Abstract
The reaction of the title lactams with triethyl phosphite prompted by phosphoryl chloride provided six-membered ring heterocyclic phosphonates or bisphosphonates. These novel scaffolds might be of interest as building blocks in medicinal chemistry. The course of the reaction was dependent on the structure of the used substrate. Thus, morpholin-3-one and thiomorpholin-3-one readily provided the corresponding 1,1-bisphosphonates (compounds 1, 2, 7, 14 and 16), whereas the protection of their nitrogen atom resulted in the formation of dehydrophosphonates (compounds 5, 6, and 8). Piperazin-2-one reacted differently yielding mixture of cis- and trans- piperazine-2,3-diyl-bisphosphonates (compounds 10 and 11). Since cytosine could be considered as an analogue of piperin-2-one, its ditosyl derivative 18 was used as a substrate affording compound 19 being a product of phosphite addition to double bond. In dependence of their structures, hydrolysis of the obtained diethyl phosphonates resulted either in corresponding cyclic phosphonic acids or in the degradation of carbon-to-phosphorus bond.
Introduction
Heterocyclic rings are key scaffold components in medicinal chemistry and are the fundamental building blocks of many drugs. However, the design and preparation of new heterocyclic building blocks is still a challenging area in the early drug discovery phase.1 The extensive literature focused on the synthesis and functionalization of azaheterocyclic phosphonates is mostly concentrated on aromatic compounds,2 with heteroalicyclic ones being less intensively studied.3a Anyway, numerous synthetic procedures were elaborated for the syntheses of aziridin-, azetidin-, pyrrolidin-, and piperidin-ylphosphonic acids and their derivatives.3 Syntheses of heteroalicyclic phosphonates bearing a second heteroatom in the ring have been scarcely described so far,4 and there remains a great need for further advance in this area.
Since simple lactams upon reaction with triethyl phosphite prompted by phosphoryl chloride, a version of Vilsmeier–Haack reaction,3h,5 readily provided cyclic aminobisphosphonates (Scheme 1), the enlargement of the scope of this reaction is a logic alternative.
Scheme 1. Reaction of Lactams by Vilsmeier–Haack-Like Reaction.
Therefore, we studied the course of this reaction using morpholin-3-one, thiomorpholin-3-one, and piperazin-2-one as substrates.
Results and Discussion
Morpholin-3-one and Thiomorpholin-3-one as Substrates
As expected, the reaction of morpholin-3-one and thiomorpholin-3-one with triethyl phosphite and phosphoryl chloride afforded the corresponding bisphosphonates 1 and 2 in satisfactory yields (Scheme 2). These compounds decompose upon hydrolysis by concentrated hydrochloric acid; therefore, the corresponding phosphonic acids 3 and 4 were obtained by classic dealkylation with trimethylbromosilane followed by methanolysis of trimethylsilyl esters (Scheme 2). When the amide nitrogen atom in both substrates was blocked with benzyl moiety, the reaction afforded corresponding diethyl N-benzyl-2,3-dehydromorpholyl-3-phosphonate (compound 5) and N-benzyl-2,3-dehydrothiomorpholyl-3-phosphonate (compound 6) (Scheme 2) as major products.
Scheme 2. Reactions of Morpholin-3-one and Thiomorpholin-3-one and Their Derivatives.
These findings support the assumption that the mechanism of this reaction is similar to the one proposed earlier3h and is presented in Scheme 3 for morpholin-3-one.
Scheme 3. Mechanism of Reaction of Mopholin-3-one and N-benzylmopholin-3-one.
It is worth to mention that we were able to isolate only bisphosphonate 7 as a product of the analogous reaction of N-benzylvalerolactam. This product was, however, obtained in low (20%) yield accompanied by many side-products (Scheme 4).
Scheme 4. Reaction of N-benzylvalerolactam.
Quite unexpectedly, the use of N-phenyl-morpholine-3-one as a substrate provided monoethyl N-benzyl-2,3-dehydromorpholyl-3-phosphonate (compound 8) (Scheme 3). Tetraethyl N-benzyl-2,3-morpholyl-3,3-bisphosphonate (compound 9) was obtained with a good yield in a separate reaction according to the procedure proposed recently by Wang (Scheme 5).6 Unfortunately, attempts to use this procedure for other substrates gave unsatisfactory results yielding mixtures of the inseparable products.
Scheme 5. Synthesis of tetraethyl N-benzyl-2,3-morpholyl-3,3-bisphosphonate (9) by procedure of Wang et al.6.
Piperazin-2-one and Its analogues as Substrates
The reaction of piperazin-2-one gave the mixture of products: tetraethyl cis-piperazine-2,3-diyl-bisphosphonate 10, which is a meso compound and trans-piperazine-2,3-diyl-bisphosphonate 11, which is a racemic mixture of RR and SS stereoisomers (Scheme 6).
Scheme 6. Products of the Reaction of Piperazin-2-one as a Substrate.
The isomers were separated by means of column chromatography. It is worth mentioning that the 1H and 13C spectra of both (cis and trans) isomers are significantly different (Figures S1.10 and S1.17 in the Supporting Information), which enabled their easy differentiation upon separation.
