Bimetallic catalytic synthesis of annelated benzazepines

Article abstract of DOI:10.1039/b503213j

A novel short synthetic route to annelated benzazepines, using additive enhanced palladium-indium catalytic 3-component cascade methodology is described. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b503213j

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COMMUNICATION
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Bimetallic catalytic synthesis of annelated benzazepines{
Laura A. T. Cleghorn,a Ronald Grigg,*a Colin Kilner,a William S. MacLachlanb and Visvanthar Sridharana
Received (in Cambridge, UK) 4th March 2005, Accepted 18th April 2005
First published as an Advance Article on the web 11th May 2005
DOI: 10.1039/b503213j
a variety of substituents in the A and B rings (Table 1), using
copper(I) iodide (20 mol %) as the additive. The use of piperidine
(1 mol eq.) proved ineffective in this case. Various catalytic systems
and temperatures were evaluated with Pd(OAc)2 (10 mol %), tri-
furyl phosphine (TFP) (20 mol %), In (1.5 mol eq.) and Cu(I)I
(20 mol %) in N,N-dimethylformamide (10 ml/mmol) at 40 uC for
20 h, proving the most effective of those surveyed.
A novel short synthetic route to annelated benzazepines, using
additive enhanced palladium–indium catalytic 3-component
cascade methodology is described.
Homoprotoberberines (1)1 are a group of alkaloids which exhibit
anti-malarial and anti-bacterial properties2 whilst homoprotober-
berine (2) has been found to be potent against human breast
carcinoma cells.3 Current synthetic routes to homoprotoberberines
are invariably multi-step procedures with low overall yields.1–4
Compounds 7f–7h were obtained as single stereoisomers.
Stereochemistry was assigned from n.O.e. data together with an
X-ray crystal structure of 7g (Fig. 1). The 7-membered ring C
adopts a chair-like conformation whilst ring B assumes a half chair
conformation. The N-lone pair adopts a pseudo equatorial
position on the same side of the molecule as the axial 14a-H,
resulting in a cis ring B/C junction. Substitution can also be
introduced into ring D as exemplified by utilising 3,4-methylene-
dioxy- and 3,4-dimethoxy-2-iodobenzyl bromides (4a and 4b)16
(Table 2).
We have developed powerful catalytic palladium–indium three-
component cascade methodology involving reductive transmetal-
lation of a p-allylpalladium(II) species, generated from allenes and
aryl iodides, with indium and subsequent addition of the
umpolung allylindium species to an electrophilic component
(aldehydes, ketones, imines). Four synthetic variants of this
process, depending upon whether the palladium-catalysed and
indium-mediated steps are inter- or intra-molecular, have been
identified.5–8 Transmetallation of allenylpalladium(II)9 and con-
ventionally generated p-allylpalladium(II) species by indium salts
has also been reported by others.10–12 The addition of an
allylindium reagent to 1-acylpyridinium salts has also been
reported.13
Annelation of benzazepines to N-protected b-carbolines 8a and
8b, (Table 3), occurs in an analogous manner. Currently the yields
of 9a and 9b are lower than when isoquinoline is used as the parent
heterocycle, possibly due to the steric encumbrance arising from
N-Me and N-Ts groups.
Pyridines (11a–d) can be utilised as annelation partners and give
rise to 13a–d in good yield (Table 4). Compounds 13a–d were
obtained as single regioisomers. An X-ray structure of 13d (Fig. 2)
indicates that the 7- and 6-membered rings adopt chair like and
half chair conformations, with the N-lone pair and 12a-H cis.
Class 1 reactions involving iminium ions (15) generated in situ
from isoquinoline (3) and the appropriate benzyl bromide (14),
aryl iodide and allene afford 1,2-dihydroisoquinolines (16) which
upon sodium cyanoborohydride reduction give 1,2,3,4-tetrahy-
droisoquinolines (17) (Scheme 2) (Table 5). Compounds related to
17a and b inhibit platelet aggregation.17
We have recently reported the beneficial effect of additives on
3-component cascade processes. Thus piperidine (1 mol eq.) or
copper(I) iodide (0.2 mol eq.) were both found to decrease the
reaction time from 18 h to 2 h while increasing the yield
significantly.14,15
In this communication we report our preliminary results using
iminium ions derived from a range of nitrogen heterocycles as
the electrophilic component of both class 2 and class 1 processes.
The former products bear a close structural relationship to the
homoprotoberberines (1).
Annelation of benzazepines to isoquinolines proceeds via
generation of iminium ion (5) in situ from isoquinoline (3) and
2-iodobenzyl bromide (4). Subsequent addition of allene,
palladium(II) acetate, indium powder and additives initiates a
class 2 Pd/In 3-component cascade reaction to generate enamines
(6) (Scheme 1) via regioselective 7-endo-trig cyclisation. Reduction
of (6) with sodium cyanoborohydride gives benzazepines (7). A
range of substituted benzazepines (7a–7h) have been prepared with
{ Electronic supplementary information (ESI) available: experimental
section. See http://www.rsc.org/suppdata/cc/b5/b503213j/
*R.Grigg@chem.leeds.ac.uk
Scheme 1
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Chem. Commun., 2005, 3071–3073 | 3071

