Synthesis of 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones: Selective antagonists of muscarinic (M3) receptors

Article abstract of DOI:10.1039/b801206g

Two approaches to tetrahydro-[1H]-2-benzazepin-4-ones of interest as potentially selective, muscarinic (M₃) receptor antagonists have been developed. Base promoted addition of 2-(tert-butoxycarbonylamino)methyl-1,3- dithiane 5 with 2-(tert-butyldimethylsiloxymethyl)benzyl chloride 14 gave the corresponding 2,2-dialkylated 1,3-dithiane 15 which was taken through to the dithiane derivative 19 of the parent 2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one by desilylation, oxidation and cyclisation via a reductive amination. After conversion into the N-tert-butyloxycarbonyl, N-toluene p-sulfonyl and N-benzyl derivatives 20-22, hydrolysis of the dithiane gave the N-protected tetrahydro-[1H]-2-benzazepin-4-ones 23-25. However, preliminary attempts to convert these into 5-cycloalkyl-5-hydroxy derivatives were not successful. In the second approach, ring-closing metathesis was used to prepare 2,3-dihydro-[1H]-2-benzazepines which were hydroxylated and oxidized to give the required 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones. Following preliminary studies, ring-closing metathesis of the dienyl N-(2-nitrophenyl) sulfonamide 48 gave the dihydrobenzazepine 50 which was converted into the 2-butyl-5-cyclobutyl-5-hydroxytetrahydrobenzazepin-4-one 55 by hydroxylation and N-deprotection followed by N-alkylation via reductive amination, and oxidation. This chemistry was then used to prepare the 2-[(N-arylmethyl)aminoalkyl analogues 69, 72, 76 and 78. N-Acylation followed by amide reduction using the borane-tetrahydrofuran complex was also used to achieve N-alkylation of dihydrobenzazepines and this approach was used to prepare the 5-cyclopentyl-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one 103 and the 5-cyclobutyl-8-fluoro-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one 126. The structures of 2-tert-butyloxycarbonyl-4,4-propylenedithio-2,3,4,5- tetrahydro-[1H]-2-benzazepine 20 and (4RS,5SR)-2-butyl-5-cyclobutyl-4,5- dihydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepine 53 were confirmed by X-ray diffraction. The racemic 5-cycloalkyl-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2- benzazepin-4-ones were screened for muscarinic receptor antagonism. For M ₃ receptors from guinea pig ileum, these compounds had log ₁₀K_B values of up to 7.2 with selectivities over M ₂ receptors from guinea pig left atria of approximately 40. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b801206g

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Synthesis of 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones:
selective antagonists of muscarinic (M3) receptors†
Benjamin Bradshaw,a Paul Evans,a Jane Fletcher,a Alan T. L. Lee,a Paul G. Mwashimba,a Daniel Oehlrich,a
Eric J. Thomas,*a Robin H. Davies,b Benjamin C. P. Allen,b Kenneth J. Broadley,c Amar Hamrounic and
Christine Escargueilc
Received 22nd January 2008, Accepted 6th March 2008
First published as an Advance Article on the web 18th April 2008
DOI: 10.1039/b801206g
Two approaches to tetrahydro-[1H]-2-benzazepin-4-ones of interest as potentially selective,
muscarinic (M3) receptor antagonists have been developed. Base promoted addition of
2-(tert-butoxycarbonylamino)methyl-1,3-dithiane 5 with 2-(tert-butyldimethylsiloxymethyl)benzyl
chloride 14 gave the corresponding 2,2-dialkylated 1,3-dithiane 15 which was taken through to the
dithiane derivative 19 of the parent 2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one by desilylation,
oxidation and cyclisation via a reductive amination. After conversion into the N-tert-butyloxycarbonyl,
N-toluene p-sulfonyl and N-benzyl derivatives 20–22, hydrolysis of the dithiane gave the N-protected
tetrahydro-[1H]-2-benzazepin-4-ones 23–25. However, preliminary attempts to convert these into
5-cycloalkyl-5-hydroxy derivatives were not successful. In the second approach, ring-closing metathesis
was used to prepare 2,3-dihydro-[1H]-2-benzazepines which were hydroxylated and oxidized to give the
required 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones. Following preliminary studies,
ring-closing metathesis of the dienyl N-(2-nitrophenyl)sulfonamide 48 gave the dihydrobenzazepine 50
which was converted into the 2-butyl-5-cyclobutyl-5-hydroxytetrahydrobenzazepin-4-one 55 by
hydroxylation and N-deprotection followed by N-alkylation via reductive amination, and oxidation.
This chemistry was then used to prepare the 2-[(N-arylmethyl)aminoalkyl analogues 69, 72, 76 and 78.
N-Acylation followed by amide reduction using the borane–tetrahydrofuran complex was also used to
achieve N-alkylation of dihydrobenzazepines and this approach was used to prepare the
5-cyclopentyl-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one 103 and the
5-cyclobutyl-8-fluoro-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one 126. The structures of
2-tert-butyloxycarbonyl-4,4-propylenedithio-2,3,4,5-tetrahydro-[1H]-2-benzazepine 20 and
(4RS,5SR)-2-butyl-5-cyclobutyl-4,5-dihydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepine 53 were
confirmed by X-ray diffraction. The racemic 5-cycloalkyl-5-hydroxy-2,3,4,5-tetrahydro-
[1H]-2-benzazepin-4-ones were screened for muscarinic receptor antagonism. For M3 receptors from
guinea pig ileum, these compounds had log10KB values of up to 7.2 with selectivities over M2 receptors
from guinea pig left atria of approximately 40.
other sites, M2 receptors are also found in the ileum, antagonism
Introduction
producing constipation. Darifenacin (1), which shows some 40-
Muscarinic receptors are intimately involved in many metabolic
fold selectivity against M2-receptors, was the first pharmaceutical
processes.1 The M3 receptor is prevalent in smooth muscle and
commercially available to treat urinary incontinence by the control
of M3 receptor antagonism.3 More selective therapies are currently
under investigation.
its regulation has therapeutic applications in muscle relaxation
ranging from the alleviation of chronic obstructive pulmonary
disease to treatments for urinary tract incontinence involving blad-
der relaxation.2 Preferential selectivity against other sub-types of
muscarinic receptors is important, the M2 receptor on stimulation
regulating the parasympathetic control of heart rate. Amongst
From an ab initio approach using a model of muscarinic recep-
tors based on bacteriorhodopsin, 5-hydroxy-2,3,4,5-tetrahydro-
[1H]-2-benzazepin-4-ones with the general structure 2, were iden-
tified as potential muscarinic antagonists with possibly improved
selectivity for the M3 receptor.4 The use of tetrahydro-[1H]-2-
benzazepines was seen to have two potential advantages. Firstly,
the alignment of a-helices on the bacteriorhodopsin receptor
structure5 indicated that M3 selectivity over M2-receptors might
be achieved by contact of the fused aromatic ring with residue
151 (Ala M1, M3, M5; Val M2, M4). Secondly, early data on
analogues of NPC-14695 36 indicated that an a-hydroxy keto
group linked through a CH2 group to a piperazine ring, has
aThe School of Chemistry, The University of Manchester, Manchester, UK
M13 9PL. E-mail: e.j.thomas@manchester.ac.uk
bMuscagen Limited, 10, North Road, Cardiff, UK CF10 3DY
cThe Welsh School of Pharmacy, Redwood Building, King Edward VII
Avenue, Cardiff, UK CF10 3NB
† Electronic supplementary information (ESI) available: Full experimental
data for procedures not included in this text are available as supplementary
data. See DOI: 10.1039/b801206g
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an advantage in overall binding even in the presence of the
second nitrogen atom (pKA ∼6.6) due to the close contact
distance of this atom with a backbone hydrogen atom. The
possibility existed, therefore, that improved potency might be
achieved with tetrahydrobenzazepinones even if the presence of
a non-interacting nitrogen atom (−2.5 log10 units on the given
model) would require increased lipophilic character for optimum
pharmacodynamics and potency. The remainder of the target
structure was completed by a benzylamino C2 or C3 linkage to
give compounds 2.
We report syntheses of these compounds and of N-acyl and
N-alkyl derivatives of 2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one
4 together with aspects of their biological activities. Prior to
this work, 2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones were un-
known.
Two strategies for the assembly of the 2,3,4,5-tetrahydro-[1H]-
2-benzazepin-4-ones have been investigated. In the first approach,
the 2-(tert-butoxycarbonylaminomethyl)-1,3-dithiane 57 was used
as an umpolung reagent to prepare intermediates for a ring-closing
reductive amination. In the second, more intensively investigated
approach, ring-closing metathesis,8 which has been used to prepare
seven-membered ring heterocycles9 including 2,3-dihydro-[1H]-
2-benzazepines,10 was used to prepare 5-cycloalkyl-2,3-dihydro-
[1H]-2-benzazepines which were hydroxylated and oxidised to give
the required 5-hydroxytetrahydrobenzazepin-4-ones 2.
protection of the alcohol as its tert-butyldimethylsilyl ether to
prevent reversion to the lactone, see Scheme 1. The amide 6
then gave the aryl cyclobutyl ketone 7 on reaction with an ex-
cess of cyclobutyllithium. 2-(tert-Butoxycarbonylamino)methyl-
1,3-dithiane 5 has been prepared from the tert-butoxycarbonyl
(Boc) protected aminoacetal 9 using propane-1,3-dithiol and
boron trifluoride diethyletherate7 but, in our hands, this procedure
was complicated by competing loss of the Boc-group.11 However,
conversion of the unprotected aminoacetal 8 into 2-aminomethyl-
1,3-dithiane followed by Boc-protection gave a reliable procedure
for the synthesis of the required dithiane 5. Lithiation of dithiane
5 using two equivalents of n-butyllithium followed by addition
of the ketone 7 gave the tertiary alcohol 10. In this reaction,
it would appear that deprotonation of the carbamate prevented
elimination of the Boc fragment. Indeed, the lithiated dithiane also
reacted with the Weinreb amide 6 to give ketone 12. Desilylation
◦
of the adduct 10 to the diol 11 was carried out at 0 C12 using
tetra-n-butylammonium fluoride since prolonged reaction at room
temperature appeared to result in cleavage of the dithiane–benzylic
carbon bond.
The diol 11 contains most of the elements required for a
synthesis of 5-hydroxytetrahydro-[1H]-2-benzazepin-4-ones but
attempts to effect an oxidation of the primary alcohol in anticipa-
tion of ring formation using reductive amination were complicated
by the presence of the tertiary alcohol. Alternative procedures
could be imagined for this cyclisation, e.g. via a Mitsunobu
reaction,13 although this would require protection of the tertiary
alcohol to avoid competing formation of a tetrahydrofuran ring.
To avoid these complications, it was decided to prepare the
core 2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one ring system first
with incorporation of the 5-hydroxy and 5-cycloalkyl substituents
later in the synthesis. This strategy would have the advantage of
allowing the cycloalkyl group to be varied more easily.
Results and discussion
Synthesis of 2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones by
dithiane alkylation
The Weinreb amide 6 was prepared from phthalide by treat-
ment with N,O-dimethylhydroxylamine followed by immediate
Scheme 1 Reagents and conditions: i, (a) NHMe·OMe·HCl, AlMe3, CH2Cl2, 0 ◦C to r.t. (b) TBSCl, imid., DMF (60% over the two steps);
ii, bromocyclobutane, t-BuLi, −78 ◦C, 1 h, add 6 (59%); iii, (a) propane-1,3-dithiol, BF3·Et2O, CH2Cl2, r.t. (b) Boc2O, Et3N, CH2Cl2 (63% over the
two steps); iv, 5, n-BuLi, DMPU, THF, −40 to −20 ◦C, add to 7 or 6, −78 ◦C (10, 42%; 12, 69%); v, TBAF, THF, 0 ◦C (71%).
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1,2-Bis(hydroxymethyl)benzene was protected as its mono-tert-
butyldimethylsilyl ether 1314 which was converted into the chloride
14 using thionyl chloride with simultaneous addition of pyridine
to avoid desilylation, see Scheme 2. Alkylation of the dithiane 5
using the chloride 14 gave the 2,2-bis-alkyldithiane 15 which was
desilylated and the alcohol 16 oxidised to the aldehyde 17 at room
temperature using manganese dioxide. Attempts to carry out this
oxidation at reflux in dichloromethane led to the formation of
side-products which were not fully identified.
Removal of the Boc-group was achieved using concentrated
aqueous hydrogen chloride in ethyl acetate for 5 h at room
temperature15 and generated the imine 18. This was reduced using
sodium cyanoborohydride16 to give the tetrahydrobenzazepine
19 in an overall yield of 73%. If the deprotection step was
quenched after 1 h, side-products were isolated after the reduction.
Protection of the tetrahydrobenzazepine 19 using Boc-anhydride
or toluene p-sulfonyl chloride gave the corresponding derivatives
20 and 21 and reductive amination with benzaldehyde gave the N-
benzyl derivative 22. The 1H NMR spectrum of the Boc-protected
azepine 20 was broadened due to the interconversion of rotamers
in solution, but its structure was confirmed by X-ray diffraction.
Fig. 1 shows a projection of the compound as established by a
single crystal X-ray study which confirmed the structure as shown.
In all cases hydrolysis of the dithiane using mercuric oxide and
boron trifluoride17 gave the parent ketones 23–25. Perhaps of
interest was the position of the carbonyl stretching peak in the
IR spectrum of the N-benzyltetrahydro[1H]-2-benzazepin-4-one
25 which was observed at 1749 cm−1 indicative of little bonding
interaction between the tertiary amine and the ketone.
Fig. 1 ORTEP projection of the 2,3,4,5-tetrahydro-[1H]-2-benzazepine
20 as determined by X-ray crystallography, ellipsoids shown at the 30%
probability.
lithium di-isopropylamide and lithium hexamethyldisilazide with
an in situ quench using triethylsilyl trifluoromethanesulfonate18
gave rise to the formation of mixtures of regioisomers, but the use
of triethylamine as base at room temperature19 was more success-
ful. The structures of the enol ethers were confirmed by NOE data,
but attempts to use them to introduce an oxygen substituent via
epoxidation using dimethyl dioxirane20 and rearrangement of the
epoxides so formed using fluoride, acid or base, led to mixtures of
products which could not be identified.
At this point, it was decided to embark on an alternative route
based on ring-closing metathesis9,10 to prepare 2,3-dihydro-[1H]-2-
benzazepines 28 which would be hydroxylated and oxidised to give
5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones 2. Using
an asymmetric Sharpless hydroxylation, this route could provide
an asymmetric synthesis of these compounds.
Ketones 23–25 have the required tetrahydro-[1H]-2-benzazepin-
4-one structure albeit protected on nitrogen, but it remained
to introduce the hydroxyl and alkyl substituents at C-5 and
the aminoalkyl groups on nitrogen, to complete syntheses of
the derivatives 2 required for evaluation as muscarinic receptor
antagonists. To effect a regioselective oxidation, the conversion of
ketones 23 and 24 into silyl enol ethers was investigated. Initial
attempts to prepare the triethylsilyl enol ethers 26 and 27 using
Scheme 2 Reagents and conditions: i, SOCl2, py., CH2Cl2, 0 ◦C (53%); ii, 5, n-BuLi, THF, −40 to −20 ◦C, DMPU, −78 ◦C, add 14 (67%); iii, TBAF,
THF, 0 ◦C (89%); iv, MnO2, CH2Cl2 (70%); v, aq. HCl, EtOAc, 5 h, r.t.; vi, NaBH3CN, MeOH, cat. HCl, r.t. (73% over the two steps); vii, Boc2O, Et3N,
CH2Cl2, r.t. (ca. 100%); viii, TsCl, py., r.t. (68%); ix, PhCHO, NaBH3CN, THF, r.t. (66%); x, HgO, BF3·Et2O, THF, H2O, r.t. (23, 86%; 24, 72%; 25, 84%);
xi, Et3N, TESOTf, CH2Cl2, r.t. (26, 65%; 27, 67%).
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Preliminary studies of the synthesis of
2,3-dihydro-[1H]-2-benzazepines using ring-closing metathesis
Ring-closing metathesis has been used to prepare 2,3-dihydro-
[1H]-2-benzazepines albeit lacking alkyl or aryl substituents at
the 4- or 5-positions.10 Initial studies were undertaken to confirm
this approach in our hands. o-Ethenylbenzaldehyde 2921 was
converted into the amine 30 by reductive amination and the amine
protected as its toluene p-sulfonyl (tosyl) and 2-nitrobenzene
sulfonyl (nosyl)22 derivatives 31 and 32. Ring-closing metathesis
using Grubbs’ I catalyst, see Fig. 2,23,24 gave the 2,3-dihydro-
[1H]-2-benzazepines 33 and 34 in excellent (≥90%) yields and
deprotection of the nosyl derivative 34 using thiophenol under
basic conditions22 gave the parent 2,3-dihydro-[1H]-2-benzazepine
35. Hydroxylation of the protected dihydrobenzazepines 33 and
34 using the Upjohn conditions in aqueous acetone25 gave
the cis-diols 36 and 37, and deprotection of the N-nosyl pro-
tected diol 37 gave the water soluble dihydroxytetrahydroben-
zazepine 38 which was converted into 2-butyl-4,5-dihydroxy-
2,3,4,5-tetrahydro-[1H]-2-benzazepine 39 by reductive amination
using butanal, see Scheme 3.
