Stereoselectivity Switch in the Trapping of Polar Organometallics with

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Cite This: J. Org. Chem. 2018, 83, 7751−7761

Stereoselectivity Switch in the Trapping of Polar Organometallics with Andersen’s ReagentAccess to Highly Stereoenriched Transformable Biphenyls Julien Bortoluzzi,†,‡ Vishwajeet Jha,†,‡ Guillaume Levitre,§ Mickael̈ J. Fer,† Jordan Berreur,† Géraldine Masson,§ Armen Panossian,*,† and Frédéric R. Leroux*,†

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Université de Strasbourg, Université de Haute-Alsace, CNRS, LIMA UMR 7042, ECPM, 25 rue Becquerel, F-67000 Strasbourg, France § Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1, avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France S Supporting Information *

ABSTRACT: The trapping of racemic polar carbometallic species with (−)-menthyl (SS)-p-toluenesulfinate (Andersen’s reagent) typically proceeds with a very low level of resolution. In this paper, we describe a strategy that allows access to highly atropoenriched and functionalizable biphenyls by means of Andersen’s reagent under kinetic resolution conditions. In particular, useful enantiopure 2-iodobiphenyls could be obtained and were employed in a challenging hypervalent iodine-catalyzed oxidation reaction.

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excellent stereoinduction achieved with the sulfinyl group.6 In the present paper, we describe the unusual kinetic resolution of biphenyls by means of Andersen’s reagent upon treatment of 2iodobiphenyls with isopropylmagnesium chloride (Scheme 1c).

INTRODUCTION Axially chiral biaryls have proven to be highly important motifs in natural compounds and in asymmetric synthesis; their preparation is a contemporary topic of research, and several strategies have been followed, among which the resolution of a pre-existing biaryl.1 In 2012, we reported on a modular access to 2,2′,6-trisubstituted biphenyls, based on the deracemization or desymmetrization of, respectively, racemic or meso-2,2′,6trihalobiphenyls (1a and 1b, Scheme 1b).2 This strategy was inspired by the work of Clayden on binaphthyls and of Knochel on naphthylquinolines3 and relied on the trapping of Andersen’s reagent (2) by biphenyllithium intermediates, separation of atropo-diastereoisomers by crystallization, and subsequent functionalization by sulfoxide/metal exchange. In our case, the difficulty lied, on one hand, in the presumably lower configurational stability of halobiphenyllithiums with regard to the (hetero)binaphthyllithiums of Clayden and Knochel and, on the other hand, in the presence of additional exchangeable atoms. Either way, in our study (Scheme 1b) as well as in Clayden’s and Knochel’s, the trapping of the biaryllithium furnished in all cases a ca. 1:1 mixture of diastereomers.2,3 In fact, the trapping of configurationally stable, chiral racemic, polar carbometalated species with Andersen’s reagent seems to proceed with a very low level of resolution in all cases, regardless of the nature of the chirality element (central, axial, planar) on the nucleophile used (Scheme 1a),2−5 which contrasts with the otherwise usually © 2018 American Chemical Society

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RESULTS AND DISCUSSION We started our investigation with (±)-2,2′-diiodo-6-chlorobiphenyl 3a as substrate, as it was easily accessible from the already described 2,2′-dibromo analogue 1a by doublebromine/lithium exchange and trapping with molecular iodine.7 Furthermore, the use of 3a offered two additional advantages: (1) Iodine is exchanged more rapidly than bromine, thus allowing for both the use of a wider array of organometallic bases (metal = Li or Mg) and a possibly easier postfunctionalization of the desired 2′-halobiarylsulfoxide; (2) since iodine is bulkier than bromine, its use as the critical 2′-substituent could impact the configurational stability of the biarylmetal intermediate; even more interestingly, it should influence the stereoselectivity of the trapping by sulfinate 2 by leading to more congested transition states. The first step of our investigation was to determine the regioselectivity of the iodine/metal exchange−sulfinylation step. In the case of 2,2′dibromobiphenyls such as compounds 1, we have shown in previous reports that it took place selectively on the aromatic Received: March 13, 2018 Published: May 25, 2018 7751

DOI: 10.1021/acs.joc.8b00648 J. Org. Chem. 2018, 83, 7751−7761

Article

The Journal of Organic Chemistry Scheme 1. Resolution of Racemic Carbometals by Means of Andersen’s Reagent

ring bearing an additional halogen substituent.7,8 The diiodo analogue 3a was thus assessed in a model reaction, in which, after single-iodine/lithium exchange, iodomethane was used as the trapping agent; to confirm the expected regioselectivity, authentic samples of the two possible regioisomeric products were prepared (see Experimental Section and Supporting Information for details). We then screened a series of conditions for the sulfinylation of 3a using BuLi as exchange reagent, based on our previous work with 1a which was shown to undergo clean exchange for 5 min in THF at −78 °C and efficient trapping in toluene.2a Surprisingly, 3a gave poor yields (≤15%) of the desired 2′iodobiphenyl-2-yl sulfoxide 4a, in THF, diethyl ether, or toluene, at −78 or 0 °C, and for 5−15 min of exchange time. Instead, byproduct 5, resulting from protonation of the biarylmetal species, was isolated (Scheme 2). We presume that this discrepancy between the dibromo and the diiodo compounds is due to the butyl halide (BuBr from 1a, BuI from 3a) generated upon exchange. Indeed, due to the better leaving

ability of iodide, iodobutane is more prone to elimination and thus serves as a better source of proton; concomitantly, hydrolysis of the biphenyllithium intermediate by BuI seems to be faster than its trapping by sulfinate 2 (which is in turn faster than hydrolysis by BuBr). On the other hand, employing 2 equiv of the bulkier t-BuLi instead of 1 equiv of BuLi only afforded the starting material. This result is coherent with related findings by our group in the case of a hindered iodine atom ortho to the aryl−aryl bond.9 As the lithium bases used proved inefficient, we then evaluated isopropylmagnesium chloride and various reaction parameters by first using a default amount of electrophile 2 (0.7 equiv). Indeed, in the case of an imperfect kinetic resolution as mechanistic scenario, we would obtain a compromise between yield and diastereomeric ratio. Results are summarized in Table 1. The iodine/magnesium exchange appeared incomplete after 5 min at −30 °C (entry 1) but more efficient after 15, 45, or 60 min of exchange time t1 (entries 2−4), although no further evolution in terms of yield or diastereomeric ratio was noted, as expected. An increase of the trapping time t2 by sulfinate 2 caused concomitantly a decrease of the dr and a raise of the yield (entries 2 and 5−8). Similarly, when the trapping temperature T2 was increased from −30 to 0 °C (entries 8 and 9), a slightly higher yield but lower dr were recorded. This trend was confirmed when we further investigated the influence of temperature by performing both the I/Mg exchange and the trapping at −30, −40, −50, and −78 °C (entries 2 and 10−12); the lower the temperature, the better the diastereoselectivity, which was total at −78 °C, whereas the yield followed an opposite evolution. Next, we varied the relative amount of

Scheme 2. Attempts of Iodine/Lithium Exchange− Sulfinylation Sequence

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Table 1. Variation of Reaction Parameters in the Iodine/Magnesium Exchange Followed by Sulfinylation of Iodobiphenyl 3a

entry

T1v

t1 (min)

n

T2 (°C)

t2

YB (%)a,b

YS (%)a,c

dra,d

YMD (%)a,e

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16g 17h

−30 −30 −30 −30 −30 −30 −30 −30 −30 −40 −50 −78 −30 −40 −40 −40 −40

5 15 45 60 15 15 15 15 15 15 15 15 15 15 15 15 15

0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.5 1 1.3 0.7 0.7

−30 −30 −30 −30 −30 −30 −30 −30 0 −40 −50 −78 −30 −40 −40 −40 −40

6h 6h 6h 6h 5 min 15 min 45 min 1h 1h 6h 6h 6h 1h 6h 6h 6h 6h

32 53 51 50 36 49 50 51 53 50 43 33 41 25 10 18 0

45 75 73 72 52 70 72 73 75 71 61 47 82 25 14 25 0

85:15 85:15 85:15 85:15 90.5:9.5 90:10 88:12 88:12 82.5:17.5 92:8 95:5 >98:2f 91:9 92:8 92:8 >98:2f

30 45 43 43 33 44 44 45 43 46 41 32 37 23 9 17 0

a Average of at least 2 experiments. bIsolated yield calculated with regard to the starting biaryl 3a. cIsolated yield calculated with regard to the starting sulfinate 2. dDiastereomeric ratio determined by 1H NMR analysis of the crude material. eEstimated yield of the major diastereomer calculated with regard to the starting biaryl 3a. fOnly one diastereomer could be detected by 1H NMR analysis of the crude material. giPrMgCl•LiCl was used as base instead of iPrMgCl. hThe bromo compound (1a) was used as starting material instead of the iodo one (3a).

