An iodoacetamide-based free radical cyclisation approach to the 7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one (paullone) system

Article abstract of DOI:10.1016/j.tet.2005.03.133

A potentially versatile route to 2-(2-aminoaryl)indoles is described based on a palladium-mediated cyclisation of N-substituted indoles, together with free radical cyclisation of their N-benzyliodoacetamide derivatives to the 7,12-dihydro-indolo[3,2-d][1]

Full text of DOI:10.1016/j.tet.2005.03.133

Tetrahedron 61 (2005) 5489–5498
An iodoacetamide-based free radical cyclisation approach to the
7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one
(paullone) system
*
John B. Bremner and Waya Sengpracha
Institute for Biomolecular Science and Department of Chemistry, University of Wollongong, Northfields Ave, Wollongong,
NSW 2522, Australia
Received 22 December 2004; revised 14 March 2005; accepted 31 March 2005
Available online 28 April 2005
Abstract—A potentially versatile route to 2-(2-aminoaryl)indoles is described based on a palladium-mediated cyclisation of N-substituted
indoles, together with free radical cyclisation of their N-benzyliodoacetamide derivatives to the 7,12-dihydro-indolo[3,2-d][1]benzazepin-
6(5H)-one system.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
area and the correlation between such inhibitory activity and
anti-tumour activity are still being pursued. In this context,
and as part of a programme aimed at the development of
synthetic methods for indole-fused 7- and 8-membered ring7
systems, we were attracted to these paullones and the
possible development of a different synthetic approach to
them and their derivatives.
Paullones, named after the late Ken Paull, are of
considerable interest as potent cyclin dependent kinase
(CDK) inhibitors1–3 and as inhibitors of glycogen synthase
kinase 3.4 As a result, these 7,12-dihydro-indolo[3,2-d][1]-
benzazepin-6(5H)-ones, also exhibit in vitro antitumour
activity and alsterpaullone (2, RZNO2, R4ZH) was
reported5 to be in preclinical development as a potential
anti-tumour agent; kenpaullone (2, RZBr, R4ZH) is in
clinical trials.6 While structure-CDK inhibitory activity
relationships have been undertaken,2 further, studies in this
Previous approaches to the paullone system (2) have been
based on two strategies. The first, involves an indole
precursor (1) and completion of the 7-membered ring by
N5–C6 bond formation (Scheme 1). The second strategy
Scheme 1. Approaches to the synthesis of the paullones.
Keywords: Indolobenzazepinones; Iodoacetamides; Radical cyclisation; 7-Membered ring.
*
Corresponding author. Tel.: C61 2 42214255; fax: C61 2 42214287; e-mail: john_bremner@uow.edu.au
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.133

5490
J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 5489–5498
Scheme 2. (a) (i) NaH, DMF (ii) 2-BrPhNCO; (b) (i) NaH, THF (ii) R0-X; (c) Pd(OAc)2, P(Ph)3, Bu4NCBrK, K2CO3, DMF, 120 8C; (d) 25% NaOH, EtOH;
(e) ClCH2COCl, K2CO3, THF.
relies on a preformed 7-membered ring (3) and construction
of the fused indole moiety by formation of the N12–C12a
and C7a–C7b bonds by Fischer indolisation with phenylhy-
drazines (Scheme 1). Examples of the first, strategy include
cyclisation8 of (1, R1ZTos, R2ZH, R3ZCOOH, R4ZEt
and Me) with HBr/AcOH to afford (2) with a 4-ethyl and
3-methyl substituent, and of (1, R1ZH, R2ZH, R3ZCN,
R4ZH), with NaOH/MeOH/H2O to give9 (2, RZH, R4ZH)
in 51% yield. In the latter case, assembly of the 2-arylindole
precursor (1) was based on a borylation/Suzuki coupling
strategy. Examples of the second paullone synthesis strategy
include the preparation10,11 of the benzazepinedione (3,
R4Z7-I) in a few step synthesis from 5-iodoanthranilic acid
and Fischer indolisation with 4-trifluoromethylphenyl-
hydrazine to give (2, RZCF3, R4Z2-I) in 50% yield from
(3), a subsequent Heck reaction was used to prepare other
substituted derivatives of (2).
7-membered ring via C7–C7a bond formation, is now
reported in this paper.
2. Results and discussion
The indolyl substrates (13, 14) (Scheme 2) required
ultimately for the radical cyclisation were prepared from
the amines 11 and 12, which in turn were accessed via a new
route developed for 2-(2-aminoaryl)indoles.
This route began with reaction of the appropriate indole 5
with 2-bromophenyl isocyanate to give the ureas 6 in
moderate yields, these ureas were then N-alkylated to give
the N-methyl (7) or N-benzyl (8) derivatives, respectively.
Palladium-mediated cyclisation of 7 and 8 then gave the
indolo[1,2-c]quinazolinones 9 and 10 in good yields.13 The
loss of the indole H-2 proton and the bromo substituent in
1
these products was apparent from the H and 13C NMR
The key benzazepinedione precursor of (2) has also been
accessed by ring expansion of 1,4-naphthoquinone12 or
7-methoxytetralone.11 A new alternative approach to the
paullone system and derivatives (2), based on a free radical
cyclisation of an indole-haloacetamide precursor to form the
spectra, together with the mass spectrometric data. Base-
induced hydrolysis and decarboxylation of the quinazoline
ring then afforded the intermediate amines 11 and 12. These
amines tended to be unstable14 and contained coloured
Scheme 3. (a) NaI, CH3CN; (b) Bu3SnH, AIBN, boiling solvents.

