Synthesis and evaluation of atropos dihydro-5H-dibenzazepinium halide PTCs derived from α-methylbenzylamine

Article abstract of DOI:10.1039/c2ob25437a

A short synthetic route to diastereoisomeric atropos dihydro-5H-dibenz[c,e] azepinium salts via reaction of a single enantiomer of (R)-α- methylbenzylamine with a racemic atropos biphenol derivative is described. Compounds prepared via this approach are used to provide strong evidence that structurally related tropos dihydro-5H-dibenz[c,e]azepinium salts preferentially react via a single conformation in PTC reactions involving glycine imine enolates.

Full text of DOI:10.1039/c2ob25437a

View Article Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Organocatalysis
web themed issue
Guest editors: Professors Keiji Maruoka, Hisashi
Yamamoto, Liu-Zhu Gong and Benjamin List
All articles in this issue will be gathered together online at
www.rsc.org/organocatalysis

Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 4968
www.rsc.org/obc
PAPER
Synthesis and evaluation of atropos dihydro-5H-dibenzazepinium halide
PTCs derived from α-methylbenzylamine†‡
Barry Lygo,* Umar Butt and Maria Cormack
Received 28th February 2012, Accepted 9th May 2012
DOI: 10.1039/c2ob25437a
A short synthetic route to diastereoisomeric atropos dihydro-5H-dibenz[c,e]azepinium salts via reaction
of a single enantiomer of (R)-α-methylbenzylamine with a racemic atropos biphenol derivative is
described. Compounds prepared via this approach are used to provide strong evidence that structurally
related tropos dihydro-5H-dibenz[c,e]azepinium salts preferentially react via a single conformation in
PTC reactions involving glycine imine enolates.
because the dihydro-5H-dibenz[c,e]azepinium ring adopts a
single atropisomeric form in the reaction transition state.
Introduction
Asymmetric phase transfer catalysis (PTC) has proved to be an
extremely powerful method for the stereoselective construction
of C–C bonds. Much of this methodology is based on the use of
chiral quaternary ammonium salts and most commonly these are
derived from either cinchona alkaloids, chiral (atropos) biaryl
However, until now we have not been able to provide strong
evidence to support this hypothesis. In this paper we describe
the development of a synthetic route that allows rapid access to
both diastereoisomers of atropos analogues of compound 2 and
discuss how compounds generated in this way have allowed
greater insight into the mode of action of catalysts 1 and 2.
1
fragments, or tartaric acid derivatives. In an effort to expand the
range of useful chiral quaternary ammonium salt architectures
we have been seeking to develop effective PTCs based on
simple commercially-available chiral amines. During the course
of these studies we were able to demonstrate that 1 mol% of qua-
ternary ammonium salt 1 (X = Br), derived from α-methyl
naphthylamine, was capable of promoting the enantioselective
Discussion
Studies in our group established that catalysts lacking the
4
,4′-methoxy and 5,5′-tert-butyl substituents in structure 2 were
also capable of delivering respectable levels of enantioselectivity
2
PTC alkylation of glycine imine esters. Follow up studies
6
(>80% e.e.) in the alkylation of glycine imines. Based on this
demonstrated that the same catalyst could also be utilised for the
enantioselective Michael addition of glycine imine esters to
observation, we initially identified structures 3–6 (Fig. 1) as
close analogues of PTC 2. It was considered that these structures
should be accessible from the readily-available racemic biphenol
3
α,β-unsaturated ketones, and that related PTC salt 2 (X = I, Br)
was also capable of delivering high enantioselectivity in these
1
4 via two related approaches. The first of these (Scheme 1)
4
processes.
7
would start with the resolution of biphenol 14. Regioselective
electrophilic substitution of the aryl rings, followed by radical
bromination would then allow access to key intermediates 8
and 11. Conversion into the dihydro-5H-dibenz[c,e]azepinium
salts 3 and 5 could then be achieved by reacting with
A key feature of structures 1 and 2 is the conformationally-
labile (tropos) dihydro-5H-dibenz[c,e]azepinium ring incorporat-
ing the amino group of the chiral amine precursor. This fragment
allows the possibility to fine-tune the catalyst by variation of the
substituents attached to the aromatic rings and also appears to be
(
3
R)-α-methylbenzylamine followed by introduction of the bis-
,5-trifluoromethylphenyl groups via Suzuki–Miyaura coupling
2
,5
essential for high enantioselectivity. Given that conformation-
ally-fixed (atropos) dihydro-5H-dibenz[c,e]azepinium salts have
proved spectacularly successful in a wide range of PTC proces-
4
and N-quaternization. The diastereoisomeric salts 4 and 6 could
be prepared simply by taking the other enantiomer of diether 13
through the same sequence of reactions. This approach is analo-
1
a–c
ses,
it seems likely that catalysts 1 and 2 are effective
8
gous to that previously reported by Maruoka and has the advan-
tage that it proceeds via a chiral diether 13 with known absolute
stereochemistry, consequently the stereochemistry of any result-
ing dihydro-5H-dibenz[c,e]azepinium salts would be known
with certainty.
The second approach (Scheme 2) would involve generating
the tetra-bromide intermediates 8 and 11 as racemates. These
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD,
UK. E-mail: b.lygo@nottingham.ac.uk; Fax: +44 (0)115 9513564;
Tel: +44 (0)115 9515000
†
This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
Electronic supplementary information (ESI) available: NMR and
HPLC data. See DOI: 10.1039/c2ob25437a
‡
4968 | Org. Biomol. Chem., 2012, 10, 4968–4976
This journal is © The Royal Society of Chemistry 2012

Scheme 3
Scheme 4
Fig. 1
Scheme 5
salts 3–6 could be prepared in fewer steps overall (e.g. 8 steps
vs. 13 steps for compounds 3 and 4) and eliminates the need for
a resolution of the starting biphenol 14. Clearly this second
approach would be more efficient, but in order for it to be useful
it would either require kinetic resolution in the formation of
the diastereoisomeric dihydro-5H-dibenz[c,e]azepines 7/15 and
9
1
0/16, or for them to be readily separable.
We also considered that it may also be possible to interconvert
Scheme 1
the diastereoisomeric dihydro-5H-dibenz[c,e]azepine intermedi-
ates (e.g. 7 and 15) via thermal isomerisation. This would open
up the possibility of converting a racemic atropos biaryl precur-
sor such as 8 into a single diastereoisomeric atropos dihydro-
5
H-dibenz[c,e]azepine product. With this in mind it was interest-
ing to note that the related dihydro-5H-dibenz[c,e]oxepine 17
has been reported to undergo thermal isomerisation at >100 °C
whereas the corresponding quaternary ammonium salt 18
10
requires substantially higher temperatures (Scheme 3).
Given these potential advantages we opted to investigate the
approach outlined in Scheme 2. Thus this study started with the
attempted preparation of the key intermediates 9 and 12. To this
end, racemic biphenol 14 and the corresponding dimethylether
7,8
1
3 were prepared as previously described. These were then
converted into intermediates 9 and 19 via regioselective electro-
philic bromination (Scheme 4). We next attempted to introduce
the tert-butyl substituents via Friedel–Crafts alkylation. A range
Scheme 2
+
of conditions were investigated (e.g. t-BuOH–H , iso-butene–
+
11,12
H ),
but all failed to deliver the desired product. All attempts
would then be reacted with (R)-α-methylbenzylamine to give the
dihydro-5H-dibenz[c,e]azepines 7, 10, 15 and 16 which in turn
could be converted into the target dihydro-5H-dibenz[c,e]azepi-
nium salts 3–6 as outlined above. This has the advantage that
to reverse the steps and introduce the tert-butyl substituents prior
to bromination were also unsuccessful.
