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Article

Primary Phosphines and Phosphine Oxides with a Stereogenic Carbon Center Adjacent to the Phosphorus Atom: Synthesis and Anti-Markovnikov Radical Addition to Alkenes

by
Toshiaki Murai
1,*,
Ryota Wada
1,
Kouji Iwata
1,
Yuuki Maekawa
1,
Kazuma Kuwabara
1 and
Mao Minoura
2
1
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan
2
Department of Chemistry, College of Science, Rikkyo University, Nishi-ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
*
Author to whom correspondence should be addressed.
Organics 2021, 2(4), 395-403; https://doi.org/10.3390/org2040023
Submission received: 29 August 2021 / Revised: 15 October 2021 / Accepted: 26 October 2021 / Published: 16 November 2021
(This article belongs to the Special Issue Progress in Synthesis and Applications of Phosphorus-Containing Compounds)
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Abstract

:
Organophosphorus compounds with stereogenic phosphorus and carbon atoms have received increasing attention. In this regards, primary phosphines with a stereogenic carbon atom adjacent to the phosphorus atom were synthesized by the reduction in phosphonates and phosphonoselenoates with a binaphthyl group. Their oxidized products, i.e., phosphine oxides with a stereogenic tetrasubstituted carbon atom, were found to undergo BEt3-mediated radical addition to cyclohexene to give P-stereogenic secondary phosphine oxides with a diastereoselectivity of 91:9. The products were characterized by ordinary analytical methods, such as Fourier transform infrared spectroscopy; 1H, 13C, and 31P NMR spectroscopies; and mass spectroscopy. Computational studies on the phosphorus-centered radical species and the obtained product implied that the thermodynamically stable radical and the adduct may be formed as a major diastereomer. The radical addition to a range of alkenes took place in an anti-Markovnikov fashion to give P-stereogenic secondary phosphine oxides. A variety of functional groups in the alkenes were tolerated under the reaction conditions to afford secondary phosphine oxides in moderate yields. Primary phosphines with an alkenyl group, which were generated in situ, underwent intramolecular cyclization to give five- and six-membered cyclic phosphines in high yields after protection by BH3.

1. Introduction

Organophosphorus compounds, and particularly those with three or four substituents on the phosphorus atom, i.e., tertiary phosphines, phosphine oxides, and their isologues, are of great importance in organic synthesis and medicinal chemistry [1,2,3]. The synthesis and reactions of primary phosphines [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18] and phosphine oxides [19,20,21] which contain two phosphorus–hydrogen (P–H) bonds have received increasing attention because these highly reactive bonds undergo various types of phosphorus-carbon (P–C) bond-forming reactions. Their highly efficient addition reactions to alkenes have been achieved with transition metal catalysts [22,23,24]. A radical reaction involving phosphorus-centered radicals generated in situ is a classical method for P–C bond formation [25,26,27,28,29,30]; however, the use of primary phosphines and phosphine oxides in a radical reaction is relatively rare compared to that of secondary phosphines and phosphine oxides [31,32,33,34,35,36,37,38]. The stereochemistry on a phosphorus atom has not received much attention, despite the fact that the introduction of at least three different substituents to the phosphorus atom gives rise to the stereogenic center on the phosphorus atom. During the course of our studies on main group chemistry [39,40], we have intensively studied the synthesis and applications of organophosphorus compounds with a binaphthyl group [41,42,43,44,45] and recently reported that the deprotonation and alkylation of phosphonoselenoates and phosphonates with a binaphthyl group creates stereogenic secondary and tertiary carbon centers adjacent to the phosphorus atom with high diastereoselectivity (Scheme 1a,b) [46]. The resulting products are potentially available as precursors of primary phosphines since phosphorus–oxygen bonds are readily reduced to P–H bonds.
Herein, we report the generation of primary phosphines and their oxides with a stereogenic carbon center adjacent to the phosphorus atom and their radical addition reaction to alkenes to give P–stereogenic secondary phosphine oxides (Scheme 1c,d).

