Synthesis and evaluation of chiral dibenzazepinium halide phase-transfer catalysts

Article abstract of DOI:10.1055/s-0028-1087810

Two complimentary routes to chiral dibenzazepinium halides have been developed. This has enabled the synthesis and evaluation of a range of potential phase-transfer catalysts (PTC) for asymmetric alkylation and Michael addition reactions involving glycine

Full text of DOI:10.1055/s-0028-1087810

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675
Synthesis and Evaluation of Chiral Dibenzazepinium Halide Phase-Transfer
Catalysts
C
hira
l
D
ibenzaze
a
pinium
H
al
r
ide Phas
r
e
-Transf
y
er Catalysts Lygo,* Bryan Allbutt, Douglas J. Beaumont, Umar Butt, James A. R. Gilks
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
E-mail: B.Lygo@Nottingham.ac.uk
Received 30 September 2008
mentary approaches that achieve this objective.
Abstract: Two complimentary routes to chiral dibenzazepinium
halides have been developed. This has enabled the synthesis and
evaluation of a range of potential phase-transfer catalysts (PTC) for
asymmetric alkylation and Michael addition reactions involving
glycine imine esters.
Application of this chemistry is illustrated by the prepara-
tion of a range of potential dibenzazepinium halide cata-
lysts 1a–g and 2a–f, designed to probe the structural
requirements for efficient catalysis of two important
asymmetric phase-transfer-catalysis processes.
Key words: amino acids, asymmetric alkylation, phase-transfer
catalysis, quaternary ammonium salts, Michael addition
The first approach (Scheme 2) starts with commercially
available phenol 4. Selective ortho bromination of this
material was initially achieved using NBS in CCl4,4d but
we have subsequently found that petroleum ether is a su-
perior solvent for this process. Presumably the nonpolar
nature of the solvent maximizes H-bonding interactions
between substrate and reagent, thus directing bromination
ortho to the phenol. Oxidative coupling5 followed by O-
methylation then provides the biphenyl intermediate 5.
Overall yields for this sequence are generally high, but the
oxidative coupling step can be capricious. This typically
gives isolated yields of 50–90%, the remainder of the ma-
terial being unreacted starting material. Attempts to im-
prove the reproducibility of this step by dispersing air or
O2 through the reaction mixture were unsuccessful and
best results were obtained by simply stirring the mixture
under an air atmosphere.
Asymmetric phase-transfer catalysis using quaternary
ammonium salts is now recognized as a powerful strategy
for accessing high-value chiral intermediates. Early suc-
cesses in this area focused on the use of chiral quaternary
ammonium salts derived from readily available alka-
loids,1 but more recently a range of highly effective phase-
transfer catalysts (PTC) derived from binaphthol and tar-
trate derivatives have also been developed.2
One of the key challenges in this area is the design of new
PTC architectures that allow facile incorporation of chiral
elements and diverse structural modification around the
quaternary ammonium ion centre.3 To this end we have
been investigating the synthesis and application of chiral
dibenzazepinium halides of type 1 and 2 (Scheme 1).4
These structures were selected for study because they in-
corporate simple chiral amines 3, a range of which are
commercially available. They also offer the opportunity to
modify the environment around the quaternary ammoni-
um centre simply by varying the nature of the R and Ar
substituents.
At this stage the Ar substituents can be introduced via
Suzuki–Miyaura coupling,6 and subsequent radical bro-
mination then provides the catalyst precursor 6. The final
OMe
t-Bu
Br
OH
In order to exploit these features to the full it was neces-
sary to develop a synthetic route to these structures which
allowed late introduction of the chiral amine 3 and Ar sub-
stituents. In this paper we report details of two compli-
t-Bu
i–iii
iv, v
5
4
t-Bu
Br
OMe
OMe
OMe
t-Bu
t-Bu
Ar
Ar
t-Bu
Ar
X–
Me
Br
vi
H2N
R
1
+
N
R
Br
H
H
3
6
t-Bu
Ar
1
2
X = Br
X = I
OMe
OMe
Scheme 2 Initial approach to chiral dibenzazepinium bromides 1
(route A). Reagents and conditions: (i) NBS, petroleum ether, r.t.
(83%); (ii) CuCl, TMEDA, MeOH, r.t. (50–90%); (iii) K2CO3, MeI,
DMF, r.t. (98%); (iv) ArB(OH)2, Pd(PPh3)4, K2CO3, THF, 70 °C; (v)
NBS, hn AIBN, CCl4, reflux; (vi) RCH(Me)N(Me)H, K2CO3, MeCN,
CH2Cl2, 60 °C.
Scheme 1
SYNLETT 2009, No. 4, pp 0675–0680
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087810; Art ID: Y01108ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
9

676
B. Lygo et al.
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step in this sequence is then achieved via reaction of di- It was found that by performing the radical bromination
bromide 6 with an appropriate chiral amine in the pres- on intermediate 5, and then reacting the resulting dibro-
ence of K2CO3. A key feature of this approach is that the mide with a chiral amine, dibenzazepines 7 could be gen-
final step can be performed under reaction conditions that erated in good overall yield. At this stage the aryl
are compatible with in situ generation and screening of substituents could be introduced, and finally the amine
catalysts to phase-transfer-catalysed alkylation reac- quaternised by reaction with methyl iodide. So far at-
tions.3,4d
tempts to reverse these latter two steps have been unsuc-
cessful as we have been unable to find conditions that give
efficient Suzuki–Miyaura coupling on the quaternary am-
monium salt derived from 7.