In order to circumvent this problem intermediate 12 was pre-
13
pared from the known biphenol 20, (Scheme 5).
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4968–4976 | 4969

Scheme 8
Scheme 6
3
Table 1 Quaternization of 21–24 with CH I
Substrate
Time (h)
Product
Yield (%)
21
22
23
24
9
2
24
3
3
4
5
6
36
76
38
74
Scheme 7
Intermediates 9 and 12 were then subjected to radical bromi-
nation, followed by coupling with (R)-α-methylbenzylamine
Suzuki–Miyaura coupling. It was found that all four substrates
reacted at a similar rate, the lower isolated yields for the (aS,R)-
diastereoisomers 22 and 24 again appeared to be a consequence
of the fact that these compounds were significantly more polar
that the corresponding (aR,R)-diastereoisomers 21 and 23.
When the quaternization of these products with methyl iodide
was attempted, a significant difference in reactivity was observed
(Table 1). It was found that the (aS,R)-dihydro-5H-dibenz[c,e]
azepines 22 and 24 reacted rapidly with methyl iodide at 80 °C
(100% conversion after 2–3 h), whereas the (aR,R)-isomers
reacted sluggishly (<40% conversion after 9 h at 80 °C).
Attempts to force the latter reactions to completion simply led to
substantial decomposition of the products and failed to improve
the isolated yields.
The low reactivity of the (aR,R)-dihydro-5H-dibenz[c,e]aze-
pines 21 and 23 towards methyl iodide, coupled with their sig-
nificantly shorter retention times on silica gel chromatography
suggests that the N-lone-pair in these compounds is significantly
less accessible than the corresponding N-lone-pair in the (aS,R)-
diastereoisomers 22 and 24.
With atropos salts 3–6 prepared we were then able to compare
their efficiency as phase-transfer catalysts with the corresponding
tropos salt 2. For this purpose we selected the alkylation of
glycine imine ester 25 under conditions previously optimised for
salts 1 and 2. The results are shown in Scheme 9. To aid com-
parison of the structures we have also included results obtained
using the related tropos salts 27 and 28.
It was found that all the atropos salts (3–6) were inferior PTC
catalysts compared with the tropos salt 2. In addition, salt 6
exhibited poor solubility in organic solvents such as toluene and
chloroform, which further compromised its ability to act as a
PTC. After 3 h at 0 °C the alkylation was complete when
1 mol% of catalyst 2 was used, whereas with all the other catalysts
(Scheme 6). This generated the desired dihydro-5H-dibenz[c,e]
azepine intermediates 7, 10, 15 and 16 in high overall yield. No
kinetic resolution was observed in the second step of this
sequence, but gratifyingly the diastereoisomeric pairs 7/15 and
1
0/16 were readily separated by chromatography on silica gel.
The slightly lower isolated yield of compound 15 compared with
its diastereoisomer 7 simply reflects the greater difficulty of re-
covering the more polar diastereoisomer from the silica gel
chromatography.
In order to assign the stereochemistry of the diastereoisomeric
products, compounds 7 and 15 were also prepared using the
1
approach outlined in Scheme 1. Comparison of H NMR and
1
4
[
(
α] values established that the less polar diastereoisomers had
D
aR,R)-stereochemistry and the more polar diastereoisomers
possess (aS,R)-stereochemistry.
With an efficient route to these key intermediates in hand we
next investigated the thermal interconversion of compounds 7
and 15. Starting with either diastereoisomer, it was found that
heating to 170 °C (bath temperature) in xylene was required to
effect interconversion. Under these conditions, the equilibrium
ratio slightly favoured the (aR,R)-diastereoisomer 7 (Scheme 7).
This confirms the atropos nature of the dihydro-5H-dibenz[c,e]
azepines 7 and 15, but also offers the possibility of cycling
material between these two structures if required. Attempts to
interconvert the more highly substituted dihydro-5H-dibenz[c,e]
azepines 10 and 16 were unsuccessful.
Conversion of the dihydro-5H-dibenz[c,e]azepines 7, 10, 15
and 16 into the target quaternary ammonium salts 3–6 was then
effected using procedures analogous to those previously devel-
4
oped for the synthesis of compound 2 (Scheme 8). The 3,5-bis-
trifluoromethylphenyl substituents were first introduced via
4970 | Org. Biomol. Chem., 2012, 10, 4968–4976
This journal is © The Royal Society of Chemistry 2012

Scheme 9
the reaction was incomplete after this time period. Most signifi-
cantly the reactions involving catalysts with the (aR,R)-stereo-
chemistry (3 and 5) were found to be very sluggish, giving low
conversion and low isolated yields. These catalysts also appear to
favour the opposite (S) enantiomer of the product 26 as evidenced
by the result observed using (aR,R)-3. The difference in reactivity
and enantioselectivity between the diastereoisomeric catalysts
(aR,R)-3 and (aS,R)-4 seems to confirm the hypothesis that the
dihydro-5H-dibenz[c,e]azepinium fragment in these structures
plays a key role in influencing both reactivity and enantioselectiv-
ity. In this respect these α-methylbenzylamine derived catalysts
appear to show similar characteristics to conformationally flexible
spirobinaphthyl ammonium salts reported by the Maruoka
Fig. 2
15
group. Taken together, these results suggest that reactions invol-
ving the tropos quaternary ammonium salts 2, 27 and 28 proceed
preferentially via ion-pair intermediates in which the dihydro-5H-
dibenz[c,e]azepinium ring adopts an (aS)-conformation. In this
way the stereochemical information in the starting α-methylbenzy-
lamine is amplified to a level that results in high enantioselectivity
in the PTC alkylation.
Based on this information, we can now propose a model for
how tropos quaternary ammonium salts 1 and 2 might interact
with the enolate derived from glycine imine 25 (Fig. 2).
This model is based on the assumption that the most favourable
ion-pair is the one with the greatest electrostatic interaction
energy, and that the positive charge in a quaternary ammonium
salt resides predominantly on the H-atoms neighbouring the
1
6
quaternary ammonium centre. Molecular modelling studies on
quaternary ammonium salt 2 with the dihydro-5H-dibenz[c,e]
azepinium ring in the (aS)-conformation, suggest that the most
accessible positive charge lies on a surface comprising four
H-atoms (the CH indicated, and two H-atoms in the N-CH3
2
Fig. 3
group) adjacent to the quaternary ammonium centre. Modelling
of ion-pairs involving this surface suggest that arrangement
1
7
depicted in Fig. 2 provides the best fit. In this arrangement the
si-face of the enolate is blocked, which is consistent with the
sense of enantioselectivity observed in both alkylation and
Michael addition processes involving glycine imine 25 and
PTCs 1 and 2.
have less favourable overlap of the positive and negative charged
surfaces. This is consistent with experimental results which
indicate that alkylation via this arrangement is highly
disfavoured.
