Novel synthetic route for (parent) phosphetanes, phospholanes, phosphinanes and phosphepanes

Abstract

A novel synthetic route for (parent) phosphorus-containing cycloalkanes such as phosphetanes, phospholanes, phosphinanes and phosphepanes is reported. By using [K(dme)₂]₂[Cp*Fe(η⁴-P₅)] (I) in combination with α,ω-dibromoalkanes C_nH_2nBr₂ [n = 3–6], unique phosphetane, phospholane, phosphinane and phosphepane precursor complexes [Cp*Fe{η⁴-P₅(CH₂)_n}] [n = 3–6] (2–5) are synthesised. They act as P-atom carriers and the corresponding phosphetane, phospholane, phosphinane and phosphepanes (6–9) can be released by nucleophiles i.e., potassium benzyl (KBn) or LiAlH₄. The latter enables the selective synthesis of parent cyclic secondary phosphines (10) in an easy and straightforward way, including the first parent phospholane (10b).

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Introduction

Heterocyclic chemistry is one of the prime topics in organic and inorganic chemistry, with billions of heterocyclic compounds synthesised and some of them widely used, e.g. in the pharmaceutical industry.¹ On the other hand, phosphines are widely employed in (asymmetric) organocatalysis,^2,3 which is still a major field, rewarded with two Nobel Prizes within the last two decades.⁴ To customise and tune (transition)metal complexes used in catalysis, a variety of phosphines have been and are still being synthesised.^5–7

While phosphorus heterocycles are of academic interest, such as e.g. the Wittig Reaction,⁸ bidentate⁶ and caged⁹ phosphines are on the rise as tuneable ligands in catalysis and Wittig-type reactions, which are widely used in industry.¹⁰ The importance of specific phosphorus heterocycles in transition-metal-assisted (asymmetric) catalysis is remarkable, as for instance the usage of phospholanes in DuPhos or BPE, representing chiral ligands for asymmetric catalysis (Scheme 1).¹¹

Scheme 1 Selected phosphorus heterocycles used in organocatalysis,¹² pharmacy,²² industry,¹⁰ and the parent phospholane.

The synthesis of cyclic phosphines is anything but trivial. Generally speaking, special reaction conditions such as liquid ammonia as solvent,¹² dilution conditions, slow fractional distillation over long columns for work-up or tedious multi-step syntheses are necessary.^5,11,13 This is accompanied by a lack of selectivity and low yields. In addition, sterically demanding substituents such as tert-butyl groups in the carbon backbone or phenyl groups attached to the phosphorus atom in the starting materials are necessary to stabilise the phosphorus-containing heterocycles by these approaches, which makes access to the corresponding parent (P–H) compounds even more difficult.^14,15 Very recently, Cummins reported the synthesis of the parent phosphirane (C₂H₅P), not coordinated to W(CO)₅,¹⁶ based on a multistep Nickel-catalysed transfer reaction of tri-tert-butylphosphatetrahedrane.¹⁷ Other parent phosphorus-containing heterocycles are usually accessible by low yields, time-consuming synthesis or less selective methods.^18,19 Specifically, secondary cyclic phosphines are prepared by hydrolysis of silylated species or protonation of suitable precursors.^17,20,21 However, the latter usually also have to be synthesised in a complex manner, using rather unselective conventional routes with low overall yields.^20,21 Therefore, there is an increasing need for a rational and direct synthesis of cyclic phosphines, especially of the parent derivatives (Scheme 1).

Herein we report the synthesis of the precursor compounds [Cp*Fe{η⁴-P₅(CH₂)_n}] (Cp* = η⁵-C₅Me₅; 2: n = 3; 3: n = 4; 4: n = 5; 5: n = 6) and the straightforward, selective and easy synthesis of cyclic phosphines of different ring sizes – phosphetane (6), phospholane (7), phosphinane (8) and phosphepane (9), via nucleophilic phosphine abstraction by a pentaphosphaferrocene-mediated route.²³ The reaction of the spiro compounds 2–5 with nucleophiles leads to the formation of unprecedented heterocyclic parent phosphines 10a–d including the first parent phospholane 10b.

