Abstract
The room temperature radical addition of sodium hypophosphite to terminal alkynes produces the previously unknown 1-alkyl-1,1-bis-H-phosphinates in moderate yield. The reaction is initiated by R3B and air and proceeds under mild conditions in an open container. The bis-sodium salts precipitate spontaneously from the reaction mixtures, thus providing a simple purification procedure and the opportunity for multigram synthesis. The 1,1-bis-H-phosphinate products are novel precursors of the biologically important 1,1-bisphosphonates.
We recently reported a novel and general approach towards H-phosphinate derivatives, based on the room temperature radical addition of hypophosphorous compounds to alkenes (Equation 1).1 Since then, we have studied the reactions of alkynes with sodium hypophosphite under similar conditions and discovered the formation of a new class of compounds: 1-alkyl-1,1-bis-H-phosphinates. 2 We now report the results of this study.
The thermal, peroxide-initiated radical reaction of hypophosphorous acid with alkynes has been studied by Nifant’ev and coworkers.3 Several products were identified depending on the conditions employed (Equation 2). A mixture of trans- and cis-alkenyl-H-phosphinic acids were produced as the major components, along with minor amounts of disubstituted 1,2-bis-H-phosphinic acids. Nifant’ev had also investigated alkenes under the same conditions.4 Previously, we found that our milder reaction conditions considerably expanded the scope of H-phosphinates which could be produced both in terms of functional group tolerance on the alkene, and hypophosphorous reagent employed.1 These differences prompted the study of alkynes as substrates under our R3B/air and room temperature conditions.
As a model study, the reaction of sodium hypophosphite with 1-hexyne was investigated using Et3B/air to promote radical formation. The results are summarized in Table 1. Methanol was initially selected as solvent, since sodium hypophosphite has no significant solubility in other common organic solvents at room temperature. Interestingly, the novel 1,1-bis-H-phosphinate was always obtained as the major product (the remaining filtrate contains some unreacted alkyne, along with small amounts of the 1,2-disubstituted isomer, and in some cases traces of the alkenyl intermediate). Additionally, the 1,1-bis-H-phosphinate disodium salt precipitated spontaneously from the reaction mixture, thereby allowing easy isolation. The only 1,1-bis-H-phosphinate derivatives reported in the literature are the unsubstituted ethyl and isopropyl esters of the parent acid,5 which were obtained from Cl2PCH2PCl2.6
Table 1.
Influence of reaction conditions with 1-hexyne.a
 | |||
|---|---|---|---|
| entry | NaH2PO2 eq. | solvent | isolated yieldb |
| 1 | 2.5 | MeOH | 13 |
| 2c | 2.5c | MeOHc | 0c |
| 3 | 2.5 | MeOH/acetone (5/1) | 44 |
| 4 | 6.0 | MeOH | 52 |
| 5 | 6.0 | MeOH/H2O (5/1) | 23 |
| 6 | 6.0 | MeOH/ CH3CN (5/1) | 27 |
| 7 | 6.0 | MeOH/acetone (5/1) | 57 |
| 8 | 6.0 | MeOH/DMF (5/1) | 67 |
| 9 | 6.0 | MeOH/dioxane (5/1) | 67 |
| 10 | 6.0 | THF/H2O (2/1) | 0 |
| 11 | 10.0 | MeOH | 62 |
| 12 | 10.0 | MeOH/dioxane (5/1) | 65 |
Reactions were conducted in a flask open to air at rt, using Et3B (1 equiv) in hexane (1 M) in reagent grade solvent. Unless otherwise noted, the concentration of 1-hexyne before addition of Et3B was 0.2 M.
All yields are isolated after filtration and washing with cold methanol.
Concentration was 0.1 M.
Under the conditions we used with alkenes,1 only a small amount of precipitate formed (entry 1). As expected, decreasing the concentration lowered the yield further (entry 2), both because of less efficient chain reaction, and increased solubility of the product which impedes its recovery. Addition of a cosolvent significantly increases the yield (entry 3). Since 2.5 eq. NaH2PO2 was optimum for reaction with olefins, and since bis-addition is required with alkynes, increased amounts of hypophosphite were tried. Not surprisingly, this resulted in significant improvements (compare entry 11 with entry 4 and entry 1). Various co-solvents were also tried. Water (entry 5) and acetonitrile (entry 6) were unsatisfactory whereas acetone (entry 7), DMF (entry 8), or dioxane (entry 9) afforded good yields of 1,1-bis-H-phosphinate. At this point, further increasing the amount of sodium hypophosphite had little effect (entry 12 versus 9). Therefore, the conditions in entry 9 appeared nearly ideal.
Next, the scope of the reaction was studied on a variety of terminal alkyne substrates (Table 2). All alkynes react to give the corresponding 1,1-bis-H-phosphinate which always precipitated out of the reaction mixture. Initially, the addition was investigated using unoptimized conditions (Method A, Table 2). Reaction in methanol generally afforded lower yields than when dioxane was employed as cosolvent (Method B, Table 2, entries a versus b). Polar alkynes also give better yields possibly because of their higher solubility in methanol. A variety of functional groups are tolerated. Although the yields were sometimes low, the reaction is convenient to run even on large scale and does not require particular precautions. Gas chromatographic analysis of the filtrate after low-yielding reactions shows that the alkyne starting material remains in significant quantity. Thus a “recycling” strategy was developed to increase conversion: after the first run, the filtrate is concentrated, taken up in the solvent, and more NaH2PO2 and Et3B are added. For example, using this method 4-phenyl-1-butyne (Table 2, entry 11b) yields the bisphosphinate in 21% yield in the first run, and 35% yield in the second run for a 56% overall yield (Method C, Table 2). The same bisphosphonate was recently shown by Szajnman and coworkers to have significant activity on Trypanosoma cruzi farnesyl pyrophosphate synthase (Ki = 0.47 µM, IC50 = 5.67 µM).7
Table 2.
