Selenoamides with two reactive sites: synthesis, structures, and dual reactivity of (selenocarbamoyl)phosphines

Abstract

Selenoamides stabilized by a phosphino group, i.e., (selenocarbonyl)phosphines, were synthesized and their solid-state structures were crystallographically determined for the first time. These (selenocarbamoyl)phosphines exhibit dual reactivity on two principal sites in reactions with electrophiles, i.e., on the phosphorus and selenium atoms, whereby the site where the reaction occurs depends on the nature of the reagent.

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Selenium isologues of carbonyl compounds, such as selenoketones and selenoaldehydes,¹ have gathered much attention owing to their highly polarized C=Se bond composed of an electrophilic carbon atom and a nucleophilic selenium atom (Fig. 1a, left). However, the isolation of monomeric selenocarbonyl compounds is difficult because they are prone to self-polymerization. To increase the stability of selenocarbonyl compounds, several methods including kinetic stabilization by bulky substituents² or mesomeric stabilization³ by introducing heteroatoms such as nitrogen, oxygen,⁴ sulfur,⁵ and selenium⁶ have been developed. Among the heteroatom-substituted selenocarbonyl compounds, selenoamides are particularly attractive in organic synthesis,^7,8 structural chemistry,^9,10 and other fields^11,12 owing to their high stability. Although recent studies have shown that the double-bond character of the C–N bond of selenoamides can be decreased through an appropriate molecular design,⁹ the strong mesomeric effects of the nitrogen atom frequently hamper the reactions with nucleophiles on the carbon atom in the C=Se bond. Hence, most reactions of selenoamides occur on the selenium atom (Fig. 1a, right), except when the selenium atom is alkylated to form selenoiminium salts.¹³ It is also not surprising that most reactions of selenoureas also occur on their selenium atom (Fig. 1b, left). To understand the chemical characteristics of selenoamides and expand their application scope by tuning their properties, the development of derivatives bearing a third heteroatom that acts not only as a mesomeric substituent but also as a second reactive center is highly desirable.

Fig. 1 (a) General reactivity of selenoketones and selenoamides. (b) Heteroatom-substituted selenoamides.

Representative examples of heteroatom-substituted selenoamides are (selenocarbamoyl)silane 1 and -germane 2¹⁴ (Fig. 1b, middle), which were synthesized in 2010 by Murai et al. using (selenocarbamoyl)lithium^14,15 as a carbanion species. We envisioned that this strategy could be also adopted to prepare selenoamides that bear heavy heteroatoms with lone pairs of electrons. Although a (thiocarbamoyl)phosphine¹⁶ was reported in 1983 by Kunze et al., its reactivity remained virtually uninvestigated. Herein, we report the first comprehensive study, including synthesis, structural characterization, and determination of inherent reactivity, on (selenocarbamoyl)phosphines 3a and 3b (Fig. 1b, right). Our structural and theoretical investigations indicate that the phosphorus atom participates weakly in the stabilization of the C=Se bond. Notably, 3a exhibited the expected dual reactivity involving two sites, i.e., the reactions with various electrophiles occurred not only on the phosphorus atom but also on the selenium atom.

We obtained (selenocarbamoyl)phosphine 3a in the form of orange crystals in 76% yield from treating (selenocarbamoyl)lithium species 5, which was generated in situ via the deprotonation of selenoamide 4^7d using lithium diisopropylamide (LDA) at −78 °C,¹⁴ with an equal amount of chlorodiphenylphosphine at −40 °C in THF (Scheme 1). To the best of our knowledge, this is the first example of a (selenocarbamoyl)phosphine. Compound 3a is remarkably stable in the solid state and in solution, allowing its isolation by flash chromatography on silica gel in air without special precaution. No decomposition was detected after heating a benzene solution of 3a at 80 °C for 24 h. The ⁷⁷Se NMR spectrum of 3a in CDCl₃ showed a doublet at 873 ppm (²J_P–Se = 13.0 Hz), which is comparable to that of Me₃Si derivative 1 (827 ppm) but shifted to lower field relative to that of the parent selenoamide 4 (571 ppm). In the ¹³C{¹H} NMR spectrum of 3a, a diagnostic doublet (¹J_P–C = 42.7 Hz) appeared at 217 ppm, consistent with a phosphorus-substituted selenoamide. Using a similar procedure, (selenocarbamoyl)phosphine 3b, which bears a bis[3,5-bis-(trifluoromethyl)phenyl]phosphino group, was obtained.

Scheme 1 Synthesis of (selenocarbamoyl)phosphines 3a and 3b.