Results and discussion

When reacting [K(dme)₂]₂[Cp*Fe(η⁵-P₅)] (I)²⁴ (dme = dimethoxyethane) with two equivalents of 1,3-dibromopropane, the ³¹P{¹H} NMR spectrum of the reaction solution exhibits sets of signals corresponding to two different AMM'XX' spin systems in a ratio of 2 : 1 (products 1 and 2). Chromatographic workup under inert conditions leads to the isolation of two complexes, [Cp*Fe{η⁴-P₅(C₃H₆Br)₂}] (1) and [Cp*Fe{η⁴-P₅(C₃H₆)}] (2) (Scheme 2), but lowers the yield. Complex 1 represents the expected reaction product and the molecular structure in the solid state exhibits an η⁴-P₅ moiety, bearing two 4-bromo-n-propyl substituents (Fig. 1 and S42†). In contrast, the XRD analysis of 2 reveals the formation of a spiro-cyclic ligand with a phosphetane-like moiety (Fig. 1). Its formation can be explained by the initial formation of the ionic compound [Cp*Fe{η-P₅(C₃H₆Br)}]⁻, followed by an intramolecular salt metathesis reaction. This side reaction competes with the formation of 1. However, the formation of 1 cannot be supressed by using a 1 : 1 stochiometric ratio between I and 1,3-dibromopropane. By using a 1 : 2 ratio, the yields of both products 1 and 2 are similar (cf. ESI).†

Scheme 2 Reactivity of I towards: (a) 1,3-dibromopropane; (b) 1,4-dibromobutane; (c) 1,5-dibromopentane; (d) 1,6-dibromohexane. Yields are given in parentheses.

Fig. 1 Molecular structure of 2–5 in the solid state; hydrogen atoms are omitted for clarity; thermal ellipsoids are drawn at 50% probability; Cp ligands are drawn in the wire frame model.

Notably, the use of 1,2-dibromoethane does lead to a redox process in which [Cp*Fe(η⁵-P₅)] (I′), KCl and ethene are formed.

When I is reacted with 1,4-dibromobutane without using dilution conditions, [Cp*Fe{η⁴-P₅(C₄H₈)}] (3) can be isolated in 71% yield (Scheme 2). This shows that there is an intrinsic driving force for the formation of homocyclic products over disubstituted bromo-functionalised alkyl derivatives. The solid-state structure was proven by XRD (Fig. S44†) and reveals a spirocyclic phospholane-type ligand.

When reacting I with one equivalent of 1,5-dibromopentane (Scheme 2), the ³¹P{¹H} NMR spectrum of the reaction solution exhibits two different (AMM′XX′) spin systems in a ratio of 10 : 1, in which the major compound can be attributed to complex 4 (Fig. S52†). After chromatographic workup, solely complex [Cp*Fe{η⁴-P₅(C₅H₁₀)}] (4) can be isolated in 61% yield. Unfortunately, the minor product cannot be isolated and decomposes during the chromatographic workup.

Similarly, I reacts with one equivalent of 1,6-dibromohexane (Scheme 2), leading to [Cp*Fe{η⁴-P₅(C₆H₁₂)}] (5), which was isolated in 30% yield. The ³¹P{¹H} NMR spectrum of the reaction solution shows the formation of two other [Cp*Fe(η⁴-P_n)]-containing species with spin systems of higher order (Fig. S53†) in an overall ratio of 1 : 1 to complex 5. Mass spectrometric analysis of the reaction solution in combination with the ³¹P{¹H} NMR data (Fig. S53†) of the reaction mixture strongly suggests the additional formation of [{Cp*Fe(η⁴-P₅)}₂(C₆H₁₂)₂] in which the two {Cp*Fe(η⁴-P₅)} moieties are bridged by two n-hexyl units. Unfortunately, the second compound decomposes during chromatographic workup and could not be isolated and further characterised.

