Synthesis of benzyl sulfidesviasubstitution reaction at the sulfur of phosphinic acid thioesters

Article abstract of DOI:10.1039/d0cc02039g

An ambident electrophilicity of phosphinic acid thioesters is disclosed. Unexpected carbon-sulfur bond formation took place in the reaction between phosphinic acid thioesters and benzyl Grignard reagents. The developed method for benzyl sulfides has a wide substrate scope and was applicable for the synthesis of a drug analog.

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Synthesis of benzyl sulfides via substitution reaction at the sulfur
of phosphinic acid thioesters†
Yoshitake Nishiyama, Takamitsu Hosoya and Suguru Yoshida*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An ambident electrophilicity of phosphinic acid thioesters is with phenylmagnesium bromide at the phosphorus atom to
disclosed. Unexpected carbon–sulfur bond formation took place in smoothly give triphenylphosphine oxide (2a), treatment of 1a
the reaction between phosphinic acid thioesters and benzyl
Grignard reagents. The developed method for benzyl sulfides has a
wide substrate scope and was applicable for the synthesis of a drug
analog.
Sulfides play significant roles in various fields such as medicinal
chemistry, agrochemistry, and materials science, and thus many
synthetic methods for sulfides have been developed.1,2
Especially, a group of benzyl sulfides have attracted synthetic
chemists because of their utility. Benzyl sulfides are used not
only as protected thiols3 or precursors of sulfenyl chlorides,4 but
also as important structures of bioactive compounds such as
sulconazole5 or dosulepin.6 However, the synthesis of benzyl
sulfides depends almost only on the nucleophilic attack of thiols
to alkyl halides, often suffering from the limited scope as well as
the unpleasant odor of thiols, especially of benzyl mercaptans.
Herein, we disclose a new synthetic method for benzyl sulfides
via the reaction between benzyl Grignard reagents and
phosphinic acid thioesters, which have a phosphorus–sulfur
bond.
Previously, we found that Grignard reagents attacked the
phosphorus atoms7,8 of phosphonic acid dithioesters to give
phosphinic acid thioesters, which also reacted with Grignard
reagents at higher temperature by further substitution reactions
on the phosphorus atoms to provide a wide range of phosphine
oxides.9 In the course of further investigation for the reactivity
of phosphinic acid thioesters, we unexpectedly found that these
compounds behaved as two-faced “ambident” electrophiles.10,11
Thus, while S-(4-tolyl) diphenylphosphinothioate (1a) reacted
Fig. 1 (A) Abnormal reactivity of a benzyl Grignard reagent toward a phosphinic acid
thioester. (B) Nucleophilic substitution reaction of heteroatom–heteroatom compounds.
(C) Sulfonyl chlorides. (D) Sulfonamides. (E) Phosphinic acid thioesters.
a. 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. E-mail: s-yoshida.cb@tmd.ac.jp
† Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization for new compounds including NMR spectra. For ESI see DOI:
with a benzyl Grignard reagent furnished the target phosphine
oxide 2b only in low yield, along with benzyl sulfide 3a as the
10.1039/x0xx00000x
major product (Figure 1A). This result suggested a possibility
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that benzyl sulfide 3a was obtained directly by the reaction of the acid ester 1f, benzyl sulfide 3a was obtained VwiewitAhrticpleeOrfnelincet
DOI: 10.1039/D0CC02039G
benzyl Grignard reagent at the sulfur atom of phosphinic acid selectivity (entry 6).
thioester 1a,12 contrary to our previous report that C–P bond
Benzylation of phosphinic acid thioester 1e using other
formation took place using alkyl and aryl Grignard reagents.
benzyl Grignard reagents allowed for efficient preparation of
To date, several reports switching the bond-forming site have various benzyl sulfides (Figure 2). Indeed, 4-chlorobenzylation
been reported in the substitution reaction using electrophiles and 1-naphthylmethylation of 1e proceeded smoothly to give 3b
bearing a heteroatom–heteroatom bond depending on the and 3c, respectively. A benzyl Grignard reagent bearing a methyl
nucleophiles examined (Figure 1B). For instance, reactions of group at the benzylic position was also applicable to the C–S
sulfonyl chlorides with aryl Grignard reagents result in C–Cl bond formation, affording benzyl sulfide 3d in high yield.