Scheme 3. Retention of the dr of 4a upon Treatment with the Biphenylmagnesium Intermediate

sulfinate 2 (entries 13−15). The use of either an equimolar amount or an excess of 2 surprisingly had a negative impact on the yield, while the diastereoselectivity remained unchanged; on the other hand, using 0.5 equiv of 2 led to a better corrected yield of biarylsulfoxide but with a slightly lower diastereomeric purity (compare entries 8 and 13). Employing the “turbo”Grignard reagent iPrMgCl·LiCl instead of iPrMgCl caused a drastic drop in yield under the same conditions, although the diastereoselectivity was optimal (entry 16 vs entry 10). Finally, when the reaction conditions of entry 10, giving the highest estimated yield of major diastereomer, were applied to the dibrominated starting material 1a instead of 3a, very little conversion of the biaryl was observed; the crude material was constituted of unreacted 3a, unreacted 2, isopropyl p-tolyl sulfoxide, and menthol in a 1/0.3/0.45/0.45 ratio as well as

trace amounts of the expected sulfoxide 4a and of unidentified biaryl-based products. This suggests that (1) bromine/ magnesium exchange using iPrMgCl is, as one could have expected, too slow at −40 °C and that instead (2) iPrMgCl reacts both as a nucleophile-attacking sulfinate 2 and, even faster, as a base deprotonating the resulting iPrS(O)pTol, in analogy to tBuLi-mediated halogen/lithium exchange. Similarly, in all other cases listed in Table 1, apart from unreacted substrate and sulfinate, the only occasional side products were biphenyl 5 and isopropyl p-tolyl sulfoxide. Overall, the data of Table 1 lead to the following conclusions: (1) when the trapping by the sulfinate takes place over a shorter period, the yield of 4a decreases and the dr increases; (2) when the trapping temperature T2 is higher, the yield increases and the dr decreases; (3) the maximum yield of the 7753


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The Journal of Organic Chemistry Table 2. Influence of Substituents of the Starting 2-Iodobiphenyl on the Resolution

entry

iodo-biphenyl

R1

R2

product

YB (%)a,b

YS (%)a,c

dra,d

YMD (%)a,e

1 2 3 4 5 6 7

3a 3b 3c 3d 3e 3f 3g

Cl Br OCH2O Cl Cl Cl Br

I I I Me OMe Br Br

4a 4b 4c 4d 4e 4f 4g

50 49 46 53 50 46 17

71 70 65 75 72 66 24

92:08 91:09 73:27 89:11 53:47 >98:2d 74:26

46 45 33 47 27 >45 12

a Average of at least 2 experiments. bIsolated yield calculated with regard to the starting biaryl 3a. cIsolated yield calculated with regard to the starting sulfinate 2. dDiastereomeric ratio determined by 1H NMR analysis of the crude material. eEstimated yield of the major diastereomer calculated with regard to the starting biaryl 3a.

Figure 1. ORTEP drawings of the major atropodiastereomer of 4a−b,e obtained by X-ray diffraction crystallography (ellipsoids at the 50% probability level). CCDC 1811739, 1811740, and 1811738 contain the supplementary crystallographic data for this paper. These data are provided free of charge by The Cambridge Crystallographic Data Centre.

biarylmagnesium, leading to lower stereodifferentiation; aggregation of the methylenedioxy-substituted biarylmagnesium intermediate; etc. Deeper investigations are required to elucidate these results. Variation on the R2 substituent also afforded interesting discrepancies in the dr with Br > I ≥ Me ≫ OMe (4a,d−f, entries 1 and 4−6). Given the relative size of these substituents (I > Br > Me > OMe),10 rationalization of the asymmetric induction does not seem to be straightforward. Interestingly, compound 4g (entry 7) was formed in a mediocre 24% yield (with regard to 2) but with 74:26 dr under this I/Mg exchange strategy, while a 1:1 mixture of diastereomers was produced in our previous Br/Li exchange method (Scheme 1b).2a The improvement is much more striking in the case of 4f (entry 6), obtained here with complete diastereoselectivity instead of the 1:1 mixture of diastereomers produced previously.2a The major diastereomer of compounds 4a−b,e could be isolated pure, either by crystallization or by column chromatography. As diastereomers of 4f and 4g had already been isolated and characterized in our previous work,2a we were able to determine that the configurations of 4f and of the major diastereomer of 4g (entries 6 and 7 of Table 2) were both (SS,M). Luckily, crystals of the major diastereomer of 4a, 4b, and 4e were found to be suitable for X-ray diffraction

major diastereomer with regard to 3a is of 46%, i.e., less than 50%. These conclusions are in agreement with a nondynamic kinetic resolution. A further argument in favor of this hypothesis is the absence of epimerization of a mixture of diastereomers of 4a upon treatment with 1 equiv of racemic biphenylmagnesium intermediate, which would have been a plausible equilibration pathway for a dynamic resolution (Scheme 3). To investigate the influence of substituents on the biphenyl backbone, we chose the reaction conditions of Table 1, entry 10. Results are summarized in Table 2. When starting from 2,2′-diiodobiphenyls substituted in position 6 by halogens or oxygenated groups (entries 1−3), yields belonged to a same range. The diastereomeric ratio was also sensibly the same in 4a,b, which would be in agreement with the fact that the R1 substituent points away from the “carbanion” being sulfinylated, i.e., remotely with regard to the stereodiscriminating trapping reagent. Yet, in the case of the parent methylenedioxysubstituted substrate 4c (entry 3), a much lower 73:27 ratio was obtained. One could envisage several tentative explanations for this drop of selectivity: an electronic effect of the R1 moiety on the relative rate, for each enantiomer of the biarylmagnesium, of trapping by 2; a different dihedral angle of the 7754


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The Journal of Organic Chemistry Scheme 4. Initial Attempts of Selective Sulfoxide/Metal Exchange in the Presence of an Iodo Substituent

Scheme 5. Successful Sulfoxide/Magnesium Exchange-Borylation Sequence Affording Valuable 2′-Iodobiphenyl-2-Ylboronic Ester 7a

a

Corrected yield, based on the yield of the 89:11 mixture of 9 and 10, respectively.

