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. Author manuscript; available in PMC: 2011 Oct 20.
Published in final edited form as: Tetrahedron Lett. 2010 Oct 20;51(42):5550–5554. doi: 10.1016/j.tetlet.2010.08.039

Rapid synthesis of an electron-deficient t-BuPHOX ligand: cross-coupling of aryl bromides with secondary phosphine oxides

Nolan T McDougal 1, Jan Streuff 1, Herschel Mukherjee 1, Scott C Virgil 1, Brian M Stoltz 1,*
PMCID: PMC2976555  NIHMSID: NIHMS230237  PMID: 21076623

Abstract

Herein an efficient and direct copper-catalyzed coupling of oxazoline-containing aryl bromides with electron-deficient secondary phosphine oxides is reported. The resulting tertiary phosphine oxides can be reduced to prepare a range of PHOX ligands. The presented strategy is a useful alternative to known methods for constructing PHOX derivatives.

Phosphinooxazoline (PHOX) ligands have found broad applications in transition metal catalysis.1 Developed by Pfaltz,2 Helmchen,3 and Williams,4 PHOX ligands have become a preeminent class of P,N-ligands,5 with t-BuPHOX (L1, Scheme 1) representing a most prominent example.6 We have recently demonstrated the utility of t-BuPHOX in palladium-catalyzed enantioselective decarboxylative alkylation7 and protonation8 reactions. We, however, became aware of examples where t-BuPHOX provided only moderate results with respect to yields and enantioselectivities, and designed an electronically-modified version of this ligand, p-(CF3)3-t-BuPHOX (L2). In some cases, the electron-withdrawing trifluoromethyl groups affected the reactivity of the corresponding transition metal complex, leading to significantly shorter reaction times and enhanced selectivities. For example, we were able to achieve 99% yield and 87% ee in our palladium-catalyzed, enantioselective allylic alkylation reaction of allyl enol carbonate 1 within only 10 min at 25 °C with the use of (S)-L2, while the use of (S)-L1 required 120 min reaction time to give 96% yield and 88% ee.9 Further, this ligand was successfully applied in the catalytic asymmetric total synthesis of (+)-elatol where the key allylic alkylation of chloroallyl enol carbonate 2 was performed with (R)-L2, resulting in 82% yield of product in 87% ee, compared to only 81% ee and a poor 23% yield with the use of (S)-L1.10 Moreover, we recently published a palladium-catalyzed, enantioselective enolate alkylation cascade, which provides products with up to 99% enantiomeric excess,11 where (S)-p-(CF3)3-t-BuPHOX was far superior to (S)-t-BuPHOX for the alkylation of β-keto ester 3.

Scheme 1.

Scheme 1

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PHOX ligands and their use in synthesis and methodology development.

Previously, we published a convenient and scalable synthesis for t-BuPHOX,12 using an Ullmann-type coupling developed by Buchwald.13 While this approach proved useful for the coupling aryl halides and secondary phosphines, most substituted secondary phosphines are not commercially available. Similarly, substituted secondary phosphines (e.g., bis(4-(trifluoromethyl)phenyl)phosphine) are difficult to prepare in the required purity due to their propensity to oxidize upon exposure to air.14 Although the preparation of synthetically challenging PHOX variants was possible using our previously described conditions, a more efficient and higher yielding protocol was desired. Therefore a synthetic strategy for the synthesis of p-(CF3)3-t-BuPHOX (L2) that avoids phosphine intermediates was needed. We envisioned a preparative route toward this electron-deficient PHOX ligand in which an oxazoline-containing aryl bromide is joined directly with a secondary phosphine oxide.15,16 Herein, we demonstrate a copper-catalyzed coupling of aryl halides to secondary phosphine oxides for the synthesis of electron-deficient PHOX ligands.

Oxazoline-containing aryl bromide 4 and secondary phosphine oxide 5 can be readily synthesized on multi-gram scale (Scheme 2). Aryl bromide 4 was prepared using modified conditions from a published route,10 requiring only one purification by flash chromatography. The treatment of (S)-t-leucinol with acid chloride 67 in the presence of sodium carbonate provided amide 7 in 93% yield.17 Subsequent mesylation of the free hydroxyl of 7, followed by in situ mesylate displacement results in formation of oxazoline 4 in 99% yield.18 Bis(4-(trifluoromethyl)phenyl)phosphine oxide 519 is produced in 80% yield by careful exposure of 4-(trifluoromethyl)phenylmagnesium bromide 8, synthesized via the Leazer method,20 to diethyl phosphite.21 Unlike the related secondary phosphine, phosphine oxide 5 can be purified by column chromatography and is stable to air at room temperature for several months.