Examples of chiral dibenzazepinium bromides prepared
in this way are given in Table 1. Overall yields are gener-
ally good, but hindered amines (e.g., Table 1 entry 6,
Scheme 2) give poor conversion in the final step.
This alternative approach gives similar overall yields and
has successfully been employed in the synthesis of dibenz-
azepinium iodides 2a–f (Scheme 3, Table 2). Of particu-
lar note being the preparation of compound 2e (entry 5), a
compound that could not be accessed via the original
route.
Table 1 Synthesis of Dibenzazepinium Bromides 17
Entry 1
R
Ar
Yield (%)
Step Step Step
(iv)
72
75
69
63
(v)
(vi)
90
84
93
76
88
28
70
Table 2 Synthesis of Dibenzazepinium Iodides 28
1
2
3
4
5
6
7
1a
Ph
Ph
100
100
100
95
Entry
2
R
Ar
Yield (%)
1b
1c
1d
1e
1f
4-PhC6H4
4-t-BuC6H4
3,5-(CF3)2C6H3
Step Step Step
(ii)
(iii)
(iv)
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
Ph
3,5-(CF3)2C6H3
3,5-(MeO)2C6H3
3,5-Ph2C6H3
85
63
82
4-MeC6H4
t-Bu
92
69
59
85
1g
1-naphthyl
3,4,5-F3C6H2
3,5-Me2C6H3
74a
39b
89
71
100
61
Although the route outlined in Scheme 2 allows a wide
range of different structures to be prepared,4d the Ar sub-
stituents cannot possess functionality that is reactive to-
wards radical bromination. As we were keen to
incorporate aryl groups possessing methyl substituents, it
was necessary to overcome this limitation. Thus a modi-
fied approach to the dibenzazepinium halides was investi-
gated (Scheme 3).
n-C5H11
72
a Using Pd(OAc)2, Ph3P, K2CO3, DMF, 150 °C.
b Using Pd2(dba)3, dppf, aq K3PO4, PhMe, 110 °C.
The effectiveness of the dibenzazepinium halide catalysts
1a–g and 2a–f was evaluated in the alkylation of glycine
imine 9. This type of alkylation has wide application in
the synthesis of a-amino acid derivatives.2,9,10 Hence a
greater understanding of the structural requirements for
efficient catalysis are of general interest.
OMe
t-Bu
Br
i, ii
For the majority of the dibenzazepinium halides, 1 mol%
was sufficient to generate the desired product 10 in high
yield within three hours (Table 3). Highest enantioselec-
tivity was obtained using 1g. This catalyst was originally
identified via combinatorial screening,4d so the results
obtained here further emphasise the usefulness of
this approach in PTC development. The corresponding
a-methylbenzylamine and 3,3-dimethyl-2-butylamine de-
rived catalysts 1d–f and 2a also deliver 10 with useful lev-
els of enantioselectivity.12 This suggests that a bulky R
substituent on the amine stereogenic centre is required for
high selectivity. These results also demonstrate the key
role of the 3,5-bistrifluoromethylphenyl substituent in cat-
alysts 1 and 2 as all other Ar substituents studied resulted
in substantially lower enantioselectivities.
iii
N
R
5
H
t-Bu
Br
7
OMe
OMe
t-Bu
Ar
iv
2
N
R
H
t-Bu
Ar
8
OMe
Scheme 3 Alternative approach to chiral dibenzazepinium halides 2
(route B). Reagents and conditions: (i) NBS, hn, AIBN, CCl4, reflux
(100%); (ii) RCH(Me)NH2, K2CO3, CHCl3, 60 °C; (iii) ArB(OH)2,
Pd(Ph3P)4, K2CO3, THF, 70 °C; (iv) MeI, CHCl3, 60 °C.
Dibenzazepinium halide catalysts 1a,d–g and 2a–f were
also evaluated in the Michael addition of glycine imine 11
Synlett 2009, No. 4, 675–680 © Thieme Stuttgart · New York

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Chiral Dibenzazepinium Halide Phase-Transfer Catalysts
677
Table 3 Alkylation of Glycine Imine 8 with Benzyl Bromide11
have generally proved more challenging than the corre-
sponding alkylations,14 but we have previously shown that
they can be readily achieved using catalysts of type 1g
(entry 5).4a
catalyst 1 or 2 (1 mol%)
Ph2C=N
Ph
CO2t-Bu
Ph2C=N
CO2t-Bu
15 M aq KOH
PhMe, 3 h, 0 °C
BnBr
H
9
As with the alkylations, 1 mol% catalyst generally proved
sufficient to produce the desired product 12 within a few
hours at 0 °C, and again catalyst 1g (entry 5) gave the
highest enantioselectivity. For this reaction the trends be-
tween catalyst structure and enantioselectivity are clearly
less straightforward, and a wider range of enantioselectiv-
ities are observed. This echoes our previous observation
that the Michael additions are far more sensitive to the
reaction conditions than alkylations.4a
10
Entry
1
Catalyst
Yield (%)
93
ee (%)
20
1a
1b
1c
1d
1e
1f
2
84
33
3
87
35
4
89
91
In conclusion, we have developed two complimentary ap-
proaches to chiral dibenzazepinium halides which should
allow access to a wide range of potential PTC for asym-
metric catalysis. This study has also provided more in-
sight into the key structural features that make 1g an
effective catalyst for alkylation and Michael additions of
glycine imines.
