Practical Reagents and Methods for Nucleophilic and Electrophilic Phosphorothiolations

Article abstract of DOI:10.1002/adsc.201701549

New late-stage phosphorothiolation methods are disclosed that allow the efficient transfer of SP(O)(OR)₂ groups to diversely functionalized substrates using nucleophilic and electrophilic reagents. The nucleophilic reagent, tetramethylammonium O,O-dimethyl phosphorothioate, was synthesized in near-quantitative yield from Me₃SiP(O)(OMe)₂, elemental sulfur and Me₄NF. Its umpolung with N-bromophthalimide provided the electrophilic reagent, O,O-dimethyl-S-(N-phthalimido)phosphorothioate. Complementary methods based on these reagents enable the phosphorothiolation of diversely functionalized alkyl halides, arenediazonium salts, arylboronic acids and electron-rich arenes in good yields under mild conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.201701549

Title: Practical Reagents and Methods for Nucleophilic and
Electrophilic Phosphorothiolations
Authors: Szabolcs Kovacs, Bilguun Bayarmagnai, Alexandre Aillerie,
and Lukas J. Goossen
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10.1002/adsc.201701549
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Practical Reagents and Methods for Nucleophilic and
Electrophilic Phosphorothiolations
Szabolcs Kovacs,a Bilguun Bayarmagnai,a Alexandre Ailleriea and Lukas J. Gooßena*
a
Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstr. 150, 44801 Bochum, Germany
Email: lukas.goossen@rub.de
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))
studied due to the lower accessibility of the starting
nucleotides.[4]
Abstract: New late-stage phosphorothiolation methods
are disclosed that allow the efficient transfer of
SP(O)(OR)2 groups to diversely functionalized substrates
using nucleophilic and electrophilic reagents. The
nucleophilic reagent, tetramethylammonium O,O-
dimethyl phosphorothioate, was synthesized in near-
quantitative yield from Me3SiP(O)(OMe)2, elemental
sulfur and Me4NF. Its umpolung with N-
bromophthalimide provided the electrophilic reagent,
O,O-dimethyl-S-(N-phthalimido)phosphorothioate.
demeton-S
omethoate
AChE inhibitor
AChE inhibitor
Complementary methods based on these reagents enable
the phosphorothiolation of diversely functionalized alkyl
halides, arenediazonium salts, arylboronic acids and
electron-rich arenes in good yields under mild conditions.
malathion
AChE inhibitor
dimethoate
AChE inhibitor
mipomersen
Phosphorothionate-RNA
antisense agents
Keywords: phosphorothiolation; sulfur; phosphorus;
reagents; copper; Sandmeyer reaction
echothiophate
amifostine
glaucoma agent
Cytoprotective prodrug
Organothiophosphates have found widespread
application as insecticides and pharmaceuticals,
acting for example as acetylcholinesterase (AChE)
inhibitors or as stabilizing groups in antisense drugs
Figure 1. Selected examples of biologically active
organothiophosphates.
(Figure
1).[1]
Classical
phosphorothiolate
or (RO)3P
((RO)2P(O)SR’) insecticides, including demeton-S or
omethoate, once dominated the market, and have now
[C]
[A]
Z: SCl, SSPh,
mostly
been
replaced
by
less
toxic
SO2Cl, SO2NHNH2
phosphorodithioate ((RO)2P(S)SR’) derivatives such
as malathion or dimethoate.[2] Hydrolysis to the more
active P=O form occurs in vivo.[3] Pharmaceutically
relevant phosphorothiolates include the AChE
inhibitor echothiopate (Phospholine Iodide®), a
topical glaucoma agent, and the cytoprotective drug
amifostine (Ethyol®). Amifostine is a prodrug,
dephosphorylated in functional body cells by alkaline
phosphatase to release a scavenger for platinum
agents or DNA alkylators. In antisense drug therapy,
the replacement of phosphate by phosphorothionate
((RO)2P(S)OR’) subunits imparts greater metabolic
stability to the oligonucleotides. This has been
exploited e.g. in the hypercholesterolemia drug
mipomersen (Kynamro®) and the antiviral
fomivirsen (Vitravene®). 3’- or 5’-Phosphorothiolate
oligonucleotides are as interesting, but less well
[B]
[D]
Z: B(OH)2, N2+, ArI+
X: Cl, Br
Scheme 1. Synthesis of organothiophosphates.