We speculate that the mechanism of the formation of a mixture of compounds 10 and 11 conforms to the general mechanism of the formation of bisphosphonates with the difference being in a shift of keto-enol equilibrium toward enamine rather than to imine upon the action of phosphoryl chloride. The addition of phosphite to enamine favors the production of gen-bisphosphonates (Scheme 7).
Scheme 7. Presumable Mechanism of the Formation of gem-bisphosphonates 10 and 11.
The hydrolysis of compounds 10 and 11 with concentrated hydrochloric acid provided the corresponding acids 12 and 13 in good yields (Scheme 6). Their structures were unequivocally supported by crystallographic studies (Figure 1).
Figure 1.
Crystal structures for compounds 12 (left panel) and 13 (right panel).
The use of 4-ethyl-piperazin-2,3-dione as a substrate quite readily provided corresponding tetraethyl 4-ethyl-3-oxopiperazine-2,2-diyl-bisphosphonate 14 (Scheme 7). The hydrolysis of this compound resulted in the degradation of carbon-to-phosphorus bond and the product of this degradation, (N′-ethyl-2-aminoethyl)glycine 15, was isolated and characterized by X-ray studies (Figure 2).
Figure 2.
Crystal structure of the product of the degradation of C–P bonds upon hydrolysis of compound 14.
Similarly, the 3,4-dihydroqinoxline-2-one provided low yield of the corresponding bisphosphonate 16, which appeared to be also unstable under hydrolytic conditions yielding products of the breakage of the C–P bonds (Scheme 8). Such instability of benzoannulated bisphosphonates has been observed earlier.3h
Scheme 8. Reactions of Derivatives of Piperazin-2,3-dione.
Finally, when using 3-methyl-piperazin-3-one as the substrate, only the product of monophosphonylation 17 was isolated, albeit in a very small yield (Scheme 9). The formation of this unexpected product suggests that the reaction has, at least in part, radical mechanism.
Scheme 9. Reaction of 3-methyl-piperazin-3-one.
Cytosine as a Substrate
Cytosine could be also considered as an analogue of piperin-2-one. Unprotected cytosine did not react, but blocking of its amino groups by toluenesulfonyl chloride leads to its ditosyl derivative 18, which reacted quite smoothly yielding the product 19 of the addition of phosphite to double bond (Scheme 10). Its structure, as determined by crystallography, is shown in Figure 3.
Scheme 10. Addition of Phosphite to Double Bond of Ditosyl–Cytosine.
Figure 3.
Crystal structure of compound 19.
This compound upon hydrolysis with concentrated hydrochloric acid yielded a mixture of unseparable products with 1-tosyl-2,4-dioxo-pirymidyn-6-ylphosphonic acid 20 being one of the major components.
Conclusions
These, as well as previous studies, indicate that a version of the Vilsmeier–Haack reaction of lactams with triethyl phosphite prompted by phosphoryl chloride is a promising mean to synthesize azaheterocyclic phosphonates. The course of this reaction is strongly dependent on the structure of the starting lactam, and in some cases, unexpected products are also formed. Thus, in the case of lactams possessing unsubstituted nitrogen, the formation of amino-gem-bisphosphonates (compounds 1, 2, 7, 14, and 16) was observed as the major products, whereas the use of N-substituted lactams unusually resulted in dehydrophosphonates (compounds 5, 6, and 8). Piperazin-2-one and 2-methyl-piperazin-3-one and cytosine reacted differently yielding unexpected products. All of the obtained compounds might be considered as novel building blocks for medicinal chemistry.
Experimental Section
General Methods and Materials
All solvents and reagents, purchased from commercial suppliers, were of analytical grade and were used without further purification. Unless otherwise specified, solvents were removed with a rotary evaporator. Infrared spectra were measured on a 1600 FT-IR Perkin Elmer spectrometer. The 1H-, 31P-, and 13C NMR spectroscopic experiments were performed on a Bruker Avance II Ultrashield Plus (Bruker, Rheinstetten, Germany) operating at 600.58 MHz (1H), 243.12 MHz (31P{1H}), and 151.016 MHz (13C{1H}), on a Bruker Avance III HD operating at 500.13 MHz (1H), 202.46 MHz (31P{1H}), and 125.75 MHz (13C{1H}), or on a Jeol JNM-ECZ 400S Research FT NMR Spectrometer (JEOL Ltd., Tokyo, Japan) operating at 399.78 MHz (1H), 161.83 MHz (31P{1H}), and 100.53 (13C{1H}). Measurements were made in solutions of CDCl3 or D2O + NaOD at 300 K, and solvents were supplied by ARMAR AG (Dottingen, Switzerland). Chemical shifts are reported in ppm relative to tetramethylsilane (TMS) and 85% H3PO4, used as external standards, and coupling constants are reported in Hz. Melting points were determined on an SRS Melting Point Apparatus OptiMelt MPA 100 (Stanford Research Systems, Sunnyvale, CA) and are reported uncorrected. Mass spectra (MS) were recorded at the Faculty of Chemistry, Wroclaw University of Science and Technology using a Waters LCT Premier XE mass spectrometer (method of electrospray ionization, ESI) (Waters, Milford, MA).
