Letter pubs.acs.org/OrgLett
Nucleophilic Substitution of P‑Stereogenic Chlorophosphines: Mechanism, Stereochemistry, and Stereoselective Conversions of Diastereomeric Secondary Phosphine Oxides to Tertiary Phosphines Jing-Jing Ye,† Shao-Zhen Nie,† Ji-Ping Wang, Jing-Hong Wen, Yu Zhang, Mao-Ran Qiu, and Chang-Qiu Zhao* College of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng, Shandong 252059, China S Supporting Information *
ABSTRACT: A diastereomeric mixture of secondary phosphine oxide is stereospecifically converted to chlorophosphine salt by treatment with oxalyl chloride, which stereoselectively affords P-inverted or retained tertiary phosphines, depending on the substitution with aliphatic or aromatic Grignard reagents, respectively, in high to 99% yield and 99:1 dr. The repulsion of πelectron on aryl to lone electron pair on phosphorus is proposed for the P-retained substitution.
hiral tertiary phosphines attract extensive attention because of their important applications in asymmetric synthesis, as ligands of metallic catalysts1 and as organocatalysts.2 Because the stereogenic center is closer to the active center, P-stereogenic tertiary phosphines exhibit excellent asymmetric induction.3 Traditionally, the compounds are generated from multistep conversions,4 tedious resolutions,5 or by asymmetric reactions.6 Several recent reviews have documented the preparation of stereogenic phosphines.7 The stereogenic secondary phosphine oxides (SPO) can be easily converted to tertiary phosphines oxides (TPO) via alkylating, cross-coupling, addition (Figure 1),8−10 and
C
halogenation followed by substitution with metallic reagents,11 with good stereoselectivity. However, the optically pure SPOs are difficult to acquire.12 Another precursor SPB (secondary phosphine borane), usually prepared from SPO, is similarly converted to TPB (tertiary phosphines borane) but is also restricted by poor availability.13 Thus, the use of an accessible racemic or epimeric SPO or SPB in the strategy is highly valuable. The above-obtained TPO or TPB contains oxygen or boron that have to be removed to form TP.14 The straightforward conversion of SPO to TP, even for the nonchiral ones, has rarely been reported (Figure 1). In addition, the P-chirality is probably lost during the multistep conversions from SPO to TP.14,15 Shortening the pathway can reduce the loss. The traditional nucleophilic substitutions of the Pheteroatom species16 can be applied for the preparation of stereogenic TPO11b,17 and TPB18 (Figure 1b). The strategy has been used for the synthesis of the famous DIPAMP, as reported by Knowles.4 Obviously, unprotected stereogenic chlorophosphines are more straightforward precursors of TP. However, perhaps due to configurationally instability,18a,19 to the best of our knowledge, their substitution, mechanism and stereochemistry have rarely been reported. Herein we disclose a stereospecific conversion of epimeric (−)-menthyl alkylphosphine oxide 1/1′20 to a hydrochloride salt of chlorophosphine (Figure 1). The salt was stereoselectively converted to P-inverted and retained TP via the
Figure 1. Comparison of our work to traditional reactions.
Received: August 27, 2017 Published: September 26, 2017
© 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b02667 Org. Lett. 2017, 19, 5384−5387
Letter
Organic Letters substitution with aliphatic and aromatic metallic reagents, respectively. When RP-1a was chlorinated with oxalyl chloride at 0 °C14c,21 and then reacted in situ with benzyl magnesium chloride 2a, RP3a and SP-3a′ were detected, as evidenced by the peaks at −16.0 and −12.7 ppm (72:28) on 31P NMR spectrum. After protection with borane, RP-4a and SP-4a′ were formed. Compound 3a/3a′ was oxidized to SP-5a and RP-5a′ when exposed to air (Scheme 1). The structures of 3a, 4a, and 5a were confirmed on the basis of X-ray diffraction.