bond formation to afford aryl chlorides10a or C–S bond formation Furthermore, bulky (2-phenylpropan-2-yl)magnesium chloride
to afford sulfones10b according to the type of Grignard reagents successfully reacted with 1e to furnish sulfide 3e, which is not
(Figure 1C). Two types of substitution reactions of sulfonamides easy to synthesize by the conventional method using thiols and
have been also developed; P–N bond formation occurred by the alkyl halides. In addition, a 1-phenylvinyl Grignard reagent did
reaction with phosphide anion,10c while various nucleophiles not participate in the C–S bond forming reaction.
such as water attacked selectively on the sulfur atom (Figure
1D). However, limited numbers of the ambident electrophiles
were reported so far and controlling the ambident electrophilicity
is not easy.11 These limited but significant site-selective
reactions motivated us to examine the C–S bond-forming
reaction of phosphinic acid thioesters with benzyl Grignard
reagents in terms of the site-selectivity for efficient synthesis of
benzyl sulfides (Figure 1E).
Table
1 Effect of Substituents on the Phosphorus Atom upon the Selectivity of
Nucleophilic Attack
Fig. 2 Reactions of a phosphinic acid thioester with various benzyl Grignard reagents.
Table 2 Alkylation of Thiophosphinic Acid and Benzylation of Phosphinic Acid Thioesters
yield (%)a
entry
R
1
2
3a
62
12
33
2
7
1
2
3
4
5
6
Ph
1a
1b
1c
1d
1e
1f
2b
2c
2d
2e
2f
n-Bu
c-Hex
o-Tol
Mes
OEt
30
7
86 (88)b
69
5 (6)b
10
NDc
2g
79
entry
R–X
MeI
1
yield
(%)a
97
product
MeS–Bn
3
yield
(%)a
82
aNMR yields unless otherwise noted. bIsolated yields in parentheses. cNot detected.
1
2
1g
1h
3g
3h
To improve the site-selectivity and to clarify the generality
of the reaction, a variety of phosphinic acid thioesters 1, which
have different substituents on the phosphorus atoms, were
subjected to the reaction with a benzyl Grignard reagent (Table
1). Changing the substituents on the phosphorus atom from a
phenyl group to alkyl groups such as butyl or cyclohexyl group
decreased the selectivities, affording the desired sulfide 3a in low
yields (entries 2 and 3). On the other hand, S-benzylation of S-
(4-tolyl) di(2-tolyl)phosphinothioate (1e) proceeded smoothly to
afford benzyl sulfide 3a in the highest yield among tested,
accompanying with a small amount of phosphine oxide 2f (entry
4). Thus, we successfully controlled the ambident
electrophilicity of phosphinic acid thioesters by changing the
substrates, enabling efficient S-benzylation in terms of the yield
and selectivity. With a bulkier mesityl group, the selectivity
rather degraded (entry 5). In addition, when using thiophosphoric
TsO
OTs
11
96
78
80
3
4
5
1i
3i
Br
Br
O
O
1j
quant
83
3j
40
Br
Ph
Me
1k
3k
NDb
aIsolated yields. bNot detected.
The use of readily available thiophosphinic acid 4 enabled
easy access to various alkyl di(2-tolyl)phosphinothioates 1,
which were also benzylated by treating with a benzyl Grignard
reagent (Table 2). Alkylation of 4 with a variety of alkyl halides
afforded phosphinothioates 1g–k without damaging functional
groups such as amino, bromo, and tosyloxy groups (entries 1–4).
