Enantioseparation of P-Stereogenic Secondary Phosphine Oxides and Their Stereospecific Transformation to Various Tertiary Phosphine Oxides and a Thiophosphinate

Secondary phosphine oxides incorporating various aryl and alkyl groups were synthesized in racemic form, and these products formed the library reported in this study. TADDOL derivatives were used to obtain the optical resolution of these P-stereogenic secondary phosphine oxides. The developed resolution method showed a good scope under the optimized reaction conditions, as 9 out of 14 derivatives could be prepared with an enantiomeric excess (ee) ≥ 79% and 5 of these derivatives were practically enantiopure >P(O)H compounds (ee ≥ 98%). The scalability of this resolution method was also demonstrated. Noncovalent interactions responsible for the formation of diasteromeric complexes were elucidated by single-crystal XRD measurements. (S)-(2-Methylphenyl)phenylphosphine oxide was transformed to a variety of P-stereogenic tertiary phosphine oxides and a thiophosphinate in stereospecific Michaelis–Becker, Hirao, or Pudovik reactions.


■ INTRODUCTION
P-Stereogenic phosphines, phosphine oxides, or phosphonium salts represent an important class among organophophorus compounds, as these chiral derivatives have found widespread application as ligands, 1 organocatalysts, 2 or even biologically active compounds. 3 The preparation of enantiopure Pcompounds still represents a challenge, which inhibits their more diverse use. Most of the synthetic methods give the organophosphorus compound of interest in optically active form. 4 Syntheses involving the preparation of P-chiral precursors followed by their incorporation in the desired scaffold represent a modular strategy carrying high synthetic potential. Bench stability, low toxicity, odorless property, and the stereospecific functionalization of their P−H bond make secondary phosphine oxides (SPOs) desired P-stereogenic precursors. 5 Moreover, when the >P(O)H−>P(OH) tautomerization is utilized, 6 secondary phosphine oxides can be regarded as (pre)ligands, which can be used in transition metal catalyzed asymmetric transformations. 7 These properties make P-stereogenic SPOs valuable targets, and a variety of stereoselective syntheses or enantioseparation methods have been developed in recent years. 8 Most of the stereoselective syntheses rely on nucleophilic substitution of enantiopure H-phosphinates ( Figure 1A). The mode of preparation of the chiral H-phosphinate is a key difference between the given methods. Menthyl and later adamantyl phenyl-H-phosphinate were among the first simple optically active H-phosphinates used for stereoselective synthesis of chiral SPOs. Separation of the corresponding racemic compounds was used for the preparation of optically active H-phosphinate starting materials, and these studies also highlighted that undesired racemization may happen during nucleophilic substitution when certain organometallic reagents are used. 9 Another strategy utilizes amino-alcohols as chiral templates, and hydrolysis of the chiral oxazaphospholidine intermediate gives the corresponding H-phosphinates, which are then reacted with organometallic reagents. 10 Despite the advantages of the stereoselective syntheses, carefully controlled reaction conditions were required for each of the three key steps in order to avoid partial racemization and to obtain secondary phosphine oxides with high enantiomeric purity. In contrast, racemic secondary phosphine oxides can be prepared in just two steps considering the most straightforward synthetic path. 11 Thus, various separation methods of the corresponding racemates represent alternative methods for the preparation of optically active SPOs. In recent years, a few kinetic resolutions were developed employing chiral catalysts to give various P-stereogenic tertiary phosphine oxides with excellent enantiomeric excesses (ee's). 12 In theory, such reactions would give the unreacted portion of the SPO with high enanantiomeric purity ( Figure 1B). However, optically active SPOs were seldom isolated from the corresponding reaction mixtures, 12c−e and a few mechanistic studies revealed that optically active SPOs may racemize to some extent under the reaction conditions. 