Scheme 3 Reagents and conditions: i, prop-2-enylamine, MgSO4, r.t., 18 h,
then NaBH4, MeOH, r.t., 1 h (61%); ii, TsCl, py., DMAP (cat.), r.t.,
48 h (50%); iii, NsCl, Et3N, DMAP (cat.), r.t., 1.5 h (85%); iv, Grubbs’
I (10 mol%), CH2Cl2, r.t. (33, 97%; 34, 90%); v, PhSH, K2CO3, 18-c-6
(cat.), DMF, r.t., 4 h (84%); vi, NMO, OsO4 (2–2.5 mol%), acetone, water,
r.t., 24 h (36, 58%; 37, 82%); vii, PhSH, K2CO3, acetonitrile, r.t., 15 h, then
n-PrCHO, NaBH(OAc)3, THF, MeCO2H, r.t., 24 h (39, 46%).
the alcohol 44 to the aldehyde 45, reductive amination using prop-
2-enylamine gave amine 46 which was protected as its toluene p-
sulfonyl and 2-nitrobenzene sulfonyl derivatives 47 and 48. Initial
studies of ring-closing metathesis of the tosyl derivative 47 using
Grubbs’ I catalyst23 were rather inefficient with only a low yield
of the dihydrobenzazepine 49 (18%) together with unchanged
starting material (60%) and what appeared to be a dimeric material
being isolated after heating for 24 h under reflux in benzene.
However, the use of Grubbs’ II catalyst,31 see Fig. 2, was much
more effective and, in the case of the nosyl protected amine 48, gave
the required dihydrobenzazepine 50 in an excellent yield (96%).
Hydroxylation of the dihydrobenzazepine 50 gave the racemic
cis-diol 51. This was deprotected to give the 4,5-dihydroxy-
2,3,4,5-tetrahydro[1H]-2-benzazepine 52 which was immediately
converted into the N-butyl derivative 53 by reductive amination.
It remained to oxidise the vicinal diol to generate the required 5-
hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one system. The
Swern oxidation procedure was initially selected for this to avoid
over oxidation and C–C-bond cleavage which can be a problem
in the oxidation of vicinal diols.32 In the event, oxidation under
Swern conditions of the N-nosyl tetrahydrobenzazepine 51 gave
hydroxyketone 54 and a similar oxidation of the N-butyl analogue
53 gave the 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-
one 55 in an acceptable yield of 73%.
Fig. 2 Structures of Grubbs’ I and II catalysts.
This work confirmed the viability of ring-closing metathesis
for the synthesis of 2,3-dihydro-[1H]-2-benzazepines and further
functionalisation by hydroxylation and reductive amination. It
now remained to use this chemistry to prepare tetrahydroben-
zazepines with cycloalkyl groups at C-5.
Synthesis of N-alkyl-5-cyclobutyl-5-hydroxy-2,3,4,5-tetrahydro-
[1H]-2-benzazepin-4-ones by ring closing metathesis followed by
N-alkylation using reductive amination
In the earlier work, the aryl cyclobutyl ketone 7 had been
prepared from the reaction of the Weinreb amide 6 with cy-
clobutyllithium generated from cyclobutyl bromide. Cyclobutyl
bromide is commercially available and can be prepared from
cyclobutyl carboxylic acid via a Hunsdiecker reaction.26 However,
subsequently it was found to be more convenient to prepare ketone
7 from cyclobutyl phenyl carbinol 4027 by ortho lithiation28 and
addition of formaldehyde to give diol 41, see Scheme 4. After
regioselective protection of the primary alcohol, oxidation of the
secondary alcohol using the Dess–Martin periodinane29 gave the
ketone 7 in an excellent yield. This was converted into the alkene 43
using the Petasis reagent30 since the standard Wittig reaction was
difficult to drive to completion. After desilylation and oxidation of
The structures assigned to the products in Scheme
4
were consistent with their spectroscopic data and the struc-
ture of the 2-butyl-5-cyclobutyl-4,5-dihydroxy-2,3,4,5-tetrahydro-
[1H]-2-benzazepine 53 was confirmed by X-ray crystallography,
1
see Fig. 3. The H and 13C NMR spectra of the hydroxyketones
obtained on oxidation of the diols 51 and 53 indicated that
single products had been obtained in each case, consistent
with the formation of 54 and 55, respectively. However, a-
hydroxyketones can undergo 1,2-rearrangements33 and so it was
necessary to confirm that the hydroxytetrahydrobenzazepine 55
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Scheme 4 Reagents and conditions: i, n-BuLi, THF, Et2O, 0 ◦C–reflux, 2 h, HCHO, r.t., 12 h (74%); ii, TBSCl, imid., DMF, −10 ◦C, 2 h (80%);
iii, Dess–Martin periodinane, CH2Cl2, r.t., 2 h (96%); iv, Cp2TiMe2, THF, reflux, 15 h (92%); v, TBAF, THF, r.t., 2 h (83%); vi, MnO2, CH2Cl2, r.t., 48 h
(93%); vii, prop-2-enylamine, MgSO4, CH2Cl2, r.t., 24 h, then NaBH4, MeOH, r.t., 2 h (91%); viii, TsCl, Et3N, DMAP (cat.), CH2Cl2, r.t., 4 h (96%);
ix, NsCl, Et3N, DMAP (cat.), r.t., 3 h (79%); x, Grubbs’ I cat., benzene, reflux, 24 h (49, 18%) or Grubbs’ II (cat.), CH2Cl2, reflux, 18 h (50, 96%);
xi, NMO, OsO4 (10 mol%), acetone, water, r.t., 18 h (80%); xii, PhSH, K2CO3, DMF (86%); xiii, n-PrCHO, NaBH(OAc)3, MeCO2H, r.t., 15 h (53%);
xiv, (COCl)2, DMSO, CH2Cl2, −78 ◦C, 15 min, then Et3N, −78 ◦C (54, 58%; 55, 73%).
NOe spectroscopy confirmed hydrogen proximity and HMBC
1
and HMQC spectra established the long-range H-13C coupling
and carbon–hydrogen correlations consistent with structure 55.
However 2D 13C-13C INADEQUATE spectra unambiguously
confirmed the presence of the bonds shown in bold in structure
55, see Fig. 4, and ruled out the alternative structures 55a and 55b.
Again the carbonyl stretching peak at 1728 cm−1 indicated little
interaction between the tertiary amine and the ketone carbonyl
group.
It now remained to attach the arylmethylaminoalkyl side-chains
to the nitrogen of the tetrahydrobenzazepinones to complete syn-
theses of the derivatives 2 required for biological evaluation. Syn-
theses of the side-chains are outlined in Scheme 5. 3-(N-Benzyl-
N-trifluoroacetyl)aminopropanal 56 is a known compound.34
2-(N-Benzyl-N-2-nitrophenylsulfonyl)aminoethanal 59 was pre-
pared by ozonolysis of the N-(2-nitrophenylsulfonyl) derivative
5835 of N-benzylprop-2-enylamine 57. 3-(N-Naphth-2-ylmethyl-
N-2-nitrophenylsulfonyl)aminopropanal 62 was prepared by N-
nosylation of 3-(N-naphth-2-ylmethyl)aminopropan-1-ol36 fol-
lowed by oxidation, and the 6-methylnaphth-2-yl analogue 66
was similarly prepared from the alcohol 64 which had been
obtained by reductive amination of 6-methyl-2-naphthaldehyde
63.37
Fig.
3
ORTEP projection of the 4,5-dihydroxy-2,3,4,5-tetrahydro-
[1H]-2-benzazepine 53 as determined by X-ray crystallography, ellipsoids
shown at 30% probability.
and not one of the isomeric hydroxyketones 55a or 55b was
the product isolated on oxidation of the diol 53, see Fig. 4.
Fig. 4 Isomeric hydroxyketones which could originate from oxidation of 4,5-dihydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepine 53.
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Scheme 5 Reagents and conditions: i, NsCl, Et3N, DMAP, CH2Cl2, r.t., 3 h (76%); ii, ozone, CH2Cl2, −78 ◦C, 30 min, then Me2S, r.t., 15 h (92%);
iii, (a) 60, 3-aminopropanol, MgSO4, CH2Cl2, then NaBH3CN, MeOH (75%) (b) NsCl, Na2CO3, n-Bu4NI, acetone, water, r.t., 4 h (68%); iv, Dess–Martin
periodinane, CH2Cl2, r.t. (62, 41%; 66, 97%); v, 3-aminopropanol, MgSO4, CH2Cl2, r.t., 24 h, then NaBH3CN, r.t., 1 h (58%); vi, NsCl, Na2CO3, n-Bu4NI,
acetone, water (77%).
Reductive amination of the N-benzyl-N-trifluoroacetyl-
aminopropanal 56 by the tetrahydro-[1H]-2-benzazepine 52 was
carried out using sodium cyanoborohydride and gave the N-
alkylated tetrahydrobenzazepine 67 in an acceptable yield of
76%. Following this procedure the N-nosyl protected aldehydes
59, 62 and 66 gave the corresponding N-alkylated dihydroxyte-
trahydrobenzazepines 70, 73 and 74, in modest to acceptable
yields (31–66%). Oxidation of the dihydroxytetrahydro-[1H]-2-
benzazepines under Swern conditions, or using the Dess–Martin
periodinane, gave the corresponding N-alkyl-5-hydroxy-2,3,4,5-
tetrahydro-[1H]-2-benzazepin-4-ones 68, 71, 75 and 77, and these
were deprotected to give the target compounds 69, 72, 76 and 78,
see Scheme 6.
Structures were assigned to these products on the basis of
spectroscopic data. In particular, the protons attached to C-3 were
observed as two doublets with very similar chemical shifts and
coupling constants to those observed for hydroxyketone 55 (55,
d 3.95, 4.18, J 16; 69, d 3.85, 4.14, J 16; 72, d 3.76, 4.15, J 16.5;
76 d 3.90, 4.18, J 16; 78, d 3.84, 4.12, J 16). These chemical shifts
contrast with those of the protons attached to C-3 for the 4,5-
dihydroxytetrahydrobenzazepines, e.g. 53, 70, 73 and 74, which
were all within the range d 2.7–3.1. These data confirmed that no
a-hydroxyketone rearrangement to give isomeric hydroxyketones
analogous to 55a and 55b had occurred. However, the carbonyl
stretching peak in the IR spectrum of 72 was observed at
1693 cm−1, i.e. at a lower frequency than had been observed
earlier for the simpler compounds 25 and 55. This may be due to
additional hydrogen bonding. These compounds together with the
N-butyl analogue 55 were subjected to biological evaluation, see
below.
Introduction of N-alkyl side-chains into 2,3,4,5-tetrahydro-
[1H]-2-benzazepines via N-acylation and reduction
Although N-alkylation of the tetrahydrobenzazepine 52 by reduc-
tive amination had delivered sufficient quantities of the adducts
for further investigation, it was decided to see whether N-acylation
and reduction was more generally useful, see Scheme 7. 3-[N-
Benzyl-N-(2-nitrophenyl)sulfonylamino]propanoic acid 81 was
prepared from 3-(N-benzylamino)propan-1-ol 79 by N-nosylation
to give the amide 8038 followed by oxidation. It was coupled with
the 2,3-dihydro-[1H]-2-benzazepine 82 prepared by deprotection
of the N-nosyl derivative 50 to give the N-acyl-2,3-dihydro-2-
benzazepine 83 in a reasonable yield (79%). Since it was thought
that a tertiary amine might cause problems at the dihydroxylation
stage, it was decided to carry out the dihydroxylation and removal
of the side-chain N-nosyl protecting group before reduction of the
amide. In the event, dihydroxylation of the dihydrobenzazepine
83 under the Upjohn conditions gave the diol 84 which was
denosylated to give the N-acyldihydroxytetrahydrobenzazepine
85. Reduction using the borane·THF complex then pro-
ceeded smoothly to give the N-alkyl-4,5-dihydroxy-2,3,4,5-
tetrahydrobenz-[1H]-2-azepine 86. Although slightly longer
than the reductive amination route, this preparation of the
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Scheme 6 Reagents and conditions: i, 56, 59, 62 or 66, NaBH3CN, MeOH, c.HCl (cat.), r.t. (67, 76%; 70, 66%; 73, 32%; 74, 31%); ii, (COCl)2, DMSO,
CH2Cl2, −78 ◦C, then Et3N, 0 ◦C (68, 67%; 71, 77%); iii, K2CO3, MeOH, water, r.t., 24 h (80%); iv, PhSH, K2CO3, DMF, r.t., 18 h (72, 52%; 76, 41%; 78,
97%); v, Dess–Martin periodinane, CH2Cl2, r.t., 2 h (75, 85%; 77, 80%).
Scheme 7 Reagents and conditions: i, NsCl, Na2CO3, n-Bu4NI, acetone, r.t., 2 h (78%); ii, (a) Dess–Martin periodinane, CH2Cl2, r.t., 2 h (b) NaOCl2,
2-methyl-2-butene, NaH2PO4, t-BuOH–water, r.t., 12 h (81% from 80); iii, 81, TBTU, i-Pr2NEt, CH2Cl2, 0 ◦C, add 82, r.t., 12 h (79%); iv, NMO, OsO4
(10 mol%), t-BuOH–water, r.t., 12 h (ca. 99%); v, PhSH, K2CO3, DMF, r.t., 12 h (94%); vi, BH3·THF, THF, 0 ◦C–r.t. 3 h, then aq. HCl, reflux, 1 h (57%).
N-alkylbenzazepines by acylation and reduction was found to
be more reliable for less reactive tetrahydrobenzazepines, vide
infra.
The benzazepine acylation and reduction procedure was
used to prepare the 5-cyclopentyl-5-hydroxytetrahydro-[1H]-2-
benzazepin-4-one 103, see Scheme 8. In this case, the tetrahydropy-
ranyl ether 88, prepared from (2-bromophenyl)methanol 87, was
converted into the corresponding aryllithium reagent which was
reacted with cyclopentanecarboxaldehyde followed by oxidation
to give ketone 89. Following a Wittig reaction, deprotection
and oxidation, reductive amination and nosyl protection gave
the metathesis precursor 94. Metathesis using the Grubbs’ II
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Scheme 8 Reagents and conditions: i, DHP, TsOH (cat.), CH2Cl2, r.t., 3 h (98%); ii, (a) t-BuLi, THF, −78 ◦C, 15 min, then cyclopentanecarboxaldehyde,
THF, −78 ◦C, 30 min (89%) (b) Dess–Martin periodinane, CH2Cl2, py., r.t., 4 h (98%); iii, Ph3PMe+Br−, n-BuLi, r.t., 30 min, then add 89, r.t., 18 h (80%);
iv, TsOH (cat.), MeOH, r.t., 4 h (86%); v, Dess–Martin, CH2Cl2, r.t., 2 h (92, 86%; 102, 60%); vi, prop-2-enylamine, CH2Cl2, MgSO4, r.t., 24 h, then
NaBH4, MeOH, r.t., 3 h (91%); vii, NsCl, DMAP (cat.), Et3N, CH2Cl2, r.t., 20 min (92%); viii, Grubbs’ II (cat.), CH2Cl2, 45 ◦C, 24 h (40%); ix, PhSH,
K2CO3, DMF, r.t., 24 h (99, 75%; 103, 75%); x, 81, TBTU, CH2Cl2, i-Pr2NEt, r.t., 15 min, then add 96, r.t. 16 h (91% from 95); xi, NMO, OsO4 (cat.),
acetone, t-BuOH, water, r.t., 12 h (91%); xii, BH3·THF, THF, r.t., 12 h, then aq. HCl, 80 ◦C, 1 h (60%); xiii, NsCl, Na2CO3, n-Bu4NI, acetone, water, r.t.,
4 h.
catalyst then gave the 2,3-dihydro-[1H]-2-benzazepine 95 which
was converted to the N-acyl-2,3-dihydro-[1H]-2-benzazepine 97
by denosylation and N-acylation. After hydroxylation and re-
moval of the side-chain N-nosyl group, reduction of the amide
99 using the borane·THF complex gave the tertiary amine 100.
The secondary amine then had to be reprotected before selective
oxidation of the secondary alcohol gave the cyclopentyl substi-
tuted 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one 103
after a final deprotection. The activity of this compound towards
muscarinic receptors was also evaluated, vide infra.
