Synthesis of 2-substituted 1-benzyl-2,3,4,5-tetrahydro-1-benzazepines by palladium catalysis. Observation of a competitive β-hydride elimination pathway

Article abstract of DOI:10.1016/S0040-4039(03)00676-2

A synthetic route to 1-benzyl-tetrahydro-1-benzazepine is reported, which also permits access to analogous structures with alkyl and aryl substituents at position-2 of the aliphatic ring. Palladium catalysis is utilized in two of the three steps, construc

Full text of DOI:10.1016/S0040-4039(03)00676-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3675–3678
Synthesis of 2-substituted
1-benzyl-2,3,4,5-tetrahydro-1-benzazepines by palladium catalysis.
Observation of a competitive b-hydride elimination pathway
Maryiam Qadir,a Rachael E. Priestley,a Thomas W. D. F. Rising,a Thomas Gelbrich,b
Simon J. Coles,b Michael B. Hursthouse,b Peter W. Sheldrake,c Neil Whittallc and K. K. (Mimi) Hiia,*
aDepartment of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
bEPSRC National X-Ray Crystallography Service, University of Southampton, Highfield, Southampton SO17 1BJ, UK
cGlaxoSmithKline, Old Powder Mills, Nr. Leigh, Tonbridge, Kent TN11 9AN, UK
Received 3 February 2003; revised 12 March 2003; accepted 12 March 2003
Abstract—A synthetic route to 1-benzyl-tetrahydro-1-benzazepine is reported, which also permits access to analogous structures
with alkyl and aryl substituents at position-2 of the aliphatic ring. Palladium catalysis is utilized in two of the three steps,
constructing the seven-membered rings effectively from 2-bromoiodobenzene. Competitive b-hydride elimination was observed in
the attempted carbonꢀnitrogen bond formation with a sterically bulky substrate (when R=tert-butyl). © 2003 Elsevier Science
Ltd. All rights reserved.
Molecules bearing saturated tetrahydro-1-benzazepine
core structures are often found to inhibit selectively
certain receptors of the AVP neuropeptide (V1A and V2)
and may have potential applications in the treatment of
a number of disorders such as diabetes,1 congestive
heart failure,2 hypertension,3 and dysmenorrhea.4
Orally active V2 antagonists bearing this fused bicyclic
structure have been applied successfully to the treat-
ment of hyponatremia.5
(Scheme 1), which gave moderate yields of 2-substituted
1-benzazepines from 2-iodoaniline.10 However, the
reaction is limited by the nature of the R substituent,
and failed to work when R=H.
Herein we report a milder synthetic route for the syn-
thesis of 1-benzyl-tetrahydro-1-benzazepine 1a that uti-
lizes palladium catalysed CꢀC and CꢀN bond forming
steps in the construction of the heterocyclic ring. The
scope of the methodology will be demonstrated by the
synthesis of structures incorporating alkyl 1b and aryl
substituents 1c at the 2-position (Fig. 1).
Tetrahydro-1-benzazepines are most commonly
accessed through reduction of the products of
Beckmann6 or Schmidt7 ring expansion reactions from
derivatives of 1-tetralone. These methods require the
use of hazardous reagents (e.g. azides) and are thus not
amenable to large-scale synthesis. Moreover, the suc-
cess of these ring expansion methodologies is highly
dependent on the nature of the substrate.
Adopting a reported procedure,11 the tandem Heck
isomerisation reaction proceeded smoothly between 2-
bromo-iodobenzene and but-4-en-1-ol under mild reac-
tion conditions, furnishing aldehyde 3a in high yield
(Scheme 2). With slight modifications, the ketones 3b–d
can also be obtained from their corresponding 1-substi-
tuted homoallylic alcohols.12 Even though the conver-
Conversely, formation of the seven-membered ring by
the cyclisation of an aliphatic chain often proceeds in
low yield.8,9 An interesting exception is the report of a
tandem Heck isomerisation–condensation reaction
Keywords: palladium catalysis; heterocycles; benzazepines; b-hydride
elimination.
* Corresponding author. Fax: (44)20-7848-2810; e-mail: mimi.hii@
kcl.ac.uk
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00676-2

