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

View Article Online / Journal Homepage / Table of Contents for this issue

PAPER

www.rsc.org/obc | Organic & Biomolecular Chemistry

Synthesis of 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones:

selective antagonists of muscarinic (M₃) receptors†

Benjamin Bradshaw,^aPaul Evans,^aJane Fletcher,^aAlan T. L. Lee,^aPaul G. Mwashimba,^aDaniel Oehlrich,^a

Eric J. Thomas,*^aRobin H. Davies,^bBenjamin C. P. Allen,^bKenneth J. Broadley,^cAmar Hamrouni^cand

Christine Escargueil^c

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 M₃receptors from

guinea pig ileum, these compounds had log₁₀K_Bvalues of up to 7.2 with selectivities over M₂receptors

from guinea pig left atria of approximately 40.

other sites, M₂receptors 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.¹The M₃receptor is prevalent in smooth muscle and

commercially available to treat urinary incontinence by the control

of M₃receptor antagonism.³More 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.²Preferential selectivity against other sub-types of

muscarinic receptors is important, the M₂receptor 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 M₃receptor.⁴The use of tetrahydro-[1H]-2-

benzazepines was seen to have two potential advantages. Firstly,

the alignment of a-helices on the bacteriorhodopsin receptor

structure⁵indicated that M₃selectivity 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 3⁶indicated that an a-hydroxy keto

group linked through a CH₂group 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

2138 | Org. Biomol. Chem., 2008, 6, 2138–2157

This journal is

The Royal Society of Chemistry 2008

©

View Article Online

an advantage in overall binding even in the presence of the

second nitrogen atom (pK_A∼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 log₁₀units 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 C₂or C₃linkage 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 5⁷was used

as an umpolung reagent to prepare intermediates for a ring-closing

reductive amination. In the second, more intensively investigated

approach, ring-closing metathesis,⁸which has been used to prepare

seven-membered ring heterocycles⁹including 2,3-dihydro-[1H]-

2-benzazepines,¹⁰was 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 diethyletherate⁷but, in our hands, this procedure

was complicated by competing loss of the Boc-group.¹¹However,

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 C¹²using

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,¹³although 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%).

This journal is

The Royal Society of Chemistry 2008

Org. Biomol. Chem., 2008, 6, 2138–2157 | 2139

©

View Article Online

1,2-Bis(hydroxymethyl)benzene was protected as its mono-tert-

butyldimethylsilyl ether 13¹⁴which 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

temperature¹⁵and generated the imine 18. This was reduced using

sodium cyanoborohydride¹⁶to 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 triﬂuoride¹⁷gave 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⁻¹indicative 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 temperature¹⁹was 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 dioxirane²⁰and 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 metathesis^9,10to 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%).

2140 | Org. Biomol. Chem., 2008, 6, 2138–2157

This journal is

The Royal Society of Chemistry 2008

©

View Article Online

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.¹⁰Initial studies were undertaken to conﬁrm

this approach in our hands. o-Ethenylbenzaldehyde 29²¹was

converted into the amine 30 by reductive amination and the amine

protected as its toluene p-sulfonyl (tosyl) and 2-nitrobenzene

sulfonyl (nosyl)²²derivatives 31 and 32. Ring-closing metathesis

using Grubbs’ I catalyst, see Fig. 2,^23,24gave 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 conditions²²gave the parent 2,3-dihydro-[1H]-2-benzazepine

35. Hydroxylation of the protected dihydrobenzazepines 33 and

34 using the Upjohn conditions in aqueous acetone²⁵gave

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 catalyst²³were 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,³¹see 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.³²In 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.²⁶However,

subsequently it was found to be more convenient to prepare ketone

7 from cyclobutyl phenyl carbinol 40²⁷by ortho lithiation²⁸and

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 periodinane²⁹gave the

ketone 7 in an excellent yield. This was converted into the alkene 43

using the Petasis reagent³⁰since 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-rearrangements³³and so it was

necessary to conﬁrm that the hydroxytetrahydrobenzazepine 55

This journal is

The Royal Society of Chemistry 2008

Org. Biomol. Chem., 2008, 6, 2138–2157 | 2141

©

View Article Online

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⁻¹indicated 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

58³⁵of 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-ol³⁶fol-

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.

