Novel biphenyl organocatalysts for iminium ion-catalyzed asymmetric epoxidation

Tetrahedron 69 (2013) 758e769

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Novel biphenyl organocatalysts for iminium ion-catalyzed asymmetric epoxidation Mohamed M. Farah b, Philip C. Bulman Page a, *, Benjamin R. Buckley b, A. John Blacker c, Mark R.J. Elsegood b a b c

School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4 7TJ, UK Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK School of Chemistry, University of Leeds, Leeds LS2 9JT, UK

a r t i c l e i n f o

a b s t r a c t

Article history: Received 10 August 2012 Received in revised form 13 October 2012 Accepted 29 October 2012 Available online 6 November 2012

Two novel chiral biphenyl iminium salts derived from L-acetonamine, containing electron-withdrawing 3,30 -substituents on the biphenyl unit, have been prepared and tested as asymmetric catalysts for epoxidation of prochiral alkenes. The results are compared with those achieved using the corresponding unsubstituted system. Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: Epoxidation Asymmetric catalysis Asymmetric synthesis Iminium salt Oxaziridinium salt

1. Introduction Oxaziridinium salts generated in situ from iminium salts with oxone were first shown by Lusinchi to be effective electrophilic oxidants for epoxidation of alkenes, rendering the development of a catalytic process possible.1 The first enantiomerically pure iminium salt to be used in this way was 1, with the controlling asymmetric centres sited in the heterocyclic ring of a dihydroisoquinolinium salt, and it was shown to catalyze epoxidation of alkenes with ees of up to about 40% (Fig. 1).2 A number of advances have since been made in the field in terms of catalyst structure and enantioselectivity.3 Even exocyclic iminium salts, such as 2, derived from condensation of enantiopure pyrrolidine moieties with aromatic aldehydes, can afford moderate ees (up to 22%) with relatively high catalyst loadings (up to 100 mol %), necessary perhaps due to in situ hydrolysis of the iminium units.4 Our own contribution has been to design chiral iminium salts that contain asymmetric centres in the exocyclic nitrogen substituent, based upon the reasoning that such designs would bring the enantiocontrolling asymmetric centres closer to the site of oxygen transfer, and hence potentially increase enantioselectivity. We have shown that iminium salts based on dihydroisoquinolinium,5

biphenylazepinium6 and binaphthylazepinium7 motifs, such as 3e6 can provide ees of up to 98% in epoxidation under our standard conditions using oxone as stoichiometric oxidant in aqueous acetonitrile, or using tetraphenylphosphonium monoperoxysulfate under non-aqueous conditions.8 We have also shown that other oxidants, including hydrogen peroxide,9 bleach10 and even electrochemical oxidation,11 may be used in conjunction with these catalysts.

1

0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2012.10.076

3 BPh4

BPh4 N Ph

4 * Corresponding author. E-mail address: [email protected] (P.C.B. Page).

2

N

O O

O S Me

O

BPh4 O

N

O

Ph

O

O

5

6

Catalysts incorporating an azepinium structure are highly reactive, inducing complete epoxidation of alkenes within 1e10 min

M.M. Farah et al. / Tetrahedron 69 (2013) 758e769

759

catalysts as rapidly interconverting atropoisomeric mixtures (Rax and Sax), resulting from the rotation about the arylearyl bond.17 Recently, there have been considerable advances in the development and use of atropoisomerically stable biphenyl ligands in asymmetric catalysis.18 Configurational stability in biphenyl atropoisomers rests on slowing the arylearyl bond rotation. This is usually obtained by incorporating at least three ortho-substituents adjacent to the arylearyl bond.19

7

Fig. 1. Single crystal X-ray structure of biphenyl 12. One of two similar molecules is shown.

in aqueous acetonitrile at 0  C; they are the most reactive iminium salt epoxidation catalysts discovered to date. We have applied the chemistry to the synthesis of several natural products including lomatin12 and scuteflorin A.13 Related chiral secondary amines have also been shown to catalyze the asymmetric epoxidation of alkenes, giving up to 66% ee.14 We have reported that amines corresponding to a number of our binaphthyl-derived iminium salt catalysts are indeed effective epoxidation catalysts under our standard conditions, giving yields and ees very similar to the corresponding iminium species. We have postulated that the amine catalysts are oxidized in situ to the corresponding iminium salts, which in turn epoxidize the alkenes via the oxaziridinium salts.15 Yang has screened a range of chiral secondary amines for catalytic activity;16 these studies revealed the presence of an electron-withdrawing substituent (such as hydroxyl or fluorine groups) at the b-position to the amine group to be beneficial for catalytic activity. The biphenyl catalysts described above suffer from limited generality in terms of inducing high enantioselectivities over a wide range of substrates. A possible explanation for the lower enantioselectivities sometimes obtained is the existence of these

OH

Recently, Lygo has synthesized a number of chiral quaternary ammonium salt catalysts for use in the asymmetric phase transfer alkylation of glycine imine enolates.20 These catalysts were conveniently prepared by bis-alkylation of a conformationally dynamic biphenyl unit with a range of chiral amines. Catalyst 7 emerged as the most effective phase transfer catalyst in terms of reactivity (requiring 1 mol % catalyst loading), and enantioselectivities (89e97% ee). Interestingly, comparison studies utilizing chiral ammonium salt catalysts derived from an unsubstituted biphenyl unit, gave low ees (2e6%), highlighting the importance of substituting the biphenyl unit to achieve high asymmetric induction. We envisaged that the asymmetric induction available from our biphenyl azepinium salt catalysts might be enhanced if we combined the substitution pattern of Lygo’s biaryl unit with our 1,3dioxane chiral appendage, to access, for example, catalyst 8. We also envisaged that the powerfully electron-withdrawing bis(trifluoromethyl)-phenyl group might lead to increased reactivity, as both the iminium salt and the corresponding oxaziridinium species are electrophilic. 2. Results and discussion We embarked upon the synthesis of the target catalyst 8, starting with the synthesis of the biphenyl unit. Treatment of commercially available phenol 9 using NBS in CCl4 at room temperature gave the ortho-brominated product 10 and the para-brominated product 11 in 55% and 33% yield, respectively, alongside starting material (10%) (Scheme 1).

OH

OH Br

i Me

9

8

+

Me

10 Scheme 1. Reagents and conditions: i: NBS (1.0 equiv), CCl4, rt, 3 h, 55%þ33%.

Me Br

11

760

M.M. Farah et al. / Tetrahedron 69 (2013) 758e769

Copper-catalyzed oxidative coupling is often used to obtain both symmetrical and unsymmetrical biaryl compounds.21 This method, using stoichiometric amounts of a copper(II)ediamine complex, has been used extensively in the preparation of racemic and enantio-enriched binaphthols from the corresponding 2naphthols.22 Several research groups have also developed catalytic copper-catalyzed oxidative coupling procedures, rendering this method attractive for use in organic synthesis.23,24 These catalytic processes are based on the reoxidation of Cu(I) to Cu(II) using oxidants, such as silver chloride21 or molecular oxygen.22 Using the catalytic procedure developed by Nakajima, the orthobrominated phenol 10 was treated with a catalytic amount of Cu(OH)Cl$TMEDA complex, which is readily prepared from a mixture of CuCl, TMEDA and molecular oxygen in aqueous methanol over 2 h. The aerobic oxidative coupling reaction using this complex in dichloromethane or methanol at room temperature proceeded well to furnish the desired biphenyl unit 12 in 54% yield alongside 5e7% of isomer 13 (Scheme 2).

Azepine 18 was obtained in 91% yield by heating a solution of 16, Lacetonamine 17 and K2CO3 in acetonitrile under reflux overnight. Subsequent oxidation of 18 using NBS in CCl4 under reflux followed by cation exchange provided the desired catalyst 8 in good overall yield (Scheme 4). When the same oxidation procedure was attempted using dichloromethane as a solvent, no iminium salt was formed. We were interested to ascertain if catalyst 8 was diastereoisomerically pure or consisted of a mixture of atropoisomers. We therefore performed 1H NMR spectroscopic analysis of salt 8 at temperatures between 40  C and 20  C while monitoring the iminium proton signal (Fig. 2). At these temperatures, we observed only two signals: a major and a minor signal for the iminium proton, indicating the existence of a diastereoisomeric mixture.17 The ratio of the two iminium proton signals was 1:10.2 at 20  C, increasing to a ratio of 1:32 at 40  C, suggesting that the atropoisomers readily interconvert, but clearly showing the dominance of one diastereoisomer in the mixture. However, we were unable to determine the absolute

Br

OH Br

OH Br

i

Me Me

Me

Me

Me

OH

+

Br

10

HO

OH

Br

12

13

Scheme 2. Reagents and conditions: i: Cu(OH)Cl$TMEDA (0.1 equiv), air, MeOH/CH2Cl2, rt, 16 h, 54%þ5e7%.

