Novel biphenyl organocatalysts for iminium ion-catalyzed asymmetric epoxidation

Article abstract of DOI:10.1016/j.tet.2012.10.076

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.

Full text of DOI:10.1016/j.tet.2012.10.076

Tetrahedron 69 (2013) 758e769
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel biphenyl organocatalysts for iminium ion-catalyzed
asymmetric epoxidation
,
b
c
Mohamed M. Farah b, Philip C. Bulman Page a , Benjamin R. Buckley , A. John Blacker ,
*
Mark R.J. Elsegood b
a School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4 7TJ, UK
b Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
c 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 ep-
oxidation 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
biphenylazepinium6 and binaphthylazepinium7 motifs, such as
3e6 can provide ees of up to 98% in epoxidation under our stan-
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 imi-
nium salt to be used in this way was 1, with the controlling
asymmetric centres sited in the heterocyclic ring of a dihy-
droisoquinolinium salt, and it was shown to catalyze epoxidation
of alkenes with ees of up to about 40% (Fig. 1).2 A number of ad-
vances 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
dard 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 elec-
trochemical oxidation,11 may be used in conjunction with these
catalysts.
1
2
3
BPh4
O
BPh4
Ph
BPh4
N
O
O
O
O
N
N
O
O
Ph
S
Me
O
4
5
6
Catalysts incorporating an azepinium structure are highly re-
* Corresponding author. E-mail address: p.page@uea.ac.uk (P.C.B. Page).
active, inducing complete epoxidation of alkenes within 1e10 min
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.076

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 de-
velopment and use of atropoisomerically stable biphenyl ligands in
asymmetric catalysis.18 Configurational stability in biphenyl atro-
poisomers 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
8
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 con-
veniently 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.
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
We envisaged that the asymmetric induction available from our
biphenyl azepinium salt catalysts might be enhanced if we com-
bined the substitution pattern of Lygo’s biaryl unit with our 1,3-
dioxane chiral appendage, to access, for example, catalyst 8. We
also envisaged that the powerfully electron-withdrawing bis(tri-
fluoromethyl)-phenyl group might lead to increased reactivity, as
both the iminium salt and the corresponding oxaziridinium species
are electrophilic.
Related chiral secondary amines have also been shown to cat-
alyze 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 ep-
oxidation 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 cor-
responding iminium salts, which in turn epoxidize the alkenes via
the oxaziridinium salts.15 Yang has screened a range of chiral sec-
ondary amines for catalytic activity;16 these studies revealed the
presence of an electron-withdrawing substituent (such as hydroxyl
2. Results and discussion
or fluorine groups) at the
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
b-position to the amine group to be
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 tem-
perature gave the ortho-brominated product 10 and the para-bro-
minated product 11 in 55% and 33% yield, respectively, alongside
starting material (10%) (Scheme 1).
OH
OH
OH
Br
+
i
Me
Me
Me
Br
9
10
11
Scheme 1. Reagents and conditions: i: NBS (1.0 equiv), CCl4, rt, 3 h, 55%þ33%.

760
M.M. Farah et al. / Tetrahedron 69 (2013) 758e769
Copper-catalyzed oxidative coupling is often used to obtain both
Azepine18 was obtained in 91%yieldby heating a solution of 16, L-
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 2-
naphthols.22 Several research groups have also developed cata-
lytic copper-catalyzed oxidative coupling procedures, rendering
this method attractive for use in organic synthesis.23,24 These cat-
alytic 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 ortho-
brominated phenol 10 was treated with a catalytic amount of
Cu(OH)Cl$TMEDA complex, which is readily prepared from a mix-
ture of CuCl, TMEDA and molecular oxygen in aqueous methanol
over 2 h. The aerobic oxidative coupling reaction using this complex
in dichloromethane or methanol at room temperature proceeded
well to furnish the desired biphenyl unit 12 in 54% yield alongside
5e7% of isomer 13 (Scheme 2).
acetonamine 17 and K2CO3 in acetonitrile under reflux overnight.
Subsequent oxidation of 18 using NBS in CCl4 under reflux followed
by cation exchange provided the desired catalyst 8 in good overall
yield (Scheme 4). When the same oxidation procedure was attemp-
ted using dichloromethane as a solvent, no iminium salt was formed.
We were interested to ascertain if catalyst 8 was diaster-
eoisomerically pure or consisted of a mixture of atropoisomers. We
therefore performed 1H NMR spectroscopic analysis of salt 8 at
temperatures between ꢁ40 ꢀC and 20 ꢀC while monitoring the
iminium proton signal (Fig. 2).
At these temperatures, we observed only two signals: a major
and a minor signal for the iminium proton, indicating the existence
of a diastereoisomeric mixture.17 The ratio of the two iminium
proton signals was 1:10.2 at 20 ꢀC, increasing to a ratio of 1:32 at
ꢁ40 ꢀC, suggesting that the atropoisomers readily interconvert, but
clearly showing the dominance of one diastereoisomer in the
mixture. However, we were unable to determine the absolute
Br
OH
HO
Me
Br
OH
Br
i
Me
Me
+
Me
Me
OH
Br
Br
OH
10
12
13
Scheme 2. Reagents and conditions: i: Cu(OH)Cl$TMEDA (0.1 equiv), air, MeOH/CH2Cl2, rt, 16 h, 54%þ5e7%.
CF3
CF3
OH
OMe
OMe
OMe
Br
Br
CF3
CF3
CF3
CF3
Br
Br
Me
Me
Me
Me
i
ii
Me
Me
iii
Br
Br
OH
OMe
OMe
OMe
CF3
CF3
12
14
15
16
Scheme 3. Reagents and conditions: i: KOH (2.5 equiv), MeI (2.5 equiv), 0 ꢀCert, 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
(2.2 equiv), AIBN (0.1 equiv), CCl4, reflux, 1.5 h, 92%.
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-(tri-
fluoromethyl)-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 sub-
strate. 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 1-
phenylcyclohexene within 10 min, and 60% ee for the corre-
sponding epoxide.

M.M. Farah et al. / Tetrahedron 69 (2013) 758e769
761
16
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
Alkene
4
8
In all cases: ee (%);b conv. (%);c configurationd
Ph
60, 100
22, 63
(ꢁ)-1S,2S
(ꢁ)-1S,2Se
Ph
Me
37, 95
0, 15
d
Ph
Ph
(ꢁ)-1S,2Se
Ph
59, 90
8, 7
(þ)-S
(þ)-Se
Fig. 2. 1H VT NMR spectra of catalyst 8 e iminium signal region.
Ph
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 fa-
cilitating 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.
15, 90
14, 15
(ꢁ)-1S,2S
(ꢁ)-1S,2Se
Ph
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 col-
umn, or by chiral GC on a Chiraldex B-DM column.