(Scheme 4) that we had already observed in previous work.13 The same outcome was obtained with methyllithium as the base. We then screened organomagnesium bases (RMgX with R = Me, Ph, allyl, vinyl, iPr, as well as the “turbo-Grignard reagent” iPrMCl·LiCl) under various reactions conditions using sequential trapping by iodomethane or chlorotrimethylsilane or in situ trapping by chlorotrimethylsilane. These experiments afforded either the unreacted starting material (SS,M)-4a or 2chloro-2′-iodobiphenyl 5, showing, in the latter case, that a selective sulfoxide/magnesium exchange indeed occurred but could not be followed by an efficient trapping. Finally, inspired by work on borylation by selective I/Mg exchange under in situ quenching conditions,14 we treated a mixture of (SS,M)-4a and isopropoxy pinacolborane with iPrMgCl. In this case, the use of only 1 equiv of iPrMgCl led mainly to hydrolyzed product 5. Gratifyingly, when using 2 equiv of the base, the desired biphenylboronic ester (M)-7 could then be isolated in 62% yield, which seems to indicate that the resulting isopropyl p-tolyl sulfoxide is deprotonated by the second equivalent of iPrMgCl, as in Table 1, entry 17, faster than by the biarylmagnesium. Quite surprisingly, unlike PhLimediated successful transformations of both diastereomers of 4f−g,2a (SS,P)-4a proved unable to lead to enantiomer (P)-7 under the conditions mentioned above. We then managed to oxidize boronic ester (M)-7 into the corresponding biphenyl alcohol (M)-8, and we could show that it was highly enantioenriched by chiral phase HPLC analysis. Alternately, the boronic functionality could be converted into an aryl

crystallography, which could establish that they were all of (SS,M) configuration (Figure 1), similarly to 4g and 4f. We assume accordingly that the relative configuration of the major diastereomer of 4a−g is always the same and controlled by the configuration of the chiral sulfinate 2. Having set up this kinetic resolution method, we were interested in the discrimination between the sulfinyl group and the iodo substituent (R2 = I) in compounds 4a−c by means of polar organometallics. Indeed, we had already shown that a selective sulfoxide/metal exchange−electrophile trapping sequence could be performed with perfect efficiency on compounds 4f−g, bearing at least one bromo substituent as an alternative exchange site in position 2′.2 In the present case, however, attaining such an optimal chemoselectivity was expected to be much more difficult, since iodine undergoes halogen/metal permutation more easily than bromine; in fact, the p-toluenesulfinyl/magnesium and iodine/magnesium exchange rates are believed to be comparable.11 Another strategy would have been to reduce the sulfoxide into the corresponding thioether, which should be less prone to sulfur/metal exchange, and then to transform the iodo substituent; however, previous attempts by our group to generate and trap a 2-arylthio-2′lithiobiphenyl led to complex mixtures.12 Therefore, starting from (SS,M)-4a, we first attempted an exchange mediated by phenyllithium as in the case of bromo analogues 4f−g,2a followed by trapping with iodomethane. Unfortunately, an iodine/lithium exchange took place followed by cyclization and ligand−ligand coupling at sulfur, leading to terphenyl 6 7755


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sulfoxides obtained in this study also proved efficient in λ3iodane-catalyzed enantioselective oxytosylation. Our next efforts will focus on the understanding of the remarkable stereoselectivity difference between the Br/Li vs I/Mg exchange−sulfinate trapping sequences.

substituent by means of a Suzuki−Miyaura coupling. The reaction afforded the desired terphenyl (M)-9 by selective coupling at the borylated carbon and without formation of homocoupling products, although 9 was accompanied by a small portion of inseparable triphenylene 10 as side product. (M)-9 was formed with a lower er of 88:12 with regard to (M)8, which can be ascribed to the harsher conditions used for the cross-coupling (Scheme 5). The axially chiral iodo compounds obtained in this study could serve as potent precursors of numerous highly atropostereoenriched biphenyl-based ligands, catalysts, or auxiliaries by transformation of the C−I bond; in fact, these iodobiphenyls are themselves highly interesting for λ3-iodane-mediated enantioselective catalysis.15 Indeed, axially chiral iodocatalysts have already been employed in spirolactonization reactions.16 Moreover, previous work by our groups demonstrated the efficiency of highly stereoenriched 2-iodo-2′-(tertbutanesulfinyl)biphenyls as catalysts for iodane-mediated enantioselective oxytosylation.17 We were curious about the influence of the substituent at sulfur on enantioselectivity when comparing the present C 1 -symmetric 2-iodo-2′-(ptoluenesulfinyl)biphenyls to the parent tBuS(O)-bearing catalysts. Gratifyingly, propiophenone 11 was successfully oxytosylated to yield 12 in 45% and 55% yield and 63% and 60% ee employing (SS,M)-4a and -4b respectively (Scheme 6).

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EXPERIMENTAL SECTION

General Considerations. All reactions were performed in flamedried glassware using sealed tubes or Schlenk tubes. Liquids and solutions were transferred with syringes. Air- and moisture- sensitive materials were stored protected and handled under an atmosphere of argon with appropriate glassware. Tetrahydrofuran (THF) was distilled from sodium and benzophenone, and toluene was distilled from sodium prior to use. Technical-grade solvents for extraction and chromatography (cyclohexane, dichloromethane, n-pentane, ether, toluene, and ethyl acetate) were used without purification. All reagents were purchased from standard suppliers (Sigma-Aldrich, Fluorochem, ABCR, Alfa Aesar, and Apollo scientific). Starting materials, if commercial, were purchased and used as such, provided that adequate checks (NMR) had confirmed the claimed purity. Butyllithium and tert-butyllithium were purchased as solutions (respectively, 1.6 M in hexanes and 1.7 M in pentanes) from Sigma-Aldrich, and their concentrations were determined prior to use following the Wittig− Harborth double-titration method ((total base) − (residual base after reaction with 1,2-dibromoethane)).18a Isopropylmagnesium chloride was purchased as a solution (2 M in THF) from Sigma-Aldrich and titrated prior to use with Love’s method using salicylaldehyde phenylhydrazone.18b (−)-Menthyl (SS)-p-toluenesulfinate (2) was synthesized according to Solladié’s method.19 Analytical thin-layer chromatography (TLC) was performed on silica gel. Flash column chromatography was performed on silica gel 60 (40−63 μm, 230−400 mesh, ASTM) by Merck using the indicated solvents. 1H, 13C, and 11B NMR spectra were recorded in CDCl3 unless stated otherwise on Bruker Ascend 400 (1H 400 MHz, 11B 128 MHz, 13C 100 MHz) and Bruker Avance III HD 500 (1H 500 MHz, 13C 126 MHz) instruments. 1 H, 13C, and 11B NMR chemical shifts are reported in parts per million (ppm), either downfield from tetramethylsilane and referenced to the residual solvent resonance as the internal standard (e.g., chloroform residual signals δ [1H] = 7.26 and accordingly δ [13C] = 77.16 ppm) or calibrated on an external reference for 11B NMR. Data are reported as follows: chemical shift, multiplicity (br s = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, coupling constant (Hz)) and integration. The spectra were processed with the program NMR Notebook (NMRtec) or with MestreNova (Mestrelab). Experiments under microwave irradiation were carried out on an Initiator apparatus from Biotage. Infrared (IR) spectra of neat products were recorded on a PerkinElmer Spectrum One spectrometer. The angles of rotation were measured at 589 nm and 20 °C on a PerkinElmer Polarimeter 341 and denoted as specific rotations: [α]D20. Chiral phase HPLC (chiral HPLC) analyses were performed on a Shimadzu Prominence chromatograph. Melting points (Mp) were determined for crystalline or amorphous compounds with a Melting Point Apparatus M-560 and are not corrected. Lowresolution gas chromatography coupled mass spectra (GC-MS) were recorded with a quadrupole mass analyzer under electron ionization mode on an Agilent 7820A GC-5977E MSD apparatus. Highresolution mass spectrometry (HRMS) analysis (measurement accuracy ≤ 15 ppm), elemental analysis (EA), and X-ray diffraction crystallographic analysis were performed by the analytical facility at the University of Strasbourg. Synthesis of 2-Iodobiphenyls 3a−h. The syntheses of compounds 3a−c and 3f−g were already described in our previous work.2a,7 2-Chloro-6-iodo-2′-methyl-1,1′-biphenyl (3d). In a microwave reaction vial were added 1-bromo-3-chloro-2-iodobenzene (952 mg, 3 mmol, 1 equiv), Pd(PPh3)4 (104 mg, 0.09 mmol, 3 mol %), potassium carbonate (1.66 g, 4 mmol, 4 equiv), o-tolueneboronic acid (449 mg, 3.3 mmol, 1.1 equiv), and 1,4-dioxane/water (5:1) (12 mL). The reaction mixture was degassed with argon, and the vial was heated to

Scheme 6. Axially Chiral Biphenyl-Based λ3-IodaneCatalyzed Oxytosylation of Propiophenone

Under identical conditions, the tBuS(O) analogue 4a′ led to 56% yield and 65% ee the best result so far in this reaction under catalysis by iodanes,17 i.e., to closely ranging values, which may indicate that the pTol or tBu substituent of the in situ-formed sulfonyl-bearing catalyst lies quite far away from the reacting sites in the stereodetermining transition state.

