Chloroform-based Atherton-Todd-type reactions of alcohols and thiols with secondary phosphine oxides generating phosphinothioates and phosphinates

Article abstract of DOI:10.1039/c5ra16015d

Chloroform-based Atherton-Todd-type reactions of alcohols and thiols with secondary phosphine oxides, generating phosphinothioates and phosphinates, respectively, are described. Various valuable phosphinothioates and phosphinates including those with functional groups are readily prepared under mild reaction conditions.

Full text of DOI:10.1039/c5ra16015d

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DOI: 10.1039/C5RA16015D
Chloroform-Based Atherton-Todd-Type Reactions of
Alcohols and Thiols with Secondary Phosphine Oxides
Generating Phosphinothioates and Phosphinates
Shan Li, Tieqiao Chen, Yuta Saga and Li-Biao Han
Chloroform-based Atherton-Todd-type reactions of alcohols and thiols with secondary phosphine oxides,
generating phosphinothioates and phosphinates, respecetively, are described. Various valuable
phosphinothioates and phosphinates including those with functional groups are readily prepared under
mild reaction conditions.

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Chloroform-Based Atherton-Todd-Type Reactions of
Alcohols and Thiols with Secondary Phosphine Oxides
Generating Phosphinothioates and Phosphinates
Received 00th January 20xx,
Accepted 00th January 20xx
Shan Li,a Tieqiao Chen,*a Yuta Saga,b and Li-Biao Han*c
DOI: 10.1039/x0xx00000x
www.rsc.org/
Chloroform-based Atherton-Todd-type reactions of alcohols and Moreover, aliphatic thiols are applicable to this reaction to produce
thiols with secondary phosphine oxides, generating the corresponding products in high yields. It is known that aliphatic
phosphinothioates and phosphinates, respectively, are described. thiols react with CCl4. Therefore, these substrates could not be used
Various valuable phosphinothioates and phosphinates including under the traditional Todd-conditions.16
those with functional groups are readily prepared under mild
Table 1 Chloroform-based Atherton-Todd-type reaction of 4-tert-
butylphenyl thiol with diphenylphosphine oxides.a
reaction conditions.
Because of the unique properties, phosphinothioates and
phosphinates are widely applied in organic synthesis,
pharmacochemistry and agrochemistry.1-6 The reaction of P(O)-H
compounds with alcohols and thiols, namely Atherton-Todd
reaction, is one of the most powerful methods for the preparation
of these compounds.7-23 Unfortunately, however, this reaction
usually requires the use of the toxic tetrachloromethane as the
halogenating reagent and solvent. Although other reactive
halocompounds such as CHBr3, CHI3 could also serve well for this
reaction,19-22 the Atherton-Todd reaction hardly took place in
simple CHCl3 under similar reaction conditions.21,22 However, there
is a practical need to replace CCl4 with CHCl3 since CHCl3 is cheaper
and easier handling than CCl4.
a Conditions: 1a, 2a (0.1 mmol), base and 1 mL CHCl3 were stirred at room
temperature (25 oC) for 3 h. b 31P NMR yield using triphosphine oxide as an
internal standard.. c 0.5 h.
During the ongoing studies on the construction of P(O)-Z bonds
via P(O)-H/Z-H bonds cross coupling,15,16,24,25 we found that
chloroform acted as the right halogenating reagent and solvent in
the Atherton-Todd type reaction in the presence of LiOBu-t. Thus, in
the presence of 2 equiv LiOBu-t, diphenylphosphine oxide coupled
readily with equivalent 4-tert-butylphenyl thiol in chloroform at
room temperature (25 oC) in 3 h, affording the corresponding
phosphorothioate 3a in 28% yield (Table 1, entry 5). The reaction
efficiency could be further improved. When 1.5 equiv
diphenylphosphine oxide was loaded, 59% yield of 3a was obtained
(Table 1, entry 6). By increasing the amount of diphenylphosphine
oxide to 2 equiv, 3a was generated almost quantitatively (Table 1,
entry 7). Worth noting is that this reaction proceed rapidly and
could complete in half an hour (Table 1, entry 10).
(1)
Herein, we report the phosphorylation of alcohols and thiols
with secondary phosphine oxides could be accomplished in
chloroform, producing the corresponding phosphinothioates and
phosphinates in moderate to high yields (eqn 1). This
transformation is very facile and is complete in half an hour.
a.State Key Laboratory of Chemo/Biosensing and Chemometrics, College of
Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China.
E-mail: chentieqiao@hnu.edu.cn.
b.Katayama Chemical Industries Co., Ltd., 26-22, 3-Chome, Higasinaniwa-cho,
Amagasaki, Hyogo 660-0892, Japan;
c.National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba,
Ibaraki 305-8565, Japan. E-mail: libiao-han@aist.go.jp.
Electronic Supplementary Information (ESI) available: [General information,
experimental procedures, characterized data and copies of 1H, 13C and 31P NMR
spectra for products]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Table 2 Cross coupling of secondary phosphine oxides with Z-H compounds