2. Materials and Methods

General Remarks: The IR spectra were obtained on a JASCO FT-IR spectrophotometer. The 1H NMR spectra were measured on a JEOL AL400 (400 MHz), ECX-400P (400 MHz), or ECA-500 (500 MHz) in CDCl3. Chemical shifts of protons are reported in δ values referred to tetramethylsilane as an internal standard in CDCl3, and the following abbreviations are used: s: singlet, d: doublet, t: triplet, and m: multiplet. The 13C NMR spectra were measured on a JEOL AL400 (100 MHz), ECX-400P (100 MHz), or ECA-500 (125 MHz) in CDCl3. The 31P NMR spectra were measured on a JEOL AL400 (162 MHz), ECX-400P (162 MHz), or ECA-500 (202 MHz) in CDCl3 with 85% H3PO4 as an external standard. All spectra were acquired in the proton-decoupled mode. The mass spectra (MS) and high resolution mass spectra (HRMS) were taken on a JMS-700 mass spectrometer. Preparative recycling gel permeation chromatography (GPC) was carried out using CHCl3 as the eluent. All these instruments are made in Japan.
Materials: Lithium aluminum hydride, allyl alcohol, allyltrimethylsilane, 6-bromo-1-hexene, 5-hexene-2-one, and 1,5-hexadiene were purchased from Tokyo chemical industry Co., Ltd., Tokyo, Japan. Magnesium sulfate anhydrous (MgSO4), α,α′-azobisisobutyronitrile, hexane, tetrahydrofuran (THF) dehydrate, toluene, ethyl acetate, chloroform, and triethylborane 1.0 M solution in hexane were purchased from Kanto Chemical Co., Ltd., Tokyo, Japan. Chloroform-d, triethylborane 1.0 M solution in THF, and 1,2:3,4-di-O-isoprorylidene-α-d-galactopyranose were purchased from Aldrich Chemical Company, Inc., Milwaukee, WI, USA. Cyclohexene was purchased from Nacalai Tesque Inc., Kyoto, Japan. Dichloromethane and alumina activated were purchased from Waco Inc., Tokyo, Japan. All manipulations were carried out under argon atmosphere.

3. Results and Discussion

Initially, phosphonate (Sax, Sp)-1a with a trisubstituted carbon atom adjacent to the phosphorus atom was reduced with lithium aluminum hydride (LAH) (Scheme 2) [47].
The reaction proceeded smoothly under reflux in diethyl ether to give the primary phosphine 2a in 65% yield. The use of diastereomerically enriched substrate 1a (dr > 95:5) was expected to give an enantiomerically enriched product 2a. In fact, 2a and 2d showed a specific rotation of +9.48 and +24.5, respectively, but the enantiomeric purity of 2a was not determined because of its lability under HPLC analytical conditions and in the presence of chiral shift reagents. The efficiency of the reduction was further proved in the reaction of 1b–1d with LAH leading to the formation of 2b–2d. The reduction in phosphonate 3 having a tetrasubstituted atom adjacent to the phosphorus atom with LAH also took place to give the corresponding primary phosphine 4 (Scheme 3).
The oxidation of primary phosphine 4 selectively gave primary phosphine oxide 5 with high efficiency, although similar oxidation of 2 with a trisubstituted carbon atom at the phosphorus atom did not give the desired oxides with high efficiency. The absolute configuration of the product 5 was not determined at this point, but was later determined by converting it to an alkene adduct.
Radical addition of the resulting primary phosphines 2 and 4 and phosphine oxide 5 to alkenes under radical reaction conditions was then carried out. However, unlike the reported addition reaction of primary phosphines with an aromatic group and a tertiary alkyl group on the phosphorus atom [30], the AIBN-mediated reaction of primary phosphines 2 and 4 to alkenes gave complex mixtures containing a small amount of the expected adducts. In contrast, the reaction of primary phosphine oxide 5 with cyclohexene (6a) gave an isolable product 7a (Table 1).
The AIBN-mediated reaction [48] did not proceed at room temperature (entry 1). An increase in temperature gave a small amount of the product 7a. Attempts to enhance the yield of 7a by using a catalytic amount of BEt3 [49] (entry 2) were not successful. As solvents, CH2Cl2 and THF were not effective (entries 5 and 6). The reaction in MeOH gave two diastereomers in a ratio of 91:9, and the reaction temperature did not affect this ratio (entries 3 and 4). The molecular structure and absolute configurations at the phosphorus and carbon atoms of the major diastereomer of 7a were unequivocally determined by X-ray molecular structure analysis [50] (Figure 1). The results showed that the phosphorus and carbon atoms adopted S configurations.
The reaction in Table 1 should begin with the formation of phosphorus-centered radical 8 [51] (Figure 2), which then adds to the alkene 6a. To elucidate the structure of 8, molecular orbital calculations at the UHF/6-31G (d, p) level of theory [52] were carried out. The results showed two stable diastereomers: 8a and 8b, whereby the radical center at the phosphorus atom was oriented in the same or opposite direction toward the carbon-silicon bond. The diastereomer 8b was more stable than 8a by about 0.5 kcal/mol. The relative stability of the major product 7a and its diastereomer 7a′ was also estimated by DFT calculations at the B3LYP/6-31G (d, p) level of theory. On the basis of these calculations, interconversion of the phosphorus radicals 8a and 8b may be possible, but 8b may mainly attack cyclohexene to form thermodynamically stable diastereomer 7a.
We next investigated the scope of alkenes with phosphine oxide 5 under the BEt3-mediated addition reaction conditions (Table 2). Terminal alkenes having hydroxy, trimethylsilyl, acetyl, acetoxy, and acetal groups 6b–6g reacted with the phosphorus-centered radical generated from 5 to give the corresponding products 7b–7f (entries 1–5).
In all cases, 31P NMR and 1H NMR spectra showed the formation of anti-Markovnikov adducts (See Supplementary Materials). This regioselectivity is in accordance with the addition reaction of phosphorus-centered radical to terminal alkenes [35]. They were isolated by column chromatography on Al2O3 and gel permeation chromatography to give the corresponding products with high purity, but in low yields due to their lability during purification. In the isolated product, 7g from the reaction of 6-bromo-1-hexene (6g) and a bromine atom remained intact (entry 6). The reaction of 1,5-hexadiene (6h) gave the product 7h, in which only one alkenyl group participated in the reaction (entry 7). Products derived from the intramolecular cyclization of a terminal alkene in 7h were not observed, which is in a marked contrast to the reported reaction of phosphorus-centered radical to 1,5-hexadiene [35].
Finally, primary phosphines with a terminal alkenyl group were subjected to the radical reaction conditions (Table 3). Reduction in phosphonoselenolate 9a with LAH followed by alkaline aqueous workup generated primary phosphines 11, which were then treated with AIBN in toluene for 2 h. Attempts to purify the crude products failed to give the phosphorus-containing cyclic compounds, probably because of the lability of presumed phospholanes 12, although similar phospholanes were characterized by their NMR spectra [53]. Thus, we treated the reaction mixture containing 12 with a THF solution of BH3 to give boron complexes 13. The use of 9a and 10a gave boron complexes of phospholanes 13a and 13b, and the reaction of 9b led to the formation of the boron complex of phosphorinane 13c in high yield with good diastereoselectivities (entries 1–3).

