A Robust Methodology for the Synthesis of Phosphorothioates, Phosphinothioates and Phosphonothioates

Article abstract of DOI:10.1002/adsc.202000059

A robust methodology for the synthesis of phosphorothioates, phosphinothioates and phosphonothioates, including those bearing low molecular weight S-alkyl side-chains, is presented. Application of the “caesium effect” in conjunction with the disulfide 3,3’-dithiobis(propionitrile), which acts as a shelf-stable sulfur source, avoids recourse to malodorous alkanethiols and toxic P?Cl precursors. A diverse range of sulfur-containing organophosphorus targets, including phosphorus-based heterocycles, may be prepared in consistently high yields. This chemistry also provides ready access to the corresponding DBU salts which are potential substrates for Pd-catalysed coupling reactions. (Figure presented.).

Full text of DOI:10.1002/adsc.202000059

Title: A robust methodology for the synthesis of phosphorothioates,
phosphinothioates and phosphonothioates.
Authors: David Jones, Eileen O'Leary, and Tim O'Sullivan
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Advanced Synthesis & Catalysis
10.1002/adsc.202000059
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Robust Methodology for the Synthesis of Phosphorothioates,
Phosphinothioates and Phosphonothioates
a,b
c
a,b,d*
David J. Jones, Eileen M. O’Leary, and Timothy P. O’Sullivan
a
School of Chemistry, University College Cork, Cork, Ireland. Phone: 353-21-4901655. Fax: 353-21-4901656. Email:
tim.osullivan@ucc.ie
Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland.
Department of Physical Sciences, Cork Institute of Technology, Cork, Ireland.
School of Pharmacy, University College Cork, Cork, Ireland.
b
c
d
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A robust methodology for the synthesis of
phosphorothioates,
phosphinothioates
and
phosphonothioates, including those bearing low molecular
weight S-alkyl side-chains, is presented. Application of the
“
caesium effect” in conjunction with the disulfide 3,3’-
dithiobis(propionitrile), which acts as a shelf-stable sulfur
source, avoids recourse to malodorous alkanethiols and
toxic P–Cl precursors. A diverse range of sulfur-containing
organophosphorus targets, including phosphorus-based
heterocycles, may be prepared in consistently high yields.
This chemistry also provides ready access to the
corresponding DBU salts which are potential substrates for
Pd-catalysed coupling reactions.
Figure 1. Commercially important sulfur-containing
organophosphorus compounds.
Keywords: Phosphorus; sulfur; caesium effect;
phosphorothioates; phosphinothioates; phosphonothioates.
Phosphorothioates,
phosphonothioates
and
The preparation of these compounds using P–S
phosphinothioates are all examples of P(V) bond forming chemistry has been the subject of
organophosphorus compounds which contain a extensive study in recent years. Metal-catalysed
phosphorus-sulfur single bond.[1] These classes of coupling reactions employing copper, rhodium,
[12]
[13]
[14]
[15]
[16]
compound are particularly important in agrochemicals, palladium,
iron
and iridium
catalysts have
where a significant number of pesticides incorporate been developed. Unfortunately, these routes are
phosphorus-sulfur bonds.[2] In particular, the largely restricted to S-aryl products and are often low
insecticides Azamethiophos and Demeton, alongside yielding or incompatible with S-alkyl targets.
related analogues, have enjoyed widespread Methods for the preparation of S-alkyl products with
[3]
application in crop protection (Figure 1). Molecules low molecular weight sidechains (e.g. S-methyl or S-
containing the P–S(alkyl) bond include potential anti- ethyl) are conspicuously absent in the literature,
[
4]
[5]
cancer agents,
antivirals,
cardioprotective despite the pervasiveness of these motifs in
[6]
[7]
therapeutics, and acetylcholine esterase inhibitors.
organophosphorus
chemistry.
S-Alkyl
The therapeutic potential of sulfur-containing organophosphorus compounds prepared via non-
organophosphorus compounds has already been metal-catalysed methods typically employ[19]the
[8]
[17]
[18]
realised in the broad-spectrum radioprotector and corresponding thiocyanate, disulfide, thiol or
anti-cancer[ drug, Amifostine, as well as the anti- sulfonyl chloride
9]
[20]
as starting materials which, for
[10]
glaucoma drug, Echothiophate. These compounds complex substrates, may not be readily available.
also have broad application in synthetic chemistry, These methods may also suffer from limited substrate
particularly in heterocyclic synthesis and in C–C and scope with respect to the organophosphorus precursor.
