Evaluation and development of methodologies for the synthesis of thiophosphinic acids

Article abstract of DOI:10.1021/acs.joc.0c01151

Thiophosphorus acids R1R2P(S)OH constitute an important class of organophosphorus compounds, in which the phosphorus atom is intrinsically chiral if R1 ≠ R2. In connection with a project aimed at the preparation of chiral thiophosphorus acids, various available literature methods were considered, but few fit the requirement of odorless reagents. Herein, the results of our studies on the synthesis of thiophosphinic acids are reported. Ultimately, two major approaches were selected: (1) the Stec reaction of phosphorus amides with carbon disulfide; and (2) the one-pot synthesis of thiophosphorus acids from H-phosphinates, an organometallic nucleophile, and quenching with elemental sulfur. An application to the preparation of a potential chiral phosphorus organocatalyst is also reported.

Full text of DOI:10.1021/acs.joc.0c01151

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Article
Evaluation and Development of Methodologies
for the Synthesis of Thiophosphinic Acids
Karen R. Winters, and Jean-Luc Montchamp
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01151 • Publication Date (Web): 28 Jul 2020
Downloaded from pubs.acs.org on August 9, 2020
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Evaluation and Development of Methodologies for the Synthesis of Thiophosphinic Acids
Karen R. Winters, and Jean-Luc Montchamp*
Department of Chemistry, Box 298860, Texas Christian University, Fort Worth, Texas 76129
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(USA). E-mail: j.montchamp@tcu.edu
Table of Contents Graphic:
2O
P
R1
base, CS2
S
P
2
O
P
R2
1) R M
R
H
NHR3
2) S8
Stec reaction
R1
OH
OR
R1
Thiophosphorus Acids
1
2
Abstract: Thiophosphorus acids R R P(S)OH constitute an important class of organophosphorus
1
2
compounds, in which the phosphorus atom is intrinsically chiral if R ≠ R . In connection with a
project aimed at the preparation of chiral thiophosphorus acids, various available literature
methods were considered, but few fit the requirement of odorless reagents. Herein, the results of
our studies on the synthesis of thiophosphinic acids are reported. Ultimately, two major
approaches were selected: 1) the Stec reaction of phosphorus amides with carbon disulfide; and
2
) the one-pot synthesis of thiophosphorus acids from H-phosphinates, an organometallic
nucleophile, and quenching with elemental sulfur. An application to the preparation of a
potential chiral phosphorus organocatalyst is also reported.
Introduction
Recently, our laboratory became interested in the preparation of thiophosphorus acids
1
2
1
R R P(S)OH 1, in connection with a project aimed at developing novel chiral phosphorus acids
(
CPAs) organocatalysts.2 Thiophosphorus acids have been known for a long time,1a and
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resolution to a chiral compound was described as early as 1958.1b They exist as a mixture of
tautomers: thionic acid 1a and thiolic acid 1b (Scheme 1).1a The major tautomer depends on the
substituents, although it is generally thionic acid 1a.
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Scheme 1. Prototropic Tautomerism in Thiophosphorus acids.
OH
P
OH
P
O
P
R2
R2
R2
2O
P
R
R1
S
R1
S
R1
SH
R1
SH
thionic 1a
thiolic 1b
Table 1. Summary of Methodologies for the Preparation of Thiophosphinic Acids and Related
Compounds
Entry
Reaction
Comments
Ref.
3
O
P
S
P
R2
H S, MSH, etc.
R2
2
commonly used method
stench, toxic
1
2
R1
Cl
R1
OH
2O
S
commonly used method
odorless
R2
base or silylation
R
4
5
P
P
R1
H
S8
R1
OH
S, Se, BH derivatives
3
commonly used method
stench
often problems during
purification
1
) Lawesson’s
reagent
O
P
S
R2
R2
3
P
2
) dealkylation
R1
OR
R1
OH
1
) (EtO) P(O)CN
2
O
S
R2
Ph CHSH, Et N
R2
2
3
only one literature report
stench
4
5
6
7
P
P
2
) CF COOH
R1
OH
3
R1
OH
(dealkylation)
2O
S
base, CS2
R2
general reaction, stereospecific
odorless
R
P
P
NHR3
(Stec reaction)
R1
R1
OH
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O
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S
P
only one literature example
odorless
S, Se, BH derivatives
1
) R M
R2
OR
6
1
8
R P
2
) S8
R1
OH
H
3
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When reviewing the literature, we realized that many methods utilized conditions that involved
foul-smelling reagents such as Lawesson’s reagent,5,9 phosphorus pentasulfide, thiols, or metal
3
sulfides (Table 1). We desired an approach which would circumvent this drawback.
9
Whereas Lawesson’s reagent has often been used, two issues remain: 1) the foul-smelling
characteristic due to hydrolysis of the reagents to form rotten egg-smelling and highly toxic
hydrogen sulfide H S; and 2) difficulties during isolation and purification of the product
2
1
0
associated with byproducts. In our hands, even the reported Lawesson’s reagent alternatives to
solve problem 2 were not successful. Therefore, we embarked on a study aimed at preparing
thiophosphinates (and related compounds) that would solve these problems. We investigated
various possibilities (Table 1) for the synthesis of thiophosphorus acids, mainly thiophosphinates
(phosphinothioates) and the results are described herein. Ultimately, two methodologies were
selected: 1) the Stec reaction (the Wadsworth-Emmons olefination focusing on the phosphorus
reactant (Table 1, entry 5), and 2) the displacement of H-phosphinates with an organometallic
nucleophile followed by in situ trapping of the intermediate with elemental sulfur (Table 1, entry
6).
Results and Discussion
Any and all literature methods were considered toward our objective of synthesizing
thiophosphorus acids.1,3-8 Very quickly various issues were identified in some of the methods,
and as a result they were deemed unacceptable.
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Our investigation initially focused on the reaction of P(O)Cl (Table 1, entry 1), with the direct
conversion of P(O)(OR) into P(O)LVG (LVG = leaving group, such as chlorine) as its starting
point. Even though the conversion of P(O)(OR) into P(O)Cl is widely reported, the conditions
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typically employ excess chlorinating agent (SOCl
2
, (COCl)
2
, or POCl ) and do not proceed in a
3
one-pot process.11 Alternatives include the use of triflic anhydride (Tf
approach has its own limitations in terms of scope and expense.12
O) even though this
2
Unlike what is claimed in publications championing triflic anhydride chemistry,12 the
transformation has a broad scope and is generally high-yielding, with CH
2
Cl
2
, CH CN, and DMF
3
the best solvents (~90+% yield for the formation of the acid chloride). Thus, we found that using
a small excess (1.2 equiv) of oxalyl chloride produces the acid chloride P(O)Cl cleanly, and in
high yield. The next step was to convert this intermediate into the desired thiophosphorus acid
(Table 1, entry 1). Reaction with NaSH or Na
2
S gave low yields of the desired product because
of the salts' lack of solubility in organic solvents, and competing hydrolysis with the formation of
1
2
1
2
acid R R P(O)OH, anhydride [R R P(O)(OH)] O, and a trace of mixed anhydride
2
1
2
1
2
R R P(S)OP(O)R R . On top of that, the reagents have an awful stench.
The next step was to replace the sulfur nucleophile with organic-soluble, odorless, and
inexpensive (6 $/mol) n-dodecyl thiol.13 However, although the formation of the corresponding
thioester was successful, cleavage to the desired thioacid was not. Various conditions were
attempted, such as S
PhMeP(O)SC12
unsuccessful (< 20% NMR yield of desired product in the best case). On the other hand, Na
N
2 with various nucleophiles, but all those failed. Cleavage of
2 with various nucleophiles (DABCO, NaN , TFA/thiourea) was
S (2
H
25 4 via S
N
3
2
equiv)/DMF 100 °C did give a 76% NMR yield (+ 16% unreacted starting material) of desired
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salt, but obviously these conditions are far from odorless, the same reason why thiophenol was
not tried.
a
Scheme 2. Synthesis of Thiophosphorus Acids via TmobSH.