Synthetic Procedures
Synthesis of Substrates
4-Benzylmorpholin-3-one
A round-bottom flask was charged with morpholin-3-one (1 g, 9.85 mmol) and N,N-dimethylformamide (30 mL). The resulting solution was cooled to 0 °C, and sodium hydride (60% in mineral oil, 0.51 g, 12.85 mmol) was added. The suspension was allowed to warm to room temperature, and benzyl bromide (2.47 mL, 20.77 mmol) was added. The reaction mixture was stirred for 16 h. Upon completion, the reaction was quenched with brine (10 mL), extracted with ethyl acetate (3 × 20 mL), and dried over anhydrous Na2SO4. The crude residue was purified by flash chromatography on silica using 40% acetone in pentane as eluent. Yield 1.88 g (100%) of a colorless oil. 1H NMR (399.78 MHz, CDCl3, ppm): δ = 3.25 (m, 2H, CH2O), 3.82 (m, 2H, CH2N), 4.23 (s, 2H, CH2O), 4.61 (s, 2H, CH2Ph), 7.29 (m, 5H, Ar); 13C{1H}NMR (100.53 MHz, CDCl3, ppm): δ = 45.56, 49.54, 64.01, 68.27, 127.84, 128.35, 128.85, 136.27, 166.90 ppm; high-resolution mass spectrometry (HRMS) (time-of-flight (TOF) MS ESI): calcd for C11H14NO2 [M + H]+, m/z 192.1024; found m/z 192.1024.
4-Benzylthiomorpholin-3-one
4-Benzylthiomorpholin-3-one was obtained analogously as above yielding as a colorless oil; yield 1.88 g (99%). 1H NMR (500.13 MHz, CDCl3, ppm): δ = 2.77 (m, 2H, CH2S6), 3.39 (s, 2H, CH2S), 3.54 (m, 2H, CH2N), 4.65 (s, 2H, CH2Ph), 7.30 (m, 5H, Ar) ppm. 13C{1H}NMR (125.75 MHz, CDCl3): δ = 26.6, 30.7, 48.8, 50.9, 127.9, 128.2, 129.0, 137.0, 166.8 ppm. HRMS (TOF MS ESI): calcd for C11H14NOS [M + H]+, m/z 208.0796; found m/z 208.0788.
4-Methyl-N-(2-oxo-1-tosyl-1,2-dihydropyrimidin-4-yl)benzenesulfonamide (ditosyl–cytidine, 18)
A solution of cytosine (1 g, 9 mmol) and tosyl chloride (7.72 g, 40.5 mmol) in dry pyridine (135 mL) was stirred at room temperature for 6 h. The pyridine was evaporated, the oily residue dissolved in ethyl acetate, and extracted twice with water. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated. The dark brown oil was separated and purified by column chromatography using silica/chloroform/methanol (95:5) resulting in a white solid. Yield 1.56 g (68%); mp 169–172 °C. 1H NMR (399.78 MHz, CDCl3, ppm): δ = 2.39 and 2.46 (s, 3H each, CH3), 7.28 (d, J = 8.00 Hz, 2H, Ar), 7.38 (d, J = 8.16 Hz, 2H, Ar), 7.77 (d, J = 8.34 Hz, 2H, Ar), 7.93 (d, J = 8.47 Hz, 2H, Ar), 7.98 (d, J = 8.32 Hz, 1H, C=CH) ppm; 13C{1H}NMR (100.53 MHz, CDCl3, ppm): δ = 21.7, 22.0, 126.9, 127.1, 129.8, 129.9, 130.1, 130.3, 132.3, 137.8, 147.6 ppm; HRMS (TOF MS ESI): calcd for C18H18N3O5S2 [M + H]+, m/z 420.0687; found m/z 420.0685.
General Procedure for Reacting of Amides with Phosphoryl Chloride and Triethyl Phosphite
Appropriate amide (5 mmol) and triethyl phosphite (1.79 mL, 10.48 mmol) were mixed in an ice bath followed by the dropwise addition of phosphoryl chloride (0.97 mL, 10.48 mmol) for 20 min under an argon atmosphere. The solution was left for 24 h, and to the mixture was poured a cold solution of ammonia (final pH 7). The product was extracted with methylene chloride (3 × 50 mL). The methylene chloride layers were combined and dried over sodium sulfate. The drying agent was then removed by filtration, and the volatile components of the reaction mixture removed under reduced pressure. The crude product was purified by column chromatography using silica/chloroform/methanol.
Tetraethyl (Morpholine-3,3-diyl)bisphosphonate (1)
Tetraethyl (morpholine-3,3-diyl)bisphosphonate (1) was obtained as a yellow oil; yield 0.8 g (58%). 1H NMR (399.78 MHz, CDCl3, ppm): δ = 1.14 (m, 12H, 4 × CH3CH2O), 3.07 (t, J = 4.00 Hz, 2H, CH2NH), 3.64 (t, J = 4.00 Hz, 2H, CH2CH2O), 4.07 (t, JPH = 14 Hz, 2H, CH2CP2), 4.17 (m, 8H, 4 × CH2OP) ppm; 13C{1H}NMR (100.53 MHz, CDCl3, ppm): δ = 16.51 and 16.54 (d, J = 3.0 Hz, each of CH3), 40.7 (d, J = 5.5 Hz, CH2NH), 40.8 (d, J = 5.5 Hz, CH2NH), 57.1 and 58.5 (d, J = 138.0 Hz, each of CP2), 63.17 and 63.20 and 63.53 and 63.56 (d, J = 3.5 Hz, each of CH2OP), 67.0 (CCH2O), 67.1 (CH2CH2O)ppm. 31P{1H}NMR (161.83 MHz, CDCl3, ppm): δ = 20.72; HRMS (TOF MS ESI): calcd for C12H28NO7P2 [M + H]+, m/z 360.1341; found m/z 360.1341.