2142 | Org. Biomol. Chem., 2008, 6, 2138–2157 This journal is The Royal Society of Chemistry 2008

©

View Article Online

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 80³⁸followed 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

This journal is

The Royal Society of Chemistry 2008

Org. Biomol. Chem., 2008, 6, 2138–2157 | 2143

©

View Article Online

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

2144 | Org. Biomol. Chem., 2008, 6, 2138–2157

This journal is

The Royal Society of Chemistry 2008

©

View Article Online

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 M₃and M₂receptors. 1-Bromo-2-bromomethyl-4-

ﬂuorobenzene 105³⁹is 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%).

This journal is

The Royal Society of Chemistry 2008

Org. Biomol. Chem., 2008, 6, 2138–2157 | 2145

©

View Article Online

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 log₁₀K_Bfor 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 M₃re-

ceptors in the guinea pig ileum was 6.7 with a selectivity over

the M₂receptors 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 M₃over the M₂receptors. However, the

simpler 2-butyltetrahydrobenzazepinone 55 was signiﬁcantly less

potent towards the M₃receptors, 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 M₃and 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 M₂muscarinic 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%).

2146 | Org. Biomol. Chem., 2008, 6, 2138–2157

This journal is

The Royal Society of Chemistry 2008

©

View Article Online

Table 1 Activities of tetrahydrobenzazepin-4-ones as muscarinic (M₃) and (M₂) antagonists

Compound no.

n

X

m

Ar

Log₁₀K_Bguinea pig ileum

Log₁₀K_Bguinea pig left atria

Log₁₀selectivity

69

1

2

1

H

F

1

0

1

Ph

6.7 0.4(4)

6.5 0.4(4)

<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

—

1.0 0.3(2)

—

H

2-Butyl

Table 2 Activities of racemic dihydroxytetrahydrobenzazepines as muscarinic (M₃) and (M₂) antagonists

Compound no.

n

Log₁₀K_Bguinea pig ileum

Log₁₀K_Bguinea pig left atria

86

100

1

2

5.5

5.6 0.5(2)

—

5.4 0.1

Compound No.

X

Log₁₀K_Bguinea pig ileum

Log₁₀K_Bguinea 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 M₃receptors in the guinea pig ileum with

useful selectivities over the M₂receptors 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

CaH₂and 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

This journal is

The Royal Society of Chemistry 2008

Org. Biomol. Chem., 2008, 6, 2138–2157 | 2147

©

View Article Online

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); d_H(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);

d_C(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); m_max

3067, 1676, 1601, 1573, 1471, 1253, 1217, 1194, 1129, 1081 and

967 cm⁻¹; d_H(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); d_C(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); m_max

(CH₂Cl₂) 3097, 3073, 3025, 1533, 1437, 1373, 1340, 1164, 1076

and 907 cm⁻¹; d_H(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); d_C

(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); d_H(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, 2^ꢀꢀ-H), 5.49 (1 H, m, 2-H), 5.62 (1 H,

dd, J 1, 17.5, 2^ꢀꢀ-H^ꢀ), 7.03 (1 H, dd, J 11, 17.5, 1^ꢀꢀ-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); m_max3334, 3065, 3028, 1452, 1000 and 755;

d_H(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); d_C(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

2148 | Org. Biomol. Chem., 2008, 6, 2138–2157

This journal is

The Royal Society of Chemistry 2008

©

View Article Online

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); m_max1543, 1373, 1164, 1125, 911, 851, 766 and 745; d_H

(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); d_C(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 Celite^ꢀ. 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);

d_H(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); d_C(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); m_max3075, 1543,

1372, 1352, 1163, 1126, 915 and 778; d_H(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, 2^ꢀꢀ-H), 5.01–5.12