Conversions were evaluated from the 1H NMR spectra by integration of alkene
c
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 electron-
withdrawing 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 un-
able 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 un-
successful, 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
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 as-
sembly 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.
presence of activated copper powder, has been utilized extensively
in the synthesis of racemic30 and chiral biphenyls.31 The ortho-
substituents 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.
CO2H
CO2H
i, ii
COR
COR
Ullmann coupling of 26 using a stoichiometric amount of acti-
vated 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
21
22 R = OiPr, 23 R = NEt2
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
763
failed when commercially available copper powder was used
directly.
more reactive in catalyzing the epoxidation of alkenes. For example,
amine 33 mediated the conversion of triphenylethylene and trans-
stilbene to their corresponding epoxides in 82% and 62% conver-
sion, 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-phenylcyclo-
hexene in 3 h, compared to 63% conversion with iminium salt 8 in
5 h. Catalyst 19 also induces generally higher enantioselectivities
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. Suzu-
kieMiyaura 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
24
30
31
Scheme 9. Reagents and conditions: i: NH2NH2$H2O, H2O, 100 ꢀC, 16 h, 86%; ii: H2SO4, H2O, NaNO2 (2.2 equiv), 0 ꢀC, 1 h; iii: KI (6 equiv), H2O, 0e50 ꢀC, 16 h, 82%; iv: Pd(PPh3)4
(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;
than catalyst 8. For example, 1-phenylcyclohexene and trans-
methylstilbene were epoxidized in 44% ee and 26% ee, respectively,
using catalyst 19 (Table 2), while catalyst provided 1-
phenycyclohexene oxide with 22% ee and racemic trans- -methyl-
stilbene oxide (Table 1). This improvement in reactivity and selec-
tivity perhaps results from decreased steric congestion around the
a-
dibromide 32 was subsequently treated with
L-acetonamine 17
8
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).
a
30
32
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.
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 bi-
phenyl catalysts 8 and 19, with electron-withdrawing 3,30-sub-
stituents on the biphenyl unit, and an identical chiral nitrogen
Interestingly, while the ees of epoxide products derived using
both amine and iminium salt catalysts were identical, amine 33 was

764
M.M. Farah et al. / Tetrahedron 69 (2013) 758e769
Table 2
or stained by exposure to an ethanolic solution of phosphomo-
lybdic acid (acidified with concentrated sulfuric acid), followed by
charring where appropriate. Column chromatography was typi-
cally carried out by adjusting solvent mixtures to give Rf values of
approximately 0.3 on TLC.32 Reactions requiring anhydrous con-
ditions 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 de-
termined by proton nuclear magnetic resonance spectroscopy in
the presence of europium (III) tris[3-(hepta-fluropropylhydroxy-
methylene)-(þ)-camphorate] as the chiral shift reagent, by chiral
HPLC using a Chiracel OD column on a TSP Thermo-Separating-
Products Spectra Series P200 instrument, with a TSP Spectra Se-
ries 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.
Catalytic asymmetric epoxidation of alkenes using amine and iminium catalystsa
Catalyst
Alkene
33
19
In all cases: ee (%);b conv. (%);c configurationd
Ph
47, 100
44, 100
(ꢁ)-1S,2S
(ꢁ)-1S,2S
Ph
Me
de
26, 67
(ꢁ)-1S,2S
Ph
Ph
Ph
13, 82
11, 34
(þ)-S
(þ)-S
Ph
7, 62
6, 30
(ꢁ)-1S,2S
(ꢁ)-1S,2S
Ph
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 col-
umn, or by chiral GC on a Chiraldex B-DM column.
4.1.1. 2-Bromo-6-tert-butyl-3-methyl-phenol (10). N-Bromosucci-
nimide (5.42 g, 30.4 mmol) was added over 5 min to a solution of 2-
tert-butyl-5-methyl-phenol (9) (5.00 g, 30.4 mmol) in carbon tet-
rachloride (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 (2ꢂ30 mL) and brine (2ꢂ30 mL), dried
(Na2SO4), and the solvents removed in vacuo. Column chromatog-
raphy using petrol as an eluent gave the product as a colourless oil
(4.07 g, 55%); nmax (film)/cmꢁ1 3495, 3075, 2956, 2914, 2871, 1662,
1486, 1444, 1401, 1363, 1320, 1271, 1192, 1142, 1032, 957, 842, 806,
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 sub-
stitution on the biphenyl unit introduces steric bulk that is dele-
terious for catalytic activity and enantioselectivity.
746, 684; 1H NMR (400 MHz, CDCl3):
d 1.38 (9H, s, ArC(CH3)3), 2.35
4. Experimental section
(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,
4.1. General experimental detail
CDCl3):
d
23.1 (CH3, ArCH3), 29.5 (3ꢂ 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; C11H1579BrO [MþH]þ re-
quires 242.0306.
All infrared spectra were obtained using a PerkineElmer Par-
agon 1000 FT-IR spectrophotometer; thin film spectra were ac-
quired 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 un-
less otherwise stated, using TMS (tetramethylsilane) as the in-
ternal reference. Mass spectra were recorded using a Jeol-SX102
instrument utilizing electron-impact (EI), fast atom bombard-
ment (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 mꢂ0.25 mm DB-5 column and an electron-
impact low resolution mass spectrometer. Melting points were
recorded using an Electrothermal-IA 9100 melting point in-
strument and are uncorrected. Optical rotation values were
measured with an Optical Activity-polAAar 2001 instrument,
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-tert-
butyl-5-methyl-phenol (9) to give (10), using N-bromosuccinimide
as described above; isolated as a colourless oil (2.34 g, 33%); nmax
(film)/cmꢁ1 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):
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 1.28 (9H, s, ArC(CH3)3), 2.18 (3H, s, ArCH3),
d
21.1 (CH3, ArCH3), 28.4 (3ꢂ 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;
C11H1579BrO [MþH]þ requires 242.0306.
