An alternative C–P cross-coupling route for the synthesis of novel V-shaped aryldiphosphonic acids

The synthesis of phosphonate esters is a topic of interest for various fields, including the preparation of phosphonic acids to be employed as organic linkers for the construction of metal phosphonate materials. We report an alternative method that requires no solvent and involves a different order of addition of reactants to perform the transition-metal-catalyzed C–P cross-coupling reaction, often referred to as the Tavs reaction, employing NiCl2 as a pre-catalyst in the phosphonylation of aryl bromide substrates using triisopropyl phosphite. This new method was employed in the synthesis of three novel aryl diphosphonate esters which were subsequently transformed to phosphonic acids through silylation and hydrolysis.


Methods
H, 13 C, 31 P, and HSQC NMR spectra were recorded on a Bruker Avance III 500 MHz instrument. Phosphonate esters were dissolved in CDCl3. Phosphonic acids were dissolved in a 0.1 M solution of NaOH in D2O. 1   Bis(4-bromophenyl)amine (4.0 g, 12.2 mmol) was placed into a screw powder addition funnel and attached to a 100 mL round-bottomed flask. Triisopropyl phosphite (42 mL, 170 mmol, 7 equivalents) and anhydrous nickel chloride (13 mol % per Br -0.41 g, 3.16 mmol) were then added to the round-bottomed flask and set to reflux (160 °C) under argon. Once the mixture had reached temperature, the bis(4bromophenyl)amine was added slowly over 4 hours and the reaction monitored via S7 TLC using an acetone/ethyl acetate mixture in a 1:9 ratio. Once the addition was complete, the reaction mixture was left for a further 1 hour and again monitored by TLC to identify when the reaction had gone to completion. The gas flow rate was increased in order to remove excess phosphite and remaining byproducts, resulting in a dark treacle-like substance. This was left to cool and subsequently washed overnight in hexane, resulting in the formation of a fine white powder. This was washed two more times in hexane and separated via centrifugation. The solid was then purified using S8 3,6-Dibromo-9H-carbazole (5.0 g, 15.4 mmol) was placed into a screw powder addition funnel and attached to a 100 mL round-bottomed flask. Triisopropyl phosphite (52.5 mL, 214 mmol, 7 equivalents) and anhydrous nickel chloride (13 mol % per Br -0.52 g, 4.00 mmol) were then added to the round-bottomed flask and set to reflux (160 °C) under argon. Once the mixture in the round-bottom had reached temperature, the 3,6-dibromo-9H-carbazole was added slowly over 4.5 hours and monitored via TLC. Once the addition was complete, the reaction mixture was left for a further 1 hour and monitored by TLC to identify when the reaction had gone to completion. The gas flow was then increased to remove excess phosphite, resulting in a brown sticky crude.
This was washed overnight in hexane, resulting in the formation of an off-white powder. This was washed two more times in hexane and the final white powder was Triisopropyl phosphite (25.7 mL, 104.2 mmol, 7 equivalents) and anhydrous nickel chloride (13 mol % per Br -0.25 g, 1.92 mmol) were then added to the round-bottomed flask and set to reflux (160 °C) under argon. Once the mixture in the round-bottom had reached temperature, the 4-bromo-N-(4-bromophenyl)-N-phenylaniline was added slowly over 2.5 hours and monitored via TLC. Once the addition was complete, the reaction mixture was left for a further 3 hours and monitored by TLC to identify when the reaction had gone to completion. After 3 hours, the gas flow rate was increased in order to remove excess phosphite and remaining byproducts. The mixture was then left to cool and became a sticky, treacle-like substance, and was subsequently washed overnight in hexane, resulting in the formation of a fine white solid. The hexane was decanted, and the powder again washed in hexane, resulting in 3.86 g of a white solid.