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M. Qadir et al. / Tetrahedron Letters 44 (2003) 3675–3678
analysis (Fig. 2).† The solid-state structure shows that the
benzazepine ring adopts a chair-like conformation, with
the benzyl substituent in the axial position.15 The confor-
mation is probably fairly rigid in solution—distinct NMR
resonances are observed for each of the nuclei present in
thering, whicharenotaffectedbychanges intemperature.
Figure 1. R=H (a), Me (b), Ph (c), t-Bu (d).
When the tert-butyl substituted amine 4d was subjected
to the ring closure, the major product isolated from the
reaction mixture was a dehalogenated imine 5,16 the
product of a competitive b-hydride reductive elimination
pathway (Scheme 4).
Scheme 2. Synthesis of 4: (i) when R=H: 2 mol% Pd(OAc)2,
nBu4NCl, NaHCO3, DMF, 40°C; when R"H: 2 mol%
Pd(OAc)2, LiCl, iPr2NEt, DMF, 80°C; (ii) a. BnNH2, Ti(OiPr)4,
NaBH4, THF, reflux,13 b. H3O+.
sions are high, the isolated yields of 3c and 3d are lower,
as we found these alkyl ketones difficult to purify by
conventional column chromatography. Nevertheless, all
the carbonyl compounds were isolated as pale yellow oils
with varying degrees of thermal stability. If not used
immediately, they are best kept at −20°C, where they
solidify as cream solids. Subsequent reductive amination
under pH-neutral conditions afforded amines 4a–d in
good yields.13
Figure 2. ORTEP drawing for compound 1a·HCl at 50%
probability. Aromatic hydrogen atoms are omitted for clarity.
A reported procedure for intramolecular aryl amination
was adopted for the ring closure step, where a combina-
tion of two bases was found to be necessary to attain the
optimal yield for 1a.14 The method can also be adopted
to afford the substituted rings 1b and 1c in moderate yields
(Scheme 3).
In all cases the formation of the ring was accompanied
by a downfield shift of the 13C resonance of the substituted
aromatic carbon from 124 to 146 ppm. The connectivity
was supported by relevant 2D NMR spectroscopy
(HMBC) and the observation of the monomeric M+ ion.
Addition of conc. HCl to 1a yielded the corresponding
salt, which was recrystallized from methanol to give
colourless prisms suitable for X-ray crystallographic
Scheme 4. Competitive b-H elimination pathway.
† Crystallographic data (excluding structure factors) for compounds
1a and 4d have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication numbers CCDC 202838
and 202839, respectively. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44 (0) 1223-336033 or e-mail: deposit@
ccdc.cam.ac.uk].
Scheme 3. Intramolecular aryl amination.