Scheme 2.

Scheme 2

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Synthesis of oxazoline-containing aryl bromide 4 and secondary phosphine oxide 5.

Our modification to Buchwald’s copper iodide-catalyzed conditions for the coupling of secondary phosphines with aryl bromides9,12 was tested for the coupling of secondary phosphine oxide 5 with oxazolinyl aryl bromide 4 (Table 1, entries 1 and 2). Gratifyingly, when a catalytic amount of CuI (12.5 mol %) was used in combination with N,N′-dimethylethylenediamine as ligand and Cs2CO3 as base, secondary phosphine oxide 5 could be successfully coupled with aryl bromide 4 to produce 9 in 57 % yield (entry 1). Reaction times could be reduced, and product yields improved to 65% yield with the use of a stoichiometric amount of CuI at a higher reaction concentration (entry 2).22 To our satisfaction, secondary phosphine oxide 5 could be coupled with other aryl bromides 10–12 in moderate to good yields using catalytic amounts of CuI (entries 3–5). Similarly, bis(3,5-bis(trifluoromethyl)phenyl)phosphine oxide (13) could be coupled with oxazoline-containing aryl bromides using catalytic loadings of CuI (entries 6 and 7).

Table 1.

Copper-catalyzed coupling of aryl bromides with secondary phosphine oxides.a

graphic file with name nihms230237u1.jpg
Entry Aryl bromide Secondary phosphine oxide Product Yield (%)b
1
2c 		graphic file with name nihms230237t1.jpg
4 		graphic file with name nihms230237t2.jpg
5 		graphic file with name nihms230237t3.jpg
9 		57
65
3 graphic file with name nihms230237t4.jpg
10 		graphic file with name nihms230237t5.jpg
5 		graphic file with name nihms230237t6.jpg
14 		85
4 graphic file with name nihms230237t7.jpg
11 		graphic file with name nihms230237t8.jpg
5 		graphic file with name nihms230237t9.jpg
15 		62
5 graphic file with name nihms230237t10.jpg
12 		graphic file with name nihms230237t11.jpg
5 		graphic file with name nihms230237t12.jpg
16 		55
6 graphic file with name nihms230237t13.jpg
10 		graphic file with name nihms230237t14.jpg
13 		graphic file with name nihms230237t15.jpg
17 		46
7 graphic file with name nihms230237t16.jpg
12 		graphic file with name nihms230237t17.jpg
13 		graphic file with name nihms230237t18.jpg
18 		36
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a

Reactions were performed with aryl bromide (1.0 equiv), secondary phosphine oxide (1.3 equiv), CuI (12.5 mol %), N,N′-dimethylethylenediamine (87.5% mol %), and Cs2CO3 (3.7 equiv) in PhCH3 (0.1 M) at 110 °C for 38–42 h.

b

Yield of isolated product.

c

Reaction was performed with 1.0 equiv of CuI and 3.0 equiv of N,N′-dimethylethylenediamine in PhCH3 (0.25 M) for 15 h.

The resulting triarylphosphine oxides 9 and 14–18 can be smoothly purified by column chromatography and reduced to the corresponding PHOX ligands via silane reduction.23 For example, reduction of 9 to the desired p-(CF3)3-t-BuPHOX ligand was accomplished with neat diphenylsilane, yielding L2 in 86% isolated yield (Scheme 3).24

Scheme 3.

Scheme 3

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Reduction of 9 to afford (S)-p-(CF3)3-t-BuPHOX.

In conclusion, we have developed a rapid synthesis of p-(CF3)3-t-BuPHOX (L2) that results in an overall 51% yield starting from (S)-t-leucine under relatively mild conditions in four linear steps. The route utilizes a copper iodide-catalyzed coupling of oxazoline-containing aryl bromide 4 to secondary phosphine oxide 5, followed by a silane-mediated reduction of the resulting triarylphosphine oxide, to prepare the phosphinooxazoline core structure. We believe that the copper-catalyzed coupling of aryl bromides to secondary phosphine oxides provides a convenient alternative to the coupling of air-sensitive secondary phosphines for the preparation of tertiary phosphines.

Acknowledgments

This publication is based on work supported by Award No. KUS-11-006-02, made by King Abdullah University of Science and Technology (KAUST). Additionally, the authors wish to thank NIH-NIGMS (R01 GM 080269-01), the German Academic Exchange Service (DAAD, postdoctoral fellowship to J. S.), Abbott Laboratories, Amgen, the Gordon and Betty Moore Foundation, and Caltech for financial support.

Footnotes

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