Axial stereocontrol in: Tropos dibenz [c, e] azepines: The individual and cooperative effects of alkyl substituents

Article abstract of DOI:10.1039/c7ob02385e

6,7-Dihydro-5H-dibenz[c,e]azepines, a class of secondary amine incorporating a centre-axis chirality relay, can be prepared from N-(2-bromobenzyl)-N-(1-arylalkyl)methanesulfonamides via Pd-catalysed intramolecular direct arylation, and methylated at C(7)

Full text of DOI:10.1039/c7ob02385e

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Axial stereocontrol in tropos dibenz[c,e]azepines:
the individual and cooperative effects of alkyl
substituents†
Cite this: Org. Biomol. Chem., 2017,
15, 10184
Sinead M. C. Balgobin, Dominic J. Brookes, Junxiang Jiang, Robin G. Pritchard and
Timothy W. Wallace
*
6,7-Dihydro-5H-dibenz[c,e]azepines, a class of secondary amine incorporating a centre-axis chirality
relay, can be prepared from N-(2-bromobenzyl)-N-(1-arylalkyl)methanesulfonamides via Pd-catalysed
intramolecular direct arylation, and methylated at C(7) via the 5,7-trans diastereoselective addition of
methylmagnesium bromide to the derived N-benzylazepinium tetraphenylborate. Using these methods,
the 4,5-dimethylated and 4,5,7-trimethylated homologues 13 and 14 were obtained and shown by 1H
NMR spectroscopy to be axially biased in opposite senses, as defined by the respective pseudoaxial or
pseudoequatorial orientation of the 5-substituent in the preferred conformers, while retaining their
tropos nature (the Arrhenius activation energy, EA, for the conformational exchange process in 14 was
estimated to be 57 kJ mol−1 using 2D-EXSY NMR spectroscopy at 233–248 K). These results serve to illus-
trate how substituent effects might be exploited in new designs of bridged biaryl ligand in which tropos
dynamics operate in combination with a pre-existing axial stereochemical bias.
Received 23rd September 2017,
Accepted 17th November 2017
DOI: 10.1039/c7ob02385e
rsc.li/obc
rise to diastereoisomers. This type of chirality transfer under-
Introduction
pins the role of 2 in structural assignment2 and synthesis, as
The three-atom bridged biaryl motif 1 is prominent in syn- exemplified by the use of 3,3 4,4 55 and 66 in stereoselective
thesis, encompassing the key features of a wide variety of catalysis.
metal-phosphine complexes and catalytic ligands with
azepine, phosphepine and phosphonate cores. In its simplest
forms this type of structure possesses two non-planar energy-
minimised conformations which are enantiomeric, having
opposite configurations at the stereogenic biaryl axis. The
rotation of the axis can be restricted or prevented with bulky
R-substituents, giving rise to atropisomers (‘non-turning
isomers’) which do not interconvert at ambient temperatures.
In the absence of blocking R-groups, the barrier to axis inver-
sion is generally low (≤80 kJ mol−1) and the interconversion
rapid, a situation which has been termed tropoisomerism and
whose dynamic stereochemistry is exploited in various analyti-
cal and synthetic methods.1 A variety of structures 2, in which
the tropos amine 6,7-dihydro-5H-dibenz[c,e]azepine is com-
bined with a ‘chiral activator’ group R*, can manifest a degree
of conformational bias at the biaryl axis, whose inversion gives
School of Chemistry, The University of Manchester, Oxford Road, Manchester M13
9PL, UK. E-mail: tim.wallace@manchester.ac.uk; Fax: +44 (0)161 275 4939
†Electronic supplementary information (ESI) available: Crystal structure files;
1H, 13C and 19F NMR spectra; structures generated via molecular mechanics cal-
culations; data from 2D-EXSY kinetic analysis. CCDC 1008371 and 1008372. For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c7ob02385e
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For an unsymmetrical dibenzazepine such as the (5R)-methyl complex NMR spectra. In seeking to avoid this minor inconve-
system (−)-7,7,8 the absence of substituents at C(1) and C(11) nience, our initial attempt to prepare the amine 12 explored
ensures that the seven-membered ring remains conformation- the alternative use of 2-nitrobenzenesulfonyl (nosyl) protec-
ally flexible, but the preference of the methyl group for a tion. The sulfonamide ( )-16, prepared in the usual way,15 was
pseudoequatorial orientation induces
a bias towards the alkylated using 17 and the product 18 subjected to the stan-
depicted (S)-configuration of the biaryl axis; this was first seen dard cyclisation conditions (Scheme 1).8 Analysis of the
with Kündig’s amine 89 and predicted on the basis of molecular product mixture by 1H NMR spectroscopy indicated that two
mechanics calculations.7 The heights of the respective barriers products, 19 and 20, had been formed in almost equal
to axis inversion in 7 and 8 are unknown, but a first approxi- amounts, along with a small quantity of the debrominated
mation is provided by the meso system 9, for which a value for compound 21.
ΔG‡ of 56.9 kJ mol−1 at 285 K was estimated from VT-NMR
In the light of related ring-closure reactions involving
measurements.9 With inversion barriers of this order, amines N-tosyl analogues,16,17 the competitive formation of both the
such as 7 and 8 will undergo the rapid axis inversion associated sultam 19 and the sulfonamide 20 as indicated in Scheme 1 is
with tropos systems, but with the possibility of conformational unsurprising. Statistically the benzenesulfonyl ring of 18
bias without the need for a chiral activator group.‡
appears to undergo intramolecular palladation more rapidly
Alkylated dibenzazepines have illustrated some new oppor- than the phenyl group, and this is consistent with the accumu-
tunities for axial chirality control. For example, acylation of the lating evidence for a concerted metallation–deprotonation
amine (−)-7 proceeds with inversion of the biaryl axis due to (CMD) pathway in Pd-catalysed processes of this type,18,19 with
the steric effects arising from trigonalisation at N(6),7,8 while C–H bond cleavage being the kinetically significant step in the
the efficiency of the lithium derivative of (−)-8 in enantio- catalytic cycle. The structures of 19 and 20 were tentatively
1
selective deprotonation11 is consistent with the 5,7-diaxial (aR) identified on the basis of their distinctive H NMR spectra, in
conformation being the active species.9 More recently the which the key signal was an upfield doublet (δ 0.35 ppm) con-
iminium salts 10 and 11 were screened as epoxidation catalysts sistent with the proximity of one of the methyl groups of 20 to
and latter shown to be superior, the extra methyl group taking the distal A-ring. Both structures were confirmed by X-ray crys-
up a pseudoaxial orientation and effectively locking the biaryl tallographic analysis (Fig. 1 and 2).20
axis, which is of the tropos type in 10.12,13
The potential for new approaches to axial stereocontrol, as
revealed by the amines 7 and 8, prompted us to develop a Pd-
catalysed intramolecular direct arylation (IDA) route8 for their
rapid assembly. The recent focus of this project has been the
allylic A1,3-strain that exists between C(4) and C(5) of such
structures, which in principle should counteract the preference
of a single 5-alkyl substituent for a pseudoequatorial orien-
tation, offering further scope for axis control. We describe
herein the application, modification and extension of our IDA
methodology14 for the preparation of amines 12–14, which
molecular mechanics calculations placed near the crossover
point for axial stereocontrol based on the conformational pre-
ference of the 5-alkyl group. The characteristics of the struc-
tures acquired in this study provide further insight into the
dynamics of the centre-axis chirality relay present in cyclic
amines of this type.
Synthesis of dibenzazepines
In our original IDA route to 5-alkyl-6,7-dihydrodibenz[c,e]aze-
pines, based on the cyclisation of trifluoroacetyl- or Boc-pro-
tected diarylamines,8 the intermediates are invariably obtained
as mixtures of geometric isomers, which can give rise to
‡We propose the terms enantiotropos or diastereotropos for distinguishing biaryls
that meet the tropos condition [axial stereoisomers with half-lives of less than
1000 s, corresponding to a free energy barrier of 93.3 kJ mol−1 at 300 K (ref. 10)]
but differ in respect of the local stereochemical relationship between the exchang-
ing conformers, which may be enantiomeric or diastereoisomeric respectively.
Scheme 1 An approach to the amine ( )-12 using nosyl protection.
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Fig. 1 X-ray structure of the thiadiazine 19.
Scheme 2 Preparation of amine
N-protection.
( )-12 using trifluoroacetyl
temperature showed the signal broadening associated with the
conformational dynamics of this type of compound. The
chemical shifts associated with the methyl groups of 12
(δ 1.01, 0.70 ppm) are very similar to those of the starting
amine 15, and the absence of significant magnetic anisotropy
effects suggests that the 5-substituent of 12 tends to assume a
pseudoequatorial orientation despite the allylic A1,3-strain that
this entails.
Fig. 2 X-ray structure of the dibenz[c,e]azepine 20.
For the preparation of the amine 13 we again pursued the
N-trifluoroacetyl IDA protocol, but encountered what is prob-
ably a limiting feature. The amine ( )-28 was transformed into
29, and hence trifluoroacetamide 30 without difficulty, but the
attempted cyclisation to 31 was unsuccessful, the reaction
returning mostly unchanged 30 along with a small amount of
the debromination product 32, an authentic sample of which
was obtained from 33 (Scheme 3). The formation of 32 appears
to confirms the viability of the Pd(0) oxidative addition step in
the IDA catalytic cycle, and we speculate that the subsequent
arylation step fails to compete with protodepalladation due to
steric interactions involving the o-methyl group.
Speculating that the problem encountered with the amide
30 might be avoided using a cyclisation precursor with a
pyramidalised N-atom, a second IDA sequence with sulfonyl
protection was initiated, the choice this time being the methane-
sulfonyl group. Treatment of the amine ( )-28 with mesyl
chloride/triethylamine afforded the sulfonamide 34, which
Returning to the original IDA protocol, we prepared a quan-
tity of 12 using N-trifluoroacetylated intermediates. Reductive
amination of o-bromobenzaldehyde 22 with the amine 15, fol-
lowed by trifluoroacetylation, gave the desired cyclisation pre-
cursor 24 in good overall yield (Scheme 2). Subjecting 24 to the
IDA cyclisation conditions provided the crystalline amide 25 as
a mixture of isomers (total 69%, ratio 9 : 1), accompanied by
the expected by-product 26 (ca. 6%), an authentic sample of
which was obtained from 27. The 1H NMR spectrum of 25
showed upfield doublets due to the methyl groups (minor
δ 0.76, 0.51, major δ 0.70, 0.45 ppm), indicating that the iso-
propyl group occupied a pseudoaxial orientation in both
isomers.
Hydrolysis of the amide 25 provided the amine 12 as a
1
colourless viscous oil whose H- and 13C-NMR spectra at room
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Scheme 3 Attempted preparation of amine ( )-13 using trifluoroacetyl
N-protection.
Scheme 4 Preparation of amine
N-protection.