Compounds 2–5 were characterised comprehensively by XRD, mass spectrometry, NMR spectroscopy and elemental analysis. They represent complexes of a rare class of phosphetane-, phospholane-, phosphinane- and phosphepane-like spirocyclic ligands containing complexes which can be easily synthesised.

Knowing that a doubly substituted phosphorus atom can be removed from the P₅ unit of the Cp*Fe fragment,²³ this strategy was also applied for compounds 2–5. It paved the way for a novel synthetic route for substituted phosphetane, phospholane, phosphepane and phosphinane derivatives, starting from white phosphorus, where the side product [K][Cp*Fe(η⁴-P₄)] can be recycled in a “semi-catalytic-cyclic-process”.²³ When reacting compound 2–5 with one equivalent of potassium benzyl (KBn) at −80 °C in THF, the corresponding phosphetane BnP(CH₂)₃ (6), phospholane BnP(CH₂)₄ (7), phosphinane BnP(CH₂)₅ (8) and phosphepane BnP(CH₂)₆ (9) (Scheme 3) can be isolated as colourless viscous liquids after extraction with n-pentane and slow removal of the solvent under reduced pressure in yields of 60–80% (Scheme 3). In addition, [K][Cp*Fe(η⁴-P₄)] is formed. The identity of the phosphines was proven by NMR spectroscopy and, after oxidation with sulphur by the corresponding phosphine sulphides (cf. compounds 6′–9′), also by single crystal X-ray diffraction analysis (Fig. 2 and S47–S50†). Via this procedure, compounds 6–9 can be easily and selectively synthesised without the need of bulky substituents on the phosphorus atom or special starting materials, and at that in much better overall yields.

Scheme 3 Reactivity of 2–5 towards KBn. Yields are given in parentheses (*NMR yield with PPh₃ capillary as internal standard; cf. ESI;† note that the yields given in parentheses are not optimised).

Fig. 2 Molecular structure of 8′ (left) and 11 (right) in the solid state; hydrogen atoms of 8′ are omitted for clarity; thermal ellipsoids are drawn at 50% probability.

Furthermore, we were interested in whether it is possible to use nucleophiles other than KBn to cleave off the phosphine. It has to be noted that MeLi and PhLi do not lead to the formation of the corresponding phosphines. However, using KPh shows the formation of phenylphospholane¹⁵ in the reaction of 3 with KPh.

An interesting class of substances are secondary phosphines, representing functionalisable compounds which can be converted to many different products e.g. phosphides or act as ligands themselves. As stated before, in order to synthesise cyclic secondary phosphines, harsh or cumbersome reactions conditions are needed. And even then, such reactions are not very selective, limited in their scope, and long-lasting workup by fractional distillation is necessary. Therefore, LiAlH₄ was used as a hydride source to cleave off the P(CH₂)_n unit from 2–5. The reaction of 4 and 5 with LiAlH₄ leads to the formation of the desired parent-phosphinine (HP(C₅H₁₀)) in 71% and -phosphepane (HP(C₆H₁₂)) in 73% yield, respectively, according to NMR spectroscopy (Scheme 3, Fig. S56 and S57†). The ³¹P/³¹P{¹H} NMR data are in agreement with those products reported in the literature.^20,21 To our surprise, (parent-)phospholane (HP(C₄H₈)) has not been reported so far. To validate the versatility of this synthetic procedure, we reacted 3 with LiAlH₄ in THF-d₈ (Scheme 4), leading to the parent phospholane (HP(C₄H₈)) (10b), which can be distilled off from the reaction mixture (1 × 10⁻³ mbar, 60 °C, 30 minutes) and isolated as a THF-d₈ solution in 68% yield.

Scheme 4 Reactivity of 3 towards LiAlH₄.

The ³¹P NMR spectra (THF-d₈) of 10b show a doublet of triplets at δ = −70.8 ppm (¹J_P–H = 187 Hz, ²J_P–H = 21 Hz) (Fig. S25 and S26†). To determine its molecular structure, compound 10b was reacted with [Pt(PhCN)₂Cl₂], leading to complex 11 (Scheme 4). The molecular structure of 11 in the solid state (Fig. 2) reveals the expected formation of the parent phospholane 10b, coordinating to a [PtCl₂] unit in a κ¹-fashion, forming the square planar cis-complex [({C₄H₈}PH)₂PtCl₂] (11) (Fig. 2).