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CONCLUSIONS In conclusion, we have shown how 2-iodobiphenyls could be efficiently deracemized by kinetic resolution via a selective iodine/magnesium exchange followed by trapping with Andersen’s reagent. This process distinguishes drastically from the related bromine/lithium exchange−sulfinate trapping procedure on biaryls, which afforded unselectively both atropodiastereomers, or with the resolution of other racemic polar organometallic nucleophiles. The sulfinyl group of a resulting atropo-stereoenriched 2′-iodobiphenyl-2-yl p-tolyl sulfoxide could be transformed selectively by element/metal exchange under in situ quenching conditions by a boron electrophile, thus leaving the yet highly reactive iodo substituent untouched. Moreover, this transformation could be effected with complete retention of axial stereoenrichment. 2′-Iodobiphenyl-2-yl p-tolyl 7756


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The Journal of Organic Chemistry 120 °C for 1 h in a microwave reactor. The mixture was allowed to cool down to room temperature and was diluted with diethyl ether. The aqueous layer was extracted thrice with diethyl ether. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Silica gel column chromatography of the crude product with cyclohexane as the eluent afforded 2-bromo-6-chloro-2′-methyl-1,1′-biphenyl as a colorless liquid (659 mg, 78% yield). 1H NMR (400 MHz, CDCl3): δ = 7.58 (dd, J = 8.1 Hz, 1.1 Hz, 1H), 7.43 (dd, J = 8.1 Hz, 1.2 Hz, 1H), 7.36− 7.26 (m, 3H), 7.13 (t, J = 8.1 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 2.08 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 141.1, 139.0, 135.9, 134.9, 131.2, 130.0, 129.5, 129.0, 128.6, 128.5, 125.9, 125.2, 19.5 ppm. GC-MS: m/z = 282.0. Anal. Calcd for C13H10BrCl: C, 55.45; H, 3.58. Found: C, 55.31; H, 3.72. IR (film, cm−1): νmax 3062, 2921, 1551, 1424, 1189. At −78 °C, n-butyllithium (0.63 mL, 1 mmol, 1 equiv) in hexanes was added dropwise to a solution of 2-bromo-6-chloro-2′-methyl-1,1′biphenyl (0.280 g, 1 mmol, 1 equiv) in THF (4 mL). After 5 min, a solution of molecular iodine (0.254 g, 1 mmol, 1 equiv) in THF was added in one portion, the cooling bath was immediately removed, and the mixture was allowed to reach rt. A saturated solution of sodium thiosulfate was added. The aqueous layer was extracted thrice with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. After purification by column chromatography on silica gel using cyclohexane as eluent, 3d was obtained as a colorless liquid (305 mg, 93% yield). 1 H NMR (400 MHz, CDCl3): δ = 7.80 (dd, J = 8.0 Hz, 1.1 Hz, 1H), 7.42 (dd, J = 8.1 Hz, 1.1 Hz, 1H), 7.32−7.19 (m, 3H), 6.98-.96 (m, 1H), 6.93 (t, J = 8.1 Hz, 1H), 2.0 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 144.7, 142.7, 137.6, 135.7, 133.5, 130.1, 130.0, 129.5, 128.9, 128.6, 126.1, 101.2, 19.6 ppm. GC-MS: m/z = 328.0. Anal. Calcd for C13H10ClI: C, 47.52; H, 3.07. Found: C, 47.56; H, 3.32. IR (film, cm−1): νmax 3060, 2919, 1546, 1418, 1189, 1064. Synthesis of an Authentic Sample of 2-Chloro-2′-iodo-6-methyl1,1′-biphenyl (3′d). 2-Chloro-2′,6-dibromo-1,1′-biphenyl 1a3a,7 (346 g, 1 mmol, 1 equiv) was treated with BuLi (0.63 mL, 1 mmol, 1 equiv) in THF (4 mL) at −78 °C for 5 min and then with iodomethane (0.06 mL, 1 mmol, 1 equiv) and allowed to warm up to rt. Usual workup and silica gel column chromatography afforded 2′-bromo-2-chloro-6methyl-1,1′-biphenyl (251 mg, 89% yield), whose analytical data matched those we previously described.2a At −78 °C, butyllithium (0.56 mL, 0.89 mmol, 1 equiv) in hexanes was added dropwise to a solution of the latter compound in THF (4 mL). After 5 min, a solution of molecular iodine (226 g, 0.89 mmol, 1 equiv) in THF was added in one portion, the cooling bath was immediately removed, and the mixture was allowed to reach rt. A saturated solution of sodium thiosulfate was added. The aqueous layer was extracted thrice with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. After purification by column chromatography on silica gel using cyclohexane as eluent, 3′d was obtained as a colorless solid (263 mg, 90% yield). 1 H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 8.0 Hz, 1H), 7.48 (td, J = 7.6 Hz, 0.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.24−7.19 (m, 2H), 7.12 (td, J = 7.9 Hz, 1.3 Hz, 1H), 2.06 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 144.1, 142.6, 139.2, 138.5, 133.6, 129.8, 129.3, 128.9, 128.6, 128.4, 126.9, 99.9, 20.8 ppm. GC-MS: m/z = 328.0 Anal. Calcd for C13H10ClI: C, 47.52; H, 3.07. Found: C, 47.38; H, 3.00. IR (film, cm−1): νmax 3004, 2938, 2834, 1545, 1497, 1418, 1229, 1049, 1025. Confirmation of the Regioselectivity of the Iodine/Lithium Exchange−Iodomethane Trapping Sequence Carried out on 3a. At −78 °C, butyllithium (1.25 mL, 2 mmol, 1 equiv) in hexanes was added dropwise to a solution of 3a (880 mg, 2 mmol) in THF (10 mL). After 5 min, iodomethane (0.25 mL, 2 mmol, 1 equiv) was added and the reaction mixture allowed to reach rt. A saturated solution of ammonium chloride was added. The aqueous layer was extracted thrice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. After purification by column chromatography on silica gel

