Atroposelective formation of dibenz[c,e]azepines via intramolecular direct arylation with centre-axis chirality transfer

Article abstract of DOI:10.1039/c0ob00889c

5-Substituted 6,7-dihydrodibenz[c,e]azepines, a class of secondary amine incorporating a centre-axis chirality relay, are accessible from 1-substituted N-(2-bromobenzyl)-1-phenylmethanamines via N-acylation and ring-closing intramolecular direct arylation. The ring closure proceeds with high atropodiastereoselectivity due to strain effects that are induced by trigonalisation of the nitrogen atom, as predicted using molecular mechanics calculations.

Full text of DOI:10.1039/c0ob00889c

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 1831
www.rsc.org/obc
PAPER
Atroposelective formation of dibenz[c,e]azepines via intramolecular direct
arylation with centre-axis chirality transfer†
Caroline A. Cheetham, Richard S. Massey, Silvain L. Pira, Robin G. Pritchard and Timothy W. Wallace*
Received 16th October 2010, Accepted 10th December 2010
DOI: 10.1039/c0ob00889c
5-Substituted 6,7-dihydrodibenz[c,e]azepines, a class of secondary amine incorporating a centre-axis
chirality relay, are accessible from 1-substituted N-(2-bromobenzyl)-1-phenylmethanamines via
N-acylation and ring-closing intramolecular direct arylation. The ring closure proceeds with high
atropodiastereoselectivity due to strain effects that are induced by trigonalisation of the nitrogen atom,
as predicted using molecular mechanics calculations.
The importance of biaryls in biological, synthetic and materials
chemistry has inspired the development of numerous methods
Introduction
for their assembly with control of axial chirality,3,4 a common
strategy being to link a pair of functionalised aryl units through a
centrally chiral tether prior to aryl–aryl coupling, which may then
proceed atroposelectively. With this in mind, we were attracted
by the retrosynthesis shown in Fig. 1, as it allows the centre-
axis relay to direct its own atroposelective formation and exploits
the availability of numerous amines of the form 7 in enantiopure
form.5
Three-atom bridged biaryls have unique conformational fea-
tures arising from their connectivity, which obliges the Ar–
bridge and Ar–Ar bonds to twist in concert. In 6,7-dihydro-
5H-dibenz[c,e]azepines 1 this has the effect of transforming
conformational bias at the benzylic carbon atoms into torque
at the biaryl axis and vice versa, so that in the presence of a
substituent at C(5) or C(7) the system operates as a centre-axis
chirality relay that can be controlled through substitution at N(6).
This is illustrated by the behavior of the amines (-)-2 and (-)-3,
whose respective Boc derivatives (+)-4 and (+)-5 have inverted,
conformationally stable, biaryl axes, as predicted on the basis
of molecular mechanics calculations.1 As a corollary it can be
suggested that the dynamics of the biaryl axis in derivatives of 1,
which are potential tropos ligands,2 will be subject to the integrated
effect of all pairwise interactions between adjacent substituents on
C(4), C(5), N(6), C(7) and C(8), in addition to those at the usual
biaryl control sites, C(1) and C(11). To facilitate a broad study of
this phenomenon we required a more flexible synthetic route to
amines such as (-)-2, which we first prepared from the lactam 6
and used as the precursor to 3–5.1
Fig. 1 Proposed atroposelective route to dibenz[c,e]azepines.
A literature search revealed that the existing Ar–Ar coupling
routes to dibenz[c,e]azepines lack generality,6,7 involve toxic
reagents6,8,9 or use activating substituents in both coupling part-
ners (X, Y = I, Br, OTf, etc.).8–10 However, a potential solution
to this problem was offered by intramolecular direct arylation,
which Fagnou and coworkers had shown to be capable of closing
seven-membered rings.11–13 We now report the successful use of this
methodology14 in concise atroposelective routes to 5-substituted
6,7-dihydro-5H-dibenz[c,e]azepines.
Synthesis of Materials
We initially targeted the amine (+)-2, preparing the substituted
dibenzylamine required for the cyclisation step in a reductive
amination sequence (Scheme 1). The condensation of (S)-1-
phenylethylamine (-)-8 with o-bromobenzaldehyde 9 gave the
imine 10, which was reduced to the amine 11 in good yield.
Trifluoroacetylation gave the corresponding amide 12 as a mixture
of E- and Z-rotamers (ratio ca. 2 : 1).15
School of Chemistry, The University of Manchester, Oxford Road, Manch-
ester, UK, M13 9PL. E-mail: tim.wallace@manchester.ac.uk; Fax: +44 (0)
161 275 4939
1
† Electronic supplementary information (ESI) available: H, 13C and 19F
NMR spectra; structures generated via molecular mechanics calculations.
CCDC reference number 793197. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0ob00889c
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 1831–1838 | 1831
©

View Article Online
Scheme 2 Preparation of amines 2 and 22 via N-alkylation.
Boc azepine (-)-4 (50%) which was confirmed as the pure (5S,aS)-
diastereoisomer by NMR [dH (400 MHz, CDCl3) 0.88 (3 H, d, J =
7 Hz, 5-Me)] and polarimetry {[a]2D4 -322 9 (c 0.61, CHCl3); lit.1
for (5R)-4 [a]2D5 +321 10 (c 0.82, CHCl3)}. The conversion of
(-)-4 into (+)-2 (87%) was effected with phosphoric acid in THF.17
The N-alkylation route was also used to assemble the amine 22
via a short sequence in which the intramolecular direct arylation
also effects the desymmetrisation of a diphenylmethyl group.
Thus, treating the Boc derivative 19 of diphenylmethylamine with
base and 17 gave the alkylation product 20 in 80% yield. The
Pd-mediated cyclisation of 20 gave the carbamate ( )-21 (72%),
which was shown to be the 5-axial diastereoisomer by X-ray
crystallography (Fig. 2). Hydrolysis of ( )-21 with phosphoric acid
gave the amine ( )-22 (96%) as colorless crystals, m.p. 117–118 ◦C.
Scheme 1 Preparation of amine 2 via reductive amination.
Discussion
The cyclisation of 12 under Fagnou’s original conditions,11b
using 0.1 mol equivalents each of Pd(OAc)2 and the phosphine 13,
provided the product 14 in 60% yield as a 9 : 1 mixture of rotamers
(mainly 14a). The by-product 15, expected to arise through
reductive debromination of12, was detected inthe productmixture
but its formation was observed to be minimal when the ligand:Pd
ratio did not exceed 1 : 1. The pseudoaxial orientation of the methyl
groups in each of the rotamers of 14 is apparent from their upfield
chemical shifts [dH (400 MHz, CDCl3) 0.92 and 0.97 respectively],
which confirm their proximity to the A-ring, and that the biaryl
axis is therefore (S)-configured. Hydrolysis of 14 gave the amine
(+)-2 (97%), whose structure and configuration were confirmed by
comparison with a sample of (-)-2.1
As an alternative route to the amine 2, we established that a
cyclisation substrate can also be assembled using N-alkylation as
the key step (Scheme 2).16 Treatment of the Boc derivative 16, de-
rived from (S)-8, with base and then 17 gave the alkylation product
18 in moderate yield. The cyclisation of 18 was attempted using
Fagnou’s later conditions,12 in which the reaction temperature is
130 ◦C and acetate is supplanted with pivalate. This provided the
The distinctive features of 21 and 22 serve to illustrate how the
axial configuration, and associated properties, of a 5-substituted
dibenz[c,e]azepine can be induced to ‘switch’ by changing the N-
1
substituent. The H NMR spectra of both of these compounds
display resonances attributable to upfield-shifted aromatic pro-
tons, two at 6.6 ppm for 21 (Fig. 2b) and one at 6.8 ppm for
22 (Fig. 2c). On the basis of the X-ray data, the upfield signal
from the carbamate 21 can be assigned to H(2¢) and H(6¢), which
˚
pass within 3 A of the face of the biaryl A-ring as the phenyl group
rotates and thus experience a shielding effect. In contrast, it is clear
from molecular mechanics calculations that the phenyl group in
the parent amine 22 prefers a pseudoequatorial orientation, from
where it exerts a local shielding effect on H(4), the upfield-shifted
proton in this case. The switchable features of amines such as 22
should provide new opportunities for probing the edge-to-face
interactions of aromatic rings.18
The key step in this approach to dibenz[c,e]azepines is an
intramolecular direct arylation that proceeds with high atropo-
diastereoselectivity. The detailed mechanism of Pd-mediated
arylation remains the subject of speculation, but the generally
1832 | Org. Biomol. Chem., 2011, 9, 1831–1838
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
conformational minima (Fig. 3). The DE values (12–20 kJ mol-1)
are◦consistent with conformational equilibria dominated (>99% at
25 C) by the respective (5S,aS)-diastereoisomers, which behave
as ‘fixed axis’ systems despite lacking the usual axis-restraining
features, viz. substituents at C(1) and C(11) or the fusion of a
5-membered ring to the C(5)–N(6) bond.19
Conclusions
We have described two variants of a new route to 5-substituted
6,7-dihydrodibenz[c,e]azepines, a unique class of secondary amine
incorporating a centre-axis chirality relay. In both variants the
pivotal step is the ring closure of an N-acylated 1-substituted
N-(2-bromobenzyl)-1-phenylmethanamine via Pd-mediated in-
tramolecular direct arylation, which proceeds with high atropodi-
astereoselectivity due to strain effects that can be predicted using
molecular mechanics calculations. We are currently exploring
the scope of these reactions in various synthetic contexts, and
evaluating the potential of the dibenzazepine centre-axis relay as
a mechanistic and structural tool.