operating at
l
¼589 nm, corresponding to the sodium D line, at the
temperatures indicated. Microanalyses were performed on a Per-
kin Elmer Elemental Analyser 2400 CHN. All chromatographic
manipulations used silica gel as the adsorbent. Reactions were
monitored using thin layer chromatography (TLC) on aluminium-
backed plates coated with Merck Kieselgel 60 F254 silica gel. TLC
plates were visualized by UV radiation at a wavelength of 254 nm,
4.1.3. 3,30-Dibromo-5,50-di-tert-butyl-4,40-dihydroxy-2,20-dimethyl-
1,10-biphenyl (12). Copper(I) chloride CuCl (0.0700 g, 0.707 mmol)
was added to a solution of N,N,N0,N0-tetramethyl-ethane-1,2-
diamine 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
765
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)/cmꢁ1 3492 (OH), 2956, 1595, 1465, 1384,
1310, 1255, 1184, 1028, 906, 734, 675; 1H NMR (400 MHz, CDCl3):
colourless foam (0.36 g, 73%); nmax (film)/cmꢁ1 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, 2ꢂ
ArC(CH3)3),1.79 (6H, s, 2ꢂ ArCH3), 3.17 (6H, s, 2ꢂ ArOCH3), 7.20 (2H,
s, 2ꢂ CH arom., biphenyl-6,60), 7.88 (2H, s, 2ꢂ CH arom., H12, H120),
7.91 (4H, dd, J¼4.4, 0.4 Hz, 4ꢂ CH arom., H8, H80eH9, H90); 13C NMR
(100 MHz, CDCl3):
d
18.1 (2ꢂ CH3, 2ꢂ ArCH3), 31.0 (6ꢂ CH3, 2ꢂ
d
1.40 (18H, s, 2ꢂ ArC(CH3)3), 2.35 (6H, s, 2ꢂ ArCH3), 5.96 (2H, s, 2ꢂ
ArC(CH3)3), 35.1 (2ꢂ C quat., 2ꢂ ArC(CH3)3), 60.6 (2ꢂ OCH3, 2ꢂ
ArOCH3),120.8 (2ꢂ CH arom., septet, J¼3.7 Hz, C12, C120),123.4 (4ꢂ C
quat., q, J¼271.0 Hz, 4ꢂ CF3),129.1 (2ꢂ CH arom., biphenyl-6,60),131.1
(4ꢂ CH arom., C8, C80eC9, C90),131.6 (4ꢂ C quat., arom., q, J¼33.0 Hz,
C10, C100eC11, C110), 133.1 (2ꢂ C quat., arom., biphenyl-3,30), 133.2
(2ꢂ C quat., arom., biphenyl-1,10), 137.5 (2ꢂ C quat., arom., biphenyl-
5,50),140.5 (2ꢂ C quat., arom., biphenyl-2,20),141.0 (2ꢂ C quat., arom.,
C7, C70), 156.3 (2ꢂ C quat., arom., biphenyl-4,40); m/z (MALDI-TOF)
778.3; C40H38F12O2 [M]þ requires 778.2680.
ArOH), 6.96 (2H, s, 2ꢂ CH arom., biphenyl-6,60); 13C NMR (100 MHz,
CDCl3):
d
20.9 (2ꢂ CH3, 2ꢂ ArCH3), 29.5 (6ꢂ CH3, 2ꢂ ArC(CH3)3),
35.2 (2ꢂ C quat., 2ꢂ ArC(CH3)3), 116.0 (2ꢂ C quat., arom., biphenyl-
3,30), 127.6 (2ꢂ CH arom., biphenyl-6,60), 134.0 (4ꢂ C quat., arom.,
biphenyl-1,10-5,50), 134.1 (2ꢂ C quat., arom., biphenyl-2,20), 149.4
(2ꢂ C quat., arom., biphenyl-4,40); m/z (EI) 482.0461; C22H2879Br2O2
(M)þ requires 482.0456.
4.1.4. 4,40-Dibromo-2,20-di-tert-butyl-3,30-dihydroxy-5,50-dimethyl-
1,10-biphenyl (13). This compound was isolated as a by-product
obtained in the oxidative coupling of 2-bromo-6-tert-butyl-3-
methyl-phenol (10) to give (12), using CuCl and TMEDA as de-
scribed above; isolated as a colourless powder; nmax (film)/cmꢁ1
3492 (OH), 2955, 1459, 1385, 1265, 1184, 1029; 1H NMR (400 MHz,
4.1.7. 2,20-Bis-bromomethyl-3,30-bis-(3,5-(trifluoromethyl)phenyl)-
5,50-di-tert-butyl-4,40-dimethoxy-1,10-biphenyl (16). 3,30-Bis-(3,5-
(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 (2ꢂ20 mL) and brine (2ꢂ20 mL), dried
(Na2SO4), and the solvents removed under reduced pressure. Col-
umn chromatography of the crude material using ethyl acetate/
petroleum ether (1:15) as eluent afforded the product as a colour-
less powder (0.29 g, 92%); mp 208e209 ꢀC; nmax (film)/cmꢁ1 2960,
1462, 1394, 1358, 1278, 1244, 1178, 1137, 1083, 1047, 906, 847, 735;
CDCl3):
d
1.37 (18H, s, 2ꢂ ArC(CH3)3), 2.53 (6H, s, 2ꢂ ArCH3), 5.92 (2H,
s, 2ꢂ ArOH), 7.39 (2H, s, 2ꢂ CH arom., biphenyl-2,20); 13C NMR
(100 MHz, CDCl3):
d
24.0 (2ꢂ CH3, 2ꢂ ArCH3), 29.2 (6ꢂ CH3, 2ꢂ
ArC(CH3)3), 35.3 (2ꢂ C quat., 2ꢂ ArC(CH3)3),114.6 (2ꢂ C quat., arom.,
biphenyl-4,40), 115.5 (2ꢂ C quat., arom., biphenyl-2,20), 129.7 (2ꢂ CH
arom., biphenyl-6,60), 134.7 (2ꢂ C quat., arom., biphenyl-1,10), 136.2
(2ꢂ C quat., arom., biphenyl-5,50), 149.8 (2ꢂ C quat., arom., biphenyl-
3,30); m/z (EI) 482.0448; C22H2879Br2O2 (M)þ requires 482.0456.