The solid-state structures of 3a and 3b were unequivocally established by means of a single-crystal X-ray diffraction analysis (Fig. 2a and b). The length of the C–Se bond (1.836(12) and 1.830(11) Å for two crystallographically independent molecules per unit cell) of 3a resembles those in Me₃Si- and Me₃Ge-containing analogues 1 (1.834 Å) and 2 (1.830 Å),¹⁴ while it is longer than that of the parent selenoamide 4 (1.805 Å),¹⁴ reflecting the electron-donating effect of the p-block elements. In stark contrast, the C–Se bond lengths are much shorter than that of (tetramethyl)selenourea (1.873(6) Å),¹⁷ indicating that the phosphino group participates, albeit weakly, in the stabilization of the C=Se center, which stands in contrast to the amino groups. The C–N bond lengths (1.312(14) and 1.310(14) Å) are comparable to that of 4 (1.316 Å).¹⁴ Similar characteristics were observed in the single-crystal X-ray structure of 3b (Fig. 2b and c).

Fig. 2 Structures of (selenocarbamoyl)phosphines 3a (a) and 3b (b) with thermal ellipsoids drawn at 50% probability. In 3a, only one of the two crystallographically independent molecules per unit cell is shown. (c) Selected bond lengths and angles. (d) Selected frontier Kohn–Sham orbitals of 3a (isovalues = 0.04).

To gain further insights into the bonding characteristics of 3a, the frontier molecular orbitals and natural bond orbitals (NBOs) were calculated at the M06-2X/def2-TZVPP/ECP(Se)//TPSS-D3/def2-SVP/def2-TZVP(Se)/ECP(Se) level (Fig. 2d). The optimized structure adequately reproduced the experimentally determined crystal structure of 3a. The HOMO (−6.48 eV) and HOMO−1 (−7.06 eV; for details, see the ESI†) primarily consist of the lone pair orbital at Se1, while the HOMO−2 (−7.67 eV) corresponds to the lone pair orbital at P1 and the C1–P1 σ-bonding orbital. A natural population analysis (NPA) revealed the presence of a large positive charge on P1 (+ 0.79) and more negative charges on C1 (−0.20) and N1 (−0.42) compared to the corresponding carbon (−0.10) and nitrogen (−0.37) atoms in parent selenoamide 4 (for details, see the ESI†), confirming that P1 donates electron density toward the C1=Se1 bond. The Wiberg bond index (WBI) of the C1–P1 bond (0.90) and the relatively low second-order perturbation energy (E⁽²⁾) of (5.7 kcal mol⁻¹; for details, see the ESI†) are indicative of a single-bond character for C1–P1 and hyperconjugation likely occurs, at least in the solid state, albeit with relatively small effects. Taken together, these results suggest that the phosphino group in 3a acts as a σ-donating group toward the C=Se bond.

Unlike hitherto reported selenoamides, 3a exhibits dual reactivity at two centers. First, we examined the reactivity of the phosphorus atom of 3a (Scheme 2a). Treatment of 3a with THF·BH₃ afforded phosphine–borane complex 6 in 70% yield. Moreover, the reaction of 3a with an equimolar amount of 2,6-dichlorophenylazide produced iminophosphorane 7 as ruby-red crystals in 98% yield. Treatment of 3a with elemental selenium (1.05 equiv.) led to the formation of phosphine selenide 8 in 96% yield. It is noteworthy that no significant amounts of byproducts derived from the reaction on the selenium atom were observed. This high selectivity of the phosphorus atom toward various agents is a manifestation of the sufficiently nucleophilic character of the phosphorus atom of 3a as well as the thermal stability of the products.

Scheme 2 (a) Reactions on the phosphorus atom of 3a. (b) Synthesis of 9a and 9c. Solid-state structures of 7, 8, and 9a with thermal ellipsoids drawn at 50% probability. Selected bond lengths [Å] for 7: C1–Se1 1.8214(14), C1–P1 1.8704(15), C1–N1 1.3312(19), P1–N2 1.5581(13); for 8: C1–Se1 1.8065(15), C1–P1 1.8515(15), C1–N1 1.3348(19), P1–Se2 2.1041(4); for 9a: C1–Se1 1.8163(15), C1–P1 1.8516(15), C1–N1 1.332(2).

Although (thiocarbamoyl)phosphine oxides and -sulfides have already been reported,¹⁸ their selenocarbamoyl counterparts are unprecedented. The molecular structures of 7, 8, and phosphine oxide 9a, which were prepared as reference compounds via treatment of 5 with chlorodiphenylphosphine oxide (Scheme 2b), are shown in Scheme 2. Notably, the short C–Se bond lengths (ca. 1.81–1.82 Å) of these compounds are comparable to that of 2-tert-butylindolizine-3-selenoaldehyde (1.805(5) Å).¹⁹ In the ⁷⁷Se NMR spectra in CDCl₃, the selenium signals of the C=Se bonds of 7 (946 ppm), 8 (1035 ppm), 9a (983 ppm), and 9c (959 ppm) appeared at lower field relative to that of 3a, indicating the presence of deshielding effects of the P=N, P=Se, and P=O groups, respectively.