1
1
1
1
1
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1
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1
) (COCl) (1.2 equiv)
2
O
2) TmobSH (1 equiv)
S
Ph
Ph
a)
P OH
P OH
Me
3) CF COOH (6 equiv)
Me
3
H NC(S)NH (2 equiv)
2
2
2
1
c, 87 %
TmobSH (3 equiv)
NaH (3 equiv)
O
S
b)
EtO
EtO
EtO
EtO
P Cl
P OH
3
1d, 76 %
a
31
All yields are determined by P-NMR.
1
4
Thus, we turned to Node's odorless 2,4,6-trimethoxybenzyl thiol (TmobSH) in the place of n-
dodecyl thiol. TmobSH is easily synthesized in three steps from the commercially available
14
aldehyde. In principle, if thiourea were added during the cleavage step, the thiol could be
1
4
recycled, but this recycling was unsuccessful even though the reaction gave the correct product
in an 87% NMR yield (Scheme 2a). This transformation was also tried with an excess of
TmobSH in the hope that the excess deprotonated thiol would cleave the benzyl position of the
phosphothioester. This proved to be successful in a 76% NMR yield (Scheme 2b). However,
despite this sequence of reactions accomplishing the desired transformation, 2 → 1c and 3 → 1d,
the fact that TmobSH could not be recycled (and took 3 steps to synthesize) seemed wasteful and
a significant drawback, thus the approach was set aside.
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The reduction of P(O)SC12
H
25 into P(O)H was considered next, since P(O)H is easily converted
into P(S)OH with elemental sulfur (Table 1, entry 2), and is also a key intermediate in numerous
other transformations. Since the transformation P(O)SR to P(O)H was unknown, this reduction
was briefly examined through the use of alkali metals sodium naphthalide (NaNp) and lithium
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biphenylide (LiDBB), as they have been shown to reduce phosphorus-halogen bonds. (Scheme
3). Interestingly, depending on the stoichiometry of the reducing agent, either the
thiophosphorus acid P(S)OH 1c (Scheme 3a), or the phosphinylidene P(O)H 5 (Scheme 3b)
could be obtained. It appears that 2 equivalents give the thiophosphinic acids 1c, 1d as the major
products (Scheme 3a, 3c, 3e); whereas 4 equivalents produce the more fully reduced
phosphinylidene P(O)H 5 (Scheme 3b, 3d), and the nature of the reducing agent is not as
important as the stoichiometry.
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a
Scheme 3. Naphthalenide and Biphenylide Reduction of Thioesters.
O
NaNp (1M in THF) 2 equiv
THF, rt, Ar
S
a)
b)
Ph
Ph
P SC H
P OH
12 25
Me
Me
1
1
1
1
1
1
1
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1c, 89 %
O
NaNp (1M in THF) 4 equiv
THF, rt, Ar
O
Ph
Ph
P SC H
P H
12 25
Me
Me
4
5, 56 % (+ 42 % 4)
O
S
Ph
LiDBB (1M in THF) 2 equiv
THF, -78 °C, Ar
c)
d)
Ph
P SC H
P OH
Me
1
2
25
Me
4
1c, 51 % (+ 34 % 4)
O
LiDBB (1M in THF) 4 equiv
THF, -78 °C, Ar
O
Ph
Ph
P SC H
P H
Me
1
2
25
25
Me
4
5, 100 %
O
NaNp (1M in THF) 2 equiv
THF, rt, Ar
S
EtO
EtO
EtO
e)
P SC H
1
2
P OH
EtO
6
1d, 87 %
a
31
All yields are determined by P-NMR.
However, although successful, this transformation was not ideal, because it is lengthy and
15
wasteful. Since the direct conversion of P(O)Cl into P(O)H has been reported a few times, the
reduction of P(O)Cl would be a more efficient approach. Our own work to develop this useful
transformation will be reported at a later time.
Considered next, was the reaction of ester P(O)(OR) with Lawesson's reagent (and related
thionating agent),9,10 followed by the cleavage of the intermediate thioester P(S)(OR), perhaps
5
the most commonly employed method (Table 1, entry 3). However, Lawesson's reagent and
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related thionating agents such as phosphorus pentasulfide, all stench (of toxic hydrogen sulfide).
Additionally, the presence of byproducts often impedes purification and lowers the yields of the
intermediate P(S)(OR). Finally, when R = Me, Et, the final cleavage is relatively easy, but we
could not find conditions for the cleavage of menthyl thioesters P(S)(OMen), which limits
applications to P-stereogenic products. Because this approach (Table 1, entry 3) did not meet
several of our requirements, it was quickly abandoned.
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Scheme 4. The Wadsworth-Emmons-Stec Reaction.
OH
O
base, CS2
R2
R1
R2
R1
P NHR3
P
S
Wadsworth-Emmons-Stec
reaction:
8
1
stereospecific
retention
base
CS2
+
H O
3
O
2O
R2
S
R
P NR3
O
P NR3
R2
+
C
NR3
R1
S
R1
P
R1
S
S
S
S
The next iteration focused on the Wadsworth-Emmons-Stec reaction (Table 1, entry 5).16 The
Stec reaction converts a phosphorus amide P(O)NHR 8 using a base and carbon disulfide, into
1
7
the thiophosphorus acid 1, stereospecifically, and isothiocyanate (Scheme 4). Wadsworth and
Emmons made the initial discovery, but Stec was the first to realize the reaction's usefulness in
organophosphorus chemistry.
Reaction of the acid chloride P(O)Cl (either from a commercial reagent, or formed in situ from
the reaction of P(O)(OR) (R = Alk, H)) with a primary amine/aniline unsurprisingly gave good
yields of the corresponding amide P(O)NHR 8. From that point, treatment with a base and CS
2
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delivered the corresponding thiophosphorus acid 1 uneventfully (Table 2). As expected, various
bases were successful in this process. Because the resolutions of various thiophosphorus acid
4
products have been described, this transformation fits all our requirements. It should be noted
1
1
1
1
1
1
1
1
1
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that a comprehensive study of this transformation has not been reported in the literature, and Stec
used it mostly in the area of nucleic acids. An additional advantage is that using inexpensive
chiral 1-phenylethylamine (either isomer: 15-20 $/mol) gives an opportunity for resolution, not
only by crystallization, but also perhaps standard chromatography.