4.1.5. 3,30-Dibromo-5,50-di-tert-butyl-4,40-dimethoxy-2,20-dimethyl-
1,10-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 (6ꢂ50 mL)
and brine (6ꢂ50 mL), and dried (Na2SO4). The solvents were re-
moved under reduced pressure to yield a colourless solid (0.38 g,
98%); mp 123e125 ꢀC; nmax (film)/cmꢁ1 2956, 1459, 1359, 1258,
1223, 1044, 1003, 976, 908, 847, 734; 1H NMR (400 MHz, CDCl3):
1H NMR (400 MHz, CDCl3):
d
1.37 (18H, s, 2ꢂ ArC(CH3)3), 3.14 (6H, s,
2ꢂ ArOCH3), 3.82 (2H, d, J¼10.2 Hz, ArCH2Br), 3.88 (2H, d,
J¼10.2 Hz, ArCH2Br), 7.33 (2H, s, 2ꢂ CH arom., biphenyl-6,60), 7.90
(4H, d, J¼8.0 Hz, 4ꢂ CH arom., H12, H120and H8, H80 or H9, H90),
8.08 (2H, s, 2ꢂ CH arom., H8, H8 or H9, H90); 13C NMR (100 MHz,
CDCl3):
d
29.3 (2ꢂ CH2, 2ꢂ ArCH2Br2), 29.7 (6ꢂ CH3, 2ꢂ ArC(CH3)3),
34.4 (2ꢂ C quat., 2ꢂ ArC(CH3)3), 59.9 (2ꢂ OCH3, 2ꢂ ArOCH3), 120.6
(2ꢂ CH arom., septet, J¼3.7 Hz, C12, C120), 122.25 (2ꢂ C quat., q,
J¼271.4 Hz, 2ꢂ CF3),122.28 (2ꢂ C quat., q, J¼271.4 Hz, 2ꢂ CF3),129.2
(2ꢂ CH arom., biphenyl-6,60), 129.7 (2ꢂ CH arom., C8, C80or C9, C90),
130.1 (2ꢂ CH arom., C8, C80or C9, C90), 130.8 (2ꢂ C quat., arom., q,
J¼33.3 Hz, C10, C100 or C11, C110), 130.9 (2ꢂ C quat., arom., q,
J¼33.3 Hz, C10, C100 or C11, C110), 131.7 (2ꢂ C quat., arom., biphenyl-
3,30), 133.0 (2ꢂ C quat., arom., biphenyl-1,10), 134.8 (2ꢂ C quat.,
arom., biphenyl-5,50), 137.9 (2ꢂ C quat., arom., biphenyl-2,20), 142.9
(2ꢂ C quat., arom., C7, C70), 156.4 (2ꢂ C quat., arom., biphenyl-4,40);
m/z (FAB) 934.0871; C40H3679Br2F12O2 [MþH]þ requires 934.0890.
d
1.39 (18H, s, 2ꢂ ArC(CH3)3), 2.10 (6H, s, 2ꢂ ArCH3), 3.97 (6H, s, 2ꢂ
ArOCH3), 7.00 (2H, s, 2ꢂ CH arom., biphenyl-6,60); 13C NMR
(100 MHz, CDCl3):
d
21.0 (2ꢂ CH3, 2ꢂ ArCH3), 31.0 (6ꢂ CH3, 2ꢂ
ArC(CH3)3), 35.3 (2ꢂ C quat., 2ꢂ ArC(CH3)3), 61.5 (2ꢂ OCH3, 2ꢂ
ArOCH3), 122.0 (2ꢂ C quat., arom., biphenyl-3,30), 127.5 (2ꢂ CH
arom., biphenyl-6,60), 135.8 (2ꢂ C quat., arom., biphenyl-1,10), 137.7
(2ꢂ C quat., arom., biphenyl-5,50), 141.6 (2ꢂ C quat., arom., biphenyl-
2,20), 155.8 (2ꢂ C quat., arom., biphenyl-4,40); m/z (FAB) 510.0776;
C24H3279Br2O2 [MþH]þ requires 510.0769.
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)phenyl-
boronic 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 ammo-
nium chloride (30 mL), and extracted with diethyl ether (3ꢂ30 mL).
The combined organic extracts were washed with water (4ꢂ30 mL)
and brine (4ꢂ30 mL), dried (Na2SO4), and the solvents removed
under reduced pressure. The residue was purified by column chro-
matography 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-2,7-
dihydrodibenzo[c,e]azepine (18). -Acetonamine (17) (0.0600 g,
L
0.289 mmol) was added to a nitrogen-purged stirred solution of
dibromide (16) (0.250 g, 0.267 mmol), followed by potassium car-
bonate (0.110 g, 0.796 mmol) in dry acetonitrile (4 mL) at room
temperature. The reaction mixture was heated under reflux over-
night. The solvents were removed under reduced pressure and the
residue was diluted with dichloromethane (40 mL), washed with
water (2ꢂ30 mL) and brine (2ꢂ30 mL), dried (Na2SO4), and the
solvents removed under reduced pressure to give the product as an
orange foam (0.24 g, 91%); ½a D20
þ8.6 (c 0.93, CHCl3); nmax (film)/
ꢃ
cmꢁ1 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

766
M.M. Farah et al. / Tetrahedron 69 (2013) 758e769
H20), 1.21 (3H, s, CH3, H19 or H20), 1.37 (18H, s, 2ꢂ ArC(CH3)3),
1.90e1.91 (1H, m, NCH, H17), 2.99 (6H, s, 2ꢂ 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, 2ꢂ CH
arom., H22, H23), 7.00e7.02 (3H, m, 2ꢂ CH arom., H24, H25 and
H26), 7.33 (2H, s, 2ꢂ CH arom., biphenyl-6,60), 7.60 (2H, s, 2ꢂ CH
arom., H8, H8 or H9, H90), 7.86 (2H, s, 2ꢂ CH arom., H8, H8 or H9,
H90), 7.90 (2H, s, 2ꢂ CH arom., H12, H120); 13C NMR (100 MHz,
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 so-
lution 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 (3ꢂ30 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 chroma-
tography using ethyl acetate/petroleum ether (1:10) to afford the
product as a yellow solid (7.43 g, 85%); mp 36e37 ꢀC; nmax (film)/
cmꢁ1 3082, 1591, 1519, 1443, 1348, 1273, 1204, 1087, 1001, 860, 794,
CDCl3):
d
17.7 (CH3, C19 or C20), 27.9 (CH3, C19 or C20), 29.9 (6ꢂ
CH3, 2ꢂ ArC(CH3)3), 34.2 (2ꢂ C quat., 2ꢂ ArC(CH3)3), 48.7 (2ꢂ CH2,
2ꢂ ArCH2N), 57.9 (CH, NCH, C17), 59.7 (2ꢂ OCH3, 2ꢂ ArOCH3), 60.3
(CH2, C18), 73.4 (CH, ArCH, C16), 97.6 (C quat., C14), 120.1 (2ꢂ CH
arom., septet, J¼3.7 Hz, C12, C120), 122.2 (2ꢂ C quat., q, J¼271.3 Hz,
2ꢂ CF3), 122.4 (2ꢂ C quat., q, J¼271.3 Hz, 2ꢂ CF3), 124.7 (2ꢂ CH
arom., C22, C23), 125.6 (CH arom., C26), 126.4 (2ꢂ CH arom., C24,
C25), 126.7 (2ꢂ CH arom., biphenyl-6,60), 130.32 (2ꢂ CH arom., C8,
C80or C9, C90), 130.34 (4ꢂ C quat., arom., q, J¼33.3 Hz, C10,
C100eC11, C110), 130.5 (2ꢂ CH arom., C8, C80or C9, C90), 131.4 (2ꢂ C
quat., arom., biphenyl-3,30), 131.8 (2ꢂ C quat., arom., biphenyl-1,10),
136.2 (2ꢂ C quat., arom., biphenyl-2,20), 138.1 (2ꢂ C quat., arom.,
biphenyl-5,50), 139.2 (2ꢂ C quat., arom., C7, C70), 141.4 (C quat.,
arom., C21), 155.9 (2ꢂ C quat., arom., biphenyl-4,40).