17
In contrast, an analogous ion-pair arrangement in which the
quaternary ammonium salt 2 has the dihydro-5H-dibenz[c,e]aze-
pinium ring in the (aR)-conformation would have the re-face of
the enolate blocked (Fig. 3). This is consistent with the obser-
vation that atropos (aR)-analogues of 2 favour the opposite enan-
tiomer in the glycine imine alkylation (Scheme 9). This ion-pair
Conclusions
In conclusion, we have developed a short synthetic route to dia-
stereoisomeric atropos dihydro-5H-dibenz[c,e]azepinium salts
via reaction of a single enantiomer of (R)-α-methylbenzylamine
with racemic atropos biphenol derivatives. Compounds prepared
−1
arrangement is predicted to be >10 kcal mol less stable and
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4968–4976 | 4971

via this approach have provided strong evidence that structurally
related tropos dihydro-5H-dibenz[c,e]azepinium salts preferen-
tially react via a single conformation in PTC reactions involving
glycine imine enolates. The intermediate atropos dihydro-5H-
dibenz[c,e]azepines 7, 10, 15, 16 also have the potential to
serve as precursors for a range of other organocatalyst structures
chromatography on silica gel (petroleum ether) to give the
product (23.4 mg, 74%) as a white solid, m.p. 144–145 °C; R
f
−1
0.5 (98 : 2 petroleum ether–EtOAc); νmax(CHCl )/cm 3011,
3
1602; δH (400 MHz, CDCl ) 7.54 (2H, s, ArH), 3.13 (6H, s,
3
OCH ), 2.09 (6H, s CH ), 1.37 (18H, s, C(CH ) ); δ
C
3
3
3 3
(100 MHz, CDCl ) 157.0 (C), 142.7 (C), 135.7 (C), 133.4 (C),
3
18
(
e.g. chiral iminium salts for asymmetric epoxidation, chiral
130.4 (CH), 119.4 (C), 59.5 (CH ), 35.0 (C), 30.5 (CH ), 20.6
3
3
19
+
81
+
secondary and tertiary amines for asymmetric aldol chemistry )
and studies into these applications will be reported in due
course.
(CH ); m/z (ESI) 537 (M + Na , Br , 44), 535 (M + Na ,
3 2
8
1
79
+ 79
Br Br, 100), 533 (M + Na , Br , 52%); m/z (ESI) found
2
+
81 79
+
[M + Na] 535.0628, C H
Br BrO Na requires 535.0641.
2
24
32
Experimental
(
± ±-5,5′-Dibromo-6,6′-bis(bromomethyl±-2,2′-
General
dimethoxybiphenyl, 8
All solvents and chemicals were used as provided by the sup-
plier. Reactions were monitored by thin layer chromatography
using Merck silica gel 60 F254 pre-coated glass TLC plates, visu-
alized using UV light and then basic potassium permanganate
solution. Flash chromatography was performed using Merck
silica gel (230–400 mesh) as the stationary phase. Melting points
were determined using a Kofler hot-stage apparatus and are
uncorrected. Infrared spectra were recorded using either a
Perkin-Elmer FT 1600 or a Nicolet Avatar 360 FT-IR infrared
A
stirred solution of (±)-5,5′-dibromo-2,2′-dimethoxy-6,6′-
dimethylbiphenyl 9 (2.67 g, 6.68 mmol) in CCl (25 mL) was
4
placed under a nitrogen atmosphere. NBS (2.73 g, 15.3 mmol)
was added followed by AIBN (38 mg). The mixture was stirred
at reflux, heated by light bulb irradiation, (100 W bulb, 1 cm
from flask) for 2 h. After cooling to room temperature, the
mixture was filtered through a short plug of silica, washing
through with CCl (3 × 60 mL). The solution was concentrated
4
under reduced pressure and the residue purified by chromato-
graphy on silica gel (9 : 1 petroleum ether–EtOAc) to give the
product 15 (2.82 g, 76%) as a white solid, m.p. 203–206 °C;
νmax(neat)/cm− 3004, 2933, 2835, 1567; δ (400 MHz, CDCl )
1
13
spectrophotometer. H NMR and
C NMR spectra were
recorded on a Bruker AV3400 or DPX400 spectrometer at
ambient temperature. Chemical shifts are quoted relative to
residual solvent and J values are given in Hz. Multiplicities are
designated by the following abbreviations: s, singlet; d, doublet;
t, triplet; q, quartet; br., broad; m, multiplet. Mass spectra were
obtained on a Micromass Autospec or Micromass LCT instru-
ments using electron impact (EI) or electrospray (ES) ionization.
Specific rotations were measured using a Bellingham and
Stanley ADP440 polarimeter at ambient conditions and are
1
H
3
7
.64 (2H, d, J 9.0, ArH), 6.87 (2H, d, J 9.0, ArH), 4.26 (2H, d,
J 10.0, CH H Br), 4.24 (d, J 10.0, CH H Br), 3.71 (6H, s,
OCH ); δC (100 MHz, CDCl ) 156.4 (C), 135.8 (C), 134.0
a
b
a b
3
3
(CH), 126.6 (C), 116.3 (C), 112.7 (CH), 56.0 (CH ), 32 (CH );
3 2
+
79 81
+
79
81
m/z (EI) 560 (M , Br Br , 28), 558 (M , Br2 Br , 43), 556
3
2
+
79
81
(M , Br3 Br, 30), 275 (100), 273 (40), 86 (57), 84 (93%);
Found: C, 34.47; H, 2.49, Calc for C H Br O : C, 34.45; H,
16
14
4 2
2
−1
given in units of deg cm g ; c is in g per 100 mL of solvent.
HPLC analysis was performed on Hewlett-Packard
2
.53%.
a
LC-1100 machine fitted with a diode array detector. All e.e.s
were determined by HPLC comparison with racemates using a
Chiralcel OD-H analytical column. HPLCs were run in duplicate
and the ratio of integrals checked for consistency at four separate
wavelengths (220 nm, 232 nm, 254 nm, 280 nm). DFT calcu-
lations were performed using B3LYP/6-31G* as implemented in
(
± ±-5,5′-Dibromo-6,6′-bis-(bromomethyl±-3,3′-di-tert-butyl-2,2′-
dimethoxybiphenyl, 11
A stirred solution of (±)-biphenyl 12 (1.52 g, 2.97 mmol) in
CCl (15 mL) was placed under a nitrogen atmosphere. NBS
(
0
bulb irradiation, (100 W bulb, 1 cm from flask) for 3 h. After
cooling to room temperature, the mixture was filtered through
silica, washing through with Et O (3 × 30 mL). The solution
4
20
Spartan ′10 v1.1.0. Biphenol 14 was prepared and resolved as
1.16 g, 6.53 mmol) was added followed by AIBN (17.1 mg,
.10 mmol). The mixture was stirred at reflux, heated by light
7
previously described. Diethers (±)-9, (aS)-9, (aR)-9, were all
prepared from 14 following the procedure previously reported
8
for the (aS)-isomer. Biphenol 20 was prepared as previously
13
described.
2
was concentrated under reduced pressure and the residue purified
by chromatography on silica gel (98 : 2 petroleum ether–EtOAc)
to give the product (1.99 g, 100%) as a yellow solid,
(
± ±-5,5′-Dibromo-3,3′-di-tert-butyl-2,2′-dimethoxy-6,6′-
dimethylbiphenyl, 12
m.p. 67–68 °C; R 0.3 (98 : 2 petroleum ether–EtOAc); νmax(neat)/
f
−1
A mixture of 5,5′-dibromo-3,3′-di-tert-butyl-2,2′-dihydroxy-6,6′-
dimethylbiphenyl 20 (29.7 mg, 0.06 mmol) and anhydrous
K CO (25.4 mg, 0.18 mmol) in dry DMF (1 mL) was placed
cm 2967, 1602; δH (400 MHz, CDCl ) 7.68 (2H, s, ArH),
3
4.35 (2H, d, J 10.5, CHaHbBr), 4.31 (2H, d, J 10.5, CHaHbBr),
3.23 (6H, s, OCH ), 1.40 (18H, s, C(CH ) ); δ (100 MHz,
2
3
3
3 3
C
under argon. MeI (10 μl, 0.15 mmol) was added and the mixture
stirred at room temperature for 18 h. Water (5 mL) was then
added and the resulting solution extracted with EtOAc (5 ×
CDCl ) 156.2 (C), 146.2 (C), 134.2 (C), 132.9 (CH), 131.7 (C),
3
120.7 (C), 59.9 (CH ), 35.4 (C), 32.4 (CH ), 30.3 (CH ); m/z
3
79 81
2
3
+
+
79
81
(EI) 672 (M , Br Br , 30), 670 (M , Br2 Br , 48), 668
3
2
+
79
81
5
mL). The combined organics were dried (Na SO ) and concen-
(M , Br3 Br, 32), 512 (48), 510 (100), 508 (48%); m/z (EI)
found [M] 669.8945, C H
2
4
+
79
81
+
trated under reduced pressure. The residue was purified by
Br2 Br O requires 669.8932.