EXPERIMENTAL
Melting points were determined using a Kofler hot-stage or Stuart
Scientific SMP10 apparatus and are uncorrected. IR spectra were
recorded for neat thin films using Perkin–Elmer FT-IR Spectrum
RX1 or BX spectrometers. NMR spectra were recorded on Bruker
DPX300 or Avance 400 spectrometers and calibrated internally
by reference to signals from the solvent (CDCl3 at 77.16 ppm
for 13C spectra; CHCl3 at 7.26 ppm for 1H spectra)20 or externally
(referenced to CFCl3 at 0 ppm for 19F spectra). Coupling constants
(J values) are given in Hz; multiplicities are given as singlet (s),
doublet (d), triplet (t), quartet (q), quintet (qn) or multiplet (m).
NMR spectra were assigned with the aid of COSY, HMBC,
HMQC and DEPT spectra where appropriate. Low-resolution
mass spectra were recorded on a Micromass Trio 2000 instrument
using the electrospray ionisation method; data for most of the
peaks of intensity <20% of that of the base peak are omitted. High-
resolution (accurate mass) data were recorded using a Thermo
Finnigan MAT95XP instrument. HPLC analyses were carried
out using a PE Series 200 system with Gemini ODS column
(25 cm ¥ 4.6 mm, 5 #x3bc;m) and the following parameters:
column temperature ambient; mobile phase A methanol, mobile
phase B water, A : B 70 : 30; flow rate 1 mL min-1; injection volume
1 mL, detection at 254 nm. Elemental analyses were carried out by
the University of Manchester microanalytical services using Carlo
Erba EA1108 equipment. Optical rotations were measured at 589
nm using an AA-100 polarimeter (Optical Activity Ltd.).
Fig. 2 (a) Structures of 21 and 22 showing the edge-to-face interactions
of the aromatic rings; (b), (c) Aromatic regions of 400 MHz 1H NMR
spectra of 21 and 22 respectively.
accepted sequence13 would start with the oxidative addition of
a Pd(0) species to the bromoaryl subunit of the substrate, and
proceed to a palladacycle 23 via an electrophilic substitution
(under the conditions used in Scheme 2, this may feature pivalate
in a proton-transfer role12). The final product is formed when the
palladacycle 23 undergoes reductive elimination of the Pd moiety,
which returns to the catalytic cycle (Fig. 3). The stereoselectivity
of this final step is essentially complete, with the (S)-configured
precursor 23 being transformed into an (aS)-configured biaryl.
The origin of this selectivity is ultimately the carbonyl substituent
on N(6), whose presence causes the 5-substituent to favour an
axial orientation. Molecular mechanics calculations were used
to quantify this preference in the form of the difference in
steric energy (DE) between the respective (5S,aS) and (5S,aR)
Reactions were routinely carried out under nitrogen.
Most reagents and solvents were used as supplied com-
mercially, including anhydrous N,N-dimethylacetamide (DMA;
Sigma Aldrich 271012). Anhydrous THF was distilled from
sodium/benzophenone ketyl immediately before use.21 Organic
solutions were dried using anhydrous magnesium sulfate and
concentrated by rotary evaporation. TLC was carried out using
Macherey–Nagel Polygram SIL G/UV254 plates and the chro-
matograms were routinely visualised using UV light (254 nm) and
alkaline aq. KMnO4. Preparative column (flash) chromatography
was carried out on 60H silica gel (Merck 9385) using the flash
Fig. 3 Generalised precursor and product isomers in the catalytic cycles
leading to 4, 14 and 21, with the difference in steric energy (DE) between
the isolated product and the alternative least-strained axial invertomer
(Macromodel 8.0, MM3).
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 1831–1838 | 1833
©

View Article Online
C17H15BrF3NO requires C, 52.87; H, 3.91; N, 3.63%); [a]2D4 -49
technique.22 Compositions of solvent mixtures are quoted as ratios
of volume. ‘Ether’ refers to diethyl ether. ‘Petrol’ refers to a fraction
of light petroleum, b.p. 60–80 ◦C, unless indicated otherwise.
2
(c 1.2, CHCl3); nmax/cm-1 (film) 1681, 1448, 1197, 1183, 1133, 1078,
1027, 748, 728, 694, 670; dH (400 MHz, CDCl3) (2 : 1 mixture of
rotamers a and b) 7.49 (0.33 H, dd, J 1.0, 8.0 Hz, ArH, rotamer b),
7.44 (0.66 H, dd, J 1.0, 8.0 Hz, ArH, rotamer a), 7.37–7.22 (5.33
H, m, ArH, rotamers a and b), 7.18 (0.66 H, dt, J 1.0, 7.5 Hz,
ArH, rotamer a), 7.13–7.09 (0.66 H, m, ArH, rotamer a), 7.04
(0.66 H, dt, J 1.5, 7.5 Hz, ArH, rotamer a), 6.92 (0.66 H, d, J
8.0 Hz, ArH, rotamer a), 5.73 (0.33 H, q, J 7.1 Hz, NCHCH3,
rotamer b), 5.48 (0.66 H, q, J 6.9 Hz, NCHCH3, rotamer a),
4.67 (0.66 H, d, J 16.5 Hz, NCHAHB, rotamer a), 4.62 (0.33 H,
d, J 18.2 Hz, NCHAHB, rotamer b), 4.53 (0.33 H, d, J 18.2 Hz,
NCHAHB, rotamer b), 4.28 (0.66 H, d, J 16.5 Hz, NCHAHB,
rotamer a), 1.59 (2 H, d, J 6.9 Hz, NCHCH3, rotamer a), 1.51 (1
H, d, J 7.1 Hz, NCHCH3, rotamer b); dC (100 MHz, CDCl3) (2 : 1
mixture of rotamers) 158.2 (C, q, J 35.5 Hz, rotamer b), 157.5 (C,
q, J 35.5 Hz, rotamer a), 138.6 (C, rotamer a), 137.7 (C, rotamer
b), 135.6 (C, rotamer a), 135.1 (C, rotamer b), 132.7 (CH, rotamer
b), 132.6 (CH, rotamer a), 129.0 (CH), 128.9 (CH), 128.7 (CH),
128.5 (CH), 128.45 (CH), 128.3 (CH), 128.1 (CH), 127.8 (CH),
127.4 (CH), 127.3 (CH), 127.29 (CH), 122.2 (C), 121.9 (C), 117.0
(C, q, J 288 Hz, rotamer a), 116.5 (C, q, J 289 Hz, rotamer b),
56.0 (CH, q, J 3 Hz, rotamer a), 55.9 (CH, rotamer b), 48.2 (CH2,
q, J 3 Hz, rotamer b), 46.8 (CH2, rotamer a), 18.0 (CH3, rotamer
a), 17.2 (CH3, rotamer b); dF (376.5 MHz, CDCl3) (2 : 1 mixture
of rotamers) -67.5 (2 F, s, rotamer a), -68.8 (1 F, s, rotamer b);
m/z (ES+) 410 (MNa+, 43%), 408 (MNa+, 45) (Found: MNa+
408.0181; C17H15BrF3NONa requires 408.0182); Rf 0.74 (hexane–
EtOAc, 3 : 1); HPLC tR 40.0 min.