We then turned our attention to the reactivity of the selenium atom of 3a (Fig. 3a). Murai et al. have previously reported that MeOTf can effectively methylate the selenium atom of selenoamides.¹³ Accordingly, we treated 3a with an equimolar amount of MeOTf in Et₂O at ambient temperature. The corresponding selenoiminium salt 10 was obtained in 95% NMR yield together with a small amount of phosphonium salt 11. The upfield shift of the ⁷⁷Se NMR signal of the main product of this reaction to 512 ppm and the absence of any change in the ³¹P{¹H} spectrum relative to those of 3a allow excluding the tentative formation of 11. This selectivity is consistent with the relatively charge-dominating character of MeOTf and the negative NPA charge of the selenium atom (Fig. S15, ESI†). These results confirm the highly selective and dual reactivity of the (selenocarbamoyl)phosphine, in which not only the phosphorus atom but also the selenium atom act as reactive centers.

Fig. 3 (a) Synthesis of selenoiminium salt 10. (b) DFT-derived free-energy profile (kcal mol⁻¹) for the reaction of 3a with MeOTf.

To further investigate this selectivity, we conducted DFT calculations on the methylation of 3a (Fig. 3b). The methyl carbons exhibited normal five-coordinated structures in the transition states leading to 10 and 11, i.e., TS1a and TS1b, respectively. The activation energy of TS1a (17.3 kcal mol⁻¹) was slightly lower than that of TS1b (18.2 kcal mol⁻¹). Given that 10 (−11.9 kcal mol⁻¹vs. 3a) is thermally more labile than 11 (−27.1 kcal mol⁻¹vs. 3a), it can be concluded that the methylation of 3a proceeds via a kinetically controlled process. To consider the thermodynamic control of the methylation, we treated 3a with MeOTf (0.83 equiv.) at room temperature for 2 h, and the resulting mixture was heated to reflux for 1.5 h, but the proportion of 11 did not increase (Fig. S1 and S2; for details, see the ESI†).

Considering that thioamide-substituted phosphines have been reported to act as P,S-bidentate ligands,²⁰ we subjected (selenocarbamoyl)phosphine 3a to a complexation reaction with Buchwald's palladium dimer (12)²¹ to further demonstrate the formal dual reactivity on two reaction sites, i.e., on the phosphorus atom and the selenium atom of 3a. Gratifyingly, this reaction proceeded cleanly, affording 13 as pale-yellow crystals in 96% yield (Scheme 3). Since the bond lengths of the Se1–Pd1 (2.4816(3) Å) and P1–Pd1 (2.2202(6) Å) bonds were shorter than the sum of the van der Waals radii in the crystal structure of 13, it can be concluded that 3a acts as a P,Se-bidentate ligand. Notably, the C–Se–Pd–P moiety forms a unique four-membered ring with a sum of the internal angles of 385°. Although a similar four-membered ring has been reported for C–Se–Pt–Au,²² the present C–Se–Pd–P ring is unprecedented.

Scheme 3 Synthesis and structure of metal complexes 13–15. Thermal ellipsoids are drawn at 50% probability. Selected bond lengths [Å] and angles [°] for 13: C1–Se1 1.854(2), C1–P1 1.846(3), C1–N1 1.313(3), Se1–Pd1 2.4816(3), P1–Pd1 2.2202(6); Se1–C1–P1:103.54(12); for 14: C1–Se1 1.824(5), C1–P1 1.865(5), C1–N1 1.322(6).

Finally, to investigate the ability of 3a to act as a monodentate ligand, complexation reaction with gold(I) sources were also conducted. Gold complexes coordinated by the selenium atom of selenourea derivatives have been explored relatively well so far.²³ In stark contrast, analogous reactions of 3a with [Au(SMe₂)Cl] or [Au(IPr)]NTf₂ (IPr = 1,3-bis(2,6-diisopropyl-phenyl)imidazole-2-ylidene) quantitatively yielded the phosphine-ligated, stable, and reddish gold(I) complexes 14 and 15, respectively (Scheme 3). In combination with the production of 13, these results well illustrate the inherent reactivity differences between the (selenocarbamoyl)phosphines and selenoureas.

In conclusion, we have reported the first synthesis and structural characterization of crystalline (selenocarbamoyl)phosphines. The reactions with electrophiles and complexations with metal precursors proceeded on the selenium atom and/or the phosphorus atom depending on the nature of the reagents. We expect that the presence of a second reactive site will broaden the application scope of selenoamides as platform for muti-functionalized molecules. Further work on the synthesis of other, main-group-substituted heavy amides is currently underway in our laboratory.

This work was supported by JSPS KAKENHI grants JP23K23351 (to H. K.), JP22K20541 (to R. M.), and JP23K13751 (to R. M.) as well as by the Takahashi Industrial and Economic Research Foundation (to R. M.). The computational studies were performed at the Research Center for Computational Science, Okazaki, Japan (Project: IMS-RCCS-A-ja).

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2420890–2420896 and 2420898. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5cc00607d

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