12b−d In a recent publication, Zhang and co-workers demonstrated an organocatalytic kinetic resolution using chiral phosphine catalysts. Besides the TPO products, the corresponding optically active SPOs were also isolated in good to excellent ee-s, showing a wide scope among Pstereogenic diaryl secondary phosphine oxides. 13 Classical resolutions, which are based on the formation and separation of crystalline diastereomeric salts or complexes, were among the first few methods developed for the enantioseparation of P-stereogenic secondary phosphine oxides. It is noteworthy that t-butyl-phenylphosphine oxide was the main focus of those studies. One type of resolution method involves the transformation of SPOs to the corresponding thiophosphinic acids or phosphinous acidboranes. The enantioseparation of these acidic derivatives was elaborated with chiral bases, and optically active SPOs were obtained after the removal of the sulfur or borane. Haynes et al. used this reaction sequence for the preparation of enantiopure t-Bu(Ph)P(O)H in multigram quantities via a thiophosphinic intermediate, 14 whereas the phosphinous acidborane route was explored by Stankevičand Pietrusiewicz. 15 There are a few other reports detailing the resolution of the acidic derivatives of other SPOs, but deprotection is generally omitted in those studies. 16 These optical resolution methods comprise two additional steps, which potentially lower the yield and increase the risk of undesired racemization ( Figure  1C). 15,17 Enantiomeric separation without derivatization is a more straightforward approach to obtain optically active secondary phosphine oxides. Chromatographic separation using chiral stationary phases was used to prepare the enantiomers of chiral SPOs on a small scale ( Figure 1D). 18 Considering classical resolutions of secondary phosphine oxides, enantiopure t-butyl-phenylphosphine oxide could be prepared using mandelic acid or O,O′-dibenzoyltartaric acid (DBTA) as the resolving agents, 11a, 19 and partial enantiomeric separation was achieved with BINOL 19 or chalcone sulfonic acid. 11a Minnaard and co-workers found that the radical racemization of t-Bu(Ph)P(O)H could be promoted using a catalytic amount of iodine. When this racemization process was implemented into the optical resolution with O,O′-dibenzoyltartaric acid, a dynamic resolution procedure was developed, which afforded nearly full conversion of the racemate to (R)-t-Bu(Ph)P(O)H with high enantiomeric purity. 20 Despite these promising results, such direct resolutions have never been extended to other secondary phosphine oxides, leaving the enantiomers of t-butyl-phenylphosphine oxide as the sole example prepared by this method ( Figure 1E). This summary shows that renewed interest in P-stereogenic SPOs populated especially the stereoselective or kinetic resolution methods, whereas the number of classical resolutions still remains low with limited scope. One of our ongoing interests involves the preparation of chiral organophosphorus compounds, and the high synthetic potential of Pstereogenic SPOs prompted us to develop enantiomeric separation methods for this compound class. To date, only tertiary phosphine oxides were made available in optically active form by our resolution methods. 21 The elaboration of such a method for P-stereogenic SPOs is not straightforward, as one of the TPO functional groups capable of the formation of secondary interactions is replaced by a proton, which makes the enantiomeric recognition and the separation of SPOs challenging.
The aim of this research was to develop a versatile enantioseparation method for the preparation of optically active secondary phosphine oxides (1). On the one hand, diaryl secondary phosphine oxides (1a−i) containing substituents in the ortho-, meta-, or para-position were our focus in order to investigate the effect of the substitution pattern on the efficiency of the enantiomeric separation and to increase the number of separation methods for such SPOs. On the other hand, alkyl-aryl derivatives (1j−n) were also included in this study in order to investigate the general scope of our resolution method. The secondary interactions within the diastereomers were investigated by single crystal X-ray crystallography. Starting from a selected secondary phosphine oxide, the synthesis of various optically active P-stereogenic tertiary phosphine oxides and thiophosphinates were attempted using stereospecific transformations (Figure 2).