Table 2. Summary of Methodologies for the Preparation of Thiophosphinic Acids and
Related Compounds
O
S
1
) base
R2
R1
R2
R1
P NHR3
P OH
2) CS2
+
3) H O
8a-i
3
1c-h
Entry
Substrate
Conditionsa
Product
Yield (%)b
1
a
A
B
C
90 (88)
88
O
S
EtO
EtO
EtO
1
b
1d
P NHi-Pr
8a
P OH
EtO
1c
77
2a
A
B
C
91
97 (95)
91
O
S
EtO
EtO
EtO
EtO
2
b
1
d
P NHn-Bu
8b
P OH
2
c
3
a
A
B
C
96
100 (99)c
O
S
EtO
EtO
EtO
EtO
3b
8
c
1d
1d
P NHPh
P OH
95c
3
c
4
a
A
B
C
45
81 (75)c
44
S
O
EtO
EtO
4
b
EtO
EtO
8d
P OH
P NH
4c
Ph
Ph
P
Ph
P
5
8e
B
1e
96 (85)
Ph
NH
O
S
OH
Ph
Me
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
O
S
Ph
Ph
6
7
B
D
100 (79)
90 (76)
P NHPh
8f
P OH
1f
EtO
EtO
O
S
EtO
EtO
8
g
1g
P NHPh
P OH
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
S
8
a
B
D
79
94 (85)c
Ph
Ph
8h
1
c
P NHPh
P OH
8
b
Me
Me
O
Ph
S
Ph
P
Ph
P
1
h
88 (72)
HO
N
H
8i
9
E
Me
OBn
OBn
> 99 % de
> 99 % de
a
Conditions A: NaH (3 equiv), THF, 0 °C to rt, 1 h; then CS
BuLi (2 equiv), THF, -78 °C to rt, 1 h; then CS (3 equiv), 2 h. Conditions C: LiHMDS (1.5
equiv), THF, 0 °C to rt, 1 h; then CS (3 equiv), 2 h. Conditions D: LiHMDS (1.25 equiv), THF,
0 °C to rt, 2 h; then CS (5 equiv), overnight. Conditions E: NaH (2.0 equiv), THF, 0 °C to rt,
then CS (5 equiv), overnight. Determined by P-NMR. In parentheses: yield of product (>
5% purity) after extractive work-up. c The reaction with CS
was conducted overnight instead
of 2 h.
2
(3 equiv), 2 h. Conditions B: n-
2
2
2
b
31
2
9
2
Next, the direct transamidation of P(O)OR was investigated.18 In 1968, Cram reported the
reactions of chiral menthyl and cholesteryl phosphinate esters 9a and 9b with lithium amides
derived from aniline and 1-phenylethylamine.18a These reactions proceed stereospecifically with
formation of 10a, 10b and 11, although the yields were mediocre and the stoichiometry wasteful
(Scheme 5a-b). In our case, the reaction of PhP(O)(OMen)CH
OBn19 12 with S-1-
2
phenylethylamine/n-BuLi also proved to take place stereospecifically and in satisfactory yield to
deliver 8i (Scheme 5c). Unfortunately, a similar one-pot transamidation approach was not
successful on phosphonate diesters. In principle, the intermediate phosphorus amide could be
deprotonated in situ with an excess of base and then reacted with CS . This one-pot method was
2
successful in the case of butyl phosphinate 13, however it failed on menthyl phosphinate 12
which was shown to be successful in a stepwise fashion (Table 2, entry 9).
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Scheme 5. Transamidation with Lithium Amides.
O
Ph
n-BuLi/PhNH (10 equiv)
O
OR
Me
2
P
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a)
P
Cram 1968
Me
N
H
Ph
C H , reflux, 12 h
6
6
9a, 9b > 99 % de
a R = Men; b R = cholesteryl
10a, 38 %, > 99 % de
10b, 35 %, > 99 % de
n-BuLi/(S)-PhCH(Me)NH2
10 equiv)
O
Ph
(
O
OMen
Me
Ph
P
P
Me
Cram 1968
b)
c)
N
H
Ph
C H , reflux, 12 h
6 6
Me
9a > 99 % de
11, 25 %, > 99 % de
1
) (S)-PhCH(Me)NH2
(
3 equiv)
O
OMen
OBn
O
Ph
Ph
Me
P
P
Ph
2) n-BuLi (3 equiv)
N
H
THF, - 78 °C
OBn
1
2 (S )-96 % de
8i, 66 %, > 99 % de
p
1
) PhNH (3 equiv)
2
LiHMDS (3 equiv)
THF, 0 °C to rt, 2 h
O
Ph
S
Ph
d)
P OBu
Me
P OH
Me
2
) CS (5 equiv)
2
rt, overnight
1
3
1c, 85 %
An application of these investigations is shown on Scheme 6. In order to replace the expensive,
high molecular weight, and C -symmetrical chiral phosphoric acids based on binaphthol
2
introduced in 2004 by Akiyama20a and Terada,20b we looked for alternatives. 9,10-Dihydro-9-
oxa-10-phosphaphenanthrene-10-oxide (DOPO) is an industrial flame-retardant (> 10,000
tons/year).21 Terphenol 14 was reacted with phosphorus trichloride and cyclized to the
corresponding chloride.22 At this point the P(III)-Cl intermediate 15 can be reacted with chiral
amine PhCH(Me)NH
2
followed by oxidation with H
2
2
O to provide amide 17, or hydrolysis of 15
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
leads to 8-phenyl-DOPO 16. Atherton-Todd reaction23 of 16 with S-1-phenylethylamine
provides the same intermediate 17. This can be resolved easily by column chromatography,
albeit in low yield, into chiral amide S
P
-17 and R
P
-17. The absolute configuration at phosphorus
-17 and R -17 (base
) led to either a racemic ring-opened product or the desired thiophosphorus acid 18,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
was determined by X-ray crystallography. Finally, the Stec reaction on S
P
P
2
4
then CS
2
depending on the nucleophilicity of the base. With sodium hydride, 18 was obtained
2
stereospecifically. The evaluation of Brønsted chiral phosphorus acid (CPA) 18 as a Brønsted
organocatalyst will be reported at a later time.
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Scheme 6. Synthesis of 8-Phenyl-DOPO Chiral Acid Derivative.
Ph
Ph
1) PCl (1.25 equiv)
3
1) PCl (2 equiv)
OH
ZnCl (1.5 mol %),
2
3
ZnCl (0.43 equiv)
150 °C, 8 h
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
1
4
1
50 °C, 8 h
2) H O
2
5
4
1
8
Ph
Ph
1
0
O
O 9
H
2
P
P
O
Cl
1
6 (8-Ph-DOPO)
1
5
1) (S)-PhCH(Me)NH2
CHI (1.2 equiv)
3
(2 equiv)
Et N (1.2 equiv)
3
Et N (2 equiv)
(S)-PhCH(Me)NH2
3
PhCH , 0 °C to rt, 2 h
(1.2 equiv)
3
2
) H O (2 equiv), 4 h
CH CN, 0 °C to rt, 12 h
2
2
3
Ph
Ph
O
O
P
P
HN
O
HN
O
Ph
Me
Ph
Me
17, 78 % from 14
17, 58 % from 14
resolution by
column chromatography
Ph
*
O
P
HN O S -17 (X-ray), 22 %, > 99 % de
P
R -17, 15 %, > 99 % de
P
Ph
Me
1) NaH (3 equiv),
THF, 0 °C to rt, 1 h
2
) CS (10 equiv), 4 h
2
Ph
O
S
*
P
HO
S -18, 76 %, > 98 % ee
P
R -18, 76 %, > 99 % ee
P
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2
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2
2
2
2
2
2
2
2
3
3
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4
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5
5
5
5
5
5
5
5
6
Because our laboratory has been a major contributor in the chemistry of H-phosphinates 19,25
one last approach (Table 1, entry 6) was examined. The displacement of H-phosphinates with
organometallics (RLi, RMgX) is well known to deliver the corresponding secondary phosphine
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
oxide.26 Surprisingly, only one example of functional group interconversion from R1P(O)(OR)H
1
2
to R R P(S)OH could be found in the literature as a two-step process via the isolated secondary
1
2
8
phosphine oxide R R P(O)H intermediate. Because the nucleophilic substitution of a H-
1
2
phosphinate should form R R POM as the intermediate, quenching with elemental sulfur (or
selenium) would deliver the thiophosphorus acid 1 (or selenophosphorus acid 20) directly, in a
one-pot transformation. Indeed, this transformation does occur and the preliminary results are
summarized in Table 3.