N,N-Bis(4-diisopropylphosphonophenyl)amine (iPr4BPA) (1A)
The first synthetic target obtained was N,N-bis(4-diisopropylphosphonophenyl)amine, known herein as iPr4BPA (1A). The procedure to obtain this compound was relatively simple and reproducible, whereby the product could be obtained consistently at yields above 80%. Before the workup of the crude reaction product, which took the form of a dark brown treacle-like mixture, thin layer chromatography (TLC) analysis often showed that some starting material was still present, alongside what is reasoned to be phenylamine. This is easily removed by employing flash chromatography, using a mixture of acetone and ethyl acetate in a 1:9 ratio. The first product to elute off the column is the starting material, followed by the mono-substituted intermediate. This   Looking specifically at the aromatic region ( Figure S11) we see three peaks, including a singlet at δ 7.28 ppm, which is due to the deuterated solvent (chloroform-d) and two doublets of doublets at δ 7.71 ppm and δ 7.19 ppm, which correspond to the protons on the phenyl rings. On first viewing of these signals, it was tempting to assign the more downfield of the two (δ 7.71 ppm) to the protons nearest to nitrogen, represented as Ha in Figure S9, though examination of the coupling constants reveals that the downfield signal has a larger coupling constant. This implies that the signal actually represents the protons closest to the phosphonate group (Hb), since phosphorus, like a proton, has a quantum spin number of 1/2, and will thus be involved in coupling with protons. This means that the upfield signal at δ 7.19 ppm can be assigned to the protons nearest to nitrogen (Hb). S17 Figure S11: Aromatic region of the 1 H NMR spectrum for iPr4BPA.
Moving further upfield ( Figure S12), there is a signal at δ 4.68 ppm which is easily attributed to the methine group (Hc) of the isopropyl moiety. One might expect to see a septuplet here arising from the six aliphatic protons on each isopropyl moiety, though it appears to be a sextet. Closer analysis would appear to suggest that, in fact, the signal is a pair of overlapping sextets, since there are clear shoulders on some of the peaks. In this sense, however, multiplet analysis appears to miss two shoulders that would in fact make this a doublet of "leaning" septets. This analysis appears to be confirmed in the 1 H NMR spectrum for iPr4DPC (2A), as seen in Figure S32, whereby a multiplet analysis appears to identify the previously hidden shoulders. The complicated nature of this signal is likely brought about by the coupling of 31 P and 1 H nuclei, as was mentioned in the discussion for the aromatic signals. Most importantly, S18 the signal integrates to give the correct number of protons for the methine groups on the molecule. The final signals on this spectrum, as seen in Figure S13, were originally thought to be a well-resolved doublet of doublets that corresponds to the terminal methyl groups (Hd) on the phosphonate ester. However, due to the relatively large coupling constant and the need to integrate the peaks separately, it was determined that the signals are more likely two doublets, indicating that there are two types of chemically inequivalent isopropyl groups present on the molecule, though how these arise has not been investigated. Working on this basis, the signal integrates to a total of 24 protons, as expected. Each of the doublets arises from the coupling with the methine proton. S19 Figure S13: Methyl region of the 1 H NMR spectrum for iPr4BPA.
Moving to the 13 C NMR spectrum, as shown in Figure    With NMR data clearly showing successful synthesis of iPr4BPA, mass spectral analysis was carried out to provide further support. Figure S17 shows the full mass spectrum, where the base peak can be seen with an m/z of 498.22 and is shown in more detail in Figure S18.  S23

