Synthesis of Unsymmetrical Tertiary Phosphine Oxides via Sequential Substitution Reaction of Phosphonic Acid Dithioesters with Grignard Reagents

Article abstract of DOI:10.1021/acs.orglett.7b01796

A facile synthetic method for unsymmetrical tertiary phosphine oxides is reported. Sequential treatment of phosphonodithioic acid S,S-di(p-tolyl) esters with two Grignard reagents enabled the stepwise introduction of different carbon substituents on the phosphorus atom. The chemical stability of dithioesters and monosubstituted thioesters has enhanced the utility of this method, rendering a wide range of organophosphorus compounds easily available.

Full text of DOI:10.1021/acs.orglett.7b01796

Letter
pubs.acs.org/OrgLett
Synthesis of Unsymmetrical Tertiary Phosphine Oxides via
Sequential Substitution Reaction of Phosphonic Acid Dithioesters
with Grignard Reagents
Yoshitake Nishiyama, Yuki Hazama, Suguru Yoshida,* and Takamitsu Hosoya*
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU),
2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
S
* Supporting Information
ABSTRACT: A facile synthetic method for unsymmetrical tertiary
phosphine oxides is reported. Sequential treatment of phosphonodithioic
acid S,S-di(p-tolyl) esters with two Grignard reagents enabled the
stepwise introduction of different carbon substituents on the phosphorus
atom. The chemical stability of dithioesters and monosubstituted
thioesters has enhanced the utility of this method, rendering a wide
range of organophosphorus compounds easily available.
of exactly 1 equiv of an organometallic reagent is necessary
during the first substitution reaction (A to B) to avoid the
overreaction that affords the undesired product F, which made
the method difficult to apply to the synthesis of unsymmetrical
phosphines especially in a small laboratory scale. Therefore, for
convenience, an alternative method was developed that uses a
secondary amino group as a temporary protective group (A to
D).7,8 However, this approach necessitates the regeneration of
the P−Cl bond via chlorination under acidic conditions (E to B).
Moreover, starting materials and intermediates used and
produced in these conventional methods are unstable
phosphorus electrophiles, which contain P−Cl and/or phos-
phorus−nitrogen bonds and are difficult to purify by silica-gel
column chromatography. In this context, a more convenient
method for the synthesis of organophosphorus compounds is
required. Herein, we report an efficient synthetic method for
unsymmetrical tertiary phosphine oxides through a sequential
substitution reaction of stable phosphonic acid dithioesters,
which can be readily prepared from phosphonic dichlorides
(Figure 1B, A to 1), with Grignard reagents (1 to 3 via 2).
Screening of several phenylphosphonic acid ester derivatives 1
in the reaction with a phenyl Grignard reagent indicated that
di(p-tolyl)thioester 1a14 suited our purpose in terms of chemical
stability15 and reactivity (Table 1). Treatment of a solution of 1a
in tetrahydrofuran (THF) with 2 equiv16 of phenylmagnesium
bromide at −40 °C for 1 h afforded the desired monosubstituted
compound 2a in high yield (entry 1). In this reaction, formation
of only a small amount of undesired diphenylated product 3a,
resulting from the overreaction of the Grignard reagent with 2a,
was observed. By contrast, when S,S-dialkyl phenylphosphono-
dithioate 1b was used, a large amount of the starting material 1b
remained unreacted (entry 2). Replacing the leaving group of 1a
with a bulky o-tolylthio or an electron-deficient p-
rganophosphorus compounds play significant roles in
Osynthetic organic chemistry, and they have a wide range of
applications in various fields, including organometallic chem-
istry,1 medicinal chemistry,2 chemical biology,3 and materials
science.4 To prepare useful organophosphorus compounds,
numerous carbon−phosphorus (C−P) bond-forming reactions
have been developed.5−13 For the synthesis of unsymmetrical
tertiary phosphines or phosphine oxides, which have three
different substituents on the phosphorus atom, a sequential
substitution reaction of an organodichlorophosphorus com-
pound with organometallic reagents, which involves the
formation of C−P bonds via cleavage of phosphorus−chlorine
(P−Cl) bonds, has been conventionally employed (Figure 1A).6
However, this approach requires the experiment to be conducted
under precisely controlled conditions. In particular, the addition
Figure 1. Synthetic methods for unsymmetrical tertiary phosphines and
phosphine oxides. (A) Conventional methods. (B) Our method
reported herein.
Received: June 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01796
Org. Lett. XXXX, XXX, XXX−XXX