Table 3. Preparation of Thiophosphinic Acids and Related Compounds via Nucleophilic
Substitution of H-Phosphinates with Organometallics, Followed by Trapping with Elemental
Sulfur or Selenium
O
2
X
P
1) R M
RO
R2
R1
P H
R1
OH
2) S8 or Se
+
3
) H O
3
1 X = S
0 X = Se
1
9
2
Organometallics
equiv)
Trapping
(equiv)
Substrate
Product
Yield (%)a
Entry
1a
(
H
2
C=CHCH
2.4)
C=CHCH
3.5)
2
MgBr
MgBr
O
BuO
P H
Ph
S
(
S
S
8
8
(3/8)
(5/8)
100 (57)
83 (67)
P OH
Ph
H
2
2
1
b
1i
1
9a
(
O
S
BuO
Ph
P H
37 (-)b
1c
1d
t-BuMgCl (5)
S
S
8
8
(5/8)
(3/8)
P OH
Ph
1
9a
1j
O
S
BuO
Ph
Me
P H
MeLi (2.5)
P OH
100 (91)
Ph
1
c
1
9a
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9
O
S
BuO
Ph
P H
P OH
1
2
e
a
n-BuLi (2.5)
S
8
(3/8)
100 (80)
94 (65)
Ph
1
9a
1k
O
H C=CHCH MgBr
Se
2
2
BuO
Ph
Se (5)
Se (3)
P H
P
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(3.5)
OH
Ph
2
0a
1
9a
2
b
O
Se
P OH
BuO
Ph
P H
n-BuLi (2.5)
100 (72)
97 (62)
Ph
1
9a
20b
O
S
EtO
Bn
H
2
C=CHCH
3.5)
2
MgBr
P H
P OH
3
S (5/8)
8
Bn
(
1
9b
1l
a
31
Determined by P-NMR. In parentheses: yield of product (> 95% purity) after extractive
work-up. b Complex mixture of products; not isolated.
In most instances, the product can be obtained in good purity (> 95%) by a simple extractive
work-up. However, with t-BuMgCl (Table 3, entry 1c) a significant amount of unreacted H-
1
phosphinate 19a is converted into the thiophosphonic acid R P(S)(OR)OH, which prevents
purification. In this case, a two-step process via the secondary phosphine oxide would then be
better (Table 1, entry 2). The organolithium organometallics are superior to the Grignard
reagents (Table 3, entries 1d-e versus 1a-c). Trapping of the phosphinite anion with elemental
selenium was also successful (Table 3, entries 2a-b). Ethyl benzyl-H-phosphinate and butyl
phenyl-H-phosphinate worked equally well (Table 3, entry 3 versus 1b).
1
2
1
Because phosphinates R R P(O)(OR) are typically derived from H-phosphinates R P(O)(OR)H,
this transformation could well be the most efficient approach to thiophosphinic acids
1
2
R R P(S)(OH). In terms of fulfilling our requirement for odorless conditions, this one-pot two-
step reaction, is much better than the multiple pot four-step reaction via the phosphorus amide
1
1
2
1
2
1
2
1
2
(R P(O)(OR)H → R R P(O)(OR)/R R P(O)(OH) → R R P(O)Cl → R R P(O)NHR →
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
2
R R P(S)OH). One drawback (unless the H-phosphinate ester is chiral) is that the racemic
thiophosphinic acid will need to be resolved via a diastereoisomeric salt. Regardless, we intend
to explore more fully the optimization, scope, and limitations of this strategy in a forthcoming
study.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Conclusion
The odorless preparation of thiophosphinic acids and derivatives was investigated. The Stec
reaction of phosphorus amides P(O)NHR was identified as an odorless solution to foul-smelling
conditions (Lawesson’s reagent and related).
Stec and others have investigated the
1
2
1
2
transformation of phosphorus amides into thiophosphorus acids (R R P(O)NHR to R R P(S)OH
and this solves a number of issues. In this report, we confirm the superiority of the Stec reaction
over Lawesson’s reagent and related approaches. The application of compound 18 in
asymmetric organocatalysis will be reported in due course. We also provide an alternative based
on the displacement of H-phosphinate esters with organometallics, followed by trapping of the
intermediate with elemental sulfur or selenium. In the final analysis, the latter strategy seems the
most efficient. Therefore, this promising method will be explored in more detail at a later time.
Notably and in most cases, the two methods (Stec reaction or displacement of H-phosphinates)
that were utilized during this study deliver products in excellent purity without chromatographic
purification, through a straightforward extractive work-up. We expect this work will be useful to
others who may be interested in developing alternatives to the currently widely used C2-
symmetrical chiral phosphorus acids organocatalysts.
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Experimental Section
General Chemistry:
1H NMR spectra were recorded on a 400-MHz Bruker Avance spectrometer. Chemical shifts for
1H NMR spectra (in parts per million) relative to internal tetramethylsilane (Me
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
Si, δ = 0.00
1
3
1
ppm) with deuterated chloroform. C{ H} NMR spectra were recorded at 101 MHz. Chemical
1
3
1
shifts for C{ H} NMR spectra are reported (in parts per million) relative to CDCl (δ = 77.0
3
3
1
ppm). P NMR spectra were recorded at 162 MHz, and chemical shifts reported (in parts per
million) relative to external 85% phosphoric acid (δ = 0.0 ppm). Flash chromatography
experiments were carried out on Silica Gel premium Rf grade (40−75 μm). Ethyl acetate/hexane
or ethyl acetate/methanol mixtures were used as the eluent for chromatographic purifications.
TLC plates were visualized by UV or immersion in permanganate potassium (3 g KMnO
4
, 20 g
K
2
CO , 5 mL 5% aq. NaOH and 300 mL of water) followed by heating. Enantiomeric excess
3
was determined by Chiral HPLC analysis on an (S,S)-Whelk-O1 column in comparison to
authentic racemates. Chiral HPLC analyses were recorded on the Agilent 1100 Series HPLC
system. High resolution mass spectra (HRMS) were obtained by electrospray ionization using a
TOF analyzer.
Reagent and solvents:
All starting materials were purchased from commercial sources and used as received, unless
otherwise noted. Anhydrous THF and DMF were purchased and used as received. The solvents
were distilled under N
2
and dried according to standard procedures (CH
).
3
CN, toluene and
dichloromethane from CaH
2
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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5
6
27
Methyl-phenylphosphinic acid 2. To a solution of phenyl phosphinic acid (10.0 g, 70.38
mmol, 1.0 equiv) in DCM (140 mL) was added bis(trimethylsilyl)acetamide (37.86 mL, 154.83
mmol, 2.2 equiv) at 0 °C under argon. The reaction mixture stirred for 30 min and iodomethane
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
5.26 mL, 84.45 mmol, 1.2 equiv) was added at 0 °C and stirred overnight. The reaction mixture
was quenched with methanol and concentrated under vacuum. Ethyl acetate was added and
washed with a saturated aqueous solution of NaHCO . The two layers were separated the
aqueous layer was acidified with 3 M HCl until pH = 1 and extracted with ethyl acetate. The
3
organic layer was dried over MgSO
4
, filtered and concentrated to afford acid as a white solid 2
3
1
1
(
7.3 g, 66%). P NMR (162 MHz, CDCl
3
) δ 43.3 (s); H NMR (400 MHz, CDCl
3
) δ 11.84 (s,
1H), 7.77 (ddd, J = 12.4, 8.3, 1.4 Hz, 2H), 7.51 (dd, J = 7.6, 1.4 Hz, 1H), 7.44 (ddd, J = 7.6, 3.4,
1
.1 Hz, 2H), 1.63 (d, J = 14.7 Hz, 3H).