The ³¹P{¹H} NMR spectrum (CD₂Cl₂) of 11 shows a singlet at δ = −15.4 ppm with ¹⁹⁵Pt satellites (¹J_P–Pt = 3384 Hz). The corresponding ³¹P NMR spectrum (CD₂Cl₂) of 11 shows a doublet (at δ = −15.4 ppm) with a ¹J_P–H coupling constant of 377 Hz. The NMR data are in agreement with those of similar secondary phosphines coordinating to platinum²⁵ and prove, in combination with the corresponding FD-MS data of 11, unarguably the identity of the formerly unknown parent-phospholane HP(C₄H₈) (10b). It has to be noted that the reaction of 2 with LiAlH₄ leads presumably to the formation of the desired (parent)phosphetane (HP(C₃H₆)). According to ³¹P NMR spectroscopy, this cyclic phosphine (10a) is formed (δ = −29.1 ppm (¹J_P–H = 164 Hz, ²J_P–H = 18 Hz)) (Fig. S54†) in 42% yield alongside with unidentified volatile side products, which can unfortunately not be separated from 10a. ³¹P NMR spectra of the distillate suggest the additional formation of a di-phosphine, bearing one P–H bond, alongside of 10a (Fig. S58†).

Conclusions

In summary, the reaction of the dianionic polyphosphorus complex I with 1,3-dibromopropane yields complex 1, bearing two terminal bromine groups, as well as a spirocyclic ligand complex 2 containing a phosphetane-like moiety. When increasing the chain length of the di-bromoalkanes, the formation of the analogous two-fold substituted complex 1 is not observed. Instead, the intramolecular salt metathesis reaction is favoured and the corresponding free phospholane- and phosphinane-type spirocyclic ligands are obtained in high to moderate yields. When reacting I with 1,6-dibromohexane, a rare seven-membered phosphepane-like ligand complex 5 was isolated. Given the different alkyl chain lengths, the trend is towards yielding the functionalisation and ring formation for 1,3-dibromopropane, towards cyclisation exclusively when using 1,4-dibromobutane and towards ring formation and presumably linkage of two Cp*FeP₅ moieties with longer alkyl chains. Moreover, complexes 2–5 represent very versatile precursors for the synthesis of the corresponding free phosphines by a nucleophilic phosphine abstraction reaction. The presented synthetic route offers great variability towards different reagents and can easily be extended, without the usage of large steric substituents. This procedure can be easily extended to other organo-substituted ring compounds. That way, the substituted phosphetane, phospholane, phosphinane and phosphepane (6–9) ring compounds could be synthesised in good yields, which are otherwise not accessible. In addition to this, we demonstrated that it is also possible to synthesise parent secondary phosphines derivatives 10a–dvia this route, as represented by the parent-phosphetane HP(C₃H₆) (10a) as well as the parent-phospholane HP(C₄H₈) (10b), which have been synthesised for the very first time. This synthetic strategy paves the way for having access to secondary phosphines, as a whole class of substances, in a straightforward way.

Data availability

All experimental procedures, spectroscopic data, information on the theoretical calculations and crystallographic data can be found in the ESI.†

Author contributions

The conceptualization (together with GB and MS), experimental work and writing of the manuscript of this work were achieved by SR. The entire work was supervised, guided, and revised by MS. The final manuscript was reviewed and edited by SR, GB and MS.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft within the project Sche 384/38-3. Stephan Reichl is grateful to the Studienstiftung des Deutschen Volkes for his PhD fellowship.