using cyclohexane as eluent, a colorless solid was obtained (572 mg, 87% yield). Analytical data were identical to those of 3′d. 2-Chloro-6-iodo-2′-methoxy-1,1′-biphenyl (3e). The synthesis of 3e was carried out similarly to that of 3d. The Suzuki−Miyaura coupling was performed on 1-bromo-3-chloro-2-iodobenzene (952 mg, 3 mmol, 1 equiv), Pd(PPh3)4 (104 mg, 0.09 mmol, 3 mol %), potassium carbonate (1.66 g, 4 mmol, 4 equiv), and 2-methoxybenzeneboronic acid (592 mg, 3.9 mmol, 1.3 equiv) in 1,4-dioxane/ water (5:1) (12 mL) and afforded 2-bromo-6-chloro-2′-methoxy-1,1′biphenyl as a colorless solid (464 mg, 52% yield). 1H NMR (400 MHz, CDCl3): δ = 7.60 (dd, J = 8.1 Hz, 1.0 Hz, 1H), 7.47−7.42 (m, 2H), 7.18−7.12 (m, 2H), 7.08 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 3.80 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 156.6, 138.7, 135.4, 131.1, 130.7, 129.9, 129.5, 128.5, 128.3, 125.7, 120.6, 111.4, 55.9 ppm. GC-MS: m/z = 298.0. Anal. Calcd for C13H10BrClO: C, 52.47; H, 3.39. Found: C, 52.72; H, 3.54. IR (film, cm−1): νmax 3005, 2923, 2837, 1552, 1497, 1421, 1281, 1021. The bromine/lithium exchange on 2-bromo-6-chloro-2′-methoxy1,1′-biphenyl (297 mg, 1 mmol) followed by trapping with iodine afforded 3e as a colorless solid (303 mg, 88% yield). 1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.0 Hz, 1H), 7.47−7.42 (m, 2H), 7.08−7.05 (m, 2H), 7.01 (d, J = 8.1 Hz, 1H), 6.97 (t, J = 8.1 Hz, 1H), 3.79 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 156.4, 142.4, 137.5, 133.9, 131.9, 130.7, 130.0, 129.9, 129.4, 120.7, 111.4, 101.8, 55.9 ppm. GC-MS: m/z = 344.0. Anal. Calcd for C13H10ClIO: C, 45.31; H, 2.93. Found: C, 45.52; H, 3.13. IR (film, cm−1): νmax 3001, 2937, 2834, 1496, 1419, 1230, 1020. Synthesis of (SS)-2-(p-Toluenesulfinyl)biphenyls 4a−g. General Procedure for Iodine/Magnesium Exchange and Trapping with Chiral Sulfinate 2. To a solution of iodobiphenyl 3a−g (1 mmol) in THF (2 mL, [iodobiphenyl] = 0.50 M) at −40 °C was added a solution of iPrMgCl (1 mmol, 1 equiv) in THF dropwise. After a period of 15 min, the solution of Grignard reagent was added slowly via cannula to a gel of (−)-menthyl (SS)-p-toluenesulfinate 2 (0.7 mmol, 0.7 equiv) in toluene (2 mL, [2] = 0.35 M) at −40 °C. After slow addition of the first few drops, the gel dissolved and cannulation could be continued dropwise with a faster flow. After 6 h of stirring at −40 °C, water (2 mL) was added. The aqueous layer was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The diastereomeric ratio was determined by 1H NMR spectroscopy of the crude product. 2-Chloro-2′-iodo-6-((SS)-p-tolylsulfinyl)-1,1′-biphenyl (4a). The product was prepared according to the general procedure and starting from 2-chloro-2′,6-diiodo-1,1′-biphenyl 3a (440 mg, 1 mmol) and sulfinate 2 (206 mg, 0.7 mmol, 0.7 equiv). The dr was estimated to be 92:08 by means of 1H NMR of the crude material and was confirmed after purification by column chromatography on silica gel using cyclohexane/EtOAc (85:15) as eluent, which afforded 4a as a mixture of atropo-diastereomers (dr 92:08, 71%, 0.50 mmol). The major diastereomer (SS,aR)-4a was separated by crystallization from EtOAc by slow evaporation of the solvent to yield colorless crystals, which were suitable for X-ray diffraction crystallography and ascertained the absolute configuration of the major diastereomer. 1H NMR (400 MHz, CDCl3): δ = 8.06 (dd, J = 7.3 Hz, 1.8 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.62−7.52 (m, 3H), 7.40 (d, J = 7.8 Hz, 1H), 7.17−7.11 (m, 3H), 7.05 (d, J = 7.0 Hz, 2H), 2.35 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 145.9, 142.6, 140.3, 139.4, 139.3, 134.9, 131.7, 131.1, 130.4, 130.3, 130.1, 128.5, 126.9, 122.9, 102.2, 21.7 ppm. [α]D20: −168.51 (c = 0.94, CHCl3). Anal. Calcd for C19H14ClIOS: C, 50.41; H, 3.12. Found: C, 50.50; H, 3.13. IR (film, cm−1): νmax 2921, 2850, 1555, 1492, 1420, 1092, 1043. Mp: 162−164 °C. 2-Bromo-2′-iodo-6-((SS)-p-tolylsulfinyl)-1,1′-biphenyl (4b). The product was prepared according to the general procedure and starting from 2-bromo-2′,6-diiodo-1,1′-biphenyl 3b (484 mg, 1 mmol) and sulfinate 2 (206 mg, 0.7 mmol, 0.7 equiv). The dr was estimated to be 91:09 by means of 1H NMR of the crude material and was confirmed after purification by column chromatography on silica gel using cyclohexane/EtOAc (85:15) as eluent, which afforded 4b as a mixture of atropo-diastereomers (dr 91:09, 70%, 0.49 mmol). The major 7757


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cm−1): νmax 2923, 2856, 1600, 1556, 1497, 1428, 1224, 1090, 1040. Mp: 86−88 °C. (SS,P)-4e was obtained as a colorless solid (0.227 mmol, 32.4%). 1H NMR (400 MHz, CDCl3): δ = 8.11 (dd, J = 7.5 Hz, 1.8 Hz, 1H), 7.57−7.51 (m, 2H), 7.43 (td, J = 7.9 Hz, 1.6 Hz, 1H), 7.07−7.04 (m, 3H), 6.97 (d, J = 8.1 Hz, 2H), 6.87 (t, J = 7.5 Hz, 1H), 6.53 (dd, J = 7.5 Hz, 1.6 Hz, 1H), 3.83 (s, 3H), 2.30 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 156.2, 147.4, 141.9, 141.8, 134.7, 134.6, 132.5, 131.8, 130.6, 129.6, 129.5, 126.0, 122.9, 121.9, 120.5, 111.4, 55.9, 21.6 ppm. [α] D20: −143.44 (c = 0.25, CHCl3). Anal. Calcd for C20H17ClO2S: C, 67.31; H, 4.80. Found: C, 66.91; H, 4.83. IR (film, cm−1): νmax 2923, 2853, 1581, 1497, 1429, 1257, 1090, 1040. 2′-Bromo-2-chloro-6-((SS)-p-tolylsulfinyl)-1,1′-biphenyl (4f).2a The product was prepared according to the general procedure and starting from 2′-bromo-2-chloro-6-iodo-1,1′-biphenyl 3f (393 mg, 1 mmol) and sulfinate 2 (206 mg, 0.7 mmol, 0.7 equiv). The dr was estimated to be >98:2 by means of 1H NMR of the crude material. After purification by column chromatography on silica gel using cyclohexane/EtOAc (85:15) as eluent, 4f was obtained as a mixture of atropo-diastereomers (dr > 98:02, 66%, 0.46 mmol). The dr was estimated to be >98:2 by means of 1H NMR of the crude material. The major diastereomer was crystallized from EtOAc by slow evaporation of the solvent to yield colorless crystals. 1H NMR (400 MHz, CDCl3): δ = 8.06 (dd, J = 6.8 Hz, 2.1 Hz, 1H), 7.61−7.55 (m, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 7.3 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 2.33 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 146.2, 142.4, 139.6, 137.5, 135.4, 135.0, 132.9, 131.7, 131.5, 130.6, 130.3, 129.9, 127.6, 126.6, 125.9, 122.9, 21.6 ppm. [α]D20: −234.6 (c = 1, CHCl3). Anal. Calcd for C19H14ClBrOS: C, 56.25; H, 3.48. Found: C, 56.30; H, 3.54. These data were in agreement with our previous work.2a 2,2′-Dibromo-6-((SS)-p-tolylsulfinyl)-1,1′-biphenyl (4g).2a The product was prepared according to the general procedure and starting from 2,2′-dibromo-6-iodo-1,1′-biphenyl 4g (437 mg, 1 mmol) and sulfinate 2 (206 mg, 0.7 mmol, 0.7 equiv). The dr was estimated to be 74:26 by means of 1H NMR of the crude material. After purification by column chromatography on silica gel using cyclohexane/EtOAc (85:15) as eluent, 4g was obtained as a mixture of atropodiastereomers (dr 74:26, 24%, 0.17 mmol). The major diastereomer was separated by crystallization from EtOAc by slow evaporation of the solvent to yield colorless crystals. 1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.53−7.47 (m, 3H), 7.39−7.30 (m, 2H), 7.10 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 2.34 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 146.4, 142.4, 139.7, 139.4, 137.0, 134.7, 132.9, 131.6, 130.6, 130.5, 129.9, 127.7, 126.6, 125.9, 125.5, 123.6, 21.6 ppm. [α]D20: −240.1 (c = 0.81, CHCl3). Anal. Calcd for C19H14Br2OS: C, 50.69; H, 3.13. Found: C, 50.88; H, 3.14. These data were in agreement with our previous work.2a Transformation of the Sulfinyl Group of 4a. (±)-2-(6-Chloro2′-iodo-[1,1′-biphenyl]-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane ((±)-7). A solution of iPrMgCl (2 mL, 2 equiv, 4 mmol) in THF was added to a −20 °C solution of 3a (880 mg, 2 mmol) and isopropoxy pinacolborane (0.82 mL, 1 equiv, 2 mmol) in THF (8 mL). After 30 min of stirring at −20 °C, the cooling bath was removed and the reaction mixture was allowed to warm to 25 °C. Water was added (20 mL). The aqueous layer was extracted with Et2O (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The crude mixture was purified by chromatography on silica gel (eluent: pentane/AcOEt (98/2)) affording (±)-7 (616 mg, 70%) as a colorless liquid, which could crystallize upon scratching. [Note: The compound could be prepared alternately by treatment of 3a (1.5 g, 3.4 mmol) in THF (13.4 mL) at −20 °C with BuLi (2.20 mL, 1 mmol, 1 equiv), followed after 25 min by addition of isopropoxy pinacolborane (1.39 mL, 6.8 mmol, 2 equiv) and warming to rt (1,1 g, 73% yield)]. 1H NMR (CDCl3, 400 MHz): δ 7.88 (d, J = 7.8 Hz, 1 H), 7.71 (d, J = 7.5 Hz, 1 H), 7.54 (d, J = 7.8 Hz, 1 H), 7.39−7.32 (m, 2 H), 7.20 (d, J = 7.5 Hz, 1 H), 7.04 (t, J = 7.5 Hz, 1 H), 1.09 (s, 12 H) ppm. 13C NMR (CDCl3, 101 MHz): δ 148.0,