■ RESULTS AND DISCUSSION
A synthetic strategy employing the diethylamino protecting group was selected for the synthesis of the racemic diaryl phosphine oxides (1a−i) (Scheme 1). First, P,P-dichlorophenylphosphine (4) was reacted with diethylamine, and pure N,N-diethylamino-chloro-phenylphosphine (6) could be isolated by vacuum distillation. N,N-Diethylamino-chloro-phenylphosphine (6) was the key intermediate in our divergent synthetic strategy, and it was reacted with aryllithiums to give the corresponding aminophosphines (7). Then, the toluene solution of the protected intermediate (7) was treated with cc. HCl (aq.) in order to remove the diethylamino group and to facilitate hydrolysis to give the corresponding secondary phosphine oxides (1a−i). The overall yield of this reaction sequence (1a−i) was in between 42% and 77% after a final purification by column chromatography. This one pot strategy for the aminophosphine SPO transformation was first demonstrated by Hoge et al., 22 and it has advantages over other literature procedures in which the removal of the protecting group and the hydrolysis of the intermediate are performed in two separate steps. 23 The racemic alkyl-aryl secondary phosphine oxides (1j−n) were prepared according to a literature procedure by reacting PhPCl 2 with ethanol and treating the in situ formed ethyl phenyl-H-phosphinate with the corresponding organometallic reagent. 12b,24 With the racemic secondary phosphine oxides (1) in hand, we began our investigation to find a suitable resolving agent. Our previous research 21a−c suggested that TADDOL derivatives might be good candidates for the optical resolution of the target secondary phosphine oxides (1). From our SPO library, the (2-methylphenyl)-phenylphosphine oxide (1a) was selected as the model racemic compound, and its resolution was attempted by various TADDOL derivatives and in a variety of solvents or solvent mixtures selected on the basis of our previous study (see the Supporting Information for details) (Scheme 2). 21c Even the first few experiments suggested that spiro-TADDOL [(R,R)-2] is the most suitable resolving agent, as a change either in the aromatic groups or in the dioxolane ring of the TADDOL scaffold led to a significant decrease in the enantioseparation of secondary phosphine oxide 1a.
Considering the solvents and the crystallization techniques, a precipitation-mediated crystallization from a mixture of toluene and hexane and a "classical" crystallization from 2-PrOH were the two methods that showed the most promising results affording the (S)-(2-methylphenyl)-phenylphosphine oxide [(S)-1a] in an ee above 95%. The other solvents investigated gave significantly lower ee values and yields (see the Supporting Information for details).
Considering the scope of the secondary phosphine oxides (1), diaryl SPOs incorporating either a moderately electron donating methyl group or a strong electron withdrawing trifluoromethyl group in the ortho-, meta-, or para-position were investigated (1a−f). Moreover, 1-naphthyl-, 2-methoxyphenyl, and (2-phenylphenyl)-phenylphosphine oxides (1g− i) were also included in the study. Considering the alkylphenylphospine oxide derivatives (1j−n), normal, branched, and cycloalkyl groups along with the benzyl group were selected in order to represent a variety of alkyl chains.
On the basis of the results of the preliminary studies, the optical resolution of all target secondary phosphine oxides (1) was attempted with spiro-TADDOL [(R,R)-2] using either 2propanol or a mixture of toluene and hexane as the solvent. It was found that even traces of water in the solvent cause inconsistent results; for this, dry solvents were used during the crystallization of the diastereomers. In all resolution experiments, the diastereomeric complexes were purified by recrystallization(s) in order to increase the diastereomeric purity. The given enantiomerically enriched secondary phosphine oxide (1) was liberated from the diastereomeric complexes by column chromatography, and the resolving agent [(R,R)-2] could also be recycled. Our previous study showed that organic solvent nanofiltration could be a scalable alternative process of such decompositions and recycling. 21c Most of the resolution experiments were attempted according to half-equivalent and equivalent methods in order to investigate which separation method is the more effective one. Thus, the amount of spiro-TADDOL [(R,R)-2] varied between 0.5 and 2 equiv, depending on the composition of the diastereomeric complex formed (vide infra). Results are summarized in Scheme 2 (see the Supporting Information for the complete set of experimental data).
The results indicated that the position and the nature of the substituent significantly influence the efficiency of the enantiomeric separation. Beside (2-methylphenyl)-phenylphosphine oxide (1a), the (4-methylphenyl) and (4-trifluoromethylphenyl) derivatives (1c and 1f) could be prepared in enantiopure form (ee: 99%) in yields of 40% or 29%, respectively. Interestingly, the enantiomers of (2-methylphenyl)-phenylphosphine oxide (1a) could be separated effectively (ee > 95%, S > 0.52) either in 2-propanol or in a mixture of toluene and hexane. On the other hand, only one of the two crystallization methods afforded pure enantiomers for the parasubstituted derivatives (1c and 1f). One may conclude that the substituent at the para-position has the least effect on the outcome of the resolution. A para-substituent is not in the proximity of the >P(O)H function; hence, it does not interfere with the mode of binding and noncovalent interactions formed between the given secondary phosphine oxide (1c or 1f) and spiro-TADDOL [(R,R)-2].