CF3 OH

OMe

Br Me Me

Me Me

Br OH

OMe

Br

i

CF3 OMe CF3

ii

Me Me

CF3 Br

iii

Br

CF3

Br OMe

OMe

CF3 OMe

CF3

12

14

Scheme 3. Reagents and conditions: i: KOH (2.5 equiv), MeI (2.5 equiv), 0 (2.2 equiv), AIBN (0.1 equiv), CCl4, reflux, 1.5 h, 92%.

15  Cert,

CF3

16

98%; ii: Pd(PPh3)4 (0.1 equiv), ArB(OH)2 (2.5 equiv), K2CO3 (3 equiv), DMF, 90  C, 16 h, 75%; iii: NBS

The NMR spectra of biphenyls 12 and 13 are very similar, and unambiguous structural determination of 12 was obtained by X-ray crystallography (Fig. 1).25 There are two similar molecules in the asymmetric unit. The twist angles between the two rings in the two unique molecules are 76.1(3) and 72.4(3) . Methylation of 12 using iodomethane and potassium hydroxide in DMF overnight gave the bis-methylated product 14 in excellent yield. SuzukieMiyaura coupling of 14 with 3,5-bis-(trifluoromethyl)-phenylboronic acid and Pd(PPh3)4 in DMF at 90  C furnished the 3,3-disubstituted product 15. Subsequent radical benzylic bromination using NBS in CCl4 under reflux afforded the desired product 16 in an excellent 92% yield (Scheme 3).

configuration of the predominant atropoisomer in the mixture. With salt 8 in hand, we tested it as a catalyst in the epoxidation of three alkene substrates. A comparison of the results with those obtained using the original biphenyl catalyst 4 is shown in Table 1. Catalyst 8 performed poorly in terms of both reactivity and enantioselectivity. Epoxidation using this catalyst gave at best 63% conversion in 5 h, when using 1-phenylcyclohexene as the substrate. Disappointingly, the ees obtained using this catalyst were also extremely poor, inducing at best 14% ee with trans-stilbene. Catalyst 4 is clearly superior, giving complete epoxidation of 1phenylcyclohexene within 10 min, and 60% ee for the corresponding epoxide.

M.M. Farah et al. / Tetrahedron 69 (2013) 758e769

16

761

18

8

17

Scheme 4. Reagents and conditions: i: L-acetonamine 17 (1.1 equiv), K2CO3 (3 equiv), CH3CN, reflux, 16 h, 91%; ii: NBS (1.2 equiv), AIBN (0.05 equiv), CCl4, 3 h; iii: NaBPh4 (1.1 equiv), EtOH, CH3CN, rt, 5 min, 85%.

Table 1 Catalytic asymmetric epoxidation of alkenes using catalyst 8 and a comparison with catalyst 4a Catalyst

4

Alkene

In all cases: ee (%);b conv. (%);c configurationd

Ph

Ph

Ph

Me

Fig. 2. 1H VT NMR spectra of catalyst 8 e iminium signal region.

The poor reactivity and selectivity portrayed by catalyst 8 may be due to the steric congestion around the biphenyl unit, resulting in difficulty in generation or reaction of the active oxaziridinium species. It is also possible that the powerful electron-withdrawing character of the 3,5-bis(trifluoromethyl)-phenyl group, while facilitating attack of the iminium unit by persulfate, may also slow expulsion of the sulfate to generate the oxaziridinium ion, due to the diminished nucleophilicity of the nitrogen atom, and this step may be rate-determining. With the aim of improving the reactivity and enantioselectivity, we chose iminium salt 19, lacking the tert-butyl groups and the methoxy groups at the biphenyl unit, but with the same electronwithdrawing 3,3-substituents and chiral nitrogen substituent as the previously developed iminium salt 8. Access to this catalyst would be through the main intermediate 20, which could in turn be synthesized from commercially available diphenic acid 21 (Scheme 5). While we were able to prepare the corresponding isopropyl ester 22 and diethylamide 23 of diphenic acid via the acid chloride for use in an ortho-metallation strategy (Scheme 6), we were unable to ortho-brominate 22 or 23. Attempted ortho-magnesiation of ester 22 using a solution of (TMP)2Mg and subsequent treatment with bromine under the conditions of Maruoka was also unsuccessful, resulting only in recovery of the starting material.26,27 Attempted ortho-lithiation of 22 using sec-BuLi at 78  C, in the presence or absence of TMEDA, led to the decomposition of the starting material. Amides are well known to have an excellent

Ph

Ph Ph

Ph

8

60, 100 ()-1S,2Se

22, 63 ()-1S,2S

37, 95 ()-1S,2Se

0, 15 d

59, 90 (þ)-Se

8, 7 (þ)-S

15, 90 ()-1S,2Se

14, 15 ()-1S,2S

Ph a Epoxidation conditions: iminium salt (5 mol %), oxone (2 equiv), NaHCO3 (5 equiv), MeCN/H2O (10:1), 0  C, 5 h. b Enantiomeric excesses were determined by chiral HPLC on a Chiralcel OD column, or by chiral GC on a Chiraldex B-DM column. c Conversions were evaluated from the 1H NMR spectra by integration of alkene and epoxide signals. d The absolute configurations of the major enantiomers were determined by comparison of optical rotation with literature values. e Epoxidation conditions: iminium salt (5 mol %), oxone (2 equiv), Na2CO3 (4 equiv), MeCN/H2O (1:1), 0  C, 2 h.

ortho-directing effect, and have been widely used in ortho-lithiation strategy. Repeated efforts to ortho-lithiate amide 23 using sec-BuLi and TMEDA as an additive, however, failed to give the desired product, with the complete recovery of the starting material. Accordingly, we changed our retrosynthetic analysis towards the known key intermediate 24.28 This strategy required the assembly of the biphenyl unit from commercially available aniline 25 (Scheme 7). Diazotization of aniline 25 and subsequent Sandmeyer reaction of the diazonium salt with potassium iodide provided compound 26 in 85% yield. Since its discovery in 1901, Ullmann coupling,29 which involves coupling of two molecules of aryl halides in the

762

M.M. Farah et al. / Tetrahedron 69 (2013) 758e769

19

20

21

Scheme 5. Retrosynthetic analysis of iminium salt 19.

CO2H CO2H

i, ii

presence of activated copper powder, has been utilized extensively in the synthesis of racemic30 and chiral biphenyls.31 The orthosubstituents on the aromatic ring influence the reaction outcome, with substituents, such as nitro and ester groups favouring the reaction, while substituents, such as amino and hydroxyl groups, and bulky substituents, inhibit the reaction. Ullmann coupling of 26 using a stoichiometric amount of activated copper in DMF at 190  C furnished the desired biphenyl 27 in 53% yield, alongside starting material (13%), and compound 28 (33%), resulting from the reductive dehalogenation of 26 (Scheme 8). The use of freshly activated copper was found to be crucial for the success of the Ullmann coupling, as the reaction

COR COR

22 R = OiPr, 23 R = NEt2

21

Scheme 6. Reagents and conditions: 22: i: SOCl2 (10 equiv), reflux, 4 h; ii: i-PrOH (10 equiv), pyridine (3 equiv) reflux, 2 h, 99%; 23: i: SOCl2 (10 equiv), reflux, 4 h; ii: Et2NH (10 equiv), Et3N (3 equiv), reflux, 2 h, 96%.

19

24

25

Scheme 7. New retrosynthetic analysis employing biphenyl 24.

25

26

27

28

Scheme 8. Reagents and conditions: i: NaNO2 (1.1 equiv), H2SO4, H2O, 0e5  C, 1 h; ii: KI (1.5 equiv), H2O, 0  Cert, 2 h, 85%; iii: Cu (5 equiv), DMF, 190  C, 24 h, 53%.

M.M. Farah et al. / Tetrahedron 69 (2013) 758e769

failed when commercially available copper powder was used directly. Treatment of biphenyl 27 with hydrazine hydrate at reflux for 8 h led to diamino-substituted biphenyl 29 in excellent yield. Subsequent diazotization at 0  C and iodination using potassium iodide at 50  C overnight gave the desired biphenyl 24. SuzukieMiyaura cross coupling of 24 with 3,5-bis-(trifluoromethyl)phenylboronic acid furnished the coupling product 30 in 73% yield alongside homo-coupled product 31 (5e10%) (Scheme 9).

27

29

more reactive in catalyzing the epoxidation of alkenes. For example, amine 33 mediated the conversion of triphenylethylene and transstilbene to their corresponding epoxides in 82% and 62% conversion, respectively, in 3 h, compared to 22% and 30% conversion mediated by the iminium salt 19 also in 3 h. Catalyst 19 is, however, more reactive than catalyst 8, giving, for example, 100% conversion in the epoxidation of 1-phenylcyclohexene in 3 h, compared to 63% conversion with iminium salt 8 in 5 h. Catalyst 19 also induces generally higher enantioselectivities

24

30

 C,

Scheme 9. Reagents and conditions: i: NH2NH2$H2O, H2O, 100 16 h, 86%; ii: H2SO4, H2O, NaNO2 (2.2 equiv), 0 (0.1 equiv), ArB(OH)2 (4.0 equiv), K2CO3 (4 equiv), DMF, 90  C, 16 h, 73%.