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.
4.1.9. (4S,5S)-4,8-Bis-(3,5-bis-trifluoromethyl-phenyl)-2,10-di-tert-
butyl-6-(2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-3,9-dimethoxy-
5H-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-bis-
isobutyronitrile (0.00200 g, 0.0122 mmol) were added with stir-
ring 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 tetraphe-
nylborate (0.0870 g, 0.254 mmol) in a minimum amount of aceto-
nitrile 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%);
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,N-
dimethylformamide (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 (5ꢂ100 mL), water (4ꢂ50 mL),
and brine (3ꢂ50 mL), dried (Na2SO4), and the solvents removed
under reduced pressure to yield a dark crude oil. Column chro-
matography 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)/cmꢁ1 3086, 1604, 1524, 1458, 1350, 1279,
1219, 1106, 995, 859, 807, 736, 718, 674; 1H NMR (400 MHz, CDCl3):
mp 140e142 ꢀC (dec); ½a 2D0
ꢃ
ꢁ70.8 (c 0.52, CH3OH); nmax (film)/cmꢁ1
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, 2ꢂ CH arom.,
H22, H23), 6.75 (4H, t, J¼7.2 Hz, 4ꢂ CH arom., para in BPh4 gp.), 6.91
(10H, t, J¼7.4 Hz, 8ꢂ CH arom., ortho in BPh4 gp., and 2ꢂ CH arom.,
H24, H25), 6.97e6.99 (1H, m, CH arom.), 7.18e7.20 (8H, m, 8ꢂ 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
2.13 (6H, s, 2ꢂ CH3), 7.29 (2H, dd, J¼7.6, 1.4 Hz, 2ꢂ CH arom., bi-
phenyl-5,50), 7.36 (2H, ddd, J¼8.0, 7.6, 0.5 Hz, 2ꢂ CH arom., biphenyl-
6,60), 7.83 (2H, dd, J¼8.0, 1.4 Hz, 2ꢂ CH arom., biphenyl-4,40); 13C
NMR (100 MHz, CDCl3):
d
15.4 (2ꢂ CH3, 2ꢂ ArCH3), 123.1 (2ꢂ CH
arom., biphenyl-4,40),125.7 (2ꢂ CH arom., biphenyl-5,50),129.8 (2ꢂ C
quat., arom., biphenyl-2,20), 132.6 (2ꢂ CH arom., biphenyl-6,60), 141.3
(2ꢂ C quat., arom., biphenyl-1,10), 149.9 (2ꢂ C quat., arom., biphenyl-
3,30); m/z (EI) 272.0793; C14H12N2O4 (Mþ) requires 272.0797.
d
17.0 (CH3, C19 or C20), 27.1 (CH3, C19 or C20), 29.3 (3ꢂ CH3,
ArC(CH3)3), 29.8 (3ꢂ 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 (4ꢂ CH arom., para in BPh4 gp.),
122.2 (CH arom.),123.6 (CH arom.),124.5 (CH arom.),124.9 (C quat.),
125.1 (2ꢂ CH arom., C22, C23), 125.3 (8ꢂ CH arom., ortho in BPh4
gp.), 126.6 (C quat.), 128.0 (2ꢂ 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
(8ꢂ 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 (4ꢂ C quat., arom., q, J¼49.1 Hz, 4ꢂ C-
4.1.12. 3,30-Diamino-2,20-dimethyl-1,10-biphenyl (29). 2,20-Dimethyl-
3,30-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 (4ꢂ30 mL). The combined organic
layers were washed with water (2ꢂ30 mL) and brine (2ꢂ30 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)/cmꢁ1 3463 (NH), 3364 (NH), 1615, 1579,
1455, 793; 1H NMR (400 MHz, CDCl3):
d
1.79 (6H, s, 2ꢂ CH3), 3.51
(4H, s, 2ꢂ ArNH2), 6.51 (2H, dd, J¼7.7, 1.0 Hz, 2ꢂ CH arom., biphenyl-
4,40), 6.61 (2H, dd, J¼7.7, 1.0 Hz, 2ꢂ CH arom., biphenyl-6,60), 6.96

M.M. Farah et al. / Tetrahedron 69 (2013) 758e769
767
(2H, t, J¼7.7 Hz, 2ꢂ CH arom., biphenyl-5,50); 13C NMR (100 MHz,
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
(2ꢂ20 mL) and brine (2ꢂ20 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)/cmꢁ1 2359, 2340, 1378, 1277, 1175, 1132,
CDCl3):
d
12.8 (2ꢂ CH3, 2ꢂ ArCH3), 112.7 (2ꢂ CH arom., biphenyl-
4,40), 119.2 (2ꢂ CH arom., biphenyl-6,60), 119.6 (2ꢂ C quat., arom.,
biphenyl-2,20), 124.9 (2ꢂ CH arom., biphenyl-5,50), 141.9 (2ꢂ C quat.,
arom., biphenyl-1,10),143.5 (2ꢂ 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-dimethyl-
biphenyl-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 ad-
dition 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 (3ꢂ40 mL). The combined
organic extracts were washed with saturated aqueous sodium
thiosulfate (2ꢂ50 mL), water (2ꢂ50 mL), and brine (2ꢂ50 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)/cmꢁ1 3053, 2961, 2918, 1550, 1427,
1378, 1260, 1180, 1073, 1022, 988, 781, 718, 653; 1H NMR (400 MHz,
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, 2ꢂ
CH arom., biphenyl-4,40), 7.39 (2H, dd, J¼7.6, 1.5 Hz, 2ꢂ CH arom.,
biphenyl-6,60), 7.46 (2H, t, J¼7.6 Hz, 2ꢂ CH arom., biphenyl-5,50), 7.89
(2H, d, J¼0.6 Hz, 2ꢂ CH arom., H12, H120), 7.95 (4H, s, 4ꢂ CH arom.,
H8, H80e, H9, H90); 13C NMR (100 MHz, CDCl3):
d
28.6 (2ꢂ CH2, 2ꢂ
ArCH2Br2), 120.8 (2ꢂ CH arom., septet, J¼3.8 Hz, C12, C120), 122.2
(4ꢂ C quat., q, J¼271.2 Hz, 4ꢂ CF3), 127.6 (2ꢂ CH arom., biphenyl-
5,50), 128.4 (4ꢂ CH arom., C8, C80eC9, C90), 129.6 (2ꢂ CH arom.,
biphenyl-4,40), 129.8 (2ꢂ CH arom., biphenyl-6,60), 130.6 (4ꢂ C quat.,
q, J¼33.0 Hz, C10, C100eC11, C110),132.2 (2ꢂ C quat., arom., biphenyl-
2,20), 139.6 (2ꢂ C quat., arom., C7, C70), 139.7 (2ꢂ C quat., arom.,
biphenyl-3,30), 141.2 (2ꢂ C quat., arom., biphenyl-1,10); m/z (EI)
761.9429; C30H1679Br2F12 (Mꢁ) requires 761.9427.