In contrast, ortho-and meta-substituents in a phenyl ring have a more decisive role on the overall efficiency of the resolution. 3-Methyl-or (3-trifluoromethyl-phenyl)phenylphosphine oxide (1b and 1e) could be prepared with a maximum ee of 62% or 79%, respectively. The yields were rather low (14−16%), and consequently, the resolving capability values fell in the range of 0.08−0.13. Considering the ortho-substituted derivatives (1a, 1d, 1g, and 1h), the change of the methyl group of the racemic compound to a trifluoromethyl, methoxy, or phenyl group led to a decrease in enantiomeric excess (0−67%) and in resolving capability values (0.00−0.23). The (2-trifluoromethylphenyl)-phenylphosphine oxide (1d) was the only derivative when the enantiomeric separation was completely unsuccessful, as no diastereomeric complex was formed. One may assume that the trifluoromethyl group being close to the P(O)H group lowers the Lewis basicity of the PO function; thus, the guest molecule (1d) loses its ability to form a stable H bond with the resolving agent [(R,R)-2] (vide infra). The methoxy group is another H-bond acceptor, whereas the 2-phenylphenyl group significantly increases the steric bulk in the ortho-position. Each effect has a negative impact on the enantiomeric recognition and, consequently, on the efficiency of the resolution (ee = 67% and S = 0.12 for 1g; ee = 40% and S = 0.10 for 1h).
Moderate results were obtained for (1-naphthyl)-phenylphosphine oxide (1i) (ee = 38% and S = 0.16 or ee = 83% and S = 0.12), which was another indication that increased steric demand has a negative impact on the host−guest interactions and, consequently, on the overall efficiency of the resolution. Considering the alkyl-aryl secondary phosphine oxides (1j−n), the selected derivatives could be resolved with good overall efficiency. Four (1j, 1k, 1m, and 1n) out of the five derivatives could be prepared with an ee greater than 87%, and the resolving capability values fell in the range of 0.11−0.63. The (S)-methyl-or (t-butyl)-phenylphoshine oxide [(S)-1k or (S)-1m] were the two derivatives that could be prepared in practically enantiopure form (ee > 98%). These results indicated that the optical resolution with (R,R)-spiro-TADDOL [(R,R)-2] tolerated normal, cyclo, and aralkyl chains. The butyl-phenylphosphine oxide (1l) was the only derivative that could not be separated effectively (ee ≤ 45%; S ≤ 0.10). One underlying reason might be that the normal butyl chain cannot form stable second order interactions, whereas these contacts might be more pronounced for the more compact or sterically more demanding (cyclo)alkyl groups. The resolution of a few selected SPOs of special interest, such as the 2-methoxyphenyl-, 1-naphthyl-, and t-butyl-derivative (1g, 1i, and 1m), was also attempted with two additional spiro-TADDOL derivatives. The partial separation of the enantiomers was only successful in the case of the (1-naphthyl)phenylphosphine oxide (1i), but a lower enantiomeric excess value could be obtained with 1i (ee: 70%) than with the spiro-TADDOL [(R,R)-2] (ee: 83%). These results show that better enantioseparation in this SPO library may not be obtained by changing the structure of the resolving agent (see Table S4 for details). 1 H NMR studies revealed that the composition of the diastereomeric complexes was dependent on the solvent used. Diastereomers incorporating the given secondary phosphine oxide enantiomer (1) and (R,R)-spiro-TADDOL [(R,R)-2] in a 1:1 ratio were formed in a mixture of toluene and hexane, whereas this SPO−spiro-TADDOL [1−[(R,R)-2] ratio changed predominantly to 1:2 when 2-propanol was used as solvent. This change in the composition of the host−guest complexes indicates that the mode of binding and, consequently, the ratio of 1 and [(R,R)-2] changes when the protic 2-propanol or the aprotic toluene−hexane mixture is used as solvent. The enantiopreference of the resolving agent [(R,R)-2] was not solvent dependent, 21a and the same secondary phosphine enantiomer [(R)-1 or (S)-1] was incorporated into the diastereomeric complex under both crystallization conditions. The absolute configuration of the secondary phosphine oxides 1a and 1g−n was assigned according to literature data. 9b,10b,14b Moreover, a single crystal XRD measurement has also confirmed the absolute configuration of (S)-1a (vide infra).
