Synthesis of symmetrically and unsymmetrically substituted S,S-dialkyl phosphonodithioates

Article abstract of DOI:10.1016/j.tetlet.2017.09.065

Herein, we report the synthesis of a range of S,S-dialkyl phosphonodithioates. Symmetrically substituted analogues were readily prepared from the corresponding phosphonic dichlorides in good to moderate yields, while unsymmetrically substituted variants were obtained by a sequential alkylation-deprotection-alkylation strategy.

Full text of DOI:10.1016/j.tetlet.2017.09.065

Tetrahedron Letters 58 (2017) 4212–4214
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of symmetrically and unsymmetrically substituted S,S-dialkyl
phosphonodithioates
a,b,d,
David J. Jones a,b, Eileen M. O’Leary c, , Timothy P. O’Sullivan
⇑
⇑
a School of Chemistry, University College Cork, Cork, Ireland
b Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
c Department of Physical Sciences, Cork Institute of Technology, Cork, Ireland
d School of Pharmacy, University College Cork, Cork, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we report the synthesis of a range of S,S-dialkyl phosphonodithioates. Symmetrically substituted
analogues were readily prepared from the corresponding phosphonic dichlorides in good to moderate
yields, while unsymmetrically substituted variants were obtained by a sequential alkylation-deprotec-
tion-alkylation strategy.
Received 10 August 2017
Revised 13 September 2017
Accepted 21 September 2017
Available online 22 September 2017
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Organophosphorus chemistry
Organosulfur chemistry
Phosphonodithioates
Introduction
We have found that the preparation of these compounds via
nucleophilic displacement of chloride is challenging compared to
In the course of our research regarding the synthesis of biolog-
ically active phosphonates through the bioisosteric replacement of
oxygen with sulfur, we required a robust method for accessing
symmetrically and unsymmetrically substituted S,S-dialkyl phos-
phonodithioates. The phosphonothioate motif is present in several
commercially important agrochemicals, including pesticides such
as Parathion, Ethion, Fenitrothion, Fenthion, Isoxathion and
Malathion.1 Interestingly, Parathion and Malathion both contain
a phosphorus-sulfur double bond which is key to their activity.
In contrast, compounds such as Echothiophate, Dementon,
Omethoate, Phentoate, Malaoxon and Oxydemeton contain a phos-
phorus-sulfur single bond which is required for their activity.
Little systematic study on the formation of symmetrically sub-
stituted S,S-dialkyl phosphonodithioates has occurred to date.
Older reports confirm that this underexplored functional group
may be accessed by oxidation of the corresponding dithiophos-
phite with dinitrogen tetroxide in moderate to good yields.2 The
synthesis of phosphonodithioates using phosphonic dichloride
precursors has also been demonstrated; however, reaction condi-
tions are specific to individual substrates, highlighting the absence
of a general method for accessing these compounds.3–6
the synthesis of their O,O-dialkyl equivalents. In this publication,
a general method for the synthesis of symmetrically substituted
phosphonodithioates is reported, with the majority of these consti-
tuting novel compounds. Additionally, we describe the synthesis of
unsymmetrically substituted members of this class bearing low
molecular weight side-chains using a sequential alkylation-depro-
tection-alkylation strategy.
Results and discussion
Symmetrically substituted S,S-dialkyl phosphonodithioates 1–7
were accessed by reacting the requisite phosphonic dichloride with
the corresponding alkanethiol in anhydrous THF, facilitated by tri-
ethylamine (Scheme 1).7 The reaction also proceeds in dry diethyl
ether or dichloromethane, albeit in lower yields and is accompa-
nied by disulfide formation. Unless care is taken to deoxygenate
the solvents prior to the reaction, oxidative dimerization of the
thiol to the corresponding disulfide causes considerable yield loss.
Since removing the disulfide by-products requires careful column
chromatography, minimizing their formation is highly desirable.