Methyl-phenylphosphinothioic acid via TmobSH 1c. To a solution of 2 (0.1 g, 0.64 mmol,
1
.0 equiv) in DCM (2 mL) was added dropwise oxalyl chloride (0.07 mL, 0.77 mmol, 1.2 equiv)
at 0 °C under argon. The reaction mixture stirred for 3 h rt, then 2,4,6-trimethoxybenzyl thiol14a
(0.14 g, 0.64 mmol, 1.0 equiv) dissolved in DCM (2 mL) was added at rt and stirred overnight.
The crude mixture was then washed with 1 M HCl. The two layers were separated, the organic
layer was washed with brine, dried over MgSO , filtered and concentrated under vacuum. This
4
product was used directly in the next step without further purification.
Trifluoroacetic acid (0.3 mL, 3.9 mmol, 6 equiv) was added to a mixture of the
phosphothioester (0.22 g, 0.64 mmol, 1 equiv) and thiourea (97 mg, 1.28 mmol, 2 equiv) in
toluene (1.5 mL). The mixture stirred for 6 h at rt under argon. The reaction mixture was
concentrated under vacuum and the crude was dissolved in ethyl acetate. The organic layer was
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washed with a saturated aqueous solution of NaHCO
aqueous layer was acidified with 3 M HCl until pH = 1 and extracted with ethyl acetate. The
organic layer was dried over MgSO , filtered and concentrated under vacuum to afford crude 1c
as a colorless oil. (NMR Yield: 87%). P NMR (162 MHz, CDCl
MHz, CDCl ) δ 8.36 (s, 1H), 7.90 (ddd, J = 13.7, 8.3, 1.4 Hz, 2H), 7.53 – 7.49 (m, 1H), 7.49 –
7.33 (m, 2H), 2.00 (d, J = 13.8 Hz, 3H); C{ H} NMR (101 MHz, CDCl
3
. The two layers were separated, the
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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1
3
) δ 77.28 (s); H NMR (400
3
1
3
1
3
) δ 135.2 (d, J = 104.6
Hz), 132.1 (d, J = 3.0 Hz), 130.3 (d, J = 11.8 Hz), 128.5 (d, J = 13.2 Hz), 25.1 (d, J = 78.4 Hz);
+
HRMS (EI+) m/z: [M + H] Calcd for C
7
9
H OPS 173.0184; Found 173.0185.
Diethyl-phosphorothioic acid via TmobSH 1d.28 To a solution of 2,4,6-trimethoxybenzyl
thiol (1.86 g, 8.7 mmol, 3.0 equiv) in THF (20 mL) was added NaH (60 % dispersion in mineral
oil, 0.34 g, 8.7 mmol, 3.0 equiv) at 0 °C, under argon. After 10 min, diethyl chlorophosphate (0.5
g, 2.89 mmol, 1 equiv) was added dropwise and the reaction stirred overnight at rt. Ethyl acetate
was then added and the organic layer was washed with a saturated aqueous solution of NaHCO
3
.
The two layers were separated, the aqueous layer was acidified with 3 M HCl until pH = 1 and
extracted with ethyl acetate. The organic layer was dried over MgSO
4
, filtered and concentrated
31
under vacuum to afford crude 1d as a light yellow oil. (NMR Yield: 76%). P NMR (162 MHz,
1
CDCl
3
) δ 64.5 (s); H NMR (400 MHz, CDCl
3
) δ 8.00 (s, 1H), 4.13 (m, J = 9.3, 7.0 Hz, 4H),
1
.32 (t, J = 7.1 Hz, 6H).
Dodecyl-methylphenylphosphinothioate 4. To 2 (3.0 g, 19.2 mmol, 1.0 equiv) in DCM
100 mL) was added dropwise oxalyl chloride (2.0 mL, 23.0 mmol, 1.2 equiv) at 0 °C under
(
argon. The reaction mixture stirred for 3 h rt, then directly added at 0 °C to a solution of 1-
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dodecanethiol (9.2 mL, 38.4 mmol, 2.0 equiv) and NaH (60 % dispersion in mineral oil, 1.9 g,
4
8.0 mmol, 2.5 equiv) that had previously been stirring for 1 h. The reaction mixture stirred
overnight at rt. The organic layer was washed with a saturated aqueous solution of NH Cl. The
two layers were separated, and the organic layer was washed with brine, dried over MgSO
filtered and concentrated under vacuum. The crude was purified by column chromatography
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
,
3
1
(hexanes/ethyl acetate 50:50) to afford pure 4 as a white solid (4.8 g, 78%). P NMR (162 MHz,
1
CDCl
3
) δ 46.4 (s); H NMR (400 MHz, CDCl
3
) δ 7.93 – 7.78 (m, 2H), 7.62 – 7.45 (m, 3H), 2.87
–
2.74 (m, 1H), 2.73 – 2.60 (m, 1H), 1.97 (d, J = 13.3 Hz, 3H), 1.65 – 1.50 (m, 2H), 1.36 – 1.13
1
3
1
(
m, 18H), 0.89 (s, 3H); C{ H} NMR (101 MHz, CDCl
3
) δ 134.4 (d, J = 103.2 Hz), 132.1 (d, J
= 3.2 Hz), 130.8 (d, J = 10.4 Hz), 128.7 (d, J = 13.0 Hz), 31.9, 30.6 (d, J = 4.7 Hz), 29.6, 29.5,
9.4, 29.3, 28.9, 28.7 (d, J = 2.6 Hz), 28.5, 22.7, 21.2, 20.5, 14.1; HRMS (EI+) m/z: [M + H]+
2
Calcd for C19H33SOP 341.2062; Found 341.2056.
Dodecyl-diethylphosphorothioate 6.29 To a solution of 1-dodecanethiol (5.5 mL, 23.18
mmol, 1.0 equiv) in THF (100 mL) was added at 0 °C NaH (60 % dispersion in mineral oil, 1.4
g, 34.77 mmol, 1.5 equiv) and stirred under argon for 1 h at rt, then diethyl chlorophosphate
(
3.36 mL, 23.18 mmol, 1.0 equiv) was added dropwise at rt, and stirred for 1 h. The organic
layer was washed with a saturated aqueous solution of NH Cl. The two layers were separated,
and the organic layer was washed with brine, dried over MgSO , filtered and concentrated under
vacuum. The crude was purified by column chromatography (hexanes/ethyl acetate 70:30) to
4
4
31
1
afford pure 6 as a colorless oil (5.5 g, 70%). P NMR (162 MHz, CDCl
3
) δ 28.3 (s); H NMR
(
400 MHz, CDCl ) δ 4.24 – 3.94 (m, 4H), 2.78 (dt, J = 14.4, 7.4 Hz, 2H), 1.64 (p, J = 7.4 Hz,
3
2H), 1.32 (m, J = 7.1, 0.8 Hz, 8H), 1.21 (m, 16H), 0.93 – 0.76 (t, 3H).
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General Procedure for the NaNp and LiDBB Reduction of Thioesters. LiDBB and NaNp
were prepared according to the literature. To a solution of the appropriate thioester, 4 or 6, (1
equiv) in THF (0.1 M) was added dropwise to a freshly prepared 1M solution of LiDBB or NaNp
in THF (2 – 4 equiv), at -78 °C (LiDBB) or rt (NaNp) under argon. The reaction stirred at rt for
the appropriate time (3 – 16 h). Ethyl acetate was added, and the mixture was washed with 3 M
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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2
3
4
5
6
7
8
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0
1
2
3
4
5
6
7
8
9
0
HCl. The two layers were separated, and the organic layer was dried over MgSO
4
, filtered and
concentrated under vacuum.