5
91
92
6
92
94
7
1g
2a
2b
2c
2d
2e
2f
89
97
8
96
90
9
79
48
10
11
12
13
66
67
Acknowledgment
57
77
Financial support for this work was provided by EPSRC and the
University of Nottingham.
82
44
55
43
References and Notes
(1) See, for example: (a) Lygo, B. Phase-Transfer Reactions, In
Rodd’s Chemistry of Carbon Compounds, Vol. V; Elsevier
Science Ltd.: Oxford, 2001, 101–150. (b) O’Donnell, M. J.
Asymmetric Phase-Transfer Reactions in Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Verlag
Chemie: New York, 2000. (c) Shioiri, T. Chiral Phase-
Transfer Catalysts, In Handbook of Phase-Transfer
Catalysis; Sasson, Y.; Neumann, R., Eds.; Blackie
Academic and Professional: London, 1997.
(2) For reviews covering recent developments in asymmetric
phase-transfer catalysis, see: (a) Maruoka, K. Org. Process
Res. Dev. 2008, 12, 679. (b) Hashimoto, T.; Maruoka, K.
Chem. Rev. 2007, 107, 5656. (c) Ooi, T.; Maruoka, K.
Angew. Chem. Int. Ed. 2007, 46, 4222. (d) Vachon, J.;
Lacour, J. Chimia 2006, 60, 266. (e) O’Donnell, M. J. Acc.
Chem. Res. 2004, 37, 506. (f) Lygo, B.; Andrews, B. I. Acc.
Chem. Res. 2004, 37, 518. (g) Maruoka, K.; Ooi, T. Chem.
Rev. 2003, 103, 3013.
(3) Of particular interest are approaches that are compatible
with in situ generation and screening, allowing for rapid
optimization of PTC activity and reaction enantioselectivity,
see for example: (a) Kitamura, K.; Arimura, Y.; Shirakawa,
S.; Maruoka, K. Tetrahedron Lett. 2008, 49, 2026.
(b) Lygo, B.; Andrews, B. I.; Hirst, J. D.; Melville, J. L.;
Peterson, J. A.; Slack, D. Chim. Oggi 2004, 22, 8. (c)Lygo,
B.; Andrews, B. I.; Crosby, J.; Peterson, J. A. Tetrahedron
Lett. 2002, 43, 8015.
(4) (a) Lygo, B.; Allbutt, B.; Kirton, E. H. M. Tetrahedron Lett.
2005, 46, 4461. (b) Melville, J. L.; Lovelock, K. J. R.;
Wilson, C.; Allbutt, B.; Burke, E. K.; Lygo, B.; Hirst, J. D.
J. Chem. Inf. Model. 2005, 45, 971. (c) Lygo, B.; Allbutt, B.
Synlett 2004, 326. (d) Lygo, B.; Allbutt, B.; James, S. R.
Tetrahedron Lett. 2003, 44, 5629.
Table 4 Michael Addition of Glycine Imine 10 to MVK15
Ph2C=N
CO2Dpm
catalyst 1 or 2 (1 mol%)
Ph2C=N
CO2Dpm
H
Cs2CO3
i-Pr2O, 2 h
0 °C, MVK
O
11
12
Entry
Catalyst
Yield (%)
ee (%)
18
86
85
68
94
82
15
0
1
2
1a
1d
1e
1f
97
76
83
96
87
94
94
92
92
58
89
3
4
5
1g
2a
2b
2c
2d
2e
2f
6
7
8
9
81
13
42
10
11
to MVK (Table 4). The asymmetric phase-transfer-cata-
lysed conjugate addition of glycine imines to a,b-unsatur-
ated ketones is of interest as it allows rapid access to
substituted pyrrolidines.13 Michael additions of this type
(5) Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S.-I.;
Noji, M.; Koga, K. J. Org. Chem. 1999, 64, 2264.
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678
B. Lygo et al.
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(6) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(7) Representative Procedures for Route A
were washed with brine (2 × 100 mL), dried (MgSO4), and
concentrated under reduced pressure. The residue was
recystallised (Et2O–MeOH) to afford the product (4.71 g,
62%) as a colourless solid.
Preparation of 6-tert-Butyl-2-bromo-3-methylphenol
N-Bromosuccinimide (77.6 g, 0.44 mol) was added in
batches to a solution of 4 (68.2 g, 0.42 mol) in PE (1.5 L).
The resulting mixture stirred for 3 h at r.t., then filtered
through silica gel, and concentrated under reduced pressure.