We found that reaction of the thiol with sodium hydride to form
the corresponding thiolate anion prior to addition of the phospho-
nic dichloride also affords the desired phosphonodithioates. How-
ever, formation of the disulfide by-product is increased under
these conditions and yields tended to be lower. It has been noted
⇑
Corresponding authors at: School of Chemistry, University College Cork, Cork,
Ireland (T.P. O’Sullivan).
E-mail address: tim.osullivan@ucc.ie (T.P. O’Sullivan).
https://doi.org/10.1016/j.tetlet.2017.09.065
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.

D.J. Jones et al. / Tetrahedron Letters 58 (2017) 4212–4214
4213
O
P
Cl
O
P
O
P
S
O
P
S
H
N
R2SH, NEt3
THF, 0 o
DBU
N
R1
Cl
R1
SR2
C
S
S
SR2
Various
Conditions
C
N
NC
NC
H
2
8
O
O
O
P
S
P
S
CN TsO
P
S
CN
CN
N
S
S
S
CN
N
DBU
1
2
3
52%
69%
71%
O
P
S
O
P
S
S
O
P
S
O
P
S
S
O
P
S
N
S
C
N
S
S
NC
H
N
4
5
66%
39%
O
P
6
71%
TsO
S
Scheme 2. Proposed mechanism for the formation of 8.
S
7 66%
tion reactions.11 The reaction is believed to proceed via initial
deprotonation adjacent to the nitrile group promoting E1cB
elimination to furnish the mono-deprotected product. Following
mono-deprotection of 2, acrylonitrile – a potent Michael-acceptor
– is produced. It is possible that the bis-deprotected product is
not isolated due to reaction of the dianion, which is more reactive
than the monoanion, with acrylonitrile to afford 8. Evans and
co-workers observed a similar phenomenon when attempting to
remove both cyanoethyl protecting groups from a phosphonate
and instead isolated the mono-deprotected product in the absence
of an electrophile.12
In contrast, the reaction of phosphonodithioate 2 with DBU in
the presence of a large excess of methyl iodide cleanly furnished
dimethylated phosphonodithioate 9 in good yield (Scheme 3). It
seems likely that in situ methylation of the anionic intermediates
allows for the successful removal of both cyanoethyl groups.
Additionally, it was found that the formation of 9 could take place
in a stepwise fashion with intermediates 8, 10 and 11 being
isolated and characterized. Methylation of the mono-deprotected
product 8 with methyl iodide furnished the unsymmetrically
substituted phosphonodithioate 10.13 Compound 10 was then sub-
jected to further treatment with DBU, effecting a second E1cB elim-
ination to give 11. Finally, subsequent alkylation of 11 affords
S,S-dimethyl phosphonodithioate 9. Unsymmetrically substituted
Scheme 1. Preparation of symmetrical S,S-dialkyl phosphonodithioates.
previously that disulfide formation is accelerated under strongly
basic conditions.8 An attempt to adapt the base-free methodology
employed by Acharya and co-workers9 for the preparation of clo-
sely related O,O-dialkyl phosphonates by replacing alcohols with
the analogous thiols was unsuccessful.
We next investigated whether 2 might serve as a useful synthon
for the preparation of S,S-dialkyl phosphonodithioates. Treating 2
with DBU furnished mono-deprotected 8 exclusively as its DBU
salt, irrespective of the number of equivalents of DBU employed
or the reaction time (Scheme 2). It is worth noting that when a sin-
gle equivalent of DBU is used, the reaction proceeds to completion
within 90 min and the mono-deprotected product can be isolated
cleanly by removal of the solvent in vacuo. The identification of this
compound as a 1:1 salt is supported by the matching integration of
signals arising from the DBU cation and the thiophosphonate anion
in the 1H-NMR spectrum. Additionally, the carbon adjacent to the
protonated nitrogen is deshielded in 8 compared to the same atom
in non-protonated DBU (165 ppm vs. 158 ppm).10
The probable reaction mechanism outlined in Scheme 2 is sim-
ilar to that described previously for related cyanoethyl deprotec-
O
P
S
O
P
S
O
P
S
H
N
DBU, THF
MeI, THF
CN
CN
S
S
S
CN
N
r.t., 90 min
Quant.