C–F bond-forming reactions.[11]
If the desired P–S bond is already in place in the
starting material, alkylation at sulfur represents an
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202000059
Scheme 1. Previous and current work.
attractive alternative to these other methods.[21] disulfide 2 was an interesting synthetic challenge,
Recent work by Gooßen and co-workers has owing to the base-lability of the 2-cyanoethyl groups.
demonstrated that the alkylation of shelf stable However, this chemistry would completely obviate
tetraalkylammonium
phosphorothioate
salts, the use of malodourous 3-mercaptopropionitrile and
generated from the corresponding silyl phosphite and thus warranted further investigation. If successful, this
elemental sulfur, afforded high yields of the approach would also provide access to other
corresponding phosphorothioates.[22] It is unclear, organophosphorus
however, whether this approach could be adapted to phosphinothioates
compounds,
including
and phosphonothioates.
other classes of S-alkyl organophosphorus compounds. Accordingly, an initial solvent screen confirmed
A general method with broad substrate scope which acetonitrile as the optimum reaction medium (Table 1,
provides ready access to S-alkyl phosphonothioates, entry 5). As predicted, using stoichiometric quantities
phosphorothioates and phosphinothioates would be of Cs
highly desirable. product resulting in low yields (entries 1-5). Reducing
In the course of our work in the synthesis of the loading of Cs CO to just 20 mol% resulted in a
2
CO
3
led to base-induced deterioration of the
2
3
potentially bioactive phosphonodithioates, we 83% yield of phosphorothioate 4 (entry 7). Further
communicated that phosphonodithioate 1, undergoes reductions saw a deleterious effect on yields (entries 8,
rapid E1cB deprotection when treated with DBU 9).
Scheme 1).[ Exploiting this reaction allowed us to
23]
(
prepare either symmetrically or unsymmetrically Table 1. Optimisation of caesium-mediated sulfur transfer
a)
substituted
molecular weight alkyl side-chains. Harnessing the S-
2-cyanoethyl) group as a synthon in a similar fashion
phosphonodithioates
bearing
low using base-labile 2.
(
would constitute a versatile route to a range of S-alkyl
derivatives of other organophosphorus compounds.
We initially investigated a general method for the
incorporation of the S-(2-cyanoethyl) moiety into a
range of organophosphorus substrates.
The synthesis of 1 was previously achieved
through nucleophilic substitution of commercially
available ethyl phosphonic dichloride with 3-
Entry Solvent Cs
2
CO
3
(eq.) Yield
1
2
3
4
5
6
7
8
9
THF
DMSO
DMF
MeOH
MeCN
MeCN
MeCN
MeCN
MeCN
1
1
1
1
1
0.50
0.20
0.10
0.05
19%
27%
23%
14%
31%
70%
83%
69%
40%
mercaptopropionitrile in the presence of base in
anhydrous solvent (Scheme 1).[
23]
We were keen to
avoid utilising a similar route in this study as these
reactive P–Cl reagents are toxic and prone to
hydrolysis, often leading to depressed yields as well
as handling difficulties. Likewise, while 3-
mercaptopropionitrile had served as an adequate
sulfur transfer reagent, we had hoped to avoid its use
given its high propensity toward oxidation and its
malodorous nature which required special precautions.
We postulated that 3,3’-dithiobis(propionitrile) (2),
a shelf-stable, crystalline compound, might constitute
a superior sulfur transfer reagent (Scheme 1). In
support of this approach, Song et al. recently reported
the oxidative phosphorylation of a range of thiols
employing caesium carbonate as a base, presumably
proceeding via their corresponding disulfides, to
afford phosphorothioates in good to excellent
yields.[ Extending this methodology to encompass
a)
Screening conducted with 1.00 mmol 2 & 1.00 mmol 3.
Importantly, this methodology could also be
extended to other phosphonates, phosphinates and
phosphine oxides allowing us to synthesise novel
phosphorothioate 5, phosphinothioate
6
and
phosphonothioate 7 in high yields on a multi-
millimolar scale, thus demonstrating the generality of
24]
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202000059
31
a)
this approach across the three main sulfur-containing Table 2. Deprotection reaction monitoring via P NMR.
organophosphorus groups (Figure 2).
Figure 2. Application of optimised conditions to selected
phosphorothioates,
phosphinothioates
and
phosphonothioates targets.
We next explored the DBU-mediated cleavage of
the cyanoethyl groups from 4-7. Although this
reaction had previously proven uncomplicated with
phosphonodithioate 1, it was not clear whether the
corresponding reaction with more complex substrates
would be similarly straightforward. Pleasingly,
treatment of 4-7 with an equimolar amount of DBU in
MeCN furnished the corresponding DBU salts 8-11
quantitatively, all as pale oils (Table 2). The reactions
were monitored by 31P NMR and were found to be
complete after 30 minutes in all cases. Notably, a
a)
Reactions conducted using 0.3 mmol 4-7 in 3 mL MeCN.
P NMR chemical shift data were recorded at 175 MHz
b) 31
in CDCl at 20 C using 85% aqueous phosphoric acid as
an external standard and are reported in ppm.