The residue was distilled (140–145 °C, 1.3·10–3 bar) to
afford the product (83.1 g, 83%) as a pale yellow oil. The
residue could also be purified by chromatography on silica
gel (Rf = 0.5, PE) to give the product in similar yield.
IR (neat): nmax = 3497, 1602 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.09 (1 H, d, J = 8.0 Hz, ArH), 6.72 (1 H, d, J =
8.0 Hz, ArH), 5.90 (1 H, s, OH), 2.34 (3 H, s, CH3), 1.38 [9
H, s, C(CH3)3]. 13C NMR (100 MHz, CDCl3): d = 150.4 (C),
136.0 (C), 134.7 (C), 125.5 (CH), 121.6 (CH), 115.4 (C),
35.1 (C), 29.5 (CH3), 23.1 (CH3). MS (EI): m/z calcd for
C11H15O79Br: 242.0301; found: 242.0303 [M]+.
Mp 183–184 °C. IR (neat): nmax = 2963 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.89 (4 H, s, ArH), 7.86 (2 H, s, ArH),
7.18 (2 H, s, ArH), 3.16 (6 H, s, OCH3), 1.76 (6 H, s, CH3),
1.42 [18 H, s, C(CH3)3]. 13C NMR (125 MHz, CDCl3): d =
156.4 (C), 141.1 (C), 140.6 (C), 137.6 (C), 133.3 (C), 133.1
(C), 131.5 (q, J = 33.5 Hz, C), 131.1 (CH), 129.2 (CH), 123.5
(q, J = 271.0 Hz, CF3), 120.8 (q, J = 7.7 Hz, CH), 60.7 (CH3),
35.1 (C), 31.1 (CH3), 18.2 (CH3). MS (EI): m/z calcd for
C40H38F12O2: 778.2675; found: 778.2667 [M]+.
Preparation of 5,5¢-Di-tert-butyl-4,4¢-dimethoxy-2,2¢-
bisbromomethyl-3,3¢-(3,5-bistrifluoromethylphenyl)-
biphenyl (6b)
To a solution of 5,5¢-di-tert-butyl-4,4¢-dimethoxy-2,2¢-
dimethyl-3,3¢-(3,5-bistrifluoromethylphenyl)biphenyl (1.85
g, 2.37 mmol) in CCl4 (30 mL) was added NBS (0.88 g, 4.97
mmol) and AIBN (5 mg). The mixture was placed under an
argon atmosphere and heated at reflux for 20 min using a 60
W light bulb (1 cm from flask). The mixture was then cooled
to r.t., filtered through silica gel, and concentrated under
reduced pressure to give the product (2.11 g, 95%) as a
colourless solid.
Preparation of 3,3¢-Dibromo-5,5¢-di-tert-butyl-2,2¢-
dimethyl-4,4¢-dihydroxybiphenyl
Copper(I) chloride (2.40 g, 24.0 mmol) was added to a
solution of TMEDA (3.84 mL, 25.0 mmol) in MeOH (600
mL). After stirring for 20 min, 6-tert-butyl-2-bromo-3-
methylphenol (58.9 g, 240 mmol) was added, the mixture
stirred under an air atmosphere for 3 d, then concentrated
under reduced pressure. The residue was dissolved in Et2O
and filtered through silica gel. The solution was again
concentrated under reduced pressure and the residue purified
by chromatography on silica gel to afford unreacted starting
material (36%) followed by the product (33.5 g, 58%, Rf =
0.4; PE–EtOAc, 9:1) as a colourless solid.
Mp 90–92 °C. IR (neat): nmax = 2964 cm–1. 1H NMR (400
MHz, CDCl3): d = 8.15 (2 H, s, ArH), 7.98 (2 H, s, ArH),
7.96 (2 H, s, ArH), 7.40 (2 H, s, ArH), 3.95 (2 H, d, J = 10.0
Hz, CHaHb), 3.89 (2 H, d, J = 10.0 Hz, CHaHb), 3.22 (6 H, s,
OCH3), 1.44 [18 H, s, C(CH3)3]. 13C NMR (100 MHz,
CDCl3): d = 157.4 (C), 143.9 (C), 138.9 (C), 135.8 (C), 134.1
(C), 132.8 (C), 131.7 (C, q, J = 33.5 Hz), 131.6 (C, q, J =
33.5 Hz), 131.1 (CH), 130.8 (CH), 130.3 (CH), 123.3 (C, q,
J = 273.0 Hz), 123.3 (C, q, J = 273.0 Hz), 121.7 (CH, m),
60.9 (CH3), 35.4 (C), 30.8 (CH3), 30.3 (CH2). MS (EI):
m/z calcd for C40H36O2F1281Br2: 938.0845; found:
938.0815[M]+.