After the evaluation of the substrate scope of our resolution method, the scalability was assessed. A submillimolar scale (ca. 0.10 g) was typically used for optimization, and the resolution of (2-methylphenyl)-and (t-butyl)-phenylphosphine oxide (1a and 1m) were also elaborated on a gram scale (ca. 2 g of 1a or 1m) using (R,R)-spiro-TADDOL [(R,R)-2] as the resolving agent and 2-PrOH as the solvent (Scheme 3). In both cases, the enantioseparation could be elaborated successfully on a gram scale affording (S)-1a and (R)-1m with an ee of 98%. Similarly to the optimization experiments, three crystallizations of the corresponding diastereomer (R)-1m·(spiro-TADDOL) were necessary to reach a high optical purity of (R)-1m, and the yield improved from 36% to 60%. Intriguingly, the (S)-(2methylphenyl)-phenylphosphine oxide [(S)-1a] was obtained with an ee of 98% and in a yield of 92% (S: 0.90) even after one crystallization and decomposition of the diastereomeric complex (S)-1a·(spiro-TADDOL) 2 by column chromatography. These results are somewhat better than the ones obtained after the first crystallization and decomposition of the corresponding diastereomer [(S)-1a·(spiro-TADDOL) 2 ] during the preliminary studies (ee: 79%; yield: 83%; S: 0.65). The larger scale allowed a more efficient crystallization and a better separation of the crystalline diastereomer from the mother liquor, which consequently led to a better yield in both cases and a more simple procedure for (S)-1a. It is noteworthy that the mother liquor of the optical resolutions contained the other SPO antipode (R)-1a in excess. Enantiopure (R)-1a could be obtained by the optical resolution of this mother liquor with (S,S)-spiro-TADDOL under the same crystallization conditions, as it was demonstrated in our previous studies. 21a ,c The diastereomeric complex (S)-1a·(spiro-TADDOL) (diastereomeric excess (de): 95%) prepared from a mixture of toluene and hexane was selected for X-ray analysis, and the single crystals were grown from the same solvent mixture. The absolute configuration of (S)-(2-methylphenyl)-phenylphosphine oxide [(S)-1a] was determined using the known absolute configuration of (R,R)-spiro-TADDOL [(R,R)-2] as reference. The crystal lattice comprises the SPO (S)-1a and the Scheme 3. Gram-Scale Resolution of (2-Methylphenyl)-phenylphosphine Oxide (1a) and (t-Butyl)-phenylphosphine Oxide The Journal of Organic Chemistry pubs.acs.org/joc Article resolving agent (R,R)-2 in a 1:1 ratio, which is in accordance with our NMR measurements. A characteristic intramolecular H bond is present between the two OH groups of (R,R)-spiro-TADDOL [(R,R)-2], 21a,c and the (S)-1a and (R,R)-2 host− guest molecules are held together by an O−H···O bridge ( Figure 3). 25 Energy calculations were conducted with the Crystal Explorer program using the B3LYP/6-31G(d,p) level of theory (Table 1). 26 Total energies (E tot ) were the sum of the Coulomb interactions (E ele ), polar interactions (E pol ), dispersion interactions (E dis ), and repulsive interactions (E rep ). The four energy components were scaled in the total energy (E tot = 1.019E ele + 0.651E pol + 0.901E dis + 0.811E rep ). Interaction energies were investigated for a 3.8 Å cluster around the selected secondary phosphine oxide (S)-1a. These DFT calculations also confirmed that the two O−H···O interactions are the strongest ones in the crystal lattice (Table  1 and Figure 3). The second and third strongest interaction come from another neighboring (R,R)-spiro-TADDOL [(R,R)-2] or (S)-(2-methylphenyl)-phenylphosphine oxide [(S)-1a] molecule, respectively. The O−H···O hydrophilic contact turns the (R,R)-2 and (S)-1a molecules toward each other, creating a tight fit in between the host and guest molecules and creating a hydrophobic outer surface for this associate. Hirshfeld surface analysis also showed a high number of H contacts of the associated molecules. The H atom interactions corresponded to 84% of the intermolecular interactions, while the O atoms had a contribution of only 2.7% (see the Supporting Information for details). 