Table 1. Preparation of 4 or 4′ from 1/1′ via Chlorination− Substitution
Scheme 1. Conversion of 1a to 3a, 4a, and 5a and Their 31P NMR Spectral Data
When the reaction was carried out at −80 °C, the dr (5a/ 5a′) improved to 82:18. Surprisingly, when RP-1a was replaced by a mixture of 1a/1a′, similar dr was observed, indicating either RP-1a or SP-1a′ was similarly chlorinated and substituted. Thus, the mixture of 1/1′ was employed for the preparation of TP and their derivatives. As seen in Table 1, methyl- or tert-butyl-substituted benzyl Grignard reagents with 1a afforded 4b to 4d in higher dr than 4a. Chloro-substituted 4e was formed in poorer dr than 4a. Aliphatic 2, with primary and secondary alkyl Grignard reagents, afforded 4f to 4m in excellent dr. Aromatic 2 usually gave poorer dr than aliphatic compounds, except for methoxylsubstituted 2s to 2t that formed 4s′ to 4t′ around 10:90 dr. Similarly, 1b/1b′ (R = p-methylphenyl) or 1c/1c′ (R = benzyl) formed 4z to 4ac′ in good to excellent dr. Most 4 could be isolated as single stereoisomers. The structure of RP-4g was confirmed via the substitution of menthyl phenylphosphinic chloride 6 that was obtained from chlorination of RP-1a with NCS. Additionally, the X-ray diffraction of 4i unambiguously confirmed its RP-configuration (Figure 2). However, the substitution with aromatic 2 formed SP-4′ as major products, whose structure was confirmed by the X-ray analysis of 4r′ and 4s′. The configuration of other 4 and 4′ was determined based on their characteristic peaks on 31 1 P{ H} NMR spectrum, which were well correlated with 4i and 4r′. A chlorinated intermediate was proposed to involve in the substitution. As seen in Scheme 2, the chlorination of either 1a or 1a/1a′ gave the broadly single peak at 103.8 ppm on 31P NMR spectrum, which was assigned as a hydrochloride salt 7 of chlorophosphine 8 (runs 1 and 2). The treatment of a prepared 8/8′ (75:25) with anhydrous HCl afforded 7/7′ in a similar ratio, as evidenced by the peaks at 103.8 and 98.7 ppm (runs 4 and 5). Thus, 7 was formed as a single stereoisomer during the chlorination of 1a/1a′, and could not be converted to 7′, as we observed no ratio change in runs 3 and 6. When prepared in the presence of triethylamine, or treated with base, 7 was converted to 8/8′ around 75:25 ratio (runs 7− 9). We supposed 7 was converted to 8 that was epimerized to 8′, similar to the reported slowly racemization of P-stereogenic
a
The yield and dr (RP-4/SP-4′) were estimated by 31P{1H} NMR spectrum. The structure of RP-4/SP-4′ was confirmed based on NMR spectrum and X-ray diffraction. bThe structures of RP-4ab and SP-4ac′ were determined based on NMR spectrum, which were different to the title equation (as seen in Table S2).
Figure 2. Structure of X-ray diffraction for 4i and 4r′.
chlorophosphine.19 The chiral (−)-menthyl perhaps stabilized the configuration of 7, and the maintained 8 was epimerized to 8′ in a 75:25 ratio, rather than thoroughly to 50:50.22 The deprotonation of 7 and the subsequent substitution of 8 with 2 afforded 3. The slow epimerization of 8 was proposed to lead the loss of the chirality during the substitution. Active 2 reacted with 8 rapidly before the epimerization, giving excellent dr. The sluggish reaction of less active 2 led to more epimerization of 8 and poor dr (Scheme 3). The rough trend of dr to the activities of 2 could be observed in Table 1. 5385
DOI: 10.1021/acs.orglett.7b02667 Org. Lett. 2017, 19, 5384−5387
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Organic Letters
11 that generated P-retained SP-3′ upon chloride loss. Thus, aromatic 2 gave poorer or reversed dr (Scheme 4).24,25 The p−π repulsion could be observed in Scheme 3. As less active nucleophiles, 2q and lithium ethoxide 2ad did not react with 8 at −80 °C. However, at room temperature, they predominantly afforded P-retained 3q′ and P-inverted 3ad, respectively. The absence of π-electron was supposed to lead to 2ad attacking at 8 opposite chloride in a P-inverted SN2-like manner. In addition, the reported P-retained substitution of cyclic chiral P−Cl species with ferrocene lithium also supported the proposal of p-π repulsion.26 Although the mechanism for the stereospecific formation of 7 was not clear, we attempted to grasp some aspects based on the observations. As aforementioned, 7 and 7′ did not converted each other. Thus, the chlorination of 1a and 1a′ to form 7 was supposed to occur via different pathways. The poor dr for the chlorination with thionyl chloride or triphosgene exhibited an intramolecular attack via a cyclic intermediate, perhaps involved with the chlorination with oxalyl chloride. As proposed in Scheme 5, the weakly bonding H or electro-