N,N-Bis(4-phosphonophenyl)amine (H4BPA) (1B)
With a clean product obtained for iPr4BPA (1A), the attention shifted to obtaining the corresponding phosphonic acid, N,N-bis(4-phosphonophenyl)amine H4BPA (1B). The initial method considered for this was hydrolysis using 6 M hydrochloric acid under reflux for 12+ h. The results here were quite hit and miss, as it was found that this route sometimes led to the cleavage of the C-P bond, which was confirmed by the absence of signals on the 31 P NMR spectrum. As an alternative to these harsh conditions, a different route which involved silylation using trimethylsilyl bromide (TMSiBr) and subsequent hydrolysis using water was chosen. Overall, this method proved very simple and required very little work up, often just requiring separate washes with water and acetone, and leading to yields between 65 to 91%. As with the ester, purity is confirmed with both 31 P, 1 H, 13 C, and HSQC NMR spectroscopy, and mass spectrometry. The solvent used for NMR was a 0.1 M solution of NaOH in D2O.
Looking first at the 31 P spectrum ( Figure S19), it is clear that the splitting pattern has completely changed this time taking the form of a singlet, which suggests that successful hydrolysis and removal of the isopropyl groups has occurred. The peaks are less resolved in this case, so no splitting patterns are observed despite the peak width remaining similar to that of the ester, as shown in Figure S8. It is also clear that no phosphorus-containing impurities are present, and thus the washing protocol used is satisfactory.
S24 Figure S19: a) Full 31 P NMR spectrum, and b) zoomed 31 P NMR spectrum for H4BPA (1B). Moving next to the 1 H NMR spectrum, as shown in Figure S21, it is clear that the isopropyl groups are no longer present, since the signals for the methyl (-CH3) and methine (-CH-) groups have disappeared, giving further confirmation that hydrolysis has successfully taken place.
Taking a closer look at the aromatic region, as shown in Figure S22, the signals can be assigned as they were for iPr4BPA (1A), whereby the downfield signal at δ 7.50 ppm (B) can be assigned to the protons nearest to phosphorus on the phenyl ring, represented by Hb, since it has a larger coupling constant. The signal at δ 7.05 ppm (A) can be assigned to the protons nearest to nitrogen on the phenyl ring, represented by Ha. This signal, while appearing as a single doublet, is more likely to be an unresolved doublet of doublets, as was seen in Figure S11 for iPr4BPA (1A).
S26 Figure S22: Aromatic region of the 1 H NMR spectrum for H4BPA.
Moving to the 13 C NMR spectrum, as shown in Figure S24, we can immediately confirm the lack of signal for the methine and methyl groups. Starting downfield, we see the peak, labelled A on the spectrum, which has been assigned to the two carbon atoms bonded to nitrogen, as was the case for iPr4BPA. The next signal, labelled D, has been assigned to the two carbons bonded to phosphorus, which has actually shifted when compared with the spectrum for iPr4BPA. The next two signals then are assigned to the carbons with bonded protons, labelled C and B respectively, with the latter of these being the more downfield. It was unfortunate here, in fact, that the acid is relatively insoluble and thus obtaining a spectrum with reasonable intensities was not possible, even though the signals were able to be assigned.
S27 Figure S23: Chemical structure of H4BPA with carbon environments labelled a-f. Figure S24: Full 13 C NMR spectrum for H4BPA.
As was done for iPr4BPA, we again use coupled C-H NMR (HSQC) to lend support for the assignments for H4BPA NMR spectra. Looking at the spectra in Figure S25, we can again see the lack of signals associated with the isopropyl groups. We can, S28 however, see the two expected signals for the two sets of aromatic carbons with associated protons. Figure S25: Full HSQC NMR spectrum for H4BPA.
As with the ester precursor, mass spectral analysis was carried out to confirm the results of the NMR analysis. Looking at Figure   S30

3,6-Bis(diisopropylphosphono)-9H-carbazole (iPr4DPC) (2A)
The second synthetic target, building upon the success of the first linker, was 3,6bis(diisopropylphosphono)-9H-carbazole (iPr4DPC, 2A). As with the previous linker, this was also a simple and reproducible procedure from which relatively high yields could be obtained. As with the amine linker, the crude reaction product was most often obtained as a dark brown treacle-like mixture, containing the target product alongside the monosubstituted side product, some starting material, and some triisopropyl phosphite. Washing this in hexane then yielded a pinky/off-white solid, which could then be purified by flash chromatography. The yields here were often higher on average than for the previous linker, with synthetic yields obtained in the range of 82-97%. The solvent used for NMR was CDCl3.
The 31 P NMR spectrum, as shown in Figure S28, again reveals a significant signal corresponding to the target product, which shows a less resolved splitting pattern than  Moving to the 1 H NMR spectrum, in Figure S30 we see that there are some unexpected signals amongst those attributed to the product. Firstly, at δ 1.76 ppm we see a slightly broadened singlet, which is likely to be water, though the chemical shift is slightly higher than you would usually expect for water, δ 1. Moving to Figure S31 to focus on the aromatic region, we see four signals, three of which are to be attributed to the aryl protons and one to the proton bound to nitrogen.
The latter of these has been attributed to the broadened signal at δ 8.95 ppm and integrates to 1 proton. Though you might not usually expect to see a signal for these protons, the solvent used, chloroform-d, is both apolar and aprotic, so there is no considerable exchange with the N-H proton. What we are left with then are the three signals associated with the aryl protons. The first of these signals (C), a doublet at δ 8.66 ppm, has been attributed to the proton labelled Hc in Figure S29. The splitting here is likely due to higher order coupling with phosphorus, causing the signal to display higher coupling constant than the other signals, which also display splitting patterns that indicate neighbouring protons, which Hc does not have. The next signal S33 (B), at δ 7.91 ppm, has been attributed to the aryl proton labelled Hb in Figure S29. Here