Tetraethyl (Thiomorpholine-3,3-diyl)bisphosphonate (2)
Tetraethyl (thiomorpholine-3,3-diyl)bisphosphonate (2) was obtained as a yellow oil; yield 0.8 g (87%). 1H NMR (500.13 MHz, CDCl3, ppm): δ = 1.34 (t, J = 7.1, 7.1 Hz, 12H, 4 × CH3CH2O), 2.60 (m, 2H, CH2NH), 3.17 (t, J = 13.8, 12.7 Hz, 2H, CH2S), 3.38 (m, 2H, CH2CH2S), 4.22 (m, 8H, 4 × CH2OP) ppm. 13C{1H}NMR (125.75 MHz, CDCl3, ppm): δ 16.68 and 16.70 and 16.73 (d, J = 3 Hz, each of CH3), 28.0 (CH2CH2S), 28.99 and 29.01 (d, J = 2.7 Hz, each of CH2NH), 41.81 and 41.85 (d, J = 5.7 Hz, each of CCH2S), 57.7 and 58.8 (d, J = 137.9 Hz, each of CP2), 63.32 and 63.35 and 63.67 and 63.70 (d, J = 3.6 Hz, each of CH2OP) ppm. 31P{1H}NMR (161.83 MHz, CDCl3, ppm): δ = 15.03 ppm. HRMS (TOF MS ESI): calcd for C12H28NO6P2S [M + H]+, m/z 376.3663; found m/z 376.1139.
Diethyl (4-Benzyl-3,4-dihydro-2H-1,4-oxazin-5-yl)phosphonate (5)
Diethyl (4-benzyl-3,4-dihydro-2H-1,4-oxazin-5-yl)phosphonate (5) was obtained as a colorless oil. Yield 0.54 g (80%); 1H NMR (399.78 MHz, CDCl3, ppm): δ = 1.34 and 1.35 (t, J = 7.1 Hz, 3H, 2 × CH3), 2.83 (m, 2H, CH2N), 3.91 (m, 2H, CH2O), 4.08 (s, 2H, CH2Ph), 4.15 (m, 4H, CH2OP), 7.00 (d, J = 6.0 Hz, 1H, CHO), 7.31 (m, 5H, Ph); 13C{1H}NMR (100.53 MHz, CDCl3, ppm): δ = 16.4 (d, J = 6.6 Hz, CH3), 45.9 (d, J = 10.2 Hz, CH2NH), 58.1 (CH2Ph), 62.1 (CH2O), 62.2 (d, J = 5.4 Hz, CH2OP), 114.9 (d, J = 221.28 Hz, CP), 127.7, 128.5, 129.1, 137.4, 144.5 (d, J = 35.1 Hz, C=CP); 31P{1H}NMR (161.83 MHz, CDCl3, ppm): δ = 17.08 ppm; HRMS (TOF MS ESI): calcd for C15H23NO4P [M + H]+, m/z 312.1364; found m/z 312.1260.
Diethyl (4-Benzyl-3,4-dihydro-2H-1,4-thiazin-5-yl)phosphonate (6)
Diethyl (4-benzyl-3,4-dihydro-2H-1,4-thiazin-5-yl)phosphonate (6) was obtained as a colorless oil. Yield 0.5 g (73%); 1H NMR (500.13 MHz, CDCl3, ppm): δ = 1.34 (t, J = 7.1, 7.1 Hz, 6H, CH3), 2.55 (m, 2H, CH2S), 2.95 (m, 2H, CH2N), 3.98 (m, 4H, CH2OP), 4.03 (s, 2H, CH2Ph), 6.38 (d, J = 14.3 Hz, 1H, CHS), 7.17 (m, 5H, Ph); 13C{1H}NMR (125.75 MHz, CDCl3, ppm): δ = 16.6 (d, J = 6.6 Hz, CH3), 22.4 (CH2S), 46.3 (d, J = 10.3 Hz, CH2N), 57.2 (CH2Ph), 62.4 (d, J = 5.8 Hz, CH2OP), 116.2 (d, J = 26.0 Hz, C = CP), 127.5, 128.6, 128.8, 131.2 (d, J = 212.1 Hz, CP), 138.6 ppm; 31P{1H}NMR (202.46 MHz, CDCl3, ppm): δ = 13.32 ppm. HRMS (TOF MS ESI): calcd for C15H23NO3PS [M + H]+, m/z 328.3868; found m/z 328.1117.