CDCl3):
d
2.08 (6H, s, 2ꢂ CH3), 6.82 (2H, t, J¼7.8 Hz, 2ꢂ CH arom.,
biphenyl-5,50), 6.96 (2H, dd, J¼7.8, 1.0 Hz, 2ꢂ CH arom., biphenyl-
6,60), 7.76 (2H, dd, J¼7.8, 1.0 Hz, 2ꢂ CH arom., biphenyl-4,40); 13C
NMR (100 MHz, CDCl3):
d
24.9 (2ꢂ CH3, 2ꢂ ArCH3), 101.5 (2ꢂ C
4.1.16. (4S,5S)-4,8-Bis-(3,5-bis-trifluoromethyl-phenyl)-6-(2,2-
dimethyl-4-phenyl-[1,3]dioxan-5-yl)-6,7-dihydro-5H-dibenzo[c,e]
quat., arom., biphenyl-3,30),126.2 (2ꢂ CH arom., biphenyl-6,60),128.3
(2ꢂ CH arom., biphenyl-5,50), 137.6 (2ꢂ CH arom., biphenyl-4,40),
137.8 (2ꢂ C quat., arom., biphenyl-1,10), 141.5 (2ꢂ C quat., arom.,
biphenyl-2,20); m/z (EI) 433.9032; C14H12I2 (Mþ) requires 433.9028.
azepine (33). -Acetonamine (17) (0.170 g, 0.820 mmol) was added
L
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 dichloro-
methane (40 mL), washed with water (2ꢂ30 mL) and brine
(2ꢂ30 mL), dried (Na2SO4), and the solvents removed under reduced
pressure. Column chromatography of the crude oily residue using
ethyl acetate/petroleum ether (1:10) gavethe product as a colourless
4.1.14. 3,30-Bis-(3,5-(trifluoromethyl)phenyl)-2,20-dimethyl-1,10-bi-
phenyl (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 ni-
trogen gas. The reaction mixture was heated to 90 ꢀC overnight,
poured into saturated aqueous ammonium chloride (30 mL), and
extracted with diethyl ether (3ꢂ30 mL). The combined organic
extracts were washed with water (4ꢂ30 mL) and brine (4ꢂ30 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)/cmꢁ1 3057, 1617, 1578,
1454,1379,1280,1176,1134,1051, 899, 846, 799; 1H NMR (400 MHz,
foam (0.55 g, 90%); ½a D20
ꢃ
þ46.8 (c 0.83, CHCl3); nmax (film)/cmꢁ1 2961,
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, 2ꢂ CH arom., H22, H23), 6.96e7.04 (3H, m, 2ꢂ CH
arom., H24, H25 and H26), 7.17 (2H, dd, J¼7.6, 1.6 Hz, 2ꢂ CH arom.,
biphenyl-4,40), 7.38 (2H, t, J¼7.6 Hz, 2ꢂ CH arom., biphenyl-5,50), 7.43
(2H, dd, J¼7.6, 1.6 Hz, 2ꢂ CH arom., biphenyl-6,60), 7.70 (4H, br s, 4ꢂ
CH arom., H8, H80e, H9, H90), 7.89 (2H, s, 2ꢂ CH arom., H12, H120); 13C
CDCl3):
d
1.90 (6H, s, 2ꢂ CH3), 7.16 (2H, d, J¼7.3 Hz, 2ꢂ CH arom.,
biphenyl-4,40), 7.17 (2H, dd, J¼7.3, 1.0 Hz, 2ꢂ CH arom., biphenyl-
6,60), 7.28 (2H, t, J¼7.3 Hz, 2ꢂ CH arom., biphenyl-5,50), 7.76 (4H, s,
4ꢂ CH arom., H8, H80e, H9, H90), 7.81 (2H, s, 2ꢂ CH arom., H12,
NMR (100 MHz, CDCl3):
d
17.7 (CH3, C19), 27.8 (CH3, C20), 48.5 (2ꢂ
CH2, 2ꢂ ArCH2N), 58.1 (CH, NCH, C17), 60.2 (CH2, C18), 73.4 (CH,
ArCH, C16), 97.6 (C quat., C14), 120.2 (2ꢂ CH arom., septet, J¼3.8 Hz,
C12, C120), 122.3 (4ꢂ C quat., q, J¼271.4 Hz, 4ꢂ CF3), 124.8 (2ꢂ CH
arom., C22, C23), 125.7 (CH arom., C26), 126.4 (2ꢂ CH arom., C24,
C25), 126.5 (2ꢂ CH arom., biphenyl-5,50), 127.6 (2ꢂ CH arom., bi-
phenyl-6,60), 128.8 (4ꢂ CH arom., C8, C80eC9, C90), 129.0 (2ꢂ CH
arom., biphenyl-4,40), 130.4 (4ꢂ C quat., J¼33.0 Hz, 4ꢂ CCF3, C10,
C100eC11, C110), 131.9 (2ꢂ C quat., arom., biphenyl-2,20), 137.7 (2ꢂ C
quat., arom., C7, C70), 137.9 (2ꢂ C quat., arom., biphenyl-3,30), 141.3
(2ꢂ C quat., arom., biphenyl-1,10),142.7 (C quat., arom., C21); m/z (EI)
809.2176; C42H31F12NO2 (Mþ) requires 809.2163.
H120); 13C NMR (100 MHz, CDCl3):
d
17.8 (2ꢂ CH3, 2ꢂ ArCH3), 120.9
(2ꢂ CH arom., septet, J¼3.8 Hz, C12, C120), 123.4 (4ꢂ C quat., q,
J¼271.2 Hz, 4ꢂ CF3), 126.0 (2ꢂ CH arom., biphenyl-5,50), 129.0 (2ꢂ
CH arom., biphenyl-4,40), 129.5 (4ꢂ CH arom., C8, C80eC9, C90), 129.8
(2ꢂ CH arom., biphenyl-6,60), 131.6 (4ꢂ C quat., q, J¼33.0 Hz, C10,
C100eC11, C110), 133.1 (2ꢂ C quat., arom., biphenyl-2,20), 139.7 (2ꢂ C
quat., arom., C7, C70), 142.7 (2ꢂ C quat., arom., biphenyl-3,30), 144.2
(2ꢂ C quat., arom., biphenyl-1,10); m/z (EI) 606.1218; C30H18F12 (Mþ)
requires 606.1217.