S34
As was previously discussed for the methine signal for iPr4BPA, the 1 H NMR spectrum for iPr4DPC, as shown in Figure S32, also shows a signal for the methine protons, though at a slightly higher shift of δ 4.75 ppm. In the case of iPr4BPA, it was mentioned that the signal is likely a pair of unresolved septets, which is something that is much clearer here, showing that the original designation as a pair of leaning septets to be quite likely. Most importantly, the signal integrates to the correct number of protons.
There is also a similar, though much less intense, signal at ≈ δ 4.64 ppm which can be attributed to the methine group of leftover triisopropyl phosphite, which is not unexpected considering the signal at δ 1.35 ppm, which is attributed to the methyl group of triisopropyl phosphite.

S35
The final signals of concern in this spectrum, which again, was initially thought to be a doublet of doublets, can be seen at δ 1.435 and 1.265 ppm in Figure S33. As was established for iPr4BPA, however, this is in fact more likely to be two doublets which are the result of two chemically distinct methyl groups, and the splitting in each of the doublets arises through coupling with the methine proton. There is also a small impurity present between the methyl peaks at δ 1.35 ppm, which, as mentioned previously, is suspected either isopropyl bromide or triisopropyl phosphite. If quantified using the integration based on the assumption that phosphite is present, this would approximate to a 1:9 ratio of phosphite to iPr4DPC. Looking to the 13 C NMR spectrum shown in Figure S35 for iPr4DPC, we can immediately see it is slightly more complicated than that of iPr4BPA. Starting  Looking to the HSQC NMR spectra for clarification, as shown in Figure S36, we can confirm that the peaks labelled C, E, and B on the 13 C NMR spectrum, are indeed correlated with those labelled B, C, and A on the 1 H NMR spectrum. We also see the expected correlations for the methine and methyl groups.
Moving the mass spectroscopy data, Figure S37   S40

3,6-Diphosphono-9H-carbazole (H4DPC) (2B)
Having successfully obtained iPr4DPC, attention again shifted to obtaining the corresponding phosphonic acid, 3,6-diphosphono-9H-carbazole (H4DPC). As with the amine, this was a relatively simple procedure and the product was obtained in yields between 87-98% when using the silylation and hydrolysis using TMSiBr, since hydrolysis using HCl again seemed to cleave the P-C bond. The solvent used for NMR was a 0.1 M solution of NaOH in D2O.
Looking first at the 31 P NMR spectrum, as seen in Figure S39, there is a major signal at δ 12.91 ppm, which corresponds to the target product, H4DPC. There is also a clear change in splitting pattern here, whereby a triplet is observed, though this can be attributed to coupling with the two nonequivalent aryl protons (Hb and Hc). There is also a minor signal upfield at δ 2.6 ppm which may correspond with hydrolysis of leftover triisopropyl phosphite, though this signal is relatively weak in comparison and can reasonably be ignored. Figure S39: a) Full 31 P NMR spectrum, and b) zoomed 31 P NMR spectrum for H4DPC (2B).
Moving next to the 1 H NMR spectrum as shown in Figure S41, it is clear that there are no signals corresponding to the isopropyl groups, thus the hydrolysis has been S41 successful, and there seem to be no signals that indicate other impurities. It is also clear that the signal observed previously for N-H has now disappeared, since a protic solvent is now being used. Figure S40: Chemical structure for H4DPC with proton environments labelled Ha-Hc. Figure S41: Full 1 H NMR spectrum for H4DPC (2B).