30 2 2
24
4972 | Org. Biomol. Chem., 2012, 10, 4968–4976
This journal is © The Royal Society of Chemistry 2012

(aR,R±-4,8-Dibromo-1,11-dimethoxy-6-(1-phenylethyl±-6,7-dihydro-
NCHaHb), 3.95 (1H, q, J 6.5, NCHCH ), 3.06 (2H, d, J 12.5,
3
5
6
H-dibenzo[c,e]azepine, 7 and (aS,R±-4,8-dibromo-1,11-dimethoxy-
-(1-phenylethyl±-6,7-dihydro-5H-dibenz[c,e]azepine, 15
NCHaHb), 3.04 (6H, s, OCH ), 1.41 (18H, s, C(CH ) ), 1.36
3
3 3
(3H, d, J 6.5, NCHCH ); δC (100 MHz, CDCl ) 156.9 (C),
3
3
1
47.1 (C), 143.8 (C), 134.0 (C), 132.0 (C), 130.7 (CH), 128.0
(
R)-α-Methylbenzylamine (0.56 g, 4.61 mmol) was added to a
solution of (±)-tetrabromide 8 (2.57 g, 4.61 mmol) in CHCl3
65 mL). Finely ground anhydrous K CO (4.20 g, 30.4 mmol)
(CH), 127.6 (CH), 126.6 (CH), 117.9 (C), 61.3 (CH), 59.9
(CH ), 51.7 (CH ), 35.2 (C), 30.2 (CH ), 22.7 (CH ); m/z (ESI)
3
2
81
3
3
(
+
+ 79 81
2
3
6
32 (M + H , Br , 50), 630 (M + H , Br Br, 100), 628
2
was added and the mixture placed under an argon atmosphere.
After stirring at reflux for 48 h, the mixture was cooled to room
temperature, filtered and washed with CHCl (30 mL). The sol-
ution was concentrated under reduced pressure and the residue
purified by chromatography on silica gel (9 : 1 petroleum ether–
EtOAc) to give the (aR,R)-isomer 7 (1.09 g, 46%) as a cream
solid, m.p. 82–85 °C; [α]D −154 (c 0.8, CHCl ); R 0.2 (9 : 1
petroleum ether–EtOAc); νmax(neat)/cm 3011, 2938, 2838,
1
+
79
+
(M + H , Br , 49%); m/z (ESI) found [M + H] 628.1379,
2
79 81
+
C H Br BrNO2 requires 630.1399.
Followed by the (aS,R)-isomer 16 (0.58 g, 37%) as a cream
solid, m.p. 96–98 °C; [α]D +194 (c 0.7, CHCl ); R 0.1 (98 : 2
32 40
3
3
f
−1
petroleum ether–EtOAc); νmax(CHCl )/cm 2965, 1452, 1401,
3
1
359, 1244, 1093; δH (400 MHz, CDCl ) 7.54 (2H, s, ArH),
3
3
f
7
.44–7.42 (2H, m, ArH), 7.36–7.32 (2H, m, ArH), 7.26 (1H, tt,
−1
J 7.0, 1.5, ArH), 4.20 (2H, d, J 13.0, NCHaHb), 3.62 (1H, q,
J 6.0, NCHCH ), 3.01 (6H, s, OCH ), 2.92 (2H, d, J 13.0,
NCHaHb), 1.70 (3H, d, J 6.0, NCHCH ), 1.40 (18H, s,
573; δH (400 MHz, CDCl ) 7.60 (2H, d, J 9.0, ArH),
3
3
3
7
.59–7.57 (2H, m, ArH), 7.36–7.30 (2H, m, ArH), 7.24 (1H, tt,
3
J 7.5, 1.5, ArH), 6.85 (2H, d, J 9.0, ArH), 4.21 (2H, d, J 12.5,
NCHaHb), 3.81 (1H, q, J 6.5, NCHCH ), 3.81 (6H, s, OCH ),
3
C(CH ) ); δ (100 MHz, CDCl ) 156.9 (C), 145.2 (C), 143.9
3
3
C
3
3
3
(C), 133.8 (C), 132.0 (C), 130.7 (CH), 128.4 (CH), 127.6 (CH),
.00 (2H, d, J 12.5, NCHaHb), 1.34 (3H, d, J 6.5, NCHCH3);
1
27.0 (CH), 117.9 (C), 61.7 (CH), 59.9 (CH ), 51.8 (CH ), 35.2
3
2
δC (100 MHz, CDCl ) 155.7 (C), 147.0 (C), 136.2 (C), 132.9
+
3 3 2
81
3
(C), 30.2 (CH ), 21.5 (CH ); m/z (ESI) 632 (M + H , Br , 54),
(
(
CH), 128.0 (CH), 127.6 (CH), 127.4 (C), 126.5 (CH), 115.7
C), 111.8 (CH), 61.2 (CH), 56.0 (CH ), 51.3 (CH ), 22.4
+
79 81
+ 79
6
30 (M + H , Br Br, 100), 628 (M + H , Br , 57%); m/z
2
3
2
+
79 81
+
(ESI) found [M + H] 630.1401, C H
Br BrNO2 requires
+
81
+
32 40
(
CH ); m/z (ESI+) 520 (M + H , Br , 50), 518 (M + H ,
Br Br, 100), 516 (M + H , Br , 48%); m/z (ESI+) found
3
79
2
6
30.1399.
8
1
+ 79
2
+
81 79
+
[M + H] 518.0135, C H
Br BrNO requires 518.0147.
24 2
2
4
(
(
aR,R±-4,8-Bis-(3,5-bis-trifluoromethylphenyl±-1,11-dimethoxy-6-
1-phenylethyl±-6,7-dihydro-5H-dibenz[c,e]azepine, 21
Followed by the (aS,R)-isomer 15 (0.96 g, 40%) as a cream
solid, m.p. 82–85 °C; [α] +156 (c 0.7, CHCl ); R 0.1 (9 : 1 pet-
roleum ether–EtOAc); νmax(neat)/cm 3000, 2934, 2835, 1562;
δ (400 MHz, CDCl ) 7.58 (2H, d, J 9.0, ArH), 7.43–7.38 (2H,
D
3
f
−1
(
aR,R)-Dibromide 7 (0.75 g, 1.5 mmol), 3,5-bis-trifluoromethyl-
H
3
phenylboronic acid (1.81 g, 7.0 mmol) and finely ground anhy-
drous K CO (1.16 g, 8.4 mmol) were added under an argon
atmosphere. Pd(PPh ) (80 mg, 0.07 mmol) was added followed
by degassed 1,4-dioxane (15 mL). After stirring at reflux for 2
days, the reaction mixture was cooled to room temperature,
filtered through Celite and washed with CHCl (3 × 15 mL). The
m, ArH), 7.34–7.29 (2H, m, ArH), 7.25 (1H, tt, J 7.5, 1.5, ArH),
.15 (2H, d, J 13.0, NCHaHb), 3.79 (6H, s, OCH ), 3.61 (1H, q,
2
3
4
3
3
4
J 6.0, NCHCH ), 2.87 (2H, d, J 13.0, NCHaHb), 1.70 (3H, d,
J 6.0, NCHCH ); δ (100 MHz, CDCl ) 155.6 (C), 145.0 (C),
1
(
3
3
C
3
35.9 (C), 132.9 (CH), 128.3 (CH), 127.7 (CH), 127.4 (C), 127.0
3
CH), 115.6 (C), 111.9 (CH), 61.6 (CH), 56.0 (CH ), 51.6 (CH ),
3
2
solution was concentrated under reduced pressure and the
residue purified by chromatography on silica gel (1 : 1 toluene–
petroleum ether) to give the product 21 (0.74 g, 65%) as a
yellow solid, m.p. 229–231 °C; [α]D −181 (c 0.7, CHCl ); R
+
81
+
2
3.5 (CH ); m/z (ESI+) 520 (M + H , Br , 51), 518 (M + H ,
3 2
Br Br, 100), 516 (M + H , Br , 48%), m/z (ESI+) found
8
1
79
+ 79
2
+
81 79
24 24 2
+
[M + H] 518.0143, C H Br BrNO requires 518.0147.