(
)-13 using methanesulfonyl
was then alkylated using 17 to obtain the cyclisation precursor
35 (60%) as a colourless crystalline solid. IDA cyclisation of 35 (−)-40, prepared from a commercial sample of the amine
under the standard conditions gave a good yield of the desired (S)-39, was alkylated using 17 to obtain the sulfonamide (S)-41
sulfonamide 36, together with a small amount of 37 (identified [the alternative route to (S)-41 from (S)-45 was much less
by comparison with an authentic sample). The 1H NMR efficient]. The IDA cyclisation of 41 provided the desired diben-
spectrum of 36 confirmed that the 5-methyl substituent zazepine (S)-42 (85%) along with the expected by-product 43
(δ 0.89 ppm) was in the expected pseudoaxial orientation (ca. 7%), whose structure was confirmed by comparison with
(Scheme 4). The desulfonylation of methanesulfonamides can an authentic sample prepared from ( )-40. The desulfonation
often be achieved by treatment with Red-Al in toluene,21 and step using Red-Al/toluene gave (+)-7 (81%) as a colourless oil,
this method proved highly effective in the case of 36, giving [α]2D6 +32.7 0.9 (c 0.69, CHCl3) {lit.8 [α]2D2 +27.0 (c 0.8, CHCl3)}.
the target amine 13 (78%) as a colourless oil, along with a by- These polarimetric data suggest that no racemisation had
product identified as 38 (5%). The by-product is presumed to taken place during the four-step sequence leading to (+)-7.
arise via deprotonation of the methanesulfonyl group, followed
The formamide 46 was used to test the viability of N-formyl
by elimination of the amide anion and a molecule of sulfene protection in the IDA approach to amine 13. Alkylation of 46
(CH2vSO2); these recombine to give an N–CH2SO2 species with the bromide 17 was inefficient, but gave a sample of
which eventually undergoes reductive desulfurisation.22 The ( )-47 for submission to the IDA reaction (Scheme 6). TLC ana-
characteristic 1H NMR signals from 13 (δ 0.80 ppm) and 38 lysis of the product suggested the formation of a major
(δ 0.72 ppm) indicated that the preferred orientations of the product, which was isolated by flash chromatography and
5-methyl substituents were pseudoaxial in each case. The identified as the lactam ( )-48 (77%) on the basis of HRMS
1H NMR spectrum of 13 at 235 K is well-defined and reveals and spectroscopic data. The Pd-catalysed arylation of a formyl
the presence of the pseudoequatorial conformer (δ 1.58 ppm) group in the observed manner has close analogy,23,24 but we
to the extent of about 5%. The 2-D NOESY spectrum of 13 at are not aware of any examples of lactam formation by this
248 K confirmed that the signals at δ 0.80 and 1.58 ppm were method. The absence of 49 as a product could also be due to
exchanging (see discussion).
steric interactions of the type used to rationalise the failed
The convenience of using methanesulfonamide intermedi- approach to 31 (Scheme 3).
ates in the IDA sequence was confirmed by preparing a sample
Having secured access to quantities of the amine 13, we
of (+)-7 in this manner (Scheme 5). The methanesulfonamide exploited the chemistry of azepinium salts for the controlled
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Scheme 5 Preparation of amine (S)-7 using methanesulfonyl
N-protection.
Scheme 7 Axis-controlled methylation of the amine ( )-13 leading to
(
)-14.
and a detailed analysis of this compound by NMR spec-
troscopy confirmed that the 5- and 7-methyl substituents were
in pseudoaxial orientations [δ 0.73 (5-Me), 0.99 (7-Me)].
Catalytic hydrogenation of 52 gave the free amine ( )-14 (95%),
1
a colourless oil, whose H NMR spectrum at 235 K indicated
that the 5- and 7-methyl groups were predominantly (ca. 90%)
pseudoequatorial at this temperature. The detailed spectro-
scopic analysis of the amine 14 is discussed below.
The selective formation of 52 from 51 (Scheme 7) was to be
expected, given that such additions are usually guided by a pre-
ference for axial attack and proceed under kinetic (product
development) control. With tropos azepinium systems, the
pathway to a stable product conformation can involve axis
inversion, but if the axis is constrained (as in the case of 51),
only one face of the electrophile meets the requirements,
Scheme 6 Pd-Catalysed oxidative cyclisation of the formamide 47.
introduction of a second alkyl group at C(7) of the dibenz[c,e] making the process strictly diastereoselective.26 This aspect of
azepine framework. The Page and Lacour groups have made azepinium salt reactivity was further demonstrated by the
extensive contributions to this chemistry in developing their iterative use of the oxidation–methylation sequence to install
epoxidation catalysts.12,13 For our purposes, we protected the two methyl groups on to the dibenzazepine 53 (Scheme 8).
amine ( )-13 as the benzyl derivative 50, which was then oxi- Oxidation of 53 with NBS provided the azepinium salt 54,
dised to the azepinium tetraphenylborate 51 with NBS using which was transformed into 55 using MeMgBr. A second oxi-
Lacour’s procedure25 (Scheme 7). Treating 51 with MeMgBr in dation–methylation sequence then provided 56 and hence 57.
THF at −78 °C provided the crystalline adduct ( )-52 (86%), The amine 57 was not fully characterised due to contami-
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enantiopure targets the starting materials are homochiral sub-
stituted benzylamines, which are accessible using a wide
variety of synthetic and biocatalytic methods.28 The azepinium
chemistry exemplified in Scheme 7 provides a useful com-
plement to the IDA-based dibenzazepine synthesis: with the
biaryl bond and a stereogenic C(5) in place, subsequent reac-
tions are subject to, and can exploit, the stereoelectronic pro-
perties of the axis-centre relay. The trans-selective addition of
the Grignard reagent to 51 to give 52 (Scheme 7) is illustrative
in this context.
The relative stereochemistry of each of the synthetic dibenz
[c,e]azepines was assigned using NMR spectroscopy.
Conformational mobility in such molecules is evident in the
temperature dependence of both 1H and 13C spectra. When
alkyl groups are located on C(5) or C(7), their orientation can
be deduced from the associated 1H NMR signals, which are
subject to upfield chemical shifts when the group is pseudo-
axial, and therefore close to the distal aromatic ring.7 On this
basis, it was concluded that all of the amines 12–14 undergo
rapid conformational exchange at room temperature, but with
significant variation in the distribution of conformers. The key
elements of the NMR-based structural analysis of 12–14 are
summarised in Fig. 3.29 For the amine 12 at −35 °C, the major
conformer (>90%) has the isopropyl group in a pseudoequator-
ial orientation (this was assigned by comparison with the pre-
cursor 25, in which the pseudoaxial orientation of the alkyl
group can be assumed7). No minor (5-axial) conformer of 12
Scheme 8 Sequential oxidation/methyl addition route to ( )-57.
nation with 55,27 but it was evident from the 1H NMR spec-
trum that the 5- and 7-methyl groups were in the expected
trans-diequatorial relationship [δ 1.32 (6 H, d, J 6.8 Hz)].
Discussion
The steric demands of amines 12–14 provided a useful chal-
lenge for the IDA-based synthetic route to dibenzazepines.
While the 5-isopropyl system 12 proved accessible using the
original N-trifluoroacetylation strategy,8 the extra methyl sub-
stituent at C(4) of the target 13 served to expose a significant
limitation, manifested in the failure of 30 in the IDA cyclisa-
tion. This prompted a return to N-sulfonyl precursors, in the
belief that substrates with a pyramidal N-atom would be less
susceptible to the effects of angle strain and the incipient
allylic A1,3-strain as the ring-closure proceeded. The cyclisation
of 18 to the dibenzazepine 20 (Scheme 1), as well as various
precedents,16 confirmed the viability of sulfonamide pre-
cursors, but the competitive formation of 19 militated against
the use of arenesulfonyl. As an alternative, N-methanesulfonyl
analogues proved highly effective as sources of ( )-13 and (+)-7,
Fig. 3 Diagnostic NMR signals (1H, 500 MHz, CDCl3, 235 or 238 K) used
and offer a convenient approach to amines of this type. For to assign the relative configurations of amines 12–14.
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was identified, although candidate trace-level signals were
visible in NMR spectra.
For the amine 13 at −38 °C, the predominant conformation
(95%) involves a pseudoaxial orientation for the 5-Me group
(δ 0.79 ppm), the pseudoequatorial conformer (δ 1.58 ppm)
being the minor component of the equilibrium. In this case,
both the spectroscopic assignments and the conformational
exchange of the 5-methyl group were verified in a 2D-NOESY
NMR experiment. In contrast, the amine 14 at −35 °C exists
predominantly (90%) with the 5,7-trans methyl groups in pseudo-
equatorial orientations (δ 1.59, 1.52 ppm), the exchanging
pseudoaxial conformer (δ 0.99, 0.95 ppm) again being identi-
fied using the 2D-NOESY technique.
With the properties of the amines 12–14 established, it is
instructive to re-evaluate the molecular mechanics calculations
which prompted their synthesis. The calculations have been
extended to most of the dibenz[c,e]azepines prepared, and the
results [Table 1 (ref. 30)] include a breakdown of the main
components of the global steric energy (GSE), ΔE, in each
case. Taking the amine 7 as a reference point, the known7 pre-
ference for a pseudoequatorial 5-methyl group can be inter-
preted in terms of the van der Waals (steric strain) element of
the GSE, encompassing the C(4)–C(5) allylic A1,3-strain, being
outweighed by the accumulated bend (angle strain) and torsion
(eclipsing) elements, which will include inter alia a contri-
bution from the Me–C(7) gauche interaction depicted in Fig. 4.
With amine 8, the second methyl group at C(7) reinforces the
effect of the first, amplifying the conformational preference
accordingly. In the cases of the amines 12, 13 and 14, the
Fig. 4 Newman projections of 6,7-dihydro-5-methyl-5H-dibenz[c,e]
azepines.
molecular mechanics analysis offers some useful pointers as
to the origins of their properties, but also reflects the limit-
ations of the method. Comparing 7 and 13 confirms that, as
predicted, a methyl group at C(4) of the amine has more influ-
ence on the conformational bias than the increased bulk of
the 5-substituent in 12 and possibly the unknown t-butyl homo-
logue 59. On the other hand, the predicted conformational
balance in 12 and 14 was not observed. It is clear that these
amines undergo conformational exchange more slowly than 7,
but remain strongly biased towards the same relative configur-
ation, featuring the C(5) substituent in a pseudoequatorial
orientation.
For the amines in Table 1 bearing a substituent at N(6),
additional gauche and buttressing effects come into play (see
Fig. 4). The amines 50 and 52 show no sign of conformational
exchange at room temperature, each being strongly biased
towards a conformation with the 5-methyl group in a pseudo-
axial orientation. The amine 57 is also conformationally stable
Table 1 Calculated differences in steric energy (kJ mol−1) of the (aR)- and (aS)-configured conformational minima of various 6,7-dihydro-5H-
dibenz[c,e]azepine derivatives (MacroModel v. 8.0, MM3 force field)
Selected components of ΔEc
Compound
R4
R5
R6
R7
R8
ΔEa
4.4
11.6
0.5
−6.8
−0.4
−16.7
−21.2
−5.3
−1.4
−14.3
Ratiob
Bend
Torsion
van der Waals
Electrostatic
7
8
H
H
H
Me
Me
Me
Me
H
H
Me
Me
Me
Pri
Me
Me
Me
Me
Me
But
Me
H
H
H
H
H
Me
H
H
Me
H
Me
Me
H
H
H
H
H
H
H
H
H
H
Me
85 : 15
99 : 1
4.5
10.5
2.0
−2.8
3.5
−9.2
0.9
9.9
1.9
−3.6
2.9
5.5
2.8
2.6
4.6
4.3
2.1
2.8
2.8
3.9
−3.7
−7.6
0.8
3.7
2.9
1.6
4.1
2.3
3.5
3.3
6.4
4.5
12
13
14
50
52
57
59
60
55 : 45d
6 : 94e
−6.8
−7.6
H
46 : 54 f
0.1 : 99.9
0 : 100
11 : 89
36 : 64
0.3 : 99.7
−11.2
−12.3
−22.5
−17.8
−11.8
−16.3
Bn
Bn
Bn
H
H
Me
a Calculated difference in steric energy EaS − EaR (kJ mol−1) of the respective global conformational minima in the aS and aR manifolds. b The
ratio C(5)eq : C(5)ax at 298 K assuming dynamic equilibrium. c Positive values favour the aR [C(5)eq] configuration. d Ratio by NMR > 90 : 10
at 238 K. e Ratio by NMR 5 : 95 at 235 K. f Ratio by NMR 90 : 10 at 238 K.
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at room temperature, but the chemical shifts of the methyl dimethyl-substituted structures of this series. The IDA meth-
groups (δ 1.32 ppm)29 suggest that they are pseudoequatorial, odology was used with methanesulfonyl-protected intermedi-
which is consistent with the properties of 55 (Scheme 8) but ates, and extended by transforming a 5-methyldibenz[c,e]
not the calculated GSE value in Table 1.
azepine into the trans-5,7-dimethyl homologue, using the
addition of MeMgBr to an intermediate azepinium salt as the
diastereoselective step.