(2 H, m, 3-H₂), 5.22 (1 H, t, J 1.5, 2^ꢀꢀ-H^ꢀ), 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); d_C(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); m_max(CDCl₃) 3540,

3093, 1590, 1545, 1445, 1371, 1352, 1266, 1164 and 1065 cm⁻¹; d_H

(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-H^ꢀ), 4.46 (1 H, d, J 16, 1-H), 4.83

(1 H, dd, J 2, 16, 1-H^ꢀ), 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); d_C(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); d_H(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

This journal is

The Royal Society of Chemistry 2008

Org. Biomol. Chem., 2008, 6, 2138–2157 | 2149

©

View Article Online

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. C₁₄H₂₀NO₂requires M, 234.1494); m_max

3363, 3059, 1667, 1652, 1446, 1264, 1148, 1083, 1000, 967, 755 and

734; d_H(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-H^ꢀ), 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); d_C(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); m_max(CDCl₃) 3481, 3092,

1713, 1545, 1440, 1361, 1168, 1126 and 1095 cm⁻¹; d_H(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-H^ꢀand 3-H^ꢀ), 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); d_C(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. C₁₈H₂₆NO₂requires M, 288.1963); m_max3469, 3156, 3054,

1728, 1705, 1466, 1455, 1375, 1264, 1249 and 1168 cm⁻¹; d_H

(400 MHz, CDCl₃) 0.91 (3 H, t, J 7.25, 4^ꢀ-H₃), 1.32 (2 H, sex,

J 7.25, 3^ꢀ-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-H^ꢀ),

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); d_C(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. C₁₈H₂₈NO₂requires M,

290.2120); m_max(CDCl₃) 3437, 3054, 1265 and 739 cm⁻¹; d_H

(400 MHz, CDCl₃) 0.93 (3 H, t, J 7, 4^ꢀ-H₃), 1.33 (3 H, m, 3^ꢀ-

H₂and 3^ꢀꢀ-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, 1^ꢀ-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-H^ꢀ), 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-H^ꢀ), 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); d_C(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

2150 | Org. Biomol. Chem., 2008, 6, 2138–2157

This journal is

The Royal Society of Chemistry 2008

©

View Article Online

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. C₂₆H₃₁F₃N₂O₃requires

M, 476.2290); d_H(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);

m_max(CDCl₃) 3468, 3065, 1544, 1455, 1370, 1162, 1068, 1000 and

911 cm⁻¹; d_H(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, 1^ꢀ-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,

2^ꢀ-H₂), 3.58 (1 H, d, J 3.5, 4-H), 3.69 (1 H, d, J 15, 1-H^ꢀ), 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); d_C(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. C₂₆H₃₀F₃N₂O₃requires M, 475.2208);

m_max3466, 3065, 1690, 1452, 1202 and 1144 cm⁻¹; d_H(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,

CH₂and 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); m_max3466, 3065, 1698, 1544, 1454, 1369 and 1163 cm⁻¹;

d_H(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, 1^ꢀ-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. C₂₄H₃₁N₂O₂requires M, 379.2385);

d_H(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); d_C(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,

This journal is

The Royal Society of Chemistry 2008

Org. Biomol. Chem., 2008, 6, 2138–2157 | 2151

©

View Article Online

5-Cyclobutyl-5-hydroxy-2-[2-(phenylmethylamino)ethyl]-2,3,4,5-

tetrahydro-[1H]-2-benzazepin-4-one 72

M, 546.2063); m_max3059, 1669, 1634, 1543, 1455, 1434, 1372,

1346, 1162, 768 and 736; d_H(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, 2^ꢀ-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);

d_C(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. C₂₃H₂₉N₂O₂requires M, 365.2229);

m_max3454, 3054, 1693, 1673, 1453, 1265, 1133 and 1106 cm⁻¹; d_H

(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, 1^ꢀ-H₂and 2^ꢀ-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-H^ꢀ), 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. C₂₄H₃₃N₂O₂requires

M, 381.2543); m_max3406, 3059, 3023, 1455, 1310, 1277, 1243, 1217,

1158, 1142, 1081, 998, 747 and 699; d_H(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-H^ꢀ), 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); d_C(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); m_max3059, 1713, 1633, 1589, 1563, 1517, 1334, 1304,

851, 752 and 734; d_H(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, 1^ꢀ-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); d_C

(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,N^ꢀ,N^ꢀ-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); m_max1540, 1354, 1163, 1126, 1065, 914 and 777 cm⁻¹;

d_H(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); d_C(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).