When the synthesized phosphinic acid thioesters 1g–j were
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treated with benzylmagnesium chloride, S-benzylation is shown in Figure 3A including direct substitution reaction of
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proceeded smoothly to give benzyl sulfides 3g–j. Notably, a phosphinic acid thioesters 1 with a benzDyOl IG: 1r0i.g1n03a9rd/Dr0eCaCg0e2n0t39oGn
bromo group and a tosyloxy group were tolerated under the the sulfur atom (path a). Other reaction mechanisms involving
benzylation conditions. On the other hand, S-benzylation of the ligand coupling of pentavalent organophosphorus
bulky -methylbenzyl ester prepared from 1k did not occur intermediate I (path b) or the single-electron transfer (SET) (path
(entry 5).
c) could not be excluded at this stage. Considering that C–P bond
Not only alkyl phosphinothioates, an array of aryl formation took place using various alkyl or aryl Grignard
phosphinothioates were also prepared via the Chan–Lam–Evans- reagents probably through pentavalent phosphorus intermediates,
type deborylthiolation (Table 3).13 Treatment of the the S-benzylation via P-benzylation and subsequent ligand
corresponding boronic acid with thiophosphinic acid 4 in the coupling14 of the resulting pentavalent phosphorus intermediate
presence of triethylamine and a catalytic amount of copper(II) I to give the benzyl sulfide is also possible (path b). Another
triflate and bipyridyl afforded a variety of phosphinic acid possibility is shown as path c through the SET mechanism,
thioesters, such as substituted phenyl thioesters 1l–p (entries 1– followed by S-benzylation between thiyl radical III and benzyl
5), 2-naphthyl thioester 1q (entry 6), 3-thienyl thioester 1r (entry radical to give the benzyl sulfide.
7), and styryl thioester 1s (entry 8). Benzylation of these
phosphinic acid thioesters proceeded smoothly to give
corresponding benzyl sulfides 3l–s (entries 1–8). It is noteworthy
that benzyl 3-thienyl sulfide (3r) and benzyl styryl sulfide (3s)
were generally difficult to synthesize because of the lack of the
availability of the corresponding thiols. Thus, these results
clearly demonstrated the utility of this method via the Chan–
Lam–Evans-type deborylthiolation.
Table 3. Chan–Lam–Evans-type Synthesis and Benzylation of Phosphinic Acid Thioesters
yield
(%)a
yield
(%)a
entry
1
R
1
3
1l
86
83
59
82
74
3l
97
88
61
77
57
MeO
2
3
4
5
1m
1n
1o
1p
3m
3n
3o
3p
Me2N
F3C
Fig. 3 Reactions of a phosphinic acid thioester with various benzyl Grignard reagents.
Me
Br
To gain insight into the mechanism, we at first examined the
products of the reaction between di(2-tolyl)phosphinic acid
thioester 1e and a benzyl Grignard reagent (Figure 3B). The
result showed that di(2-tolyl)phosphine oxide (5) was obtained
after the protonation of the phosphinate anion in paths a–c as a
leaving group,15 along with benzyl sulfide 3a. Then, we next
treated phosphinic acid thioester 1t, equipped with a benzyl
group in advance, with phenylmagnesium bromide to verify the
possibility of path b involving the pentavalent phosphorus
intermediate having benzyl and sulfanyl groups (Figure 3C). As
a result, phosphine oxide 2a was obtained similar to our previous
report9 without generation of benzyl sulfide 3a and
diarylphosphine oxide 5, suggesting that path b involving
6
7
8
1q
1r
1s
83
41
53
3q
3r
3s
67
87
61
S
aIsolated yields. bpy = 2,2’-bipyridyl.
We next turned our attention to the mechanism of this
unusual S-benzylation (Figure 3). Plausible reaction mechanism
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reductive elimination of the phosphorus is not plausible. In order
to verify the possibility of the SET mechanism, S-(4-penten-1-
yl) di(4-tolyl)phosphinic acid thioester (1u) was subjected to the
S-benzylation reaction (Figure 3D). While benzyl 4-penten-1-yl
sulfide (3t) was obtained in high yield, any radical-cyclization
products16 were not detected in the reaction.17 From these results,
benzyl sulfides would be generated via direct attack of benzyl
Grignard reagents on the sulfur atoms of phosphinic acid
thioesters.
Notes and references
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DOI: 10.1039/D0CC02039G
1
(a) T. Yamamoto and K. Takimiya, J. Am. Chem. Soc., 2007, 129,
2224; (b) M. Feng, B. Tang, S. H. Liang and X. Jiang, Curr. Top. Med.
Chem., 2016, 16, 1200; (c) N. Wang, P. Saidhareddy and X. Jiang, Nat.