Tetraethyl (N-Benzylpiperidine-2,2-diyl)bisphosphonate (7)
Tetraethyl (N-benzylpiperidine-2,2-diyl)bisphosphonate (7) was isolated from a mixture of products as a yellow oil. Yield 0.5 g (20%); 1H NMR (500.13 MHz, CDCl3, ppm): δ = 1.35 (m, 12H, 4 × CH3CH2O), 1.49 (m, 2H, CH2CH2N), 1.69 (m, 2H, CH2CH2CP2), 2.31 (m, 2H, CH2CP2), 2.74 (m, 2H, CH2N), 4.22 (m, 8H, 4 × CH2OP), 4.33 (s, 2H, CH2Ph), 7.32 (m, 5H, Ph) ppm; 13C{1H}NMR (125.75 MHz, CDCl3, ppm): δ = 16.52 and 16.55 and 16.57 and 16.59 (d, J = 3 Hz, each of CH3), 19.97 and 20.03 (d, J = 6.8 Hz, CH2CH2CP2), 25.3 (CH2CH2N), 29.72 and 29.75 (d, J = 3.7 Hz, each of CH2CP2), 47.32 and 47.37 (d, J = 6 Hz, CH2N), 58.4 (CH2Ph), 62.20 and 62.23 and 62.75 and 62.78 (d, J = 4 Hz, each of CH2OP), 64.3 and 65.4 (d, J = 137.1 Hz, CP2) ppm; 31P{1H}NMR (202.46 MHz, CDCl3, ppm): δ = 24.12 ppm. HRMS (TOF MS ESI): calcd for C20H35NO6P2Na [M + Na]+, m/z 470.1837; found m/z 470.1835.
Ethyl (4-Phenyl-3,4-dihydro-2H-1,4-oxazin-5-yl)phosphonate (8)
Ethyl (4-phenyl-3,4-dihydro-2H-1,4-oxazin-5-yl)phosphonate (8) was obtained as a colorless oil. Yield 0.3 g (25%); 1H NMR (399.78 MHz, CDCl3, ppm): δ = 1.14 (t, J = 7.1, 7.1 Hz, 3H, CH3), 3.43 (m, 2H, CH2N), 3.92 (m, 2H, CH2OP), 3.98 (m, 2H, CH2O), 7.02, (m, 1H, Ph), 7.12 (m, 2H, Ph), 7.24 (d, J = 0.5 Hz, 1H, C=CHO), 7.27 (m, 2H, Ph); 13C{1H}NMR (100.53 MHz, CDCl3, ppm): δ = 16.30 (d, J = 6.8 Hz, CH3), 51.8 (d, J = 8.4, CH2N), 60.6 and 60.7 (d, J = 4 Hz, each CH2OP), 62.85 (CH2O), 114.6 (d, J = 204.9 Hz, CP), 123.6, 124.0, 129.1, 146.7 (CHO), 149.4 ppm; 31P{1H}NMR (161.83 MHz, CDCl3, ppm): δ = 20.48 ppm; HRMS (TOF MS ESI): calcd for C12H15NO4P [M + H]+, m/z 268.0738; found m/z 268.0730.
Tetraethyl (cis-Piperazine-2,3-diyl)bisphosphonate (10)
Tetraethyl (cis-piperazine-2,3-diyl)bisphosphonate (10) was obtained as a yellow oil. After column chromatography, fractions of pure cis and trans isomers were obtained and a fraction containing both isomers in a nonequimolar ratio. Yield 0.1 g (6%); 1H NMR (399.78 MHz, CDCl3, ppm): δ = 1.31 and 1.32 (d, J = 7.1 Hz, 6H each of 4 × CH3), 2.82 and 2.94 (m, 2H each, CH2N), 3.29 and 3.32 (d, J = 14 Hz, 2H, 2 × CHP), 4.18 (m, 8H, 4 × CH2OP). 13C{1H}NMR (100.53 MHz, CDCl3, ppm): δ = 16.47 and 16.50 and 16.53 and 16.56 and 16.60 (d, J = 3 Hz; each of CH3), 41.44 and 41.50 (d, J = 6 Hz, CH2N), 44.9 (CH2N) 46.2 (2 × CHP), 62.98 and 63.03 and 63.86 and 63.89 (d, J = 3.0 Hz, each of 4 × CH2OP) ppm. 31P{1H}NMR (161.83 MHz, CDCl3, ppm): δ = 21.31 ppm. HRMS (TOF MS ESI): calcd for C12H29N2O6P2 [M + H]+, m/z 359.1500; found for [M + H]+, m/z 359.1501.
Tetraethyl (trans-Piperazine-2,3-diyl)bisphosphonate (11)
Tetraethyl (trans-piperazine-2,3-diyl)bisphosphonate (11) was obtained as a yellow oil. Yield 0.4 g (36%); 1H NMR (600.58 MHz, CDCl3, ppm): δ = 1.28 and 1.30 (t, J = 7.1, 7.1 Hz, 6H each, 4 × CH3), 2.67 and 3.13 (m, 2H each, CH2N), 3.38 (d, J = 7.5 Hz, 2H, CHP), 4.12 (m, 8H, 4 × CH2OP) ppm; 13C{1H}NMR (151.016 MHz, CDCl3, ppm): δ = 16.50 and 16.56 (d, J = 3.0 Hz, each of CH3), 42.5 (bt, J = 2.1 Hz, 2 × CH2N), 48.8 and 50.6 (d, J = 174.7 Hz, each of CHP), 62.69 and 62.72 and 63.35 and 63.38 (d, J = 13 Hz, each of CH2OP) ppm. 31P{1H}NMR (243.12 MHz, CDCl3, ppm): δ = 25.61. HRMS (TOF MS ESI): calcd for C12H29N2O6P2 [M + H]+, m/z 359.1500; found for [M + H]+, m/z 359.1501.