27 As the last step of this study, a few typical SPO transformations were also elaborated in order to prepare the corresponding tertiary phosphine oxides [(S)-3a−d], hydroxyphosphine-oxides [(S)-3f and (S P ,R C )-3g], and a tiophosphonate [(R)-3e] (Scheme 4). Previously, such transformations were described using mainly the t-butyl-phenylphosphine oxide (1m) as the benchmark starting material. As the nature of the substituents may influence the P-inversion barrier, 28 the (S)-(2-methylphenyl)phenylphosphine oxide [(S)-1a] with an ee of 98% was chosen as a diaryl-SPO model compound for these stereoselective transformations. One method for the preparation of P-stereogenic tertiary phosphine oxides is the alkylation of metalated secondary phosphine oxides (Michaelis−Becker reaction). 14b, 29 First, (S)-1a was added to the THF suspension of NaH at 0°C to prepare (2-MePh)PhP(ONa), and it was treated with the corresponding primary alkyl halide to give (S)methyl-, ethyl-or benzyl-(2-methylphenyl)-phenylphosphine oxide [(S)-3a−c] in yields of 76−87%. The enantiomeric purity of the tertiary phosphine oxides (S)-3a−c was in the range of 95−98%, indicating high configurational stability of the secondary phosphine oxides and their deprotonated derivatives under the reaction conditions (Scheme 4A). Literature data suggested that this reaction proceeds with a retention at the P-stereogenic center. 14b, 29 Hirao coupling of (S)-(2-methylphenyl)-phenylphosphine oxide [(S)-1a] with 1-bromonaphtalene was also elaborated. Despite the popularity of this method for the formation of P−  Table 1). Table 1. Calculated Total Energies for the Neighboring Molecules of (S)-1a b a R is the distance within the center of the molecules. b The color of the first column corresponds to the color of the given molecules in Figure 3b. C sp2 bonds, 30 only a few reports can be found on the stereospecific arylation of P-stereogenic secondary phosphine oxides, 10c,13,31 and the chiral SPOs might be prone to (partial) racemization under the reaction conditions. 12b The P−C cross coupling of (S)-1a was performed in toluene under reflux conditions in the presence of Pd(PPh 3 ) 4 using K 2 CO 3 as the base, and these conditions were successfully applied for t- ] could be prepared with a yield of 85% and in an ee of 88%. The high reaction temperature might be responsible for the partial racemization observed (ee 0 = 98% → ee = 88%). This cross-coupling is expected to take place with retention of the P absolute configuration (Scheme 4B). 31 The addition of (S)-1a to formaldehyde or benzaldehyde was also studied in the presence of aq. NaOH. The (S)hydroxymethyl-(2-methylphenyl)-phenylphosphine oxide [(S)-3f] could be prepared in nearly quantitative yield (98%) and with an ee of 96%. The addition of benzaldehyde to Pstereogenic SPOs involves the formation of a new carbon stereogenic center. 31 P NMR spectra indicated that this reaction was highly diastereoselective, as the ratio of the two diastereomers was 97.5:2.5 in the crude product. Moreover, the (S P ,R C ) enantiomer could be prepared with excellent enantiomeric purity (ee > 98%) and in a yield of 80% (Scheme 4D). We believe that a crystallization induced asymmetric transformation is the underlying reason for this high diastereoselectivity. 20,32 Crystalline product (3g) was immediately formed when (S)-1a was reacted with benzaldehyde at room temperature. The subsequent stirring of the aqueous suspension at 80°C for 16 h allows the dissolution of the more soluble diastereomer and its transformation to the less soluble stereoisomer via an equilibrium cascade, which involves a retro-Pudovik reaction in the supernatant. This hypothesis was supported by a few control experiments. When the reaction was performed either at a lower temperature or with shorter reaction times, a significant decrease in the diastereomeric excess of 3g could be observed. As in the literature, 33 X-ray crystallography was used for characterization. The XRD measurement of (S P ,R C )-3g confirmed that the reaction proceeds with retention of the P-configuration, which is in accordance with the literature. 20,34 Moreover, the (R) absolute configuration of the formed carbon stereogenic center could also be established. The neighboring hydroxy(phenyl)methyl-(2-methylphenyl)-phenylphosphine oxides [(S P ,R C )-3g] were held together by H bonds formed between OH and PO functional groups of two different (S P ,R C )-3g molecules (see the Supporting Information for details). (S)-1a was also reacted with elemental sulfur to prepare the corresponding thiophosphonic acid 3e with retention of the P-configuration (Scheme 4C). 9b,16d Interestingly, the enantiomeric excess values of 3g could be determined by 31 P NMR using (S)-1naphthylethylamine as a chiral solvating agent, as no chiral chromatographic method could be developed for 3g.