Preparation of 8-fluorinated
2,3,4,5-tetrahydro-[1H]-2-benzazepines
8-Fluorinated 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-
ones were of interest to check the effect of the additional
aromatic substituent on the selectivity of binding to the
muscarinic M3 and M2 receptors. 1-Bromo-2-bromomethyl-4-
fluorobenzene 10539 is commercially available and can also be
prepared by free-radical bromination of 2-bromo-5-fluorotoluene
104, see Scheme 9. Hydrolysis gave the benzyl alcohol 10640
Scheme 9 Reagents and conditions: i, NBS, (BzO)2 (cat.), CCl4, reflux (99%); ii, CaCO3, dioxane, water, 100 ◦C, 24 h (99%); iii, NaH, THF, DMF,
0 ◦C–r.t., 2 h, PMBCl, r.t. (94%); iv, Mg, THF, reflux, 3 h, then 108, r.t., 12 h (60%); v, Cp2TiMe2, THF, 0 ◦C–65 ◦C, 15 h (93%); vi, DDQ, CH2Cl2, water,
r.t., 2 h (94%); vii, Dess–Martin periodinane, CH2Cl2, r.t., 12 h (85%); viii, prop-2-enylamine, MgSO4, CH2Cl2, r.t., 24 h, then NaBH4, MeOH, r.t., 2 h
(99%); ix, NsCl, Et3N, DMAP (cat.), CH2Cl2, r.t., 12 h (86%); x, Grubbs’ II (cat.), CH2Cl2, reflux, 20 h (97%); xi, NMO, OsO4 (cat.), acetone, water, r.t.,
36–48 h (97%); xii, PhSH, K2CO3 (ca. 100%); xiii, n-PrCHO, MeOH, NaBH3CN, r.t., 12 h (90%).
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which was protected as its p-methoxybenzyl ether 107. The
Grignard reagent generated from this bromide was reacted with
the Weinreb amide 108 derived from cyclobutyl carboxylic acid to
give the ketone 109 which was converted into the alkene 110 using
the Petasis reagent. After deprotection and oxidation, reductive
amination of the aldehyde 112 with prop-2-enylamine gave the
sulfonamide 114 after nosylation. Ring-closing metathesis using
Grubbs’ II catalyst then gave the 2,3-dihydro-[1H]-2-benzazepine
115 which was hydroxylated and deprotected to give the 4,5-
dihydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepine 117. Reductive
amination of this secondary amine with butanal gave the N-
butyltetrahydrobenzazepine 118, but the use of other more
complex aldehydes, e.g., 66, were unsuccessful, perhaps due to
the reduced nucleophilicity of the nitrogen because of the fluorine
substituent. However, the N-alkyl side-chain could be attached by
acylation.
Denosylation of the dihydrobenzazepine 115 followed by N-
acylation and dihydroxylation, gave the 4,5-dihydroxytetrahydro-
[1H]-2-benzazepine 121 which was also available by N-acylation
of the parent 4,5-dihydroxytetrahydro-[1H]-2-benzazepine 117,
see Scheme 10. Following removal of the side-chain nosyl group,
reduction gave the tertiary amine 123 which was renosylated before
Swern oxidation to give the hydroxyketone 125. A final deprotec-
tion gave the required 8-fluoro-5-hydroxy-2,3,4,5-tetrahydro-[1H]-
2-benzazepin-4-one 126 which was subjected to binding assays.
number of the compounds showed membrane sensitization at
higher doses. For these compounds, data at 30% response only
were utilised to determine the binding constant or measurements
were confined to lower doses of the antagonist. The results
for selected compounds including representative 4,5-dihydroxy-
2,3,4,5-tetrahydro-[1H]-2-benzazepines, are given in Tables 1
and 2.
The value of log10KB for the racemic 5-cyclobutyl-5-hydroxy-
2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one 69 with the 3-(N-
phenylmethyl)aminopropyl group on nitrogen, for the M3 re-
ceptors in the guinea pig ileum was 6.7 with a selectivity over
the M2 receptors from the guinea pig left atria of about 40, see
Table 1. This selectivity is comparable to that of darifenacin
(1) but the overall potency was less (by one to two orders
of magnitude). The potency of the cyclopentyl analogue 103
was slightly, but not significantly, higher, whereas analogue 72,
with the 2-aminoethyl side-chain, was a little less potent. The
8-fluorinated benzazepinone 126 did not show any increase
in selectivity for the M3 over the M2 receptors. However, the
simpler 2-butyltetrahydrobenzazepinone 55 was significantly less
potent towards the M3 receptors, as were the analogues 76 and
78 with (N-naphthylmethyl)aminopropyl substituents. The 4,5-
dihydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepines 53, 86, 100 and
118 showed only moderate binding to both the M3 and M2
receptors, see Table 2.
Biological evaluation of 5-hydroxy-2,3,4,5-tetrahydro-
Summary and conclusions
[1H]-2-benzazepin-4-ones and related compounds
Binding data ‘in vitro’ using contraction of the guinea pig ileum
(M3) and guinea pig left atria (M2) were evaluated. Both M3
and M2 muscarinic tests utilised methacholine as agonist, the
measurements being determined as a percentage inhibition of
contractility (M3) and of twitch height (M2), respectively. Binding
constants were determined from the dose-response curves. A
A series of 2,3-dihydro-[1H]-2-benzazepines has been pre-
pared using ring-closing metathesis as the key step and
converted into 5-cycloalkyl-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-
benzazepin-4-ones 2, a hitherto unknown class of benzazepine
derivative, by hydroxylation and selective oxidation. Reductive
amination or N-acylation followed by reduction were used for
Scheme 10 Reagents and conditions: i, PhSH, K2CO3, DMF, rt, 16 h (ca. 100%); ii, 81, EDC, DMAP, DMF, rt, 16 h (73%); iii, NMO, OsO4, acetone,
t-butanol, water, rt, 16 h (94%); iv, 81, i-Pr2EtN, TBTU, CH2Cl2, rt, 16 h (95%); v, PhSH, K2CO3, DMF, r.t., 16 h (87%); vi, LiAlH4, THF, reflux, 4 h;
vii, nosyl chloride, i-Pr2EtN, CH2Cl2, rt, 16 h (91% from 122); viii, DMSO, (COCl)2, CH2Cl2, −78 ◦C, Et3N, 0 ◦C, 30 min (81%); ix, PhSH, K2CO3,
MeCN, rt, 16 h (95%).
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Table 1 Activities of tetrahydrobenzazepin-4-ones as muscarinic (M3) and (M2) antagonists
Compound no.
n
X
m
Ar
Log10KB guinea pig ileum
Log10KB guinea pig left atria
Log10selectivity
69
1
1
1
1
2
1
1
H
H
H
H
H
F
1
0
1
1
1
1
Ph
Ph
6.7 0.4(4)
6.5 0.4(4)
<5.0
<5.0
7.2
6.4 0.3(2)
<5.0
5.2 0.3(4)
4.9 0.6(4)
—
—
—
5.4 0.1
—
1.5 0.3(4)
1.6 0.7(4)
—
—
72
76
78
103
126
55
2-Naph
2-(6-Me-naph)
Ph
Ph
—
1.0 0.3(2)
—
H
2-Butyl
Table 2 Activities of racemic dihydroxytetrahydrobenzazepines as muscarinic (M3) and (M2) antagonists
Compound no.
n
Log10KB guinea pig ileum
Log10KB guinea pig left atria
86
100
1
2
5.5
5.6 0.5(2)
—
5.4 0.1
Compound No.
X
Log10KB guinea pig ileum
Log10KB guinea pig left atria
Log10selectivity
53
118
H
F
6.2 0.2(2)
5.4
< 5.0
—
>1.2
—
the synthesis of N-alkylated derivatives and 8-fluorinated ana-
logues were also prepared. The 5-cycloalkyl-5-hydroxy-2,3,4,5-
tetrahydro-[1H]-2-benzazepin-4-ones 2, albeit racemic, were an-
tagonists towards the M3 receptors in the guinea pig ileum with
useful selectivities over the M2 receptors in the guinea pig left atria,
but the overall potencies were 10–100 times less than optimal.
Preliminary work also showed the usefulness of the dithiane 5 for
the preparation of 2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones.
In the accompanying paper, a Mitsunobu reaction is used to form a
more complex 2,3-dihydro-[1H]-2-benzazepine when ring-closing
metathesis was unsuccessful.
before use and refers to the fraction boiling between 40 and
60 ◦C. Tetrahydrofuran was dried over sodium-benzophenone
and was distilled prior to use. Dichloromethane was dried over
CaH2 and was distilled before use. Ether refers to diethyl ether.
Reactions under non-aqueous conditions were carried out under
an atmosphere of nitrogen or argon.
Electron impact (EI) or chemical ionisation using ammonia
(CI) mass spectra were recorded using a Fisons VG Trio 200
spectrometer and high resolution mass spectra on a Kratos
Concept IS spectrometer. Infra-red spectra were measured using
a Genesis FTIR spectrometer on NaBr plates, either neat or
as evaporated films unless otherwise stated. Nuclear magnetic
resonance spectra were recorded in deuteriated chloroform unless
otherwise indicated on either a Varian Unity 500 (500 MHz),
Varian INOVA 300 (300 MHz), or a Varian Gemini 200 (200 MHz)
spectrometer. Coupling constants (J) are given in Hertz (Hz) and
chemical shifts relative to tetramethylsilane.
Experimental
General
Flash column chromatography was performed using Merck silica
gel (60H; 40–60 l, 230–240 mesh). Light petroleum was redistilled
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2-(tert-Butyldimethylsilyloxymethyl)phenyl cyclobutyl ketone 7
of the residue using light petroleum–ethyl acetate (5 : 1) as eluent
gave the title compound 33 (292 mg, 97%) as a colourless solid
recrystallised from ether, m.p. 116–118 ◦C (found: C, 68.0; H,
5.75; N, 4.65; S, 10.35%. C17H17NO2S requires C, 68.2; H, 5.7; N,
4.7; S, 10.7%. Found: M+ + H, 300.1056. C17H18NO2S requires M,
300.1058); dH (300 MHz, CDCl3) 2.36 (3 H, s, CH3), 4.28 (2 H,
m, 3-H2), 4.49 (2 H, s, 1-H2), 5.69 (1 H, dt, J 12.5, 3, 4-H), 6.33
(1 H, dt, J 12.5, 1.5, 5-H), 6.97 (1 H, m, ArH), 7.06 (2 H, d, J
8, ArH), 7.18–7.28 (3 H, m, ArH) and 7.39 (2 H, d, J 8, ArH);
dC (75 MHz, CDCl3) 21.33, 51.20, 52.70, 127.05, 127.28, 127.63,
127.76, 128.56, 128.97, 129.98, 130.66, 135.19, 135.81, 136.31 and
142.62; m/z (CI) 317 (M+ + 18, 60%) and 300 (M+ + 1, 100).
tert-Butyllithium (1.7 M in pentane, 16 cm3, 27.31 mmol) was
added dropwise at −78 ◦C under argon to cyclobutyl bromide
(1.3 cm3, 13.66 mmol) in tetrahydrofuran (THF) (15 cm3). The
solution was stirred for 1 h before adding via a cannula to the
◦
amide 6 (2.11 g, 6.83 mmol) in THF (30 cm3) at −78 C. After
1 h, saturated aqueous ammonium chloride (50 cm3) was added
and the mixture was warmed to room temperature. Following
extraction with ether (3 × 50 cm3), the organic extracts were
dried (MgSO4) and concentrated under reduced pressure. Chro-
matography of the residue using light petroleum–ethyl acetate (8 :
1 → 5 : 1) afforded the title compound 7 (1.10 g, 59%) as a clear
oil (found: M+, 304.1847. C18H28O2Si requires M, 304.1859); mmax
3067, 1676, 1601, 1573, 1471, 1253, 1217, 1194, 1129, 1081 and
967 cm−1; dH (300 MHz, CDCl3) 0.02 (6 H, s, 2 × SiCH3), 0.83
[9 H, s, C(CH3)3], 1.74 and 1.91 (each 1 H, m, CH), 2.08–2.18 and
2.19–2.31 (each 2 H, m, CH2), 3.82 (1 H, pent, J 8.5, CH), 4.95
(2 H, s, OCH2), 7.19 and 7.39 (each 1 H, t, J 7.5, ArH) and 7.52
and 7.73 (each 1 H, d, J 7.5, ArH); dC (75 MHz, CDCl3) −5.40,
17.87, 18.35, 25.15, 25.95, 43.61, 63.47, 126.04, 126.64, 128.98,
131.97, 133.05, 143.77 and 203.78; m/z (EI) 304 (2%), 247 (50),
155 (40) and 75 (100).
2-(2-Nitrophenyl)sulfonyl-2,3-dihydro-[1H]-2-benzazepine 34
Following the procedure outlined for the synthesis of the dihy-
drobenzazepine 33, the dienyl sulfonamide 32 (444 mg, 1.24 mmol)
and Grubbs’ I catalyst (102 mg, 0.12 mmol, 10 mol%) in
dichloromethane (25 cm3) gave, after stirring for 4 h and chro-
matography using light petroleum–ethyl acetate (3 : 1) as eluent,
the title compound 34 (368 mg, 90%) as a pale grey solid, which
was recrystallised from dichloromethane, m.p. 114–116 ◦C (found:
C, 57.8; H, 4.3; N, 8.5; S, 10.05%; M+, 330.0670. C16H14N2O4S
requires C, 58.2; H, 4.2; N, 8.5; S, 9.7%; M, 330.0674); mmax
(CH2Cl2) 3097, 3073, 3025, 1533, 1437, 1373, 1340, 1164, 1076
and 907 cm−1; dH (300 MHz, CDCl3) 4.41 (2 H, m, 3-H2), 4.62
(2 H, s, 1-H2), 5.85 (1 H, dt, J 12.5, 3.5, 4-H), 6.46 (1 H, dt, J
12.5, 1, 5-H), 7.09 (1 H, d, J 7.5, ArH), 7.18–7.29 (3 H, m, ArH),
7.37 (1 H, dt, J 1.5, 7.5, ArH) and 7.49–7.62 (3 H, m, ArH); dC
(75 MHz, CDCl3) 51.02, 52.75, 123.44, 127.19, 127.88, 128.17,
128.34, 129.69, 130.36, 130.78, 130.83, 132.66, 132.86, 134.97,
135.50 and 147.85; m/z (CI) 348 (M+ + 18, 100%) and 331 (M+ +
1, 30).
The alcohol 42 (10.32 g, 33.73 mmol) was added to the Dess–
Martin periodinane (21.45 g, 50.59 mmol) in dichloromethane
(170 cm3, 0.2 M) at room temperature and the mixture was stirred
for 2 h then cooled to 0 ◦C and aqueous sodium hydroxide
(1.3 M, 200 cm3) was added. After 10 min, the aqueous phase
was extracted with ether (3 × 150 cm3) and the organic extracts
were washed with aqueous sodium hydroxide (1.3 M, 200 cm3),
deionised water (150 cm3), dried (Na2SO4) and concentrated under
reduced pressure to give the ketone 7 (9.87 g, 32.47 mmol, 96%).
2-(4-Methylphenyl)sulfonyl-2,3-dihydro-[1H]-2-benzazepine 33
Toluene p-sulfonyl chloride (419 mg, 2.20 mmol) and 4-
dimethylaminopyridine (ca. 2 mg) were added to the amine 30
(362 mg, 2.09 mmol) in pyridine (20 cm3) at room temperature.
After stirring for 2 days, ether (50 cm3) and aqueous hydrogen
chloride (3.5 M, 50 cm3) were added. The aqueous phase was
extracted with ether (3 × 50 cm3) and the organic extracts
were washed with saturated aqueous copper sulfate (50 cm3)
and dried (MgSO4). After concentration under reduced pressure,
chromatography of the residue using light petroleum–ethyl acetate
(5 : 1) gave the N-(2-ethenylphenyl)methyl-N-prop-2-enyl toluene
p-sulfonamide 31 (339 mg, 50%) as a colourless solid, used without
further purification (found: M+ + H, 328.1372. C19H22NO2S
requires M, 328.1371); dH (300 MHz, CDCl3) 2.50 (3 H, s, CH3),
3.78 (2 H, d, J 7, NCH2), 4.21 (2 H, s, ArCH2), 4.92–5.08 (2 H, m,
3-H2), 5.29 (1 H, dd, J 1, 11, 2ꢀꢀ-H), 5.49 (1 H, m, 2-H), 5.62 (1 H,
dd, J 1, 17.5, 2ꢀꢀ-Hꢀ), 7.03 (1 H, dd, J 11, 17.5, 1ꢀꢀ-H), 7.21–7.38
(3 H, m, ArH), 7.39 (2 H, d, J 8, ArH), 7.52 (1 H, dd, J 1, 7.5,
ArH) and 7.79 (2 H, d, J 8, ArH); m/z (CI) 345 (M+ + 18, 25%)
and 328 (M+ + 1, 100).