NC
r.t., 90 min
89%
10
8
2
EtI, THF
MeI, DBU
THF
r.t., 24 h
71%
DBU, THF
r.t., 90 min
Quant.
r.t., 90 min
84%
O
P
S
O
P
S
S
O
P
S
S
O
P
S
H
N
CN
S
MeI, THF
13
S
N
9
r.t., 90 min
89%
9
11
EtI, THF
r.t., 90 min
73%
O
P
S
S
12
Scheme 3. Synthesis of unsymmetrical S,S-dialkyl phosphonodithioates.

4214
D.J. Jones et al. / Tetrahedron Letters 58 (2017) 4212–4214
to room temperature then stirred overnight after which time the starting thiol
was no longer evident by TLC. The reaction mixture was then filtered by gravity
and the flask washed with THF (10 mL). The filtrate was concentrated in vacuo
and the oily yellow remains were reconstituted in CH2Cl2 (40 mL) and
sequentially washed with 1M NaOH (15 mL), brine (15 mL), 2M HCl (15 mL)
and brine (15 mL), before being dried over magnesium sulfate and concentrated
in vacuo to furnish the title compound as a yellow oil which was used without
further purification. IR mmax (NaCl, cmÀ1): 2985, 2935, 2251, 1640, 1457, 1418,
1289, 1193, 1032, 742, 708, 559. dH (400 MHz, CDCl3, ppm): 1.24 (CH3-CH2-P
(@O), 3H, dt, JH-P = 24.29 Hz, JH-H = 7.61 Hz), 2.23 (CH3CH2-P(@O), 2H, dq, JH-
P = 12.61 Hz, JH-H = 7.61 Hz), 2.75-2.88 (CN-CH2, 4H, m) 3.07–3.21 (S-CH2, 4H,
m). dC (100 MHz, CDCl3, ppm): 6.95 (CH3-CH2-P(@O), d, JP-C = 6.10 Hz), 20.2
(CN-CH2, d, JP-C = 2.12 Hz), 26.1 (S-CH2, d, JP-C = 3.26 Hz), 32.4 (CH3-CH2-P(@O),
d, JP-C = 73.27 Hz), 117.7 (CN). dP (175 MHz, CDCl3, ppm): 71.45. HRMS (ESI+):
Calc. mass C8H14N2OPS2 [M+H] = 249.0280; Found 249.0283.
phosphonodithioates 12 and 13 were accessed upon the ethylation
of 8 and 11, respectively. The synthesis of 9, 10, 12 and 13 avoids
the use of low molecular weight thiols which are difficult to handle
owing to their volatility and strongly unpleasant odour.
Conclusion
Symmetrically substituted S,S-dialkyl phosphonodithioates
were conveniently prepared according to the method described.
This work demonstrates the synthetic utility of 8 as a convenient
precursor to unsymmetrically substituted members of this series.
This approach has the further advantage of avoiding malodorous,
low molecular weight thiols.
8. Wallace TJ, Schriesheim A. Tetrahedron Lett. 1963;4(17):1131–1136;
Wallace TJ, Schriesheim A. Tetrahedron. 1965;21(9):2271–2280.
9. Acharya J, Shakya PD, Pardasani D, Palit M, Dubey DK, Gupta AK. J Chem Res.
2005;3:194.