Benzylic bromination of 30 using NBS in CCl4 under reflux with AIBN as the radical initiator afforded the desired compound 32; dibromide 32 was subsequently treated with L-acetonamine 17 and potassium carbonate in boiling acetonitrile to form azepine 33 in 90% yield. The desired catalyst 19 was obtained over two steps from azepine 33 by treatment with NBS (Scheme 10).

30

32

763

 C,

31

1 h; iii: KI (6 equiv), H2O, 0e50

 C,

16 h, 82%; iv: Pd(PPh3)4

than catalyst 8. For example, 1-phenylcyclohexene and trans-amethylstilbene were epoxidized in 44% ee and 26% ee, respectively, using catalyst 19 (Table 2), while catalyst 8 provided 1phenycyclohexene oxide with 22% ee and racemic trans-a-methylstilbene oxide (Table 1). This improvement in reactivity and selectivity perhaps results from decreased steric congestion around the

33

19

Scheme 10. Reagents and conditions: i: NBS (2.2 equiv), AIBN (0.1 equiv), 2 h, 85%; ii: L-acetonamine 17 (1.1 equiv), K2CO3 (3 equiv), CH3CN, reflux, 16 h, 90%; iii: NBS (1.2 equiv), AIBN (0.05 equiv), CCl4, 3 h; iv: NaBPh4 (1.1 equiv), EtOH, CH3CN, rt, 5 min, 67%.

We employed both azepine 33 and the iminium salt 19 in the catalytic asymmetric epoxidation of alkene substrates (Table 2). Both amine 33 and iminium salt 19 gave epoxides with very similar enantioselectivities and configurations, again suggesting the involvement of the same chiral intermediate when using these two different catalysts. Interestingly, while the ees of epoxide products derived using both amine and iminium salt catalysts were identical, amine 33 was

iminium unit. Both iminium salts 8 and 19 are, however, less reactive and enantioselective than the previously developed catalyst 4. 3. Conclusion In conclusion, we have successfully prepared two novel biphenyl catalysts 8 and 19, with electron-withdrawing 3,30 -substituents on the biphenyl unit, and an identical chiral nitrogen

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M.M. Farah et al. / Tetrahedron 69 (2013) 758e769

Table 2 Catalytic asymmetric epoxidation of alkenes using amine and iminium catalystsa Catalyst

33

Alkene

In all cases: ee (%);b conv. (%);c configurationd

Ph

Ph

Ph

47, 100 ()-1S,2S

44, 100 ()-1S,2S

de

26, 67 ()-1S,2S

13, 82 (þ)-S

11, 34 (þ)-S

7, 62 ()-1S,2S

6, 30 ()-1S,2S

Me Ph

Ph Ph

Ph

19

Ph a Epoxidation conditions: iminium salt (5 mol %), oxone (2 equiv), NaHCO3 (5 equiv), MeCN:H2O (10:1), 0  C, 3 h. b Enantiomeric excesses were determined by chiral HPLC on a Chiralcel OD column, or by chiral GC on a Chiraldex B-DM column. c Conversions were evaluated from the 1H NMR spectra by integration of alkene versus epoxide signals. d The absolute configurations of the major enantiomers were determined by comparison with literature values. e Not tested.

substituent to catalyst 4. These catalysts are, however, less reactive and enantioselective than catalyst 4, perhaps suggesting that substitution on the biphenyl unit introduces steric bulk that is deleterious for catalytic activity and enantioselectivity. 4. Experimental section 4.1. General experimental detail All infrared spectra were obtained using a PerkineElmer Paragon 1000 FT-IR spectrophotometer; thin film spectra were acquired using sodium chloride plates. All 1H and 13C NMR spectra were measured at 250.13 and 62.86 MHz with a Bruker AC 250 MHz spectrometer or at 400.13 and 100.62 MHz with a Bruker DPX 400 MHz spectrometer, in deuteriochloroform solution unless otherwise stated, using TMS (tetramethylsilane) as the internal reference. Mass spectra were recorded using a Jeol-SX102 instrument utilizing electron-impact (EI), fast atom bombardment (FAB) and by the EPSRC national mass spectrometry service at the University of Wales, Swansea, utilizing electrospray (ES). Analysis by GCeMS was carried out on a Fisons GC 8000 series (AS 800), using a 15 m0.25 mm DB-5 column and an electronimpact low resolution mass spectrometer. Melting points were recorded using an Electrothermal-IA 9100 melting point instrument and are uncorrected. Optical rotation values were measured with an Optical Activity-polAAar 2001 instrument, operating at l¼589 nm, corresponding to the sodium D line, at the temperatures indicated. Microanalyses were performed on a Perkin Elmer Elemental Analyser 2400 CHN. All chromatographic manipulations used silica gel as the adsorbent. Reactions were monitored using thin layer chromatography (TLC) on aluminiumbacked plates coated with Merck Kieselgel 60 F254 silica gel. TLC plates were visualized by UV radiation at a wavelength of 254 nm,

or stained by exposure to an ethanolic solution of phosphomolybdic acid (acidified with concentrated sulfuric acid), followed by charring where appropriate. Column chromatography was typically carried out by adjusting solvent mixtures to give Rf values of approximately 0.3 on TLC.32 Reactions requiring anhydrous conditions were carried out using glassware dried overnight at 150  C, under a nitrogen atmosphere unless otherwise stated. Reaction solvents were used as obtained commercially unless otherwise stated. Light petroleum (bp 40e60  C) was distilled from calcium chloride prior to use. Ethyl acetate was distilled over calcium sulfate or chloride. Dichloromethane was distilled over calcium hydride. Tetrahydrofuran was distilled under a nitrogen atmosphere from the sodium/benzophenone ketyl radical or from lithium aluminium hydride. Enantiomeric excesses were determined by proton nuclear magnetic resonance spectroscopy in the presence of europium (III) tris[3-(hepta-fluropropylhydroxymethylene)-(þ)-camphorate] as the chiral shift reagent, by chiral HPLC using a Chiracel OD column on a TSP Thermo-SeparatingProducts Spectra Series P200 instrument, with a TSP Spectra Series UV100 ultra-violet absorption detector set at 254 nm and a Chromojet integrator, or by chiral GC-FID using a Chiradex B-DM column on a CE instruments GC 8000 series spectrometer, with flame ionization detector and a Chrome-card integrator. Solvents used fro chromatography-based measurements were of HPLC grade. 4.1.1. 2-Bromo-6-tert-butyl-3-methyl-phenol (10). N-Bromosuccinimide (5.42 g, 30.4 mmol) was added over 5 min to a solution of 2tert-butyl-5-methyl-phenol (9) (5.00 g, 30.4 mmol) in carbon tetrachloride (122 mL, c 0.25 M). The reaction mixture was stirred for 3 h and the solvents removed under reduced pressure. The residue was dissolved in dichloromethane (40 mL) and the organic phase washed with water (230 mL) and brine (230 mL), dried (Na2SO4), and the solvents removed in vacuo. Column chromatography using petrol as an eluent gave the product as a colourless oil (4.07 g, 55%); nmax (film)/cm1 3495, 3075, 2956, 2914, 2871, 1662, 1486, 1444, 1401, 1363, 1320, 1271, 1192, 1142, 1032, 957, 842, 806, 746, 684; 1H NMR (400 MHz, CDCl3): d 1.38 (9H, s, ArC(CH3)3), 2.35 (3H, s, ArCH3), 5.91 (1H, s, OH), 6.73 (1H, dd, J¼8.0, 0.8 Hz, CH arom., H4), 7.09 (1H, d, J¼8.0 Hz, CH arom., H5); 13C NMR (100 MHz, CDCl3): d 23.1 (CH3, ArCH3), 29.5 (3 CH3, ArC(CH3)3), 35.1 (C quat., ArC(CH3)3), 115.3 (C quat., arom., C2), 121.6 (CH arom., C4), 125.5 (CH arom., C5), 134.6 (C quat., arom., C6), 136.0 (C quat., arom., C3), 150.4 (C quat., arom., C1); m/z (FAB) 242.0311; C11 H15 79 BrO [MþH]þ requires 242.0306. 4.1.2. 4-Bromo-2-tert-butyl-5-methyl-phenol (11). This compound was isolated as a by-product obtained in the bromination of 2-tertbutyl-5-methyl-phenol (9) to give (10), using N-bromosuccinimide as described above; isolated as a colourless oil (2.34 g, 33%); nmax (film)/cm1 3490 (OH), 3074, 2953, 2914, 2871, 1660, 1490, 1444, 1401, 1360, 1320, 1278, 1190, 1142, 1032, 957, 847, 806, 740, 684; 1H NMR (400 MHz, CDCl3): d 1.28 (9H, s, ArC(CH3)3), 2.18 (3H, s, ArCH3), 4.81 (1H, s, OH), 6.45 (1H, s, CH arom., H6), 7.27 (1H, s, CH arom., H3); 13C NMR (100 MHz, CDCl3): d 21.1 (CH3, ArCH3), 28.4 (3 CH3, ArC(CH3)3), 33.3 (C quat., ArC(CH3)3), 114.2 (C quat., arom., C4), 117.8 (CH arom., C6), 129.6 (CH arom., C3), 134.8 (C quat., arom., C2), 135.1 (C quat., arom., C5), 152.2 (C quat., arom., C1); m/z (FAB) 242.0302; C11 H15 79 BrO [MþH]þ requires 242.0306. 4.1.3. 3,30 -Dibromo-5,50 -di-tert-butyl-4,40 -dihydroxy-2,20 -dimethyl1,10 -biphenyl (12). Copper(I) chloride CuCl (0.0700 g, 0.707 mmol) was added to a solution of N,N,N0 ,N0 -tetramethyl-ethane-1,2diamine TMEDA (0.130 mL, 0.820 mmol) in dichloromethane (10 mL) and the mixture sonicated under an oxygen atmosphere to afford a green solution. A solution of 2-bromo-6-tert-butyl-3-