(S)-N-(2-Bromobenzylidene)-1-phenylethanamine 10
To a solution of (-)-1-phenylethylamine (S)-8 (6.45 mL, 6.14 g,
50 mmol) in toluene (50 mL) was added 2-bromobenzaldehyde
9 (5.84 mL, 9.26 g, 50 mmol) followed by p-toluenesulfonic acid
monohydrate (380 mg, 2.0 mmol). The mixture was heated to
145 ◦C (bath temperature) under Dean–Stark conditions for 5 h,
allowed to cool to room temperature and concentrated under
reduced pressure to afford the imine 10 (14.2 g, 98%) as a pale
yellow oil. The crude product, which was used directly in the next
step, had dH (400 MHz, CDCl3) 8.75 (1 H, s, N CH), 8.12 (1 H,
dd, J 2.0, 8.0 Hz, ArH), 7.56 (1 H, dd, J 1.5, 8.0 Hz, ArH), 7.45
(2 H, d, J 7.5 Hz, ArH), 7.38–7.31 (3 H, m, ArH), 7.28–7.26 (2
H, m, ArH), 4.63 (1 H, q, J 6.5 Hz, NCHCH3), 1.61 (3 H, d, J
6.5 Hz, NCHCH3); m/z (ES+) 290 (MH+, 100%), 288 (MH+, 90)
(Found: MH+ 288.0383; C15H15BrN requires 288.0383); Rf 0.76
(hexane–EtOAc, 3 : 1).
(S)-N-(2-Bromobenzyl)-1-phenylethanamine 11
A solution of the crude imine (S)-10 (13.9 g, 48 mmol) in EtOH
◦
(24 mL) was cooled to 0 C and NaBH4 (2.01 g, 53 mmol) was
added in five equal portions. On completion of the addition the
solution was allowed to warm to room temperature and stirred
for 18 h. The solution was concentrated under reduced pressure
and the residue taken up in ether (100 mL). The organic solution
was washed with sat. aq. NaHCO3 (2 ¥ 50 mL) and sat. aq.
NaCl (50 mL), dried and concentrated under reduced pressure.
Chromatography of the residue (hexane–EtOAc, 9 : 1) gave the
title compound 11 (12.9 g, 92%) as a colourless oil (Found: C,
61.8; H, 5.6; N, 4.8. C15H16BrN requires C, 62.08; H, 5.56; N,
4.83%); [a]2D4 -51 4 (c 1.2, CHCl3); nmax/cm-1 (film) 3058, 3020,
2963, 2924, 2863, 2840, 1491, 1465, 1450, 1440, 1121, 1025; dH
(400 MHz, CDCl3) 7.54 (1 H, dd, J 1.0, 8.0 Hz, ArH), 7.41–7.24
(7 H, m, ArH), 7.12 (1 H, td, J 1.8, 7.6 Hz, ArH), 3.83 (1 H, q, J
6.6 Hz, NHCHCH3), 3.74 (1 H, d, J 13.7 Hz, NHCHAHB), 3.69
(1 H, d, J 13.7 Hz, NHCHAHB), 1.82 (1 H, br s, NH) 1.38 (3 H,
d, J 6.6 Hz, NHCHCH3); dC (100 MHz, CDCl3) 145.4 (C), 139.6
(C), 132.9 (CH), 130.7 (CH), 128.7 (CH), 128.6 (CH), 127.5 (CH),
127.1 (CH), 126.9 (CH), 124.1 (C), 57.5 (CH), 51.8 (CH2), 24.7
(CH3); m/z (ES+) 292 (MH+, 100%), 290 (MH+, 92) (Found: MH+
290.0537; C15H17BrN requires 290.0539); Rf 0.55 (hexane–EtOAc,
3 : 1).
1-[(aS,5S)-5,7-Dihydro-5-methyl-6H-dibenz[c,e]azepin-6-yl]-
2,2,2-trifluoroethanone (-)-14
To a solution of (S)-12 (1.43 g, 3.7 mmol) in DMA (25 mL)
under nitrogen was added anhydrous K2CO3 (1.03 g, 7.4 mmol)
followed by Pd(OAc)2 (83 mg, 0.37 mmol) and DavePhos 13
(146 mg, 0.37 mmol), and the mixture was heated to 145 ◦C
(bath temperature) for 24 h. The mixture was allowed to cool to
room temperature, diluted with ether (25 mL) and sat. aq. NaCl
(65 mL) and the layers separated. The organic layer was washed
with sat. aq. NaCl (5 ¥ 65 mL), dried and concentrated under
reduced pressure. The residual brown oil was chromatogaphed
over silica gel (hexane–EtOAc, 19 : 1), affording the title compound
14 (679 mg, 60%) as an off-white solid, m.p. 114–116 ◦C; [a]D25 -301
10 (c 0.6, CHCl3); nmax/cm-1 (CHCl3) 3011, 1711, 1679, 1443,
1188, 1159; dH (400 MHz, CDCl3) (9 : 1 mixture of rotamers) 7.61–
7.50 (4 H, m, ArH, rotamers a and b), 7.46–7.28 (4 H, m, ArH,
rotamers a and b), 5.44 (0.9 H, q, J 7.0 Hz, 5-H, rotamer a), 5.26
(0.1 H, d, J 14.0 Hz, 7-Heq, rotamer b), 5.16 (0.1 H, br q, J 7.0 Hz,
5-H, rotamer b), 4.76 (0.9 H, dd, J 1.0, 14.0 Hz, 7-Heq, rotamer
a), 4.12 (0.9 H, d, J 14.0 Hz, 7-Hax, rotamer a), 3.83 (0.1 H, d, J
14.0 Hz, 7-Hax, rotamer b), 0.97 (0.3 H, d, J 7.0 Hz, 5-Me, rotamer
b), 0.92 (2.7 H, d, J 7.0 Hz, 5-Me, rotamer a); dC (100 MHz,
CDCl3) (9 : 1 mixture of rotamers, quoted signals for rotamer a
only) 154.2 (C, q, J 35.5 Hz), 140.9 (C), 138.9 (C), 137.3 (C), 132.4
(C), 130.6 (CH), 129.8 (CH), 129.6 (CH), 129.1 (CH), 128.8 (CH),
128.68 (CH), 128.67 (CH), 127.8 (CH), 116.8 (C, q, J 287.5 Hz),
58.5 (CH), 48.1 (CH2, q, J 3.5 Hz), 19.9 (CH3); m/z (ES+) 328
(S)-N-(2-Bromobenzyl)-2,2,2-trifluoro-N-(1-
phenylethyl)acetamide 12
A solution of the amine (S)-11 (6.20 g, 21.4 mmol) in pyridine
(40 mL) under nitrogen was treated with trifluoroacetic anhydride
(3.0 mL, 4.53 g, 21.6 mmol) and the solution was stirred at room
temperature for 24 h. The mixture was diluted with water (100 mL)
and CH2Cl2 (100 mL) and the layers separated. The organic layer
was washed with water (3 ¥ 100 mL), dried and concentrated
under reduced pressure. Chromatography of the residue (hexane–
EtOAc, 9 : 1) gave the title compound 12 (7.58 g, 92%) as a yellow
◦
crystalline solid, m.p. 52–54 C (Found: C, 52.8; H, 3.9; N, 3.5.