J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 5489–5498
5491
Table 1. Free radical cyclisation of iodoacetamides 15a–c with Bu3SnH/AIBN in boiling solvents
Entry
Substrate
mmol
Solvent
Product (%)
16
17
1
2
3
4
5
6
15a
15a
15a
15a
15b
15c
0.13
0.36
0.15
0.13
0.11
0.10
Toluene
Toluene
Toluene
Mesitylene
Mesitylene
Mesitylene
25
—
8
52
25a
45
—
10
13
—
—
—
a Compound 18 was also isolated in 30% yield.
contaminants so they were acylated directly by reaction
with chloroacetyl chloride to give the chloroacetamides 13
1
and 14, which could be readily purified. In the H NMR
spectra of 13 and 14, a diagnostic signal appeared at d
6.40–6.64 for the H-3 proton, while the methylene of the
chloroacetmide was ascribed to a signal at ca. d 3.8.
Scheme 4.
In order to increase the proportion of cisoid indoacetamide
rotamer required for cyclisation,7 only the more bulky
N-benzyliodoacetamides 15 were subjected to free radical
cyclisation. Thus, conversion of the chloroacetamides 14 to
the iodoacetamides 15 by iodide exchange followed by
reaction with tributyltin hydride (Bu3SnH) in the presence
of azobisisobutyronitrile (AIBN) then afforded the
N-benzylated paullone derivatives 16a–c. The product of
spirocyclisation 17a, a new heterocyclic derivative, was
also observed (Scheme 3) in the case of the reaction of 15a
in toluene.
16a with sodium in liquid ammonia at K60 8C for 10 min
afforded the known17 paullone 19 (RZH) in 40% yield
(Scheme 4).
3. Conclusions
It has been shown that free radical cyclisation of indolyl
iodoacetamide derivatives is a viable new approach to the
pharmacologically significant paullone ring system. New
palladium-mediated methodology for the construction of
2-(2-aminoaryl)indoles has also been developed as part of
this work. Both this methodology and free radical cyclisa-
tion have the potential for synthesis of a variety of new
paullone analogues and derivatives.
At higher reaction temperatures (boiling mesitylene), yields
of the required paullone system were significantly
increased. In the case of 15b, reaction in mesitylene also
afforded some of the indolo[1,2-d][1,4]benzodiazepine-6-
one 18, from nucleophilic cyclisation at the indolic nitrogen.
Other related compounds containing this ring system have
been reported previously (Table 1).15
4. Experimental
4.1. General
In the 1H NMR spectra of 16a–c, no signal which could be
attributed to an indolic H-3 proton was seen, while a new
quaternary carbon signal appeared downfield at ca. d 110–
111 in the 13C NMR spectra. With the spiro derivative 17a,
Melting points were determined using a Reichert hot-stage
melting point apparatus and are uncorrected. NMR spectra
were recorded on a Varian Unity-300 Fourier transform
NMR spectrometer. Unless otherwise stated, the spectra
were obtained from solutions in CDCl3 and referenced to
TMS (proton) and chloroform mid-line (77 ppm) (carbon).
Chemical shifts are reported in parts per million (d). Where
on aromatic proton signal appeared as a triplet of doublets
(td) in the 1H NMR, the first, coupling constant given is for
both identical ortho couplings. MS were obtained using a
Shimadzu QP-5000 spectrometer. High resolution MS were
run using a Fisons/VG Autospec-TOF spectrometer. IR
spectra were recorded on a BOMEM MB-100 FTIR. TLC
and preparative thin layer chromatography was performed
using Merck silica gel 60 F254. All chromatographic solvent
proportions are volume to volume. Column chromatography
(silica gel; flash column or normal column) was performed
using Merck Kieselgel 60 (0.063–0.200 nm particle size).
Solvents were removed under reduced pressure by a Bu¨chi
rotary evaporator, and organic solvent extracts were dried
with anhydrous Na2SO4. Solvent mixtures are v/v ratios.
1
both the H and 13C NMR spectra had signals consistent
with the presence of three methylene groups, while the
molecular formula was supported by the high resolution
mass spectrum.
Mechanistically, the paullone system 16 could arise either
via a 7-endo-trig addition of the amidomethyl radical
(from the cisoid iodoacetamide), followed by oxidation, or
by 6-exo-trig addition at the indole C-2 position followed
by rearrangement and oxidation. Rearrangement could
compete with hydrogen atom abstraction by the indolic
C-3 radical which would afford 17. A related 5-exo-trig
spirocyclisation of a carbon centred radical onto the C-2
position of indole, resulting in dearomatisation after
hydrogen abstraction, has been reported recently.16
In order to access the paullone system itself in which
the lactam moiety is not N-substituted, the feasibility of
chemoselective N-debenzylation with sodium in liquid
ammonia was investigated in the case of 16a. Reaction of