Prod. Rep., 2020, 37, 246.
2
(a) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003, 42,
5400; (b) A. Ghaderi, Tetrahedron, 2016, 72, 4758; (c) Z. Qiao and X.
Jiang, Org. Biomol. Chem., 2017, 15, 1942; (d) T. Matsuzawa, S.
Yoshida and T. Hosoya, Tetrahedron Lett., 2018, 59, 4197.
J. L. Wood and V. du Vigneaud, J. Biol. Chem., 1939, 131, 267.
N. Kharasch and R. B. Langford, Org. Synth., 1964, 44, 47.
F. C. Odds, C. E. Webster and A. B. Abbott, J. Antimicrob.
Chemother., 1984, 14, 105.
3
4
5
By using the developed benzyl sulfide synthesis, we
synthesized an analog of tiopinac, which is a highly potent anti-
inflammatory, analgesic, and anti-pyretic agent.18 Treatment of
6
7
E. Richelson and M. Pfenning, Eur. J. Pharmacol., 1984, 104, 277.
For substitution reactions of compounds bearing phosphorus–
heteroatom bonds, see: (a) C. Lopin, G. Gouhier, A. Gautier and S. R.
Piettre, J. Org. Chem., 2003, 68, 9916; (b) A. Sato, H. Yorimitsu and
K. Oshima, Angew. Chem., Int. Ed., 2005, 44, 1694; (c) T. Wada, A.
Kondoh, H. Yorimitsu and K. Oshima, Org. Lett., 2008, 10, 1155; (d)
M.-C. Lamas and A. Studer, Org. Lett., 2011, 13, 2236; (e) Y. Sato,
S.-i. Kawaguchi, A. Nomoto and A. Ogawa, Angew. Chem., Int. Ed.,
2016, 55, 9700; (f) T. Murai, Y. Maekawa, Y. Hirai, K. Kuwabara and
M. Minoura, RSC Adv., 2016, 6, 15180; (g) Y. Maekawa, T. Maruyama
and T. Murai, Org. Lett., 2016, 18, 5264; (h) Y. Maekawa, K.
Kuwabara, A. Sugiyama, K. Iwata, T. Maruyama and T. Murai, Chem.
Lett., 2017, 46, 1068; (i) Y. Okugawa, Y. Hayashi, S. Kawauchi, K.
Hirano and M. Miura, Org. Lett., 2018, 20, 3670; (j) R. J. Reddy, A.
Shankar and A. H. Kumari, Asian J. Org. Chem., 2019, 8, 2269.
D. J. Jones, E. M. O'Leary and T. P. O'Sullivan, Tetrahedron Lett.,
2018, 59, 4279.
phosphinic
acid
thioester
1e
with
2-bromo-5-
methoxybenzylmagnesium bromide gave benzyl sulfide 3u
without damaging the bromo group (Scheme 1). Palladium-
catalyzed carbonylation of phenyl bromide in methanol afforded
methyl ester 6. Hydrolysis of the ester moiety, and following
intramolecular Friedel–Crafts cyclization19 of the resulting
carboxylic acid provided tiopinac analog 7 in shorter steps.
8
9
Y. Nishiyama, Y. Hazama, S. Yoshida and T. Hosoya, Org. Lett.,
2017, 19, 3899.
10 (a) N. Hendricks, P. Himmelberg and E. Fossum, Polym. Prepr. (Am.
Chem. Soc., Div. Polym. Chem.), 2007, 48, 1004; (b) W. Lin, O. Baron
and P. Knochel, Org. Lett., 2006, 8, 5673; (c) S. Yoshida, K. Igawa
and K. Tomooka, J. Am. Chem. Soc., 2012, 134, 19358.
11 For examples of studies on ambident electrophiles, see: (a) C. C. P.
Wagener, A. M. Modro and T. A. Modro, J. Phys. Org. Chem., 1991,
4, 516; (b) P. Tundo, L. Rossi and A. Loris, J. Org. Chem., 2005, 70,
2219.