Scheme 2. Chlorination and Conversion of 1a or 1a/1a′
Scheme 3. Substitution of 7 at Different Temperatures
Scheme 5. Proposed Stereospecific Chlorination of 1a/1a′
At −80 °C, the epimerization was slowed down and dr was improved. However, some less active 2 did not react with 8 at this temperature. For example, when the reaction of 2q (R = otolyl) was quenched at −80 °C, only 1a/1a′ was formed via the hydrolysis of unreacted 8/8′. Similarly quenching the reaction of 2g gave 3g/3g′ in 98:2 ratio. The better dr (1:99) for 2s at −80 °C for 7 h showed that the epimerization hardly took place (Scheme 3). When more active lithium reagent was used, expected improvement of dr was not observed. We supposed that the facile solvable lithium chloride enhanced the chloridepromoting epimerization of 8.23 In contrast, magnesium salt released less chloride ion and gave better dr. In fact, a cloudy mixture developed for the reaction with 2h, whereas a clear solution was observed for n-butyllithium. The SP-structures of 7 and 8 were confirmed via the oxidization of 8/8′ to 6/6′. For the aliphatic Grignard reagents, the normal SN2-like P-inverted substitution of 8 was supposed to occur via attacking phosphorus opposite chloride, similarly to that of P(V)−X species24 (Scheme 4). However, the repulsion of the lone electron pair of 8 to πelectron on a benzene ring led to aryl approaching to phosphorus difficultly, which was different to P(V)-X species. Some EDW-containing aryl, such as 2r to 2u, showed enhanced activity, attacking 8 opposite the lone electron pair to evade the p-π repulsion. The Berry pseudorotation (BPR) of 10 afforded
negative oxygen tended to locate at the apical position of a trigonal bipyramidal structure of 12 that was generated from 1a, and chloride attacked from another apical position.24 An intramolecular attacking opposite proton (path a) was hindered by isopropyl. Another chloride approached opposite oxygen (path b) afforded 7 in a SN2-like manner. In 13, the intramolecular attacking of chloride (path c) formed a stable cyclic intermediate 14 that was converted to 15 via a BPR then further to 7. In summary, the epimeric mixture 1/1′ was successfully converted to tertiary phosphine 3 or its borane complex 4 in excellent stereoselectivity. The chlorination of 1a and 1a′ was assumed as a SN2-like and an intramolecular route, respectively, affording the same phosphonium salt 7. When reacted with aliphatic 2, 7 was deprotonated and converted to 8 that was substituted in a normal SN2-like manner to form P-inverted RP3. For aromatic 2, the p−π repulsion of aryl to phosphorus led attacking opposite lone electron pair and formation of Pretained SP-3′ after BPR. The epimerization of 7 resulted in partial loss of chirality on phosphorus. This research supplied an example of the substitution of chlorophosphine, and the stereochemistry and mechanism were explored, which are hoped to have extensive application in asymmetric catalysis.
Scheme 4. Proposed Mechanism of Substitution of 8
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02667. 5386
DOI: 10.1021/acs.orglett.7b02667 Org. Lett. 2017, 19, 5384−5387
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Experimental procedures, spectral data for products, and crystallographic information (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Chang-Qiu Zhao: 0000-0002-9016-8151 Author Contributions †
J.-J.Y. and S.-Z.N. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge the financial support of the Natural Science Foundation of China (Grant No. 20772055) and the Natural Science Foundation of Shandong Province (Grant No. ZR2016BM18 and ZR2014BP007).
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DOI: 10.1021/acs.orglett.7b02667 Org. Lett. 2017, 19, 5384−5387