(2-Hydroxymethylphenyl)cyclobutylcarbinol 41
n-Butyllithium (2.5 M, 2.47 cm3, 6.17 mmol) was added to
cyclobutylphenylcarbinol 4027 (0.5 g, 3.09 mmol) in diethyl ether
(21 cm3) at 0 ◦C. The mixture was heated under reflux for 2 h
and then allowed to cool to room temperature. An excess of
paraformaldehyde was heated and the formaldehyde produced
was bubbled through the orange/red solution until it became
colourless. The reaction mixture was stirred overnight at room
temperature, then deionised water (30 cm3) was added and the
aqueous layer was extracted with ethyl acetate (5 × 30 cm3). The
organic fractions were dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue using light
petroleum–ethyl acetate (1 : 1) as eluent gave the title compound 41
(0.44 g, 74%) as an oil (found: M+ + NH4, 210.1499. C12H20NO2
requires M, 210.1494); mmax 3334, 3065, 3028, 1452, 1000 and 755;
dH (300 MHz, CDCl3) 1.75 (1 H, m), 1.82–2.01 (3 H, m), 2.11 and
2.27 (each 1 H, m), 2.93 (1 H, sex, J 8.5), 3.12 (2 H, br. s, 2 ×
OH), 4.66 and 4.83 (each 1 H, d, J 12, HCHO), 4.87 (1 H, d,
J 8.5, 1-H) and 7.29–7.41 (4 H, m, ArH); dC (75 MHz, CDCl3)
17.79, 24.78, 25.35, 39.90, 63.82, 75.75, 126.78, 127.85, 128.21,
130.03, 138.86 and 140.54; m/z (CI) 192 (M+, 23%), 173 (32) and
157 (100).
Grubbs’ I catalyst (83 mg, 0.10 mmol, 10 mol%) was added
to a degassed solution of the dienylsulfonamide 31 (330 mg,
1.01 mmol) in dichloromethane (25 cm3) and the mixture was
stirredatroomtemperaturefor15hbeforesilica(ca. 1g)was added
and the solvent removed under reduced pressure. Chromatography
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1-(2-tert-Butyldimethylsilyloxymethyl)phenyl-1-cyclobutylethene
43
was provisionally identified as a dimer (7 mg, 20%); m/z (CI) 752
(M+ + 18, 1%).
The ketone 7 (476 mg, 1.57 mmol) and Cp2TiMe2 (700 mg,
3.37 mmol) in THF (20 cm3) were heated to reflux for 15 h under
nitrogen in a foil covered apparatus. Light petroleum (100 cm3)
5-Cyclobutyl-2-(2-nitrophenylsulfonyl)-2,3-dihydro-[1H]-2
-benzazepine 50
The dialkenyl sulfonamide 48 (885 mg, 2.12 mmol) and the
Grubbs’ II catalyst (90 mg, 0.106 mmol) were heated under
reflux for 18 h in degassed dichloromethane (100 cm3). The
reaction mixture was cooled to room temperature and silica (ca.
3 g) was added. After concentration under reduced pressure,
chromatography of the residue using light petroleum–ethyl acetate
(3 : 1) as eluent gave the title compound 50 (780 mg, 96%) as a clear
viscous oil (found: M+ + H, 385.1224. C20H21N2O4S requires M,
385.1222); mmax 1543, 1373, 1164, 1125, 911, 851, 766 and 745; dH
(300 MHz, CDCl3) 1.77 (1 H, m), 1.83–2.04 (3 H, m), 2.13–2.24
(2 H, m), 3.49 (1 H, pent, J 8, CH), 3.67 (2 H, d, J 7.5, 3-H2),
4.19 (2 H, s, 1-H2), 5.90 (1 H, dt, J 2, 7.5, 4-H), 7.25–7.32 (2 H,
m, ArH), 7.35–7.42 (2 H, m, ArH), 7.64–7.77 (3 H, m, ArH) and
8.05 (1 H, dd, J 2, 5.5, ArH); dC (75 MHz, CDCl3) 17.80, 28.39,
39.55, 43.00, 49.22, 116.95, 124.05, 126.04, 127.95, 128.35, 129.80,
130.53, 131.42, 132.95, 133.16, 133.29, 139.94 and 151.00; m/z
(CI) 385 (M+ + 1, 5%), 355 (20), 198 (90) and 94 (100%).
R
was added and the reaction mixture filtered through Celiteꢀ. The
residue was washed with light petroleum (2 × 50 cm3) before
silica (ca. 5 g) was added and the solvent removed under reduced
pressure. Chromatography of the residue using light petroleum–
ethyl acetate (19 : 1) gave the title compound 43 (434 mg, 92%) as a
clear oil (found: M+, 302.2062. C19H30OSi requires M, 302.2066);
dH (300 MHz, CDCl3) −0.08 (6 H, s, 2 SiCH3), 0.84 [9 H, s,
C(CH3)3], 1.61 (1 H, m), 1.69–2.01 (5 H, m), 3.10 (1 H, pent, J 8,
CH), 4.58 (2 H, s, OCH2), 4.79 and 5.06 (each 1 H, d, J 1.5, 2-H),
6.94 (1 H, d, J 7.5, ArH), 7.09 and 7.17 (each 1 H, t, J 7.5, ArH)
and 7.44 (1 H, d, J 7.5, ArH); dC (75 MHz, CDCl3) −5.33, 17.63,
18.35, 25.92, 28.04, 41.97, 62.64, 112.06, 126.17, 126.69, 126.73,
127.92, 138.00, 140.18 and 151.89; m/z (CI) 320 (M+ + 18, 5%),
303 (M+ + 1, 10) and 171 (100).
N-[2-(1-Cyclobutylethenyl)phenyl]methyl-N-prop-2-enyl
2-nitrobenzene sulfonamide 48
The amine 46 (200 mg, 0.881 mmol), triethylamine (0.18 cm3,
1.29 mmol), 2-nitrophenylsulfonyl chloride (215 mg, 0.970 mmol)
and 4-dimethylaminopyridine (ca. 2 mg) in dichloromethane
(10 cm3) were stirred at room temperature for 3 h. Ether (25 cm3)
and water (25 cm3) were added and the aqueous layer was extracted
with ether (2 × 15 cm3). The organic extracts were dried (MgSO4)
then concentrated under reduced pressure. Chromatography of the
residue using light petroleum–ethyl acetate (3 : 1) as eluent gave the
title compound 48 (285 mg, 79%) as a clear viscous oil (found: M+ +
H, 413.1528. C22H25N2O4S requires M, 413.1535); mmax 3075, 1543,
1372, 1352, 1163, 1126, 915 and 778; dH (300 MHz, CDCl3) 1.70
(1 H, m), 1.82–2.11 (5 H, m), 3.16 (1 H, pent, J 8, CH), 3.94 (2 H,
d, J 6, 1-H2), 4.61 (2 H, s, ArCH2), 4.88 (1 H, s, 2ꢀꢀ-H), 5.01–5.12
(2 H, m, 3-H2), 5.22 (1 H, t, J 1.5, 2ꢀꢀ-Hꢀ), 5.61 (1 H, m, 2-H), 7.08
(1 H, m, ArH), 7.18–7.26 (2 H, m, ArH), 7.38 (1 H, m, ArH), 7.63–
7.76 (3 H, m, ArH) and 8.04 (1 H, d, J 7.5, ArH); dC (75 MHz,
CDCl3) 17.59, 28.00, 42.00, 48.09, 49.58, 112.78, 119.00, 124.06,
126.84, 127.09, 127.20, 128.64, 130.99, 131.59, 131.99, 132.17,
133.36, 134.03, 141.85, 143.80 and 151.63; m/z (CI) 430 (M+ +
18, 15%), 413 (M+ + 1, 5), 383 (30), 228 (50) and 171 (100).
(4RS,5SR)-5-Cyclobutyl-2-(2-nitrophenylsulfonyl)-2,3,4,5-
tetrahydro-[1H]-2-benzazepine-4,5-diol 51
N-Methylmorpholine-N-oxide (40 mg, 0.341 mmol) and osmium
tetroxide (8 mg, 0.0315 mmol, 10 mol%) were added at room
temperature to the dihydrobenzazepine 50 (120 mg, 0.313 mmol)
in acetone (5 cm3) and water (2.5 cm3) and the mixture was
vigorously stirred for 18 h. Dichloromethane (15 cm3) and water
(15 cm3) were added and the mixture was acidified with aqueous
hydrogen chloride (3 M) until the pH was 2. The aqueous
phase was extracted with dichloromethane (3 × 15 cm3) and
the organic extracts were dried (MgSO4). Concentration under
reduced pressure followed by chromatography of the residue using
light petroleum–ethyl acetate (2 : 1) gave the title compound 51
(104 mg, 80%) as a solid further purified by reprecipitation from
◦
ether and petroleum ether, m.p. 140–142 C (found: M+ + H,
419.1274. C20H23N2O6S requires M, 419.1277); mmax (CDCl3) 3540,
3093, 1590, 1545, 1445, 1371, 1352, 1266, 1164 and 1065 cm−1; dH
(300 MHz, CDCl3) 1.29 (1 H, m), 1.78–1.90 (3 H, m), 2.13–2.38
(2 H, m), 2.49 (1 H, d, J 9, OH), 2.91 (1 H, pent, J 8, CH), 3.22
(1 H, s, OH), 3.53 (1 H, dd, J 1, 15, 3-H), 3.86 (1 H, m, 4-H),
4.03 (1 H, ddd, J 2, 4, 15, 3-Hꢀ), 4.46 (1 H, d, J 16, 1-H), 4.83
(1 H, dd, J 2, 16, 1-Hꢀ), 7.23–7.26 (2 H, m, ArH), 7.38 (1 H, m,
ArH), 7.67–7.81 (3 H, m, ArH), 7.86 (1 H, d, J 7.5, ArH) and 8.11
(1 H, dd, J 2, 7, ArH); dC (75 MHz, CDCl3) 17.55, 21.60, 21.75,
39.34, 50.92, 54.16, 72.51, 79.21, 124.24, 127.65, 128.23, 129.24,
130.17, 131.41, 131.74, 132.17, 132.80, 133.90, 140.84 and 147.90;
m/z (CI) 436 (M+ + 18, 10%), 419 (M+ + 1, 5), 389 (20), 232 (40)
and 94 (100).
5-Cyclobutyl-2-(4-methylphenyl)sulfonyl-2,3-dihydro-[1H]-2-
benzazepine 49
The dienyl sulfonamide 47 (35 mg, 0.0919 mmol) and Grubbs’ I
catalyst (12 mg, 0.0146 mmol, 16 mol%) in benzene (10 cm3) were
heated under reflux for 24 h. Silica (ca. 1 g) was added and the
mixture was concentrated under reduced pressure. Chromatogra-
phy of the residue using (light petroleum–ethyl acetate (9 : 1 → 3 :
1) gave recovered starting material 47 (21 mg, 60%) and then the
title compound 49 (6 mg, 18%) as a solid (found: M+, 353.1452.
C21H23NO2S requires M, 353.1449); dH (300 MHz, CDCl3) 1.50–
1.62 (3 H, m), 1.79 (1 H, m), 1.93–2.04 (2 H, m), 2.36 (3 H, s,
CH3), 3.28 (1 H, br. pent, J 8, CH), 3.49 (2 H, d, J 7.25, 3-H2),
4.01 (2 H, s, 1-H2), 5.45 (1 H, dt, J 2, 7, 4-H), 7.05–7.31 (6 H,
m, ArH) and 7.67 (2 H, d, J 8, ArH); m/z (CI) 354 (M+ + 1,
80%), 198 (100) and 184 (70). The third fraction off the column
(4RS,5SR)-5-Cyclobutyl-2,3,4,5-tetrahydro-[1H]-2-benzazepine-
4,5-diol 52
Thiophenol (80 lL, 0.78 mmol) was added at room tempera-
ture to a mixture of the 2-nitrophenylsulfonamide 51 (256 mg,
0.61 mmol) and potassium carbonate (296 mg, 2.14 mmol) in
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N,N-dimethylformamide (15 cm3) and the mixture was stirred for
24 h. Ethyl acetate (25 cm3) and water (25 cm3) were added and
the aqueous layer was extracted with ethyl acetate (5 × 25 cm3).
The organic extracts were dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue using ethyl
acetate–methanol (3 : 1) containing 1% triethylamine gave the title
compound 52 (122 mg, 86%) as an amorphous colourless solid
(found: M+ + H, 234.1498. C14H20NO2 requires M, 234.1494); mmax
3363, 3059, 1667, 1652, 1446, 1264, 1148, 1083, 1000, 967, 755 and
734; dH (300 MHz) 1.32 (1 H, m), 1.69–1.88 (3 H, m), 2.07–2.28
(2 H, m), 2.88 (1 H, m, CH), 3.05 (1 H, d, J 13.5, 3-H), 3.18 (1 H,
dd, J 3.5, 13.5, 3-Hꢀ), 3.26 (3 H, br. s, 2 × OH, NH), 3.66 (1 H, d,
J 3.5, 4-H), 3.84 and 4.00 (each 1 H, d, J 15, 1-H), 7.01 (1 H, d, J
7.5, ArH), 7.16 and 7.28 (each 1 H, t, J 7.5, ArH) and 7.80 (1 H, d,
J 7.5, ArH); dC (75 MHz) 17.59, 21.57, 21.81, 39.66, 51.92, 55.84,
73.16, 79.79, 126.90, 127.10, 128.85, 129.53, 136.34 and 141.73;
m/z (CI) 234 (M+ + 1, 100%).
−78 ◦C before triethylamine (200 lL, 1.435 mmol) was added and
then for a further 15 min before saturated aqueous ammonium
chloride (10 cm3) was added. The mixture was warmed to
room temperature, dichloromethane (10 cm3) was added, and the
aqueous phase was extracted with dichloromethane (2 × 10 cm3).
The organic extracts were dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue using light
petroleum–ethyl acetate (1 : 1) as eluent gave the title compound 54
(57 mg, 58%) as a viscous yellow oil (found: M+ + NH4, 434.1377.
C20H24N3O6S requires M, 434.1386); mmax (CDCl3) 3481, 3092,
1713, 1545, 1440, 1361, 1168, 1126 and 1095 cm−1; dH (300 MHz,
CDCl3) 1.51–1.84 (5 H, m), 2.31 (1 H, m), 3.27 (1 H, m, CH),
3.99 and 4.12 (each 1 H, d, J 17, 1-H and 3-H), 4.59 and 4.90
(each 1 H, dd, J 2.5, 17, 1-Hꢀ and 3-Hꢀ), 7.06 (1 H, d, J 7, ArH),
7.15–7.29 (2 H, m, ArH), 7.60–7.74 (4 H, m, ArH) and 7.96 (1 H,
dd, J 2, 7, ArH); dC (75 MHz, CDCl3) 16.79, 21.52, 21.71, 42.36,
53.14, 57.07, 83.70, 124.42, 127.83, 127.94, 128.11, 128.24, 129.37,
131.03, 131.60, 131.93, 133.71, 134.25, 139.05 and 206.40; m/z
(CI) 434 (M+ + 18, 20%) and 230 (100).
(4RS,5SR)-2-Butyl-5-cyclobutyl-2,3,4,5-tetrahydro-[1H]-2-
benzazepine-4,5-diol 53
2-Butyl-5-cyclobutyl-5-hydroxy-1,2,3,5-tetrahydro-[1H]-2-
benzazepin-4-one 55
Butanal (150 lL, 1.70 mmol), sodium triacetoxyborohydride
(359 mg, 1.70 mmol) and glacial acetic acid (32 lL, 0.56 mmol)
were added to the crude tetrahydrobenzazepine 52 in THF
(10 cm3) prepared from the 2-nitrophenylsulfonamide 51 (472 mg,
1.13 mmol), thiophenol (130 lL, 1.27 mmol) and potassium
carbonate (500 mg, 3.62 mmol) in N,N-dimethylformamide
(20 cm3). After stirring at room temperature for 15 h, ether (25 cm3)
and water (25 cm3) were added and the mixture was basified to
ca. pH 10 with aqueous sodium hydroxide (1 M). The aqueous
layer was extracted with ether (5 × 25 cm3) and the ethereal
extracts were dried (MgSO4). After concentration under reduced
pressure, chromatography of the residue using light petroleum–
ethyl acetate (3 : 1 → 1 : 1) containing triethylamine (1%) as
eluent gave the title compound 53 (172 mg, 53%) as a colourless
solid recrystallised from ethyl acetate as colourless needles, m.p.
Dimethyl sulfoxide (162 lL, 2.28 mmol) was added dropwise at
−78 ◦C to oxalyl chloride (120 lL, 1.38 mmol) in dichloromethane
(5 cm3) under nitrogen. After 10 min, the diol 53 (132 mg,
0.46 mmol) in dichloromethane (4 cm3) was added dropwise by
syringe and the stirring was continued for 2 h during which
time the temperature was allowed to rise from −78 ◦C to
◦
0 C. Triethylamine (0.38 cm3, 2.72 mmol) was added and, after
a further 15 min, ether (15 cm3) and water (15 cm3) were added.