M.M. Farah et al. / Tetrahedron 69 (2013) 758e769

methyl-phenol (10) (1.81 g, 7.46 mmol) in dichloromethane (10 mL) was added and the mixture stirred for 16 h under oxygen. The solvents were removed under reduced pressure and the crude residue subjected to column chromatography using petrol as an eluent to give the product as a colourless solid (0.98 g, 54%); mp 202e203  C; nmax (film)/cm1 3492 (OH), 2956, 1595, 1465, 1384, 1310, 1255, 1184, 1028, 906, 734, 675; 1H NMR (400 MHz, CDCl3): d 1.40 (18H, s, 2 ArC(CH3)3), 2.35 (6H, s, 2 ArCH3), 5.96 (2H, s, 2 ArOH), 6.96 (2H, s, 2 CH arom., biphenyl-6,60 ); 13C NMR (100 MHz, CDCl3): d 20.9 (2 CH3, 2 ArCH3), 29.5 (6 CH3, 2 ArC(CH3)3), 35.2 (2 C quat., 2 ArC(CH3)3), 116.0 (2 C quat., arom., biphenyl3,30 ), 127.6 (2 CH arom., biphenyl-6,60 ), 134.0 (4 C quat., arom., biphenyl-1,10 -5,50 ), 134.1 (2 C quat., arom., biphenyl-2,20 ), 149.4 (2 C quat., arom., biphenyl-4,40 ); m/z (EI) 482.0461; C22 H28 79 Br2 O2 (M)þ requires 482.0456. 4.1.4. 4,40 -Dibromo-2,20 -di-tert-butyl-3,30 -dihydroxy-5,50 -dimethyl1,10 -biphenyl (13). This compound was isolated as a by-product obtained in the oxidative coupling of 2-bromo-6-tert-butyl-3methyl-phenol (10) to give (12), using CuCl and TMEDA as described above; isolated as a colourless powder; nmax (film)/cm1 3492 (OH), 2955, 1459, 1385, 1265, 1184, 1029; 1H NMR (400 MHz, CDCl3): d 1.37 (18H, s, 2 ArC(CH3)3), 2.53 (6H, s, 2 ArCH3), 5.92 (2H, s, 2 ArOH), 7.39 (2H, s, 2 CH arom., biphenyl-2,20 ); 13C NMR (100 MHz, CDCl3): d 24.0 (2 CH3, 2 ArCH3), 29.2 (6 CH3, 2 ArC(CH3)3), 35.3 (2 C quat., 2 ArC(CH3)3), 114.6 (2 C quat., arom., biphenyl-4,40 ), 115.5 (2 C quat., arom., biphenyl-2,20 ), 129.7 (2 CH arom., biphenyl-6,60 ), 134.7 (2 C quat., arom., biphenyl-1,10 ), 136.2 (2 C quat., arom., biphenyl-5,50 ), 149.8 (2 C quat., arom., biphenyl3,30 ); m/z (EI) 482.0448; C22 H28 79 Br2 O2 (M)þ requires 482.0456.

765

colourless foam (0.36 g, 73%); nmax (film)/cm1 2960, 2868, 1618, 1466, 1425, 1392, 1354, 1323, 1278, 1238, 1179, 1135, 1084, 1051, 903, 847, 739, 684; 1H NMR (400 MHz, CDCl3): d 1.43 (18H, s, 2 ArC(CH3)3), 1.79 (6H, s, 2 ArCH3), 3.17 (6H, s, 2 ArOCH3), 7.20 (2H, s, 2 CH arom., biphenyl-6,60 ), 7.88 (2H, s, 2 CH arom., H12, H120 ), 7.91 (4H, dd, J¼4.4, 0.4 Hz, 4 CH arom., H8, H80 eH9, H90 ); 13C NMR (100 MHz, CDCl3): d 18.1 (2 CH3, 2 ArCH3), 31.0 (6 CH3, 2 ArC(CH3)3), 35.1 (2 C quat., 2 ArC(CH3)3), 60.6 (2 OCH3, 2 ArOCH3),120.8 (2 CH arom., septet, J¼3.7 Hz, C12, C120 ),123.4 (4 C quat., q, J¼271.0 Hz, 4 CF3), 129.1 (2 CH arom., biphenyl-6,60 ), 131.1 (4 CH arom., C8, C80 eC9, C90 ), 131.6 (4 C quat., arom., q, J¼33.0 Hz, C10, C100 eC11, C110 ), 133.1 (2 C quat., arom., biphenyl-3,30 ), 133.2 (2 C quat., arom., biphenyl-1,10 ), 137.5 (2 C quat., arom., biphenyl5,50 ), 140.5 (2 C quat., arom., biphenyl-2,20 ), 141.0 (2 C quat., arom., C7, C70 ), 156.3 (2 C quat., arom., biphenyl-4,40 ); m/z (MALDI-TOF) 778.3; C40H38F12O2 [M]þ requires 778.2680.

4.1.5. 3,30 -Dibromo-5,50 -di-tert-butyl-4,40 -dimethoxy-2,20 -dimethyl1,10 -biphenyl (14). A solution of compound (12) (0.370 g, 0.764 mmol) in N,N-dimethylformamide (10 mL) was treated with ground potassium hydroxide (0.110 g, 1.96 mmol) followed by dropwise addition of iodomethane (0.120 mL, 1.91 mmol) at 0  C. The reaction mixture was stirred at room temperature for 16 h, diluted with ethyl acetate (40 mL), washed with water (650 mL) and brine (650 mL), and dried (Na2SO4). The solvents were removed under reduced pressure to yield a colourless solid (0.38 g, 98%); mp 123e125  C; nmax (film)/cm1 2956, 1459, 1359, 1258, 1223, 1044, 1003, 976, 908, 847, 734; 1H NMR (400 MHz, CDCl3): d 1.39 (18H, s, 2 ArC(CH3)3), 2.10 (6H, s, 2 ArCH3), 3.97 (6H, s, 2 ArOCH3), 7.00 (2H, s, 2 CH arom., biphenyl-6,60 ); 13C NMR (100 MHz, CDCl3): d 21.0 (2 CH3, 2 ArCH3), 31.0 (6 CH3, 2 ArC(CH3)3), 35.3 (2 C quat., 2 ArC(CH3)3), 61.5 (2 OCH3, 2 ArOCH3), 122.0 (2 C quat., arom., biphenyl-3,30 ), 127.5 (2 CH arom., biphenyl-6,60 ), 135.8 (2 C quat., arom., biphenyl-1,10 ), 137.7 (2 C quat., arom., biphenyl-5,50 ), 141.6 (2 C quat., arom., biphenyl2,20 ), 155.8 (2 C quat., arom., biphenyl-4,40 ); m/z (FAB) 510.0776; C24 H32 79 Br2 O2 [MþH]þ requires 510.0769.