1834 | Org. Biomol. Chem., 2011, 9, 1831–1838
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
(MNa+, 100%) (Found: MNa+ 328.0920; C17H14F3NONa requires
328.0920); Rf 0.72 (hexane–EtOAc, 3 : 1); HPLC tR 29.0 min.
(2 g). The mixture was heated to 145 ◦C (bath temperature) for 5 h,
allowed to cool to room temperature and filtered through Celite.
Concentration of the filtrate under reduced pressure gave the imine
( )-N-benzylidene-1-phenylethanamine A as a pale yellow oil, dH
(300 MHz, CDCl3) 8.38 (1 H, s, N CH), 7.81–7.76 (2 H, m, ArH),
7.46–7.25 (8 H, m, ArH), 4.55 (1 H, q, J 6.5 Hz, CHCH3), 1.60 (3
Variation of conditions for Pd-catalysed ring closure
Five experiments were run using the procedure described for the
preparation of 14 (above), using the amide 12 (1 mol equiv.) and
K2CO3 (2 mol equiv.) and one of five different catalytic conditions
H, d, J 6.5 Hz, Me) {lit.23
dH (500 MHz, CDCl3) 8.38 (1 H, s), 4.56
(1 H, q, J 6.6 Hz), 1.60 (3 H, d, J 6.7 Hz)}; Rf 0.73 (hexane–EtOAc,
3 : 1). A solution of the crude A in EtOH (5 mL) was treated with
NaBH4 (62 mg, 1.6 mmol) and stirred at room temperature for
18 h. The solution was concentrated and the residue taken up
in ether (20 mL). The organic solution was washed with sat. aq.
NaHCO3 (3 ¥ 15 mL), dried and concentrated. Chromatography
of the residue (hexane–EtOAc, 9 : 1) gave the amine ( )-N-benzyl-
1-phenylethanamine B (164 mg, 66%) as a colourless oil, nmax/cm-1
(film) 3083, 3060, 3024, 2962, 2923, 1492, 1452, 1369, 1126, 1028,
761, 735, 699; dH (400 MHz, CDCl3) 7.38–7.22 (10 H, m, ArH),
3.82 (1 H, q, J 6.6 Hz, NHCHCH3), 3.66 (1 H, d, J 13.1 Hz,
NHCHAHB), 3.60 (1 H, d, J 13.1 Hz, NHCHAHB), 1.59 (1 H,
br s, NH) 1.37 (3 H, d, J 6.6 Hz, NHCHCH3); dC (100 MHz,
CDCl3) 145.7 (C), 140.8 (C), 128.6 (CH), 128.5 (CH), 128.3 (CH),
127.1 (CH), 127.0 (CH), 126.8 (CH), 57.6 (CH), 51.8 (CH2), 24.7
(CH3); m/z (ES+) 212 (MH+, 100%); Rf 0.29 (hexane–EtOAc,
◦
(Table 1). Each solution was heated for 24 h at 145 C, allowed
to cool, diluted with ether (5 mL) and quenched with sat. aq.
NaCl (15 mL). The ether layer was washed with sat. aq. NaCl (5 ¥
15 mL), dried, filtered and evaporated under reduced pressure.
The residue was then diluted with MeOH (ca. 5 mL) and analysed
by HPLC.
Table 1 Effect of variation in Pd : ligand ratio on the formation of by-
product 15
Entry
Pd(OAc)2 mol%
phosphine 13 mol%
relative yield of 15a
1
2
3
4
5
10
10
10
5
40
20
10
10
5
8.00
1.73
1.76
1.91
1.00
5
1
3 : 1). The above H- and 13C-NMR spectra of B are in accord
a based on raw UV detector integrals.
with published data.24 A solution of the amine ( )-B (164 mg,
0.78 mmol) in pyridine (1 mL) under nitrogen was treated with
trifluoroacetic anhydride (0.12 mL, 181 mg, 0.86 mmol) and the
solution was stirred at room temperature for 24 h. The mixture
was diluted with water (10 mL) and CH2Cl2 (15 mL) and the layers
separated. The organic layer was washed with water (3 ¥ 15 mL),
dried and concentrated under reduced pressure. Chromatography
of the residue (hexane–EtOAc, 9 : 1) gave the title compound 15
(153 mg, 64%) as a colourless oil, nmax/cm-1 (CHCl3) 1688, 1496,
1451, 1202, 1140, 753, 697; dH (400 MHz, CDCl3) (2 : 1 mixture of
rotamers) 7.3–6.9 (10 H, m, ArH), 5.49 (0.33 H, q, J 7.2 Hz,
NCHCH3, rotamer b), 5.34 (0.66 H, q, J 6.9 Hz, NCHCH3,
rotamer a), 4.57 (0.66 H, d, J 15.3 Hz, NCHAHB, rotamer a),
4.55 (0.33 H, d, J 17.0 Hz, NCHAHB, rotamer b), 4.22 (0.33 H,
d, J 17.0 Hz, NCHAHB, rotamer b), 3.93 (0.66 H, d, J 15.3 Hz,
NCHAHB, rotamer a), 1.47 (2 H, d, J 6.9 Hz, NCHCH3, rotamer
a), 1.33 (1 H, d, J 7.2 Hz, NCHCH3, rotamer b); dC (100 MHz,
CDCl3) (2 : 1 mixture of rotamers) 158.2 (C, q, J 35.5 Hz, rotamer
b), 157.7 (C, q, J 35.5 Hz, rotamer a), 138.7 (C, rotamer b), 138.0
(C, rotamer a), 136.9 (C, rotamer a), 136.3 (C, rotamer b), 129.0
(CH), 128.7 (CH), 128.5 (CH), 128.45 (CH), 128.2 (CH), 127.9
(CH), 127.85 (CH), 127.5 (CH), 127.4 (CH), 127.3 (CH), 127.2
(C), 117.1 (C, q, J 288 Hz, rotamer a), 116.7 (C, q, J 289 Hz,
rotamer b), 56.1 (CH, rotamer b), 55.9 (CH, q, J 3 Hz, rotamer
a), 48.8 (CH2, q, J 3 Hz, rotamer b), 47.0 (CH2, rotamer a),
18.3 (CH3, rotamer a), 17.2 (CH3, rotamer b); dF (376.5 MHz,
CDCl3) (2 : 1 mixture of rotamers) -67.5 (2 F, s, rotamer a), -68.0
(1 F, s, rotamer b); m/z (ES+) 330 (MNa+, 100%), 308 (MH+, 11)
(Found: MNa+ 308.1250; C17H17F3NO requires 308.1257); Rf 0.65
(hexane–EtOAc, 3 : 1); HPLC tR 25.5 min.