2152 | Org. Biomol. Chem., 2008, 6, 2138–2157

This journal is

The Royal Society of Chemistry 2008

©

View Article Online

(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); m_max3435, 1543,

1371 and 1162 cm⁻¹; d_H(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); m_max3436, 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. C₂₅H₃₃N₂O₃requires M, 409.2486);

m_max3412, 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.

C₂₅H₃₅N₂O₂requires M, 395.2693); m_max3391, 1453, 1320 and

1062 cm⁻¹; d_H(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-H^ꢀ), 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-H^ꢀ),

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); d_C(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); m_max3430, 1649, 1452, 1364

and 1076 cm⁻¹; d_H(500 MHz, CDCl₃) 0.80–1.65 (10 H, m), 2.05–

2.18 (2 H, m, 1^ꢀ-H₂), 2.90 (1 H, quin, J 8.5, 1^ꢀꢀ-H), 3.18 and 3.28

(each 1 H, m, 3^ꢀ-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. C₂₅H₃₃N₂O₂requires M, 393.2537); m_max3437, 1668,

1520, 1454, 1361, 1208, 1176 and 1026 cm⁻¹; d_H(500 MHz, CDCl₃)

0.80 (1 H, m), 1.08–1.70 (9 H, m), 2.27 and 2.55 (each 2 H, m,

1^ꢀ-H₂and 3^ꢀ-H₂), 3.03 (1 H, quin, J 8, 1^ꢀꢀ-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-H^ꢀ), 4.32 (1 H, d, J 16, 3-H^ꢀ), 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

This journal is

The Royal Society of Chemistry 2008

Org. Biomol. Chem., 2008, 6, 2138–2157 | 2153

©

View Article Online

(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.

C₁₄H₁₉FNO₂requires M, 252.1394); m_max3318, 1610, 1590, 1490,

1445, 1412, 1238, 1144, 1098, 1074, 1056, 1002, 981, 909, 865, 815

and 732 cm⁻¹; d_H(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-H^ꢀ), 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); d_C(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, ²J_C-F19.5), 116.37 and 116.65

(d, ²J_C-F21.5), 131.52 and 131.62 (d, ³J_C-F7.5), 137.54 and 137.51

(d, ⁴J_C-F3), 139.19 and 139.27 (d, ³J_C-F6.5) and 159.94 and 163.20

(d, ¹J_C-F244.5); 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); m_max1549, 1492, 1461, 1377, 1355, 1244 and 1170 cm⁻¹;

d_H(300 MHz, CDCl₃) 1.58–2.12 (6 H, m, 3 × CH₂), 3.33 (1 H, m,

1^ꢀ-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); d_C(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

²J_C-F21), 116.41 and 116.70 (d, J_C-F22), 116.93, 124.10, 127.77

and 127.88 (d, ³J_C-F8), 130.54, 131.56, 132.70, 133.54, 135.33 and

135.42 (d, ³J_C-F7), 135.83 and 135.87 (d, ⁴J_C-F3), 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. C₁₈H₂₆FNO₂requires M, 307.1947); m_max3449–3409,

1609, 1587, 1491, 1459, 1405, 1372, 1304, 1240, 1143, 1098, 1070,

1011 cm⁻¹; d_H(300 MHz, CDCl₃) 0.84 (3 H, t, J 7, 4^ꢀ-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, 1^ꢀ-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-H^ꢀ), 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-H^ꢀ), 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); d_C(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, ²J_C-F18), 116.36 and 116.64 (d,