4.1.7. 2,20 -Bis-bromomethyl-3,30 -bis-(3,5-(trifluoromethyl)phenyl)(16). 3,30 -Bis-(3,55,50 -di-tert-butyl-4,40 -dimethoxy-1,10 -biphenyl (trifluoromethyl)phenyl)-5,50 -di-tert-butyl-4,40 -dimethoxy-2,20 dimethyl-1,10 -biphenyl (15) (0.270 g, 0.347 mmol) was dissolved in carbon tetrachloride (5 mL). N-Bromosuccinimide (0.140 g, 0.787 mmol) and azo-bis-isobutyronitrile (0.00600 g, 0.0365 mmol) were added with stirring at room temperature. The mixture was heated under reflux for 2 h; after this time complete disappearance of the starting material was observed by TLC. The solvents were removed under reduced pressure and the residue redissolved in dichloromethane (30 mL). The organic layer was washed with water (220 mL) and brine (220 mL), dried (Na2SO4), and the solvents removed under reduced pressure. Column chromatography of the crude material using ethyl acetate/ petroleum ether (1:15) as eluent afforded the product as a colourless powder (0.29 g, 92%); mp 208e209  C; nmax (film)/cm1 2960, 1462, 1394, 1358, 1278, 1244, 1178, 1137, 1083, 1047, 906, 847, 735; 1 H NMR (400 MHz, CDCl3): d 1.37 (18H, s, 2 ArC(CH3)3), 3.14 (6H, s, 2 ArOCH3), 3.82 (2H, d, J¼10.2 Hz, ArCH2Br), 3.88 (2H, d, J¼10.2 Hz, ArCH2Br), 7.33 (2H, s, 2 CH arom., biphenyl-6,60 ), 7.90 (4H, d, J¼8.0 Hz, 4 CH arom., H12, H120 and H8, H80 or H9, H90 ), 8.08 (2H, s, 2 CH arom., H8, H8 or H9, H90 ); 13C NMR (100 MHz, CDCl3): d 29.3 (2 CH2, 2 ArCH2Br2), 29.7 (6 CH3, 2 ArC(CH3)3), 34.4 (2 C quat., 2 ArC(CH3)3), 59.9 (2 OCH3, 2 ArOCH3), 120.6 (2 CH arom., septet, J¼3.7 Hz, C12, C120 ), 122.25 (2 C quat., q, J¼271.4 Hz, 2 CF3), 122.28 (2 C quat., q, J¼271.4 Hz, 2 CF3), 129.2 (2 CH arom., biphenyl-6,60 ), 129.7 (2 CH arom., C8, C80 or C9, C90 ), 130.1 (2 CH arom., C8, C80 or C9, C90 ), 130.8 (2 C quat., arom., q, J¼33.3 Hz, C10, C100 or C11, C110 ), 130.9 (2 C quat., arom., q, J¼33.3 Hz, C10, C100 or C11, C110 ), 131.7 (2 C quat., arom., biphenyl3,30 ), 133.0 (2 C quat., arom., biphenyl-1,10 ), 134.8 (2 C quat., arom., biphenyl-5,50 ), 137.9 (2 C quat., arom., biphenyl-2,20 ), 142.9 (2 C quat., arom., C7, C70 ), 156.4 (2 C quat., arom., biphenyl-4,40 ); m/z (FAB) 934.0871; C40 H36 79 Br2 F12 O2 [MþH]þ requires 934.0890.

4.1.6. 3,30 -Bis-(3,5-(trifluoromethyl)phenyl)-5,50 -di-tert-butyl-4,40 dimethoxy-2,20 -dimethyl-1,10 -biphenyl (15). A solution of compound (14) (0.330 g, 0.644 mmol) in dry N,N-dimethylformamide (8 mL) was degassed with nitrogen gas for 15 min prior to addition of Pd(PPh)4 (0.0750 g, 0.139 mmol), 3,5-bis-(trifluoromethyl)phenylboronic acid (0.420 g, 1.62 mmol), and potassium carbonate (0.670 g, 4.86 mmol). The mixture was degassed for a further 10 min and backfilled with nitrogen gas. The reaction mixture was subsequently heated to 90  C overnight, poured into saturated aqueous ammonium chloride (30 mL), and extracted with diethyl ether (330 mL). The combined organic extracts were washed with water (430 mL) and brine (430 mL), dried (Na2SO4), and the solvents removed under reduced pressure. The residue was purified by column chromatography using petrol as an eluent to give the product as

4.1.8. N-(4S,5S)-5-(2,2-Dimethyl-4-phenyl-1,3-dioxanyl)-3,30 -bis(3,5-(trifluoromethyl)-phenyl)-5,50 -di-tert-butyl-4,40 -dimethoxy-2,7dihydrodibenzo[c,e]azepine (18). L-Acetonamine (17) (0.0600 g, 0.289 mmol) was added to a nitrogen-purged stirred solution of dibromide (16) (0.250 g, 0.267 mmol), followed by potassium carbonate (0.110 g, 0.796 mmol) in dry acetonitrile (4 mL) at room temperature. The reaction mixture was heated under reflux overnight. The solvents were removed under reduced pressure and the residue was diluted with dichloromethane (40 mL), washed with water (230 mL) and brine (230 mL), dried (Na2SO4), and the solvents removed under reduced pressure to give the product as an orange foam (0.24 g, 91%); ½a20 D þ8.6 (c 0.93, CHCl3); nmax (film)/ cm1 2961, 2869, 1465, 1362, 1324, 1278, 1236, 1177, 1082, 1041, 904, 847, 736, 684; 1H NMR (400 MHz, CDCl3): d 0.93 (3H, s, CH3, H19 or

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H20), 1.21 (3H, s, CH3, H19 or H20), 1.37 (18H, s, 2 ArC(CH3)3), 1.90e1.91 (1H, m, NCH, H17), 2.99 (6H, s, 2 ArOCH3), 3.17 (2H, s, CH2N), 3.19 (2H, s, ArCH2N), 3.66 (2H, d, J¼2.4 Hz, NCHCH2O, H18), 4.36 (1H, d, J¼2.4 Hz, ArCH, H16), 6.58 (2H, dd, J¼7.2, 3.6 Hz, 2 CH arom., H22, H23), 7.00e7.02 (3H, m, 2 CH arom., H24, H25 and H26), 7.33 (2H, s, 2 CH arom., biphenyl-6,60 ), 7.60 (2H, s, 2 CH arom., H8, H8 or H9, H90 ), 7.86 (2H, s, 2 CH arom., H8, H8 or H9, H90 ), 7.90 (2H, s, 2 CH arom., H12, H120 ); 13C NMR (100 MHz, CDCl3): d 17.7 (CH3, C19 or C20), 27.9 (CH3, C19 or C20), 29.9 (6 CH3, 2 ArC(CH3)3), 34.2 (2 C quat., 2 ArC(CH3)3), 48.7 (2 CH2, 2 ArCH2N), 57.9 (CH, NCH, C17), 59.7 (2 OCH3, 2 ArOCH3), 60.3 (CH2, C18), 73.4 (CH, ArCH, C16), 97.6 (C quat., C14), 120.1 (2 CH arom., septet, J¼3.7 Hz, C12, C120 ), 122.2 (2 C quat., q, J¼271.3 Hz, 2 CF3), 122.4 (2 C quat., q, J¼271.3 Hz, 2 CF3), 124.7 (2 CH arom., C22, C23), 125.6 (CH arom., C26), 126.4 (2 CH arom., C24, C25), 126.7 (2 CH arom., biphenyl-6,60 ), 130.32 (2 CH arom., C8, C80 or C9, C90 ), 130.34 (4 C quat., arom., q, J¼33.3 Hz, C10, C100 eC11, C110 ), 130.5 (2 CH arom., C8, C80 or C9, C90 ), 131.4 (2 C quat., arom., biphenyl-3,30 ), 131.8 (2 C quat., arom., biphenyl-1,10 ), 136.2 (2 C quat., arom., biphenyl-2,20 ), 138.1 (2 C quat., arom., biphenyl-5,50 ), 139.2 (2 C quat., arom., C7, C70 ), 141.4 (C quat., arom., C21), 155.9 (2 C quat., arom., biphenyl-4,40 ). 4.1.9. (4S,5S)-4,8-Bis-(3,5-bis-trifluoromethyl-phenyl)-2,10-di-tertbutyl-6-(2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-3,9-dimethoxy5H-dibenzo[c,e]azepinium tetraphenylborate (8). Azepine (18) (0.230 g, 0.234 mmol) was dissolved in carbon tetrachloride (3 mL). N-Bromosuccinimide (0.050 g, 0.281 mmol) and azo-bisisobutyronitrile (0.00200 g, 0.0122 mmol) were added with stirring at room temperature. The mixture was heated under reflux for 3 h. The solvents were removed under reduced pressure and the residue redissolved in ethanol. A solution of sodium tetraphenylborate (0.0870 g, 0.254 mmol) in a minimum amount of acetonitrile was added in one portion. The mixture was stirred for 5 min, and a few drops of water were added. The resulting yellow solid was collected by filtration and washed with hexane (0.26 g, 85%); 1 mp 140e142  C (dec); ½a20 D 70.8 (c 0.52, CH3OH); nmax (film)/cm 3055, 2965, 1626, 1579, 1470, 1393, 1357, 1278, 1241, 1183, 1140, 1081, 1045, 904, 847; 1H NMR (400 MHz, acetonitrile-d3): d 0.43 (3H, s, CH3, H19 or H20), 1.28 (3H, s, CH3, H19 or H20), 1.42 (9H, s, ArC(CH3)3), 1.47 (9H, s, ArC(CH3)3), 2.88 (3H, s, ArOCH3), 3.06 (3H, s, ArOCH3), 3.30 (1H, t, J¼2.4, NCH, H17), 4.03 (1H, d, J¼13.4 Hz, NCHCHHO, H18), 4.25 (1H, dd, J¼13.4, 2.4 Hz, NCHCHHO, H18), 4.49 (1H, d, J¼12.4 Hz, ArCHHN), 4.53 (1H, d, J¼12.4 Hz, ArCHHN), 5.14 (1H, d, J¼2.4 Hz, ArCH, H16), 6.65 (2H, d, J¼7.3 Hz, 2 CH arom., H22, H23), 6.75 (4H, t, J¼7.2 Hz, 4 CH arom., para in BPh4 gp.), 6.91 (10H, t, J¼7.4 Hz, 8 CH arom., ortho in BPh4 gp., and 2 CH arom., H24, H25), 6.97e6.99 (1H, m, CH arom.), 7.18e7.20 (8H, m, 8 CH arom., meta in BPh4 gp.), 7.59 (1H, br s, CH arom.), 7.67 (1H, br s, CH arom.), 7.77 (1H, br s, CH arom.), 7.81 (1H, br s, CH arom.), 7.99 (1H, br s, CH arom.), 8.14 (1H, br s, CH arom.), 8.23 (1H, br s, CH arom.), 8.88 (1H, s, HC]N); 13C NMR (100 MHz, acetonitrile-d3, 40  C): d 17.0 (CH3, C19 or C20), 27.1 (CH3, C19 or C20), 29.3 (3 CH3, ArC(CH3)3), 29.8 (3 CH3, ArC(CH3)3), 34.8 (C quat., ArC(CH3)3), 36.1 (C quat., ArC(CH3)3), 57.2 (CH2, ArCH2N), 60.4 (CH3, ArOCH3), 60.6 (CH3, ArOCH3), 62.4 (CH2, C18), 65.7 (CH, CHN, C17), 70.8 (CH, ArCH, C16), 100.0 (C quat., C14), 121.4 (4 CH arom., para in BPh4 gp.), 122.2 (CH arom.), 123.6 (CH arom.), 124.5 (CH arom.), 124.9 (C quat.), 125.1 (2 CH arom., C22, C23), 125.3 (8 CH arom., ortho in BPh4 gp.), 126.6 (C quat.), 128.0 (2 CH arom., C24, C25), 128.6 (C quat.), 128.7 (CH arom.), 129.0 (CH arom.), 129.7 (CH arom.), 130.4 (C quat.), 131.1 (CH arom.), 131.3 (C quat.), 131.4 (C quat.), 131.5 (CH arom.), 132.2 (C quat., q, J¼33.4 Hz), 133.3 (CH arom.), 135.2 (C quat.), 135.4 (8 CH arom., meta in BPh4 gp.), 135.6 (C quat.), 136.0 (C quat.), 136.5 (C quat.), 136.9 (C quat.), 144.9 (C quat.), 152.7 (C quat.), 157.2 (C quat.), 158.7 (C quat.), 163.5 (4 C quat., arom., q, J¼49.1 Hz, 4 C-