(aR,5S)-6,7-Dihydro-5-methyl-5H-dibenz[c,e]azepine (+)-2
A solution of the amide 14 (679 mg, 2.22 mmol) in MeOH
(40 mL) under argon was treated with K2CO3 (1.34 g, 9.70 mmol)
followed by water (100 mL), and the mixture was stirred at 60 ◦C
for 24 h. After cooling to room temperature, the mixture was
diluted with water (200 mL) and CH2Cl2 (200 mL). The layers
were then separated, the aqueous layer was extracted with more
CH2Cl2 (3 ¥ 100 mL) and the combined organic phase was
dried and evaporated. The residual yellow oil was purified by
chromatography over silica gel (CH2Cl2–MeOH, 9 : 1), giving the
amine 2 (450 mg, 97%) as a colourless oil, [a]2D2 +27.0 (c 0.8, CHCl3)
{lit.1 for (5R)-2 [a]D25 -23.5 1 (c 0.65, CHCl3)}; nmax/cm-1 (CHCl3)
3068, 3009, 2965, 2926, 1481, 1451, 1379, 1112; dH (400 MHz,
CDCl3) 7.50–7.34 (8 H, m, ArH), 3.75 (1 H, d, J 12.5 Hz, 7-H),
3.73 (1 H, q, J 6.5 Hz, 5-H), 3.51 (1 H, d, J 12.5 Hz, 7-H), 2.23
(1 H, br s, NH), 1.49 (3 H, d, J 6.5 Hz, 5-Me); dC (100 MHz,
CDCl3) 141.33 (C), 141.29 (C), 139.3 (C), 137.0 (C), 128.5 (CH),
128.25 (CH), 128.2 (CH), 128.1 (CH), 128.08 (CH), 127.8 (CH),
127.6 (CH), 125.0 (CH), 50.3 (CH), 49.5 (CH2), 19.0 (CH3);
m/z (ES+) 210 (MH+, 100%) (Found: MH+ 210.1277; C15H16N
requires 210.1278); Rf 0.01 (hexane–EtOAc, 3 : 1), 0.73 (EtOAc–
MeOH/Et3N, 80 : 20 : 1), 0.27 (CH2Cl2–MeOH, 9 : 1). The sample
1
of (+)-2 was identical (TLC, H- and 13C-NMR) to an authentic
sample of (-)-2 obtained as described.1
(S)-N-(2-Bromobenzyl)-2,2,2-trifluoro-N-(1-
phenylethyl)acetamide 15
To a solution of 1-phenylethylamine ( )-8 (0.15 mL, 143 mg,
1.2 mmol) in toluene (15 mL) was added benzaldehyde (0.12 mL,
125 mg, 1.2 mmol) followed by p-toluenesulfonic acid monohy-
(S)-t-Butyl N-(1-phenylethyl)carbamate 16
A solution of the amine (S)-8 (4.848 g, 40 mmol) in EtOH
(20 mL) was vigorously stirred and cooled in ice-water during
˚
drate (20 mg, 0.11 mmol) and powdered 4 A molecular sieves
This journal is The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 1831–1838 | 1835
©

View Article Online
the addition a solution of di-t-butyl dicarbonate (9.60 g, 44 mmol)
in EtOH (40 mL).25 Effervescence and warming occurred almost
immediately. After the addition the cooling bath was removed
and stirring was continued at room temperature for 0.5 h. The
mixture was then evaporated in vacuo and the residual white solid
crystallised from ether (30 mL), giving the known carbamate 16
(5.66 g, 64%) as colourless rhombs, m.p. 88–89 ◦C (lit.25 87–88 ◦C).
Evaporation of the mother liquors and recrystallisation of the
residue from ether (12 mL) gave a second crop of 16 (1.74 g, 20%)
(total 7.40 g, 84%); nmax/cm-1 (film) 3380, 1685; dH (400 MHz,
CDCl3) 7.36–7.21 (5 H, m, ArH), 4.79 (2 H, br s, MeCH and
NH), 1.49–1.35 (12 H, br s, Me and CMe3); dC (100 MHz, CDCl3)
155.2 (C), 155.1 (C), 128.7 (CH), 127.2 (CH), 126.0 (CH), 79.6
(C), 50.3 (CH), 28.5 (CH3), 22.8 (CH3); m/z (ES+) 244 (MNa+,
100%); Rf 0.49 (hexane–EtOAc, 4 : 1).
hexylphosphonium tetrafluoroborate (77 mg, 0.21 mmol), pivalic
acid (64 mg, 0.63 mmol) and Pd(OAc)2 (24 mg, 0.107 mmol) and
a stirrer bar. The flask was purged with nitrogen for 20 min, DMA
(20 mL) was added, and the stirred mixture was heated to 130 ◦C
(bath temperature). After 72 h at 130 ◦C the DMA was evaporated
in vacuo and the black residue was digested with CH2Cl2 (30 mL)
and filtered. The filtrate was concentrated and the residual oil
purified by chromatography (h 5 cm, d 4.5 cm; CH2Cl2), giving the
title compound 4 (321 mg, 50%) as a colourless oil; [a]2D4 -322
9
(c 0.61, CHCl3) {lit.1 for 5R-4 [a]D25 +321 10 (c 0.82, CHCl3)};
n
max/cm-1 (film) 2972, 1681, 1397, 1361, 1156, 1117, 1038, 868,
761, 752, 736; dH (400 MHz, CDCl3) 7.55–7.33 (8 H, m, ArH),
5.12a (1 H, br s, 5-H), ca. 5.0a (1 H, br s, 7-H), 3.73 (2 H, br d, J
11.9 Hz, 7-H), 1.55 (9 H, s, CMe3), 0.88 (3 H, d, J 6.9 Hz, Me);
dC (100 MHz, CDCl3) 153.7 (C), 141.0 (C), 139.2 (2 ¥ C), 135.3
(C), 130.2 (CH), 129.7 (CH), 129.2 (CH), 128.6 (CH), 128.3 (CH),
128.2 (2 ¥ CH), 127.6 (CH), 79.8 (C), 57.7 (CH), 47.3 and 46.6
(both br, 7-CH2, rotamers), 28.7 (CH3), 21.5 (br, CH3); Rf 0.50
(CH2Cl2).
(S)-t-Butyl N-(1-phenylethyl)-N-[(2-
bromophenyl)methyl]carbamate 18
a
In a 100 mL two-necked flask fitted with a stirrer bar, nitrogen
inlet and septum cap, a portion of NaH (60% dispersion in
mineral oil, 500 mg, 12.5 mmol) was freed from oil by decantation
with hexane (5 mL) and covered with dry DMF (10 mL).16 With
Broad overlapping signals.
(aR,5S)-6,7-Dihydro-5-methyl-5H-dibenz[c,e]azepine (+)-2
◦
stirring and cooling to 5–10 C, a solution of the carbamate 16
To a solution of (-)-4 (309 mg, 1.0 mmol) in THF (3 mL) was added
85% aq. phosphoric acid17 (2.0 mL, 29 mmol) at room temperature.
The mixture was vigorously stirred at room temperature for 72 h,
(2.66 g, 12.0 mmol) in dry DMF (20 mL) was quickly added. The
mixture was stirred for 5 min at 5–10 ◦C followed by 30 min
at room temperature, and then treated with a solution of 2-
bromobenzyl bromide 17 (3.21 g, 12.8 mmol) in dry DMF (4 mL).
A beige solution slowly formed and stirring was continued at
room temperature for 20 h. The solution was then evaporated in
vacuo and the residual oil partitioned between EtOAc (40 mL) and
water (40 mL). The layers were separated, the aqueous phase was
extracted with EtOAc (2 ¥ 20 mL) and the combined organic phase
was washed with sat. aq. NaCl (25 mL), dried and evaporated.
The residual oil (4.62 g) was dissolved in hot hexane (20 mL).
On cooling, the solution provided a portion of unreacted 16
◦
then diluted with water (10 mL), cooled to 0 C and basified to
pH 11 by the dropwise addition of 10 M aq. KOH (≥ 9 mL). After
warming to room temperature, the aqueous phase was extracted
with CH2Cl2 (3 ¥ 10 mL). The combined organic extract was
washed with brine (15 mL), dried and concentrated under reduced
pressure to give the title compound (+)-2 (181 mg, 87%) as a
colourless oil; [a]2D4 +30.3 1.4 (c 1.05, CHCl3). The material was
identical (TLC, 1H- and 13C-NMR) to that obtained from (-)-14
as described above.