12 For recent reviews of masked thiols as electrophilic sulfur surrogates,
see: (a) H. Liu and X. Jiang, Chem. Asian J., 2013, 8, 2546; (b) Z. Qiao
and X. Jiang, Org. Biomol. Chem., 2017, 15, 1942; (c) P. Mampuys,
C. R. McElroy, J. H. Clark, R. V. A. Orru and B. U. W. Maes, Adv.
Synth. Catal., 2020, 362, 3.
13 To our knowledge, this is the first example of Chan–Lam–Evans-type
coupling between a boronic acid and a thiophosphinic acid. For a
related reaction, Tang and coworkers reported one-pot synthesis of S-
aryl phosphorothioates probably including a Chan–Lam–Evans-type
process: J. Xu, L. Zhang, X. Li, Y. Gao, G. Tang and Y. Zhao, Org.
Lett., 2016, 18, 1266.
Scheme 1 Synthesis of Tiopinac Analog. DPPP = 1,3-bis(diphenylphosphino)propane.
PPA = polyphosphoric acid.
In summary, we found an ambident electrophilicity of
phosphinic acid thioesters. While the reactions using various
alkyl and aryl Grignard reagents results in C–P bond formations,
S-benzylation took place by treatment of phosphinic acid
thioesters with benzyl Grignard reagents, probably via the direct
nucleophilic S-benzylation reaction at the sulfur atom. The
developed S-benzylation reaction allowed for synthesizing a
variety of benzyl sulfides involving an intermediate of a drug
analog from phosphonic acid thioesters and Grignard reagents.
Further studies of ambident electrophiles based on the
heteroatom chemistry are now underway.
This work was supported by JSPS KAKENHI Grant
Numbers JP19K05451 (C; S.Y.), JP19K15711 (Young
scientists; Y.N.), JP18H02104 (B; T.H.), and JP18H04386
(Middle Molecular Strategy; T.H.); the Naito Foundation (S.Y.);
the Japan Agency for Medical Research and Development
(AMED) under Grant Number JP19am0101098 (Platform
Project for Supporting Drug Discovery and Life Science
Research, BINDS); and the Cooperative Research Project of
Research Center for Biomedical Engineering.
14 Y. Uchida, K. Onoue, N. Tada, F. Nagao and S. Oae, Tetrahedron
Lett., 1989, 30, 567.
15 (a) C. Tejo, J. H. Pang, D. Y. Ong, M. Oi, M. Uchiyama, R. Takita and
S. Chiba, Chem. Commun., 2018, 54, 1782; (b) T. Yano, T. Kawasaki,
T. Yuhki, N. Ishida and M. Murakami, Org. Lett., 2018, 20, 1224.
16 M. P. Winters, C. A. Teleha, F.-A. Kang, D. McComsey, J. C. O'Neill,
C. Hou, T. Kirchner, P. Wang, D. Johnson and Z. Sui, Bioorg. Med.
Chem. Lett., 2014, 24, 2137.
17 The possibility of the reaction pathway involving the benzyl radical
generated only from benzylmagnesium chloride by the dissociation
was not excluded.
18 J. Ackrell, Y. Antonio, F. Franco, R. Landeros, A. Leon, J. M.
Muchowski, M. L. Maddox, P. H. Nelson, W. H. Rooks, A. P.
Roszkowski and J. M. Muchowski, J. Med. Chem., 1978, 21, 1035.
19 S. A. Laufer, G. M. Ahrens, S. C. Karcher, J. S. Hering and R. Niess,
J. Med. Chem., 2006, 49, 7912.
Conflicts of interest
There are no conflicts to declare.
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Graphical abstract for the contents page
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DOI: 10.1039/D0CC02039G
xxx
Synthesis of benzyl sulfides via substitution reac-
tion at the sulfur of phosphinic acid thioesters
Yoshitake Nishiyama, Takamitsu Hosoya and Suguru
Yoshida*
An ambident electrophilicity of phosphinic acid thioesters is
disclosed. Unexpected carbon–sulfur bond formation took place in
the reaction between phosphinic acid thioesters and benzyl
Grignard reagents. The developed method for benzyl sulfides has
a wide substrate scope and was applicable for the synthesis of a
drug analog.
6 | Chem. Commun., 20XX, 00, 1-4
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