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Table 1 Benzazepines (7) derived from substituted isoquinolines (3)a
Entry
1
Isoquinoline 3
Enamine 6 (%)b
Benzazepine 7 (%)c
3a
3b
6a (70)
7a (58)
2
3
Fig. 1 X-Ray crystal structure of 7g.
7b (94)
6b (80)
Table 2 Incorporation of substituted 2-iodobenzyl bromides (4)
Enamine
Entry Aryl iodide 4 6 (%)a
Benzazepines
7 (%)b
6c (52)
7c (84)
3c
1
2
3
a
4
7d (85)
7e (69)
3d
3e
6d (70)
6e (49)
6i (80)
6j (50)
6k (81)
4a
7i (75)
7j (74)
7k (78)
5
6
4b
3f
7f (68)
6f (84)
7
8
a
4b
Yield calculated using an internal standard of MeOH 1 mmol/2 ml
b
CDCl3. Isolated yield for the reduction of (6) to (7).
3g
7g (66)
6g (63)
Table 3 b-Carboline derived annelated benzazepines
Enamine
Entry b-Carboline 8 9 (%)a
Benzazepines
10 (%)b
1
6h (75)
7h (73)
3h
Standard reaction procedure: isoquinoline (3) (1 mmol), 2-iodobenzyl
bromide (4) (1 mmol), Pd(OAc)2 (10 mol %), TFP (20 mol %), indium
(1.5 mol eq.), CuI (20 mol %), DMF (AR, 10 ml/mmol), 40 uC, 20 h.
8a
8b
10a (65)
10b (64)
9a (40)
9b (30)
2
b
Yield calculated using an internal standard of MeOH 1 mmol/2 ml
CDCl3. c Isolated yield for the reduction of (6) to (7).
Further work on these and related palladium–indium cascades
is currently underway.{
We thank EPSRC, the University of Leeds and
a
Yield calculated using an internal standard of MeOH 1 mmol/2 ml
CDCl3. Isolated yield for the reduction of (9) to (10).
b
GlaxoSmithKline for support.
3072 | Chem. Commun., 2005, 3071–3073
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Table 4 Pyridine (11a–d) derived annelated benzazepines (13a–d)
Entry
1
Pyridine 11
Enamine 12 (%)a,b
Benzazepine 13 (%)c
11a
11b
12a (60)
12b (75)
13a (60)
13b (63)
13c (61)
2
3
Fig. 2 X-Ray crystal structure of 13d.
Scheme 2
Laura A. T. Cleghorn,a Ronald Grigg,*a Colin Kilner,a
12c (82)
12d (64)
11c
11d
William S. MacLachlanb and Visvanthar Sridharana
4
aMolecular Innovation, Diversity and Automated Synthesis (MIDAS)
Centre, School of Chemistry, Leeds University, Leeds, UK LS2 9JT.
E-mail: R.Grigg@chem.leeds.ac.uk; Fax: 0113 343 6530;
Tel: 0113 343 6501
bGlaxoSmithKline, New Frontiers Science Park (North), Third Avenue,
Harlow, UK CM19 5AW
13d (72)
a
Yield calculated using an internal standard of MeOH 1 mmol/2 ml
CDCl3. Thiophene (2 mol eq.) used as an additional additive.
Isolated yield for the reduction of (12) to (13).
b
Notes and references
c
{ Crystallographic data: 7g (C26H25N), M 5 351.47, orthorhombic,
3
˚
˚
a 5 10.3740(2), b 5 19.2830(7), c 5 9.7330(3) A, V 5 1947.01(10) A ,
T 5 150(2) K, space group Pna21, Z 5 4, m 5 0.069 mm21, R1 5 0.0395,
wR2 5 0.1031 for 10989 reflections, CCDC 266425. 13d (C19H19NO),
Table 5 Class 1 inter–inter 1,2,3,4-tetrahydroisoquinoline (17)
˚
M 5 277.35, monoclinic, a 5 10.0020(3), b 5 13.1350(4), c 5 10.9480(4) A,
3
˚
V 5 1436.56(8) A , T 5 150(2) K, space group P21/c, Z 5 4, m 5
1,2-
Dihydroisoquinoline Tetrahydroisoquinoline
16 (%)a 17 (%)b
1,2,3,4-
0.079 mm21, R1 5 0.0419, wR2 5 0.1166 for 12805 reflections, CCDC
266424. See http://www.rsc.org/suppdata/cc/b5/b503213j/ for crystallo-
graphic data in CIF or other electronic format.
Aryl
Entry iodide
1
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16a (49)
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16c (70)
17c (48)
a
Yield calculated using an internal standard of MeOH 1 mmol/2 ml
CDCl3 Isolated yield for the reduction of (16) to (17)
b
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Chem. Commun., 2005, 3071–3073 | 3073