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Table 1. Leaving Group (LG) Screening
Table 2. First Substitution Reaction of Phosphonodithioic
S,S-Di(p-tolyl) Esters
a
Yields determined by 1H NMR analysis unless otherwise noted. N.D.
b
c
= not detected. Isolated yield in parentheses. The reaction was
performed at 0 °C for 2 h using 3.0 equiv of PhMgBr.
(trifluoromethyl)phenylthio group resulted in the increase of the
amount of undesired diphenylated compound 3a (entries 3 and
4). In sharp contrast to S,S-diaryl phenylphosphonodithioates,
which reacted smoothly with a phenyl Grignard reagent at −40
°C (entries 1, 3, and 4), the reaction of the same Grignard
reagent with di-p-tolyl phenylphosphonate (1e) did not proceed
at all at −40 °C (entry 5) and proved sluggish even at a higher
temperature (0 °C) to nonselectively give a mixture of products
in low yields (entry 6).17 These results clearly demonstrated the
advantage of using the p-tolylthio group as a leaving group for the
monoselective substitution reaction.
a
b
Isolated yields. The reaction was performed at room temperature for
c
2 h. The reaction was performed at room temperature for 12 h.
d
Yields using 1.2 equiv of Grignard reagents in parentheses.
Various phosphinic acid thioesters 2 were prepared by the
monoselective substitution reaction of phosphonodithioic acid
S,S-di(p-tolyl) esters 1 with slight modifications of the reaction
conditions depending on the substrates (Table 2). Various
Grignard reagents were utilized in the monosubstitution reaction
of phenylphosphonodithioate 1a. For example, p-methoxy-, p-
chloro-, and o-methylphenylation took place to yield the
monosubstituted products 2f−h, respectively, using the
corresponding Grignard reagents (entries 1−3). Notably, the
introduction of bulky mesityl and 2,4,6-triisopropylphenyl
groups could also be achieved by increasing the reaction
temperature and reaction time to afford 2i and 2j in high yields
(entries 4 and 5). Various alkyl groups, including primary,
secondary, tertiary, and cyclic alkyl groups, could also be
introduced to give 2k−n, demonstrating the remarkable leaving
ability of the p-tolylthio group (entries 6−9). Moreover,
monophenylation of arylphosphonodithioates, such as 1f and
1g, which bear either an electron-donating or an electron-
withdrawing group, and alkylphosphonodithioate 1h proceeded
smoothly to afford the corresponding phosphinic acid thioesters
2f, 2o, and 2k, respectively (entries 10−12). All phosphinic acid
thioesters 2f−o prepared by this method were sufficiently stable
to be purified by standard silica-gel column chromatography
without special care.
Figure 2. Synthesis of various tertiary phosphine oxides by second
substitution reaction.
changing the Grignard reagent, other substituents, such as p-
methoxyphenyl, bulky o-tolyl, acyclic alkyl, and cyclic alkyl
groups, could also be installed to efficiently afford unsymmetrical
tertiary phosphine oxides 3c−f, which are difficult to synthesize
by the conventional methods. The second substitution reaction
using significantly bulky Grignard reagents such as tert-
butylmagnesium chloride did not proceed at all even when the
reaction temperature was increased. This could be attributed to
the sterically hindered character of phosphinic acid thioesters
when compared with phosphonic acid dithioesters.
Synthesis of a phosphine oxide bearing a bulky substituent was
achieved by performing the reactions with the relevant Grignard
reagents in the appropriate order. In particular, the bulky
Grignard reagent needs to be used in the first substitution
reaction, and then the less sterically hindered counterpart must
Further substitutive arylation or alkylation of phosphinic acid
thioesters using the remaining p-tolylthio group as a leaving
group enabled the synthesis of a wide range of tertiary phosphine
oxides (Figure 2). For example, upon treatment of phosphinic
acid thioester 2g with a phenyl Grignard reagent at room
temperature, the second substitution reaction proceeded
smoothly to afford phosphine oxide 3b in high yield. By
B
DOI: 10.1021/acs.orglett.7b01796
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
be used in the second substitution reaction. For example,
although phosphine oxide 3h was prepared efficiently by the
reaction of 2i, which has a preinstalled mesityl group, with a p-
chlorophenyl Grignard reagent, 3h was not obtained from the
reaction of 2g with a bulky mesityl Grignard reagent even
performing the reaction at a higher temperature (Scheme 1).18
Scheme 1. Changing the Order of Addition of Grignard
Reagents
The large difference in reactivity between phosphonic acid
dithioesters and phosphinic acid thioesters toward Grignard
reagents enabled the preparation of tertiary phosphine oxides in a
simple one-pot reaction (Scheme 2). For example, treatment of