The three amines ( )-12, ( )-13 and ( )-14 were targeted on
the basis of molecular mechanics calculations, which high-
lighted their potential as tropos ligands with either finely
balanced or strongly biased conformational preferences.
Although limited in its predictive power, the molecular mech-
anics method provided a useful basis for interpreting the pro-
1
perties of the acquired dibenz[c,e]azepines, as observed by H
NMR spectroscopy. In CDCl3 at 235 K, 6,7-dihydro-4,5-
dimethyl-5H-dibenz[c,e]azepine 13 exists as an exchanging pair
of conformational isomers, with the 5-methyl group predomi-
nantly (19 : 1) in a pseudoaxial orientation. This behaviour con-
trasts with that of the monoalkyl systems 7 and 12, in which
the 5-substituent prefers a pseudoequatorial orientation. In
CDCl3 at 238 K, trans-6,7-dihydro-4,5,7-trimethyl-5H-dibenz[c,e]
azepine 14 also exists as a pair of exchanging conformers, in
this case with the 5- and 7-methyl groups predominantly (9 : 1)
in pseudoequatorial orientations. Kinetic analysis of 14 by
2D-EXSY NMR spectroscopy (CDCl3, 233–248 K) gave a value of
57 kJ mol−1 for the activation barrier, EA, of the conformational
exchange process in this amine.
The properties 13 and 14 differ markedly from those of the
Ar-unsubstituted homologue 8, whose 1H NMR spectrum is
invariant over the temperature range 183–423 K.9 We speculate
that the bias, inherent in 13, towards a pseudoaxial orientation
of the 5- and 7-substituents, and the associated configuration
of the biaryl axis, will be most emphatic in the 4,5,7,8-tetra-
methyl homologue 60, favouring an exaggerated C2-symmetry
in the domain of the N-atom of this hitherto unknown chiral
base. In comparison, the conformational bias observed with
amine 14 is modest, and might be reversed as a result of a
coordination event at the N-atom, e.g. in the course of its oper-
ation as a tropos ligand. Further experimentation is required in
order to test these possibilities.
It is noteworthy that, of the amines 13, 14, 38, 50 and 52 fea-
turing a C(4) methyl group, only the 4,5,7-trimethyl system 14
displays the conformation with the 5-substituent in a pseudo-
equatorial orientation. In the other four structures, the C(4)
methyl group tips the balance in favour of a pseudoaxial
5-methyl group and the corresponding configuration at the
biaryl axis. In a further study, the conformational exchange in
14 was analysed in a series of 2D-EXSY NMR experiments,31,32
monitoring the signals due to the 5-H and 7-H methines. The
relevant diagonal and cross-peak signals were well resolved in
the temperature range used for data acquisition (233–248 K),
and the slope of the relevant Arrhenius plot31 gave a value of
57 kJ mol−1 for the Arrhenius energy of activation, EA, of the
exchange process. The error associated with this value is
difficult to specify: given the narrow temperature range and
reliance on 1D 1H NMR integration data for estimating the
conformer distribution at each temperature, a lower limit of
3 kJ mol−1 is proposed. Using the intercept from the data plot,
the value for EA, and the appropriate form of the Eyring
equation, the corresponding activation parameters ΔH‡, ΔS‡
and ΔG‡ for exchange were calculated to be 54 kJ mol−1, +8
J K−1 mol−1, and 52 kJ mol−1 respectively at 298 K, which align
quite closely with the published data for the cis-5,7-dimethyl
system 8.9 The properties of 13 and 14 thus serve to illustrate
how amines of this type can be invested with a chosen confor-
mational bias without compromising their underlying flexi-
bility as tropos ligands.
Experimental
Melting points were determined using Kofler hot-stage, Buchi
512 or Stuart Scientific SMP10 equipment and are uncorrected.
Unless otherwise indicated, IR spectra were recorded for neat
thin films using PerkinElmer 1710FT or Nicolet Nexus 670/870
spectrometers. NMR spectra were measured using Bruker spec-
trometers (Avance HD III 400, Ascend 400, Avance II+ 500) and
are calibrated by reference to signals from the solvent (CDCl3
at 77.16 ppm and CD3OD at 49.00 ppm for 13C spectra;
Conclusions
6,7-Dihydro-5H-dibenz[c,e]azepines incorporate a centre-axis residual protium in CDCl3 at 7.26 ppm, CD3OD at 3.31 ppm
1
chirality relay, which offers some unusual opportunities for and D2O at 4.79 ppm for H spectra).33 Chemical shifts for 19F
conformational control. In seeking to explore these opportu- are quoted relative to CFCl3 at 0 ppm. Coupling constants
nities, we used Pd-catalysed intramolecular direct arylation (J values) are given in Hz; multiplicities are given as singlet (s),
(IDA) reactions to prepare 5-isopropyl-, 5-methyl- and 4,5- doublet (d), triplet (t), quartet (C), quintet (qn) or multiplet (m).
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NMR assignments were supported using COSY, HMBC, HMQC and, by flash chromatography of the mother liquor (h 6 cm,
and DEPT spectra where appropriate. Low-resolution mass d 3.5 cm, eluting with toluene), a further portion of 20 (142 mg,
spectra were recorded on a Micromass Trio 2000 instrument 13%). Crystallisation the third fraction C (246 mg, mainly 19
using the electrospray ionisation method; data for peaks of by TLC) from toluene (2 mL) overnight gave more 19 (194 mg,
intensity <20% of that of the base peak are omitted. High- 18%). The title compound 19 (total 330 mg, 31%) formed col-
resolution (accurate mass) data were recorded using a Thermo ourless prisms, m.p. 215–217 °C (toluene) (found: C, 65.14; H,
Finnigan MAT95XP instrument or a Thermo Scientific Exactive 5.50; N, 6.53; S, 7.52. C23H22N2O4S requires C, 65.38; H, 5.25;
Plus EMR Orbitrap system. Elemental analyses were carried N, 6.63; S, 7.59%); νmax/cm−1 2957, 1538, 1445, 1371, 1353,
out by the University of Manchester microanalytical service.
1334, 1175, 1022, 881, 809, 793, 767, 734, 714, 635; δH
Starting materials and solvents were routinely purified by (400 MHz, CDCl3) 7.63 (1 H, apparent t, J 7.8 Hz, 2-H), 7.57
conventional techniques.34 Reactions were routinely carried (1 H, dd, J 7.8, 1.3 Hz, 3-H), 7.46–7.36 (5 H, m, ArH), 7.34–7.28
out in a nitrogen atmosphere. Tetrahydrofuran (THF) was (3 H, m, ArH), 7.27–7.21 (1 H, m, ArH), 7.17 (1 H, br d, J 7.2 Hz,
dried immediately prior to use, by distillation from sodium- 1-H), 4.94 (1 H, d, J 11.2 Hz, 1′-H), 3.99 (1 H, d, J 12.6 Hz, 7-H),
benzophenone ketyl under nitrogen. Organic solutions were 3.57 (1 H, d, J 12.6 Hz, 7-H), 2.54 (1 H, apparent dq, J 11.2, 6.5
dried using anhydrous MgSO4 and concentrated by rotary Hz, 2′-H), 1.18 (3 H, d, J 6.6 Hz, Me), 0.88 (3 H, d, J 6.5 Hz,
evaporation under reduced pressure. Analytical thin layer Me); δC (101 MHz, CDCl3) 147.7 (C), 141.8 (C), 139.5 (C), 136.8
chromatography (TLC) was carried out using Macherey-Nagel (C), 134.0 (C), 132.9 (CH), 132.2 (CH), 129.9 (CH), 129.8 (C),
Polygram SIL G/UV254 plates and the chromatograms were rou- 129.6 (CH), 129.4 (CH), 129.3 (CH), 129.2 (CH), 128.7 (CH),
tinely visualised using UV light (254 nm). Preparative column 128.1 (CH), 122.8 (CH), 68.8 (CH), 47.2 (CH2), 28.0 (CH), 20.6
(flash) chromatography was carried out on 60H silica gel (CH3), 20.4 (CH3); m/z (ES+) 445 (MNa+, 100%), 440 (60), 301
(Merck 9385) using the flash technique.35 Compositions of (35), 291 (80); Rf 0.25 (hexane/EtOAc, 2 : 1); 0.11 (toluene). The
solvent mixtures are quoted as ratios of volume. ‘Petroleum’ title compound 20 (total 393 mg, 37%) formed colourless
refers to a light petroleum fraction, b.p. 60–80 °C, unless rosettes, m.p. 172–174 °C (EtOAc/hexane, 1 : 3) (found: C,
otherwise stated. ‘Ether’ refers to diethyl ether.
65.28; H, 5.48; N, 6.63; S, 7.44. C23H22N2O4S requires C, 65.38;
Preparative details for the following compounds are pro- H, 5.25; N, 6.63; S, 7.59%); νmax/cm−1 3016, 2971, 2869, 1543,
vided in the ESI:† 15, 16, 18, 21, 23, 24, 26–30, 32–35, 37, 40, 1377, 1342, 1160, 1105, 1060, 1010, 931, 772, 747, 651, 639,
41, 43, 45–47, 50, 53.
611; δH (400 MHz, CDCl3) 7.91–7.88 (1 H, m, 3′-H), 7.66–7.61
(1 H, m, 4′-H or 5′-H), 7.58–7.53 (2 H, m, ArH), 7.52–7.34 (6 H,
m, ArH), 7.23–7.19 (2 H, m, ArH), 4.73 (1 H, d, J 11.5 Hz, 7-H),
4.58 (1 H, d, J 10.5 Hz, 5-H), 3.70 (1 H, d, J 11.5 Hz, 7-H),
1.05–0.91 (1 H, m, CHMe2), 0.84 (3 H, d, J 6.6 Hz, Me), 0.35
(3 H, d, J 6.5 Hz, Me); δC (101 MHz, CDCl3) 149.0 (C), 141.8 (C),
6,7-Dihydro-6-[(2-methyl-1-phenyl)propyl]-4-nitrodibenzo
[d,f][1,2]thiazepine 5,5-dioxide ( )-19 and 6,7-dihydro-5-(1-
methylethyl)-6-[(2-nitrophenyl)sulfonyl]-5H-dibenz[c,e]azepine
( )-20
A 25 mL round-bottomed flask was charged with the sulfon- 138.5 (C), 135.8 (C), 133.6 (CH), 132.1 (C), 131.9 (C), 131.3
amide ( )-18 (1.26 g, 2.5 mmol), anhydrous K2CO3 (518 mg, (CH), 130.4 (CH), 130.1 (CH), 129.6 (CH), 129.2 (CH), 128.8
3.75 mmol), tricyclohexylphosphonium tetrafluoroborate (CH), 128.6 (CH), 128.1 (CH), 127.7 (CH), 124.0 (CH), 69.9
(92 mg, 0.25 mmol), pivalic acid (77 mg, 0.75 mmol) and (CH), 49.8 (CH2), 32.5 (CH), 20.7 (CH3), 20.5 (CH3); m/z (ES+)
Pd(OAc)2 (28 mg, 0.125 mmol) and a stirrer bar. The flask was 445 (MNa+, 21%), 423 (MH+, 54), 221 (100), 179 (28); Rf 0.32
purged with nitrogen for 20 min, DMA (20 mL) was added, (hexane/EtOAc, 2 : 1); 0.22 (toluene).