3
f
−1
0
.5 (1 : 1 toluene–petroleum ether); νmax(CHCl )/cm
3011,
3
2
940, 2839, 1586, 1491, 1463, 1380, 1279, 1182, 1140; δH
(
aR,R±-4,8-Dibromo-2,10-di-tert-butyl-1,11-dimethoxy-6-(1-
(500 MHz, CDCl ) 8.60–7.81 (3H, m, ArH), 7.78 (2H, s, ArH),
3
phenylethyl±-6,7-dihydro-5H-dibenz[c,e]azepine, 10 and (aS,R±-
4
6
7
.75–7.48 (1H, m, ArH), 7.44 (2H, d, J 8.5, ArH), 7.14 (2H, d,
J 8.5, ArH), 7.04–6.97 (3H, m, ArH), 6.80 (2H, d, J 6.5, ArH),
.94–3.92 (2H, m, NCHaHb), 3.94, (6H, s, OCH ), 3.14–3.12
,8-dibromo-2,10-di-tert-butyl-1,11-dimethoxy-6-(1-phenylethyl±-
,7-dihydro-5H-dibenz[c,e]azepine, 16
3
3
(
R)-α-Methylbenzylamine (0.35 mL, 2.76 mmol) was added to a
solution of (±)-tetrabromide 11 (1.68 g, 2.51 mmol) in CHCl3
65 mL). Finely ground anhydrous K CO (2.29 g, 16.5 mmol)
(1H, m, NCHCH ), 3.13 (2H, d, J 12.5, NCHaHb), 0.97 (3H, d,
3
J 6.5, NCHCH ); δC (125 MHz, CDCl ) 156.6 (C), 145.3 (C),
3
3
(
143.2 (C), 133.7 (C), 131.8 (C), 131.3 (C, q, J 33.0), 131.2
(CH), 129.9 (CH), 127.8 (CH), 126.6 (C), 126.1 (CH), 125.7
(CH), 123.4 (C, q, J 273.0), 120.5 (m, CH), 110.5 (CH), 61.1
(CH), 56.0 (CH ), 48.3 (CH ), 23.2 (CH ); m/z (ESI+) 784
2
3
was then added and the mixture placed under an argon atmos-
phere. After stirring at reflux for 72 h, the mixture was cooled to
room temperature and filtered, washing through with CHCl3
3
2
3
+
+
(50 mL). The solution was then concentrated under reduced
(M + H , 100%); m/z (ESI+) found [M + H] 784.2079,
C H F NO requires 784.2079.
+
pressure and the residue purified by chromatography on silica
gel (1 : 1 petroleum ether–toluene) to give the (aR,R)-isomer 10
40
30 12
2
(
(
0.58 g, 37%) as a cream solid, m.p. 96–98 °C; [α]D −183
c 0.7, CHCl ); R 0.2 (98 : 2 petroleum ether–EtOAc);
(
(
aS,R±-4,8-Bis-(3,5-bis-trifluoromethylphenyl±-1,11-dimethoxy-6-
1-phenylethyl±-6,7-dihydro-5H-dibenz[c,e]azepine, 22
3
−
f
1
νmax(CHCl )/cm 2967, 1450, 1401, 1359, 1245, 1093; δH
3
(
400 MHz, CDCl ) 7.59–7.56 (4H, m, ArH), 7.34–7.30 (2H, m,
(aS,R)-Dibromide 10 (1.45 g, 2.80 mmol), was reacted with 3,5-
bis-trifluoromethyl phenylboronic acid following the procedure
3
ArH), 7.24 (1H, tt, J 7.5, 1.5, ArH), 4.24 (2H, d, J 12.5,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4968–4976 | 4973

described above to afford the product 22 (1.09 g, 50%) as a
white solid, m.p. 94–96 °C; [α]D +85 (c 0.7, CHCl ); R 0.2
(aR,R±-4,8-Bis-(3,5-bis-trifluoromethylphenyl±-1,11-dimethoxy-6-
methyl-6-(1-phenylethyl±-6,7-dihydro-5H-dibenz[c,e]azepinium
iodide, 3
3
f
−1
(
1 : 1 toluene–petroleum ether); νmax(CHCl )/cm 3012, 2940,
3
2
7
839, 1587, 1492, 1462, 1380, 1279; δH (500 MHz, CDCl3)
.90–7.81 (6H, m, ArH), 7.34 (2H, d, J 8.5, ArH), 7.09 (2H, d,
A solution of (aR,R)-21 (91.4 mg, 0.12 mmol) in CH CN
3
(
4 mL) was placed under an argon atmosphere. CH I (112 μL,
3
J 8.5, ArH), 7.01 (1H, tt, J 7.5, 1.5, ArH), 6.94 (2H, dd, J 7.5,
1
.80 mmol) was added and the resulting solution stirred at 80 °C
7
3
2
.0, ArH), 6.82 (2H, dd, J 7.0, 1.5, ArH), 3.92 (6H, s, OCH3),
.56 (2H, d, J 13.0, NCHaHb), 3.07 (1H, q, J 6.5, NCHCH3),
.97 (2H, d, J 13.0, NCHaHb), 0.51 (3H, d, J 6.5, NCHCH3);
for 9 h. The solution was cooled to room temperature, concen-
trated under reduced pressure and the residue was purified by
chromatography on silica gel (19 : 1 CH Cl –MeOH) to give the
2
2
δC (125 MHz, CDCl ) 156.5 (C), 143.5 (C), 143.4 (C), 134.1
3
recovered starting material starting material 21 (44.5 mg, 49%),
followed by the product 3 (39.0 mg, 36%) as an off white solid,
m.p. 148–149 °C; [α]D +32 (c 0.9, CHCl ); R 0.2 (19 : 1
(
C), 131.7 (C), 131.4 (C, q, J 33.0), 130.6 (CH), 130.0 (CH),
27.9 (CH), 126.9 (CH), 126.8 (CH), 126.3 (C), 123.4 (C, q,
J 273.0), 120.6 (m, CH), 61.3 (CH), 56.0 (CH ), 48.2 (CH ),
1
3
f
3
2
−1
+
CH
1379, 1280, 1185, 1144; δ
m, ArH), 7.61 (2H, br s, ArH), 7.45 (1H, d, J 8.5, ArH), 7.44
1H, d, J 8.5, ArH), 7.32–7.22 (3H, m, ArH), 7.29 (1H, d, J 8.5,
ArH), 7.28 (1H, d, J 8.5, ArH), 7.12 (2H, dd, J 8.0, 7.5, ArH),
Cl
2
2
–MeOH); νmax(CHCl
3
)/cm 2945, 1598, 1494, 1462
1
9.5 (CH ); m/z (ESI+) 784 (M + H , 100%); m/z (ESI+) found
3
+
+
H
(400 MHz, CDCl
3
) 7.95–7.74 (4H,
[M + H] 784.2089, C H F NO requires 784.2079.