■ CONCLUSIONS
In conclusion, a series of P-stereogenic secondary phosphine oxides (1) was prepared in racemic form, and their enantiomeric separation was elaborated with (R,R)-spiro-TADDOL [(R,R)-2]. The scope of the SPOs comprised several diaryl-derivatives containing a phenyl group and another aryl moiety with various substitution patterns (1a−i) and alkyl-phenylphospine oxides (1j−n) incorporating normal, branched, or cycloalkyl groups or a benzyl function. According to the preliminary experiments, the optical resolution of the target secondary phosphine oxides (1) was elaborated with (R,R)-spiro-TADDOL [(R,R)-2] in 2-propanol or in a mixture of toluene and hexane. Nine derivatives (1a, 1c, 1e, 1f, 1i−k, 1m, and 1n) could be prepared with an ee > 79% (yield: 12− 65%), and five of these derivatives (1a, 1c, 1f, 1k, and 1m) were practically enantiopure secondary phosphine oxides (ee > 98%, yield 27−65%). To date, this current method has the widest scope among classical resolution methods developed for P-chiral secondary phosphine oxides. Our results indicated that substituents in the para-position of a phenyl group has the least effect on the overall efficiency of the resolution. On the contrary, an increased steric bulk, especially in the orthoposition, had a negative effect on the enantiomeric separation. Several alkyl-phenylphospine oxides (1j, 1k, 1m, and 1n) containing various normal, cyclo, or aralkyl chains could be prepared with good enantiomeric purity and in acceptable yields (ee: 87−99%; yield: 12−41%). A gram-scale resolution of (2-methylphenyl)-phenylphosphine oxide (1a) was performed, indicating the scalability of this resolution method. Xray quality crystals were prepared from (S)-1a·(spiro-TADDOL), which was complemented with the DFT calculation to study the main interaction between the secondary phosphine oxide and the resolving agent.