M. Qadir et al. / Tetrahedron Letters 44 (2003) 3675–3678
3677
6. (a) Sasatami, S.; Miyazaki, T.; Marouka, K.; Yamamoto,
H. Tetrahedron Lett. 1983, 24, 4711–4712; (b) Maruoka,
K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane, S.;
Hattori, K.; Yamamoto, H. J. Am. Chem. Soc. 1983, 105,
2831–2843.
7. Grunewald, G. L.; Dahanukar, V. H.; Ching, P.;
Criscione, K. R. J. Med. Chem. 1996, 39, 3539–3546.
8. Kaoudi, T.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z.
Angew. Chem., Int. Ed. Engl. 2000, 39, 731–737.
9. A recent paper reported an iridium-catalysed oxidative
cyclization reaction of 4-(2-aminophenyl)butanol to give
2,3,4,5-tetrahydro-1-benzazepine in 71% yield: Fujita, K.;
Yamamoto, K.; Yamaguchi, R. Org. Lett. 2002, 4, 2691–
2694.
Figure 3. Bulky ligands for aryl amination reactions.
In a previous study by Hartwig et al., the size of the
phosphine ligand, as well as the substitution pattern of
the amide ligands and the aryl ring, were found to
influence the relative rates for CꢀN bond-forming
reductive elimination and b-hydrogen elimination of
amides.17 With this in mind, we attempted the aryl
amination reaction under milder reaction conditions
with bulky ligands 6 (Fig. 3, R=cyclo-hexyl, a; tert-
butyl, b)18 in the hope of suppressing the b-hydride
elimination pathway. However, this resulted only in the
recovery of the starting material.
10. Dyker, G.; Markwitz, H. Synthesis 1998, 1750–1754.
11. Gibson, S. E.; Jones, J. O.; McCague, R.; Tozer, M. J.;
Whitcombe, N. J. Synlett 1999, 954–956.
12. Typical procedure: In a dry, thick-walled, Young’s tube
was placed Pd(OAc)2 (32 mg), LiCl (1.8 g) and dried
DMF (13 mL). The solution was magnetically stirred to
afford a yellow suspension, before the addition of diiso-
propylethylamine (3.8 mL), homoallylic alcohol (14.6
mmol) and 2-bromo-iodobenzene (1.95 mL, 15.0 mmol)
successively. The reaction vessel was then sealed via a
PTFE tap and placed in a thermostated oil bath at 80°C.
After 18 h, the reaction mixture was poured into H2O
and extracted with ether. The combined ether extracts
were washed successively with aq. HCl (2N), H2O, aq.
CaCl2 and H2O. The solution was finally dried over
MgSO4, filtered and evaporated. The dark oil was then
subjected to column chromatography to furnish the
required product.
In summary, we have developed a synthetic route to the
synthesis of 1-benzyl-tetrahydro-1-benzazepine 1a,
which also permits access to structures 1b and 1c,
incorporating alkyl and aryl substituents at position-2
of the aliphatic ring. The synthesis constructs the seven-
membered ring in three steps from 2-bromo-iodoben-
zene, utilizing palladium catalysis in two key
bond-forming reactions (CꢀC and CꢀN). Competitive
b-hydride elimination was observed in the CꢀN bond
formation step of a sterically bulky substrate (when
R=tert-butyl).
13. Typical procedure: A solution of the corresponding
ketone (1 equiv.), Ti(OiPr)4 (1.2 equiv.) and benzyl amine
(1.5 equiv.) was stirred in dry THF at ambient tempera-
ture overnight, after which time NaBH4 (1.2 equiv.) was
added in one portion and the reaction mixture was
refluxed for 7 h. In the workup, excess reducing agent
was carefully destroyed by the addition of 2 M HCl (aq)
at 0°C. The solution was then refluxed for a further 2 h.
After cooling, the pH was adjusted to 11 by the addition
of 1 M NaOH (aq). The suspension was then filtered
through a pad of Celite, and the residue was washed with
several portions of CH2Cl2. The filtrate was then
extracted with CH2Cl2 and the combined organic extracts
were dried over Na2SO4, filtered and evaporated. The
residue was subjected to flash column chromatography
(silica gel, 20% EtOAc in pentane) to yield the required
product as colourless to pale yellow oils. Microanalyti-
cally pure samples may be obtained by the precipitation
of the compounds as HCl salts, recrystallised from etha-
nol. However, due to their low solubility in common
organic solvents, the NMR spectra and subsequent reac-
tions were carried out using the unprotonated amine.
14. Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron
1996, 52, 7525–7546.
Acknowledgements
M.Q. is supported by the Engineering and Physical
Sciences Research Council (EPSRC) and Glaxo-
SmithKline through an industrial CASE studentship
(grant number 00314292). We thank Johnson Matthey
plc for the generous loan of palladium salts.
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M. Qadir et al. / Tetrahedron Letters 44 (2003) 3675–3678
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