Notes and references

1. L. D. Quin and J. A. Tyrell, Fundamentals of Heterocyclic Chemistry: Importance in Nature and in the Synthesis of Pharmaceuticals, Wiley & Sons Ltd, 1st edn, 2010.
2. H. Guo, Y. C. Fan, Z. Sun, Y. Wu and O. Kwon, Chem. Rev., 2018, 118, 10049–10293.
3. L. Pignolet, Homogeneous Catalysis with Metal Phosphine Complexes, Springer US, Boston, MA, 1983.
4. (a) The Nobel Prize in Chemistry, 2001, https://www.nobelprize.org/prizes/chemistry/2001/summary/; (b) The Nobel Prize in Chemistry, 2010, https://www.nobelprize.org/prizes/chemistry/2010/summary/.
5. P. C. J. Kamer and P. W. N. van Leeuwen, Phosphorus(III) Ligands in Homogeneous Catalysis: Design and Synthesis, John Wiley & Sons, Ltd, Chichester, UK, 2012.
6. A. L. Clevenger, R. M. Stolley, J. Aderibigbe and J. Louie, Chem. Rev., 2020, 120, 6124–6196.
7. J. F. Teichert, Homogeneous Hydrogenation with Non-Precious Catalysts, Wiley, 2019.
8. K. Dimroth, in Comprehensive Heterocyclic Chemistry, ed. A. R. Katritzky and C. W. B. T.-C. H. C. Rees, Elsevier, Oxford, 1984, pp. 493–538.
9. H. Shet, U. Parmar, S. Bhilare and A. R. Kapdi, Org. Chem. Front., 2021, 8, 1599–1656.
10. G. Wittig and H. Pommer, German Pat., DBP954247, 1956.
11. A. Marinetti and D. Carmichael, Chem. Rev., 2002, 102, 201–230.
12. R. I. Wagner, L. D. Freeman, H. Goldwhite and D. G. Rowsell, J. Am. Chem. Soc., 1967, 89, 1102–1104.
13. R. Emrich and P. W. Jolly, Synthesis, 1993, 39–40.
14. R. A. Baber, M. F. Haddow, A. J. Middleton, A. G. Orpen, P. G. Pringle, A. Haynes, G. L. Williams and R. Papp, Organometallics, 2007, 26, 713–725.
15. F. Mathey and M. Regitz, in Comprehensive Heterocyclic Chemistry II, Elsevier, 1996, pp. 277–304.
16. A. A. Khan, P. Junker, G. Schnakenburg, A. Espinosa Ferao and R. Streubel, Chem. Commun., 2019, 55, 9987–9990.
17. M.-L. Y. Riu, A. K. Eckhardt and C. C. Cummins, J. Am. Chem. Soc., 2022, 144, 7578–7582.
18. K. Issleib and S. Häusler, Chem. Ber., 1961, 94, 113–117.
19. F. Mathey, Compounds with One Saturated Carbon Heteroatom Bond, in Science of Synthesis, ed. F. Mathey and B. M. Trost, Georg Thieme Verlag, Stuttgart, 2009, vol. 42(5).
20. D. M. Schubert and A. D. Norman, Inorg. Chem., 1984, 23, 4130–4131.
21. D. M. Schubert, M. L. J. Hackney, P. F. Brandt and A. D. Norman, Phosphorus, Sulfur Silicon Relat. Elem., 1997, 123, 141–160.
22. A. Emadi, R. J. Jones and R. A. Brodsky, Nat. Rev. Clin. Oncol., 2009, 6, 638–647.
23. S. Reichl, E. Mädl, F. Riedlberger, M. Piesch, G. Balázs, M. Seidl and M. Scheer, Nat. Commun., 2021, 12, 5774.
24. M. V. Butovskiy, G. Balázs, M. Bodensteiner, E. V. Peresypkina, A. V. Virovets, J. Sutter and M. Scheer, Angew. Chem., Int. Ed., 2013, 52, 2972–2976.
25. M. R. Eberhard, E. Carrington-Smith, E. E. Drent, P. S. Marsh, A. G. Orpen, H. Phetmung and P. G. Pringle, Adv. Synth. Catal., 2005, 347, 1345–1348.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2232605–2232614. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3sc00580a

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