Preparation of (R)-2,10-Di-tert-butyl-3,9-dimethoxy-6-
methyl-6-(1-naphthalen-1-ylethyl)-4,8-bis(3,5-bistri-
fluoromethylphenyl)-6,7-dihydro-5H-dibenzo[c,e]-
azepinium Bromide (1g)
Dibromide 6b (0.57 g, 0.61 mmol) was dissolved in MeCN
(15 mL) and CH2Cl2 (3 mL), then (R)-a-methylnaphth-1-
ylamine (0.13 g, 0.67 mmol) and anhyd K2CO3 (0.50 g 3.60
mmol) added. The mixture was stirred at 60 °C for 16 h then
filtered, and concentrated under reduced pressure. The
residue purified by recrystallisation (PhMe) to afford the
product 1g (0.45 g, 70%) as a colourless solid.
Mp 183–184 °C. IR (neat): nmax = 3494 cm–1. 1H NMR (400
MHz, CDCl3): d = 6.95 (2 H, s, ArH), 5.96 (2 H, s, OH), 2.09
(6 H, s, CH3), 1.40 [18 H, s, C(CH3)3]. 13C NMR (100 MHz,
CDCl3): d = 149.5 (C), 134.2 (C), 134.1 (C), 134.0 (C), 127.6
(CH), 116.0 (C), 35.2 (C), 29.6 (CH3), 20.9 (CH3). MS (EI):
m/z calcd for C22H28O281Br2: 482.0450; found: 482.0456
[M]+.
Preparation of 3,3¢-Dibromo-5,5¢-di-tert-butyl-4,4¢-
dimethoxy-2,2¢-dimethylbiphenyl (5)
Methyl iodide (3.8 mL, 60.9 mmol) was added dropwise to
a mixture of 3,3¢-dibromo-5,5¢-di-tert-butyl-2,2¢-dimethyl-
4,4¢-dihydroxybiphenyl (11.8 g, 24.4 mmol) and anhyd
K2CO3 (10.1 g, 73.1 mmol) in dry DMF (300 mL). The
mixture was stirred at r.t. for 18 h, then H2O (350 mL) added,
and the solution extracted with EtOAc (2 × 200 mL). The
combined extracts were washed with brine (2 × 200 mL),
dried (MgSO4), and concentrated under reduced pressure.
The residue was purified by chromatography on silica gel
(Rf = 0.3; PE–EtOAc, 49:1) to give the product (12.2 g,
98%) as a colourless solid.
Mp 105–107 °C. IR (neat): nmax = 3048, 2960, 2868, 2841
cm–1. 1H NMR (400 MHz, CDCl3): d = 7.00 (2 H, s, ArH),
3.96 (6 H, s, OCH3), 2.10 (6 H, s, CH3), 1.39 [18 H, s,
C(CH3)3]. 13C NMR (100 MHz, CDCl3): d = 155.8 (C), 141.6
(C), 137.7 (C), 135.8 (C), 127.5 (CH), 122.0 (C), 61.5 (CH3),
35.3 (C), 31.1 (CH3), 21.0 (CH3). MS (EI): m/z calcd for
C24H32O279Br81Br: 512.0743; found: 512.0752[M]+.
Preparation of 5,5¢-Di-tert-butyl-4,4¢-dimethoxy-2,2¢-
dimethyl-3,3¢-(3,5-bistrifluoromethylphenyl)biphenyl
3,5-Bistrifluoromethylphenylboronic acid (7.56 g, 29.3
mmol) was added to a solution of 5 (5.00 g, 9.76 mmol) in
degassed THF (175 mL), then degassed 2 M aq K2CO3 (115
mL) and Pd(PPh3)4 (1.13 g, 0.98 mmol) were added. The
mixture was heated at 70 °C for 24 h under a nitrogen
atmosphere, then cooled to r.t., acidified with 2 M HCl, and
extracted with Et2O (2 × 100 mL). The combined extracts
Mp 102–104 °C. [a]D +78 (c 0.4, CHCl3). IR (neat): nmax
=
2964 cm–1. 1H NMR (400 MHz, CDCl3): d = 8.28 (1 H, s,
ArH), 8.07 (2 H, s, ArH), 8.04 (1 H, s, ArH), 7.95 (1 H, d,
J = 8.0 Hz, ArH), 7.91 (1 H, dd, J = 8.0, 1.0 Hz, ArH), 7.85
(1 H, s, ArH), 7.55 (1 H, s, ArH), 7.54 (1 H, s, ArH), 7.49 (1
H, dd, J = 7.5, 7.0 Hz, ArH), 7.39–7.28 (3 H, m, ArH), 7.07
(1 H, d, J = 8.5 Hz, ArH), 6.80 (1 H, s, ArH), 5.51 (1 H, d,
J = 15.0 Hz, NCHaHb), 5.20 (1 H, q, J = 6.5 Hz, CHCH3),
4.19 (1 H, d, J = 15.0 Hz, NCHaHb), 3.38 (1 H, d, J = 13.0
Hz, NCHaHb), 3.19 (3 H, s, OCH3), 3.02 (3 H, s, OCH3), 2.98
(3 H, s, NCH3), 2.81 (1 H, d, J = 13.0 Hz, NCHaHb), 1.60 [9
H, s, C(CH3)3], 1.46 [9 H, s, C(CH3)3], 1.09 (3 H, d, J = 6.5
Hz, NCHCH3). 13C NMR (100 MHz, CDCl3): d = 158.3 (C),
128.1 (C), 147.9 (C), 147.8 (C), 137.8–119.4 (complex CAr
and CF3), 62.3 (CH), 61.2 (CH3), 61.0 (CH3), 59.7 (CH2),
57.9 (CH2), 43.2 (CH3), 36.0 (C), 35.8 (C), 30.9 (CH3), 30.8
(CH3), 15.9 (CH3). 19F NMR (282 MHz, CDCl3, referenced
to CFCl3 = 0 ppm): d = –62.1, –62.9, –63.2, –63.3. MS (ES+):
Synlett 2009, No. 4, 675–680 © Thieme Stuttgart · New York

CLUSTER
Chiral Dibenzazepinium Halide Phase-Transfer Catalysts
679
m/z calcd for C53H50F12NO2: 960.3644; found: 960.3682 [M
The residue was purified by chromatography on silica gel
(Rf = 0.2; CHCl3–MeOH, 19:1) to give the product as a pale
yellow solid (20.4 mg, 82%).