B ipso in BPh4 gp.), 167.8 (HC]N); m/z (ESI) 980.3553; C52H50F12NO4 (cation) requires 980.3543. 4.1.10. 2-Methyl-3-nitro-iodobenzene (26).33 Concentrated sulfuric acid (8 mL) was added to a solution of 2-methyl-3-nitroaniline (25) (5.00 g, 32.9 mmol) in water (50 mL). The mixture was cooled to 0  C, and a solution of sodium nitrite (2.49 g, 36.2 mmol) in water (5 mL) added dropwise. The mixture was stirred for 1 h, and a solution of potassium iodide (8.18 g, 49.3 mmol) in water (20 mL) added dropwise. The mixture was stirred for 1 h, and extracted with dichloromethane (330 mL). The combined organic extracts were washed with saturated aqueous sodium thiosulfate (Na2S2O3), dried (Na2SO4), and the solvents removed under reduced pressure to yield a crude oil. The residue was purified by column chromatography using ethyl acetate/petroleum ether (1:10) to afford the product as a yellow solid (7.43 g, 85%); mp 36e37  C; nmax (film)/ cm1 3082, 1591, 1519, 1443, 1348, 1273, 1204, 1087, 1001, 860, 794, 735, 696; 1H NMR (400 MHz, CDCl3): d 2.52 (3H, s, CH3), 6.96 (1H, t, J¼8.0 Hz, CH arom., H5), 7.64 (1H, dd, J¼8.0, 1.2 Hz, CH arom., H6), 7.80 (1H, dd, J¼8.0, 1.2 Hz, CH arom., H4); 13C NMR (100 MHz, CDCl3): d 25.0 (CH3, ArCH3), 103.6 (C quat., arom., C1), 123.9 (CH arom., C4), 128.0 (CH arom., C5), 135.0 (C quat., arom., C2), 143.1 (CH arom., C6), 150.4 (C quat., arom., C3); m/z (EI) 262.9439; C7H6INO2 (M)þ requires 262.9443. 4.1.11. 2,20 -Dimethyl-3,30 -dinitro-1,10 -biphenyl (27) 4.1.11.1. Activation of copper powder:.34 Copper powder (2.00 g) was stirred with 2% iodine (w/w wrt copper) in acetone (100 mL) for 10 min. The powder was filtered and stirred to form a slurry with 1:1 solution of concentrated hydrochloric acid in acetone (200 mL). The copper iodide dissolved, and the copper powder remaining was removed by filtration and washed with acetone (200 mL). The activated copper was dried in a vacuum desiccator and used immediately. 2-Methyl-3-nitro-iodobenzene (26) (1.00 g, 3.80 mmol) and activated copper (1.21 g, 19.0 mmol) were added to dry N,Ndimethylformamide (8 mL), and the mixture was heated to 190  C for 24 h. The mixture was diluted with dichloromethane (100 mL), washed with 4% aqueous ammonia (5100 mL), water (450 mL), and brine (350 mL), dried (Na2SO4), and the solvents removed under reduced pressure to yield a dark crude oil. Column chromatography of the residue using ethyl acetate/petroleum ether (1:10) gave the product as a yellow solid (0.27 g, 53%); mp 120e121  C; nmax (film)/cm1 3086, 1604, 1524, 1458, 1350, 1279, 1219, 1106, 995, 859, 807, 736, 718, 674; 1H NMR (400 MHz, CDCl3): d 2.13 (6H, s, 2 CH3), 7.29 (2H, dd, J¼7.6, 1.4 Hz, 2 CH arom., biphenyl-5,50 ), 7.36 (2H, ddd, J¼8.0, 7.6, 0.5 Hz, 2 CH arom., biphenyl6,60 ), 7.83 (2H, dd, J¼8.0, 1.4 Hz, 2 CH arom., biphenyl-4,40 ); 13C NMR (100 MHz, CDCl3): d 15.4 (2 CH3, 2 ArCH3), 123.1 (2 CH arom., biphenyl-4,40 ), 125.7 (2 CH arom., biphenyl-5,50 ), 129.8 (2 C quat., arom., biphenyl-2,20 ), 132.6 (2 CH arom., biphenyl-6,60 ), 141.3 (2 C quat., arom., biphenyl-1,10 ), 149.9 (2 C quat., arom., biphenyl3,30 ); m/z (EI) 272.0793; C14H12N2O4 (Mþ) requires 272.0797. 4.1.12. 3,30 -Diamino-2,20 -dimethyl-1,10 -biphenyl (29). 2,20 -Dimethyl3,30 -dinitro-biphenyl (27) (0.250 g, 0.918 mmol) was dissolved in aqueous hydrazine hydrate (85%) (20 mL). The solution was heated to reflux for 16 h, allowed to cool to room temperature, and extracted with ethyl acetate (430 mL). The combined organic layers were washed with water (230 mL) and brine (230 mL), dried (Na2SO4), and the solvents removed under reduced pressure to afford the product as an orange powder (0.17 g, 86%); mp 162e164  C; nmax (film)/cm1 3463 (NH), 3364 (NH), 1615, 1579, 1455, 793; 1H NMR (400 MHz, CDCl3): d 1.79 (6H, s, 2 CH3), 3.51 (4H, s, 2 ArNH2), 6.51 (2H, dd, J¼7.7, 1.0 Hz, 2 CH arom., biphenyl4,40 ), 6.61 (2H, dd, J¼7.7, 1.0 Hz, 2 CH arom., biphenyl-6,60 ), 6.96