in chloroform.a
producing the corresponding organophosphorus compounds in
good to high yields. Thus, the derivatives of benzenethiol with Me,
t-Bu and MeO groups on the benzene ring all coupled with
diphenylphosphine oxide to give the corresponding products in
good yields (Table 2, entries 1-3). A substrate with amido group was
phosphorylated to produce the expected phosphorothioate 3d in
83% yield (Table 2, entry 4). 4-F-benzenethiol also reacted with
diphenylphosphine oxide readily under similar reaction conditions
(Table 2, entry 5). However, when benzenethiol analogue with
electron-withdrawing CF3 group was employed, only trace of
product was generated (Table 2, entry 6). Phosphinothioate 3g was
also obtained in high yield from the cross coupling of naphthalene-
1-thiol with diphenylphosphine oxide in chloroform (Table 2, entry
7). Worth noting is that aliphatic thiols, which did not react with H-
phosphinates under the standard Atherton-Todd reaction
conditions,16 also served as the good substrates in the present
reaction system. For example, both cyclohexanethiol and octane-1-
thiol coupled with diphenylphosphijne oxide in chloroform to give
the corresponding products 3h and 3i in 72% and 89% yields,
respectively (Table 2, entries 8 and 9). Secondary phosphine oxides
(p-MeC6H4)2P(O)H and Cy2P(O)H could also couple with thiols in
chloroform, generating the expected products phosphinothioates in
good yields (Table 2, entries 10 and 11). However, when secondary
phosphine oxides with small alkyl group were used as substrate,
low yields were given (Table 2, entries 12 and 13).
Interestingly, phosphinates can also be prepared from the
facile cross coupling of alcohols with secondary phosphine oxide in
chloroform by the aid of LiOBu-t. As shown as entries 14-21 in Table
2, both electron-rich and electron-deficient phenols acted as good
coupling partners to yield the corresponding phosphinates in high
yields. Thus, phenol coupled readily with diphenylphosphine oxide
in chloroform to produce 4a in 82% yield (Table 2, entry 14). Phenol
analogues with t-Bu and MeO groups served well and were
converted to the expected phosphinates in high yields (Table 2,
entries 15 and 16). 4-Fulorophenol reacted with 1a smoothly in this
coupling system (Table 2, entry 17). Intriguingly, the substrate with
electron-withdrawing
CF3
group
also
coupled
with
diphenylphosphine oxide to yield phosphinate 4e in 81% yield
(entry 18). Aliphatic alcohols like phenylmethanol and styralyl
alcohol were also phosphorylated by diphenylphosphine oxide to
give 4f and 4g in 70% and 85% yields, respectively (Table 2, entries
19 and 20). In the presence of LiOBu-t, chloroform also promoted
the phosphorylation of complex molecules with diphenylphosphine
oxide, facilitating the introduction of the Ph2P(O) group into the
bioactive molecules estrone and estradiol (Table 2, antries 21 and
22). Worth noting is that a phenolic hydroxy group is more reactive
than an alcoholic hydroxy group, resulting in the highly selective
phosphorylation of the phenolic OH group under the present
reaction conditions.26 For example, product from the cross coupling
of the phenolic hydrox group was produced predominately in the
phosphorylation of estradiol with diphenylphosphine oxide (Table 2,
entry 22). Benzeneselenol also worked well to couple with 1a,
furnishing the corresponding phosphinoselenoate 5a in high yield
(Table 2, entry 23).27
a Conditions: 1 (0.4 mmol), thiols or alcohols or selenol (0.2 mmol), LiOBu-t
b
(0.4 mmol), CHCl3 (1.0 mL), room temperature (25 oC), 0.5 h. Isolated
yield. c 0.3 mmol 1 was loaded. d regioselectivity: 10:1
This cross coupling is applicable to other substrates; various Z-
H compounds including thiols, alcohols and selenols reacted with
secondary phosphine oxides in chloroform under similar conditions,
Conclusions
2 | J. Name., 2012, 00, 1-3
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27 For synthesis of phosphinothioates and phosphinoselenoates,
also see: (a) N. Liu, L.-L. Mao, B. Yang and S.-D. Yang, Chem.
Commun., 2014, 50, 10879; (b) M. Arisawa, T. Ono and M.
Yamaguchi, Tetrahedron Lett., 2005, 46, 5669; (c) M.
In summary, we disclosed that chloroform served well in the
Atherton-Todd-type reactions of alcohols and thiols with
secondary phosphine oxides, replacing the highly toxic CCl4, as
the halogenating reagent and solvent. This transformation
completed rapidly and provided an efficient method for the
preparation of phosphinothioates and phosphinates under
mild reaction conditions.
Grayson, C. E. Farley and C. A. Streuli, Tetrahedron, 1967, 23
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Nomoto, M. Sonoda and A. Ogawa, Organometallics, 2011,
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Notes and references
‡ Parꢀal financial supports from NFSC (21403062, 21373080),
HNNSF 2015JJ3039, the Fundamental Research Funds for the
Central Universities (Hunan University) are gratefully
acknowledged.
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