diastereomer (SS,M)-4b was separated by crystallization from EtOAc by slow evaporation of the solvent to yield colorless crystals, which were suitable for X-ray diffraction crystallography and ascertained the absolute configuration of the major diastereomer. 1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.52 (q, J = 8.0 Hz, 2H), 7.38 (dd, J = 7.7 Hz, 1.1 Hz, 1H), 7.17−7.11 (m, 3H), 7.07 (d, J = 8.1 Hz, 2H), 2.34 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 146.1, 142.6, 142.1, 140.8, 139.3, 134.8, 131.0, 130.6, 130.4, 130.1, 128.5, 126.9, 125.6, 123.6, 102.3, 21.6 ppm. Anal. Calcd for C19H14BrIOS: C, 45.90; H, 2.84. Found: C, 46.04; H, 2.97. IR (film, cm−1): νmax 2919, 2850, 1737, 1548, 1418, 1093, 1052. Mp: 172−174 °C. 4-(2-Iodophenyl)-5-((SS)-p-tolylsulfinyl)benzo[d][1,3]dioxole (4c). The product was prepared according to the general procedure and starting from 5-iodo-4-(2-iodophenyl)benzo[d][1,3]dioxole 3c (450 mg, 1 mmol) and sulfinate 2 (206 mg, 0.7 mmol, 0.7 equiv). The dr was estimated to be 73:27 by means of 1H NMR of the crude material and was confirmed after purification by column chromatography on silica gel using cyclohexane/EtOAc (85:15) as eluent, which afforded 4c as a mixture of atropo-diastereomers (dr 72:28, 65%, 0.46 mmol). 1 H NMR (400 MHz, CDCl3): δ = (72:28 mixture of two atropodiastereomers) 8.15 (d, J = 8.0 Hz, 0.4H), 7.82 (d, J = 8.0 Hz, 1H), 7.66−7.59 (m, 1H), 7.54−7.48 (m, 2.4H), 7.32 (d, J = 8.2 Hz, 0.4H), 7.23 (d, J = 7.4 Hz, 0.4H), 7.13−7.03 (m, 7.6H), 6.67 (d, J = 8.2 Hz, 0.4H), 6.09−6.00 (m, 2.8H), 2.33 (s, 4.2H) ppm. 13C NMR (101 MHz, CDCl3): δ = (72:28 mixture of two atropo-diastereomers) 149.8, 148.2, 145.8, 145.6, 144.5, 141.9, 140.9, 140.7, 139.4, 136.7, 136.5, 135.2, 132.4, 131.9, 131.8, 130.7, 130.4, 130.0, 129.9, 129.8, 128.3, 126.2, 126.1, 125.9, 123.7, 123.5, 123.1, 119.1, 110.7, 109.0, 102.2, 102.1, 101.3, 89.8, 21.6 ppm. HRMS (ESI) calcd for C20H16IO3S [M + H]+: 462.9859. Found: 462.9859. IR (film, cm−1): νmax 2919, 2884, 1732, 1594, 1445, 1238, 1091, 1027. 2-Chloro-2′-methyl-6-((SS)-p-tolylsulfinyl)-1,1′-biphenyl (4d). The product was prepared according to the general procedure and starting from 2-chloro-6-iodo-2′-methyl-1,1′-biphenyl 3d (328 mg, 1 mmol) and sulfinate 2 (206 mg, 0.7 mmol, 0.7 equiv). The dr was estimated to be 89:11 by means of 1H NMR of the crude material. After purification by column chromatography on silica gel using cyclohexane/EtOAc (85:15) as eluent, 4d was obtained as a mixture of atropo-diastereomers (dr 90:10, 75%, 0.525 mmol). 1H NMR (400 MHz, CDCl3): δ = (90:10 mixture of two atropo-diastereomers) 8.22 (dd, J = 7.4 Hz, 1.6 Hz, 1H), 8.15 (dd, J = 7.0 Hz, 2.2 Hz, 0.1H), 7.61−7.53 (m, 2.3H), 7.40−7.16 (m, 3.4H), 7.11−6.94 (m, 3.6H), 6.86 (d, J = 8.1 Hz, 2H), 6.34 (d, J = 7.5 Hz, 0.1H), 2.32 (s, 0.3H), 2.30 (s, 3H), 2.16 (s, 0.3H), 1.18 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = (90:10 mixture of two atropo-diastereomers) 146.37, 142.30, 142.2, 140.32, 138.3, 137.7, 136.3, 134.8, 133.6, 131.9, 131.2, 130.9, 130.4, 130.2, 129.9, 129.7, 129.6, 129.5, 129.3, 129.0, 126.9, 126.6, 126.0, 125.7, 122.6, 122.2, 29.8, 21.6, 19.9, 18.5 ppm. [α]D20: −103.6 (c = 0.95, CHCl3). Anal. Calcd for C20H17ClOS: C, 70.47; H, 5.03. Found: C, 70.44; H, 5.08. IR (film, cm−1): νmax 3052, 2921, 2853, 1492, 1424, 1088, 1043. 2-Chloro-2′-methoxy-6-((SS)-p-tolylsulfinyl)-1,1′-biphenyl (4e). The product was prepared according to the general procedure and starting from 2-chloro-6-iodo-2′-methoxy-1,1′-biphenyl 3e (344 mg, 1 mmol) and sulfinate 2 (206 mg, 0.7 mmol, 0.7 equiv). The dr was estimated to be 53:47 by means of 1H NMR of the crude material. After purification by column chromatography on silica gel using cyclohexane/EtOAc (85:15) as eluent, both diastereomers (SS,M)-4e and (SS,P)-4e were separated. (SS,M)-4e was obtained as a colorless crystalline solid (0.277 mmol, 40%). Crystals were suitable for X-ray diffraction crystallography and ascertained the absolute configuration of the compound. 1H NMR (400 MHz, CDCl3): δ = 8.08−8.06 (m, 1H), 7.54 (d, J = 4.5 Hz, 2H), 7.40 (t, J = 7.8 Hz, 1H), 7,24 (m, 1H), 7.09−7.03 (m, 3H), 6.96 (d, J = 8.1 Hz, 2H), 6.67 (d, J = 8.3 Hz, 1H), 3.25 (s, 3H), 2.31 (s, 3H) ppm. 13 C NMR (101 MHz, CDCl3): δ = 156.9, 146.5, 141.6, 141.1, 135.7, 135.5, 131.2, 130.9, 130.8, 129.4, 126.8, 123.3, 122.8, 120.5, 110.5, 54.7, 21.5 ppm. [α]D20: −39.65 (c = 0.55, CHCl3). Anal. Calcd for C20H17ClO2S: C, 67.31; H, 4.80. Found: C, 67.09; H, 4.84. IR (film, 7758