The aqueous layer was extracted with ether (3 × 25 cm3) and
the organic extracts were dried (MgSO4). After concentration
under reduced pressure, chromatography of the residue using light
petroleum–ethyl acetate (5 : 1) containing triethylamine (1%) gave
the title compound 55 (96 mg, 73%) as a yellow oil (found: M+ + H,
288.1972. C18H26NO2 requires M, 288.1963); mmax 3469, 3156, 3054,
1728, 1705, 1466, 1455, 1375, 1264, 1249 and 1168 cm−1; dH
(400 MHz, CDCl3) 0.91 (3 H, t, J 7.25, 4ꢀ-H3), 1.32 (2 H, sex,
J 7.25, 3ꢀ-H2), 1.45–1.53 (2 H, m, CH2), 1.68 (1 H, m), 1.79 (3 H,
m), 1.90 and 2.29 (each 1 H, m), 2.38–2.45 (2 H, m), 3.54 (1 H, dd,
J 1, 16, 1-H), 3.59 (1 H, pent, J 8, CH), 3.74 (1 H, d, J 16, 1-Hꢀ),
3.95 and 4.18 (each 1 H, d, J 16, 3-H), 7.06 (1 H, dd, J 1, 7.5, ArH),
7.21 and 7.25 (each 1 H, dt, J 1, 7.5, ArH) and 7.86 (1 H, dd, J 1.5,
7.5, ArH); dC (100 MHz, CDCl3) 13.85, 17.20, 20.20, 21.66, 21.78,
29.23, 41.51, 54.47, 60.35, 64.11, 83.91, 127.16, 127.24, 127.37,
129.42, 134.86, 138.34 and 208.01; m/z (CI) 288 (M+ + 1, 100%).
◦
96–98 C (found: M+ + H, 290.2108. C18H28NO2 requires M,
290.2120); mmax (CDCl3) 3437, 3054, 1265 and 739 cm−1; dH
(400 MHz, CDCl3) 0.93 (3 H, t, J 7, 4ꢀ-H3), 1.33 (3 H, m, 3ꢀ-
H2 and 3ꢀꢀ-H), 1.49–1.59 (2 H, m, 2 × CH), 1.71–1.87 (3 H, m),
2.14–2.29 (2 H, m), 2.55–2.68 (2 H, m, 1ꢀ-H2), 2.82 (1 H, pent, J
8.5, CH), 2.90 (1 H, dd, J 1, 13, 3-H), 3.04 (2 H, br. s, 2 × OH),
3.11 (1 H, ddd, J 2.5, 5, 13, 3-Hꢀ), 3.64 (1 H, dd, J 2.5, 14.5, 1-H),
3.71 (1 H, d, J 5, 4-H), 3.76 (1 H, d, J 14.5, 1-Hꢀ), 7.05 (1 H, dd, J
1, 7.5, ArH), 7.17 (1 H, dt, J 1.5, 7.5, ArH), 7.26 (1 H, dt, J 1, 7.5,
ArH) and 7.81 (1 H, dd, J 1.5, 7.5, ArH); dC (75 MHz, CDCl3)
13.99, 17.75, 20.39, 21.70, 21.80, 29.59, 39.68, 59.45, 59.59, 63.28,
73.03, 79.56, 126.98, 127.12, 129.05, 129.95, 135.49 and 141.81;
m/z (CI) 290 (M+ + 1, 100%).
(4SR,5RS)-5-Cyclobutyl-4,5-dihydroxy-2-[3-(N-phenylmethyl-N-
trifluoroacetyl)aminopropyl]-2,3,4,5-tetrahydro-[1H]-2-
benzazepine 67
5-Cyclobutyl-5-hydroxy-2-(2-nitrophenylsulfonyl)-1,2,3,5-
tetrahydro-[1H]-2-benzazepin-4-one 54
Dimethyl sulfoxide (120 lL, 0.1.69 mmol) was added dropwise at
−78 ◦C to oxalyl chloride (84 lL, 0.963 mmol) in dichloromethane
(2 cm3) and the solution was stirred at −78 ◦C for 10 min
before the diol 51 (100 mg, 0.239 mmol) in dichloromethane
(2 cm3) was added. The mixture was stirred for 15 min at
The crude diol 52 [prepared from the 2-nitrophenylsulfonamide 51
(120 mg, 0.287 mmol), potassium carbonate (129 mg, 0.933 mmol)
and thiophenol (44 lL, 0.428 mmol) in N,N-dimethylformamide
(5 cm3)], the aldehyde 5634 (223 mg, 0.861 mmol) and sodium
cyanoborohydride (18 mg, 0.286 mmol) were dissolved in
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methanol (5 cm3) containing a drop of conc. aqueous hydrogen
chloride and the solution was stirred at room temperature for
15 h. The mixture was extracted with ether (5 × 25 cm3) which
was washed with aqueous sodium hydroxide (1 M, 25 cm3)
and dried (MgSO4). Concentration under reduced pressure and
chromatography of the residue using light petroleum–ethyl acetate
(3 : 1 → 1 : 1) containing triethylamine (1%) as eluent gave
the title compound 67 (104 mg, 76%), as an oil, a 60 : 40
mixture of rotamers (found: M+, 476.2287. C26H31F3N2O3 requires
M, 476.2290); dH (300 MHz, CDCl3) 1.37 (1 H, m), 1.63–1.91
(4 H, m), 2.14–3.10 (9 H, m), 3.20–3.90 (5 H, m), 4.52 (0.4 H, d, J
14.5, NHCHPh), 4.56 and 4.69 (each 0.6 H, d, J 15.5, NHCHPh),
4.82 (0.4 H, d, J 14.5, NHCHPh), 7.05–7.18 (2 H, m, ArH), 7.22
(1 H, m, ArH), 7.25–7.45 (5 H, m, ArH) and 7.84 (1 H, m, ArH);
m/z (CI) 477 (M+ + 1, 100%).
128.04, 128.35, 129.59, 134.49, 138.38 and 207.74; m/z (CI) 379
(M+ + 1, 50%), 284 (50), 267 (55) and 108 (100).
(4SR,5RS)-5-Cyclobutyl-4,5-dihydroxy-2-[2-(N-2-
nitrophenylsulfonyl-N-phenylmethylamino)-ethyl]-2,3,4,5-
tetrahydro-[1H]-2-benzazepine 70
Sodium cyanoborohydride (33 mg, 0.525 mmol) and concentrated
aqueous hydrogen chloride (1 drop) were added to the tetrahy-
drobenzazepine 52 (122 mg, 0.524 mmol) and the aldehyde 59
(350 mg, 1.048 mmol) in methanol (5 cm3) at room temperature.
After 15 h, ethyl acetate (25 cm3) and water (25 cm3) were added
and the pH was adjusted to ca. 12 with aqueous sodium hydroxide
(1 M). The aqueous phase was extracted with ethyl acetate (2 ×
25 cm3) and dichloromethane (3 × 25 cm3). The organic extracts
were dried (MgSO4), silica (ca. 2.5 g) was added and the mixture
was concentrated under reduced pressure. Chromatography of
the residue using light petroleum–ethyl acetate (1 : 1) → neat
ethyl acetate containing triethylamine (1%) as the eluent gave
the title compound 70 (189 mg, 66%) as a viscous yellow oil
(found: M+ + H, 552.2172. C29H34N3O6S requires M, 552.2168);
mmax (CDCl3) 3468, 3065, 1544, 1455, 1370, 1162, 1068, 1000 and
911 cm−1; dH (300 MHz, CDCl3) 1.25 (1 H, m), 1.57–1.77 (3 H,
m), 2.05–2.22 (2 H, m), 2.50–2.62 (2 H, m, 1ꢀ-H2), 2.71 (1 H, pent,
J 8.5, CH), 2.82–2.93 (2 H, m, 3-H2), 3.25–3.50 (3 H, m, 1-H,
2ꢀ-H2), 3.58 (1 H, d, J 3.5, 4-H), 3.69 (1 H, d, J 15, 1-Hꢀ), 4.40
and 4.48 (each 1 H, d, J 14 NHCHPh), 6.91 (1 H, d, J 7.5, ArH),
7.10 (1 H, dt, J 1.5, 7.5, ArH), 7.18–7.31 (6 H, m, ArH), 7.53–7.67
(3 H, m, ArH), 7.73 (1 H, dd, J 1.5, 8, ArH) and 7.95 (1 H, d, J
8, ArH); dC (100 MHz, CDCl3) 17.72, 21.67, 21.79, 39.60, 45.52,
52.18, 57.54, 60.17, 62.96, 73.06, 79.30, 124.22, 126.86, 127.17,
128.09, 128.16, 128.70, 128.82, 130.17, 130.79, 131.61, 133.11,
133.46, 134.49, 135.16, 141.43 and 147.83;. m/z (CI) 552 (M+ + 1,
2%), 363 (10) and 108 (100).
5-Cyclobutyl-5-hydroxy-2-[3-(N-phenylmethyl-N-
trifluoroacetyl)aminopropyl]-2,3,4,5-tetrahydro-[1H]-2-
benzazepin-4-one 68
Dimethyl sulfoxide (133 lL, 1.87 mmol) was added to oxalyl
chloride (98 lL, 1.12 mmol) in dichloromethane (3 cm3) at
−78 ◦C. After 10 min, the hydroxytetrahydrobenzazepine 67
(179 mg, 0.376 mmol) in dichloromethane (5 cm3) was added
and the reaction mixture was allowed to warm to 0 ◦C over
1 h. Triethylamine (0.31 cm3, 2.22 mmol) was added and, after
30 min, water (25 cm3) and ether (25 cm3). The aqueous layer
was extracted with ether (4 × 25 cm3) and the organic extracts
were dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using light petroleum–ethyl acetate
(5 : 1) containing triethylamine (1%) as eluent gave the title
compound 68 (120 mg, 67%), a mixture of rotamers, as a yellow oil
(found: M+ + H, 475.2205. C26H30F3N2O3 requires M, 475.2208);
mmax 3466, 3065, 1690, 1452, 1202 and 1144 cm−1; dH (200 MHz,
CDCl3) 1.49–1.98 (8 H, m), 2.18–2.40 (2 H, m, CH2), 3.28–3.60
(4 H, m), 3.74–3.90 (2 H, m), 4.23 (1 H, m), 4.55–4.73 (3 H, m,
CH2 and OH), 6.98 (1 H, m, ArH), 7.10–7.45 (7 H, m, ArH) and
7.77 (1 H, m, ArH); m/z (CI) 475 (M+ + 1, 5%), 261 (40), 221 (80),
108 (100) and 91 (90).
5-Cyclobutyl-4-hydroxy-2-[2-(N-2-nitrophenylsulfonyl-N-
phenylmethylamino)ethyl]-2,3,4,5-tetrahydro-[1H]-2-benzazepin-
4-one 71
Dimethyl sulfoxide (60 lL, 0.846 mmol) was added to oxalyl
chloride (42 lL, 0.481 mmol) in dichloromethane (1 cm3) at
−78 ◦C followed, after 15 min, by the addition of the diol 70
(60 mg, 0.109 mmol) in dichloromethane (2 cm3). The mixture
was allowed to warm to −10 ◦C, then triethylamine (100 lL,
0.718 mmol) was added. After 30 min, water (20 cm3) and ether
(20 cm3) were added and the aqueous phase was extracted with
ether (4 × 20 cm3). The organic extracts were dried (MgSO4) and
concentrated under reduced pressure. Chromatography using light
petroleum–ethyl acetate (3 : 1 → 1 : 1) containing triethylamine
(1%) as eluent gave the title compound 71 (46 mg, 77%) as a
yellow oil (found: M+ + H, 550.2021. C29H32N3O6S requires M,
550.2012); mmax 3466, 3065, 1698, 1544, 1454, 1369 and 1163 cm−1;
dH (300 MHz, CDCl3) 1.55 (1 H, m), 1.65–1.88 (4 H, m), 2.22 (1 H,
pent, J 9, CH), 2.33 (2 H, t, J 7, 1ꢀ-H2), 3.34–3.39 (3 H, m), 3.38
and 3.64 (each 1 H, d, J 15, 1-H), 3.76 and 4.04 (each 1 H, d, J
16, 3-H), 4.50 (2 H, s, NCH2Ph), 4.54 (1 H, br. s, OH), 6.91 (1 H,
d, J 7.5, ArH), 7.10 (1 H, dt, J 1.5, 7.5, ArH), 7.18–7.31 (6 H, m,
ArH), 7.53–7.67 (3 H, m, ArH), 7.73 (1 H, dd, J 1.5, 8, ArH) and
7.95 (1 H, dd, J 1, 8, ArH); m/z (CI) 550 (M+ + 1, 20%), 363 (40),
106 (90) and 94 (100).
5-Cyclobutyl-5-hydroxy-2-[3-(phenylmethylamino)propyl]-1,2,3,5-
tetrahydro-[1H]-2-benzazepin-4-one 69
Potassium carbonate (117 mg, 0.847 mmol) in water (0.6 cm3)
was added to the trifluoroacetamide 68 (80 mg, 0.169 mmol) in
methanol (10 cm3) and the solution was stirred for 24 h. After con-
centration under reduced pressure, chromatography of the residue
using light petroleum–ethyl acetate (1 : 2) containing triethylamine
(1%) as eluent gave the title compound 69 (50 mg, 80%) as a yellow
oil (found: M+ + H, 379.2381. C24H31N2O2 requires M, 379.2385);
dH (300 MHz, CDCl3) 1.41–1.88 (7 H, m), 2.20 (1 H, m), 2.38 (2 H,
dt, J 3.5, 7, CH2), 2.59 (2 H, t, J 7, CH2), 3.45 (1 H, m, CH), 3.45
and 3.68 (each 1 H, d, J 16, 1-H), 3.69 (2 H, s, ArCH2N), 3.85 and
4.14 (each 1 H, d, J 16, 3-H), 6.97 (1 H, d, J 7.5, ArH), 7.11 (1 H,
dt, J 1.5, 7.5, ArH), 7.14–7.26 (6 H, m, ArH) and 7.67 (1 H, d, J
7.5, ArH); dC (75 MHz, CDCl3) 17.16, 21.55, 21.71, 27.35, 30.25,
41.71, 47.08, 52.50, 60.14, 64.07, 83.99, 126.96, 127.29, 127.41,
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5-Cyclobutyl-5-hydroxy-2-[2-(phenylmethylamino)ethyl]-2,3,4,5-
tetrahydro-[1H]-2-benzazepin-4-one 72
M, 546.2063); mmax 3059, 1669, 1634, 1543, 1455, 1434, 1372,
1346, 1162, 768 and 736; dH (300 MHz, dimethyl sulfoxide-d6,
150 ◦C) 1.80 (1 H, m), 1.87–2.02 (3 H, m), 2.17–2.28 (2 H, m),
2.52 (2 H, t, J 7.5, 2ꢀ-H2), 3.51–3.73 (5 H, m), 4.22 (2 H, s, 1-H2),
4.57 (2 H, s, ArCH2N), 5.87 (1 H, dt, J 2, 7, 4-H), 7.38–7.23 (9 H,
m, Ar-H), 7.88–7.76 (3 H, m, Ar-H) and 8.01 (1 H, d, J 12, ArH);
dC (75.5 MHz, dimethyl sulfoxide-d6, 150 ◦C) 17.94, 28.92, 28.96,
33.30, 43.37, 43.41, 45.02, 48.81, 52.51, 120.33, 124.99, 126.93,
128.00, 128.33, 128.39, 128.83, 129.11, 129.84, 130.72, 132.87,
134.94, 136.43, 137.09, 139.92, 147.01 and 168.63; m/z (CI) 546
(M+ + 1, 3%), 481 (3), 359 (35), 198 (90) and 94 (100).
Potassium carbonate (212 mg, 1.534 mmol) and thiophenol (60 lL,
0.584 mmol) were added to the 2-nitrophenylsulfonamide 71
(260 mg, 0.474 mmol) in N,N-dimethylformamide (5 cm3). After
18 h, water (25 cm3) and ethyl acetate (25 cm3) were added, and
the aqueous layer was extracted with ethyl acetate (5 × 15 cm3).