1

and 160.06 and 163.36 (d, J_C-F247.5); 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); m_max3542–3435, 1609, 1590, 1541, 1461, 1376, 1241,

1165, 1002 and 905 cm⁻¹; d_H(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-H^ꢀ), 4.42

(1 H, d, J 16, 1-H), 4.75 (1 H, dd, J 16, 2, 1-H^ꢀ), 6.95–7.10 (2 H,

m, ArH), 7.69–7.89 (4 H, m, ArH) and 8.14 (1 H, m, ArH); d_C

(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, ²J_C-F20), 117.41 and 117.58 (d,

²J_C-F21.5), 124.84, 131.82 and 131.88 (d, ³J_C-F7.5), 132.01, 132.48,

134.55, 135.37 and 135.43 (d, ³J_C-F7.5), 137.04 and 137.07 (d, ⁴J_C-F

3

²J_C-F21), 130.97 and 131.07 (d, J_C-F7.5), 137.37 and 137.41 (d,

⁴J_C-F3), 137.52 and 137.60 (d, ³J_C-F6), and 159.61 and 162.87 (d,

¹J_C-F244.5); 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, J_C-F245); 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

This journal is

The Royal Society of Chemistry 2008

©

View Article Online

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.

C₂₄H₃₀FN₂O₃requires M, 413.2235); m_max3402, 1631, 1590, 1490,

1455, 1372, 1302, 1267, 1240, 1142, 1092, 1003, 980, 816, 736 and

700 cm⁻¹; d_H(500 MHz, CDCl₃) 1.13–2.92 (11 H, m, cyclobutyl-H,

5-CH, 2^ꢀ-H₂and 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-H^ꢀ), 4.39 and 4.48 (each

0.33 H, d, J 16.5, 1-H), 4.70 (0.33 H, d, J 14, 3-H^ꢀ), 5.10 (0.67 H, d,

J 15, 1-H^ꢀ), 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); d_C(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, ²J_C-F20), 114.19 and 114.35 (d, ²J_C-F19), 115.72 and 115.89 (d,

²J_C-F22), 117.56 and 117.73 (d, ²J_C-F21), 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); m_max3430, 1633, 1590,

1543, 1493, 1455, 1371, 1346, 1267, 1239, 1163, 1126, 1095, 999,

982, 939, 852, 816, 776, 735 and 703 cm⁻¹; d_H(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); d_C(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. C₂₄H₃₂FN₂O₂requires M, 399.2442);

m_max3435, 1610, 1590, 1492, 1454, 1242, 1144, 1077, 1005, 845,

814, 735 and 699 cm⁻¹; d_H(500 MHz, CDCl₃) 1.20–1.29 (2 H, m),

1.60–1.77 (5 H, m, 2^ꢀ-H₂, cyclobutyl-H and NH), 2.01–2.18 (2 H,

m), 2.54–2.73 (5 H, m, 5-CH, 1^ꢀ-H₂and 3^ꢀ-H₂), 2.80 (1 H, d, J 13,

3-H), 2.99–3.08 (2 H, m, 3-H^ꢀand OH), 3.47 (1 H, dd, J 14.5, 2,

1-H), 3.59–3.72 (4 H, m, 1-H^ꢀ, 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); d_C(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, ²J_C-F19.5), 116.66 and 116.95 (d, ²J_C-F21.5),

2

and 113.01 (d, J_C-F20), 113.17 and 113.32 (d, J_C-F19), 115.04

2

and 115.21 (d, J_C-F22), 116.61 and 116.78 (d, J_C-F22), 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, ¹J_C-F

1

246.5), 159.50 and 161.46 (d, J_C-F245), 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