Figure 3. Synthesis of phosphinate analogues of phthalides. (A) Two-
step synthesis by batch reactions. (B) Synthesis using a flow
microreactor system for the second reaction.
Scheme 2. One-Pot Synthesis of an Unsymmetrical Tertiary
Phosphine Oxide
magnesium exchange reaction with an isopropyl Grignard
reagent at −40 °C. This enabled the selective generation of the
aryl anion 4 that proceeded without a second substitution
reaction taking place on the phosphorus atom. Subsequent
treatment of the reaction mixture with chlorodiphenylphosphine
afforded o-phosphanylphenylphosphinic acid thioester 2q.
Further treatment of 2q with an ethyl Grignard reagent afforded
phosphine oxide 3j, which was successfully reduced by a
conventional method19 to give diphosphinobenzene derivative 5.
Trapping an o-magnesiated phenylphosphinic acid thioester
with an aldehyde afforded a unique multisubstituted cyclic
phosphinic acid ester (Figure 3A). Indeed, treatment of
phosphinic acid thioester 2r, which was prepared from
dithioester 1j and p-methoxyphenylmagnesium bromide, with
an isopropyl Grignard reagent, followed by the addition of p-
tolualdehyde (6) and acidic workup, afforded a mixture of cyclic
phosphinic acid esters20 8a and 8b, which are phosphorus
analogues21 of phthalides, with high diastereoselectivity.
Furthermore, conducting this transformation using a flow
microreactor system22 improved the total yield of 8a and 8b
(Figure 3B). This is probably because the unstable carbanion
species,23 generated from 2r via a bromo−magnesium exchange
reaction, was rapidly trapped by the aldehyde. Notably, using the
flow system, the reaction could be conducted in a shorter period
of time at room temperature, thus making the process more
practical.
1a with 2 equiv of o-tolylmagnesium bromide at room
temperature followed by the addition of the more reactive n-
butylmagnesium chloride at the same temperature selectively
afforded the unsymmetrical tertiary phosphine oxide 3i in high
yield.
Use of phosphinic acid thioesters with moderately reactive
phosphorus−sulfur bonds enabled the synthesis of various types
of organophosphorus compounds via the generation of a
carbanion species (Scheme 3 and Figure 3). For example,
Scheme 3. Synthesis of Unsymmetrical o-
Diphosphinobenzene Derivative
In summary, we have developed a facile synthetic method for
unsymmetrical tertiary phosphine oxides using phosphonodi-
thioic acid S,S-di(p-tolyl) esters. The two p-tolylthio groups of
dithioesters served as suitable leaving groups in a sequential
substitution reaction that proceeded in a stepwise manner
through treatment with two Grignard reagents, allowing for the
sequential introduction of different carbon substituents on the
phosphorus atom. The chemical stability of thioester inter-
mediates rendered the method practical, enabling the synthesis
of a broad range of organophosphorus compounds. Further
unsymmetrical o-diphosphinobenzene derivative 5 was easily
prepared from o-bromophenylphosphonic acid dithioester 1i via
the formation of three new C−P bonds (Scheme 3). Treatment
of 1i with a p-tolyl Grignard reagent afforded the monosub-
stituted phosphinic acid thioester 2p, which includes an
untouched bromo group that proved susceptible to a halogen−
C
DOI: 10.1021/acs.orglett.7b01796
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
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Org. Lett. 2010, 12, 1568. (b) Yoshida, S.; Hosoya, T. Chem. Lett. 2013,
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01796.
Experimental procedures, characterization for new com-
pounds including copies of NMR spectra (PDF)
́ ́
́ ́
Leonardo, C.; Raja, R.; Lopez-Ortiz, F.; del Aguila-Sanchez, M. A.;
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: s-yoshida.cb@tmd.ac.jp.
*E-mail: thosoya.cb@tmd.ac.jp.
ORCID
Takamitsu Hosoya: 0000-0002-7270-351X
Notes
The authors declare no competing financial interest.
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(15) The stability of phosphonic acid dithioester 1a was checked under
various conditions. See the Supporting Information for details.
(16) From the reaction of 1a using 1.2 equiv of PhMgBr were obtained
2a, 3a, and unreacted 1a in 66%, 3%, and 25% yields, respectively. We
generally used 2.0 equiv of Grignard reagents to consume phosphonic
acid dithioesters smoothly.
ACKNOWLEDGMENTS
■
This work was supported by the Platform Project for Supporting
Drug Discovery and Life Science Research funded by the Japan
Agency for Medical Research and Development (AMED); JSPS
KAKENHI Grant Nos. 15H03118 (B; T.H.), 16H01133
(Middle Molecular Strategy; T.H.), 26350971 (C; S.Y.),
17K13266 (Young Scientists B; Y.N.); Suntory Foundation for
Life Sciences (S.Y.); Naito Foundation (S.Y.).
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