– Br]+.
(8) Representative Procedures for Route B
Preparation of 3,3¢-Dibromo-5,5¢-di-tert-butyl-4,4¢-
dimethoxy-2,2¢-bisbromomethylbiphenyl
Mp 151–153 °C. [a]D +25 (c 0.2, CHCl3). IR (neat): nmax
=
2924 cm–1. 1H NMR (400 MHz, CDCl3): d = 8.29 (1 H, s,
ArH), 7.97–7.94 (2 H, m, ArH), 7.90 (1 H, s, ArH), 7.82 (1
H, s, ArH), 7.61 (1 H, s, ArH), 7.57 (1 H, s, ArH), 7.42–7.22
(3 H, m, ArH), 7.13–7.11 (1 H, m, ArH), 6.97 (2 H, d, J = 7.5
Hz, ArH), 5.32 (1 H, d, J = 15.5 Hz, CHaHb), 4.08 (1 H, d,
J = 15.5 Hz, CHaHb), 4.00–3.96 (1 H, m, CH), 3.38 (1 H, d,
J = 11.5 Hz, CHaHb), 3.16 (3 H, s, OCH3), 3.12 (3 H, s,
OCH3), 2.93–2.85 (4 H, m, NCH3 and CHaHb), 1.54 [9 H, s,
Bromination of 5 was performed as described for 6b, to give
the product (100%) as a colourless solid.
Mp 206–207 °C. IR (neat): nmax = 3054, 2966, 2869 cm–1. 1H
NMR (400 MHz, CDCl3): d = 7.24 (2 H, s, ArH), 4.49 (2 H,
d, J = 10.0 Hz, CHaHb), 4.19 (2 H, d, J = 10.0 Hz, CHaHb),
4.01 (6 H, s, OCH3), 1.42 [18 H, s, C(CH3)3]. 13C NMR (100
MHz, CDCl3): d = 157.3 (C), 145.1 (C), 136.3 (C), 134.6
(C), 128.5 (CH), 122.4 (C), 61.8 (CH), 35.8 (C), 33.2 (CH2),
30.9 (CH3). MS (EI): m/z calcd for C24H30O279Br281Br2:
669.8930; found: 669.8893[M]+.
C(CH3)3], 1.50 [9 H, s, C(CH3)3], 0.90 (3 H, m, CH3). 13
C
NMR (125 MHz, CDCl3): d = 158.2 (C), 158.1 (C), 147.9
(C), 147.6 (C), 137.9 (C), 137.7 (C), 137.5 (C), 136.8 (C),
135.2 (C), 133.3 (C, q, J = 34.0 Hz), 132.6 (C, q, J = 33.5
Hz), 132.6 (C, q, J = 33.5 Hz), 131.9 (CH), 131.8 (CH),
131.7 (C, m, obscured), 131.6 (CH), 130.9 (C), 130.1 (CH),
129.6 (CH), 129.4 (CH), 129.3 (C), 129.2 (CH), 124.7 (C),
123.3 (C), 122.9 (C, q, J = 273.0 Hz), 122.7 (C, q, J = 273.0
Hz), 122.7 (C, q, J = 274.0 Hz), 122.5 (CH), 122.4 (C, q, J =
273.0 Hz), 121.8 (CH), 70.7 (CH), 61.3 (CH3), 61.1 (CH3),
59.6 (CH2), 59.3 (CH2), 43.1 (CH3), 35.8 (C), 35.7 (C), 30.7
(CH3), 30.7 (CH3), 15.3 (CH3). MA (ES+): m/z calcd for
C49H48NO2F12: 910.3488; found: 910.3453[M – I]+.
(9) For a review of glycine imine chemistry see: O’Donnell,
M. J. Aldrichimica Acta 2001, 34, 3.
(10) For examples of application in target synthesis, see:
(a) Wang, Y.-G.; Ueda, M.; Wang, X.; Han, Z.; Maruoka, K.
Tetrahedron 2007, 63, 6042. (b) Lee, J.-H.; Jeong, B.-S.;
Ku, J.-M.; Jew, S.-S.; Park, H.-G. J. Org. Chem. 2006, 71,
6690. (c) Lygo, B.; Slack, D.; Wilson, C. Tetrahedron Lett.