This journal is

The Royal Society of Chemistry 2008

Org. Biomol. Chem., 2008, 6, 2138–2157 | 2155

©

View Article Online

127.34, 128.37, 128.69, 131.33 and 131.43 (d, ³J_C-F8), 137.77 and

(3 H, m, 1^ꢀ-H₂and cyclobutyl-H), 3.11–3.31 (4 H, m, 3-H, 5-CH

and 3^ꢀ-H₂), 3.55–3.62 (2 H, m, 1-H and 3-H^ꢀ), 3.96 (1 H, d, J 16.5,

1-H^ꢀ), 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); d_C(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, J_C-F3), 159.90 and 163.16 (d, J_C-F245.5); 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

and 113.06 (d, J_C-F20), 115.15 and 115.32 (d, J_C-F21), 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); m_max3468, 1609, 1590,

1543, 1494, 1455, 1372, 1348, 1265, 1242, 1162, 1126, 1076, 1003,

932, 852, 815, 780, 735, 700 and 652 cm⁻¹; d_H(500 MHz, CDCl₃)

1.09–1.31 (2 H, m), 1.40–1.75 (4 H, m, 2^ꢀ-H₂and cyclobutyl-H),

1.99–2.15 (2 H, m), 2.32 and 2.44 (each 1 H, m, 1^ꢀ-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-H^ꢀ), 2.97 (1 H, br s, OH), 3.16–3.24 (2 H, m,

3^ꢀ-H₂), 3.26 (1 H, d, J 15, 1-H), 3.49–3.55 (2 H, m, 1-H^ꢀ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); d_C(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, J_C-F7.5), 129.90,

4

130.66, 132.40, 132.54, 133.10 and 133.12 (d, J_C-F2.5), 134.61,

3

135.53 and 135.58 (d, J_C-F6.5), 146.88, 159.62 and 161.60 (d,

¹J_C-F246.5) 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.

C₂₄H₃₀FN₂O₂requires M, 397.2286); m_max3456, 3313, 3059, 3028,

1701, 1610, 1588, 1490, 1454, 1365, 1261, 1241, 1220, 1122, 1099,

1013, 977, 863, 810, 736, 699 cm⁻¹; d_H(500 MHz, CDCl₃) 1.48–

1.75 (7 H, m, 2^ꢀ-H₂, cyclobutyl-H and NH), 1.81 and 2.16 (each

1 H, m), 2.35–2.46 (2 H, m, 1^ꢀ-H₂), 2.55–2.64 (2 H, m, 3^ꢀ-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); d_C

(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, ²J_C-F20), 114.98

and 115.15 (d, ²J_C-F22), 126.15, 127.18, 127.46, 128.51 and 128.57

(d, ³J_C-F8), 133.20 and 133.23 (d, ⁴J_C-F2.5), 135.97 and 136.00 (d,

³J_C-F5.5), 139.01, 159.71 and 161.67 (d, ¹J_C-F245) and 206.58; m/z

(ES) 419 (M⁺+ 23, 2%) and 397 (M⁺+ 1, 100).

2

112.40 and 112.56 (d, J_C-F20), 115.69 and 115.86 (d, J_C-F22),

123.17, 127.07, 127.19, 127.75, 129.94, 129.99 and 130.05 (d, ³J_C-F

8), 130.65, 132.30, 132.55, 134.75, 136.03 and 136.08 (d, ³J_C-F7.5),

136.35 and 136.37 (d, ⁴J_C-F2.5), 146.91 and 159.29 and 161.24 (d,

¹J_C-F244); 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); m_max3461, 3068, 3031,

1698, 1610, 1588, 1543, 1489, 1456, 1440, 1371, 1349, 1163, 1127,

1013, 910, 852, 780 and 734 cm⁻¹; d_H(500 MHz, CDCl₃) 1.48–1.53

(3 H, m, 2^ꢀ-H₂and 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 (R_int= 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

This journal is

The Royal Society of Chemistry 2008

©

View Article Online

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,

S. Macura, A. Basu, J. S. Lazo and R. G. Ball, J. Am. Chem. Soc., 1993,

115, 3957; (b) D. L. J. Clive, S. R. Magnuson, H. W. Manning and

D. L. Mayhew, J. Org. Chem., 1996, 61, 2095.

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

(R_int= 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.‡

19 M. E. Garst, J. N. Bonﬁglio, D. A. Grudoski and J. Marks, J. Org.

Chem., 1980, 45, 2307.