◦
(250 mg, 5%) as colourless crystals, m.p. 87–89 C. Evaporation
of the mother liquors gave an oil which was purified by flash
chromatography (h 10 cm, d 4.5 cm; hexane/CH2Cl2, 1 : 2), giving
the title compound 18 (2.72 g, 58%) as a colourless oil; [a]2D4 -50.5
1.5 (c 1.28, CHCl3); nmax/cm-1 (film) 2973, 1685, 1439, 1395, 1363,
1325, 1274, 1251, 1212, 1160, 1133, 1043, 1024, 992, 861, 745, 697;
dH (400 MHz, CDCl3) 7.46 (1 H, dd, J 1, 8 Hz, ArH), 7.38–7.29
(4 H, m, ArH), 7.27–7.14 (3 H, m, ArH), 7.05 (1 H, dt, J 2, 8 Hz,
ArH), 5.71 (0.6 H, br s, CHMe, rotamer a), 5.30 (0.4 H, br s,
CHMe, rotamer b), 4.69–4.07 (2 H, br m, CH2), 1.46 (3 H, d, J
7 Hz, Me), 1.38 (9 H, s, CMe3); dC (400 MHz, CDCl3) 156.1 (C),
141.8 (C), 138.6 (C), 132.4 (CH), 128.5 (2 ¥ CH), 128.0 (CH),
127.3 (CH), 127.2 (2 ¥ CH), 122.2 (C), 80.3 (C), 53.5 (CH), 47.2
(CH2), 28.4 (CH3), 17.7 (CH3); m/z (ES+) 414 (MNa+, 100%), 412
(MNa+, 92) (Found: MNa+ 412.0894; C20H24BrNNaO2 requires
412.0883); Rf 0.40 (hexane–EtOAc, 12 : 1), 0.25 (hexane–CH2Cl2,
1 : 2), 0.75 (CH2Cl2).
t-Butyl N-(diphenylmethyl)carbamate 19
A solution of diphenylmethylamine (7.34 g, 40 mmol) in EtOH
(20 mL)25 was vigorously stirred and cooled in ice-water during
the addition a solution of di-t-butyl dicarbonate (9.60 g, 44 mmol)
in EtOH (40 mL). A white precipitate formed almost immediately,
accompanied by effervescence and warming. After the addition
the cooling bath was removed and stirring was continued at room
temperature for 0.5 h. The mixture was then heated to dissolve
the precipitate and left to cool. The resulting crystalline mass was
collected on a Buchner funnel, rinsed with a small amount of ice-
cold EtOH and dried, first by suction and then in vacuo, giving the
carbamate 19 (8.11 g, 72%) as colourless needles, m.p. 122–124 ◦C
(lit.26 120.5–121.5 ◦C). Evaporation of the mother liquors and
recrystallisation of the residue from EtOH (15 mL) gave a second
crop of 19 (2.17 g, 19%) (total 10.28 g, 91%); nmax/cm-1 (film) 3370,
1686; dH (400 MHz, CDCl3) 7.35–7.30 (4 H, m, ArH), 7.28–7.23
(6 H, m, ArH), 5.92 (1 H, br s, CH), 5.17 (1 H, br s, NH), 1.45 (9
H, br s, CMe3) (in accord with published data26); dC (100 MHz,
CDCl3) 155.2 (C), 142.2 (C), 128.7 (CH), 127.5 (CH), 127.4 (CH),
80.0 (C), 58.6 (CH), 28.5 (CH3); m/z (ES+) 306 (MNa+, 100%); Rf
0.45 (hexane–EtOAc, 4 : 1), 0.24 (hexane–CH2Cl2, 1 : 2).
(aS,5S)-t-Butyl 5-phenyl-5H-dibenz[c,e]azepine-
6(7H)-carboxylate (-)-4
A 100 mL round-bottomed flask was charged with (-)-18 (814 mg,
2.09 mmol), anhydrous K2CO3 (432 mg, 3.13 mmol), tricyclo-
1836 | Org. Biomol. Chem., 2011, 9, 1831–1838
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
t-Butyl N-(diphenylmethyl)-N-[(2-bromophenyl)methyl]carbamate
20
7.05 (1 H, dd, J 1.0, 7.5 Hz, ArH), 6.89–6.83 (3 H, m, ArH), 6.54–
6.59 (2 H, m, ArH), 6.44 (0.4 H, br s, 5-H, rotamer b), 6.24 (0.6 H,
br s, 5-H, rotamer a), 5.21 (0.6 H, br s, 7-H, rotamer a), 5.04 (0.4
H, br s, 7-H, rotamer b), 3.91 (0.6 H, br s, 7-H, rotamer a), 3.89
(0.4 H, br s, 7-H, rotamer b), 1.58 (3.5 H, br s, CMe3, rotamer b),
1.38 (5.5 H, br s, CMe3, rotamer a); dC (100 MHz, CDCl3) (major
and minor rotamers, pairings tentative) 154.5 (C), 142.5 (br, C,
major), 141.8 (br, C, minor), 140.8 (br, C), 140.0 (C), 138.3 (C),
134.7 (br, C, major), 134.5 (br, C, minor), 131.1 (br, CH), 129.9
(br, CH), 129.3 (CH), 128.7 (CH), 128.3 (CH), 128.1 (CH), 127.9
(CH), 127.7 (CH), 127.1 (CH), 125.5 (CH), 125.4 (CH), 80.3 (C),
64.5 (br, CH, major), 62.9 (br, CH, minor), 48.0 (br, CH2, minor),
47.0 (br, CH2, major), 28.5 (CH3); m/z (ES+) 394 (MNa+, 100%);
Rf 0.27 (hexane–CH2Cl2, 1 : 2).
In a 100 mL two-necked flask fitted with a stirrer bar, nitrogen
inlet and septum cap, a portion of NaH (60% dispersion in mineral
oil, 515 mg, 12.9 mmol) was freed from oil by decantation with
hexane (5 mL) and covered with dry DMF (10 mL).16 With stirring
◦
and cooling to 5–10 C, a solution of the carbamate 19 (3.40 g,
12.0 mmol) in dry DMF (20 mL) was quickly added. The mixture
was stirred for 5 min at 5–10 ◦C followed by 30 min at room
temperature, and then treated with a solution of 2-bromobenzyl
bromide 17 (3.08 g, 12.3 mmol) in dry DMF (4 mL). A pale
yellow solution slowly formed and stirring was continued at room
temperature for 20 h. The solution was then evaporated in vacuo
and the residual oil partitioned between EtOAc (40 mL) and
water (40 mL). The layers were separated, the aqueous phase was
extracted with EtOAc (2 ¥ 20 mL) and the combined organic phase
was washed with sat. aq. NaCl (25 mL), dried and evaporated. The
residual oil (5.62 g) was dissolved in hot EtOAc (5 mL) and the
solution diluted with hot hexane (15 mL). On cooling, the solution
provided a portion of unreacted 19 (460 mg, 12%) as colourless
needles, m.p. 121–123 ◦C. Evaporation of the mother liquors gave
a pale yellow oil which was purified by flash chromatography (h
10 cm, d 4.5 cm; hexane/CH2Cl2, 1 : 2), giving the title compound
20 (4.32 g, 80%) as a colourless viscous oil; nmax/cm-1 (film) 2973,
1690, 1439, 1390, 1364, 1272, 1250, 1155, 1103, 1024, 892, 745,
696; dH (400 MHz, CDCl3) 7.31 (1 H, dd, J 1, 8 Hz, ArH), 7.28–
7.17 (10 H, m, ArH), 7.04 (1 H, br t, J 7 Hz, ArH), 6.92 (1 H, dd, J
1.5, 8 Hz, ArH), 6.87 (1 H, br s, ArH), 6.66 (1 H, br s, CHPh2), 4.57
(2 H, s, CH2), 1.35 (9 H, s, CMe3); dC (400 MHz, CDCl3) 156.2
(C), 139.8 (C), 137.5 (C), 132.0 (CH), 128.9 (CH), 128.4 (CH),
128.1 (CH), 127.7 (CH), 127.4 (CH), 126.7 (CH), 122.0 (C), 80.6
(C), 64.0 (CH), 49.0 (CH2), 28.3 (CH3); m/z (ES+) 476 (MNa+,
100%), 474 (M H+, 95) (Found: MNa+ 474.1054; C25H26BrNNaO2
requires 474.1040); Rf 0.40 (hexane–EtOAc, 12 : 1), 0.35 (hexane–
CH2Cl2, 1 : 2).