Tetraethyl 4-Ethyl-3-oxopiperazine-2,2-diyl-bisphosphonate (14)
Tetraethyl 4-ethyl-3-oxopiperazine-2,2-diyl-bisphosphonate (14) was obtained as a yellow oil. Yield 0.25 g (60%); 1H NMR (600.58 MHz, CDCl3, ppm): δ = 1.17 (t, J = 7.17, 7.17 Hz, 3H, NCH2CH3), 1.35 and 1.37 (t, J = 5.0, 5.5 Hz, 6H, 4 × OCH2CH3), 3.38 and 3.44 (m, 2H, 2 × CH2N), 3.49 (q, J = 7.15, 7.15, 7.15 Hz, 2H, NCH2CH3), 4.29 (m, 8H, 4 × CH2OP). 13C{1H}NMR (151.016 MHz, CDCl3, ppm): δ = 11.9 (NCH2CH3), 16.42 and 16.50 and 16.55 and 16.58 (d, J = 3.1 Hz, POCH2CH3), 39.82 and 39.85 (d, J = 5.0 Hz, each of CH2NEt), 43.0 (NCH2CH3), 46.6 (CH2NH), 63.97 and 64.00 and 64.56 and 64.59 (d, J = 4.0 Hz, CH2OP), 65.3 and 66.7 (d, J = 140 Hz, each of CP2), 160.84 and 160.89 (d, J = 5 Hz, C=O) ppm; 31P{1H}NMR (243.12 MHz, CDCl3, ppm): δ = 14.95 ppm. HRMS (TOF MS ESI): calcd for C14H30N2NaO7P2 [M + H]+, m/z 423.1425; found m/z 423.1424.
Tetraethyl (1,3-Dihydroqinoxaline-2,2-diyl)bisphosphonate (16)
Tetraethyl (1,3-dihydroqinoxaline-2,2-diyl)bisphosphonate (16) was isolated from a mixture of products as a yellow oil. Yield 0.070 g (7%); 1H NMR (399.78 MHz, CDCl3, ppm): δ = 1.22 (m, 12H, 4 × CH3), 3.74 (t, J = 11.0, 2H, NCH2), 4.15 (m, 8H, 4 × CH2OP), 6.60 (d, J = 4.4 Hz, 2H, Ar), 6.64 (m, 1H, Ar), 6.77 (m, 1H, Ar). 13C{1H}NMR (100.53 MHz, CDCl3, ppm): δ = 16.38 and 16.41 and 16.46 and 16.49 (d, J = 2.9 Hz, CH3), 43.18 and 43.21 (d, J = 2.5 Hz, each of NCH2), 56.2 and 57.6 (d, J = 146.3 Hz, CP2), 63.48 and 63.52 and 64.11 and 64.15 (d, J = 3.4 Hz, each of CH2OP), 114.9, 115.8, 117.0, 119.0; 31P{1H}NMR (161.83 MHz, CDCl3, ppm): δ = 18.57 ppm. HRMS (TOF MS ESI): calcd for C16H29N2O6P2 [M + H]+, m/z 407.1500; found m/z 407.1500.
Diethyl (2-Methyl-3-oxopiperazin-2-yl)phosphonate (17)
Diethyl (2-methyl-3-oxopiperazin-2-yl)phosphonate (17) was isolated from a mixture of products as a yellow oil. Yield 0.080 g (6%); 1H NMR (600.58 MHz, CDCl3, ppm): δ = 1.35 and 1.36 (t, J = 6.9, 3H, 2 × CH3), 1.6 (d, J = 16.11 Hz, 3H, CCH3), 3.0 (m, 1H, CH2NHC), 3.39 (m, 3H, CH2NC=O and CH2NC), 4.23 (m, 4H, 2 × CH2OP) ppm; 13C{1H}NMR (100.53 MHz, CDCl3, ppm): δ = 16.48 and 16.51 (d, J = 4 Hz, 2 × CH3), 22.51 (CCH3), 38.85 (d, J = 4.1 Hz, CH2NHC), 42.92 (CH2NHC=O), 61.0 (d, J = 144.0 Hz, CP), 63.11 and 63.62 (d, J = 7 Hz, each of CH2OP), 169.71 (C=O) ppm; 31P{1H}NMR (161.83 MHz, CDCl3, ppm): δ = 24.11 ppm. HRMS (TOF MS ESI): calcd for C9H20N2O4P [M + H]+, m/z 251.1160; found for 251.1161. IR (ν cm–1): 1019 (P=OC), 1225 (P=O), 1661 (C=O), 3283 (N – H).