20 (a) R. W. Murray, Chem. Rev., 1989, 89, 1187; (b) W. Adam, R. Curci

and J. O. Edwards, Acc. Chem. Res., 1989, 22, 205; (c) W. Adam, L.

Hadjiarapoglou and X. Wang, Tetrahedron Lett., 1989, 30, 6497.

21 E. Peyroux, F. Berthiol, H. Doucet and M. Santelli, Eur. J. Org. Chem.,

2004, 1075; L. N. Pridgen, L. Snyder and J. Prol Jr., J. Org. Chem.,

1989, 54, 1523.

22 (a) T. Fukuyama, C.-K. Jow and M. Cheung, Tetrahedron Lett., 1995,

36, 6373; (b) W. Bowman and R. D. Coghlan, Tetrahedron, 1997, 53,

15787; (c) T. Kan and T. Fukuyama, Chem. Commun., 2004, 353.

23 P. Schwab, R. H. Grubbs and J. W. Ziller, J. Am. Chem. Soc., 1996, 118,

100.

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,

6761.

References

1 Muscarinic Receptor Subtypes in Smooth Muscle, ed. R. M. Eglen,

CRC, Ohio, 1997, ISBN-10 0849385490.

2 P. Abrams, K. E. Anderson, J. J. Buccafusco, C. Chapple, W. Chet de

Groat, A. D. Fryer, G. Kay, A. Laties, N. M. Nathanson, P. J. Pasricka

and A. J. Wein, Br. J. Pharmacol., 2006, 148, 565.

3 V. Alabaster, J. Urol., 1998, 159, 2261.

4 K. J. Broadley, A. Hamrouni, C. Escargueil, B. C. P. Allen and R. H.

Davies, unpublished observations.

25 V. VanRheenen, D. Y. Cha and W. M. Hartley, Org. Synth. Coll.

Vol. 6, 1988, 342.

26 (a) P. D. Bartlett, S. J. Tauber and W. P. Weber, J. Am. Chem. Soc., 1969,

93, 6362; (b) E. R. Buchman and J. C. Conly, J. Am. Chem. Soc., 1953,

75, 1990; (c) C. V. Wilson, Org. React., 1957, 9, 332; (d) M. Karimine,

J. Galsomais, J.-P. Lere-Porte and J. Petrissans, J. Mol. Struct., 1987,

162, 321.

5 K. Palczewski, T. Kumaska, T. Hori, C. A. Behnke, H. Motoshima,

B. A. Fax, I. Le Trong, D. C. Keller, T. Okada, R. E. Stenkamp, M.

Yamamoto and M. Miyano, Science, 2000, 289, 739.

6 (a) D. W. McPherson, J. P. Carter, US Patent 5,001,160, 1991; (b) R. E.

Howell, K. D. Laemont, M. P. Kovalsky, V. C. Lowe, P. P. Waid, W. J.

Kinnier and L. Noronha-Blob, J. Pharmacol. Exp. Ther., 1994, 270,

546; (c) C. Kaiser, V. H. Audia, J. P. Carter, D. W. McPherson, P. P.

Waid, V. C. Lowe and L. Noronha-Blob, J. Med. Chem., 1993, 36, 610.

7 D. Seebach, M. A. Maestro, M. Sefkow, G. Adam, S. Hintermann and

A. Neidlein, Annalen, 1994, 701.

27 P. T. Lansbury and V. A. Pattison, J. Am. Chem. Soc., 1962, 84, 4295.

28 V. Snieckus, Chem. Rev., 1990, 90, 879.

29 S. D. Meyer and S. L. Schreiber, J. Org. Chem., 1994, 59, 7549.

30 N. A. Petassis and E. I. Bzowej, J. Org. Chem., 1992, 57, 1327.

31 M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999, 1,

953.