40 30 12 2
(
(
1
aR,R±-2,10-Di-tert-butyl-4,8-bis-(3,5-bis-trifluoromethylphenyl±-
,11-dimethoxy-6-(1-phenylethyl±-6,7-dihydro-5H-dibenz[c,e]
azepine, 23
5
4
3
.38 (1H, d, J 14.5, NCHaHb), 5.27 (1H, q, J 7.0, NCHCH3),
.36 (1H, d, J 12.5, NCHaHb), 4.18 (1H, d, J 14.5, NCHaHb),
.99–3.93 (1H, m, NCHaHb), 3.95 (3H, s, OCH ), 3.93 (3H, s,
3
(
3
aR,R)-Dibromide 15 (200 mg, 0.32 mmol) was reacted with
,5-bis-trifluoromethyl phenylboronic acid following the pro-
OCH ), 2.59 (3H, s, NCH ), 1.47 (3H, d, J 7.0, NCHCH ); δ
C
3
3
3
(
100 MHz, CDCl ) 157.8 (C), 157.6 (C), 141.0 (C), 140.7 (C),
3
cedure described above to afford the product (218 mg, 77%) as a
white solid, m.p. 145–148 °C; [α]D −122 (c 0.8 in CHCl ); R
1
33.6 (C), 132.8 (C), 132.7 (C, q, J 33.5), 132.6 (C), 131.9
(CH), 130.5 (CH), 130.1 (CH), 129.8 (br s, C), 128.8 (CH),
28.4 (C), 126.2 (C), 126.1 (C), 124.3 (C), 123.1 (C, q,
J 273.0), 122.8 (C, q, J 273.0), 122.7–122.4 (m, CH),
21.5–121.3 (m, CH), 75.3 (CH), 63.5 (CH ), 56.4 (CH ), 56.3
3
f
−1
0
1
7
7
.2 (98 : 2 petroleum ether–EtOAc); νmax(CHCl )/cm 2964,
3
1
602, 1452, 1386, 1360, 1257, 1140; δH (400 MHz, CDCl3)
.97 (4H, br s, ArH), 7.80 (2H, br s, ArH), 7.33 (2H, s, ArH),
.05–6.97 (3H, m, ArH), 6.80–6.78 (2H, m, ArH), 3.94 (2H, d,
1
2
3
(
(
CH ), 51.3 (CH ), 50.6 (CH ), 15.9 (CH ); m/z (ESI+) 798
3 2 3 3
J 12.5, NCHaHb), 3.20–3.13 (3H, m, NCHaHb, NCHCH3),
.18 (6H, s, OCH ), 1.50 (18H, s, C(CH ) ), 0.98 (3H, d, J 6.5,
+
+
M − I , 48), 786 (100%); m/z (ESI+) found [M − I] 798.2230,
3
3
3 3
+
C H F NO requires 798.2235.
41
32 12
2
NCHCH ); δ (100 MHz, CDCl ) 158.0 (C), 145.4 (C), 143.6
3
C
3
(
C), 142.4 (C), 133.4 (C), 131.5 (C), 131.4 (C), 131.4 (C, q,
J 33.0), 129.9 (CH, br s), 128.4 (CH), 127.9 (CH), 126.2 (C),
25.7 (CH), 123.4 (C, q, J 273.0), 120.8–120.5 (CH, m), 61.1
CH), 59.9 (CH ), 48.5 (CH ), 35.2 (C), 30.4 (CH ), 23.1
1
(
(
(aS,R±-4,8-Bis-(3,5-bis-trifluoromethylphenyl±-1,11-dimethoxy-6-
3
2
3
methyl-6-(1-phenylethyl±-6,7-dihydro-5H-dibenz[c,e]azepinium
iodide, 4
+
CH ); m/z (ESI) 898 (15), 896 (M + H , 100%); m/z (ESI)
3
+
+
found [M + H] 896.3289, C H F NO requires 896.3331.
4
8
46 12
2
Following the procedure above, (aS,R)-22 (16.9 mg, 0.02 mmol)
was reacted with CH I (112 μL, 1.80 mmol) at 80 °C for 2 h
3
(
1
aS,R±-2,10-Di-tert-butyl-4,8-bis-(3,5-bis-trifluoromethylphenyl±-
,11-dimethoxy-6-(1-phenylethyl±-6,7-dihydro-5H-dibenz[c,e]
azepine, 24
to give the product 4 (15.2 mg, 76%) as a yellow solid,
m.p. 116–118 °C; [α]D +45 (c 0.85, CHCl ); R 0.2 (19 : 1
3
f
−1
CH Cl –MeOH); ν (CHCl )/cm 2944, 1594, 1496, 1461
2
2
max
3
(
3
aS,R)-Dibromide 16 (200 mg, 0.32 mmol) was reacted with
,5-bis-trifluoromethyl phenylboronic acid following the pro-
1380, 1280, 1186, 1144; δH (400 MHz, CDCl ) 7.94 (4H, br s,
3
ArH), 7.75 (2H, br s, ArH), 7.53 (1H, d, J 8.5, ArH), 7.45–7.39
(1H, m, ArH), 7.44 (1H, d, J 8.5, ArH), 7.41 (1H, d, J 8.5,
ArH), 7.34–7.21 (2H, m, ArH), 7.29 (1H, d, J 8.5, ArH), 7.01
(2H, d, J 7.5, ArH), 4.99 (1H, d, J 14.5, NCHaHb), 4.04–3.98
(2H, m, NCHCH , NCHaHb), 3.98 (3H, s, OCH ), 3.95 (3H, s,
cedure described above to afford the product (173 mg, 61%) as a
white solid; m.p. 105–107 °C; [α] +74 (c 0.7 in CHCl ); R 0.2
(
1
D
3
f
−1
98 : 2 petroleum ether–EtOAc); νmax(CHCl )/cm 2964, 1603,
3
454, 1386, 1359, 1280, 1181, 1141; δH (400 MHz, CDCl3)
.00–7.70 (6H, br m, ArH), 7.24 (2H, s, ArH), 7.04–6.95 (3H,
3
3
8
OCH ), 3.47 (1H, d, J 13.0, NCHaHb), 3.15 (1H, d, J 13.0,
3
m, ArH), 6.89–6.87 (2H, m, ArH), 3.58 (2H, d, J 13.0,
NCHaHb), 3.17 (6H, s, OCH ), 3.08 (1H, q, J 6.5, NCHCH ),
NCHaHb), 2.75 (3H, s, NCH ), 0.95 (3H, d, J 7.0, NCHCH );
3
3
δC (100 MHz, CDCl ) 157.6 (C), 157.4 (C), 141.2 (C), 140.8
3
3
3
3
.03 (2H, d, J 13.0, NCHaHb), 1.48 (18H, s, C(CH ) ), 0.53
(C), 132.7 (CH), 132.7 (CH), 132.4 (C), 131.5 (CH), 130.9 (br
s, CH), 130.7 (C), 129.9–129.3 (m, CH), 126.5 (C), 126.2 (C),
126.2–119.7 (m, C), 126.1 (C), 124.8 (C), 123.7 (C), 122.7 (C,
q, J 273.5), 122.4–122.2 (m, CH), 121.7–121.3 (m, CH), 114.3
(CH), 114.0 (CH), 70.5 (CH), 59.6 (CH ), 58.6 (CH ), 56.5
3
3
(3H, d, J 6.5, NCHCH ); δC (100 MHz, CDCl ) 157.9 (C),
3 3
1
44.0 (C), 143.8 (C), 142.1 (C), 133.4 (C), 132.0 (C), 131.4 (C,
q, J 33.5), 131.0 (C), 130.0 (CH, br s), 127.9 (CH), 126.9 (CH),
26.8 (CH), 123.4 (C, q, J 273), 120.8–120.5 (CH, m), 61.3
CH), 59.8 (CH ), 48.5 (CH ), 35.2 (C), 30.4 (CH ), 20.1
1
2
2
(
(
(CH ), 56.3 (CH ), 43.0 (CH ), 15.8 (CH ); m/z (ESI+) 798
3 3 3 3
3
2
3
+
+
+
+
CH ); m/z (ESI) 896 (M + H , 100); m/z (ESI) found [M + H]
(M − I , 100%); m/z (ESI+) found [M − I] 798.2214,
3
+
+
8
96.3346, C H F NO requires 896.3331.