4.1.15. 2,20-Bis-bromomethyl-3,30-bis-(3,5-(trifluoromethyl)phenyl)-
4.1.17. (4S,5S)-4,8-Bis-(3,5-bis-trifluoromethyl-phenyl)-6-(2,2-
dimethyl-4-phenyl-[1,3]dioxan-5-yl)-5H-dibenzo[c,e]azepinium tetra-
phenylborate (19). Azepine (33) (0.480 g, 0.593 mmol) was dis-
solved in carbon tetrachloride (3 mL). N-Bromosuccinimide (0.130 g,
1,10-biphenyl
(32). 3,30-Bis-(3,5-trifluoromethylphenyl)-2,20-di-
methyl-1,10-biphenyl (30) (0.230 g, 0.379 mmol) was dissolved in
carbon tetrachloride (5 mL). N-Bromosuccinimide (0.150 g,

768
M.M. Farah et al. / Tetrahedron 69 (2013) 758e769
ꢀ
2. Bohe, L.; Hanquet, G.; Lusinchi, M.; Lusinchi, X. Tetrahedron Lett. 1993, 34,
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 re-
duced 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,
ꢀ
7271e7274; Bohe, L.; Lusinchi, M.; Lusinchi, X. Tetrahedron 1999, 55,
141e154.
3. Aggarwal, V. K.; Wang, M. F. Chem. Commun. 1996, 191e192; Gluszynska, A.;
Mackowska, I.; Rozwadowska, M. D.; Sienniak, W. Tetrahedron: Asymmetry
2004, 15, 2499e2505; Biscoe, M. R.; Breslow, R. J. Am. Chem. Soc. 2005, 127,
10812e10813; Minakata, S.; Takemiya, A.; Nakamura, K.; Ryu, I.; Komatsu, M.
Synlett 2000, 1810e1812; Wong, M.-K.; Ho, L.-M.; Zheng, Y.-S.; Ho, C.-Y.; Yang,
D. Org. Lett. 2001, 16, 2587e2590; Crosthwaite, J. M.; Farmer, V. A.; Hallett, J. P.;
Welton, T. J. Mol. Catal. A 2008, 279, 148e152; Lacour, J.; Monchaud, D.; Marsol,
C. Tetrahedron Lett. 2002, 43, 8257e8260; Novikov, R.; Lacour, J. Tetrahedron:
Asymmetry 2010, 21, 1611e1618; Novikov, R.; Vachon, J.; Lacour, J. Chimia 2007,
61, 236e239; Vachon, J.; Lauper, C.; Ditrich, K.; Lacour, J. Tetrahedron: Asym-
metry 2006, 17, 2334e2338; Vachon, J.; Rentsch, S.; Martinez, A.; Marsol, C.;
Lacour, J. Org. Biomol. Chem. 2007, 5, 501e506.
67%); mp 221e222 ꢀC (dec); ½a D20
ꢁ144.1 (c 1.00, CH3CN); found: C,
ꢃ
67.96; H, 4.38; N, 1.21. C66H50BF12NO2$2H2O requires C, 68.11; H,
4.68; N, 1.20%; nmax (film)/cmꢁ1 3054, 1632, 1579, 1479, 1450, 1377,
4. Armstrong, A.; Ahmed, G.; Garnett, I.; Goacolou, K. Synlett 1997, 1075e1076;
Armstrong, A.; Ahmed, G.; Garnett, I.; Goacolou, K.; Wailes, S. Tetrahedron 1999,
55, 2341e2352.
1
1278, 1183, 1139, 902; H 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
5. Page, P. C. B.; Rassias, G. A.; Bethell, D.; Schilling, M. B. J. Org. Chem. 1998, 63,
2774e2777; Page, P. C. B.; Rassias, G. A.; Barros, D.; Bethell, D.; Schilling, M. B. J.
Chem. Soc., Perkin Trans. 1 2000, 3325e3334; Page, P. C. B.; Rassias, G. A.; Barros,
D.; Ardakani, A.; Buckley, B.; Bethell, D.; Smith, T. A. D.; Slawin, A. M. Z. J. Org.
Chem. 2001, 66, 6926e6931; Page, P. C. B.; Buckley, B. R.; Heaney, H.; Blacker, A.
J. Org. Lett. 2005, 7, 375e377; Page, P. C. B.; Buckley, B. R.; Appleby, L. F.; Alsters,
P. A. Synthesis 2005, 3405e3411; Page, P. C. B.; Buckley, B. R.; Rassias, G. A.;
Blacker, A. J. Eur. J. Org. Chem. 2006, 803e813.
(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, 2ꢂ CH arom.), 6.85 (4H, t, J¼7.2 Hz, 4ꢂ
CH arom., para in BPh4 gp.), 6.91e6.97 (3H, m, 3ꢂ CH arom.), 7.02
(8H, t, J¼7.6 Hz, 8ꢂ CH arom., ortho in BPh4 gp.), 7.28e7.35 (9H, m,
CH arom., and 8ꢂ 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, 2ꢂ CH
arom.), 8.00e8.06 (3H, m, 3ꢂ 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
6. Page, P. C. B.; Rassias, G. R.; Barros, D.; Ardakani, A.; Bethell, D.; Merifield, E.
Synlett 2002, 580e582.
7. Page, P. C. B.; Buckley, B. R.; Blacker, A. J. Org. Lett. 2004, 6, 1543e1546; Page, P.
C. B.; Buckley, B. R.; Farah, M. M.; Blacker, A. J. Eur. J. Org. Chem. 2009,
3413e3426.
8. Page, P. C. B.; Barros, D.; Buckley, B. R.; Ardakani, A.; Marples, B. A. J. Org. Chem.
2004, 69, 3595e3597; Page, P. C. B.; Buckley, B. R.; Barros, D.; Blacker, A. J.;
Heaney, H.; Marples, B. A. Tetrahedron 2006, 62, 6607e6613; Page, P. C. B.;
Buckley, B. R.; Barros, D.; Blacker, A. J.; Marples, B. A.; Elsegood, M. R. J. Tetra-
hedron 2007, 63, 5386e5393; Page, P. C. B.; Barros, D.; Buckley, B. R.; Marples,
B. A. Tetrahedron: Asymmetry 2005, 16, 3488e3491.
9. Page, P. C. B.; Parker, P.; Buckley, B. R.; Rassias, G. A. Adv. Synth. Catal. 2008, 350,
1867e1874.