M.M. Farah et al. / Tetrahedron 69 (2013) 758e769

(2H, t, J¼7.7 Hz, 2 CH arom., biphenyl-5,50 ); 13C NMR (100 MHz, CDCl3): d 12.8 (2 CH3, 2 ArCH3), 112.7 (2 CH arom., biphenyl4,40 ), 119.2 (2 CH arom., biphenyl-6,60 ), 119.6 (2 C quat., arom., biphenyl-2,20 ), 124.9 (2 CH arom., biphenyl-5,50 ), 141.9 (2 C quat., arom., biphenyl-1,10 ), 143.5 (2 C quat., arom., biphenyl-3,30 ); m/z (EI) 212.1310; C14H16N2 (Mþ) requires 212.1314. 4.1.13. 3,30 -Diiodo-2,20 -dimethyl-1,10 -biphenyl (24).28a Concentrated sulfuric acid (5 mL) was added to a suspension of 2,20 -dimethylbiphenyl-3,30 -diamine (29) (0.170 g, 0.801 mmol) in water (15 mL). The mixture was cooled to 0  C prior to the addition of a solution of sodium nitrite (0.120 g, 1.74 mmol) in water (3 mL). The resulting solution was stirred for 50 min at 0  C prior to the dropwise addition of a solution of potassium iodide (0.79 g, 4.74 mmol) in water (3 mL). The mixture was heated at 50  C overnight, allowed to cool, and extracted with dichloromethane (340 mL). The combined organic extracts were washed with saturated aqueous sodium thiosulfate (250 mL), water (250 mL), and brine (250 mL), dried (Na2SO4), and the solvents removed under reduced pressure. The residue was filtered through a short pad of silica gel using petrol as eluent to give the product as a brown solid (0.28 g, 81%); mp 103e105  C; nmax (film)/cm1 3053, 2961, 2918, 1550, 1427, 1378, 1260, 1180, 1073, 1022, 988, 781, 718, 653; 1H NMR (400 MHz, CDCl3): d 2.08 (6H, s, 2 CH3), 6.82 (2H, t, J¼7.8 Hz, 2 CH arom., biphenyl-5,50 ), 6.96 (2H, dd, J¼7.8, 1.0 Hz, 2 CH arom., biphenyl6,60 ), 7.76 (2H, dd, J¼7.8, 1.0 Hz, 2 CH arom., biphenyl-4,40 ); 13C NMR (100 MHz, CDCl3): d 24.9 (2 CH3, 2 ArCH3), 101.5 (2 C quat., arom., biphenyl-3,30 ), 126.2 (2 CH arom., biphenyl-6,60 ), 128.3 (2 CH arom., biphenyl-5,50 ), 137.6 (2 CH arom., biphenyl-4,40 ), 137.8 (2 C quat., arom., biphenyl-1,10 ), 141.5 (2 C quat., arom., biphenyl-2,20 ); m/z (EI) 433.9032; C14H12I2 (Mþ) requires 433.9028.

767

0.843 mmol) and azo-bis-isobutyronitrile (0.00600 g, 0.0365 mmol) were added with stirring at room temperature. The mixture was heated under reflux for 3 h; after this time complete disappearance of the starting material was observed by TLC. The solvents were removed under reduced pressure and the residue redissolved in dichloromethane (30 mL). The organic layer was washed with water (220 mL) and brine (220 mL), dried (Na2SO4), and the solvents removed under reduced pressure. Flash column chromatography of the residue using ethyl acetate/petroleum ether (1:10) as eluent afforded the product as a colourless powder (0.25 g, 85%); mp 203e205  C; nmax (film)/cm1 2359, 2340, 1378, 1277, 1175, 1132, 1106, 1047, 901; 1H NMR (400 MHz, CDCl3): d 4.00 (2H, d, J¼10.4 Hz, ArCH2), 4.09 (2H, d, J¼10.4 Hz, ArCH2), 7.27 (2H, dd, J¼7.6, 1.5 Hz, 2 CH arom., biphenyl-4,40 ), 7.39 (2H, dd, J¼7.6, 1.5 Hz, 2 CH arom., biphenyl-6,60 ), 7.46 (2H, t, J¼7.6 Hz, 2 CH arom., biphenyl-5,50 ), 7.89 (2H, d, J¼0.6 Hz, 2 CH arom., H12, H120 ), 7.95 (4H, s, 4 CH arom., H8, H80 e, H9, H90 ); 13C NMR (100 MHz, CDCl3): d 28.6 (2 CH2, 2 ArCH2Br2), 120.8 (2 CH arom., septet, J¼3.8 Hz, C12, C120 ), 122.2 (4 C quat., q, J¼271.2 Hz, 4 CF3), 127.6 (2 CH arom., biphenyl5,50 ), 128.4 (4 CH arom., C8, C80 eC9, C90 ), 129.6 (2 CH arom., biphenyl-4,40 ), 129.8 (2 CH arom., biphenyl-6,60 ), 130.6 (4 C quat., q, J¼33.0 Hz, C10, C100 eC11, C110 ), 132.2 (2 C quat., arom., biphenyl2,20 ), 139.6 (2 C quat., arom., C7, C70 ), 139.7 (2 C quat., arom., biphenyl-3,30 ), 141.2 (2 C quat., arom., biphenyl-1,10 ); m/z (EI) 761.9429; C30 H16 79 Br2 F12 (M) requires 761.9427.

4.1.14. 3,30 -Bis-(3,5-(trifluoromethyl)phenyl)-2,20 -dimethyl-1,10 -biphenyl (30). A solution of 3,30 -diiodo-2,20 -dimethyl-1,10 -biphenyl (24) (0.720 g, 1.66 mmol) in dry N,N-dimethylformamide (8 mL) was degassed for 15 min prior to the addition of Pd(PPh3)4 (0.190 g, 0.164 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (1.71 g, 6.61 mmol), and potassium carbonate (0.910 g, 6.58 mmol). The mixture was degassed for a further 10 min and backfilled with nitrogen gas. The reaction mixture was heated to 90  C overnight, poured into saturated aqueous ammonium chloride (30 mL), and extracted with diethyl ether (330 mL). The combined organic extracts were washed with water (430 mL) and brine (430 mL), dried (Na2SO4), and the solvents removed under reduced pressure. The resulting dark oil was purified by column chromatography using petrol as an eluent to give the product as a colourless solid (0.73 g, 73%); mp 143e145  C; nmax (film)/cm1 3057, 1617, 1578, 1454, 1379, 1280, 1176, 1134, 1051, 899, 846, 799; 1H NMR (400 MHz, CDCl3): d 1.90 (6H, s, 2 CH3), 7.16 (2H, d, J¼7.3 Hz, 2 CH arom., biphenyl-4,40 ), 7.17 (2H, dd, J¼7.3, 1.0 Hz, 2 CH arom., biphenyl6,60 ), 7.28 (2H, t, J¼7.3 Hz, 2 CH arom., biphenyl-5,50 ), 7.76 (4H, s, 4 CH arom., H8, H80 e, H9, H90 ), 7.81 (2H, s, 2 CH arom., H12, H120 ); 13C NMR (100 MHz, CDCl3): d 17.8 (2 CH3, 2 ArCH3), 120.9 (2 CH arom., septet, J¼3.8 Hz, C12, C120 ), 123.4 (4 C quat., q, J¼271.2 Hz, 4 CF3), 126.0 (2 CH arom., biphenyl-5,50 ), 129.0 (2 CH arom., biphenyl-4,40 ), 129.5 (4 CH arom., C8, C80 eC9, C90 ), 129.8 (2 CH arom., biphenyl-6,60 ), 131.6 (4 C quat., q, J¼33.0 Hz, C10, C100 eC11, C110 ), 133.1 (2 C quat., arom., biphenyl-2,20 ), 139.7 (2 C quat., arom., C7, C70 ), 142.7 (2 C quat., arom., biphenyl-3,30 ), 144.2 (2 C quat., arom., biphenyl-1,10 ); m/z (EI) 606.1218; C30H18F12 (Mþ) requires 606.1217.