Scope of Alkyne Radical Hydrophosphinylation.
 | |||
|---|---|---|---|
| entry | R | methoda | isolated yield (%)b |
| 1a | CH2OH | A | 20 |
| 1b | B | 52 | |
| 2a | CH2CH2CH2OH | A | 25 |
| 2b | B | 64 | |
| 3a |  |
A | 46 |
| 3b | B | 78 | |
| 4a |  |
A | 39 |
| 4b | B | 87 | |
| 5a | Me3Si | A | 33 |
| 5b | B | 41 | |
| 6a | Oct | A | 48 |
| 6b | B | 64 | |
| 7a | t-Bu | A | 39 |
| 7b | B | 46 | |
| 8a | CO2Et | A | 40 |
| 8b | B | 60 | |
| 9a | CH2OCH3 | A | 51 |
| 9b | B | 47 | |
| 10 | CH2CH2CO2H | B | 69 |
| 11a |  |
B | 21 |
| 11b | C | 56 | |
| 12 | CH2NH2.HClc | Bc | 42c |
| 13a | CBZ2NCH2CH2 | A | 22 |
| 13b | B | 48 | |
| 14a |  |
A | 24 |
| 14b | B | 41 | |
Reactions were conducted in a flask open to air at rt, using reagent grade solvent(s) with NaH2PO2 (6 equiv), and Et3B (1 equiv, 1 M in hexane). Method A: MeOH. Method B: MeOH/dioxane (5/1). Method C: after a run conducted as in Method B, the filtrate is concentrated, redissolved in the solvent mixture along with NaH2PO2 (6 equiv), and Et3B is added. The yield corresponds to the combined yield after both runs. For additional details, see Supporting Information.
1,1-bis-H-phosphinates were isolated by simple filtration after washing with cold methanol in >95% purity.
2 equiv Et3B were used.
Bisphosphonates are an important class of biologically active compounds, used for example in the treatment of bone diseases such as osteoporosis,8 or to prepare conjugates with high bone affinity.9 Thus, the oxidative conversion of 1,1-bis-H-phosphinates into the corresponding bisphosphonates was investigated. H-Phosphinic acids have been converted into phosphonates through a variety of methods.10 The acids are more reactive toward oxidation than the corresponding neutral salts because the P(V) to P(III) tautomerism of the phosphinylidene group is catalyzed by non-neutral conditions. However, we found ozonolysis to be a practical method to directly convert the 1,1-bis-H-phosphinate disodium salt into the corresponding phosphonate (Equation 3). Other reagents can also be employed (H2O2, NaOCl, Br2) but ozonolysis was generally found to be more convenient.11
The unique potential of 1,1-bis-H-phosphinates to function as precursors of bisphosphonates was then realized with the preparation of a steroid conjugate (Scheme 1). Bisphosphonate-steroid conjugates12 have been proposed as a method to direct hormones to the bone for the treatment of osteoporosis and to decrease the well-known problems associated with hormone replacement therapy. Epiandrosterone was reacted with propargyl chlorofomate to form the corresponding carbonate 1 in nearly quantitative yield. Because of the solubility profile of the steroid, a ternary solvent mixture was employed for the radical reaction with NaH2PO2 which then afforded 1,1-bis-H-phosphinate 2 as a white solid. Finally, oxidation with ozone produced the bisphosphonate-steroid conjugate 3. Thus, the present reaction can be used for the expeditious synthesis of bisphosphonates. Literature syntheses of steroid-bisphosphonate conjugates require time-consuming multistep sequences, whereas our synthesis of 3 can be conducted quickly with a reasonable overall yield.13
Scheme 1.
Preparation of a steroid-bisphosphonate conjugate.
The present reaction has obvious potential for the preparation of bisphosphonate libraries from terminal alkyne precursors. Additionally, it avoids the cumbersome and sometimes problematic9g,12a protection-deprotection strategies associated with the alkylation of methylenebisphosphonate esters.
Finally, the esterification of a 1,1-bis-H-phosphinate was studied. It was found that a direct esterification of the sodium salt with PivCl/i-PrOH delivered the corresponding ester as a mixture of stereoisomers in good yield (Equation 4).
In conclusion, we have developed a simple and practical approach to a new class of organophosphorus compounds. Through oxidation, these 1,1-bis-H-phosphinates can be converted into 1,1-bisphosphonates which are biologically important compounds. An intriguing possibility which remains for further studies would be if in vivo oxidation of the 1,1-bis-H-phosphinate can take place,14 since these compounds would then act as novel bisphosphonate prodrugs. 15 Further investigations to study the reactivity of the 1,1-bis-H-phosphinates, and to prepare various conjugates are currently underway and will be reported in a full account.
Supplementary Material
Representative experimental procedures and spectroscopic data. This material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgments
We thank the National Institute of General Medical Sciences/NIH (R01 GM067610) for the support of this research.
References
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Associated Data
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Supplementary Materials
Representative experimental procedures and spectroscopic data. This material is available free of charge via the Internet at http://pubs.acs.org.