The organic extracts were dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue using light
petroleum–ethyl acetate (1 : 1 → 1 : 2) containing triethylamine
(1%) as eluent gave the title compound 72 (90 mg, 52%) as a yellow
oil (found: M+ + H, 365.2220. C23H29N2O2 requires M, 365.2229);
mmax 3454, 3054, 1693, 1673, 1453, 1265, 1133 and 1106 cm−1; dH
(300 MHz, CDCl3) 1.44 (1 H, m), 1.58–1.76 (4 H, m), 2.08–2.16
(1 H, m), 2.48 and 2.71 (each 2 H, t, J 6, 1ꢀ-H2 and 2ꢀ-H2), 3.26 (1 H,
pent, J 8.5, CH), 3.44 and 3.75 (each 1 H, d, J 15.5, 1-H), 3.76 (1 H,
d, J 16.5, 3-H), 3.90 and 3.96 (each 1 H, d, J 13.5, NHCHPh), 4.15
(1 H, d, J 16.5, 3-Hꢀ), 6.84 (1 H, d, J 7.5, ArH), 7.05 (1 H, dt, J 1,
7.5, ArH), 7.11–7.36 (6 H, m, ArH) and 7.64 (1 H, d, J 7.5, ArH);
m/z (CI) 365 (M+ + 1, 80%), 347 (30%), 108 (100) and 74 (80).
(4SR,5RS)-5-Cyclobutyl-4,5-dihydroxy-2-[3-(N-phenylmethyl)-
aminopropyl]-2,3,4,5-tetrahydro-[1H]-2-benzazepine 86
The N-acyltetrahydrobenzazepine 85 (48 mg, 0.12 mmol) in
tetrahydrofuran (1 cm3) was added to the bor◦ane in tetrahydrofu-
ran (1 M, 0.61 cm3, 0.61 mmol) cooled to 0 C and the reaction
mixture was stirred at room temperature for 3 h. The reaction
◦
mixture was cooled to 0 C and deionised water (1 cm3) was
added followed by aqueous hydrogen chloride (1 M, 1 cm3). The
reaction mixture was then heated under reflux for 1 h, cooled
and concentrated under reduced pressure. The solid residue was
dissolved in deionised water (∼3 cm3) and the pH was adjusted to
12 by the addition of solid sodium hydroxide. The aqueous phase
was then extracted with dichloromethane (3 × 10 cm3) and the
combined organic phases were dried (MgSO4) and concentrated
under reduced pressure to give the title compound 86 (27 mg,
57%) as an oil (found: M+ + H, 381.2547. C24H33N2O2 requires
M, 381.2543); mmax 3406, 3059, 3023, 1455, 1310, 1277, 1243, 1217,
1158, 1142, 1081, 998, 747 and 699; dH (300 MHz, CDCl3) 1.35
(1 H, m) 1.73–1.96 (5 H, m), 2.14–2.33 (2 H, m, CH2), 2.64–2.83
(5 H, m), 2.87 (1 H, d, J 13, 3-H), 3.16 (1 H, br. s, OH), 3.24 (1 H,
ddd, J 13, 5, 2, 3-Hꢀ), 3.88–3.61 (5 H, m), 7.05 (1 H, d, J 8, ArH),
7.16–7.37 (7 H, m, ArH) and 7.85 (1 H, d, J 8, ArH); dC (75.5 MHz,
CDCl3) 17.97, 21.90, 22.12, 26.79, 39.91, 47.59, 53.32, 58.86, 59.21,
64.46, 73.21, 79.47, 127.20, 127.57, 127.75, 128.69, 128.89, 129.33,
130.29, 135.31 and 142.41; m/z (CI) 381 (M+ + 1, 100%).
5-Cyclobutyl-2,3-dihydro-[1H]-2-benzazepine 82
Potassium carbonate (0.63 g, 4.56 mmol) and thiophenol (0.19 g,
1.69 mmol) were added to the 2-nitrobenzene sulfonamide 50
(0.50 g, 1.302 mmol) in N,N-dimethylformamide (33 cm3) at room
temperature and the mixture was stirred for 16 h. Deionised water
(50 cm3) was added and the aqueous phase was extracted with ethyl
acetate (5 × 50 cm3). The organic extracts were dried (MgSO4) and
concentrated under reduced pressure to give the title compound 82
(0.259 g, 1.302 mmol, ca. 100%) as an oil used without further
purification (found: M+ + H, 200.1434. C14H17N requires M,
200.1439); mmax 3059, 1713, 1633, 1589, 1563, 1517, 1334, 1304,
851, 752 and 734; dH (300 MHz, CDCl3) 1.6–2.2 (6 H, m), 3.16
(2 H, d J 7, 3-H2), 3.22 (1 H, pent, J 7.5, 1ꢀ-H), 3.84 (2 H, s, 1-
H2), 5.85 (2 H, br. m, 2-H and 4-H) and 7.1–7.6 (4 H, m, ArH); dC
(75 MHz, CDCl3) 17.94, 28.47, 39.85, 40.76, 47.07, 117.57, 126.24,
128.07, 128.67, 130.40, 133.72, 140.16 and 151.68; m/z (CI) 200
(M+ + 1, 100%).
5-Cyclopentyl-2-(2-nitrophenylsulfonyl)-2,3-dihydro-[1H]-2-
benzazepine 95
5-Cyclobutyl-2-[3-(N-2-nitrophenylsulfonyl-N-phenylmethyl)-
aminopropanoyl]-2,3-dihydro-[1H]-2-benzazepine 83
A solution of the dienylamine 94 (1.00 g, 2.40 mmol) in
dichloromethane (100 cm3) was degassed by repeated freezing
under a nitrogen atmosphere and thawing under reduced pressure.
Grubbs’ II catalyst (99 mg, 0.174 mmol) was added and the
O-(Benzotriazol-1-yl)-N,N,Nꢀ,Nꢀ-tetramethyluronium tetraflu-
oroborate (TBTU) (177.5 mg, 0.553 mmol) and di-
isopropylethylamine (130 mg, 1.01 mmol) were added to
the sulfonylaminopropanoic acid 81 (183 mg, 0.50 mmol) in
dichloromethane (3.2 cm3) at 0 ◦C and the reaction mixture
was stirred for 15 min before the dihydrobenzazepine 82
(100 mg, 0.50 mmol) in dichloromethane (1 cm3) was added.
The reaction mixture was stirred at room temperature overnight,
dichloromethane (10 cm3) was added and the mixture was washed
with aqueous hydrogen chloride (3 × 15 cm3), deionised water
(1 × 15 cm3), saturated aqueous ammonium chloride (3 ×
15 cm3) and deionised water (1 × 15 cm3) then dried (MgSO4)
and concentrated under reduced pressure. Chromatography of
the residue using light petroleum–ethyl acetate (1 : 1) containing
triethylamine (1%) as eluent gave the title compound 83 (215 mg,
79%) as an oil (found: M+ + H, 546.2069. C30H32N3O5S requires
◦
resulting mixture was heated in a sealed tube at 45 C for 24 h.
It was then filtered and concentrated under reduced pressure.
Chromatography of the residue using dichloromethane as eluent
gave the title compound 95 (380 mg, 40%) as a colourless
oil (found: M+ + Na, 421.1189. C21H22N2O4SNa requires M,
421.1192); mmax 1540, 1354, 1163, 1126, 1065, 914 and 777 cm−1;
dH (500 MHz, CDCl3) 1.36 (2 H, m), 1.54–1.68 (4 H, m), 1.84
(2 H, m), 2.98 (1 H, m), 3.61 (2 H, d J 7.5, 3-H2), 4.24 (2 H, s,
1-H2), 5.89 (1 H, dt, J 1.5, 7.5, 4-H), 7.29 (1 H, m, ArH), 7.35–
7.41 (3 H, m, ArH), 7.64–7.72 (3 H, m, ArH) and 8.03 (1 H, dd,
J 1.5, 7.5, ArH); dC (125 MHz, CDCl3) 152.15, 141.89, 133.31,
131.87, 130.17, 128.90, 128.36, 127.53, 127.51, 126.76, 126.61,
124.58, 116.76, 49.61, 45.22, 43.40, 32.03 and 24.82; m/z (ES)
437 (100%) and 421 (M+ + 23, 25).
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(4RS,5SR)-5-Cyclopentyl-2-(3-phenylmethylamino)propyl-4,5-
dihydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepine 100
chloride (149 mg, 0.673 mmol) were added to the 2-
aminopropyltetrahydrobenzazepine 100 (43 mg, 0.11 mmol) in
acetone (5 cm3) and water (3.25 cm3) and the solution was stirred
for 4 h at room temperature then extracted with ethyl acetate
(2 × 15 cm3). The organic extracts were dried (MgSO4) and
concentrated under reduced pressure to afford the title compound
101 as an oil used without further purification (found: M+ + H,
580.2481. C31H38N3O6S requires M, 580.2476); mmax 3435, 1543,
1371 and 1162 cm−1; dH (500 MHz, CDCl3) 0.8 (1 H, m), 1.2 (2 H,
m), 1.35–1.63 (7 H, m), 2.18, 2.28 and 2.44 (each 1 H, m), 2.68–
2.85 (2 H, m), 3.14 (2 H, m, 3-H2), 3.32 and 3.57 (each 1 H, d,
J 10, 1-H), 3.64 (1 H, m, 4-H), 4.30 and 4.42 (each 1 H, d, J 12,
NHCHPh), 6.86 (1 H, d, J 7, ArH), 7.02–7.2 (7 H, m, ArH), 7.47
(1 H, dt, J 1.5, 7, ArH), 7.5–7.6 (2 H, m, ArH) and 7.70 and 7.80
(each 1 H, d, J 7.5, ArH); m/z (ES) 580 (M+ + 1, 100%).
N-Methylmorpholine-N-oxide (4.2 mg, 0.0413 mmol) and
osmium tetraoxide (1 mg, 0.00376 mmol) were added to the
dihydrobenzazepine 97 (21 mg, 0.0376 mmol) in acetone (1 cm3),
tert-butanol (1 cm3) and water (270 lL) and the mixture was
stirred for 16 h at room temperature then was poured into rapidly
stirred aqueous sodium sulfite (5 cm3). The mixture was extracted
with ethyl acetate, dried (Na2SO4) and concentrated under reduced
pressure. Chromatography of the residue using ethyl acetate–light
petroleum (3 : 7) as eluent gave 5-cyclopentyl-4,5-dihydroxy-2-
[3-N-(2-nitrophenylsulfonyl)-N-(phenylmethyl)amino]propanoyl-
2,3,4,5-tetrahydro-[1H]-2-benzazepine 98 (117 mg, 91%),
a
mixture of rotamers, as a colourless oil (found: M+ + H, 594.2272.
C31H36N3O7S requires M, 594.2268); mmax 3436, 1631, 1543, 1452,
1371 and 1162 cm−1; m/z (ES) 616 (100%) and 594 (M+ + 1, 50).
Potassium carbonate (49 mg, 0.36 mmol) and thiophenol
(14.5 lL, 0.134 mmol) were added to 2-nitrobenzene sulfonamide
98 (59 mg, 0.103 mmol) in N,N-dimethylformamide (1.5 cm3) and
the solution was stirred for 24 h. Water (3 cm3) was added and the
mixture extracted with ethyl acetate (3 × 5 cm3), dried (MgSO4)
and concentrated under reduced pressure. Chromatography
of the residue using methanol–ethyl acetate (1 : 4) containing
triethylamine (1%) as eluent gave 5-cyclopentyl-4,5-dihydroxy-2-
[3-(N-phenylmethyl)aminopropanoyl]-2,3,4,5-tetrahydro-[1H]-2-
benzazepine 99 (22 mg, 75%), a mixture of rotamers, as a colourless
oil (found: M+ + H, 409.2487. C25H33N2O3 requires M, 409.2486);
mmax 3412, 1633 and 1453 cm−1; m/z (ES) 409 (M+ + 1, 100%).
Borane–tetrahydrofuran complex (1 M in THF; 7.72 mmol,
7.72 cm3) was added to the 2,3,4,5-tetrahydro-[1H]-2-benzazepine
99 (590 mg, 1.54 mmol) in THF (15 cm3) and the mixture
was stirred for 16 h at room temperature. Aqueous hydrogen
chloride (1 M; 1 cm3) and water (1 cm3) were added and the
reaction mixture was heated at 80 ◦C for 1 h then cooled and
extracted with ethyl acetate (3 × 5 cm3). The organic extracts
were dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using methanol–ethyl acetate (1 :
4) containing triethylamine (1%) gave the title compound 100
(360 mg, 60%) as a colourless oil (found: M+ + H, 395.2688.
C25H35N2O2 requires M, 395.2693); mmax 3391, 1453, 1320 and
1062 cm−1; dH (500 MHz, CDCl3) 0.75–0.86 (2 H, m), 1.18–1.26
(2 H, m), 1.41–1.67 (6 H, m), 1.82 (1 H, m), 2.26 (1 H, m), 2.51–2.68
(4 H, m, 2 × CH2), 2.87 (1 H, d, J 13.5, 3-H), 3.10 (1 H, br. s, OH),
3.15 (1 H, dd, J 13.5, 3, 3-Hꢀ), 3.47 (1 H, dd, J 14.5, 2, 1-H), 3.57
and 3.62 (each 1 H, d, J 13, NHCHPh), 3.79 (1 H, d, J 14.5, 1-Hꢀ),
3.88 (1 H, m, 4-H), 6.59 (1 H, d, J 7, ArH), 7.01 (1 H, m, ArH),
7.10 (1 H, dt, J 7.5, 1, ArH), 7.16–7.20 (5 H, m, ArH) and 7.75
(1 H, d, J 8, ArH); dC (125 MHz, CDCl3) 25.00, 25.61, 26.18, 26.90,
27.30, 44.53, 47.71, 53.40, 59.01, 59.30, 64.55, 74.69, 80.41, 127.17,
127.29, 128.75, 128.97, 129.34, 129.51, 130.42, 130.56, 135.43 and
144.48; m/z (ES) 396 (25%) and 395 (M+ + 1, 100).
5-Cyclopentyl-2-[3-(N-2-nitrophenylsulfonyl-N-phenylmethyl)-
aminopropyl]-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-
benzazepin-4-one 102
Pyridine (19 mg, 0.248 mmol) was added to the Dess–Martin
periodinane (21 mg, 0.049 mmol) in dichloromethane (1 cm3) and
the mixture was stirred for 20 min then added to the 4,5-dihydroxy-
2,3,4,5-tetrahydro-[1H]-2-benzazepine 101 (24 mg, 0.0414 mmol)
in dichloromethane (1 cm3). After 2 h, aqueous sodium sulfite
(1 cm3) was added and the mixture was stirred for 1 h then
extracted with dichloromethane (3 × 5 cm3). The organic extracts
were dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using methanol–ethyl acetate (1 :
4) containing triethylamine (1%) as eluent gave the title compound
102 (17 mg, 60%) as a colourless oil (found: M+ + H, 578.2318.
C31H36N3O6S requires M, 578.2319); mmax 3430, 1649, 1452, 1364
and 1076 cm−1; dH (500 MHz, CDCl3) 0.80–1.65 (10 H, m), 2.05–
2.18 (2 H, m, 1ꢀ-H2), 2.90 (1 H, quin, J 8.5, 1ꢀꢀ-H), 3.18 and 3.28
(each 1 H, m, 3ꢀ-H), 3.40 (1 H, d, J 15), 3.74 (1 H, d, J 16) 3.92
(1 H, d, J 15), 4.23 (1 H, d, J 16), 4.34 (1 H, br. s, OH), 4.41 and
4.44 (each 1 H, d, J 14, NHCHPh), 6.93 (1 H, d, J 7.5, ArH), 7.18
(1 H, t, J 7, ArH), 7.27–7.33 (5 H, m, ArH), 7.58–7.71 (4 H, m,
ArH) and 7.83 and 7.96 (each 1 H, d, J 8, ArH); m/z (ES) 601
(25%), 600 (70) and 578 (M+ + 1, 100).
5-Cyclopentyl-2-[3-(phenylmethylamino)propyl]-5-hydroxy-
2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one 103
Potassium carbonate (49 mg, 0.36 mmol) and thiophenol (19 mg,
0.173 mmol) were added to the 2-nitrophenylsulfonamide 102
(100 mg, 0.173 mmol) in N,N-dimethylformamide (3.5 cm3) and
the solution was stirred for 24 h. Water (3 cm3) was added and the
mixture was extracted with ethyl acetate (3 × 5 cm3). The organic
extracts were dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using methanol–ethyl
acetate (1 : 4) containing triethylamine (1%) as eluent gave the title
compound 103 (50 mg, 75%) as a colourless oil (found: M+ + H,
393.2542. C25H33N2O2 requires M, 393.2537); mmax 3437, 1668,
1520, 1454, 1361, 1208, 1176 and 1026 cm−1; dH (500 MHz, CDCl3)
0.80 (1 H, m), 1.08–1.70 (9 H, m), 2.27 and 2.55 (each 2 H, m,
1ꢀ-H2 and 3ꢀ-H2), 3.03 (1 H, quin, J 8, 1ꢀꢀ-H), 3.48 (1 H, d, J 15.5,
1-H), 3.69 (2 H, s, CH2Ph), 3.83 (1 H, d, J 16, 3-H), 3.98 (1 H, d,
J 15.5, 1-Hꢀ), 4.32 (1 H, d, J 16, 3-Hꢀ), 4.38 (1 H, br. s, NH), 6.98
5-Cyclopentyl-2-[3-(N-2-nitrophenylsulfonyl-N-phenylmethyl)-
aminopropyl]-4,5-dihydroxy-2,3,4,5-tetrahydro-
[1H]-2-benzazepine 101
Sodium carbonate (79 mg, 0.739 mmol), tetra-n-butylammonium
iodide (25 mg, 0.067 mmol) and 2-nitrophenylsulfonyl
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(1 H, d, J 7, ArH), 7.10–7.16 (6 H, m, ArH), 7.42 (1 H, m, ArH)
and 7.78 (1 H, dd, J 8, 1, ArH); m/z (ES) 393 (M+ + 1, 100%).
concentrated under reduced pressure. Chromatography of the
residue using methanol–ether (up to 10% methanol) containing
triethylamine (1%) as eluent gave the title compound 117 (46 mg,
100%) as a dark coloured oil (found: M+ + H, 252.1389.