4.1.16. (4S,5S)-4,8-Bis-(3,5-bis-trifluoromethyl-phenyl)-6-(2,2dimethyl-4-phenyl-[1,3]dioxan-5-yl)-6,7-dihydro-5H-dibenzo[c,e] azepine (33). L-Acetonamine (17) (0.170 g, 0.820 mmol) was added to a nitrogen-purged stirred solution of 2,20 -bis-bromomethyl-3,30 bis-(3,5-trifluoromethylphenyl)-1,10 -biphenyl (32) (0.580 g, 0.759 mmol) and potassium carbonate (0.310 g, 2.24 mmol) in dry acetonitrile (10 mL) at room temperature. The reaction mixture was heated under reflux overnight. The solvents were removed under reduced pressure, and the residue was diluted with dichloromethane (40 mL), washed with water (230 mL) and brine (230 mL), dried (Na2SO4), and the solvents removed under reduced pressure. Column chromatography of the crude oily residue using ethyl acetate/petroleum ether (1:10) gave the product as a colourless 1 2961, foam (0.55 g, 90%); ½a20 D þ46.8 (c 0.83, CHCl3); nmax (film)/cm 1452, 1379, 1278, 1174, 1136; 1H NMR (400 MHz, CDCl3): d 0.94 (3H, s, CH3, H19),1.23 (3H, s, CH3, H20), 2.15 (1H, d, J¼2.9 Hz, NCH, H17), 3.24 (2H, d, J¼13.0 Hz, ArCH2N), 3.40 (2H, br s, ArCH2N), 3.70 (2H, d, J¼2.9 Hz, NCHCH2O, H18), 4.44 (1H, d, J¼2.9 Hz, ArCH, H16), 6.63 (2H, dd, J¼7.8, 1.6 Hz, 2 CH arom., H22, H23), 6.96e7.04 (3H, m, 2 CH arom., H24, H25 and H26), 7.17 (2H, dd, J¼7.6, 1.6 Hz, 2 CH arom., biphenyl-4,40 ), 7.38 (2H, t, J¼7.6 Hz, 2 CH arom., biphenyl-5,50 ), 7.43 (2H, dd, J¼7.6, 1.6 Hz, 2 CH arom., biphenyl-6,60 ), 7.70 (4H, br s, 4 CH arom., H8, H80 e, H9, H90 ), 7.89 (2H, s, 2 CH arom., H12, H120 ); 13C NMR (100 MHz, CDCl3): d 17.7 (CH3, C19), 27.8 (CH3, C20), 48.5 (2 CH2, 2 ArCH2N), 58.1 (CH, NCH, C17), 60.2 (CH2, C18), 73.4 (CH, ArCH, C16), 97.6 (C quat., C14), 120.2 (2 CH arom., septet, J¼3.8 Hz, C12, C120 ), 122.3 (4 C quat., q, J¼271.4 Hz, 4 CF3), 124.8 (2 CH arom., C22, C23), 125.7 (CH arom., C26), 126.4 (2 CH arom., C24, C25), 126.5 (2 CH arom., biphenyl-5,50 ), 127.6 (2 CH arom., biphenyl-6,60 ), 128.8 (4 CH arom., C8, C80 eC9, C90 ), 129.0 (2 CH arom., biphenyl-4,40 ), 130.4 (4 C quat., J¼33.0 Hz, 4 CCF3, C10, C100 eC11, C110 ), 131.9 (2 C quat., arom., biphenyl-2,20 ), 137.7 (2 C quat., arom., C7, C70 ), 137.9 (2 C quat., arom., biphenyl-3,30 ), 141.3 (2 C quat., arom., biphenyl-1,10 ), 142.7 (C quat., arom., C21); m/z (EI) 809.2176; C42H31F12NO2 (Mþ) requires 809.2163.

4.1.15. 2,20 -Bis-bromomethyl-3,30 -bis-(3,5-(trifluoromethyl)phenyl)(32). 3,30 -Bis-(3,5-trifluoromethylphenyl)-2,20 -di1,10 -biphenyl methyl-1,10 -biphenyl (30) (0.230 g, 0.379 mmol) was dissolved in carbon tetrachloride (5 mL). N-Bromosuccinimide (0.150 g,

4.1.17. (4S,5S)-4,8-Bis-(3,5-bis-trifluoromethyl-phenyl)-6-(2,2dimethyl-4-phenyl-[1,3]dioxan-5-yl)-5H-dibenzo[c,e]azepinium tetraphenylborate (19). Azepine (33) (0.480 g, 0.593 mmol) was dissolved in carbon tetrachloride (3 mL). N-Bromosuccinimide (0.130 g,

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0.730 mmol) and azo-bis-isobutyronitrile (0.00500 g, 0.0304 mmol) were added with stirring at room temperature. The mixture was heated under reflux for 3 h. The solvents were removed under reduced pressure and the residue redissolved in ethanol. A solution of sodium tetraphenylborate (0.230 g, 0.672 mmol) in a minimum amount of acetonitrile was added in one portion. The resulting mixture was stirred for 5 min, and a few drops of water were added. The resulting yellow solid was collected by filtration and washed with ethanol followed by diethyl ether, and dried at 90  C (0.46 g, 67%); mp 221e222  C (dec); ½a20 D 144.1 (c 1.00, CH3CN); found: C, 67.96; H, 4.38; N, 1.21. C66H50BF12NO2$2H2O requires C, 68.11; H, 4.68; N, 1.20%; nmax (film)/cm1 3054, 1632, 1579, 1479, 1450, 1377, 1278, 1183, 1139, 902; 1H NMR (400 MHz, acetonitrile-d6, 40  C): d 0.56 (3H, s, CH3, H19 or H20), 1.41 (3H, s, CH3, H19 or H20), 3.57 (1H, d, J¼2.0 Hz, NCH, H17), 4.26 (1H, d, J¼13.2 Hz, NCHCHHO, H18), 4.47 (1H, d, J¼13.2 Hz, NCHCHHO, H180 ), 4.78 (1H, d, J¼13.0 Hz, ArCHH), 4.86 (1H, d, J¼13.0 Hz, ArCHH), 5.39 (1H, d, J¼2.0 Hz, ArCH, H16), 6.74 (2H, d, J¼6.4 Hz, 2 CH arom.), 6.85 (4H, t, J¼7.2 Hz, 4 CH arom., para in BPh4 gp.), 6.91e6.97 (3H, m, 3 CH arom.), 7.02 (8H, t, J¼7.6 Hz, 8 CH arom., ortho in BPh4 gp.), 7.28e7.35 (9H, m, CH arom., and 8 CH arom., meta in BPh4 gp.), 7.48 (1H, t, J¼8.0 Hz, CH arom.), 7.64 (1H, d, J¼7.6 Hz, CH arom.), 7.83e7.85 (2H, m, 2 CH arom.), 8.00e8.06 (3H, m, 3 CH arom.), 8.10 (1H, s, CH arom.), 8.29 (2H, s, CH arom.), 8.36 (1H, s, CH arom.), 9.09 (1H, s, HC]N); 13C NMR (100 MHz, DMSO-d6): d 18.0 (CH3, C19 or C20), 27.2 (CH3, C19 or C20), 57.4 (2 CH2, 2 ArCH2N), 62.8 (CH2, C18), 66.6 (CH, NCH, C17), 70.7 (CH, ArCH, C16), 99.6 (C quat., C14), 121.5 (4 CH arom., para in BPh4 gp.), 121.9 (CH arom., septet, C12 or C120 ), 123.3 (CH arom., septet, C12 or C120 ), 125.0 (CH arom.), 125.1 (C quat., arom.), 125.3 (8 CH arom., ortho in BPh4 gp.), 128.0 (CH arom.), 128.3 (CH arom.), 129.6 (CH arom.), 130.7 (CH arom.), 130.9 (CH arom.), 131.1 (CH arom.), 131.5 (C quat., arom.), 131.8 (CH arom.), 135.0 (CH arom.), 135.5 (8 CH arom., meta in BPh4 gp.), 135.8 (C quat., arom.), 136.6 (C quat., arom.), 136.8 (C quat., arom.), 139.7 (C quat., arom.), 140.7 (C quat., arom.), 141.0 (C quat., arom.), 143.3 (C quat., arom.), 163.3 (4 C quat., arom., J¼49.1 Hz, 4 C-B ipso in BPh4 gp.), 167.7 (HC]N); m/ z (ESI) 808.2078; C42H30F12NO2 (cation) requires 808.2079. 4.2. General procedure for the catalytic asymmetric epoxidation of alkenes mediated by iminium salts using oxone A mixture of alkene (0.40 mmol) and catalyst (5 mol %) was dissolved in acetonitrile (1 mL) and water (0.1 mL) and the mixture cooled to 0  C. A mixture of oxone (0.492 g, 0.8 mmol, 2 equiv) and sodium hydrogen carbonate (0.168 g, 2.0 mmol, 5 equiv) was added as a solid in one portion to the mixture with vigorous stirring. The mixture was stirred at 0  C until complete conversion of the alkene was observed by TLC. Diethyl ether (10 mL) was added, and the reaction mixture was filtered through a pad of mixed MgSO4 and sodium bisulfite (NaHSO3). The solvent was then removed in vacuo. Pure epoxides were obtained by column chromatography, typically using petroleum ether or ethyl acetate/light petroleum (1:99) as eluent. Acknowledgements This investigation has enjoyed the support of NPIL Pharmaceuticals (UK) Ltd and Loughborough University. We are also indebted to the Royal Society for an Industry Fellowship (to PCBP), and to the EPSRC Mass Spectrometry Unit at the University of Wales, Swansea. References and notes 1. Hanquet, G.; Lusinchi, X.; Millet, P. Tetrahedron Lett. 1987, 28, 6061e6064; Hanquet, G.; Lusichi, X.; Millet, P. Tetrahedron Lett. 1988, 29, 3941e3944; Hanquet, C.; Lusinchi, X.; Milliet, P. C. R. Acad. Sci. Paris 1991, 313, 625e628; Lusinchi, X.; Hanquet, G. Tetrahedron 1997, 53, 13727e13738.

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