Methyl-phenylphosphinothioic acid via NaNp 1c. Following the general procedure: To a
solution of 4 (0.40 g, 1.17 mmol, 1.0 equiv) in THF (10 mL) was added dropwise NaNp (1 M in
THF, 2.34 mL, 2.34 mmol, 2.0 equiv) at rt, and stirred for 3 h at rt to afford 1c as a colorless oil
3
1
(
NMR Yield: 89%). P NMR (162 MHz, DMSO-d ) δ 75.9 (s).
6
Methyl-phenylphosphine oxide via NaNp 5.32 Following the general procedure: To a
solution of 4 (0.40 g, 1.17 mmol, 1.0 equiv) in THF (10 mL) was added dropwise NaNp (1 M in
THF, 4.7 mL, 4.7 mmol, 4.0 equiv) at rt, and stirred for 3 h at rt to afford 5 and 4 as a colorless
31
oil (NMR Yield: 56% and 42% respectively). P NMR (162 MHz, CDCl ) δ 42.3 (s), 23.0 (d, J
3
=
485.4 Hz).
Methyl-phenylphosphinothioic acid via LiDBB 1c. Following the general procedure: To a
solution of 4 (0.20 g, 0.58 mmol, 1.0 equiv) in THF (10 mL) was added dropwise LiDBB (1 M
in THF, 1.16 mL, 1.16 mmol, 4.0 equiv) at -78 °C, and stirred for 16 h at rt to afford 1c and 4 as
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6
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a colorless oil (NMR Yield: 51% and 34% respectively). P NMR (162 MHz, CDCl ) δ 77.0 (s),
3
4
0.4 (s).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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9
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Methyl-phenylphosphine oxide via LiDBB 5. Following the general procedure: To a
solution of 4 (0.23 g, 0.7 mmol, 1.0 equiv) in THF (10 mL) was added dropwise LiDBB (1 M in
THF, 2.8 mL, 2.8 mmol, 4.0 equiv) at -78 °C, and stirred for 16 h at rt to afford 5 as a colorless
31
oil (NMR Yield: 100%). P NMR (162 MHz, CDCl ) δ 21.2 (d, J = 488.1 Hz).
3
Diethyl-phosphinothioic acid via NaNp 1d.28 Following the general procedure: To a
solution of 6 (0.40 g, 1.18 mmol, 1.0 equiv) in THF (10 mL) was added dropwise NaNp (1 M in
THF, 2.36 mL, 2.36 mmol, 2.0 equiv) at rt, and stirred for 3 h at rt to afford 1d as a light yellow
3
1
oil (NMR Yield: 87%). P NMR (162 MHz, CDCl
3
) δ 65.5 (s).
1
2
3
1
2
General Procedure for the chlorination of R R P(O)OR and amination of R R P(O)Cl. The
appropriate phosphonate or phosphinate (1.0 equiv) in DCM (0.1 - 0.4 M) was added oxalyl
chloride (1.2 - 2.0 equiv) and DMF (10 mol %) dropwise under argon. The reaction mixture was
brought to reflux and stirred for the appropriate time (24 - 48 h). The crude product was
concentrated under vacuum to remove all volatiles and used directly in the next step.
To a solution of DIPEA (1.2 equiv), amine (1.2 equiv) in DCM (0.5 M) was added at 0
°C the appropriate chlorophosphinate or chlorophosphonate (1.0 equiv) dropwise under argon.
The reaction mixture was brought to room temperature and stirred overnight. The organic layer
was washed with a saturated aqueous solution of NH Cl. The two layers were separated, and the
4
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organic layer was washed with brine, dried over MgSO
4
, filtered and concentrated under vacuum
to afford the pure product either without further purification or after column chromatography.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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Diethyl-N-isopropylphosphoramidate 8a.33 Following the general procedure:
(
EtO)
2
P(O)Cl (1.47 mL, 10.0 mmol, 1.0 equiv) was reacted with isopropylamine (1.03 mL, 12.0
mmol, 1.2 equiv) and DIPEA (2.09 mL, 12.0 mmol, 1.2 equiv) in DCM (20 mL) to afford 8a as
an orange oil (1.6g, 98%). 31P NMR (162 MHz, CDCl
) δ 8.2 (s). H NMR (400 MHz, CDCl ) δ
1
3
3
4
.07 – 3.70 (m, 4H), 3.19 (m, J = 9.4, 8.0, 6.4 Hz, 1H), 2.84 (t, J = 10.1 Hz, 1H), 1.18 (t, J = 7.1
1
3
1
Hz, 6H), 1.02 (d, J = 6.5 Hz, 6H). C{ H} NMR (101 MHz, CDCl
3
) δ 61.8 (d, J = 5.4 Hz), 43.6,
25.1 (d, J = 5.7 Hz), 16.1 (d, J = 7.3 Hz).
Diethyl-N-butylphosphoramidate 8b.34 Following the general procedure: (EtO)
P(O)Cl
2
(1.47 mL, 10.0 mmol, 1.0 equiv) was reacted with n-butylamine (1.19 mL, 12.0 mmol, 1.2
equiv) and DIPEA (2.09 mL, 12.0 mmol, 1.2 equiv) in DCM (20 mL) to afford 8b as an orange
3
1
1
oil (1.8g, 86%). P NMR (162 MHz, CDCl
3.81 (m, 4H), 2.96 – 2.77 (m, 3H), 1.49 – 1.38 (m,2H), 1.33 (d, J = 22.5 Hz, 2H), 1.28 (td, J =
.1, 0.8 Hz, 6H), 0.87 (t, J = 7.3 Hz, 3H).
3
) δ 9.3 (s); H NMR (400 MHz, CDCl
3
) δ 4.12 –
7
3
5
Diethyl-N-phenylphosphoramidate 8c. Following the general procedure: (EtO) P(O)Cl
2
(1.47 mL, 10.0 mmol, 1.0 equiv) was reacted with aniline (1.09 mL, 12.0 mmol, 1.2 equiv) and
DIPEA (2.09 mL, 12.0 mmol, 1.2 equiv) in DCM (20 mL) to afford 8c as an orange oil (1.7g,
1
7
4%). 31P NMR (162 MHz, CDCl
3
) δ 2.5 (s); H NMR (400 MHz, CDCl
3
) δ 7.34 – 7.18 (m,
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H), 7.10 – 7.02 (m, 2H), 6.97 (m, J = 7.4, 1.1 Hz, 1H), 6.66 (d, J = 9.5 Hz, 1H), 4.41 – 3.96 (m,
H), 1.33 (td, J = 7.1, 0.9 Hz, 6H).
0
1
2
3
4
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Diethyl-N-((S)-1-phenylethyl)phosphoramidate 8d.36 Following the general procedure:
(EtO)
2
P(O)Cl (1.47 mL, 10.0 mmol, 1.0 equiv) was reacted with (S)-1-phenylethylamine (1.55
mL, 12.0 mmol, 1.2 equiv) and DIPEA (2.09 mL, 12.0 mmol, 1.2 equiv) in DCM (20 mL) to
afford 8d as an orange oil (1.7g, 62%). 31P NMR (162 MHz, CDCl
MHz, CDCl ) δ 7.33 (s, 2zH), 7.33 – 7.31 (m, 2H), 7.28 – 7.21 (m, 1H), 4.32 (ddd, J = 9.2, 8.5,
.8 Hz, 1H), 4.12 – 4.01 (m, 2H), 3.97 – 3.83 (m, 1H), 3.72 (dt, J = 10.0, 7.2 Hz, 1H), 3.34 (t, J
= 10.1 Hz, 1H), 1.48 (dd, J = 6.8, 1.0 Hz, 3H), 1.32 (td, J = 7.0, 0.8 Hz, 3H), 1.11 (td, J = 7.1,
.9 Hz, 3H).