and the stirred mixture was heated to 130 °C (external temp-
erature). The reaction mixture became dark as the temperature
approached 130 °C. After 42 h at 130 °C the DMA was evapor-
1-[(rel-aS,5S)-5,7-Dihydro-5-isopropyl-6H-dibenz[c,e]azepin-
6-yl]-2,2,2-trifluoroethan-1-one ( )-25
ated in vacuo, the black residue was digested with EtOAc A 25 mL round-bottomed flask was charged with the trifluoro-
(50 mL) and the mixture was filtered through a 5 mm pad of acetamide ( )-24 (1.036 g, 2.5 mmol), anhydrous K2CO3
Celite. The filtrate was concentrated and the residual black oil (518 mg, 3.75 mmol), tricyclohexylphosphonium tetrafluoro-
(1.37 g, vac. dried) was analysed by 1H NMR spectroscopy, borate (92 mg, 0.25 mmol), pivalic acid (77 mg, 0.75 mmol)
which indicated a mixture of 19 and 20 (ratio 47 : 53) together and Pd(OAc)2 (28 mg, 0.125 mmol) and a stirrer bar. The flask
with a small amount of the debrominated compound 21. Flash was purged with nitrogen for 20 min, DMA (20 mL) was added,
chromatography over silica gel (h 5 cm, d 5 cm), eluting with and the stirred mixture was heated to 130 °C (external temp-
CH2Cl2, gave three fast-moving and/or intensely coloured frac- erature). The reaction mixture became dark during the first
tions A–C which were collected and dried in vacuo. The first hour at 130 °C. After 46 h at 130 °C the DMA was evaporated
fraction A (301 mg, mainly 20 by TLC) was further purified by in vacuo, the black residue was digested with EtOAc (50 mL) and
flash chromatography over silica gel (h 12 cm, d 2.5 cm), the mixture was filtered through a 5 mm pad of Celite. The fil-
eluting with toluene, giving 20 (251 mg, 24%) as a colourless trate was concentrated and the residual dark brown oil (0.85 g,
solid after trituration with ether. Allowing the second fraction vac. dried) was analysed by 1H NMR spectroscopy (sample
B (317 mg, a mixture of 19 and 20 by TLC) to stand in toluene weight 0.04 g). The residual brown oil was chromatogaphed
(2 mL) overnight gave a crystalline sample of 19 (136 mg, 13%) over silica gel (hexane/EtOAc, 19 : 1), affording a fast-moving
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yellow band that was shown by 1H NMR spectroscopy to CDCl3, 290 K) 141.7* (C), 141.4 (C), 138.2* (C), 137.7* (C),
contain the amide 25 (isomer ratio ca. 9 : 1, total 572 mg, 69%) 128.5 (2 × CH), 128.14 (CH), 128.01 (CH), 127.96 (CH), 127.8
admixed with the debrominated product 26 (ca. 50 mg, 6%). (CH), 127.33 (CH), 127.31 (CH), 62.7* (CH), 49.4 (CH2), 30.1*
Crystallisation from EtOH gave the title compound ( )-25 as (CH), 21.1 (CH3), 20.2 (CH3) [*broadened, weak signal]; δC
thick colourless plates, m.p. 113–115 °C (found: C, 68.42; H, (126 MHz, CDCl3, 238 K) 142.0 (C), 140.9, 136.8 (C), 136.6 (C),
5.48; N, 4.15. C19H18F3NO requires C, 68.46; H, 5.44; N, 128.5 (CH), 128.2 (2 × CH), 128.1 (CH), 128.0 (CH), 127.8 (CH),
4.20%); νmax/cm−1 2969, 2932, 2875, 1678, 1435, 1250, 1182, 127.30 (CH), 127.25 (CH), 126.15 (CH), 60.9 (CH), 49.0 (CH2),
1155, 1131, 1110, 963, 942, 781, 756, 738, 695, 640; δH 29.1 (CH), 21.1 (CH3), 19.9 (CH3); m/z (ES+) 239 (30%), 238
(400 MHz, CDCl3) (ca. 10 : 1 mixture of isomers) 7.59–7.45 (MH+, 100) (found: MH+ 238.1590; C17H20N requires 238.1590);
(4 H, m, ArH), 7.43–7.33 (4 H, m, ArH), 5.23 (1 H, d, J 10.7 Hz, Rf 0.20 (EtOAc/Et3N, 100 : 1), 0.47 (EtOAc/MeOH/Et3N,
5′-H, major isomer), 5.00 (0.1 H, d, J 14.8 Hz, 7′-HA, minor 90 : 10 : 1), 0.40 (CH2Cl2/MeOH, 9 : 1).
isomer), 4.75 (1 H, br d with fine splitting, J 13.5 Hz, 7′-HA,
major isomer), 4.51 (0.1 H, br d, J 10.5 Hz, 5′-H, minor
Attempted cyclisation of the trifluoroacetamide ( )-30
isomer), 4.08 (1 H, d, J 13.5 Hz, 7′-HB, major isomer), 4.06 (0.1 A 100 mL round-bottomed flask was charged with the amide
H, d, J 14.8 Hz, 7′-HB, minor isomer), 1.31–1.20 (0.1 H, m, ( )-30 (2.00 g, 5.0 mmol), anhydrous K2CO3 (1.036 g,
1″-H, minor isomer), 1.09–0.95 (1 H, apparent d septet, J 10.7, 7.50 mmol), tricyclohexylphosphonium tetrafluoroborate
ca. 6.6, 1″-H, major isomer), 0.76 (0.3 H, br d, J 6.7 Hz, Me, (184 mg, 0.50 mmol), pivalic acid (154 mg, 1.50 mmol) and
minor isomer), 0.68 (3 H, d, J 6.7 Hz, Me, major isomer), 0.51 Pd(OAc)2 (56 mg, 0.25 mmol) and a stirrer bar. The flask was
(0.3 H, d, J 6.6 Hz, Me, minor isomer), 0.44 (3 H, d, J 6.6 Hz, purged with nitrogen for 20 min, DMA (40 mL) was added,
Me, major isomer); δC (101 MHz, CDCl3) major isomer 156.2 and the stirred mixture was heated to 130 °C (external temp-
2
(q, JCF 35 Hz, CO), 141.9 (C), 138.6 (C), 136.2 (C), 132.2 (CH), erature). The reaction mixture became dark as the temperature
129.9 (CH), 129.7 (CH), 129.2 (CH), 129.1 (CH), 128.6 (CH), reached 130 °C. After 44 h at 130 °C the DMA was evaporated
1
128.5 (CH), 127.9 (CH), 117.1 (q, JCF 288 Hz, CF3), 67.4 (CH), in vacuo, the black residue was digested with EtOAc (80 mL)
4
48.6 (q, JCF 4.3 Hz, CH2), 32.9 (CH), 20.7 (CH3), 19.3 (CH3); and the mixture was filtered through a 5 mm pad of Celite.
the following signals could be attributed to the minor isomer: The filtrate was concentrated and the residual dark brown oil
138.3 (C), 136.5 (C), 132.5 (C), 130.62 (CH), 130.57 (CH), 129.6 was analysed by 1H NMR spectroscopy, which indicated the
4
(CH), 129.5 (CH), 128.6 (CH), 128.4 (CH), 68.8 (q, JCF 2.6 Hz, presence of 30 and 32 (ratio ca. 7 : 1).
6
CH), 49.8 (CH2), 30.6 (CH), 21.0 (CH3), 19.1 (q, JCF 1.9 Hz,
(rel-aS,5S)-6,7-Dihydro-4,5-dimethyl-6-(methylsulfonyl)-
5H-dibenz[c,e]azepine ( )-36
CH3); m/z (ES+) 356 (MNa+, 93%), 334 (MH+, 80), 221 (100);
Rf 0.55 (hexane/EtOAc, 4 : 1), 0.58 (CH2Cl2).
A 250 mL round-bottomed flask was charged with the sulfon-
amide ( )-35 (3.823 g, 10.0 mmol), anhydrous K2CO3 (2.073 g,
15 mmol), tricyclohexylphosphonium tetrafluoroborate
(rel-aR,5S)-6,7-Dihydro-5-isopropyl-5H-dibenz[c,e]azepine
( )-12
A
mixture of the trifluoroacetamide ( )-25 (433 mg, (368 mg, 1.0 mmol), pivalic acid (306 mg, 3.0 mmol) and
1.30 mmol) and K2CO3 (539 mg, 3.90 mmol) in MeOH (20 mL) Pd(OAc)2 (112 mg, 0.50 mmol) and a stirrer bar. The flask was
and water (10 mL) was stirred at 65 °C for 20 h. After cooling purged with nitrogen for 15 min, DMA (50 mL) was added,
to room temperature, the mixture was diluted with water and the stirred mixture was heated to 130 °C (external temp-
(15 mL) and the bulk of the MeOH was removed by rotary evap- erature). The mixture darkened soon after the reaction temp-
oration. The residue was extracted with CH2Cl2 (3 × 20 mL) erature had been reached. After 45 h at 130 °C the DMA was
and the combined organic phase was washed with sat. aq. evaporated in vacuo, the black residue was digested with DCM
NaCl (25 mL), dried (MgSO4) and evaporated. Vacuum drying (100 mL), the mixture was filtered through a 5 mm pad of
gave the title compound ( )-12 (276 mg, 92%) as a colourless Celite, and the filtrate was concentrated, giving a dark brown
1
oil. Samples could be purified by chromatography over silica oily solid. Analysis of this material (44 mg) by H NMR spec-
gel (CH2Cl2/MeOH, 9 : 1) or short-path vacuum distillation troscopy indicated the presence of 36 and 37 (ratio ca. 9 : 1).
(oven temperature ca. 200 °C, 2 mmHg), which gave a viscous Chromatography of the crude product over silica gel (h 5 cm,
oil; νmax/cm−1 3062, 3019, 2952, 2864, 1478, 1447, 1385, 1364, d 5 cm), eluting with CH2Cl2, gave the title compound ( )-36
1192, 1096, 845, 749, 640; δH (500 MHz, CDCl3, 298 K) 7.50 (2.60 g, 86%) as an off-white solid which crystallised from
(1 H, dd, J 7.5, 1.2 Hz, ArH), 7.46–7.35 (6 H, m, ArH), 7.32 (1 H, EtOH as colourless needles (two crops, total 1.930 g, 64%),
dd, J 7.4, 1.2 Hz, ArH), 3.74 (1 H, d, J 13.1 Hz, 7-HA), 3.43 (1 H, m.p. 165–166 °C (found: C, 67.75; H, 6.53; N, 4.60; S, 10.53.
br d, J 13.1 Hz, 7-HB), 3.15 (1 H, br d, J 7.2 Hz, 5-H), 2.59 (1 H, C17H19NO2S requires C, 67.75; H, 6.35; N, 4.65; S, 10.64%);
br s, 1′-H), 2.2–1.9 (1 H, br s, NH), 1.03 (3 H, d, J 6.4 Hz, Me), νmax/cm−1 2932, 1449, 1311, 1200, 1159, 1143, 1045, 1023, 964,
0.68 (3 H, br s, Me); δH (500 MHz, CDCl3, 238 K) 7.56–7.39 920, 801, 760, 710; δH (400 MHz, CDCl3) 7.50–7.27 (7 H, m,
(7 H, m, ArH), 7.34 (1 H, br d, J 7.2 Hz, ArH), 3.77 (1 H, d, J 13.4 ArH), 5.57 (1 H, q, J 7.0 Hz, 5-H), 4.57 (1 H, d, J 12.3 Hz, 7-H),
Hz, 7-HA), 3.32 (1 H, br d, J 13.4 Hz, 7-HB), 3.2–2.7 (1 H, br s, 4.57 (1 H, d, J 12.3 Hz, 7-H), 2.89 (3 H, s, SO2Me), 2.53 (3 H, s,
NH), 3.01 (1 H, br d, J 10.2 Hz, 5-H), 2.42 (1 H, br s, 1′-H), 1.07 4-Me), 0.89 (3 H, d, J 7.0 Hz, 5-Me); δC (101 MHz, CDCl3) 141.9
(3 H, d, J 5.9 Hz, Me), 0.79 (3 H, d, J 6.0 Hz, Me); δC (101 MHz, (C), 139.6 (C), 136.0 (C), 135.6 (C), 133.0 (C), 130.9 (CH), 129.3
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(CH), 129.1 (CH), 128.5 (CH), 128.41 (CH), 128.36 (CH), 51.9 100%) (found: MH+ 238.1586; C17H20N requires 238.1590);
(CH), 48.5 (CH2), 38.9 (CH), 22.6 (CH3), 21.1 (CH3) [one hidden Rf 0.46 (EtOAc/Et3N, 19 : 1).