S42
Taking a closer look at the aromatic region, as seen in Figure S42, the signals present can be assigned exactly as they were for iPr4DPC, whereby protons labelled Ha-c correspond to signals A-C respectively. One clear difference, however, is the less resolved nature of the spectrum, which causes overlap of signals. This is immediately clear for the signal at δ 7.72 ppm, which was previously classified as a doublet of doublets of doublets (ddd), though now seems to be a triplet. This increased intensity of the central peak is caused by the overlap of multiple peaks which, when resolved, would represent the expected ddd splitting pattern as caused by coupling to the other aryl protons and phosphorus. Figure S42: Aromatic region of 1 H NMR spectrum for H4DPC (2B).

S43
Further characterization using 13 C NMR was less successful, most likely due to the insolubility of H4DPC and the subsequent inability to obtain a spectrum with sufficient peak intensities to accurately assign peaks, at least fully. Looking at Figure S44, it is clear that some of the potential signals in the area of interest are barely above the rather noisy background. S44 Figure S44: Full 13 C NMR spectrum for H4DPC (2B).
Referring to the HSQC NMR spectra, as shown in Figure S45, it is possible to at least assign the peaks for carbons with bonded protons. With this in mind, it is clear that the 13 C NMR peaks at δ 128.38, δ 122.18, and δ 110.22 ppm can be assigned to the carbons labelled E, C, and B, respectively.
Looking at the mass spectral data, Figure S46   S47
The procedure itself was essentially identical, with a simple workup in hexane to obtain the linker. The solvent used for NMR was CDCl3.
Looking first at the 31 P NMR spectrum, see Figure S48, we see just a single signal which can be attributed to the target product, iPr4DPPA. Taking a closer look at the signal, it seems that the splitting observed for the two previous linkers is not present, though this might be due to a reduction in the signal to noise ratio. Figure S48: a) Full 31 P NMR spectrum, and b) zoomed 31 P NMR spectrum for iPr4DPPA (3A).
Moving to the 1 H NMR spectrum, as shown in Figure S50, we again see the impurities suspected to be either triisopropyl phosphite and/or isopropyl bromide, as was

S49
Zooming in on the aromatic region, as seen in Figure S51, it is possible to identify five signals in total. The first of these signals has a δ-shift of 7.86 ppm, which can be assigned similarly to the iPr4BPA linker, whereby the peak corresponds to protons nearest to phosphorus on the phenyl rings, labelled Hb in Figure S49, again indicated by the large coupling constants. The integration also indicates that it at least belongs to the rings containing phosphonate groups. The next signal, at δ 7.36 ppm, has been assigned to the protons labelled Hc on the phenyl ring with no phosphonate group. The splitting on the spectrum shows a triplet, though you might expect a doublet of doublets for the associated proton, therefore it is likely that this is what we are seeing, simply unresolved. Next, we see the solvent peak at δ 7.28 ppm. Moving upfield, we see a relatively easy to assign the signal at δ 7.20 ppm, and in this case has been attributed to the proton labelled He and is supported by the 1.13 integration value. The final two signals in the aromatic region, while not fully resolved, can be assigned and the splitting can also be identified. The first one, at δ 7.15 ppm, appears to be a simple doublet, and integrates approximately to two, and should therefore be assigned to the remaining protons on the non-phosphonate-containing ring labelled Hd. By process of elimination, this leaves the final aromatic signal at δ 7.12 ppm to be assigned to the protons labelled Ha, though this assignment is supported by the doublet of doublet splitting pattern as well as the integration of approximately four.
Moving to the signal at δ 4.73 ppm, as shown in Figure S52, we see what initially looked like a sextet, though as we have previously explored, is most likely an unresolved doublet of septets, as it would be expected for the methine moiety on the isopropyl groups, labelled Hf in Figure S49. The integration of four is also in favour of this assignment.
The final signal, as shown in Figure S53, appears at δ 1.34 ppm as a pair of doublets, as was established for iPr4BPA and iPr4DPC, and corresponds to the methyl groups belonging to the isopropyl moiety. The integration for each of the doublets is 12, together totaling 24, as expected.
Moving on to the 13 C NMR spectrum, as shown in Figure S55, we can immediately assign the methyl (i) and methine (h) carbons to the signals at δ 24.02 ppm and δ 70.63 ppm, respectively. Moving downfield, things start to get slightly more complicated. The first two signals at δ 150.25 ppm and δ 145.08 ppm have both been assigned to the carbon atoms bonded to nitrogen, labelled (a) in Figure S48,   Lending support for these assignments as well as those for the proton NMR, is the HSQC NMR spectrum shown in Figure S56 and S57, in which the signals have been   S57