The synthesis of thiophosphates mainly involves
the formation of S-P bonds. Michaelis-Arbuzov-type
additions of sulfonyl halides, sulfenyl halides,
disulfides or other derivatives to phosphites usually
require harsh reaction conditions and suffer from the
1
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10.1002/adsc.201701549
Advanced Synthesis & Catalysis
highly toxicity and sensitivity of the reagents, leading
to limited substrate scopes (Scheme 1, A).[5]
Synthetic routes starting from thiols and
(RO)2P(O)Hal reagents are hampered by the toxicity
of the halogenated reagents, the harsh reaction
conditions, and their incompatibility with sensitive
functionalities.[6] The dehydrogenative coupling of
P(O)H groups with thiols was reported using
These nucleophilic reagents were turned into
electrophiles by salt metathesis with N-
bromophthalimide in dichloromethane.[16] This way,
O,O-dimethyl-S-(N-phthalimido)phosphorothioate (2)
was obtained in near-quantitative yield (Scheme 2,
bottom). The structure of this new reagent was
confirmed by X-ray analysis.
The nucleophilic reactivity of reagents 1a and 1b
was demonstrated in their SN2 reaction with benzyl
bromide.[17] The phosphorothiolate group was
transferred in near-quantitative yields at room
temperature, leading to products 4a and 4b. The
alkylation took place selectively at the sulfur, and no
decomposition was observed (Scheme 3).
[9]
copper,[7] palladium[8] and Cs2CO3 as catalysts
(Scheme 1, C).[10] This approach is limited by the low
availability of thiol starting materials.
Multicomponent reactions of alkyl halides with
sulfur and P(O)H compounds, as described by Han et
al. and Zhang et al.,[11] or Cu-catalyzed
phosphorothiolations of arylboronic acids, diazonium,
or iodonium salts using elemental sulfur and dialkyl
H-phosphonate, as reported by Tang et al., arguably
constitute the most versatile synthetic entries to this
substrate class known to date (Scheme 1, D).[12]
However, such multicomponent reactions are not
easily carried out on small scale. Especially for
applications in parallel synthesis and drug discovery,
alternative methods that allow the late-stage
introduction of phosphorothiolate groups from
broadly available starting materials and using a single,
easily accessible, bench-stable reagent would be more
practical.
Herein, we disclose a set of complementary
methods in which the phosphorothioate moiety is
transferred as a whole from easily available reagents
using practical, high-yielding synthetic protocols.
We identified phosphorothiolate salts as the
phosphorothiolation reagents of choice. Such salts
have successfully been used for the preparation of
alkyl phosphorothiolates,[13] and there are some
reports on their use in aromatic substitutions.[14]
1 (1.5 equiv.)
MeCN, r.t.
4a, 98%
4b, 77%
3
Scheme 3. Phosphorothiolation of benzyl bromide.
Next, we examined the functionalization of arenes.
The Sandmeyer-type reaction of reagent 1a with 4-
methoxybenzenediazonium tetrafluoroborate (5)
under conditions that had previously been optimized
for fluoroalkylthiolations (1 equiv. CuSCN, DMF)[18]
produced the phosphorothiolated arene 6 in an
encouraging 41% yield. The yield was improved by
decreasing the amount of copper thiocyanate and
changing the solvent to MeCN. Systematic screening
revealed that 20 mol% CuSCN in MeCN gives the
best results. After 16 hours at room temperature, the
product was obtained in 90% isolated yield (Scheme
4, see the SI).
S8
Me4NF
CuSCN (20 mol%)
1a (1.5 equiv.)
THF, -60 °C to r.t.
15 h
MeCN, r.t., 16 h
1a, (R = Me) 86%
1b, (R = Et) 84%
5
6, 90%
Scheme 4. Sandmeyer-type phosphorothiolation of
1a (1 equiv.)
diazonium salts.
DCM, r.t., 2 h
2, 97%
The reactivity of the electrophilic reagent 2 was
tested in a Chan-Evans-Lam-type coupling with 4-
Scheme 2. Preparation of the nucleophilic (1) and
electrophilic (2) phosphorothiolation reagents.
fluorophenylboronic acid. Using
a
CuCl/2,2‘-
bipyridine catalyst system under conditions that had
been
optimal
in
electrophilic
trifluoromethylthiolations by Rueping et al.,[19] the
phosphorothiolate 8 was obtained in 15% yield.