3
3
1
distinctive increase in the value of the P NMR
chemical shift was observed for each product. This
clear difference in chemical shift facilitates the
Interestingly, DBU salts 8-11 were soluble in a
variety of organic solvents such as dichloromethane,
chloroform, toluene and tetrahydrofuran, in addition
to water. Similar soluble quaternary ammonium salts
of phosphorothioates have recently been employed by
Schoenebeck and co-workers in S-arylation reactions
31
determination of reaction progress by P NMR and is
useful for reaction monitoring.
[14b]
under Pd(I)-catalysed conditions.
Since
deprotection of our S-(2-cyanoethyl)-functionalised
compounds affords soluble salts, it may be possible to
extend the scope of this Pd(I)-catalysed S-arylation
reaction to previously unexplored phosphinothioate
and phosphonothioate substrates. The salts exist in the
liquid state at room temperature and are therefore
ionic liquids – a class of materials with widespread
[25]
application in organic chemistry.
As subsequent
alkylation of 8 with methyl iodide to afford
phosphorothioate 12 also proved successful (Scheme
2
a), we wondered whether a telescoped approach was
feasible. Gratifyingly, phosphorothioate 12 was
prepared from 4 in a one pot process in improved
yield compared to the two-step process (Scheme 2b).
3
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Advanced Synthesis & Catalysis
10.1002/adsc.202000059
Scheme 2. Step-wise vs. telescoped preparation of
phosphorothioate 12.
This telescoped approach was applied to the
synthesis of a variety of phosphorothioates 12-19,
phosphinothioates 20-26, and phosphonothioates 27-
3
5 resulting in consistently excellent yields (Scheme
3
). Previously reported routes have suffered from
[21b]
much higher variability in yields.
Of the twenty-
four products produced in this manner, sixteen
constitute novel compounds. Both alkyl bromides and
iodides were found to be suitable alkylating agents,
although alkyl bromides required heating to reflux in
order to achieve complete consumption of the salt
intermediate.
Scheme 3. Investigation of substrate scope of
a)
3
b)
3
telescoped process. R I (1.0 mmol), r.t., 3 h; R Br
1.00 mmol), reflux, 3 h.
(
The alkylation reactions were highly regiospecific, as
only trace amounts of the corresponding O-alkylated
3
1
products were detectable in P NMR spectra of the
crude reaction mixtures. With iodomethyl pivalate as
4
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Advanced Synthesis & Catalysis
10.1002/adsc.202000059
the alkylating agent, the resulting pivaloxymethyl indicated in Figure 3. after which time the starting
esters 14, 22 and 29 were also obtained in excellent phosphite was no longer evident by 31P NMR. The reaction
yields. It is difficult to envisage an alternative mixture was filtered and concentrated in vacuo and the
synthesis of these S-(pivaloxymethyl) products resulting residue was purified by column chromatography
through standard P–S bond formation as the on silica gel.
corresponding thiol, a hemithioacetal ester, is unlikely
to be stable. This result is also noteworthy as the
Telescoped alkylation: To a stirred solution of 4-7 (0.50
pivaloxymethyl group is an important prodrug moiety
mmol, 1.00 eq.) in MeCN (5 mL) was added DBU (0.50
mmol, 1.00 eq.). The resulting solution was stirred for 30
minutes after which time the required alkyl iodide or alkyl
bromide (1.00 mmol, 2.00 eq.) was added. After three
hours at room temperature (alkyl iodides) or reflux (alkyl
bromides), the solvent was removed in vacuo and the
resulting residue was purified by column chromatography
on silica gel.
in medicinal chemistry and to the best of our
knowledge, this represents the first method for the
synthesis of S-(pivaloxymethyl) organophosphorus
compounds.[
26]
The alkyl iodide used in the
preparation of 19 was recently exploited as an
advanced intermediate in the synthesis of several
antiviral analogues and demonstrates that more
complex, drug-like, alkylating agents are compatible
with our methodology.[
27]
In summary, a robust methodology for the Acknowledgements
synthesis of various S-alkyl organophosphorus
compounds has been presented. We have The UCC Strategic Research Fund is gratefully acknowledged for
funding of a PhD Scholarship (DJJ).
demonstrated the application of disulfide 2 as a shelf-
stable sulfur transfer reagent for the preparation of S-
(
2-cyanoethyl)phosphorothioates, phosphonothioates
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6
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Advanced Synthesis & Catalysis
10.1002/adsc.202000059
COMMUNICATION
A robust methodology for the synthesis of
phosphorothioates, phosphinothioates and
phosphonothioates.
Adv. Synth. Catal. Year, Volume, Page – Page
David J. Jones, Eileen M. O’Leary, and Timothy P.
O’Sullivan*
7
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