C14H19FNO2 requires M, 252.1394); mmax 3318, 1610, 1590, 1490,
1445, 1412, 1238, 1144, 1098, 1074, 1056, 1002, 981, 909, 865, 815
and 732 cm−1; dH (300 MHz, CDCl3) 1.34 (1 H, m), 1.69–1.92 (3 H,
m), 2.05–2.31 (2 H, m), 2.85 (1 H, m, 5-CH), 3.14 (1 H, dd, J 13.5,
1.0, 3-H), 3.24 (1 H, dd, J 13.5, 4.5, 3-Hꢀ), 3.69 (1 H, dd, J 4.5,
1, 4-H), 3.84 and 4.02 (each 1 H, d, J 15, 1-H), 6.75 (1 H, dd, J
9.5, 3, 9-H), 6.95 (1 H, td, J 8.5, 3, 7-H) and 7.79 (1 H, dd, J 9, 6,
6-H); dC (75 MHz, CDCl3) 17.90, 21.89, 22.09, 40.13, 52.36, 56.17,
73.40, 80.10, 113.39 and 113.66 (d, 2JC-F 19.5), 116.37 and 116.65
(d, 2JC-F 21.5), 131.52 and 131.62 (d, 3JC-F 7.5), 137.54 and 137.51
(d, 4JC-F 3), 139.19 and 139.27 (d, 3JC-F 6.5) and 159.94 and 163.20
(d, 1JC-F 244.5); m/z (ES) 252 (M+ + 1, 100%).
5-Cyclobutyl-8-fluoro-2-(2-nitrophenyl)sulfonyl-2,3-dihydro-[1H]-
2-benzazepine 115
Grubbs’ II catalyst (313 mg, 5 mol%) was added to the diene
114 (3.20 g, 7.44 mmol) in degassed dichloromethane (500 cm3)
at room temperature under nitrogen and the reaction was heated
under reflux for 20 h then filtered through celite and concentrated
under reduced pressure. Chromatography of the residue using
ether–light petroleum (1 : 1) as eluent gave the title compound 115
(2.90 g, 97%) (found: M+, 402.1041. C20H19FN2O4S requires M,
402.1050); mmax 1549, 1492, 1461, 1377, 1355, 1244 and 1170 cm−1;
dH (300 MHz, CDCl3) 1.58–2.12 (6 H, m, 3 × CH2), 3.33 (1 H, m,
1ꢀ-H), 3.55 (2 H, d, J 7, 3-H2), 4.16 (2 H, s, 1-H2), 5.77 (1 H, td, J
7, 2, 4-H), 6.91–7.02 (2 H, m, ArH), 7.16 (1 H, dd, J 8, 5.5, ArH),
7.70–7.52 (3 H, m, ArH) and 7.94 (1 H, m, ArH); dC (75 MHz,
CDCl3) 17.75, 28.30, 39.63, 43.09, 48.80, 115.22 and 115.50 (d,
2-Butyl-5-cyclobutyl-8-fluoro-2,3,4,5-tetrahydro-[1H]-2-
benzazepine-4,5-diol 118
2
2JC-F 21), 116.41 and 116.70 (d, JC-F 22), 116.93, 124.10, 127.77
and 127.88 (d, 3JC-F 8), 130.54, 131.56, 132.70, 133.54, 135.33 and
135.42 (d, 3JC-F 7), 135.83 and 135.87 (d, 4JC-F 3), 148.07, 150.19,
Sodium cyanoborohydride (54 mg, 1.0 eq) and few drops of
concentrated aqueous hydrogen chloride were added to a mixture
of the diol 117 (200 mg, 0.86 mmol) and butanal (185 mg,
2.38 mmol) in methanol (15 cm3) and the mixture was stirred at
room temperature for 12 h. Water and potassium carbonate were
added and the mixture was extracted with dichloromethane, then
filtered, dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue using ethyl acetate as eluent gave
the title compound 118 (238 mg, 90%) as an oil (found: M+,
307.1949. C18H26FNO2 requires M, 307.1947); mmax 3449–3409,
1609, 1587, 1491, 1459, 1405, 1372, 1304, 1240, 1143, 1098, 1070,
1011 cm−1; dH (300 MHz, CDCl3) 0.84 (3 H, t, J 7, 4ꢀ-H3), 1.16
(3 H, m), 1.32–1.52 (2 H, m), 1.57–1.78 (3 H, m), 2.0–2.2 (2 H, m),
2.4–2.6 (2 H, m, 1ꢀ-H2), 2.68 (1 H, m, CH), 2.8 (1 H, d, J 13, 3-H),
3.94 (1 H, d, J 9, 4-OH), 3.00 (1 H, m, 3-Hꢀ), 3.06 (1 H, s, 5-OH),
3.48 (1 H, dd, J 16, 1.5, 1-H), 3.58 (1 H, dd, J 9, 6, 4-H), 3.63 (1 H,
d, J 16, 1-Hꢀ), 6.67 (1 H, dd, J 9.5, 2.5, ArH), 6.84 (1 H, td, J 8.5,
2.5, ArH) and 7.68 (1 H, dd, J 9, 6, ArH); dC (75 MHz, CDCl3)
13.89, 17.63, 20.30, 21.58, 21.70, 29.51, 39.73, 59.30, 59.53, 62.76,
72.74, 79.24, 113.13 and 113.37 (d, 2JC-F 18), 116.36 and 116.64 (d,
1
and 160.06 and 163.36 (d, JC-F 247.5); m/z (CI) 420 (M+ + 18,
40%), 297 (20) and 232 (100).
(4RS,5SR)-5-Cyclobutyl-8-fluoro-2-(2-nitrophenyl)sulfonyl-
2,3,4,5-tetrahydro-[1H]-2-benzazepine-4,5-diol 116
N-Methylmorpholine-N-oxide (592 mg, 4.98 mmol) was added to
the dihydrobenzazepine 115 (500 mg, 1.244 mmol) and osmium
tetraoxide (48 mg, 15 mol%) in acetone and water (5 : 1, 60 cm3)
and the mixture was stirred at room temperature for 48 h. Aqueous
sodium sulfite was added and the mixture was concentrated under
reduced pressure. Chromatography of the residue using ether as
eluent followed by repeated chromatography using methanol–
ether (1 : 19) as eluent gave the title compound 116 (526 mg, 97%)
as an oil (found: M+ + NH4, 454.1445. C20H25FN3O6S requires
M, 454.1448); mmax 3542–3435, 1609, 1590, 1541, 1461, 1376, 1241,
1165, 1002 and 905 cm−1; dH (300 MHz, CDCl3) 1.37 (1 H, m),
1.70–1.90 (3 H, m), 2.08–2.38 (2 H, m), 2.53 (1 H, d, J 9, 4-OH),
2.85 (1 H, m), 3.22 (1 H, d, J 2, 5-OH), 3.53 (1 H, d, J 15, 3-H),
3.86 (1 H, ddd, J 9, 4, 2, 4-H), 4.02 (1 H, ddd, J 15, 4, 2, 3-Hꢀ), 4.42
(1 H, d, J 16, 1-H), 4.75 (1 H, dd, J 16, 2, 1-Hꢀ), 6.95–7.10 (2 H,
m, ArH), 7.69–7.89 (4 H, m, ArH) and 8.14 (1 H, m, ArH); dC
(125 MHz, CDCl3) 17.97, 22.01, 22.20, 39.87, 51.28, 54.12, 66.27,
72.74, 79.47, 114.98 and 115.14 (d, 2JC-F 20), 117.41 and 117.58 (d,
2JC-F 21.5), 124.84, 131.82 and 131.88 (d, 3JC-F 7.5), 132.01, 132.48,
134.55, 135.37 and 135.43 (d, 3JC-F 7.5), 137.04 and 137.07 (d, 4JC-F
3
2JC-F 21), 130.97 and 131.07 (d, JC-F 7.5), 137.37 and 137.41 (d,
4JC-F 3), 137.52 and 137.60 (d, 3JC-F 6), and 159.61 and 162.87 (d,
1JC-F 244.5); m/z (CI) 309 (M+ + 2, 30%) and 308 (100%).
(4RS,5SR)-5-Cyclobutyl-4,5-dihydroxy-8-fluoro-2-[3-(N-2-
nitrophenylsulfonyl-N-phenylmethyl)-aminopropanoyl]-2,3,4,5-
tetrahydro-[1H]-2-benzazepine 121
1
2.5), 148.32, and 161.02 and 162.98 (d, JC-F 245); m/z (CI) 454
Thiophenol (305 lL, 2.98 mmol) was added to benzazepine
115 (920 mg, 2.29 mmol) and potassium carbonate (1.105 g,
8.01 mmol) in N,N-dimethylformamide (19 cm3) and the reaction
mixture was stirred at room temperature for 16 h. Water (90 cm3)
was then added and the aqueous phase was extracted with
ethyl acetate (5 × 90 cm3). The organic extracts were dried
(Na2SO4) and concentrated under reduced pressure to give the
crude dihydrobenzazepine 119 (479 mg, ca. 100%) which was used
without purification.
(M+ + 18, 20%), 419 (15), 407 (47), 250 (90) and 94 (100).
(4RS,5SR)-5-Cyclobutyl-8-fluoro-2,3,4,5-tetrahydro-[1H]-2-
benzazepine-4,5-diol 117
Thiophenol (56 lL, 0.55 mmol) was added to benzazepine
116 (80 mg, 0.183 mmol) and potassium carbonate (101 mg,
0.733 mmol) in acetonitrile (3.1 cm3) and the reaction mixture
was stirred at room temperature for 16 h. Water (30 cm3) was then
added and the aqueous phase was extracted with ethyl acetate
(4 × 30 cm3). The organic extracts were dried (Na2SO4) and
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDC)
(746 mg, 3.89 mmo) and 4-dimethylaminopyridine (28 mg,
2154 | Org. Biomol. Chem., 2008, 6, 2138–2157
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0.23 mmol) were added to the crude acid 81 (1.09 g, 2.98 mmol)
in N,N-dimethylformamide (6.5 cm3) and the reaction mixture
was stirred for 15 min. The amine 119 (497 mg, 2.29 mmol)
in N,N-dimethylformamide (4.5 cm3) was then added and the
mixture was stirred for 16 h at room temperature before aqueous
hydrogen chloride (1 M, 90 cm3) and dichloromethane (200 cm3)
were added. The organic layer was washed with aqueous hydrogen
chloride (1 M, 90 cm3) and saturated aqueous sodium hydrogen
carbonate (90 cm3), dried (MgSO4) and concentrated under
reduced pressure to give the crude amide 120 (936 mg, 73%)
(found: M+ + H, 564.1969. C30H31FN3O5S requires M, 564.1963)
as an oil used without further purification; m/z (ES) 602 (M+ +
39, 16%), 593 (100), 586 (15) and 564 (5).
acetate–light petroleum (50 : 50) containing triethylamine (1%)
gave the hydroxy-amide 121 (104 mg, 95%) as a white foam.
(4RS,5SR)-5-Cyclobutyl-4,5-dihydroxy-8-fluoro-2-[3-(N-
phenylmethyl)aminopropanoyl]-2,3,4,5-tetrahydro-[1H]-2-
benzazepine 122
Thiophenol (125 lL, 1.22 mmol) was added to the amide
121 (560 mg, 0.94 mmol) and potassium carbonate (453 mg,
3.28 mmol) in N,N-dimethylformamide (19 cm3) and the mixture
was stirred at room temperature for 16 h. Water (90 cm3) was then
added and the aqueous phase was extracted with ethyl acetate
(4 × 140 cm3). The organic extracts were dried (Na2SO4) and
concentrated under reduced pressure. Chromatography of the
residue using methanol–dichloromethane (up to 5% methanol)
containing triethylamine (1%) as eluent gave the title compound
122 (336 mg, 87%) as a pale yellow foam (found: M+ + H, 413.2229.
C24H30FN2O3 requires M, 413.2235); mmax 3402, 1631, 1590, 1490,
1455, 1372, 1302, 1267, 1240, 1142, 1092, 1003, 980, 816, 736 and
700 cm−1; dH (500 MHz, CDCl3) 1.13–2.92 (11 H, m, cyclobutyl-H,
5-CH, 2ꢀ-H2 and 3-H2), 3.10 (0.33 H, d, J 14.5, 3-H), 3.31 (3 H,
br s, 2 × OH and NH), 3.36–3.52 (2.67 H, m, 3-H and NCH2Ph),
3.60 (0.67 H, d, J 3, 4-H), 3.70 (0.33 H, d, J 4, 4-H), 3.94 (0.67 H,
d, J 15, 1-H), 3.99 (0.67 H, dd, J 15.5, 2, 3-Hꢀ), 4.39 and 4.48 (each
0.33 H, d, J 16.5, 1-H), 4.70 (0.33 H, d, J 14, 3-Hꢀ), 5.10 (0.67 H, d,
J 15, 1-Hꢀ), 6.74 (1 H, m, 9-H and 7-H), 6.80 (0.33 H, td, J 8.5, 2.5,
7-H), 6.95 (0.67 H, dd, J 9, 2.5, 9-H), 7.03 (1.33 H, d, J 7, ArH),
7.06 (0.67 H, d, J 7, ArH), 7.15–7.28 (3 H, m, ArH) and 7.56 (1 H,
m, 6-H); dC (125 MHz, CDCl3) 17.51, 17.53, 21.69, 21.72, 21.98,
22.01, 31.40, 33.00, 39.63, 40.22, 44.75, 45.70, 48.29, 51.44, 51.81,
53.46, 54.00, 54.18, 73.16, 73.85, 78.87, 79.19, 113.65 and 113.81
(d, 2JC-F 20), 114.19 and 114.35 (d, 2JC-F 19), 115.72 and 115.89 (d,
2JC-F 22), 117.56 and 117.73 (d, 2JC-F 21), 127.29, 127.55, 128.4,0
128.57, 128.62, 131.02, 131.08, 132.08, 132.15, 135.65, 135.71,
137.04, 137.07, 137.63, 160.16, 160.20, 162.16, 171.80 and 173.63;
m/z (ES) 435 (M+ + Na, 35%) and 413 (M+ + 1, 100).
N-Methylmorpholine-N-oxide (214 mg, 1.83 mmol) and os-
mium tetraoxide (42 mg, 0.17 mmol) were added to the crude
amide 120 (936 mg, 1.66 mmol) in acetone (26 cm3), tert-butanol
(26 cm3) and water (13 cm3). The reaction mixture was stirred
for 16 h at room temperature then saturated aqueous sodium
sulfite (140 cm3) was added. The mixture was then stirred for a
further 30 min before extracting with ethyl acetate (4 × 180 cm3).
The organic layers were dried (Na2SO4) and concentrated under
reduced pressure. Chromatography of the residue using ethyl
acetate–light petroleum (50 : 50) containing triethylamine (1%)
as eluent gave the title compound 121 (936 mg, 94%), a 50 : 50
mixture of rotamers, as a white foam (found: M+ + Na, 620.1837.