4-Methyl-N-(2-oxo-6-(oxophosphanyl)-1-tosyltetrahydropyrimidin-4(1H)-ylidene)benzenesulfonamide (19)
4-Methyl-N-(2-oxo-6-(oxophosphanyl)-1-tosyltetrahydropyrimidin-4(1H)-ylidene)benzenesulfonamide (19) was obtained as a white solid. Yield 0.55 g (70%); mp 159–162 °C; 1H NMR (399.78 MHz, CDCl3, ppm): δ = 1.25 and 1.27 (t, J = 7.2, 7.8 Hz, 3H, 2 × CH3), 2.40 and 2.42 (s, 3H each, CH3Ph), 3.07 (m, 2H, CH2C=N), 4.09 (m, 4H, CH2OP), 5.04 (m, 1H, CHP), 7.29 and 7.33 (d, J = 8.17 Hz, 2H each, Ar), 7.78 (d, J = 8.24 Hz, 2H, Ar), 8.02 (d, J = 8.32, 2H, Ar); 13C{1H}NMR (100.53 MHz, CDCl3, ppm): δ = 16.3 and 16.4 (d, J = 5.5 Hz, each of CH3), 21.7 and 21.8 (s, CH3Ph), 32.0 (CH2), 47.7 (d, J = 160.0 Hz, CP), 63.82 and 64.21 (d, J = 7.0 Hz, each of CH2OP), 126.5, 127.2, 129.4, 129.5, 129.7, 129.75, 129.81, 134.7, 136.9, 144.8, 145.9, 146.0, 158.0 (C=O); 31P{1H}NMR (161.83 MHz, CDCl3, ppm): δ = 18.56. IR (ν cm–1): 1019 (P=OC), 1225 (P=O), 1661 (C=O), 3283 (N – H); HRMS (TOF MS ESI): calcd for C22H28N3NaO7PS2Na [M+ Na]+, m/z 564.1004; found m/z 564.1004.
Hydrolysis of Esters
Method A
The obtained tetraethyl bisphosphonate (30 mmol) was refluxed for 12 h in 20 mL of 6 M aqueous hydrochloric acid solution. Then, the volatile components were evaporated, and the resulting crude product was recrystallized from water, anhydrous ethanol, or water–ethanol mixture.
trans-(Piperazine-2,3-diyl)bisphosphonic Acid (12)
trans-(Piperazine-2,3-diyl)bisphosphonic acid (12) was obtained as a white solid. Yield 100%; mp 245–248 °C. 1H NMR (399.78 MHz, D2O, ppm): δ = 2.75 (AB system, J = 11, 20 Hz, 2H, CH2NH), 3.13 (d, J = 6.9 Hz, 2H, CHP), 3.28 (AB system, J = 11, 21 Hz, 2H, CH2NH). 13C{1H}NMR (100.53 MHz, D2O, ppm): δ = 39.8, 49.8 (d, J = 18.3, CH2), 50.2 (d, J = 60.1 Hz, CHP), 50.9 (d, J = 66.3 Hz, CHP), 51.3 (d, J = 18.6, CH2). 31P{1H}NMR (161.83 MHz, D2O, ppm): δ = 15.47; HRMS (TOF MS ESI): calcd for C4H12N2NaO6P2 [M + Na]+, m/z 269.0068; found m/z 269.0072.
cis-(Piperazine-2,3-diyl)bisphosphonic Acid (13)
cis-(Piperazine-2,3-diyl)bisphosphonic acid (13) was obtained as a white solid. Yield 100%; mp 245–248 °C; very badly soluble, 1H NMR (399.78 MHz, D2O, very badly soluble, ppm): δ = 2.88 (m, 2H, CH2NH), 3.13 (m, 2H, CHP), 3.36 (m, 2H, CH2NH); 31P{1H}NMR (161.83 MHz, D2O, ppm): δ = 16.93; HRMS (TOF MS ESI): calcd for C4H12N2NaO6P2 [M + Na]+, m/z 269.0068; found m/z 269.0072.
Method B: Procedure for Dealkylation with TMSBr
Appropriate bisphosphonate (0.22 mmol) was dissolved in dry dichloromethane (200 mL) under nitrogen, and the flask cooled to 0 °C. After 5 min, bromotrimethylsilane (4.4 mL, 3.3 mmol) was added dropwise over 5 min. The reaction was carried out exactly, as described in the literature.5
Morpholine-3,3-diylbisphosphonic Acid (3)
Morpholine-3,3-diylbisphosphonic acid (3) was obtained as a white solid. Yield 0.63 g (60%); mp 139–143 °C. 1H NMR (500.13 MHz, D2O, ppm): δ = 2.13 (s, 2H, CH2O), 2.68 (dd, J = 11.82, 11.88 Hz, 2H, CH2CP2), 2.86 (s, 2H, CH2NH) ppm. 13C{1H}NMR (100.53 MHz, D2O, ppm): δ = 26.1, 28.86 and 28.94 (d, J = 9.9 Hz, each of CH2CP2), 40.7, 56.12 and 57.14 (d, J = 128.7 Hz, each of CP2) ppm; 31P{1H}NMR (202.46 MHz, CDCl3, ppm): δ = 19.37 ppm. HRMS (TOF MS ESI): calcd for C4H12NO7P2Na [M + Na]+, m/z 269.9908; found m/z 269.9905.