4-Phosphono-N-(4-phosphonophenyl)-N-phenylaniline [H4DPPA] (3B)
Although a rather repetitive statement at this point, the hydrolysis of iPr4DPPA to obtain H4DPPA was, as was the case for the other two linkers, a relatively simple procedure, and pretty reasonable yields of between 70-95% could be achieved. Unlike the previous two, this linker was not assessed for its suitability for hydrolysis using HCl, instead opting to go straight for the less harsh procedure involving silylation through the use of TMSiBr. The solvent used for NMR was a 0.1 M solution of NaOH in D2O.
Starting with the 31 P NMR spectrum, as shown in Figure S60, we can immediately see the presence of only one signal, indicating relative purity with regards to phosphoruscontaining compounds. We can already observe the loss of the isopropyl groups here from the huge change in the splitting pattern. Here, we see only a triplet, likely caused by coupling with the aromatic protons, whereas the pattern for the ester presented a much more complicated and much less resolved pattern due to the amount of coupling taking place. Figure S60: a) Full 31 P NMR spectrum, and b) zoomed 31 P NMR spectrum for H4DPPA (3B).

S58
Moving to the 1 H NMR spectrum as shown in Figure S62, we can immediately confirm the loss of the isopropyl groups through the lack of methine and methyl signals upfield.
Beyond this, the only potential impurity shown at δ 0.0 ppm, which can be attributed to phosphorus acid (H3PO3), though the amount present must be quite small as it is not seen in 31 P NMR spectrum and could easily be removed through further washing in small amounts of water or ethanol. Focusing on the aromatic region, as shown in Figure S63, and comparing it to that of the ester in Figure S51, the assignment of the signals is clear, though there is one striking difference, which is that two of the signals, C and E, have switched places on the spectrum. Turning back to the assignment of the signals, as was the case for the ester, the signal at δ 7.52 ppm has been assigned to the protons nearest to phosphorus, labelled Hb. The next signal, at δ 7.29 ppm, has been assigned to the protons labelled Hd on the non-phosphonate-containing ring. The signal at δ 7.13 ppm has been assigned to the protons nearest nitrogen on the non-phosphonatecontaining ring, labelled Hc. The next signal, and generally the easiest to assign due to the integration, has been assigned to the proton labelled He on the nonphosphonate-containing ring. This leaves the final signal at δ 7.13 ppm, which through S60 process of elimination, supported by splitting pattern and integration, be attributed to the protons labelled Ha. Figure S63: Aromatic region of the 1 H NMR spectrum for H4DPPA (3B).
As was the case for the ester, 13 C NMR, as shown in Figure S65, has proven insufficient in aiding full characterization of the linker. This is mostly due to the insolubility of the product, which has resulted in a poor signal-to-noise ratio. With this in mind, HSQC should help with assigning some of the 13 C NMR peaks. It should be noted here that the 13 C NMR spectrum clearly shows the lack of isopropyl group peaks.

S62
Looking at the HSQC NMR spectra in Figure S66, we can indeed see the switching of signals 3 and 4 when comparing with that of the ester in Figure S56. Beyond that, the assignments are identical, with the signals showing correlations between Cc-Hb (1), Ce-Hc (2), Cg-He (3), Cf-Hd (4), and Cb-Ha (5).  Figure S68, which compares the theoretical isotope profile with observed data, shown a good match between the two.