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

Abstract

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.

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Because of their 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.

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. Moreover, aliphatic thiols are applicable to this reaction to produce the corresponding products in high yields. It is known that aliphatic thiols react with CCl₄. Therefore, these substrates could not be used under the traditional Todd-conditions.¹⁶

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 °C) 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).

Table 1 Chloroform-based Atherton–Todd-type reaction of 4-tert-butylphenyl thiol with diphenylphosphine oxides^a

Run	1a	Base	Yield^b
a Conditions: 1a, 2a (0.1 mmol), base and 1 mL CHCl3 were stirred at room temperature (25 °C) for 3 h.b ^31P NMR yield using triphosphine oxide as an internal standard.c 0.5 h.
1	1 equiv.	2 equiv. LiOH	17%
2	1 equiv.	2 equiv. Li2CO3	N.R.
3	1 equiv.	2 equiv. NaOBu-t	4%
4	1 equiv.	2 equiv. KOBu-t	N.R.
5	1 equiv.	2 equiv. LiOBu-t	28%
6	1.5 equiv.	2 equiv. LiOBu-t	59%
7	2 equiv.	2 equiv. LiOBu-t	96%
8	2 equiv.	1.5 equiv. LiOBu-t	84%
9	2 equiv.	1 equiv. LiOBu-t	64%
10^c	2 equiv.	2 equiv. LiOBu-t	98%

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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, 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 diphenylphosphine 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).

Table 2 Cross coupling of secondary phosphine oxides with Z–H compounds in chloroform^a

Run	1	2	3–5, yield^b
a Conditions: 1 (0.4 mmol), thiols or alcohols or selenol (0.2 mmol), LiOBu-t (0.4 mmol), CHCl3 (1.0 mL), room temperature (25 °C), 0.5 h.b Isolated yield.c 0.3 mmol 1 was loaded.d Regioselectivity: 10 : 1.

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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, entries 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 hydroxy 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

Conclusions

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.

Acknowledgements

Partial financial supports from NFSC (21403062, 21373080), HNNSF 2015JJ3039, the Fundamental Research Funds for the Central Universities (Hunan University) are gratefully acknowledged.

Notes and references

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Footnote

† 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/c5ra16015d

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