ArC̲
H]; m/z (ES+) 324 (MNa+, 37%), 302 (MH+, 58), 207 (58), 108
(aS,5S)-6,7-Dihydro-5-methyl-6-(methylsulfonyl)-5H-dibenz[c,e]
azepine (S)-(−)-42
(95), 103 (100) (found: MH+ 302.1207; C17H20NO2S requires
302.1209); Rf 0.32 (CH2Cl2).
A 100 mL round-bottomed flask was charged with the sulfon-
amide (S)-41 (1.842 g, 5.0 mmol), anhydrous K2CO3 (1.036 g,
7.5 mmol), tricyclohexylphosphonium tetrafluoroborate
(184 mg, 0.50 mmol), pivalic acid (154 mg, 1.5 mmol) and
(rel-aS,5S)-6,7-Dihydro-4,5-dimethyl-5H-dibenz[c,e]azepine
( )-13 and (rel-aS,5S)-6,7-dihydro-4,5,6-trimethyl-5H-dibenz
[c,e]azepine ( )-38
The sulfonamide ( )-36 (802 mg, 2.66 mmol) in toluene Pd(OAc)2 (56 mg, 0.25 mmol) and a stirrer bar. The flask was
(30 mL) at room temperature under N2 was treated, dropwise purged with nitrogen for 20 min, DMA (30 mL) was added,
with stirring, with Red-Al (65 wt% in toluene, 5.0 mL, and the stirred mixture was heated to 130 °C (external temp-
16.6 mmol).21 The resulting solution was heated under reflux erature). The reaction mixture became dark as the temperature
with stirring for 6 h. The reaction was then cooled to 0 °C, approached 130 °C. After 28 h at 130 °C the DMA was evapor-
quenched by cautious addition of water (10 mL) and diluted ated in vacuo, the residue was digested with CH2Cl2 (80 mL),
with water (20 mL) and ether (60 mL). The layers were separ- and the mixture was filtered through a 10 mm pad of Celite.
ated, the organic phase was extracted with 2 M HCl (2 × Evaporation of the filtrate gave a dark brown, partly crystalline,
40 mL), and the aqueous extract was then basified (pH ≥12) oily solid, which 1H NMR spectroscopy showed to be mainly 42
with 4 M NaOH (50 mL) and extracted with ether (3 × 50 mL). and 43 (ratio 12 : 1). Chromatography over silica gel (h 9 cm,
The combined organic phase was washed with water (50 mL) d 3.5 cm), eluting with CH2Cl2, gave the title compound (S)-42
and sat. aq. NaCl (50 mL), dried (MgSO4) and evaporated. The (1.225 g, 85%) as a colourless solid. Crystallisation from EtOH
residue was purified by flash chromatography over silica gel (12 mL) gave a crop (920 mg, 64%) of colourless prisms,
(h 15 cm, d 2.5 cm), eluting with EtOAc/MeOH/Et3N (94 : 4 : 2), m.p. 176–177 °C; [α]2D2:5 −146.5 2.0 (c 2.07, CHCl3); νmax/cm−1
which gave a by-product identified as 38 (31 mg, 5%), followed 2992, 2970, 2926, 2858, 1483, 1452, 1328, 1152, 1115, 1019,
by the title compound ( )-13 (465 mg, 78%) as a colourless oil; 953, 933, 887, 808, 789, 767, 741, 714, 620; δH (400 MHz,
νmax/cm−1 3300 br, 2982, 2964, 1591, 1454, 1383, 1369, 1327, CDCl3) 7.55–7.45 (5 H, m, ArH), 7.43–7.37 (2 H, m, ArH), 7.31
1239, 1209, 1103, 1037, 798, 752, 708, 670, 642, 616; δH (1 H, dd, J 7.5, 1.4 Hz, ArH), 5.00 (1 H, q, J 7.0 Hz, 5-H), 4.60
(500 MHz, CDCl3, 235 K) 7.47 (dd, J 7.2, 0.8 Hz, 1 H), 7.43 (1 H, d, J 12.0 Hz, 7-H), 3.74 (1 H, d, J 12.0 Hz, 7-H), 2.86 (3 H,
(ddd, J 7.8, 5.6, 2.5 Hz, 1 H), 7.37–7.34 (m, 2 H), 7.33–7.29 (m, s, SO2Me), 0.95 (3 H, d, J 7.0 Hz, 5-Me); δC (101 MHz, CDCl3)
2 H), 7.28–7.25 (m, 1 H), 4.62 (q, J 7.2 Hz, 1 H), 3.69 (1 H, d, 141.0 (C), 138.9 (C), 137.6 (C), 133.1 (C), 130.0 (CH), 129.80
J 12.3 Hz, 7-HA), 3.67 (1 H, d, J 12.3 Hz, 7-HB), 2.77 (s, 1 H), (CH), 129.72 (CH), 129.4 (CH), 129.1 (CH), 128.79 (CH), 128.69
2.46 (s, 3 H), 0.79 (d, J 7.2 Hz, 3 H); δH (400 MHz, CDCl3, (CH), 128.0 (CH), 59.4 (CH), 48.8 (CH2), 37.2 (CH3), 23.5 (CH3);
290 K) 7.46 (1 H, br d, J 7.5 Hz, ArH), 7.43–7.37 (1 H, m, ArH), m/z (ES+) 288 (MH+, 100%); Rf 0.38 (CH2Cl2). A sample of
7.36–7.27 (4 H, m, ArH), 7.24–7.21 (1 H, m, ArH), 4.63 (1 H, ( )-42, prepared as above from ( )-41, formed colourless crys-
unresolved q, J 5.9 Hz, 5-H), 3.72–3.63 (2 H, m, 7-H2), 2.46 (3 tals, m.p. 180–182 °C (EtOH) (found: C, 66.81; H, 5.91; N, 4.99;
H, s, 4-Me), 2.31 (1 H, s, NH), 0.81 (3 H, unresolved d, J 5.9 Hz, S, 11.01. C16H17NO2S requires C, 66.87; H, 5.96; N, 4.87; S,
5-Me); δC (126 MHz, CDCl3, 235 K) 142.2 (C), 139.9 (C), 139.2 11.16%).
(C), 137.9 (C), 135.5 (C), 130.2 (CH), 128.2 (CH), 128.06 (CH),
128.04 (CH), 127.9 (CH), 127.8 (CH), 127.1 (CH), 50.0 (CH2),
(5S)-6,7-Dihydro-5-methyl-5H-dibenz[c,e]azepine (S)-(+)-7
48.5 (CH), 23.9 (CH3), 21.2 (CH3); δC (101 MHz, CDCl3, 290 K) The sulfonamide (S)-42 (764 mg, 2.66 mmol) in toluene
142.4 (C), 140.2 (C), 139.6 (C), 138.7 (C), 135.5 (C), 130.3 (CH), (30 mL) at room temperature under N2 was treated, dropwise
128.3 (CH), 128.04 (CH), 127.98 (CH), 127.87 (CH), 127.1 (CH), with stirring, with Red-Al (65 wt% in toluene,
5 mL,
50.5 (CH), 49.0 (CH2), 24.2 (CH3), 20.9 (CH3) [one ArCH 16.6 mmol). The resulting solution was heated under reflux
obscured]; m/z (ES+) 224 (MH+, 100%) (found: MH+ 224.1436; with stirring for 6 h. The reaction was then cooled to 0 °C,
C16H18N requires 224.1434); Rf 0.20 (EtOAc/Et3N, 19 : 1). The quenched by the initially cautious addition of water (10 mL),
N-methylated compound ( )-38 was obtained as a colourless and then diluted with more water (20 mL) and ether (60 mL).
oil; νmax/cm−1 2962, 2931, 2786, 2768, 1446, 1372, 1238, 1205, The layers were separated, the organic phase was extracted
1190, 1137, 1114, 1070, 1022, 800, 758, 698; δH (400 MHz, with 2 M HCl (2 × 40 mL), and the aqueous extract was then
CDCl3) (400 MHz, CDCl3, 290 K) 7.44–7.38 (3 H, m, ArH), basified (pH ≥12) with 4 M NaOH (50 mL) and extracted with
7.35–7.27 (3 H, m, ArH), 7.26–7.23 (1 H, m, ArH), 4.26 (1 H, q, ether (3 × 50 mL). The combined organic phase was washed
J 7.3 Hz, 5-H), 3.60 (1 H, d, J 11.1 Hz, 7-HA), 3.08 (1 H, d, J 11.1 with water (2 × 50 mL) and sat. aq. NaCl (50 mL), dried
Hz, 7-HB), 2.59 (3 H, s, Me), 2.46 (3 H, s, Me), 0.81 (3 H, d, J 7.3 (MgSO4) and evaporated. The residue (580 mg) was purified by
Hz, 5-Me); δC (101 MHz, CDCl3) 142.6 (C), 139.7 (C), 137.3 (C), flash chromatography over silica gel (h 15 cm, d 2.5 cm),
136.5 (C), 135.9 (C), 130.0 (CH), 129.1 (CH), 128.3 (CH), 127.8 eluting with EtOAc/MeOH/Et3N (94 : 4 : 2), which gave a by-
(CH), 127.71 (CH), 127.69 (CH), 127.3 (CH), 58.3 (CH), 58.1 product identified as 44 (32 mg, 5%), followed by the title com-
(CH2), 46.5 (CH3), 22.4 (CH3), 21.4 (CH3); m/z (ES+) 238 (MH+, pound (S)-7 (449 mg, 81%) as a colourless oil, [α]D26 +32.7 0.9
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(c 0.69, CHCl3) {lit.8 [α]2D2 +27.0 (c 0.8, CHCl3)}; νmax/cm−1 3060, requires 252.1383); Rf 0.39 (hexane/EtOAc, 1 : 1), 0.36 (CH2Cl2/
3023, 2959, 1480, 1448, 1374, 1351, 1192, 1114, 747; δH EtOAc, 9 : 1).
(500 MHz, CDCl3, 298 K) 7.49–7.41 (6 H, m, ArH), 7.38 (1 H,
td, J 7.3, 1.5 Hz, ArH), 7.34 (1 H, dd, J 7.4, 1.2 Hz, ArH), 3.73
(1 H, d, J 12.6 Hz, 7-H), 3.71 (1 H, q, J 6.6 Hz, 5-H), 3.50 (1 H,
6-Benzyl-4,5-dimethyl-5H-dibenz[c,e]azepin-6-ium
tetraphenylborate ( )-51
d, J 12.6 Hz, 7-H), 2.07 (1 H, s, NH), 1.47 (3 H, d, J 6.6 Hz, Me); In an adaptation of Lacour’s procedure,25 a solution of ( )-50
δC (126 MHz, CDCl3) 141.34 (C), 141.30 (C), 139.5 (C), 137.3 (402 mg, 1.28 mmol) in CH2Cl2 (10 mL) was treated portion-
(C), 128.4 (CH), 128.20 (CH), 128.18 (CH), 128.06 (CH), 127.99 wise with N-bromosuccinimide (228 mg, 1.28) (caution –
(CH), 127.80 (CH), 127.6 (CH), 125.0 (CH), 50.3 (CH), 49.6 exothermic). The resulting deep yellow solution was stirred for
(CH2), 19.1 (CH3); m/z (ES+) 210 (MH+, 100%) (found: MH+ 5 min at ambient temperature. A solution of sodium tetra-
210.1277; C15H16N requires 210.1278); Rf 0.22 (EtOAc/MeOH/ phenylborate (438 mg, 1.28 mmol) in MeCN (4 mL) was then
Et3N, 94 : 4 : 2), Rf 0.25 (EtOAc/Et3N, 19 : 1). The NMR spectra added in one portion, and the resulting mixture was stirred for
of 7 are in accord with published data.8 The by-product 6,7- 5 min. The suspension was diluted with CH2Cl2 (30 mL),
dihydro-5,6-dimethyl-5H-dibenz[c,e]azepine
(S)-44
was washed with water (2 × 30 mL), dried (MgSO4), filtered and
obtained as a colourless gum; νmax/cm−1 3061, 3024, 2974, concentrated in vacuo. Trituration with EtOH (15 mL), initially
2938, 2838, 2778, 1447, 1372, 1352, 1210, 1189, 1149, 1127, with warming, then with cooling in ice-water, gave the salt
1088, 1062, 1048, 1030, 1015, 942, 745, 622; δH (500 MHz, ( )-51 (699 mg, 86%) as an off-white solid which was dried
CDCl3, 298 K) 7.50 (1 H, br d, J 7.5 Hz, ArH), 7.49–7.40 (5 H, in vacuo at 80 °C for 1 h prior to use. A sample crystallised
m, ArH), 7.39–7.35 (2 H, m, ArH), 3.49 (1 H, d, J 12.3 Hz, 7-H), from EtOH as small colourless needles, m.p. 135–145 °C (dec.)