4. Conclusions

In summary, we have demonstrated the generation of primary phosphines with a stereogenic carbon atom adjacent to the phosphorus atom. The primary phosphine oxide with a tetrasubstituted stereogenic carbon center was subjected to BEt3-mediated radical addition reaction to cyclohexene and terminal alkenes. The reaction gave anti-Markovnikov adducts as major products. Functional groups, such as hydroxy, trimethylsilyl, acetyl, acetoxy, and acetal groups, and bromine atoms remained intact under the reaction conditions. To the best of our knowledge, these products are the first examples of compounds with a successive stereogenic secondary phosphorus atom and tetrasubstituted carbon atom, although organophosphorus compounds with a tetrasubstituted carbon atom next to a phosphorus atom have also been reported to some extent [54,55,56]. The intramolecular cyclization of in situ-generated primary phosphines with an alkenyl group was achieved to give phospholanes and phosphorinanes, which were isolated as boron complexes. Further studies on organophosphorus compounds with a binaphthyloxy group as key precursors [57] for P-stereogenic organophosphorus compounds are in progress.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/org2040023/s1, Experimental procedure, the detail of X-ray structure analysis, cartesian coordinates of DFT calculation, and 1H and 13NMR spectra of new compounds.

Author Contributions

Conceptualization, T.M.; investigation, R.W., K.I., Y.M., K.K. and M.M.; writing—original draft preparation, T.M.; writing—review and editing, Y.M., K.K. and M.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Not applicable.

Acknowledgments

This research was partly supported by a Grant-in-Aid for Scientific Research (B) (19H02712) from MEXT, and JSPS KAKENHI grants 18H04396 (Middle Molecular Strategy). We are also grateful for support from the SPring-8 synchrotron, where synchrotron radiation experiments were performed at the BL02B1 beamline with the approval of the Japan Synchrotron Radiation Research Institute (JASRI) (proposals 2020A0557, 2020A0834, 2020A1056, 2020A1644, 2020A1656, and 2021A1592).

Conflicts of Interest

The authors declare no conflict of interest.