10. Page, P. C. B.; Parker, P.; Buckley, B. R.; Rassias, G. A. Tetrahedron 2009, 50,
2910e2915.
NMR (100 MHz, DMSO-d6):
d 18.0 (CH3, C19 or C20), 27.2 (CH3, C19
or C20), 57.4 (2ꢂ CH2, 2ꢂ ArCH2N), 62.8 (CH2, C18), 66.6 (CH, NCH,
C17), 70.7 (CH, ArCH, C16), 99.6 (C quat., C14), 121.5 (4ꢂ 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 (8ꢂ 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 (8ꢂ 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 (4ꢂ
C quat., arom., J¼49.1 Hz, 4ꢂ C-B ipso in BPh4 gp.), 167.7 (HC]N); m/
z (ESI) 808.2078; C42H30F12NO2 (cation) requires 808.2079.
11. Page, P. C. B.; Marken, F.; Williamson, C.; Chan, Y.; Buckley, B. R.; Bethell, D. Adv.
Synth. Catal. 2008, 350, 1149e1154.
12. Page, P. C. B.; Appleby, L. F.; Day, D. P.; Chan, Y.; Buckley, B. R.; Allin, S. M.;
McKenzie, M. J. Org. Lett. 2009, 11, 1991e1993.
13. Page, P. C. B.; Bartlett, C. J.; Chan, Y.; Day, D.; Allin, S. M.; McKenzie, M. J. J. Org.
Chem. 2012, 77, 772e774.
14. Adamo, M. F. A.; Aggarwal, V. K.; Sage, M. A. J. Am. Chem. Soc. 2000, 122,
8317e8318; Adamo, M. F. A.; Aggarwal, V. K.; Sage, M. A. J. Am. Chem. Soc. 2002,
124, 11223; Aggarwal, V. K.; Lopin, C.; Sandrinelli, F. J. Am. Chem. Soc. 2003, 125,
7596e7601.
15. Page, P. C. B.; Farah, M. M.; Buckley, B. R.; Blacker, A. J.; Lacour, J. Synlett 2008,
1381e1385; Gonc¸ alves, M. H.; Martinez, A.; Grass, S.; Page, P. C. B.; Lacour, J.
Tetrahedron Lett. 2006, 47, 5297e5301.
4.2. General procedure for the catalytic asymmetric epoxi-
dation 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.
16. Ho, C. Y.; Chen, Y. C.; Wong, M. K.; Yang, D. J. Org. Chem. 2005, 70, 898e906.
17. Vachon, J.; Perollier, C.; Monchaud, D.; Marsol, C.; Ditrich, K.; Lacour, J. J. Org.
ꢀ
Chem. 2005, 70, 5903e5911.
18. For reviews see: (a) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002,
3221e3236; (b) Mikami, K.; Aikawa, K.; Yusa, Y.; Jodry, J. J.; Yamanaka, M.
Synlett 2002, 1561e1578.
19. Adams, R.; Yuan, H. C. Chem. Rev. 1933, 12, 261e338.
20. (a) Lygo, B.; Allbutt, B.; James, S. R. Tetrahedron Lett. 2003, 44, 5629e5632; (b)
Lygo, B.; Bryan, A. Synlett 2004, 326e328.
ꢀ
21. Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,
1359e1469.
22. See for example Smrcina, M.; Lorenc, M.; Hanus, V.; Sedmera, P.; Kocovsky, P. J.
Org. Chem. 1992, 57, 1917e1920.
ꢀ
ꢀ
23. Smrcina, M.; Polakova, J.; Vyskocil, S.; Kocovsky, P. J. Org. Chem. 1993, 58,
4534e4538.
24. (a) Noji, M.; Nakajima, M.; Koga, K. Tetrahedron Lett. 1994, 35, 7983e7984; (b)
Nakajima, M.; Kanayama, K.; Miyoshi, I.; Hashimoto, S.-I. Tetrahedron Lett. 1995,
36, 9519e9520; (c) Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S.-I.;
Noji, M.; Koga, K. J. Org. Chem. 1999, 64, 2264e2271.
Acknowledgements
25. Crystallography for 12: C22H28Br2O2, M¼484.26, triclinic, Pꢁ1, a¼8.4330(5),
This investigation has enjoyed the support of NPIL Pharmaceu-
ticals (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.
ꢁ
b¼11.2668(7), c¼24.0261(14) A,
a¼92.7306(10),
b
¼98.3758(9),
g¼102.
3
ꢀ
ꢁ
7227(9) , V¼2195.5(2) A , Z¼4, 23,572 data measured, Rint¼0.0356, wR2¼0.
0924 for all 11,380 unique data, R1¼0.0372 for 8281 data with F2ꢄ2
s
(F2). CCDC
895411 contains supplementary crystallographic data in cif format. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK. Fax þ44 1223
336033, e-mail: deposit@ccdc.cam.ac.uk.).
References and notes
26. Ooi, T.; Uematsu, Y.; Maruoka, K. J. Org. Chem. 2003, 68, 4576e4578.
27. Ooi, T.; Uematsu, Y.; Kameda, M.; Maruoka, K. Tetrahedron 2006, 62,
11425e11436.
1. Hanquet, G.; Lusinchi, X.; Millet, P. Tetrahedron Lett. 1987, 28, 6061e6064;
Hanquet, G.; Lusichi, X.; Millet, P. Tetrahedron Lett. 1988, 29, 3941e3944; Han-
quet, C.; Lusinchi, X.; Milliet, P. C. R. Acad. Sci. Paris 1991, 313, 625e628; Lusinchi,
X.; Hanquet, G. Tetrahedron 1997, 53, 13727e13738.
ꢀ
28. (a) Jaquinod, L.; Prevot, L.; Fischer, J.; Weiss, R. Inorg. Chem. 1998, 37,
1142e1149; (b) Dizabo, P.; Mouneyra, M. F. Bull. Soc. Chim. Fr. 1968, 2957e2962;

M.M. Farah et al. / Tetrahedron 69 (2013) 758e769
769
(c) Ooi, T.; Ohara, D.; Tamura, M.; Maruoka, K. J. Am. Chem. Soc. 2004, 126,
6844e6845.
31. For reviews see: Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265e555.
32. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923e2925.
29. Ullmann, F.; Bielecki, J. Ber. Dtsch. Chem. Ges. 1901, 34, 2174e2185.
30. For reviews see: (a) Fanta, P. Chem. Rev. 1964, 64, 613e632; (b) Fanta, P. E.
Synthesis 1974, 9e21.
33. Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148e13149.
34. Fuson, R. C.; Cleveland, E. A. Organic Syntheses; Wiley: New York, NY, 1955;
Collect. Vol. No. 3; 339e340.