We tested various counter-ions and found
tetramethylammonium phosphorothiolate salts to
have the best properties with regard to accessibility,
stability and solubility. Upon mixing commercially
available tetramethylammonium fluoride, elemental
sulfur and dimethyl trimethylsilyl phosphite
(TMS─OP(OMe)2) in THF, the Me4NSP(O)(OMe)2
product (1a) precipitated and was obtained in 86%
yield by simple filtration (Scheme 2, top).[15] The
ethyl derivative 1b was synthetized analogously.
Systematic optimization of catalyst and reaction
parameters led to an 88% yield within 16 hours at
room temperature. The most effective conditions
were found to be 2 equivalents of sodium carbonate
as the base, 10 mol% of CuI, 20 mol% of 2,2‘-
bipyridine and MeCN as the solvent (Scheme 5, see
the Supporting information). Starting from
2
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10.1002/adsc.201701549
Advanced Synthesis & Catalysis
phenylacetylene, no phosphorothiolation was
observed.
keto, carboxylate, and cyano groups, and the products
were isolated in 68-90% yields (23-27).
Table 1. Scope of the phosphorothiolation protocols.
2 (1.2 equiv.)
CuI (10 mol%)
biPy (20 mol%)
Na2CO3 (2 equiv.)
(A)
1
MeCN, r.t., 16 h
1 or 35
cat. [Cu]
2
7
8, 88%
cat. [Cu]
(B)
(C)
Scheme 5. Reaction of the electrophilic reagent with
boronic acids.
R1 = alkyl, Ar
R2 = Me, Et
Z = O, S
We next investigated whether 2 is also an effective
reagent for C–H phosphorothiolations (Scheme 6).
4a, R = Me, 98% (A)
4b, R = Et, 77% (A)
13, 69% (A)
16, 89% (A)
14, 78% (A)
Starting with
a
C–H trifluoromethylthiolation
protocol,[20] conditions were identified that allow the
selective C–H-phosphorothiolation of indole. At
50 °C and in acetic acid as the solvent, 10 was
15a, R = Me, 80% (A)
15b, R = Et, 89% (A)
6a, R = OMe, 90% (B), 93% (C)
6b, R = OEt, 88% (B)
obtained
in
good
isolated yield
(74%).
Phosphorothiolation
of
1,3-dimethoxybenzene
proceeded best in acetic acid in the presence of TMS-
Cl, conditions similar to those used in Shen’s
trifluoromethylthiolation.[21]
17, 82% (B)
18, 77% (B)
19, 82 % (B), 80% (C)
20, 95 % (B), 87% (C)
21, p-Ph, 95% (B), 75% (C) 23, 75% (B), 74% (C)
22, o-Ph, 92% (B)
10% NaCl
2 (1.3 equiv.)
AcOH, 50 °C, 16 h
9
10, 74%
24, 90% (B), 76% (C)
25, 72% (B), 86% (C)
26, 68% (B), 73% (C)
TMSCl (1.5 equiv.)
2 (1.1 equiv.)
AcOH, 50 °C, 16 h
27, 81% (B)
8, 78% (B), 88% (C) 28a, R = Me, 85% (B), 86% (C)
28b, R = Et, 86% (B)
11
12, 67%
Scheme 6. C–H phosphorothiolations with the
electrophilic reagent 2.
29, p-Br, 81% (B)
30, o-Br, 76% (B)
31, 67% (B)
32, 62% (B)
The general applicability of the above set of
phosphorothiolation protocols using 1 and 2 is
illustrated by the examples in Table 1.
33, 47% (B)
34, 52% (B)
Diverse S-benzyl and S-alkyl O,O-dialkyl
phosphorothioates were obtained via nucleophilic
substitution with reagent 1 (method A) in good yields,
among them demeton-S (16). Functionalities
including trifluoromethyl groups, ketones and
thioethers were tolerated.
Using the Cu-catalyzed Sandmeyer-type reaction
(method B), various diazonium tetrafluoroborates
were efficiently converted into the corresponding S-
aryl O,O-dimethyl phosphorothioates (with reagent
1a) or O,O-diethyl derivatives (with reagent 1b).