32 K. Takahashi and M. Ogata, J. Org. Chem., 1987, 52, 1877.

33 (a) D. N. Kirk and C. R. McHugh, J. Chem. Soc., Perkin Trans. 1, 1977,

893; (b) R. E. Hartung, D. G. Hilmey and L. A. Paquette, Adv. Synth.

Catal., 2004, 346, 713 .

8 (a) A. Dieters and S. F. Martin, Chem. Rev., 2004, 104, 2199; (b) K. C.

Nicolaou, S. G. Bulger and D. Sarlah, Angew. Chem., Int. Ed., 2005,

44, 4490.

9 (a) S. Brass, H. D. Gerber, S. Dorr and W. E. Diderich, Tetrahedron,

2006, 62, 1777; (b) M. Berberis, P. Garcia-Losada, S. Pleite, J. R.

Rodriguez, J. F. Soriano and J. Mendiola, Tetrahedron Lett., 2005,

46, 4847; (c) L. Delhaye, A. Merschaert, K. Diker and I. N. Houpis,

Synthesis, 2006, 1437.

34 Y. Hirai, T. Terada, A. Hagiwawa and T. Yamazaki, Chem. Pharm.

Bull., 1988, 36, 1343; Y. Hirai, T. Terada and T. Yamazaki, J. Am.

Chem. Soc., 1988, 110, 958.

35 F. Cardullo, D. Donati, G. Merlo, A. Paio, M. Salaris and M. Taddei,

Synlett, 2005, 2996.

36 (a) K. Ishihara, Y. Kuroki and H. Yamamoto, Synlett, 1995, 41; (b) Y.

Kuroki, K. Ishihara, N. Hamaki, S. Ohara and H. Yamamoto, Bull.

Chem. Soc. Jpn., 1998, 71, 1221.

10 J.-L. Panayides, R. Pathak, C. B. de Koning and W. A. L. van Otterlo,

Eur. J. Org. Chem., 2007, 4953; N. Toda, K. Tago, S. Marumoto, K.

Takami, M. Ori, N. Yamada, K. Koyama, S. Naruto, K. Abe, R.

Yamazaki, T. Hara, A. Aoyagi, Y. Abe, T. Kaneko and H. Kogen,

Bioorg. Med. Chem., 2003, 11, 4389.

11 H. H. Wasserman, R. P. Robinson and C. G. Carter, J. Am. Chem. Soc.,

1983, 105, 1697.

12 M. R. Pavia, S. J. Lobbestael, C. P. Taylor, F. M. Hershenson and D. L.

Miskell, J. Med. Chem., 1990, 33, 854.

13 O. Mitsunobu, Synthesis, 1981, 1.

37 L. K. Sydnes, I. C. Burkow and S. H. Hansen, Tetrahedron, 1985, 41,

5703.

38 T. Fukuyama, M. Cheung, C.-K. Jow, Y. Hidai and T. Kan, Tetrahedron

Lett., 1997, 38, 5831.

39 J. P. Carson, H. R. Almond, M. D. Brannan, R. J. Carmosin, S. F.

Flaim, A. Gill, M. M. Gleason, S. L. Keely, D. W. Ludovic, P. M. Pitis,

M. C. Rebarchak and F. J. Villani, J. Med. Chem., 1988, 31, 630.

40 S. J. Baker, Y.-K. Zhang, T. Akama, A. Lau, H. Zhou, V. Hernandez,

W. Mao, M. R. K. Alley, V. Sanders and J. J. Plattner, J. Med. Chem.,

2006, 49, 4447.

This journal is

The Royal Society of Chemistry 2008

Org. Biomol. Chem., 2008, 6, 2138–2157 | 2157

©

Article Doi

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

DOI: 10.1039/b801206g

Source and publish data:

Authors:

Article abstract of DOI:10.1039/b801206g

Full text of DOI:10.1039/b801206g

Products guided by the article

R&D Labs maybe for 1043927-22-5

Relevant to this article

Hot Product