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Organics 02 00023 sch001 550
Scheme 1. Organophosphorus compounds having stereogenic carbon atoms adjacent to the phosphorus atom.
Scheme 1. Organophosphorus compounds having stereogenic carbon atoms adjacent to the phosphorus atom.
Organics 02 00023 sch001
Organics 02 00023 sch002 550
Scheme 2. Reduction of phosphonoselenoates 1 with LiAIH4.
Scheme 2. Reduction of phosphonoselenoates 1 with LiAIH4.
Organics 02 00023 sch002
Organics 02 00023 sch003 550
Scheme 3. Synthesis of primary phosphine and phosphine oxide (* shows a chiral center and the carbon atom adopts either R or S configuration).
Scheme 3. Synthesis of primary phosphine and phosphine oxide (* shows a chiral center and the carbon atom adopts either R or S configuration).
Organics 02 00023 sch003
Organics 02 00023 g001 550
Figure 1. ORTEP drawing of Sp. Sc-7a at the 50% probability level.
Figure 1. ORTEP drawing of Sp. Sc-7a at the 50% probability level.
Organics 02 00023 g001
Organics 02 00023 g002 550
Figure 2. Energy diagram of phosphorus centered radicals 8a an 8b, and products 7a and its diastereomer 7a′.
Figure 2. Energy diagram of phosphorus centered radicals 8a an 8b, and products 7a and its diastereomer 7a′.
Organics 02 00023 g002
Table
Table 1. Optimization of radical addition [a].
Table 1. Optimization of radical addition [a].
Organics 02 00023 i001
EntryRadical InitiatorSolventTempYield [%] [b]dr [b]
1AIBNMeOHrt0 [c]
2BEt3MeOHrt10
3BEt3MeOH0 °C6291:9
4BEt3MeOH40 °C7591:9
5BEt3CH2Cl2rt12
6BEt3THFrt0 [c]
[a] Reaction conditions: 5 (0.5 mmol, 1 equiv), 6a (0.55 mmol, 1.5 equiv), and radical initiator (0.55 mmol, 1.1 equiv) in 2.5 mL solvent under air. [b] Yields and dr were determined on the basis of 31P NMR spectra of crude products. BEt3 (0.1 equiv) was used. [c] The substrate 5 was completely recovered.
Table
Table 2. Radical addition of 5 to a range of alkenes.
Table 2. Radical addition of 5 to a range of alkenes.
Organics 02 00023 i002
EntryAlkene 6ProductRatio of Product [%] aIsolated Yield [%] bdr c
1 Organics 02 00023 i003 Organics 02 00023 i004523781:19
2 Organics 02 00023 i005 Organics 02 00023 i006872278:22
3 Organics 02 00023 i007 Organics 02 00023 i008562081:19
4 Organics 02 00023 i009 Organics 02 00023 i010161779:21
5 Organics 02 00023 i011 Organics 02 00023 i0121002785:15
6 Organics 02 00023 i013 Organics 02 00023 i014683583:17
7 Organics 02 00023 i015 Organics 02 00023 i016352381:19
a Ratio of product indicates percentage of the integrals of the signals corresponding to the product among all the signals observed in 31P NMR spectra of the crude products. b Yields of isolated products through column chromatography on Al2O3 and gel permeation chromatography. c Diastereomric ratio of isolated products determined by 31P NMR spectra.
Table
Table 3. Intramolecular cyclization reaction of primary phosphines generated from phosphonoselenoates 9 and phosphonates 10.
Table 3. Intramolecular cyclization reaction of primary phosphines generated from phosphonoselenoates 9 and phosphonates 10.
Organics 02 00023 i017
EntrySubstrate
9 or 10 (dr)		ProductYield [%] adr b
1 Organics 02 00023 i018 Organics 02 00023 i0198788:12
2 Organics 02 00023 i020 Organics 02 00023 i0216587:13
3 Organics 02 00023 i022 Organics 02 00023 i0237887:13
a Isolated yields. b Diastereomric ratio of isolated products determined by 31P NMR spectra.
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Murai, T.; Wada, R.; Iwata, K.; Maekawa, Y.; Kuwabara, K.; Minoura, M. Primary Phosphines and Phosphine Oxides with a Stereogenic Carbon Center Adjacent to the Phosphorus Atom: Synthesis and Anti-Markovnikov Radical Addition to Alkenes. Organics 2021, 2, 395-403. https://doi.org/10.3390/org2040023

AMA Style

Murai T, Wada R, Iwata K, Maekawa Y, Kuwabara K, Minoura M. Primary Phosphines and Phosphine Oxides with a Stereogenic Carbon Center Adjacent to the Phosphorus Atom: Synthesis and Anti-Markovnikov Radical Addition to Alkenes. Organics. 2021; 2(4):395-403. https://doi.org/10.3390/org2040023

Chicago/Turabian Style

Murai, Toshiaki, Ryota Wada, Kouji Iwata, Yuuki Maekawa, Kazuma Kuwabara, and Mao Minoura. 2021. "Primary Phosphines and Phosphine Oxides with a Stereogenic Carbon Center Adjacent to the Phosphorus Atom: Synthesis and Anti-Markovnikov Radical Addition to Alkenes" Organics 2, no. 4: 395-403. https://doi.org/10.3390/org2040023

APA Style

Murai, T., Wada, R., Iwata, K., Maekawa, Y., Kuwabara, K., & Minoura, M. (2021). Primary Phosphines and Phosphine Oxides with a Stereogenic Carbon Center Adjacent to the Phosphorus Atom: Synthesis and Anti-Markovnikov Radical Addition to Alkenes. Organics, 2(4), 395-403. https://doi.org/10.3390/org2040023

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