C H F NO requires 798.2235.
41 32 12
48
46 12
2
2
4974 | Org. Biomol. Chem., 2012, 10, 4968–4976
This journal is © The Royal Society of Chemistry 2012

(
1
aR,R±-2,10-Di-tert-butyl-4,8-bis-(3,5-bis-trifluoromethylphenyl±-
,11-dimethoxy-6-methyl-6-(1-phenylethyl±-6,7-dihydro-5H-
mixture was degassed with nitrogen and cooled to 0 °C. Benzyl
bromide (35 mg, 0.20 mmol) was added followed by 15 M
aqueous KOH (1 mL) and the mixture stirred vigorously for 3 h.
The mixture was diluted with water (10 mL) and extracted
with EtOAc (3 × 10 mL). The combined organics were dried
dibenz[c,e]azepinium iodide, 5
Following the above procedure (aR,R)-23 was reacted with CH3I
(
(
(
112 μL, 1.80 mmol) at 80 °C for 24 h to give the product 5
31.0 mg, 38%) as a yellow solid, m.p. 194–195 °C; [α]D +33
c 0.5, (CH ) CO); R 0.2 (19 : 1 CH Cl –MeOH); νmax(CHCl3)/
(
Na SO ), concentrated under reduced pressure, and then
2 4
purified by chromatography on silica gel. Enantioselectivity was
3
2
f
2
2
determined by HPLC (Chiralcel OD-H (0.4 × 25 cm) 100 : 1
−1
cm 2958, 1461, 1384, 1362, 1278, 1139, 1058; δ (400 MHz,
(
br s, ArH), 8.03 (2H, br s, ArH), 7.69 (1H, s, ArH), 7.66 (1H, s,
ArH), 7.35 (1H, tt, J 7.5, 1.0, ArH), 7.18 (2H, dd, J 8.0, 7.5,
ArH), 7.05 (2H, dd, J 7.5, 1.0, ArH), 5.06 (1H, d, J 14.5,
NCHaHb), 4.29 (1H, d, J 13.5, NCHaHb), 4.82 (1H, q, J 7.0,
−1
H
(
(
hexane–IPA), 0.5 mL min , R 18 min (R)-isomer and 31 min
t
CD ) CO) 8.42 (1H, br s, ArH), 8.25 (1H, br s, ArH), 8.07 (2H,
4
3
2
S)-isomer) as previously described.
Acknowledgements
Financial support for this work was provided by EPRSC and
GlaxoSmithKline. We would also like to thank Dr Matthew Gray
for helpful discussions.
NCHCH ), 4.62 (1H, d, J 14.5, NCHaHb), 4.47 (1H, d, J 13.5,
3
NCHaHb), 3.38 (3H, s, OCH ), 3.26 (3H, s, OCH ), 2.52 (3H,
3
3
s, NCH ), 1.66 (3H, d, J 7.0, NCHCH ), 1.52 (9H, s, C(CH ) ),
3
3
3 3
1
1
1
.48 (9H, s, C(CH ) ); δ (100 MHz, (CD ) CO) 159.3 (C),
3 3 C 3 2
59.1 (C), 145.7 (C), 145.5 (C), 142.3 (C), 141.9 (C), 135.9 (C),
35.9 (C), 135.1 (C), 133.6 (C), 131.2 (CH), 130.8 (C), 130.6
Notes and references
(
1
(
7
4
br s, CH), 130.5 (C), 130.4 (CH), 130.1 (CH), 129.9 (CH),
28.8 (CH), 126.7 (C), 123.6 (C), 123.4 (C, q, J 272.5), 123.3
C, q, J 272.5), 122.2–122.0 (m, CH), 121.7–121.5 (m, CH),
1 For reviews covering recent developments in asymmetric phase-transfer
catalysis see: (a) K. Maruoka, Org. Process Res. Dev., 2008, 12, 679;
(
(
b) T. Hashimoto and K. Maruoka, Chem. Rev., 2007, 107, 5656;
c) T. Ooi and K. Maruoka, Angew. Chem., Int. Ed., 2007, 46, 4222;
5.7 (CH), 62.9 (CH ), 60.6 (CH ), 60.4 (CH ), 53.4 (CH ),
2 3 3 2
(d) J. Vachon and J. Lacour, Chimia, 2006, 60, 266; (e) M. J. O’Donnell,
Acc. Chem. Res., 2004, 37, 506; (f) B. Lygo and B. I. Andrews, Acc.
Chem. Res., 2004, 37, 518.
2 B. Lygo, B. Allbutt and S. R. James, Tetrahedron Lett., 2003, 44, 5629;
B. Lygo and B. Allbutt, Synlett, 2004, 326; B. Lygo and
L. D. Humphreys, Synlett, 2004, 2809; B. Lygo and D. J. Beaumont,
Chimia, 2007, 61, 257.
8.9 (CH ), 35.3 (C), 35.3 (C), 29.5 (CH ), 29.5 (CH ), 15.9
3
3
3
+
(
CH ); m/z (ESI+) 912 (14), 910 (M − I , 100%); m/z (ESI+)
3
+ +
found [M − I] 910.3484, C H NO requires 910.3487.
4
9
48
2
(aS,R±-2,10-Di-tert-butyl-4,8-bis-(3,5-bis-trifluoromethylphenyl±-
3
4
B. Lygo, B. Allbutt and E. Kirton, Tetrahedron Lett., 2005, 46, 4461.
B. Lygo, B. Allbutt, D. J. Beaumont, U. Butt and J. A. R. Gilks, Synlett,
1
,11-dimethoxy-6-methyl-6-(1-phenylethyl±-6,7-dihydro-5H-
dibenz[c,e]azepinium iodide, 6
2009, 675.
5
J. L. Melville, K. J. R. Lovelock, C. Wilson, B. Allbutt, E. K. Burke,
B. Lygo and J. D. Hirst, J. Chem. Inf. Model., 2005, 45, 971.
M. Cormack, PhD thesis, University of Nottingham, 2010.
R. Holzwarth, R. Bartsch, Z. Cherkaoui and G. Solladié, Eur. J. Org.
Chem., 2005, 3536.