3.40 (1 H, q, J 6.9 Hz, 5-H), 3.24 (1 H, d, J 12.3 Hz, 7-H), 2.38 (3 (found: C, 89.02; H, 6.82; N, 2.32. C47H42NB requires C, 89.37;
H, s, NMe), 1.41 (3 H, d, J 6.9 Hz, 5-Me); δC (126 MHz, CDCl3) H, 6.70; N, 2.22%); νmax/cm−1 3055, 3028, 2981, 1654, 1578,
141.28 (C), 141.17 (C), 137.7 (C), 134.6 (C), 129.4 (CH), 128.19 1558, 1477, 1454, 1426, 1130, 1064, 1030, 845, 767, 733, 707,
(CH), 128.04 (CH), 127.78 (CH), 127.60 (CH), 127.57 (CH), 611; δH (500 MHz, d6-DMSO, 298 K) 9.71 (1 H, s, 7-H), 8.07
127.40 (CH), 126.5 (CH), 59.1 (CH2), 56.9 (CH), 39.4 (CH3), 17.1 (1 H, d, J 7.4 Hz, ArH), 8.02–7.96 (2 H, m, ArH), 7.80 (1 H, ddd,
(CH3); m/z (ES+) 224 (MH+, 100%) (found: MH+ 224.1426; J 7.7, 6.6, 2.0 Hz, ArH), 7.58 (1 H, d, J 7.4 Hz, ArH), 7.52 (2 H,
C16H18
N requires 224.1434); Rf 0.31 (EtOAc/MeOH/Et3N, dd, J 7.8, 1.5 Hz, ArH), 7.47–7.37 (4 H, m, ArH), 7.29 (1 H, d,
94 : 4 : 2), Rf 0.40 (EtOAc/Et3N, 19 : 1).
J 7.1 Hz, ArH), 7.22–7.17 (8 H, m, 2,6-H of BPh4), 6.93 (8 H, t,
J 7.4 Hz, 3,5-H of BPh4), 6.79 (4 H, br t, J 7.2 Hz, 4-H of BPh4),
5.57 (1 H, d, J 13.9 Hz, PhCHAHB), 5.44 (1 H, q, J 7.1 Hz, 5-H),
Attempted IDA cyclisation of the formamide ( )-47
A 100 mL round-bottomed flask was charged with the amide 5.44 (1 H, d, J 13.9 Hz, PhCHAHB), 1.85 (3 H, s, 4-Me), 1.09 (3
( )-47 (830 mg, 2.50 mmol), anhydrous K2CO3 (518 mg, H, d, J 7.1 Hz, 5-Me); δC (126 MHz, d6-DMSO, 298 K) 170.7
1
3.75 mmol), tricyclohexylphosphonium tetrafluoroborate (CH), 163.3 (q, JCB 49 Hz, 11BC), 141.8 (C), 136.6 (C), 136.2
(92 mg, 0.25 mmol), pivalic acid (77 mg, 0.75 mmol) and (CH), 135.8 (C), 135.5 (br, CH of BPh4), 135.2 (C), 134.8 (CH),
Pd(OAc)2 (28 mg, 0.125 mmol) and a stirrer bar. The flask was 132.0 (CH), 131.9 (C), 130.0 (CH), 129.54 (CH), 129.48 (CH),
purged with nitrogen for 20 min, DMA (20 mL) was added, 129.30 (CH), 129.26 (CH), 129.0 (CH), 128.5 (CH), 125.5 (C),
3
and the stirred mixture was heated to 130 °C (external temp- 125.3 (q, JCB 2.8 Hz, CH of BPh4), 121.5 (CH of BPh4), 66.2
erature). The reaction mixture became dark as the temperature (CH2), 58.9 (CH), 18.5 (CH3), 14.5 (CH3); m/z (ES+) 312 (M+,
approached 130 °C. After 28 h at 130 °C the DMA was evapor- 100%) (found: M+ 312.1747; C23H22N requires 312.1747).
ated in vacuo, the black residue was digested with CH2Cl2
6-Benzyl-6,7-dihydro-4,5,7-trimethyl-5H-dibenz[c,e]azepine
( )-52
(40 mL) and the mixture was filtered through a 5 mm pad of
Celite. The filtrate was concentrated and the residual oil
1
(820 mg) analysed by H NMR spectroscopy. Chromatography A solution of the salt ( )-51 (632 mg, 1.0 mmol) in anhydrous
(h 15 cm, d 3.5 cm; CH2Cl2 then CH2Cl2/EtOAc, 9 : 1) gave a THF (20 mL) under N2 at −78 °C was treated dropwise with a
partially purified sample of 2-(1-(o-tolyl)ethyl)isoindolin-1-one solution of MeMgBr in ether (3 M, 3.3 mL, 9.9 mmol). The
( )-48 (485 mg, 77%) as a colourless gum; νmax/cm−1 3061, mixture was kept at −78 °C for 0.5 h, and then allowed to
3022, 2974, 2934, 2876, 1677, 1467, 1451, 1400, 1351, 1325, warm to room temperature with stirring overnight (14 h). The
1301, 1210, 1159, 1062, 1033, 783, 734, 644; δH (400 MHz, reaction mixture was then cooled to 0 °C and quenched by the
CDCl3) 7.87–7.85 (1 H, m, ArH), 7.50–7.41 (3 H, m, ArH), dropwise addition of sat. aq. NH4Cl (2 mL). The bulk of the
7.34–7.21 (4 H, m, ArH), 7.19–7.15 (1 H, m, ArH), 5.88 (1 H, q, solvent was removed by rotary evaporation, and the residue
J 7.0 Hz, CHMe), 4.24 (1 H, d, J 17.3 Hz, CHAHB), 3.69 (1 H, d, was then diluted with water (80 mL) and extracted with CH2Cl2
J 17.3 Hz, CHAHB), 2.28 (3 H, s, ArMe), 1.66 (3 H, d, J 7.0 Hz, (3 × 40 mL). The combined organic extract was washed with
CHMe); δC (101 MHz, CDCl3) 167.7 (C), 141.5 (C), 138.0 (C), water (2 × 50 mL) and brine (50 mL), dried (MgSO4) and evap-
137.7 (C), 132.8 (C), 131.3 (CH), 131.0 (CH), 128.06 (CH), orated. The residue was dissolved in a small volume of CH2Cl2,
127.98 (CH), 126.14 (CH), 126.04 (CH), 123.8 (CH), 122.9 (CH), filtered through small plug of Celite, re-evaporated, and the
46.7 (CH), 46.0 (CH2), 19.3 (CH3), 17.5 (CH3); m/z (ES+) 274 residue (344 mg) analysed by 1H NMR spectroscopy.
(MNa+, 60%), 252 (MH+, 100) (found: MH+ 252.1381; C17H18NO Chromatography of the residue (h 15 cm, d 2.5 cm; EtOAc/
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hexane, 1 : 9) gave the title compound ( )-52 (282 mg, 86%) as a EtOAc containing 0.1% Et2NH; flow rate 15 mL min−1; UV
colourless oil which crystallised on scratching. detection at 254 nm. The minor conformer (rel-aS,5S,7S)-( )-14
Recrystallisation from EtOH (2.8 mL) gave ( )-52 (180 mg) as was characterised by the following data: δH (500 MHz, CDCl3,
small colourless crystals, m.p. 102 °C (found: C, 87.80; H, 238 K) 4.58 (1 H, br q, J 7.0 Hz, 5-H), 4.24 (1 H, br q, J 6.7 Hz,
7.68; N, 4.17. C24H25N requires C, 88.03; H, 7.70; N, 4.28%); 7-H), 2.44 (3 H, s, 4-Me), 0.99 (3 H, d, J 6.7 Hz, 7-Me), 0.95
νmax/cm−1 2966, 2866, 2808, 1491, 1452, 1363, 1307, 1254, (3 H, d, J 7.0 Hz, 5-Me). For 2D-EXSY NMR analysis, a sample
1197, 1151, 1134, 1120, 1063, 1050, 1026, 982, 801, 753, 733, of ( )-14 was purified by preparative HPLC using an Agilent
713, 701; δH (500 MHz, CDCl3, 298 K) 7.52–7.50 (2 H, m, ArH), Technologies system with an ACE 5 µm SIL column (250 ×
7.45 (1 H, dd, J 7.6, 1.4 Hz, ArH), 7.40–7.35 (3 H, m, ArH), 21.2 mm) and the following parameters: column temperature
7.33–7.22 (5 H, m, ArH), 7.19 (1 H, ddd, J 7.4, 1.5, 0.5 Hz, ArH), 25 °C; mobile phase EtOAc containing 0.1% Et2NH; flow rate
4.38 (1 H, q, J 7.0 Hz, 5-H), 4.08 (1 H, d, J 13.8 Hz, PhCHAHB), 15 mL min−1; UV detection at 254 nm.
3.98 (1 H, d, J 13.8 Hz, PhCHAHB), 3.975 (1 H, q, J 7.0 Hz, 7-H),
2.34 (3 H, s, 4-Me), 0.80 (3 H, d, J 7.0 Hz, 7-Me), 0.73 (3 H, d,
6-Benzyl-5H-dibenz[c,e]azepin-6-ium tetraphenylborate 54
J 7.0 Hz, 5-Me); δC (126 MHz, CDCl3, 298 K) 142.3 (C), 141.1 A stirring solution of 53 (1.46 g, 5.12 mmol) in CH2Cl2 (40 mL)
(C), 141.0 (C), 140.9 (C), 140.7 (C), 135.2 (C), 129.9 (CH), 129.3 was treated portionwise with N-bromosuccinimide (912 mg,
(CH), 129.1 (CH), 128.8 (2 × CH), 128.3 (CH), 127.64 (CH), 5.12 mmol) (caution – exothermic). The resulting deep yellow
127.55 (CH), 127.50 (CH), 127.0 (CH), 62.2 (7-C), 59.3 (1′-C), solution was stirred for 5 min at ambient temperature. A solu-
53.9 (5-C), 20.9 (4-CH3), 20.4 (7-CH3), 18.3 (5-CH3); m/z (ES+) tion of sodium tetraphenylborate (1.752 g, 5.12 mmol) in
328 (MH+, 100%) (found: MH+ 328.2054; C24H26N requires MeCN (16 mL) was then added in one portion, and the result-
328.2060); Rf 0.28 (EtOAc/hexane, 1 : 9). The HMBC NMR spec- ing mixture was stirred for 5 min. The suspension was diluted
trum of 52 shows coupling of the 4-methyl hydrogens to only with CH2Cl2 (120 mL), washed with water (2 × 120 mL), dried
one of C(N) atoms (δ 53.8 ppm), which was thereby identified (MgSO4), filtered and concentrated in vacuo. The residual
as C(5).
