang, H. Li, J. Yan, J. Organomet. Chem. 859 (2018) 75;
(e) Y.- X. Gao, G. Tang, Y. Cao, Y.- F. Zhao, Synthesis 7 (2009) 1081;
(f) S. K. Bhunia, P. Das, R. Jana, Org. Biomol. Chem. 16 (2018) 9243;
(g) D.-J. Chen, Z.-C. Chen, J. Chem. Research (S) (2000) 370;
(h) D.-J. Chen, Z.-C. Chen, Synth. Commun. 31 (2001) 421.
[9] (a) S. Dutta, A. Saha, ChemistrySelect 3 (2018) 11895;
(b) N. Mukherjee, S. Pal, A. Saha, B. C. Ranu, Can. J. Chem. 95 (2017) 51.
Click here to remove instruction text...
0
0
Et0II
Et0
solventEtO,1 1
—
P—H + PhS N 1
0
Et0 ,P—SPh
entry solvent temp. (°C)
DMF
time
4 h
yield (%)
48
1
80
2
DMF
THE
RT
4 h
63
3
4
RT
RT
RT
4 h
4 h
4 h
57
69
60
DMSO
MeCN
5
6
7
Toluene
neat
RT
RT
4 h
45
40 min
86
72
8
9
neat
H2O
RT
RT
30 min
4 h
Highlights
 Thiophosphates, selenophosphates

6
Tetrahedron
 solvent, catalyst, base free reaction
 RT protocol
Graphical Abstract
Benign synthesis of thiophosphates,
Leave this area blank for abstract info.
thiophosphinates and selenophosphates in
neat condition using N-chalcogenoimides as
the source of electrophilic sulfur/selenium
Manas Mondal and Amit Saha*
O
O
P
O
R1
R1
R1
Neat
XR2
R2X
N
H
+
P
R1
Yield 83-91%
RT, air
O
Solvent Free
Catalyst Free
Base Free
R1 = OEt, OiPr, Ph
X = S, Se