C30H32FN3NaO7S requires M, 620.1837); mmax 3430, 1633, 1590,
1543, 1493, 1455, 1371, 1346, 1267, 1239, 1163, 1126, 1095, 999,
982, 939, 852, 816, 776, 735 and 703 cm−1; dH (500 MHz, CDCl3–
D2O) 1.22 (1 H, m), 1.58–1.80 (2.5 H, m), 1.94–2.06 (2 H, m),
2.06–2.20 (1.5 H, m), 2.33 (0.5 H, m), 2.47–2.62 (1.5 H, m), 2.77
(0.5 H, m), 3.04 (0.5 H, d, J 15), 3.31–3.48 (2 H, m), 3.53 (0.5 H,
m), 3.62 (0.5 H, d, J 3.5), 3.72 (0.5 H, dd, J 15.5, 3.5), 3.75 (0.5 H,
d, J 3), 3.87 (0.5 H, d, J 15), 4.23 (1 H, s), 4.33 (0.5 H, d, J 15.5),
4.38 (0.5 H, d, J 15.5), 4.43 (0.5 H, d, J 15.5), 4.50 (0.5 H, d, J
15.5), 4.95 (0.5 H, d, 15), 6.43 (0.5 H, dd, J 8.5, 2.5, 9-H), 6.82
(0.5 H, td, J 8.5, 2.5, 7-H), 6.85–6.91 (1 H, m, 7-H and 9-H),
7.15–7.28 (5 H, m, ArH), 7.47 (0.5 H, t, J 7.5, ArH), 7.53–7.64
(3 H, m, 6-H and ArH), 7.69 (0.5 H, dd, J 8.5, 6, 6-H), 7.78 and
7.87 (each 0.5 H, d, J 8, ArH); dC (125 MHz, CDCl3) 16.50, 20.60,
20.66, 20.86, 20.99, 31.22, 31.77, 38.52, 39.09, 43.56, 43.58, 46.92,
49.77, 49.84, 51.85, 52.38, 52.45, 72.16, 72.63, 77.89, 78.08, 112.85
(4RS,5SR)-5-Cyclobutyl-4,5-dihydroxy-8-fluoro-2-[3-(N-phenyl-
methyl)aminopropyl]-2,3,4,5-tetrahydro-[1H]-2-benzazepine 123
A solution of the amide 122 (319 mg, 0.77 mmol) and lithium
aluminium hydride (235 mg, 6.19 mmol) in terahydrofuran (7 cm3)
was h◦eated under reflux for 4 h. The mixture was then cooled
to 0 C and aqueous sodium hydroxide (2 M, 30 cm3) was
added cautiously followed by ethyl acetate (25 cm3). The aqueous
phase was extracted with ethyl acetate (2 × 25 cm3) and the
organic extracts were washed with water, brine and dried (MgSO4).
Concentration under reduced pressure gave the title compound 123
(327 mg) as a pale yellow oil used without further purification
(found: M+ + H, 399.2445. C24H32FN2O2 requires M, 399.2442);
mmax 3435, 1610, 1590, 1492, 1454, 1242, 1144, 1077, 1005, 845,
814, 735 and 699 cm−1; dH (500 MHz, CDCl3) 1.20–1.29 (2 H, m),
1.60–1.77 (5 H, m, 2ꢀ-H2, cyclobutyl-H and NH), 2.01–2.18 (2 H,
m), 2.54–2.73 (5 H, m, 5-CH, 1ꢀ-H2 and 3ꢀ-H2), 2.80 (1 H, d, J 13,
3-H), 2.99–3.08 (2 H, m, 3-Hꢀ and OH), 3.47 (1 H, dd, J 14.5, 2,
1-H), 3.59–3.72 (4 H, m, 1-Hꢀ, 4-H and NCH2Ph), 6.66 (1 H, dd, J
9, 3, 9-H), 6.86 (1 H, td, J 8.5, 2.5, 7-H), 7.10–7.24 (5 H, m, ArH)
and 7.70 (1 H, dd, J 8.5, 6, 6-H); dC (75 MHz, CDCl3) 17.91, 21.87,
22.04, 27.92, 39.99, 47.63, 54.06, 58.43, 59.48, 63.38, 73.06, 79.43,
113.52 and 113.78 (d, 2JC-F 19.5), 116.66 and 116.95 (d, 2JC-F 21.5),
2
2
and 113.01 (d, JC-F 20), 113.17 and 113.32 (d, JC-F 19), 115.04
2
2
and 115.21 (d, JC-F 22), 116.61 and 116.78 (d, JC-F 22), 123.22,
123.24, 127.00, 127.23, 127.43, 127.70, 127.85, 129.75, 129.91,
129.98, 130.04, 130.58, 130.64, 130.82, 130.84, 131.78, 131.95,
132.50, 132.68, 133.50, 133.56, 134.64, 134.70, 134.90, 135.03,
135.13, 136.47, 136.49, 146.93, 146.98, 159.24 and 161.26 (d, 1JC-F
1
246.5), 159.50 and 161.46 (d, JC-F 245), 169.43 and 170.77; m/z
(ES) 620 (M+ + 23, 100%) and 598 (M+ + 1, 4).
TBTU (65 mg, 0.20 mmol) was added to the acid 81
(67 mg, 0.18 mmol) and Hu¨nig’s base (64 lL, 0.37 mmol)
in dichloromethane (1.0 cm3) and the mixture was stirred for
15 min. The amine 117 (46 mg, 0.18 mmol) in dichloromethane
(0.7 cm3) was then added and the mixture was stirred for 16 h at
room temperature. Saturated aqueous sodium hydrogen carbonate
(20 cm3) and dichloromethane (20 cm3) were added. The aqueous
layer was washed with dichloromethane (3 × 20 cm3) and the
organic extracts were dried (Na2SO4) and concentrated under
reduced pressure. Chromatography of the residue using ethyl
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127.34, 128.37, 128.69, 131.33 and 131.43 (d, 3JC-F 8), 137.77 and
(3 H, m, 1ꢀ-H2 and cyclobutyl-H), 3.11–3.31 (4 H, m, 3-H, 5-CH
and 3ꢀ-H2), 3.55–3.62 (2 H, m, 1-H and 3-Hꢀ), 3.96 (1 H, d, J 16.5,
1-Hꢀ), 4.40 and 4.44 (each 1 H, d, J 15.5, NHCHPh), 4.61 (1 H,
br s, 5-OH), 6.54 (1 H, dd, J 9, 2.5, 9-H), 6.85 (1 H, td, 8.5, 2.5,
7-H), 7.18–7.26 (5 H, m, ArH), 7.51–7.67 (4 H, m, ArH and 6-H)
and 7.89 (1 H, d, J 8, ArH); dC (125 MHz, CDCl3) 16.05, 20.33,
20.52, 24.39, 40.79, 44.47, 49.68, 50.75, 58.20, 62.52, 82.70, 112.90
4
1
137.85 (d, JC-F 3), 159.90 and 163.16 (d, JC-F 245.5); m/z (ES)
421 (M+ + 23, 19%) and 399 (M+ + 1, 100).
(4RS,5SR)-5-Cyclobutyl-4,5-dihydroxy-8-fluoro-2-[3-(N-2-
nitrophenylsulfonyl-N-phenylmethyl)-aminopropyl]-2,3,4,5-
tetrahydro-[1H]-2-benzazepine 124
2
2
and 113.06 (d, JC-F 20), 115.15 and 115.32 (d, JC-F 21), 123.27,
3
2-Nitrobenzene sulfonyl chloride (167 mg, 0.75 mmol) in
dichloromethane (7 cm3) was added to the amine 123 (300 mg,
0.75 mmol) and Hu¨nig’s base (130 lL, 0.75 mmol) in
dichloromethane (5 cm3) and the mixture was stirred at room
temperature for 16 h. Water (20 cm3) was then added and the
aqueous phase was extracted with dichloromethane (4 × 20 cm3).
The organic extracts were washed with brine, dried (MgSO4)
and concentrated under reduced pressure. Chromatography of
the residue using ethyl acetate–light petroleum (50 : 50 → 100 :
0) containing triethylamine as eluent gave the title compound
124 (399 mg, 91%) as a pale foam (found: M+ + Na, 606.2047.
C30H34FN3NaO6S requires M, 606.2045); mmax 3468, 1609, 1590,
1543, 1494, 1455, 1372, 1348, 1265, 1242, 1162, 1126, 1076, 1003,
932, 852, 815, 780, 735, 700 and 652 cm−1; dH (500 MHz, CDCl3)
1.09–1.31 (2 H, m), 1.40–1.75 (4 H, m, 2ꢀ-H2 and cyclobutyl-H),
1.99–2.15 (2 H, m), 2.32 and 2.44 (each 1 H, m, 1ꢀ-H), 2.54–2.69
(2 H, m, 5-CH and OH), 2.69 (1 H, d, J 13, 3-H), 2.81 (1 H,
dd, J 13, 4.5, 3-Hꢀ), 2.97 (1 H, br s, OH), 3.16–3.24 (2 H, m,
3ꢀ-H2), 3.26 (1 H, d, J 15, 1-H), 3.49–3.55 (2 H, m, 1-Hꢀ and 4-
H), 4.39 and 4.45 (each 1 H, d, J 15.5, NHCHPh), 6.58 (1 H,
dd, J 9, 2.5, 9-H), 6.86 (1 H, td, 8.5, 2.5, 7-H), 7.15–7.25 (5 H,
m, ArH), 7.51–7.64 (3 H, m, ArH), 7.68 (1 H, dd, J 8.5, 6, 6-H)
and 7.87 (1 H, d, J 8, ArH); dC (125 MHz, CDCl3) 16.63, 20.55,
20.69, 25.24, 38.60, 44.99, 51.04, 55.50, 58.42, 61.39, 71.77, 78.14,
127.09, 127.22, 127.78, 128.46 and 128.52 (d, JC-F 7.5), 129.90,
4
130.66, 132.40, 132.54, 133.10 and 133.12 (d, JC-F 2.5), 134.61,
3
135.53 and 135.58 (d, JC-F 6.5), 146.88, 159.62 and 161.60 (d,
1JC-F 246.5) and 206.01; m/z (ES) 604 (M+ + 23, 100%), 582 (M+ +
1, 15) and 564 (9).
2-(3-Benzylaminopropyl)-5-cyclobutyl-8-fluoro-5-hydroxy-1,2,3,5-
tetrahydro-[1H]-2-benzazepin-4-one 126
Thiophenol (18 lL, 0.175 mmol) was added to the sulfonamide
125 (34 mg, 0.058 mmol) and potassium carbonate (32 mg,
0.234 mmol) in acetonitrile (0.98 cm3) and the mixture was
stirred for 16 h at room temperature. Water (20 cm3) and ether
(20 cm3) were added and the aqueous phase was extracted with
ether (3 × 20 cm3). The organic extracts were washed with
brine, dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue using ether–light petroleum (50 :
50 → 100 : 0) containing triethylamine (1%) followed by methanol–
ether (10 : 90) containing triethylamine (1%) as eluent gave the title
compound 126 (22 mg, 95%) as a pale oil (found: M+ + H, 397.2295.
C24H30FN2O2 requires M, 397.2286); mmax 3456, 3313, 3059, 3028,
1701, 1610, 1588, 1490, 1454, 1365, 1261, 1241, 1220, 1122, 1099,
1013, 977, 863, 810, 736, 699 cm−1; dH (500 MHz, CDCl3) 1.48–
1.75 (7 H, m, 2ꢀ-H2, cyclobutyl-H and NH), 1.81 and 2.16 (each
1 H, m), 2.35–2.46 (2 H, m, 1ꢀ-H2), 2.55–2.64 (2 H, m, 3ꢀ-H2), 3.42
(1 H, m, 5-CH), 3.45 and 3.68 (each 1 H, d, J 16, 3-H), 3.70 (2 H, s,
NCH2Ph), 3.79 and 4.10 (each 1 H, d, J 16.5, 1-H), 4.77 (1 H, br s,
5-OH), 6.68 (1 H, dd, J 9.5, 2.5, 9-H), 6.86 (1 H, td, J 8.5, 2.5,
7-H), 7.15–7.27 (5 H, m, ArH) and 7.65 (1 H, dd, J 9, 6, 6-H); dC
(125 MHz, CDCl3) 16.14, 20.50, 20.62, 26.24, 40.87, 45.98, 51.43,
52.80, 58.85, 62.85, 82.65, 112.87 and 113.03 (d, 2JC-F 20), 114.98
and 115.15 (d, 2JC-F 22), 126.15, 127.18, 127.46, 128.51 and 128.57
(d, 3JC-F 8), 133.20 and 133.23 (d, 4JC-F 2.5), 135.97 and 136.00 (d,
3JC-F 5.5), 139.01, 159.71 and 161.67 (d, 1JC-F 245) and 206.58; m/z
(ES) 419 (M+ + 23, 2%) and 397 (M+ + 1, 100).
2
2
112.40 and 112.56 (d, JC-F 20), 115.69 and 115.86 (d, JC-F 22),
123.17, 127.07, 127.19, 127.75, 129.94, 129.99 and 130.05 (d, 3JC-F
8), 130.65, 132.30, 132.55, 134.75, 136.03 and 136.08 (d, 3JC-F 7.5),
136.35 and 136.37 (d, 4JC-F 2.5), 146.91 and 159.29 and 161.24 (d,
1JC-F 244); m/z (ES) 606 (M+ + 23, 100%) and 584 (M+ + 1, 4).
5-Cyclobutyl-8-fluoro-5-hydroxy-2-[3-(N-2-nitrophenylsulfonyl-
N-phenylmethyl)aminopropyl]-2,3,4,5-tetrahydro-[1H]-
2-benzazepin-4-one 125
Dimethyl sulfoxide (26 lL, 0.36 mmol) in dichloromethane
(475 lL) was added dropwise to oxalyl chloride (19 lL, 0.22 mmol)
in dichloromethane (0.52 cm3) at −78 ◦C and the mixture was
stirred for 30 min before the diol 124 (42 mg, 0.07 mmol) in
dichloromethane (1 cm3) was added. The mixture was stirred
for 30 min then triethylamine (60 lL, 043 mmol) was added.
The mixture was allowed to warm to 0 ◦C and was stirred for
30 min before water (20 cm3) was added. Following extraction
with ether (4 × 20 cm3), the organic extracts were washed with
brine, dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue using ethyl acetate–light petroleum
(25 : 75 → 50 : 50) as eluent gave the title compound 125
(34 mg, 81%) as a pale yellow gum (found: M+ + Na, 604.1872.
C30H32FN3NaO6S requires M, 604.1888); mmax 3461, 3068, 3031,
1698, 1610, 1588, 1543, 1489, 1456, 1440, 1371, 1349, 1163, 1127,
1013, 910, 852, 780 and 734 cm−1; dH (500 MHz, CDCl3) 1.48–1.53
(3 H, m, 2ꢀ-H2 and cyclobutyl-H), 1.53–1.80 (4 H, m), 2.05–2.17
Crystal data for the 4,4-trimethylenedithiotetrahydrobenzazepine
20
C18H25NO2S2, M = 351.51, monoclinic, a = 10.712(6), b =
◦
3
˚
˚
11.368(4), c = 15.945(4) A, b = 103.78(3) , U = 1885.6(13) A ,
T = 296(1)◦, space group P 21/n (no. 142), Z = 2, l(CuKa) =
2.621 mm−1, 7554 reflections measured, 3619 unique (Rint = 0.041),
2942 reflections with I > 2.00 r(I) were used in the final refinement.
The final R = 0.055 for reflections with I > 2.00 r(I), wR2 = 0.169
(all data). Data deposited with the Cambridge Crystallographic
Data Centre, number CCDC 655337.‡
‡ CCDC reference numbers 655337 and 655338. For crystallographic data
in CIF or other electronic format see DOI: 10.1039/b801206g
2156 | Org. Biomol. Chem., 2008, 6, 2138–2157
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Crystal data for the 4,5-dihydroxy-2,3,4,5-tetrahydrobenzazepine
53
14 (a) A. P. Kozikowski, D. Ma, Y.-P. Pang, P. Shum, V. Likic, P. K. Mishra,
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115, 3957; (b) D. L. J. Clive, S. R. Magnuson, H. W. Manning and
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15 G. L. Stahl, R. Walter and C. W. Smith, J. Org. Chem., 1978, 43, 2285.
16 R. F. Borch, M. D. Bernstein and H. D. Durst, J. Am. Chem. Soc.,
1971, 93, 2897.
17 A. B. Smith III, T. A. Rano, N. Chida, G. A. Sulikowski and J. L. Wood,
J. Am. Chem. Soc., 1992, 114, 8008.
18 D. Brosius, L. E. Overman and L. Schwink, J. Am. Chem. Soc., 1999,
121, 700.
C18H27NO2, M = 289.41, triclinic, a = 7.783(2), b = 9.850(4),
◦
˚
c = 12.119(2) A, a = 110.81(2), b = 103.93(4), c = 97.43(2) , U =
◦
3
¯
˚
819.0(4) A , T = 293(1) , space group P1 (no. 2) Z = 4, l(MoKa) =
0.075 mm−1, 3092 measured reflections, 2860 unique reflection
(Rint = 0.015), 1644 reflections with I > 2.00 r(I) were used in the
final refinement. The final R = 0.056 for reflections with I > 2.00
r(I), wR2 = 0.1409 (all data). Data deposited with the Cambridge
Crystallographic Data Centre, number CCDC 655338.‡
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Acknowledgements
We thank Professor G. A. Morris and Dr M. J. Stchedoff for
NMR studies particularly in connection with confirmation of
the structure of hydroxyketone 55 and Mr S. Snee for help in
characterisation of novel compounds.
24 R. Stragies and S. Blechert, J. Am. Chem. Soc., 2000, 122, 9584; P. A.
Evans, J. E. Robinson and J. D. Nelson, J. Am. Chem. Soc., 1999, 121,
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