6,7-Dihydro-5-phenyl-5H-dibenz[c,e]azepine 22
To a solution of ( )-21 (371.5 mg, 1.0 mmol) in THF (3 mL)
was added 85% aq. phosphoric acid17 (2.0 mL, 29 mmol) at
room temperature. The mixture was vigorously stirred at room
temperature for 72 h, then diluted with water (10 mL), cooled to
0
◦C and basified to pH 11 by the dropwise addition of 10 M
aq. KOH (≥ 9 mL). After warming to room temperature, the
aqueous phase was extracted with CH2Cl2 (4 ¥ 10 mL). The
combined organic extract was washed with brine (20 mL), dried
and concentrated under reduced pressure to give the title compound
( )-22 (261 mg, 96%) as a cream solid which formed white needles,
m.p. 117–118 ◦C (EtOH) (Found: C, 88.47; H, 6.39; N, 5.13.
C20H17N requires C, 88.52; H, 6.31; N, 5.16%); nmax/cm-1 (film)
3313w, 3055, 1492, 1476, 1442, 1291, 1265, 1216, 1190, 1103, 1071,
1029, 1006, 926, 877, 846, 749, 711, 697, 633; dH (400 MHz, CDCl3)
7.59 (1 H, dd, J 1.5, 7.5 Hz, ArH), 7.53–7.28 (10 H, m, ArH), 7.25
(1 H, dt, J 1.5, 7.5 Hz, ArH), 6.83–6.80 (1 H, m, ArH), 4.87 (1 H,
s, 5-H), 3.89 (1 H, d, J 13.6, 7-H), 3.66 (1 H, d, J 13.6, 7-H), 2.43 (1
H, br s, NH); dC (100 MHz, CDCl3) 141.9 (C), 141.1 (C), 141.0 (C),
139.5 (C), 137.4 (C), 128.6 (CH), 128.4 (CH), 128.30 (CH), 128.28
(CH), 128.1 (CH), 128.01 (CH), 127.96 (CH), 127.85 (CH), 127.82
(CH), 127.6 (CH), 127.4 (CH), 60.2 (CH), 49.7 (CH2); m/z (ES+)
272 (MH+, 100%); Rf 0.01 (hexane–EtOAc, 3 : 1), 0.73 (EtOAc–
MeOH/Et3N, 80 : 20 : 1).
t-Butyl 5-phenyl-5H-dibenz[c,e]azepine-6(7H)-carboxylate 21
A 100 mL round-bottomed flask was charged with 20 (1.415 g,
3.13 mmol), anhydrous K2CO3 (648 mg, 4.69 mmol), tricyclo-
hexylphosphonium tetrafluoroborate (115 mg, 0.31 mmol), pivalic
acid (96 mg, 0.94 mmol) and Pd(OAc)2 (35 mg, 0.155 mmol)
and a stirrer bar. The flask was purged with nitrogen for 20 min,
DMA (30 mL) was added, and the stirred mixture was heated to
130 ◦C (bath temperature). The reaction mixture became yellow–
orange as the bath temperature approached 130 ◦C. After 72 h at
Crystal data and structure refinement
t-Butyl 5-phenyl-5H-dibenz[c,e]azepine-6(7H)-carboxylate 21.
CCDC deposition number 793197; Empirical formula C25H25NO2;
Formula weight 371.46; Temperature 100(2) K; Radiation wave-
˚
length 0.71073 A; Crystal system monoclinic, space group P21/c;
◦
◦
˚
˚
130 C the DMA was evaporated in vacuo and the black residue
Unit cell dimensions a = 9.4053(3) A; a = 90 ; b = 9.7021(4) A;
was digested with CH2Cl2 (40 mL) and filtered. The filtrate was
concentrated and the residual oil purified by chromatography (h 6
cm, d 4.5 cm; CH2Cl2), which gave the title compound 21 (833 mg,
72%) as a pale yellow solid after trituration with ether/hexane
(1 : 1). Crystallisation from etha◦nol gave the analytical sample as
colourless cubes, m.p. 169–171 C (Found: C, 80.95; H, 6.84; N,
3.78. C25H25NO2 requires C, 80.83; H, 6.78; N, 3.77%); nmax/cm-1
(film) 2973, 1684, 1397, 1361, 1168, 1157, 1129, 1117, 903, 870,
745, 735, 697, 637, 599; dH (400 MHz, CDCl3) (mixture of rotamers
a and b, ratio = ca. 3 : 2) 7.58 (1 H, br s, ArH), 7.51–7.30 (4 H, m,
ArH), 7.21 (1 H, t, J 7.3 Hz, ArH), 7.14 (1 H, t, J 7.3 Hz, ArH),
b = 92.978(2)◦; c = 21.9587(10) A◦ ; g = 90◦; Cell volume
3
-3
˚
2001.05(14) A ; Z 4; Calculated density 1.233 Mg m ; Absorption
coefficient 0.077 mm-1; F(000) 792; Crystal size 0.10 ¥ 0.15 ¥
0.25 mm3; Data collection method Enraf Nonius FR 590 CCD
diffractometer; Theta range for data collection 3.02 to 25.50◦;
Index ranges 0 ꢀ h ꢀ 11, 0 ꢀ k ꢀ11, -26 ꢀ l ꢀ 26; Reflections
collected 14457; Independent reflections 3710 [R(int) = 0.096];
Completeness to theta = 25.50◦ 99.7%; Refinement method
Full-matrix least-squares on F2; Data/restraints/parameters
3710/0/354; Goodness-of-fit on F2 1.056; Final R indices [I >
2s(I)] R1 = 0.0861, wR2 = 0.1660; R indices (all data) R1 = 0.1888,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 1831–1838 | 1837
©

View Article Online
wR2 = 0.2154; Extinction coefficient 0.0046(12); Largest diff. peak
and hole 0.411 and -0.405 e.A .
7 (a) T. Takada, M. Arisawa, M. Gyoten, R. Hamada, H. Tohma and Y.
Kita, J. Org. Chem., 1998, 63, 7698–7706; (b) H. Tohma, H. Morioka,
S. Takizawa, M. Arisawa and Y. Kita, Tetrahedron, 2001, 57, 345–352;
(c) H. Hamamoto, G. Anilkumar, H. Tohma and Y. Kita, Chem.–
Eur. J., 2002, 8, 5377–5383; (d) S. Miyake, A. Sasaki, T. Ohta and K.
Shudo, Tetrahedron Lett., 1985, 26, 5815–5818; (e) J. L. Huppatz, Aust.
J. Chem., 1973, 26, 1307–1318; (f) P. W. Jeffs, J. F. Hansen and G. A.
Brine, J. Org. Chem., 1975, 40, 2883–2890.
8 (a) R. Grigg, A. Teasdale and V. Sridharan, Tetrahedron Lett., 1991,
32, 3859–3862; (b) B. A. Frazier, P. T. Wolczanski and E. B. Lobkovsky,
Inorg. Chem., 2009, 48, 11576–11585.
9 L. A. Saudan, G. Bernardinelli and E. P. Ku¨ndig, Synlett, 2000, 483–
486.