2005, 46, 6629. (d) Fukuta, Y.; Ohshima, T.; Gnanadesikan,
V.; Shibuguchi, T.; Nemoto, T.; Kisugi, T.; Okino, T.;
Shibasaki, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5433. (e) Lygo, B.; Humphreys, L. D. Synlett 2004, 2809.
(f) Kim, S.; Lee, J.; Lee, T.; Park, H.-G.; Kim, D. Org. Lett.
2003, 5, 2703. (g) Armstrong, A.; Scutt, J. N. Org. Lett.
2003, 5, 2331. (h) Lygo, B.; Andrews, B. I. Tetrahedron
Lett. 2003, 44, 4499. (i) Boeckman, R. K. Jr.; Clark, T. J.;
Shook, B. C. Org. Lett. 2002, 4, 2109.
Preparation of (R)-4,8-Bisbromo-2,10-di-tert-butyl-3,9-
dimethoxy-6-(1-phenylethyl)-6,7-dihydro-5H-dibenzo-
[c,e]azepine (7a)
To a stirred solution of 3,3¢-dibromo-5,5¢-di-tert-butyl-4,4¢-
dimethoxy-2,2¢-bisbromomethylbiphenyl (221 mg, 0.33
mmol) in CHCl3 (10 mL) was added (R)-1-phenylethyl-
amine (38.7 mL, 0.30 mmol) and anhyd K2CO3 (0.27 g, 1.98
mmol). The mixture was stirred at 60 °C for 18 h then
filtered and concentrated under reduced pressure. The
residue was purified by chromatography on silica gel (Rf =
0.6; Et2O–PE, 1:4) to yield the product (160 mg, 85%) as
colourless crystals.
Mp 88–92 °C. [a]D22 +14 (c 0.7, CHCl3). IR (neat): nmax
=
2957 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.55 (1 H, s,
ArH), 7.53 (1 H, s, ArH), 7.39–7.32 (4 H, m, ArH), 7.30–
7.23 (1 H, m, ArH), 4.10–3.00 (5 H, m, 2 × CH2 and CH),
3.99 (6 H, s, OCH3), 1.47 [18 H, s, C(CH3)3], 0.90 (3 H, m,
CH3). 13C NMR (100 MHz, CDCl3): d = 156.4 (C), 146.1
(C), 144.0 (C), 137.6 (C) 135.0 (C), 128.2 (CH), 127.7 (CH),
126.8 (CH), 125.5 (CH), 122.0 (C), 61.7 (CH3), 52.4 (CH2),
35.5 (C), 31.0 (CH3), 23.3 (CH3). MS (ES+): m/z calcd for
C32H40NO279Br2: 628.1420; found: 628.1456 [M + H]+.
Preparation of (R)-2,10-di-tert-butyl-3,9-dimethoxy-6-
(1-phenylethyl)-4,8-bis(3,5-bistrifluoromethylphenyl)-
6,7-dihydro-5H-dibenzo[c,e]azepine (8a)
Reaction of (R)-4,8-dibromo-2,10-di-tert-butyl-3,9-
dimethoxy-6-(1-phenylethyl)-6,7-dihydro-5H-dibenzo-
[c,e]azepine with 3,5-bistrifluoromethylphenylboronic acid
was performed using the coupling procedure described
above. The residue was purified by chromatography on silica
gel (Rf = 0.2; CH2Cl2–PE, 1:4) to give the product (63%) as
colourless crystals.
Mp 101 °C; [a]D +1 (c 0.1, CHCl3). IR (neat): nmax = 2977
cm–1. 1H NMR (400 MHz, CDCl3): d = 8.40–8.20 (2 H, m,
ArH), 7.83 (2 H, s, ArH), 7.80–7.70 (1 H, m, ArH), 7.55 (2
H, s, ArH), 7.36 (1 H, s, ArH), 7.02–6.98 (3 H, m, ArH),
6.81–6.79 (2 H, m, ArH), 3.80–3.55 (2 H, m, CH2), 3.20–
3.05 (3 H, m, CH and CH2), 3.09 (6 H, s, OCH3), 1.51 [18 H,
s, C(CH3)3], 0.95–0.80 (3 H, m, CH3). 13C NMR (100 MHz,
CDCl3): d = 156.9 (C), 142.8 (C), 139.6 (C), 137.5 (C),
133.2–121.1 (complex C, CH, CF3), 61.1 (CH), 60.5 (CH3),
48.5 (CH2), 35.3 (C), 31.0 (CH3). MS (ES+): m/z calcd for
C48H46NO2F12: 896.3331; found: 896.3455 [M + H]+.
Preparation of (R)-2,10-Di-tert-butyl-3,9-dimethoxy-6-
methyl-6-(1-phenylethyl)-4,8-bis(3,5-bistrifluoromethyl-
phenyl)-6,7-dihydro-5H-dibenzo[c,e]azepinium Iodide
(2a)
(11) General Procedure for the Alkylation of Glycine Imine 9
with Benzyl Bromide
A mixture of the catalyst (1 mol%) and imine 9 (50 mg, 0.17
mmol) in PhMe (2 mL) was degassed, placed under nitrogen,
and cooled to 0 °C. Benzyl bromide (35 mg, 0.20 mmol) was
added followed by 15 M aq KOH (1 mL) and the mixture
stirred at 0 °C for 3 h. The mixture was then diluted with
H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The
combined extracts were dried (Na2SO4), concentrated under
reduced pressure, and purified by chromatography on silica
gel (Rf = 0.5; PE–EtOAc–Et3N, 89:10:1) to give 10 as a
colourless oil.