Acknowledgements
10. Representative procedure: Preparation of DBU Salt (8). To a stirred solution of 2
(100 mg, 0.40 mmol, 1.00 eq.) in THF (5 mL) was added DBU (61 mg,
0.40 mmol, 1.00 eq.) in THF (5 mL) at room temperature. The resulting
suspension was stirred for 90 min after which time complete consumption of
the starting material was confirmed by TLC. The solvent was removed in vacuo
affording the title compound as a pale oil (136 mg, 0.39 mmol, 99%). IR mmax
(NaCl, cmÀ1): 3375, 2920, 2847, 2134, 1961, 1647, 1403, 1384, 1101. dH (400
MHz, CDCl3, ppm): 1.23 (3H, dt, JH-P = 22.10 Hz, JH-H = 7.41 Hz), 1.75 (6H, m),
2.00-2.15 (4H, m), 2.80-2.93 (4H, m), 2.98-3.09 (2H, m), 3.47–3.53 (6H, m), 6.29
(DBU-H+ bs). dC (100 MHz, CDCl3, ppm): 8.78 (d, JC-P = 5.01 Hz), 21.42 (d, JP-
C = 2.71 Hz), 24.11, 26.25, 26.82. 28.49 (d, JC-P = 2.98 Hz), 29.00, 32.21 32.43,
36.63 (JC-P = 79.83 Hz), 48.66, 54.33, 119.11 (CN), 165.92 (DBU; N-C(@N)). dp
(175 MHz, CDCl3, ppm): 85.38. HRMS (ESI-): Calc. mass (C5H9NOPS2À):
194.2268; Found: 194.2277.
This work was supported by funding from the University Col-
lege Cork Strategic Research Fund PhD Scholarship (DJJ).
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.09.
065.
11. Raz R, Rademann J. Org Lett. 2012;14:5038–5041.
References
12. Evans DA, Gage JR, Leighton JL. J Org Chem. 1992;57:1964–1966.
13. Representative Procedure: S-Methyl-S-(2-Cyanoethyl) Ethylphosphonodithioate
(10). To a stirred solution of DBU salt (8) (193 mg, 1.00 mmol, 1.00 eq.) in
anhydrous THF (5 mL) was added methyl iodide (283 mg, 2.00 mmol, 2.00 eq.)
in anhydrous THF (5 mL). The reaction was stirred for 90 min at room
temperature after which time no starting material was evident by TLC. The
solvent was then removed in vacuo, and the yellow oily remains were
reconstituted in CH2Cl2 (20 mL) and washed with water (3 Â 20 mL). The
organic solution was dried over magnesium sulfate and concentrated in vacuo
to afford the title compound as a yellow oil (184 mg, 0.89 mmol, 89%). IR mmax
(NaCl, cmÀ1): 2986, 2937, 2251, 1640, 1453, 1422, 1276, 1173, 1032, 742, 728,
555. dH (400 MHz, CDCl3, ppm): 1.23 (3H, dt, JH-P = 23.63 Hz, JH-H = 7.48 Hz,
CH2CH3), 2.19 (2H, dq, JH-P = 12.50 Hz, JH-H = 7.48 Hz, CH2CH3), 2.33 (3H, d, JH-
P = 13.37 Hz, SCH3), 2.82 (2H, td, JH-H = 6.91 Hz, JH-P = 3.26 Hz SCH2CH2CN), 3.10
(2H, dt, JH-P = 14.38 Hz, JH-H = 6.91 Hz, SCH2CH2CN). dC (100 MHz, CDCl3, ppm):
6.94 (d, JC-P = 6.13 Hz, CH3CH2), 12.14 (d, JC-P = 4.38 Hz, SCH3), 20.41 (d, JC-
P = 3.11 Hz, CH2CN), 25.90 (d, JC-P = 3.55 Hz, CH2S), 31.36 (d, JC-P = 72.18 Hz,
CH2P), 117.14 (CN). dP (175 MHz, CDCl3): 71.94. HRMS (ESI+): Calc. Mass for
C6H13NOPS2 [M+H] = 210.0071; Found = 210.0087.
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7. Representative Procedure: S,S-Di(2-Cyanoethyl) Ethylphosphonodithioate (2). To a
stirred solution of ethyl phosphonic dichloride (587 mg, 4 mmol, 1.00 eq.) in
anhydrous THF (40 mL) under a nitrogen atmosphere at ca. 0 °C, was added a
solution of 3-mercaptopropionitrile (700 mg, 8 mmol, 2.00 eq.) and
triethylamine (800 mg, 8.00 mmol, 2.00 eq.) in THF (10 mL) over five minutes.
This was accompanied by the instantaneous precipitation of triethylamine
hydrochloride as a colourless solid. The reaction mixture was allowed to warm