-3
˚
Molecular mechanics calculations (Fig. 3)
Minimised steric energy (MSE) structures for the 5S stereoisomers
of compounds 4, 14, 21 and 22 were calculated on a Mac Mini
2.6 GHz Intel Core 2 Duo running Linux (Fedora Core 12, x86
64-bit), using MacroModel v. 8.0 (Maestro v. 9.0.211 interface)
with the MM3 force field and Monte Carlo conformational search
(csearch) method (1000 iterations). The csearch parameters were:
no solvent; PRCG method; convergence on gradient; max. number
of iterations 3000; convergence threshold 0.0200. For structure
graphics see ESI.†
10 (a) S. Zhang, D. Zhang and L. S. Liebeskind, J. Org. Chem., 1997, 62,
2312–2313; (b) M. Yu, R.-Y. Tang and J.-H. Li, Tetrahedron, 2009, 65,
3409–3416.
11 (a) L.-C. Campeau, M. Parisien, M. Leblanc and K. Fagnou, J. Am.
Chem. Soc., 2004, 126, 9186–9187; (b) M. Leblanc and K. Fagnou, Org.
Lett., 2005, 7, 2849–2852.
Acknowledgements
12 M. Lafrance, D. Lapointe and K. Fagnou, Tetrahedron, 2008, 64, 6015–
6020.
13 For reviews on direct arylation, see (a) L.-C. Campeau and K. Fagnou,
Chem. Commun., 2006, 1253–1264; (b) D. Alberico, M. E. Scott and M.
Lautens, Chem. Rev., 2007, 107, 174–238; (c) S. Pascual, P. de Mendoza
and A. M. Echavarren, Org. Biomol. Chem., 2007, 5, 2727–2734; (d) M.
Catellani, E. Motti, N. Della Ca’ and R. Ferraccioli, Eur. J. Org. Chem.,
2007, 4153–4165; (e) B.-J. Li, S.-D. Yang and Z.-J. Shi, Synlett, 2008,
949–957; (f) G. P. McGlacken and L. M. Bateman, Chem. Soc. Rev.,
2009, 38, 2447–2464; (g) L. Ackermann, R. Vicente and A. R. Kapdi,
Angew. Chem., Int. Ed., 2009, 48, 9792–9826.
We thank the University of Manchester for financial support,
and remember Prof. Keith Fagnou (University of Ottawa)
for his kind provision of information. We are grateful to
Val Boote, Martin Jennings and Rehana Sung (University of
Manchester) for technical assistance, and also wish to acknowl-
edge the use of the EPSRC’s Chemical Database Service at
Daresbury.27
14 For
related
cyclisations
of
achiral
N,N-bis(o-
bromobenzyl)arenesulfonamides using Pd under ligand-free
conditions, see K. C. Majumdar, S. Mondal and N. De, Synthesis,
2009, 3127–3135.
References
15 For assigning the geometry of substituted trifluoroacetamides by 1H
NMR spectroscopy, see L. L. Graham, Org. Magn. Reson., 1972, 4,
335–342.
1 S. L. Pira, T. W. Wallace and J. P. Graham, Org. Lett., 2009, 11, 1663–
1666.
2 For discussions, see (a) K. Mikami, K. Aikawa, Y. Yusa, J. J. Jodry and
M. Yamanaka, Synlett, 2002, 1561–1578; (b) E. Fjellander, Z. Szabo´
and C. Moberg, J. Org. Chem., 2009, 74, 9120–9125 and references cited
therein.
3 For reviews, see (a) G. Bringmann, A. J. Price Mortimer, P. A. Keller, M.
J. Gresser, J. Garner and M. Breuning, Angew. Chem., Int. Ed., 2005, 44,
5384–5427; (b) O. Baudoin, Eur. J. Org. Chem., 2005, 4223–4229; (c) T.
W. Wallace, Org. Biomol. Chem., 2006, 4, 3197–3210; (d) K. Tanaka,
Synlett, 2007, 1977–1993.
16 For a related reaction, see K. Miyawaki, F. Ueno and I. Ueda,
Heterocycles, 2001, 54, 887–900.
17 B. Li, M. Berliner, R. Buzon, C. K.-F. Chiu, S. T. Colgan, T. Kaneko,
N. Keene, W. Kissel, T. Le, K. R. Leeman, B. Marquez, R. Morris, L.
Newell, S. Wunderwald, M. Witt, J. Weaver, Z. Zhang and Z. Zhang,
J. Org. Chem., 2006, 71, 9045–9050.
18 For a review, see C. A. Hunter, K. R. Lawson, J. Perkins and C. J. Urch,
J. Chem. Soc., Perkin Trans. 2, 2001, 651–669.
19 For examples, see (a) L. Wu, A. E. Aliev, S. Caddick, R. J. Fitzmaurice,
D. A. Tocher and F. D. King, Chem. Commun., 2010, 46, 318–320;
(b) D. J. Edwards, D. House, H. M. Sheldrake, S. J. Stone and T.
W. Wallace, Org. Biomol. Chem., 2007, 5, 2658–2669; (c) G. Hilt, F.
Galbiati and K. Harms, Synthesis, 2006, 3575–3584.
4 For recent examples, see (a) G. Nishida, K. Noguchi, M. Hirano and
K. Tanaka, Angew. Chem., Int. Ed., 2007, 46, 3951–3954; (b) B. Schulte,
R. Fro¨hlich and A. Studer, Tetrahedron, 2008, 64, 11852–11859; (c) G.
Nishida, S. Ogaki, Y. Yusa, T. Yokozawa, K. Noguchi and K. Tanaka,
Org. Lett., 2008, 10, 2849–2852; (d) W.-W. Chen, Q. Zhao, M.-H. Xu
and G.-Q. Lin, Org. Lett., 2010, 12, 1072–1075.
5 For selected sources and leading references, see (a) K. Kinbara,
K. Sakai, Y. Hashimoto, H. Nohira and K. Saigo, Tetrahedron:
Asymmetry, 1996, 7, 1539–1542; (b) E. P. Ku¨ndig, C. Botuha, G.
Lemercier, P. Romanens, L. Saudan and S. Thibault, Helv. Chim. Acta,
2004, 87, 561–579; (c) M.-J. Kim, W.-H. Kim, K. Han, Y. K. Choi and
J. Park, Org. Lett., 2007, 9, 1157–1159; (d) L. M. Klingensmith, K.
A. Nadeau and G. A. Moniz, Tetrahedron Lett., 2007, 48, 4589–4593;
(e) L. K. Thale´n, D. Zhao, J.-B. Sortais, J. Paetzold, C. Hoben and J.-E.
Ba¨ckvall, Chem.–Eur. J., 2009, 15, 3403–3410; (f) D. Guijarro, O. Pablo
and M. Yus, J. Org. Chem., 2010, 75, 5265–5270.
20 H. E. Gottlieb, V. Kotlyar and A. Nudelman, J. Org. Chem., 1997, 62,
7512–7515.
21 D. D. Perrin, W. L. F. Armarego and D. R. Perrin, Purification of
Laboratory Chemicals, 2nd Edition, Pergamon, Oxford, 1980.
22 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923–2925.
23 J. Albert, L. D’Andrea, J. Granell, R. Tavera, M. Font-Bardia and X.
Solans, J. Organomet. Chem., 2007, 692, 3070–3080.
24 Z. Han, Z. Wang, X. Zhang and K. Ding, Angew. Chem., Int. Ed., 2009,
48, 5345–5349.
25 T. Vilaivan, Tetrahedron Lett., 2006, 47, 6739–6742.
26 E. Breuer, T. Berger and S. Sarel, Chem. Commun., 1968, 1596–1597.
27 D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf. Comput.
Sci., 1996, 36, 746–749.
6 E. C. Taylor, J. G. Andrade, G. J. H. Rall and A. McKillop, J. Am.
Chem. Soc., 1980, 102, 6513–6519.
1838 | Org. Biomol. Chem., 2011, 9, 1831–1838
This journal is
The Royal Society of Chemistry 2011
©