■ EXPERIMENTAL SECTION
General Information. The commercially available reagents were purchased from commercial sources, and they were used without further purification unless otherwise stated. The TADDOL derivatives [(R,R)-2, (R,R)-SI-1, (R,R)-SI-3, and (R,R,R,R)-SI-4], 35,36 benzylphenylphosphine oxide (1j), methyl-phenylphosphine oxide (1k), butyl-phenylphosphine oxide (1l), tert-butyl-phenylphosphine oxide (1m), and cyclohexyl-phenylphosphine oxide (1n) were synthesized as described in the literature, and their analytical data were identical to the ones reported in the literature. 12b, 24 The solvents were purchased from Merck Chemical Ltd., and they were used without further purification. Solvents used in moisture sensitive reactions were purified and dried according to the standard procedures. 37 Dry solvents were stored over molecular sieves of 3 or 4 Å. The 31 P, 19 F, 13 C, and 1 H NMR spectra were taken on a Bruker AV-300 or DRX-500 spectrometer operating at 121.5, 282.4, 75.5, and 300 MHz or 202.5, 470.6, 125.8, and 500 MHz, respectively. Chemical shifts (δ) are given in parts per million (ppm). Chemical shifts (δ) were for 1 H and 13 C in CDCl 3 and referenced to 7.26 and 77.16 ppm, respectively. An 85% solution of H 3 PO 4 was the external reference for 31 P NMR chemical shifts. Coupling constants are expressed in Hertz (Hz). The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, and dd = doublet of doublets. The exact mass measurements were performed using an Agilent 6230C TOF LCMS System with Agilent Jet Stream source in positive ESI mode (buffer: ammonium-formate in water/acetonitrile; drying gas: 325°C; capillary: 3000 V; Fragmentor 100 V). LCMS measurements were performed using an Agilent 1100 and Agilent 6130 LCMS system in positive and negative electrospray mode. For the single crystal The Journal of Organic Chemistry pubs.acs.org/joc Article structure determination, the intensity data were collected on a Rigaku RAXIS-RAPID II diffractometer (using a graphite monochromator; Mo Kα radiation, λ = 0.71075 Å). The crystals were measured with fiber. Crystal Clear (developed by Rigaku Company) software was used for data collection and refinement. 38 Numerical and empirical absorption corrections were applied to the data. 39 The structures were solved by direct methods. Anisotropic full-matrix least-squares refinements were performed on F2 for all non-hydrogen atoms.
Hydrogen atoms bonded to C atoms were placed in calculated positions and refined in a riding-model approximation. The computer programs used for the structure solution, refinement, and analysis of the structures were Shelx, 40 Sir2014, 41 Wingx, 42 Platon, 43 and Crystal Explorer. 44 Melting points were obtained on a melting point apparatus and are uncorrected. The preparation of the air and moisture sensitive intermediates (6 and 7) or racemic secondary phosphine oxides (1a−n) was carried out under a nitrogen atmosphere in Schlenk-type reaction vessels using standard Schlenk techniques. 45 Table  S7. Optical rotations were determined on a Perkin−Elmer 341 polarimeter.
Preparation of Racemic Diaryl Secondary Phosphine Oxides (1a−i). N,N-Diethylamino-chloro-phenylphosphine (6). Under nitrogen atmosphere, 21 mL (260 mmol) of anhydrous pyridine was added dropwise over 5 min to a solution of 17 mL (130 mmol) of P,P-dichlorophenylphosphine (4) in 100 mL of anhydrous hexane, and then, the opaque solution was stirred for 10 min at 25°C. To this reaction mixture, 27 mL (260 mmol) of anhydrous diethylamine (5) was added dropwise over 20 min. The resulting white suspension was refluxed in an oil bath for 3 h, and it was cooled to 25°C . The precipitated salt was filtered through a sintered glass funnel under nitrogen atmosphere, and it was washed 2× with 50 mL of anhydrous hexane. The filtrate was concentrated on the rotary evaporator. Distillation under reduced pressure yielded 24 g (84%) of N,N-diethylamino-chloro-phenylphosphine (6) as colorless oil. bp: 95°C @ 0.5 mbar; (lit. bp: 68−70°C @ 0.13 mbar). 46 The distillate was used immediately.
[(4-(tert-butyl)phenyl)magnesium bromide was prepared from 7.6 mL (44 mmol) of 1-bromo-4-(tert-butyl)benzene and 1.2 g (48 mmol) of Mg in 35 mL of anhydrous THF]. The resulting solution was heated at reflux in an oil bath for 4 h; then, it was allowed to cool to room temperature, and it was stirred overnight. 40 mL of saturated NH 4 Cl and 20 mL of water were added. The phases were separated, and the aqueous layer was extracted with DCM (3 × 40 mL). The organic layers were combined, dried (Na 2 SO 4 ), and evaporated. The crude product was purified by flash column chromatography (silica gel, gradient elution, hexane to CHCl 3 ) to give 4.3 g (67%) of ((2R,3R)-1,4-dioxaspiro Representative Resolution Procedures. Over the course of this research project, it was observed that even the residual water content of the solvent may influence the outcome of the resolution in a negative manner. Thus, all the solvents used for resolution were dried according to the standard procedures. Dry solvents were stored over molecular sieves of 3 or 4 Å.