1H NMR (400 MHz, CDCl3): d = 7.59–7.56 (2 H, m, ArH),
7.38–7.26 (6 H, m, ArH), 7.20–7.14 (3 H, m, ArH), 7.06–
7.03 (2 H, m, ArH), 6.61 (2 H, d, J = 6.5 Hz, ArH), 4.11 (1
H, dd, J = 9.0, 4.5 Hz, CH), 3.23 (1 H, dd, J = 13.5, 4.5 Hz,
CHaHb), 3.16 (1 H, dd, J = 13.5, 9.0 Hz, CHaHb), 1.44 [9 H,
s, C(CH3)3]. These 1H NMR data are in agreement with those
previously recorded.4d HPLC: Chiralcel OD-H (25 × 0.46
cm + guard) hexane–2-PrOH (100:1), 0.5 mL min–1; tR =
14.8 min (R)-isomer; tR = 28.2 min (S)-isomer.
Methyl iodide (200 mL, 3.2 mmol) was added to a solution of
tertiary amine 8a (16 mg, 24 mmol) in CHCl3 (1.5 mL). The
mixture stirred at 60 °C in a sealed tube for 2 h. After cooling
to r.t., the solution was concentrated under reduced pressure.
(12) For a discussion relating to enantiomeric enrichment of
scalemic amino acid derivatives by crystallisation, see:
O’Donnell, M. J.; Delgado, F. Tetrahedron 2001, 57, 6641.
Synlett 2009, No. 4, 675–680 © Thieme Stuttgart · New York

680
B. Lygo et al.
CLUSTER
added followed by anhyd Cs2CO3 (0.06 mmol) and the
(13) See, for example: (a) Lygo, B.; Kirton, E. H. M.; Lumley, C.
Org. Biomol. Chem. 2008, 6, 3085. (b) Shibuguchi, T.;
Mihara, H.; Kuramochi, A.; Sakuraba, S.; Ohshima, T.;
Shibasaki, M. Angew. Chem. Int. Ed. 2006, 45, 4635.
(c) van der Werf, A.; Kellogg, R. M. Tetrahedron Lett. 1991,
32, 3727.
(14) See, for example: (a) Shibuguchi, T.; Mihara, H.;
Kuramochi, A.; Ohshima, T.; Shibasaki, M. Chem. Asian J.
2007, 2, 794. (b) Arai, S.; Takahashi, F.; Tsuji, R.; Nishida,
A. Heterocycles 2006, 67, 495. (c) Akiyama, T.; Hara, M.;
Fuchibe, K.; Sakamoto, S.; Yamaguchi, K. Chem. Commun.
2003, 1734. (d) O’Donnell, M. J.; Delgado, F.; Dominguez,
E.; de Blas, J.; Scott, W. L. Tetrahedron: Asymmetry 2001,
12, 821. (e) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron
Lett. 1998, 39, 5347.
mixture stirred at 0 °C for 2 h. The mixture was then filtered
and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (Rf = 0.2; PE–
EtOAc–Et3N, 89:10:1) to give 12 as a colourless oil.
IR (CHCl3): nmax = 1739, 1715, 1622 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.67–7.63 (2 H, m, ArH), 7.43–7.26 (16
H, m, ArH), 7.10–7.06 (2 H, m, ArH), 6.89 (1 H, s, CHPh2),
4.19 (1 H, app. t, J = 6.0 Hz, NCH), 2.58–2.50 (1 H, m),
2.44–2.36 (1 H, m), 2.23–2.18 (2 H, m), 2.05 (3 H, s, Me).
13C NMR (100 MHz, CDCl3): d = 208.0 (C), 171.0 (C),
170.7 (C), 140.0 (2 × C), 139.3 (C), 136.1 (C), 130.5 (CH),
128.8 (CH), 128.7 (CH), 128.6 (CH), 128.5 (2 × CH), 128.1
(CH), 128.0 (CH), 127.9 (CH), 127.7 (CH), 127.4 (CH),
127.0 (CH), 77.2 (CH), 64.1 (CH), 39.5 (CH2), 29.9 (CH3),
27.5 (CH2). MS (CI): m/z calcd for C32H30NO3: 476.2226;
found: 476.2241[M + H]+. HPLC: Chiralpak AD (25 × 0.46
cm + guard), hexane–2-PrOH (95:5), 1.0 mL min–1; tR = 23.7
min (R)-isomer; tR = 29.5 min (S)-isomer.
(15) General Procedure for the Michael Addition of Glycine
Imine 11 to MVK
A mixture of imine 11 (0.12 mmol) and catalyst (1 mol%) in
i-Pr2O (4 mL) was cooled to 0 °C. MVK (0.24 mmol) was
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