) δ 7.5 (s); H NMR (400
1
3
3
6
0
1-N-((S)-1-phenylethyl)-2,3-diphenyl-1-phosphindole 8e. Following the general
37
procedure: 1-butyl-2,3-diphenyl-1-phosphindole (8.5 g, 22.70 mmol, 1 equiv) in DCM (200
mL) was added oxalyl chloride (3.96 mL, 45.40 mmol, 2.0 equiv) and DMF (0.17 mL, 2.27
mmol, 10 mol %). The mixture was stirred 24 h at reflux. The crude obtained was solubilized in
DCM (20 mL) and reacted with DIPEA (4.74 mL, 27.24 mmol, 1.2 equiv), (S)-1-
phenylethylamine (3.51 mL, 27.24 mmol, 1.2 equiv), DMAP (0.28 g, 2.27 mmol, 10 mol %) in
3
1
DCM (45 mL) to afford 8e as an orange oil (6.7g, 71%). P NMR (162 MHz, CDCl ) δ 40.38
3
1
(s), 40.34 (s); H NMR (400 MHz, CDCl
3
) δ 7.65 (ddd, J = 10.2, 6.9, 1.5 Hz, 1H), 7.41 (d, J =
7
1
.5 Hz, 1H), 7.39 – 7.35 (m, 4H), 7.21 – 7.05 (m, 11H), 7.04 – 6.95 (m, 2H), 4.30 – 4.07 (m,
1
3
1
H), 3.22 – 3.05 (m, 1H), 1.35 (d, J = 6.8 Hz, 3H); C{ H} NMR (101 MHz, Chloroform-d) δ
148.2 (dd, J = 75.7, 25.6 Hz), 144.5 (d, J = 3.6 Hz), 144.4 (d, J = 2.6 Hz), 142.4 (dd, J = 58.0,
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1.9 Hz), 134.3 (dd, J = 16.9, 5.0 Hz), 133.1 (m), 132.6 (m), 129.1 (m), 128.8 (d, J = 12.2 Hz),
28.6, 128.5, 128.4, 128.3, 128.2, 128.1 (d, J = 2.6 Hz), 128.1 (d, J = 19.7 Hz), 127.6 (d, J =
1
21.9 Hz), 127.0 (d, J = 12.1 Hz), 125.8 (d, J = 17.7 Hz), 123.5 (dd, J = 18.4, 12.5 Hz), 51.0 (d, J
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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2
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7
8
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
=
25.2 Hz), 25.6 (d, J = 7.2 Hz); HRMS (EI+) m/z: [M + H] Calcd for C28
H
24NOP 422.1668;
Found 422.1660.
38
Ethyl-phenyl-N-phenylphosphoramidate 8f. Following the general procedure: diethyl
phenylphosphonate (1.91 mL, 10.0 mmol, 1.0 equiv) in DCM (25 mL) was added oxalyl chloride
(1.04 mL, 12.0 mmol, 1.2 equiv) and DMF (0.08 mL, 1.0 mmol, 10 mol %). The mixture was
stirred 48 h at reflux. After cooling down the reaction to rt, the reaction mixture was added
directly at 0 °C to the aniline (9.11 mL, 100 mmol, 10.0 equiv) and was stirred for 5 h at rt. The
organic layer was washed with a saturated aqueous solution of NH
separated, and the organic layer was washed with brine, dried over MgSO
concentrated under vacuum. The crude product was crystalized in a mixture of ethyl acetate and
4
Cl. The two layers were
4
, filtered and
3
1
1
hexanes to afford 8f as a brown solid (1.8 g, 70%). P NMR (162 MHz, CDCl
NMR (400 MHz, CDCl ) δ 8.05 – 7.81 (m, 2H), 7.50 (dd, J = 7.5, 1.7 Hz, 1H), 7.43 (m, J = 7.8,
.8 Hz, 2H), 7.15 (m, J = 7.7 Hz, 2H), 7.01 – 6.94 (m, 2H), 6.89 (d, J = 7.4 Hz, 1H), 4.41 – 4.29
3
) δ 17.5 (s); H
3
3
(m, 1H), 4.26 – 4.09 (m, 1H), 1.41 (t, J = 7.1 Hz, 3H).
Allyl-O-ethyl-N-phenylphosphoramidate 8g. Under neat conditions allyl bromide (0.87
mL, 10.0 mmol, 1.0 equiv) and triethyl phosphite (1.71 mL, 10.0 mmol, 1.0 equiv) were brought
to reflux for 24 h under argon. After concentration under vacuum, following general procedure,
the crude product was solubilized in DCM (25 mL) and oxalyl chloride (1.05 mL, 12.0 mmol,
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.2 equiv) and DMF (0.08 mL, 1.0 mmol, 10 mol %) were added and stirred at reflux for 24 h.
After cooling down the reaction to rt, the reaction mixture was added directly at 0 °C to the
aniline (9.11 mL, 100 mmol, 10.0 equiv) and was stirred for 5 h at rt. The organic layer was
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washed with a saturated aqueous solution of NH
organic layer was washed with brine, dried over MgSO
vacuum. The crude obtained was purified by column chromatography (ethyl acetate 100%) to
4
Cl. The two layers were separated, and the
4
, filtered and concentrated under
31
1
afford 8g as a brown oil (1.6 g, 88%). P NMR (162 MHz, CDCl
MHz, CDCl ) δ 7.25 (dd, J = 8.5, 7.2 Hz, 2H), 7.09 – 7.02 (m, 3H), 6.98 – 6.86 (m, 1H), 5.91 –
.69 (m, 1H), 5.19 – 5.00 (m, 2H), 4.23 mt, J = 10.2, 7.2 Hz, 1H), 4.06 (m, J = 10.2, 7.8, 7.0 Hz,
3
) δ 25.9 (s); H NMR (400
3
5
1
3
1
1H), 2.85 – 2.67 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H); C{ H} NMR (101 MHz, Chloroform-d) δ
1
40.6, 129.4, 127.1 (d, J = 10.4 Hz), 121.2, 120.3 (d, J = 14.2 Hz), 117.3 (d, J = 6.3 Hz), 60.3 (d,
+
J = 7.2 Hz), 31.7 (d, J = 127.1 Hz), 16.2 (d, J = 6.9 Hz); HRMS (EI+) m/z: [M + H] Calcd for
C
11
H
16NO P 226.0991; Found 226.0991.
2
3
9
Methyl-N,P-diphenylphosphinic amide 8h. Following the general procedure: To 2 (7.3
g, 46.75 mmol, 1.0 equiv) in DCM (125 mL) was added dropwise oxalyl chloride (5.4 mL, 62.52
mmol, 1.2 equiv) at 0 °C under argon. The reaction mixture stirred overnight at rt, then was
added directly at 0 °C to the aniline (42.6 mL, 467.5 mmol, 10.0 equiv) and was stirred for 5 h at
rt. The organic layer was washed with a saturated aqueous solution of NH
were separated, and the organic layer was washed with brine, dried over MgSO
concentrated under vacuum. The crude obtained was purified by column chromatography (ethyl
4
Cl. The two layers
4
, filtered and
3
1
acetate 100%) to afford 8h as a brown solid (9.2 g, 85%). P NMR (162 MHz, DMSO-d ) δ 23.9
6
1
(s); H NMR (400 MHz, DMSO-d
6
) δ 8.09 (d, J = 11.8 Hz, 1H), 7.79 – 7.71 (m, 2H), 7.49 (m, J
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=
7.6, 7.2, 3.9 Hz, 3H), 7.08 (dd, J = 8.5, 7.3 Hz, 2H), 7.03 – 6.86 (m, 2H), 6.80 – 6.59 (m, 1H),
1
3
1
1
.70 (d, J = 14.2 Hz, 3H); C{ H} NMR (101 MHz, DMSO-d ) δ 142.8, 134.8 (d, J = 120.1
6
Hz), 131.9 (d, J = 2.7 Hz), 131.6 (d, J = 10.1 Hz), 129.3, 129.0 (d, J = 12.3 Hz), 120.6, 117.8 (d,
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+
J = 6.8 Hz), 17.7 (d, J = 91.7 Hz); HRMS (EI+) m/z: [M + H] Calcd for C13
H14NOP 232.0886;
Found 232.0891.