Thiomorpholine-3,3-diylbisphosphonic Acid (4)
Thiomorpholine-3,3-diylbisphosphonic acid (4) was obtained as a white solid. Yield 0.138 g (60%); mp 245–248 °C. 1H NMR (500.13 MHz, D2O, ppm): δ = 2.81 (AB system, J = 5.2, 5.3 Hz, 2H, CH2S), 3.19 (dd, J = 9.1, 12.4 Hz, 2H, CH2CP2), 3.69 (AB system, J = 5.3, 5.4 Hz, 2H, CH2NH) ppm; 13C{1H}NMR (125.75 MHz, D2O, ppm): δ = 23.86, 28.79, 42.0, 57.4 and 58.3 (d, J = 109.6 Hz, each of CP2) ppm; 31P{1H}NMR (202.46 MHz, D2O, ppm): δ = 10.99 ppm. HRMS (TOF MS ESI): calcd for C4H12NO6P2SNa [M + Na]+, m/z 285.9680; found m/z 285.9674.
Tetraethyl (4-Benzylmorpholine-3,3-diyl)bisphosphonate (9) by Procedure of Wang et al.6
Trifluoromethanesulfonic anhydride (0.2 mL, 1.2 mmol, 1.2 equiv) was added dropwise to a cooled (−78 °C) solution of 4-benzylmorpholin-3-one (0.28 g, 1.0 mmol, 1.0 equiv) and DTBMP (0.82 g, 4.0 mmol, 4.0 equiv) in dichloromethane (5 mL) and stirred for 30 min, then at 0 °C (in an ice bath) for 10 min. Then, diethyl phosphite (0.386 mL, 3.0 mmol, 3.0 equiv) was added to the mixture and stirred for 5 h. The reaction was quenched with a saturated sodium hydrogen carbonate solution (10 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfonate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: DCM/MeOH = 50:1) to afford 0.3 g (70%) of the desired product as a colorless oil. 1H NMR (399.78 MHz, CDCl3, ppm): δ = 1.35 (m, 12H 4 × CH3), 2.87 (t, J = 5.2, 5.2 Hz, 2H, CH2N), 3.72 (t, J = 5.2, 5.2 Hz, 2H, CH2O), 4.25 (m, 8H, 4 × CH2OP), 4.42 (s, 2H, CH2Ph), 7.29 (m, 5H, Ph); 13C{1H}NMR(100.53 MHz, CDCl3, ppm): δ = 16.55 and 16.59 and 16.62 and 16.64 (d, J = 3 Hz, each of CH3), 46.25 and 46.30 (d, J = 4.8 Hz, CH2N), 58.6 (CH2Ph), 62.91 and 62.95 and 63.31 and 63.34 (d, J = 3.3 Hz, CH2OP), 64.69 and 66.03 (d, J = 134.6 Hz, each of CHP2), 67.5 (s, CH2O), 69.61 and 69.64 (d, J = 3 Hz, each of CH2O), 127.25, 128.23, 129.20, 138.14; 31P{1H}NMR (161.83 MHz, CDCl3, ppm): δ = 20.91; HRMS (TOF MS ESI): calcd for C19H34NO7P2 [M + H]+, m/z 450.1810; found m/z 450.1807.
Crystallography
Relevant crystallographic data for the molecules and the full geometrical information are summarized in Tables S2.1–S2.3 of the Supporting Information
The single-crystal X-ray diffraction experiments were performed at 100.0(1) K (12, 13, and 19) and at 293(2) K (14) on an Xcalibur diffractometer (Rigaku Oxford Diffraction, Sevenoaks, Kent, U.K.), equipped with a CCD detector and a graphite monochromator (Rigaku Oxford Diffraction) with Mo Kα radiation and furnished with an Oxford Cryosystem N2 gas stream device. The reciprocal space was explored by ω scans. The reflections were measured with a radiation exposure time from 4 to 25 s, according to diffraction intensities. The detector was positioned at a 60-mm distance from the crystal. Procession of the diffraction data was performed using the CrysAlis CCD.7 Structures for compounds 12, 13, and 19 were solved in the triclinic crystal system, P̅1 space group. Compound 14 solved in the monoclinic crystal system, P21/c space group (Table S2.1), by direct methods and refined by a full-matrix least-squares method using the SHELXL14 program.8 Lorentz and polarization corrections were applied. Nonhydrogen atoms were refined anisotropically. In structures, H atoms were refined using a riding model. The structure drawings were prepared using the OLEX2 program.9 The crystallographic data for all compounds have been deposited at the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 1888865 (12), CCDC 1888866 (13), CCDC 1888867 (14), CCDC 1888868 (19). These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk.
Acknowledgments
The financial support from statutory founds of Faculty of Chemistry, Wrocław University of Science and Technology is gratefully acknowledged. R.O.A.-V. wish to thank Consejo Nacional de Ciencia y Tecnología for Graduate Scholarship 332980.
Supporting Information Available
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.9b01137.
The authors declare no competing financial interest.
Supplementary Material
References
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