yellow oil was triturated with EtOH (15 mL), initially with
warming, then with cooling in ice-water, and the solid was
collected on a filter, rinsed with ice-cold EtOH and dried
in vacuo at 70–80 °C for 1 h, giving the title compound 54
(rel-aR,5S,7S)-6,7-Dihydro-4,5,7-trimethyl-5H-dibenz[c,e]
azepine ( )-14
To a solution of ( )-52 (205 mg, 0.63 mmol) in EtOH (7 mL) (2.83 g, 92%) as a bright yellow crystals, m.p. 172–174 °C
was added 10% Pd/C (67 mg, 0.063 mmol). The flask was (acetone) (found: C, 89.70; H, 6.44; N, 2.34. C45H38NB requires
fitted with a balloon containing hydrogen and stirred at room C, 89.54; H, 6.35; N, 2.32%); νmax/cm−1 3049, 3031, 2996, 2979,
temperature for 4 h, at which point TLC (EtOAc/hexane, 1 : 4) 1648, 1596, 1578, 1553, 1478, 1253, 1208, 1068, 1028, 844, 754,
indicated that no starting material remained. The reaction 733, 698, 608; δH (400 MHz, d6-DMSO, 298 K) 9.69 (1 H, s,
mixture was filtered through Celite, the pad was rinsed with 7-H), 8.10 (1 H, dd, J 7.8, 1.3 Hz, ArH), 8.06 (1 H, dd, J 8.0, 1.0
EtOAc and the solvents were evaporated under reduced Hz, ArH), 7.99 (1 H, dt, J 7.7, 1.3 Hz, ArH), 7.82 (1 H, dt, J 7.6,
pressure. Chromatography of the residue (h 15 cm, d 2.5 cm; 1.3 Hz, ArH), 7.76 (1 H, dd, J 7.8, 1.0 Hz, ArH), 7.61–7.57 (2 H,
EtOAc/MeOH/Et3N, 94 : 4 : 2) gave the title compound ( )-14 m, ArH), 7.54 (1 H, dt, J 7.6, 1.3 Hz, ArH), 7.45–7.36 (4 H, m,
(141 mg, 95%) as a colourless oil; νmax/cm−1 3060, 2960, 2925, ArH), 7.22–7.17 (8 H, m, 2,6-H of BPh4), 7.01 (1 H, dd, J 7.7, 1.0
2870, 1450, 1370, 1268, 1214, 1109, 1028, 799, 754, 724; δH Hz, ArH), 6.93 (8 H, t, J 7.4 Hz, 3,5-H of BPh4), 6.80 (4 H, dt,
(500 MHz, CDCl3, 298 K) 7.49–7.45 (1 H, m, ArH), 7.43–7.35 (3 J 7.2, 1.2 Hz, 4-H of BPh4), 5.41 (2 H, s, CH2Ph), 5.0–4.4 (2 H,
H, m, ArH), 7.28–7.25 (2 H, m, ArH), 7.19–7.15 (1 H, m, ArH), apparent br d, 5-H2); δC (101 MHz, d6-DMSO, 298 K) 170.1
1
3.8 (1 H, br s, 5-H), 3.6 (1 H, br s, 7-H), 2.55 (3 H, s, 4-Me), (CH), 163.3 (q, JCB 49 Hz, 11BC), 141.0 (C), 136.5 (C), 135.6
2.15–1.95 (1 H, br s, NH), 1.65–1.25 (6 H, br s, 5-Me, 7-Me); (CH), 135.5 (br, CH of BPh4), 134.6 (CH), 134.0 (C), 131.8 (C),
δH (500 MHz, CDCl3, 238 K) 7.54–7.43 (4 H, m, ArH), 7.34–7.27 129.9 (CH), 129.9 (CH), 129.73 (CH), 129.66 (CH), 129.5 (CH),
(2 H, m, ArH), 7.21 (1 H, br dd, J 7.2, 1.3 Hz, 3-H), 3.73 (1 H, q, 129.3 (CH), 128.9 (CH), 128.8 (CH), 128.6 (CH), 126.6 (C), 125.3
3
J 7.0 Hz, 5-H), 3.52 (1 H, q, J 6.6 Hz, 7-H), 2.59 (3 H, s, 4-Me), (q, JCB 2.8 Hz, CH of BPh4), 121.5 (CH of BPh4), 64.6 (CH2),
1.59 (3 H, d, J 7.0 Hz, 5-Me), 1.52 (3 H, d, J 6.6 Hz, 7-Me); 54.8 (CH2); m/z (ES+) 284 (M+, 100%); m/z (ES−) 319 (Ph4B−,
δC (126 MHz, CDCl3, 238 K) 142.4 (11b-C), 141.9 (C; 11a-C), 100%) (found: M+ 284.1447; C21H18N requires 284.1439).
138.8 (7a-C), 137.0 (4a-C), 135.7 (4-C), 132.2 (3-CH), 128.1
6-Benzyl-6,7-dihydro-5-methyl-5H-dibenz[c,e]azepine ( )-55
(9-CH), 127.5 (10-CH, 11-CH), 126.9 (2-CH), 126.4 (1-CH), 124.0
(8-CH), 53.0 (5-CH), 50.3 (7-CH), 23.0 (4-CH3), 20.6 (5-CH3), A solution of the salt 54 (2.414 g, 4.0 mmol) in anhydrous THF
18.3 (7-CH3); m/z (ES+) 240 (65%), 238 (MH+, 100), 221 (92) (50 mL) under N2 at −78 °C was treated dropwise with a solu-
(found: MH+ 238.1584; C17H20N requires 238.1590); Rf 0.31 tion of MeMgBr in ether (3 M, 13.3 mL, 40 mmol). The
(EtOAc/MeOH/Et3N, 94 : 4 : 2) [SM has Rf 0.82 with this mixture was kept at −78 °C for 1 h, and then allowed to warm
solvent]. For 2D-EXSY NMR analysis, a sample of 14 was puri- to room temperature with stirring overnight (14 h). The reac-
fied by preparative HPLC using an Agilent Technologies system tion mixture was then cooled to 0 °C and quenched by the
with an ACE 5 µm SIL column (250 × 21.2 mm) and the follow- dropwise addition of a solution of MeOH (2 mL) in THF
ing parameters: column temperature 25 °C; mobile phase (10 mL). The solution was concentrated by rotary evaporation
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and the residue diluted with CH2Cl2 (80 mL). Water (150 mL) with CH2Cl2 (90 mL). Water (180 mL) was added and the
was added, the phases were gently mixed without shaking to phases were gently mixed without strong shaking. The water
effect partition, and the layers were separated. This washing layer was extracted similarly with a second portion of CH2Cl2
process was repeated with more water (2 × 150 mL), and the (60 mL). The combined organic extract was washed with water
organic phase was then washed with brine (80 mL), dried (2 × 150 mL) and brine (90 mL), dried (MgSO4) and evaporated.
(MgSO4) and evaporated. The residue was freed of white solid The residue was filtered through a column of flash silica
by filtration through a plug of silica gel (h 4 cm, d 3.5 cm), (h 5 cm, d 3.5 cm), eluting with EtOAc/hexane (1 : 1), and the
washing with CH2Cl2/Et3N (24 : 1). Evaporation, chromato- filtrate was evaporated and dried in vacuo. The residual oil was
graphy of the residue (h 15 cm, d 2.5 cm; CH2Cl2/Et3N, 98 : 2) purified by flash chromatography (h 15 cm, d 2.5 cm; EtOAc/
and drying at 50–60 °C in vacuo gave the title compound ( )-55 hexane, 1 : 4), which gave the title compound ( )-57 in a mixed
(950 mg, 79%) as a colourless viscous oil; νmax/cm−1 3058, fraction containing also ( )-55 (total 290 mg, 51%, ratio ca.
1
3023, 2974, 2934, 2796, 1493, 1479, 1450, 1365, 1345, 1308, 1 : 1.3 by H NMR spectroscopy); δH (400 MHz, CDCl3, 298 K)
1194, 1115, 1081, 1054, 1027, 1007, 942, 750, 697; δH [characterising signals using COSY] 4.06 (1 H, d, J 17 Hz,
(400 MHz, CDCl3, 289 K) 7.53 (1 H, dd, J 7.5, 1.3 Hz, ArH), PhCHAHB), 3.63 (1 H, q, J 6.8 Hz, 5,7-H), 3.37 (1 H, d, J 17 Hz,
7.50–7.41 (7 H, m, ArH), 7.40–7.35 (3 H, m, ArH), 7.32–7.26 PhCHAHB), 1.32 (6 H, d, J 6.8 Hz, 5,7-Me); δC (126 MHz, CDCl3)
(2 H, m, ArH), 3.75 (1 H, d, J 13.3 Hz, PhCHAHB), 3.65 (1 H, d, [distinguishing signals] 143.8 (C), 141.3 (C), 138.8 (C), 128.2
J 13.3 Hz, PhCHAHB), 3.57 (1 H, q, J 6.8 Hz, 5-H), 3.35 (1 H, d, (CH), 128.0 (CH), 127.5 (CH), 126.2 (CH), 58.6 (CH), 53.5
J 12.5 Hz, 7-H), 3.24 (1 H, d, J 12.5 Hz, 7-H), 1.38 (3 H, d, J 6.8 (CH2), 18.0 (CH3); Rf 0.28 (EtOAc/hexane, 1 : 9).
Hz, 5-Me); δC (101 MHz, CDCl3) 141.5 (C), 141.0 (C), 140.0 (C),
* This was later shown to be contaminated with ( )-58, as
138.6 (C), 134.9 (C), 129.6 (CH), 129.2 (CH), 128.50 (CH), indicated by the prominent MS peak at 300 m.u. and the for-
128.32 (CH), 128.1 (CH), 127.68 (CH), 127.66 (CH), 127.57 mation of ( )-55 as a co-product in the Grignard step.
(CH), 127.39 (CH), 127.35 (CH), 127.1 (CH), 57.5 (CH), 56.4
Crystal data and structure refinement
(CH2), 54.8 (CH2), 18.8 (CH3); m/z (ES+) 300 (MH+, 100) (found:
MH+ 300.1747; C22H22N requires 300.1747); Rf 0.25 (CH2Cl2/
6,7-Dihydro-6-[(2-methyl-1-phenyl)propyl]-4-nitrodibenzo[d,f]
[1,2]thiazepine 5,5-dioxide 19. CCDC deposition number
1008371; empirical formula C23H22N2O4S; formula weight
422.49; temperature 100(2) K; radiation wavelength 0.71073 Å;
MeOH, 19 : 1).