(S
p
)-N-((S)-1-phenylethyl)(benzoxymethyl)phenylphosphinic amide 8i. To a solution of
(S)-1-phenylethylamine (0.48 mL, 3.74 mmol, 3.0 equiv) in THF (6 mL) at -78 °C was added
dropwise n-BuLi (2.5 M in Hexanes, 1.30 mL, 3.25 mmol, 2.6 equiv) and stirred for 1 h under
argon. (Sp)-menthyl(benzoxymethyl)phenylphosphinate19a 12 (0.5 g, 1.25 mmol, 1.0 equiv), in
THF (4 mL) at -78 °C was added dropwise to the reaction mixture and stirred for 3 h at rt. The
organic layer was washed with a saturated aqueous solution of NH
acetate. The two layers were separated, and the organic layer was washed with brine, dried over
MgSO , filtered and concentrated under vacuum. The crude obtained was purified by column
chromatography (ethyl acetate/methanol 100:0 – 90:10) to afford 8i as a white solid (300 mg,
4
Cl and extracted with ethyl
4
3
1
1
66%). P NMR (162 MHz, CDCl
3
) δ 25.3 (s); H NMR (400 MHz, CDCl ) δ 7.95 (ddd, J =
3
1
1.7, 8.2, 1.4 Hz, 2H), 7.57 (dd, J = 7.5, 1.5 Hz, 1H), 7.53 – 7.46 (m, 2H), 7.45 – 7.40 (m, 2H),
.36 – 7.26 (m, 6H), 7.20 – 7.14 (m, 2H), 4.59 (td, J = 8.7, 6.7 Hz, 1H), 4.42 (s, 2H), 3.80 – 3.73
7
1
3
1
(m, 2H), 3.32 (t, J = 8.6 Hz, 1H), 1.49 (d, J = 6.7 Hz, 3H); C{ H} NMR (101 MHz, CDCl ) δ
3
145.2 (d, J = 4.2 Hz), 137.1, 132.3 (d, J = 2.9 Hz), 132.1 (d, J = 9.5 Hz), 132.1, 130.9, 128.5 (d,
J = 12.5 Hz), 128.4 (d, J = 12.4 Hz), 127.9, 127.9, 127.2, 126.2, 75.1 (d, J = 12.9 Hz), 67.1 (d, J
+
=
110.0 Hz), 50.1 (d, J = 1.4 Hz), 25.6 (d, J = 5.0 Hz); HRMS (EI+) m/z: [M + H] Calcd for
C
22
H
24NO P 366.1617; Found 366.1631.
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General Procedure of Stec Reaction with Conditions A. To the appropriate phosphoramidate
or phosphinic amide (1 equiv) in THF (0.1 M) was added NaH (60 % dispersion in mineral oil,
3.0 equiv) at 0 °C under argon. The reaction mixture stirred at rt for 1 h. Carbon disulfide (3.0
equiv) was then added dropwise and stirred for 2 h at rt. Ethyl acetate was then added and the
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organic layer was washed with a saturated aqueous solution of NaHCO
separated, the aqueous layer was acidified with 3 M HCl until pH = 1 and extracted with ethyl
acetate. The organic layer was washed with brine, dried over MgSO , filtered and concentrated
3
. The two layers were
4
under vacuum to afford the pure product either without further purification.
General Procedure of Stec Reaction with Conditions B. To the appropriate phosphoramidate
or phosphinic amide (1 equiv) in THF (0.1 M) was added n-BuLi (2.5 M in Hexanes in mineral
oil, 2.0 equiv) at -78 °C under argon. The reaction mixture stirred at rt for 1 h. Carbon disulfide
(3.0 equiv) was then added dropwise and stirred for 2 h at rt. The workup and purification
followed the same procedure as in the general procedure with conditions A.
General Procedure of Stec Reaction with Conditions C. To the appropriate phosphoramidate
or phosphinic amide (1 equiv) in THF (0.1 M) was added lithium bis(trimethylsilyl)amide (1.25
M in toluene, 1.5 equiv) at 0 °C under argon. The reaction mixture stirred at rt for 1 h. Carbon
disulfide (3.0 equiv) was then added dropwise and stirred for 2 h at rt. The workup and
purification followed the same procedure as in the general procedure with conditions A.
General Procedure of Stec Reaction with Conditions D. To the appropriate phosphoramidate
or phosphinic amide (1 equiv) in THF (0.1 M) was added lithium bis(trimethylsilyl)amide (1.25
M in toluene, 1.5 equiv) at 0 °C under argon. The reaction mixture stirred at rt for 1 h. Carbon
disulfide (5.0 equiv) was then added dropwise and stirred overnight at rt. The workup and
purification followed the same procedure as in the general procedure with conditions A.
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General Procedure of Stec Reaction with Conditions E. To the appropriate phosphoramidate
or phosphinic amide (1 equiv) in THF (0.1 M) was added NaH (60 % dispersion in mineral oil,
2.0 equiv) at 0 °C under argon. The reaction mixture stirred at rt for 1 h. Carbon disulfide (5.0
equiv) was then added dropwise and stirred overnight at rt. The workup and purification
followed the same procedure as in the general procedure with conditions A.
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Diethyl-phosphorothioic acid 1d (Table 2, Entry 1a). Following general procedure A:
8
a (0.19 g, 1.0 mmol, 1.0 equiv) was reacted with NaH (60 % dispersion in mineral oil, 3.0
mmol, 3.0 equiv) in THF (10 mL). Carbon disulfide (0.18 mL, 3.0 mmol, 3.0 equiv) was added
3
1
1
to afford 1d as a light yellow oil. (0.15 g, 88%). P NMR (162 MHz, CDCl
3
) δ 65.4; H NMR
(400 MHz, CDCl
3
) δ 8.00 (s, 1H), 4.13 (m, J = 9.3, 7.0 Hz, 4H), 1.32 (t, J = 7.1 Hz, 6H).
2
8
Diethyl-phosphorothioic acid 1d (Table 2, Entry 2b). Following general procedure B:
b (0.21 g, 1.0 mmol, 1.0 equiv) was reacted with n-BuLi (0.8 mL, 2.5 M in Hexanes, 2.0 mmol,
.0 equiv) in THF (10 mL). Carbon disulfide (0.18 mL, 3.0 mmol, 3.0 equiv) was added to afford
8
2
3
1
1
1d as a light yellow oil (0.16 g, 95%). P NMR (162 MHz, CDCl
3
) δ 65.4 (s); H NMR (400
MHz, CDCl ) δ 8.00 (s, 1H), 4.13 (m, J = 9.3, 7.0 Hz, 4H), 1.32 (t, J = 7.1 Hz, 6H).
3
2
8
Diethyl-phosphorothioic acid 1d (Table 2, Entry 3b). Following general procedure B:
8c (0.23 g, 1.0 mmol, 1.0 equiv) was reacted with n-BuLi (0.8 mL, 2.5 M in Hexanes, 2.0 mmol,
2
.0 equiv) in THF (10 mL). Carbon disulfide (0.18 mL, 3.0 mmol, 3.0 equiv) was added and
3
1
stirred overnight to afford 1d as a light yellow oil (0.17 g, 99%). P NMR (162 MHz, CDCl ) δ
3
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