Electron-rich substrates bearing single or multiple
methoxy, phenoxy and phenyl groups in different
positions gave similarly high yields (6a, 6b, 17-22,
77-95%). Many common functionalities were
tolerated, including trifluoromethyl, ester, amino,
36, 90% (B)
37, 91% (B)
38, 88% (B)
a)
Isolated yields; brackets indicate method used. Method
A: alkyl bromide (1 mmol), 1 (1.5 mmol), MeCN (4 mL),
r.t., 15 h; Method B: arenediazonium tetrafluoroborate (1
mmol), 1 (1.5 mmol), CuSCN (0.2 mmol), MeCN (4 mL),
r.t., 15 h; Method C: arylboronic acid (1 mmol), 2 (1.2
mmol), CuI (0.1 mmol), 2,2‘-bipyridine (0.2 mmol),
Na2CO3 (2 mmol), MeCN (10 mL), r.t., 16 h
Halo-substituents remained intact and may serve as
handles for further, orthogonal functionalization of
the products (8, 28-31, 67-86%). Phosphorothiolation
of heterocycles, such quinoline, carbazole, and
3
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10.1002/adsc.201701549
Advanced Synthesis & Catalysis
organic layers were dried over MgSO4, filtered and
concentrated. The product was purified by flash
chromatography.
thiophene derivatives was also successful (32-34, 47-
62%).
Method B was also applicable to the synthesis of
aryl phosphorodithioates. By changing reagent 1 to
the commercially available ammonium O,O-diethyl
phosphorodithioate salt (35, H4NSP(S)(OEt)2),
dithiophosphate derivatives 36-38 were obtained in
good yields.
Method B: An oven-dried 20 mL crimp-cap vessel was
filled with CuSCN (24.6 mg, 0.20 mmol, 0.2 equiv.), 1
(1.50 mmol, 1.5 equiv.) and MeCN (2 mL) under inert
conditions. An arenediazonium salt (1.00 mmol, 1 equiv.)
in MeCN (2 mL) was added dropwise and the reaction
mixture was stirred at r. t. for 15 h. The resulting mixture
was diluted with diethyl ether (20 mL), washed with water
(2 × 10 mL) and brine (10 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated.
The crude product was purified by flash chromatography.
S-Aryl O,O-dimethyl phosphorothioates were
alternatively obtained by the Chan-Evans-Lam-type
reaction of boronic acids using the electrophilic
reagent 2 (method C). Methods B and C were found
to be comparable in terms of yields and functional
group tolerance. They complement each other due to
differences in readily available substitutions patterns
for aromatic amines and boronates.
Method C: An oven-dried 20 mL crimp-cap was charged
with an arylboronic acid (1 mmol, 1 equiv.), 2 (345 mg,
1.2 mmol, 1.2 equiv.), CuI (19 mg, 0.1 mmol, 0.1 equiv),
dry K2CO3 (276 mg, 2 mmol, 2 equiv.) and 2,2’-bipyridine
(37.6 mg, 0.2 mmol, 0.2 equiv.) under inert conditions.
MeCN (10 mL) was added by syringe and reaction mixture
was stirred at r. t. for 16 h. The reaction mixture was
diluted with CH2Cl2 (10 mL) and filtered through a short
plug of silica, and eluted with additional CH2Cl2 (50 mL).
The filtrate was concentrated and the residue was purified
by flash chromatography.
The
mechanism
of
the
Cu-mediated
phosphorothiolation of diazonium salts (method B)
was confirmed to follow a Sandmeyer-type radical
pathway.[22] In the presence of the radical quenchers
2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) or p-
benzoquinone, the formation of 6a is completely
suppressed. Moreover, the phosphorothiolation of 2-
(allyloxy)diazonium tetrafluoroborate (39) afforded
exclusively the cyclized product (40, Scheme 7). In
the presence of TEMPO the cyclized TEMPO adduct
41 could be isolated in 90% yield.[23]
Acknowledgements
We thank the Heinrich-Böll-Stiftung e.V. (scholarship to B.B.)
and DFG (EXC/1069 „RESOLV“) for financial support.
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4
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10.1002/adsc.201701549
Advanced Synthesis & Catalysis
COMMUNICATION
Practical Reagents and Methods for Nucleophilic
and Electrophilic Phosphorothiolations
[-SP(Z)(OR)2]
or
- direct nucleophilic and
electrophilic functionalization
- stable reagents
- mild conditions
- excellent FG tolerance
- high yields
[+SP(O)(OR)2]
Adv. Synth. Catal. Year, Volume, Page – Page
Cat.
R = Ar, alkyl
X = Br, N2+, B(OH)2 or H
Z = O, S
Szabolcs Kovács, Bilguun Bayarmagnai, Alexandre
Aillerie, Lukas J. Goossen*
6
This article is protected by copyright. All rights reserved.