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J = 9.1, 2.3 Hz, 1H), 7.84 (dd, J = 7.7, 1.2 Hz, 1H), 7.77 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 7.71 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ = 147.1, 134.2, 133.1, 132.4, 131.6, 130.9, 130.0, 129.2, 128.62, 128.60, 128.2, 127.5, 127.3, 125.3, 123.6, 123.3, 121.4, 119.3. GC-MS (ESI): 307.0 ([M+•]), 273.0 ([M − Cl]+), 262.0 ([M − NO2]+), 228.1 ([M − Cl − NO2]+). IR (oil, cm−1) of the 9/10 (92:8) mixture: νmax 3504, 1577, 1441, 1280, 902, 757. Suzuki−Miyaura Coupling of (M)-7 with 3-Iodonitrobenzene. The same procedure as for (±)-7 was applied to (M)-7 (35 mg, 0.0795 mmol) using 3-nitrophenyl iodide (1.2 equiv, 24 mg, 0.0953 mmol), potassium carbonate (2 equiv, 22 mg, 0.159 mmol), tetrakis(triphenylphosphine) palladium (5 mol %, 4.6 mg, 3.97 μmol), degassed DMF (0.40 mL), and later on KHF2 (40 mg, 0.512 mmol). The mixture of (M)-9 and 10 (89:11 as determined by 1H NMR) was obtained as a yellow oil (18 mg; corrected yield for 9 = 45%, corrected yield for 10 = 8%). Chiral HPLC (Chiralpak IA column; eluent hexane/2-propanol 99:1; flow rate 0.5 mL/min, λmax 250 nm) for (M)-9 (mixture with 10): tR1 = 14.67 min and tR2 = 15.60 min, er = 12:88. Evaluation of 4a and 4b in λ3-Iodane-Mediated Enantioselective Oxytosylation. (R)-2-[(4-Toluenesulfonyl)oxy]-1-phenylpropan-1-one (12). In a test tube, p-toluenesulfonic acid hydrate (0.3 mmol, 3.0 equiv), propiophenone (0.1 mmol, 1.0 equiv), and the precatalyst (0.01 mmol, 0.1 equiv) were dissolved in Et2O (1.0 mL) at room temperature. Then m-CPBA (0.3 mmol, 3.0 equiv, ≤77%) was added, and the reaction mixture was stirred for 72 h. The resulting solution was quenched with a saturated aqueous Na2S2O3 solution (1 mL) and a saturated aqueous Na2CO3 solution (1 mL). The aqueous layer was extracted with Et2O (3 × 5 mL); the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified over a preparative TLC plate using heptane/EtOAc 7/3 as an eluent to give the desired product 12. Analytical data were identical to those of our previous work.17 Chiral HPLC (Chiralpak IA column; eluent heptane/2-porpanol 90:10, flow rate 1.0 mL/min; λmax 254 nm): major isomer tR1 = 10.9 min, minor isomer tR2 = 12.2 min.

145.5, 138.2, 133.5, 133.1, 131.6, 131.5, 130.3, 128.8, 128.7, 127.4, 100.3, 83.7, 24.8, 24.5 ppm. 11B NMR: 30.44 ppm. Anal. Calcd for C18H19BClIO2: C, 49.08; H, 4.35. Found: C, 50.23; H, 4.38. HRMS (ESI) calcd for C18H19BClIKO2 [M+ K]+: 478.9848 Found: 478.9846. IR (film, cm−1): νmax 2977, 2924, 1728, 1583, 1482, 1423, 1351, 1140. (M)-2-(6-Chloro-2′-iodo-[1,1′-biphenyl]-2-yl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane ((M)-7). The compound was prepared analogously to (±)-7 but starting from (SS,M)-4a (50 mg, 0.11 mmol) by sulfoxide/magnesium exchange with iPrMgCl (1.75 M, 0.13 mL, 0.22 mmol, 2 equiv) in the presence of isopropoxy pinacolborane (23 μL, 0.11 mmol, 1 equiv) (in situ quench). (M)-7 was obtained in 62% yield (30 mg). [α]D20: + 36.85 (c = 0.90, CHCl3). (±)-6-Chloro-2′-iodo-[1,1′-biphenyl]-2-ol ((±)-8). This compound was obtained following Zhu and Falck’s procedure.20 In a vial were added N-methyl morpholine N-oxide (NMO; 80 mg, 0.68 mmol, 10 equiv) and DCM (0.6 mL). The boronic ester (±)-7 (30 mg, 0.068 mmol) was then added in one portion. The vial was seal capped, and the mixture was warmed to 50 °C for 15 h. After cooling down to rt, the mixture was diluted with EtOAc (10 mL) and water was added (10 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a brown residue. After purification by column chromatography on silica gel using cyclohexane/EtOAc (100:0 to 80:20 gradient) as eluent, (±)-8 was obtained as a dark yellow sticky oil (19 mg, 86%). 1H NMR (400 MHz, CDCl3): δ = 8.03 (dd, J = 8.0, 1.2 Hz, 1H), 7.51 (td, J = 7.5, 1.2 Hz, 1H), 7.33−7.22 (m, 2H), 7.21−7.12 (m, 1H), 7.08 (dd, J = 8.0, 1.1 Hz, 1H), 6.93 (dd, J = 8.2, 1.1 Hz, 1H), 4.68 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3): δ = 153.7, 140.0, 139.0, 134.0, 131.4, 130.6, 130.2, 130.1, 129.2, 121.7, 114.3, 101.2 ppm. GC-MS: 329.9 (M+•), 203.0 ([M − I]+), 168.1 ([M − I − Cl]+). IR (oil, cm−1): νmax 3504, 1577, 1441, 1280, 902, 757. (M)-6-Chloro-2′-iodo-[1,1′-biphenyl]-2-ol ((M)-8). This compound was obtained analogously to (±)-8, starting from (M)-7 (50 mg, 0.11 mmol), and was obtained in 87% yield (33 mg). Chiral HPLC (Chiralpak IA column; eluent: hexane/2-propanol 80:20; flow rate 0.5 mL/min, λmax: 230 nm): tR1 = 16.53 min and tR2 = 18.34 min, er = 0.5:99.5. [α]D20: −8 (c = 0.5, DCM). Suzuki−Miyaura Coupling of (±)-7 with 3-Iodonitrobenzene. A mixture of (±)-2-(6-chloro-2′-iodo-[1,1′-biphenyl]-2-yl)4,4,5,5-tetramethyl-1,3,2-dioxaborolane (±)-7 (1 equiv, 70 mg, 0.159 mmol), 3-nitrophenyl iodide (1.2 equiv, 48 mg, 0.191 mmol), potassium carbonate (2 equiv, 44 mg, 0.318 mmol), tetrakis(triphenylphosphine) palladium (5 mol %, 9.2 mg, 7.95 μmol), and degassed DMF (0.79 mL) in a seal-capped tube was heated at 110 °C in an oil bath for 24 h. Water (10 mL) was added, and the mixture was extracted with 3 × 50 mL of Et2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford an orange residue. The crude material was purified by flash chromatography (eluent petroleum ether/EtOAc, 100:0 to 98:2 gradient). The fraction containing the product was taken up in methanol, and a solution of potassium hydrogen fluoride (6 equiv, 75 mg, 0.953 mmol) in 1 mL of water was added. The mixture was stirred overnight, concentrated, and taken up in acetone. The excess of KHF2 was filtered off, and the filtrate was concentrated. The yellow solid was triturated in cyclohexane. The whole sample was filtered through a syringe filter. After concentration, the 92:8 mixture (as determined by 1 H NMR) of (±)-9 and 10 was obtained as a yellow oil (42 mg; corrected yield for 9 = 55%, corrected yield for 10 = 9%). Analytical Data for (±)-9. 1H NMR (500 MHz, CDCl3): δ = 8.07 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.52−7.43 (m, 2H), 7.37−7.31 (m, 2H), 7.26 (t, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.94 (t, J = 7.7 Hz, 1H) ppm. 13C NMR (126 MHz, CDCl3): δ = 147.7, 142.6, 141.8, 141.5, 140.8, 139.1, 135.6, 134.8, 131.3, 129.7, 129.6, 129.5, 128.7, 128.4, 128.1, 124.6, 122.2, 100.9 ppm. GC-MS: 435.0 (M+•), 308.0 ([M − I]+), 262.1 ([M − I − NO2]+), 226.1 ([M − I − NO2 − Cl]+). Analytical Data for 10. 1H NMR (400 MHz, CDCl3) δ = 9.60 (dd, J = 8.5, 1.3 Hz, 1H), 9.48 (d, J = 2.4 Hz, 1H), 8.68 (d, J = 9.1 Hz, 1H), 8.68 (dd, J = 8.2, 1.4 Hz, 1H), 8.59 (dd, J = 8.3, 1.2 Hz, 1H), 8.42 (dd,