6-Benzyl-6,7-dihydro-5,7-dimethyl-5H-dibenz[c,e]azepine ( )-57
A solution of ( )-55 (937 mg, 3.13 mmol) in CH2Cl2 (25 mL) crystal system orthorhombic, space group Pbca; unit cell
was treated portionwise with N-bromosuccinimide (557 mg, dimensions a = 14.3715(5) Å; α = 90°; b = 14.9202(5) Å; β = 90°;
3.13 mmol) (caution – exothermic). The resulting yellow solu- c = 19.0907(6) Å; γ = 90°. For a numbered graphic and compre-
tion was stirred for 10 min at ambient temperature. A solution hensive data tables, see ESI.†
of sodium tetraphenylborate (1.071 g, 3.13 mmol) in MeCN
6,7-Dihydro-5-(1-methylethyl)-6-[(2-nitrophenyl)sulfonyl]-5H-
(10 mL) was then added in one portion, and the resulting dibenz[c,e]azepine 20. CCDC deposition number 1008372;
mixture was stirred for 5 min. The suspension was diluted empirical formula C23H22N2O4S; formula weight 422.49; temp-
with CH2Cl2 (75 mL), washed with water (2 × 75 mL), dried erature 150(2) K; radiation wavelength 0.71073 Å; crystal
(MgSO4), filtered and concentrated in vacuo. Trituration with system monoclinic, space group P21/c; unit cell dimensions a =
cold EtOH (20 mL) followed by drying in vacuo for 1 h at 10.1508(10) Å; b = 14.2203(12) Å; β = 106.099°; c = 14.6966(14)
70–80 °C gave 6-benzyl-5-methyl-5H-dibenz[c,e]azepin-6-ium Å. For a numbered graphic and comprehensive data tables, see
tetraphenylborate ( )-5636 (1.256 g, 65%) as a beige solid,* ESI.†
m.p. 155–165 °C (dec.); νmax/cm−1 3052, 3032, 2998, 2980,
1646, 1578, 1555, 1478, 1451, 1423, 1137, 1067, 1031, 845, 732,
Molecular mechanics calculations (Table 1)
704, 612; δH (400 MHz, d6-DMSO, 298 K) [characterising Minimised steric energy (MSE) structures for the (5S)-stereo-
signals] 9.73 (1 H, s, 7-H), 5.48 (1 H, d, J 13.3 Hz, PhCHAHB), isomers of 7, 8, 12, 13, 14, 50, 52, 57, 59 and 60 were calculated
5.40 (1 H, d, J 13.3 Hz, PhCHAHB), 5.32 (1 H, q, J 7.1 Hz, 5-H), on a Mac Pro 3.33 GHz computer running Linux Fedora Core
1.01 (1 H, d, J 7.1 Hz, 5-Me); δC (101 MHz, d6-DMSO, 298 K) 15 (x86 64-bit), using MacroModel v. 8.0 (Maestro v. 9.1 inter-
[characterising signals] 169.6 (CH), 66.0 (CH2), 64.0 (CH), 15.2 face) with the MM3 force field and Monte Carlo conformation-
(CH3); m/z (ES+) 300 [(M + 2)+, 100%], 298 (M+, 75) (found: M+ al search (csearch) method (1000 iterations). The standard
298.1585; C22H20N requires 298.1590). A solution of ( )-56 minimisation parameters were: no solvent; PRCG method; con-
(1.112 g, 1.8 mmol)* in anhydrous THF (35 mL) under N2 at vergence on gradient; max. number of iterations 3000; conver-
−78 °C was treated dropwise with a solution of MeMgBr in gence threshold 0.0200. For images of the relevant structures,
ether (3 M, 6.0 mL, 18.0 mmol). The mixture was kept at see ESI.†
−78 °C for 1 h, and then allowed to warm to room temperature
with stirring overnight (14 h). The reaction mixture was then
Exchange spectroscopy (2D-EXSY) analysis of the amine 14
cooled to 0 °C and quenched by the dropwise addition of a 2D-EXSY NMR experiments were used to provide a quantitative
solution of MeOH (1.0 mL) in THF (9 mL). The solution was measurement of the conformational exchange in ( )-14, moni-
concentrated by rotary evaporation and the residue diluted toring the signals due to the 5-H and 7-H methines of the two
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Organic & Biomolecular Chemistry
conformers. Spectra were acquired on a Bruker Avance II+ 12 P. C. Bulman Page, C. J. Bartlett, Y. Chan, D. Day, P. Parker,
500 MHz NMR spectrometer at 233–248 K. For the full details,
including spectra and the data set, see ESI.†
B. R. Buckley, G. A. Rassias, A. M. Z. Slawin, S. M. Allin,
J. Lacour and A. Pinto, J. Org. Chem., 2012, 77, 6128–6138.
13 P. C. Bulman Page, C. J. Bartlett, Y. Chan, S. M. Allin,
M. J. McKenzie, J. Lacour and G. A. Jones, Org. Biomol.
Chem., 2016, 14, 4220–4232.
14 For recent alternative approaches to this type of compound,
see: (a) S. P. France, G. A. Aleku, M. Sharma, J. Mangas-
Sanchez, R. M. Howard, J. Steflik, R. Kumar, R. W. Adams,
I. Slabu, R. Crook, G. Grogan, T. W. Wallace and N. J. Turner,
Angew. Chem., Int. Ed., 2017, DOI: 10.1002/anie.201708453;
(b) T. J. A. Corrie, L. T. Ball, C. A. Russell and G. C. Lloyd-
Jones, J. Am. Chem. Soc., 2017, 139, 245–254; (c) V. Narbonne,
P. Retailleau, G. Maestri and M. Malacria, Org. Lett., 2014, 16,
628–631; (d) S. Bhowmik, S. Bhattacharyya and S. Batra,
Tetrahedron, 2014, 70, 4031–4037.
15 (a) T. Fukuyama, M. Cheung, C.-K. Jow, Y. Hidai and
T. Kan, Tetrahedron Lett., 1997, 38, 5831–5834;
(b) W. Kurosawa, T. Kan and T. Fukuyama, Org. Synth.,
2002, 79, 186–191.
16 (a) K. C. Majumdar, S. Mondal and N. De, Synthesis, 2009,
3127–3135; (b) J. K. Laha, N. Dayal, R. Jain and K. Patel,
J. Org. Chem., 2014, 79, 10899–10907.
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
We are grateful to the University of Manchester for funding
this work. We also thank Dr Ralph Adams for assistance with
2D-EXSY NMR experiments, and the staff of the analytical lab-
oratories of the School of Chemistry (University of Manchester)
for their expertise, especially Carlo Bawn (NMR), Martin
Jennings (microanalysis), Gareth Smith (mass spectrometry)
and Rehana Sung (HPLC). We also wish to acknowledge the
use of the EPSRC-funded Chemical Database Service at
Daresbury.37
17 (a) D. K. Rayabarapu, A. Zhou, K. O. Jeon, T. Samarakoon,
A. Rolfe, H. Siddiqui and P. R. Hanson, Tetrahedron, 2009,
65, 3180–3188; (b) C. B. Bheeter, J. K. Bera and H. Doucet,
Adv. Synth. Catal., 2012, 354, 3533–3538.
Notes and references
1 For pertinent discussions, see: (a) K. Mikami, K. Aikawa,
Y. Yusa, J. J. Jodry and M. Yamanaka, Synlett, 2002, 1561–
1578; (b) K. Mikami and M. Yamanaka, Chem. Rev., 2003, 18 (a) M. LaFrance, C. N. Rowley, T. K. Woo and K. Fagnou,
103, 3369–3400; (c) M. T. Reetz, Angew. Chem., Int. Ed.,
2008, 47, 2556–2588; (d) K. Aikawa and K. Mikami, Chem.
Commun., 2012, 48, 11050–11069; (e) L. Théveau, R. Bellini,
P. Dydio, Z. Szabo, A. van der Werf, R. Afshin Sander,
J. N. H. Reek and C. Moberg, Organometallics, 2016, 35,
1956–1963.
J. Am. Chem. Soc., 2006, 128, 8754–8756; (b) M. Lafrance
and K. Fagnou, J. Am. Chem. Soc., 2006, 128, 16496–16497;
(c) M. Lafrance, D. Lapointe and K. Fagnou, Tetrahedron,
2008, 64, 6015–6020; (d) S. I. Gorelsky, D. Lapointe and
K. Fagnou, J. Am. Chem. Soc., 2008, 130, 10848–10849;
(e) S. I. Gorelsky, D. Lapointe and K. Fagnou, J. Org. Chem.,
2012, 77, 658–668.
2 (a) S. Superchi, R. Bisaccia, D. Casarini, A. Laurita and
C. Rosini, J. Am. Chem. Soc., 2006, 128, 6893–6902; 19 (a) D. García-Cuadrado, A. A. Braga, F. Maseras and
(b) L. Dutot, K. Wright, M. Wakselman, J.-P. Mazaleyrat,
C. Peggion, M. De Zotti, F. Formaggio and C. Toniolo,
Tetrahedron Lett., 2008, 49, 3475–3479.
3 A. M. Costa, C. Jimeno, J. Gavenonis, P. J. Carroll and
P. J. Walsh, J. Am. Chem. Soc., 2002, 124, 6929–6941.
4 P. Scafato, G. Cunsolo, S. Labano and C. Rosini,
Tetrahedron, 2004, 60, 8801–8806.
A. M. Echavarren, J. Am. Chem. Soc., 2006, 128, 1066–1067;
(b) D. García-Cuadrado, P. de Mendoza, A. A. C. Braga,
F. Maseras and A. M. Echavarren, J. Am. Chem. Soc., 2007,
129, 6880–6886.
20 Crystallographic data for 19 and 20 have been deposited
with the Cambridge Crystallographic Data Centre as sup-
plementary publication numbers CCDC 1008371 and
1008372.†
5 B. Lygo, C. Davison, T. Evans, J. A. R. Gilks, J. Leonard and
C.-E. Roy, Tetrahedron, 2011, 67, 10164–10170.
21 E. Gold and E. Babad, J. Org. Chem., 1972, 37, 2208–2210.
6 L. Pisani, C. Bochicchio, S. Superchi and P. Scafato, 22 For related processes, see: (a) W. E. Truce, R. W. Campbell
Eur. J. Org. Chem., 2014, 5939–5945.
7 S. L. Pira, T. W. Wallace and J. P. Graham, Org. Lett., 2009,
11, 1663–1666.
and J. R. Norell, J. Am. Chem. Soc., 1964, 86, 288;
(b) C. A. Broka and T. Shen, J. Am. Chem. Soc., 1989, 111,
2981–2984.
8 C. A. Cheetham, R. S. Massey, S. L. Pira, R. G. Pritchard 23 A. Flores-Gaspar, A. Gutiérrez-Bonet and R. Martin, Org.
and T. W. Wallace, Org. Biomol. Chem., 2011, 9, 1831–1838. Lett., 2012, 14, 5234–5237.
9 L. A. Saudan, G. Bernardinelli and E. P. Kündig, Synlett, 24 (a) D. Solé, F. Mariani, I. Fernández and M. A. Sierra, J. Org.
2000, 483–486.
10 M. Oki, Top. Stereochem., 1983, 14, 1–81.
Chem., 2012, 77, 10272–10284; (b) D. Solé and I. Fernández,
Acc. Chem. Res., 2014, 47, 168–179.
11 S. Pache, C. Botuha, R. Franz, E. P. Kündig and J. Einhorn, 25 R. Novikov, G. Bernardinelli and J. Lacour, Adv. Synth.
Helv. Chim. Acta, 2000, 83, 2436–2451.
Catal., 2008, 350, 1113–1124.
10198 | Org. Biomol. Chem., 2017, 15, 10184–10199
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Paper
26 M. Tichy, M. Budesinsky, J. Günterova, J. Zavada, 29 For a larger figure containing the diagnostic NMR data for
J. Podlaha and I. Cisarova, Tetrahedron, 1999, 55, 7893–
7906.
27 The batch of salt 56 used for the only run of this reaction
other dibenzazepines prepared in this work, see ESI.†
30 See ESI† for the full data set and images of the energy-
minimised structures.
was later shown to be contaminated with ( )-58, resulting 31 C. L. Perrin and T. J. Dwyer, Chem. Rev., 1990, 90, 935–967.
in the formation of ( )-55 as a co-product in the Grignard 32 See ESI† for the full data set, calculations and graphics.
addition step. See ESI† for further details.
28 For selected examples, see: (a) F. G. Mutti, T. Knaus,
33 H. E. Gottlieb, V. Kotlyar and A. Nudelman, J. Org. Chem.,
1997, 62, 7512–7515.
N. S. Scrutton, M. Breuer and N. J. Turner, Science, 2015, 34 D. D. Perrin, W. L. F. Armarego and D. R. Perrin,
349, 1525–1529; (b) C. E. Paul, M. Rodríguez-Mata,
Purification of Laboratory Chemicals, Pergamon, Oxford, 2nd
E. Busto, I. Lavandera, V. Gotor-Fernández, V. Gotor,
edn, 1980.
S. García-Cerrada, J. Mendiola, O. de Frutos and I. Collado, 35 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43,
Org. Process Res. Dev., 2014, 18, 788–792; (c) T. C. Nugent 2923–2925.
and S. M. Marinova, Synthesis, 2013, 153–166, and refs 36 For the corresponding bromide, see: M. Weitzberg, E. Abu-
cited therein. (d) Y. Xie, H. Pan, X. Xiao, S. Lia and Y. Shi,
Org. Biomol. Chem., 2012, 10, 8960–8962; (e) O. Pablo,
Shakra, A. Azeb, Z. Aizenshtat and J. Blum, J. Org. Chem.,
1987, 52, 529–536.
D. Guijarro, G. Kovács, A. Lledós, G. Ujaque and M. Yus, 37 D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf.
Chem. – Eur. J., 2012, 18, 1969–1983.
Comput. Sci., 1996, 36, 746–749.
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