Following the above procedure (aR,R)-24 (82.1 mg, 0.09 mmol)
6
7
was reacted with CH I (112 μL, 1.80 mmol) at 80 °C for 3 h to
3
give the product 6 (70.7 mg, 74%) as a yellow solid,
m.p. 136–138 °C; [α]D +59 (c 0.8, CHCl ); R 0.2 (19 : 1
3
f
8 Y.-G. Wang, M. Ueda, X. Wang, Z. Han and K. Maruoka, Tetrahedron,
2007, 63, 6042; Y.-G. Wang and K. Maruoka, Org. Process Res. Dev.,
−1
CH Cl –MeOH); ν (CHCl )/cm 2957, 1459, 1385, 1361,
2
2
max
3
2007, 11, 628.
1
280, 1186, 1145; δ (500 MHz, CDCl ) 8.13 (1H, br s, ArH),
H 3
9
Diastereoisomeric dihydronaphthazepines incorporating an α-methylben-
zylamine fragment have been shown to be separable via silica gel chrom-
atography, see: M. Periasamy, J. V. B. Kanth and C. K. Reddy, J. Chem.
Soc., Perkin Trans. 1, 1995, 427.
7
.98 (2H, br s, ArH), 7.77 (1H, br s, ArH), 7.43–7.39 (2H, m,
ArH), 7.32–7.27 (5H, m, ArH), 7.09 (2H, br s, ArH), 5.02 (1H,
d, J 14.5, NCHaHb), 4.25 (1H, d, J 14.5, NCHaHb), 4.07 (1H,
10 J. M. Insole, J. Chem. Soc., Perkin Trans. 2, 1972, 1168.
q, J 7.0, NCHCH ), 3.59 (1H, d, J 14.5, NCHaHb), 3.36 (3H, s,
3
11 J. Cornforth, L. M. Huguenin and J. R. H. Wilson, J. Chem. Soc., Perkin
OCH ), 3.22 (3H, s, OCH ), 3.18 (1H, d, J 13.0, NCHaHb),
3
3
Trans. 1, 1987, 871.
2
.74 (3H, s, NCH ), 1.52 (9H, s, C(CH ) ), 1.48 (9H, s, C
12 K. Mukai, K. Takamatsu and K. Ishizu, Bull. Chem. Soc. Jpn., 1984, 57,
3
3 3
3
507.
3 Biphenol 20 was prepared in two steps from commercially-available
-tert-butyl-m-creosol following the procedure of Y. Ito, Y. Kubota and
T. Inoue, Nippon Soda Co. Ltd. Patent, EP2241545, 2010.
(CH ) ), 0.98 (3H, d, J 7.0, NCHCH ); δ (126 MHz, CDCl )
3 3 3 C 3
1
1
1
59.6 (C), 159.0 (C), 147.2 (C), 147.0 (C), 141.7 (C), 141.3 (C),
35.5 (C), 135.1 (C), 132.7 (C, q, J 33.5), 131.4 (CH), 131.2
6
(
(
C), 131.1 (br s, CH), 130.9 (C), 130.1 (C), 130.1 (CH), 130.0
CH), 129.5 (br s, CH), 124.4 (C), 123.9 (br s, C), 123.0 (C, q,
14 For a detailed discussion on the correlation between specific rotation
and configuration in related atropos biphenyls see: K. Mislow,
M. A. W. Glass, R. E. O’Brien, P. Rutkin, D. H. Steinberg, J. Weiss and
C. Djerassi, J. Am. Chem. Soc., 1962, 84, 1455.
J 273.5), 122.9 (C), 122.6 (C, q, J 273.0), 122.5–122.3 (m, CH),
21.7–121.5 (m, CH), 70.5 (CH), 61.3 (CH ), 60.8 (CH ), 59.6
1
15 T. Ooi, Y. Uematsu, M. Kameda and K. Maruoka, Tetrahedron, 2006, 62,
3
3
1
1425.
(
3
CH ), 59.3 (CH ), 42.8 (CH ), 35.8 (C), 35.7 (C), 30.0 (CH ),
2 2 3 3
+
16 C. E. Cannizzaro and K. N. Houk, J. Am. Chem. Soc., 2002, 124, 7163.
0.0 (CH ), 15.6 (CH ); m/z (ESI+) 910 (M − I , 100%); m/z
3
3
+ +
1
7 Qualitative analyses of potential ion-pair structures between the (aS)-2
and both E- and Z-enolate of the glycine imine were performed using
DFT calculations (B3LYP/6-31G*). Because of the size of the structures
involved it is not possible to provide an accurate estimation of ground
state or interaction energies for these ion-pairs.
8 See for example: P. C. B. Page, B. R. Buckley, M. M. Farah and A.
J. Blacker, Eur. J. Org. Chem., 2009, 3413; R. Novikov, G. Bernardinelli
and J. Lacour, Adv.Synth. Catal., 2009, 351, 596; R. Novikov,
G. Bernardinelli and J. Lacour, Adv. Synth. Catal., 2008, 350, 1113;
(ESI+) found [M − I] 910.3481, C H NO requires 910.3487.
4
9
48
2
General procedure for alkylation of benzophenone glycine imine
tert-butyl ester, 25
1
The PTC (1 mol%) and benzophenone glycine imine ester
(50 mg, 0.17 mmol) were dissolved in toluene (2 mL). The
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4968–4976 | 4975

P. C. B. Page, M. M. Farah, B. R. Buckley, A. J. Blacker and J. Lacour,
Synlett, 2008, 1381; J. Vachon, S. Rentsch, A. Martinez, C. Marsol and
J. Lacour, Org. Biomol. Chem., 2007, 5, 501; V. K. Aggarwal and M.
F. Wang, Chem. Commun., 1996, 191.
9 See for example: T. Kano, A. Noishiki, R. Sakamoto and K. Maruoka,
Chem. Commun., 2011, 47, 10626; B. Lygo, J. Leonard, C. Davison,
T. Evans and C.-E. Roy, Tetrahedron, 2011, 67, 10164; T. Kano,
Y. Yamaguchi and K. Maruoka, Chem.–Eur. J., 2009, 15, 6678;
F.-Z. Peng, Z.-H. Shao, X.-W. Pu and H.-B. Zhang, Adv. Synth. Catal.,
R. A. DiStasio, R. C. Lochan, T. Wang, G. J. O. Beran, N. A. Besley,
J. M. Herbert, C. Y. Lin, T. Van Voorhis, S. H. Chien, A. Sodt, R.
P. Steele, V. A. Rassolov, P. E. Maslen, P. P. Korambath, R. D. Adamson,
B. Austin, J. Baker, E. F. C. Byrd, H. Dachsel, R. J. Doerksen, A. Dreuw,
B. D. Dunietz, A. D. Dutoi, T. R. Furlani, S. R. Gwaltney, A. Heyden,
S. Hirata, C. P. Hsu, G. Kedziora, R. Z. Khalliulin, P. Klunzinger, A.
M. Lee, M. S. Lee, W. Liang, I. Lotan, N. Nair, B. Peters, E. I. Proynov,
P. A. Pieniazek, Y. M. Rhee, J. Ritchie, E. Rosta, C. D. Sherrill, A.
C. Simmonett, J. E. Subotnik, H. L. Woodcock, W. Zhang, A. T. Bell, A.
K. Chakraborty, D. M. Chipman, F. J. Keil, A. Warshel, W. J. Hehre, H.
F. Schaefer, J. Kong, A. I. Krylov, P. M. W. Gill and M. Head-Gordon,
Phys. Chem. Chem. Phys., 2006, 8, 3172.
1
2
2
008, 350, 2199.
0 Y. Shao, L. F. Molnar, Y. Jung, J. Kussmann, C. Ochsenfeld, S. T. Brown,
A. T. B. Gilbert, L. V. Slipchenko, S. V. Levchenko, D. P. O’Neill,
4976 | Org. Biomol. Chem., 2012, 10, 4968–4976
This journal is © The Royal Society of Chemistry 2012