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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.joc.8b00648. Additional experiments, 1H NMR spectra for the determination of diastereomeric ratio, X-ray crystallographic data for compounds (SS,M)-4a, (SS,M)-4b, and (SS,M)-4e, 1H, 13C, and 11B NMR spectra of purified compounds and chiral HPLC chromatograms (PDF) (CIF) (CIF) (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] *E-mail: [email protected] ORCID

Géraldine Masson: 0000-0003-2333-7047 Armen Panossian: 0000-0003-2317-1200 Frédéric R. Leroux: 0000-0001-8900-5753 Author Contributions ‡

J.B. and V.J.: These authors contributed equally and are listed in alphabetical order. Notes

The authors declare no competing financial interest. 7759


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the other hand, achiral o-lithiobenzamides could lead to the corresponding atropo-diastereopure sulfoxides upon trapping with Andersen’s reagent: (a) Clayden, J.; Mitjans, D.; Youssef, L. H. Lithium−Sulfoxide−Lithium Exchange for the Asymmetric Synthesis of Atropisomers under Thermodynamic Control. J. Am. Chem. Soc. 2002, 124, 5266−5267. (b) Clayden, J.; Stimson, C. C.; Keenan, M. Asymmetric Ortholithiation of Amides by Conformationally Mediated Chiral Memory: An Enantioselective Route to Naphtho- and Benzofuranones. Synlett 2005, 1716−1720. (6) For selected reviews, see the following reviews and references cited therein: (a) Hanquet, G.; Colobert, F.; Lanners, S.; Solladié, G. Recent developments in chiral non-racemic sulfinyl-group chemistry in asymmetric synthesis. ARKIVOC 2003, 328−401. (b) Carmen Carreno, M.; Hernandez-Torres, G.; Ribagorda, M.; Urbano, A. Enantiopure sulfoxides: recent applications in asymmetric synthesis. Chem. Commun. 2009, 6129−6144. (c) Otocka, S.; Kwiatkowska, M.; Madalinska, L.; Kielbasinski, P. Chiral Organosulfur Ligands/Catalysts with a Stereogenic Sulfur Atom: Applications in Asymmetric Synthesis. Chem. Rev. 2017, 117, 4147−4181. (7) Bonnafoux, L.; Gramage-Doria, R.; Colobert, F.; Leroux, F. R. Catalytic palladium phosphination: modular synthesis of C1symmetric biaryl-based diphosphines. Chem. - Eur. J. 2011, 17, 11008−11016. (8) (a) Bonnafoux, L.; Nicod, N.; Leroux, F.; Quissac, B.; Colobert, F. New Vistas in Halogen/Metal Exchange Reactions: The Discrimination between Seemingly Equal Halogens. Lett. Org. Chem. 2006, 3, 165−169. (b) Bonnafoux, L.; Leroux, F. R.; Colobert, F. Bromine-lithium exchange: An efficient tool in the modular construction of biaryl ligands. Beilstein J. Org. Chem. 2011, 7, 1278− 1287. (9) Augros, D.; Yalcouye, B.; Choppin, S.; Chesse, M.; Panossian, A.; Leroux, F. R. Transition-Metal-Free Synthesis of a Known Intermediate in the Formal Synthesis of (−)-Steganacin. Eur. J. Org. Chem. 2017, 2017, 497−503. (10) (a) Ruzziconi, R.; Spizzichino, S.; Lunazzi, L.; Mazzanti, A.; Schlosser, M. B values as a sensitive measure of steric effects. Chem. Eur. J. 2009, 15, 2645−2652. (b) Mazzanti, A.; Lunazzi, L.; Ruzziconi, R.; Spizzichino, S.; Schlosser, M. The torsional barriers of 2-hydroxyand 2-fluorobiphenyl: small but measurable. Chem. - Eur. J. 2010, 16, 9186−9192. (c) Ruzziconi, R.; Spizzichino, S.; Mazzanti, A.; Lunazzi, L.; Schlosser, M. The biphenyl-monitored effective size of unsaturated functional or fluorinated ortho substituents. Org. Biomol. Chem. 2010, 8, 4463−4471. (d) Lunazzi, L.; Mancinelli, M.; Mazzanti, A.; Lepri, S.; Ruzziconi, R.; Schlosser, M. Rotational barriers of biphenyls having heavy heteroatoms as ortho-substituents: experimental and theoretical determination of steric effects. Org. Biomol. Chem. 2012, 10, 1847− 1855. (11) (a) Furukawa, N.; Shibutani, T.; Fujihara, H. A new source for generation of benzyne and pyridyne: Reactions of O-halophenyl (or 3bromo-4-pyridyl) phenyl sulfoxides with grignard reagants. Tetrahedron Lett. 1987, 28, 2727−2730. (b) Shi, L.; Chu, Y.; Knochel, P.; Mayr, H. Leaving group dependence of the rates of halogenmagnesium exchange reactions. Org. Lett. 2012, 14, 2602−2605. (12) (a) Bonnafoux, L. Modular Synthesis of New C1-Biaryl Ligands and Application in Catalytic Hydrogenation and Coupling Reactions; Université de Strasbourg, 2008. In two related processes described by Knochel, an iodine/magnesium exchange performed on a 2(benzylthio)-2′-iodobiphenyl and a bromine/lithium exchange performed on a 2-bromo-2’-(vinylthio)biphenyl led to dibenziothiophene with release of a benzyl- or vinylmetal species: (b) Stoll, A. H.; Krasovskiy, A.; Knochel, P. Functionalized benzylic magnesium reagents through a sulfur-magnesium exchange. Angew. Chem., Int. Ed. 2006, 45, 606−609. (c) Unsinn, A.; Dunst, C.; Knochel, P. Stereoselective synthesis of tetrasubstituted alkenes via a sequential carbocupration and a new sulfur-lithium exchange. Beilstein J. Org. Chem. 2012, 8, 2202−2206. (13) Augros, D.; Yalcouye, B.; Berthelot-Bréhier, A.; Chessé, M.; Choppin, S.; Panossian, A.; Leroux, F. R. Atropo-diastereoselective

ACKNOWLEDGMENTS This work was supported by the CNRS (Centre National de la Recherche Scientifique, France), the International Centre for Frontier Research in Chemistry (IcFRC), the Indo-French Centre for the Promotion of Advanced Research (IFCPAR), and the University of Strasbourg Institute for Advanced Study (USIAS).

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