5492
J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 5489–5498
Petroleum spirit (pet. spirit) refers to the boiling point range
40–60 8C.
9.62 mmol) to give 6c (1.3 g, 53%) as white needles; mp
108–110 8C; H NMR (CDCl3) d 6.70 (d, JZ3.6 Hz, 1H,
1
H-3), 7.06 (t, JZ8.4 Hz, 1H, H-40), 7.14 (td, JZ9.0, 2.7 Hz,
1H, H-6), 7.29 (dd, JZ9.0, 2.4 Hz, 1H, H-4), 7.41 (t, JZ
7.8 Hz, 1H, H-50), 7.63 (m, 2H, H-2 and H-30), 7.93 (br s,
1H, NH), 8.23 (dd, JZ9.0, 4.5 Hz, 1H, H-7), 8.34 (d, JZ
8.1 Hz, 1H, H-60); 13C NMR (CDCl3) d 106.9 (d, JZ
23.8 Hz, 13C–19F, C4–F), 108.5 (d, JZ3.9 Hz, 13C–19F,
C3–F), 113.0 (d, JZ25.2 Hz, 13C–19F, C6–F), 114.00 (C-20),
4.2. General procedure for the preparation of ureas
(6a–c)
To a stirred suspension of sodium hydride (NaH) (60%
dispersion in mineral oil, 1.1 equiv) in dry DMF (10 mL) at
0–5 8C was added a solution of the indole 5 (1.0 equiv) in
dry DMF (40 mL) under a nitrogen atmosphere and the
solution was then stirred at rt for 2 h. An excess of DMF
(20 mL) was then added and the mixture was cooled to
K60 8C. 2-Bromophenyl isocyanate (1.2 equiv) in DMF
(20 mL) was slowly added and the reaction mixture was
stirred at rt overnight. Solvent was evaporated and DCM
(30 mL) was added and then washed with water several
times. The organic layer was dried, concentrated and
chromatographed on a column by elution with 10%
EtOAc/pet. spirit.
13
115.8 (d, JZ9.2 H0z, C–19F, C7–F), 121.8 (C-6 ), 125.1
(C-2), 125.7 (C-4 ), 128.9 (C-50), 131.3 (C-3a), 132.1
(C-7a), 132.6 (C-30), 135.3 (C-10), 148.9 (CO), 159.5 (d, JZ
238.0 Hz, 13C–19F, C5–F); CI-MS m/z 333 ([MCH; 79Br]C,
100%), 335 ([MCH; 81Br]C, 95%); HRCI-MS m/z calcd for
[MCH]C C15H11N2O2F81Br: 335.0018, found: 335.0006.
4.3. General procedure for the N-methylation of the
ureas (6a–c)
To a stirred suspension of sodium hydride (NaH) (60%
dispersion in mineral oil, 1.1 equiv) in dry THF (10 mL) at
0–5 8C was added a solution of the urea 6a–c (1.0 equiv) in
dry THF (40 mL) under a nitrogen atmosphere. The solution
was stirred at rt for 2 h., and a solution of methyl iodide
(2.5 equiv) in THF (10 mL) was added, and then the
reaction mixture was stirred at rt overnight. THF was
evaporated and water (15 mL) was added and the mixture
extracted with DCM (3!20 mL). The combined DCM
extracts were dried, concentrated and chromatographed on a
column by elution with 10% EtOAc/pet. spirit.
4.2.1. N-(2-Bromophenyl)-1H-indole-1-carboxamide
(6a). Following the general procedure, NaH (0.12 g,
2.80 mmol) was reacted with a solution of 5a (0.30 g,
2.56 mmol) and 2-bromophenyl isocyanate (0.40 mL,
3.28 mmol) to give 6a (0.35 g, 43%) as white needles; mp
120–121 8C; IR (KBr) nmax: 3258 (NH), 1676 (C]O) cmK1
;
1H NMR (CDCl3) d 6.73 (dd, JZ3.3, 0.9 Hz, 1H, H-3), 7.05
(td, JZ7.2, 1.5 Hz, 1H, H-40), 7.29 (dd, JZ8.1, 0.9 Hz, 1H,
H-4), 7.36 (m, 2H, H-6 and H-50), 7.60 (m, 3H, H-2, H-5 and
H-30), 8.00 (br s, 1H, NH), 8.25 (d, JZ8.1 Hz, 1H, H-7),
8.36 (dd, JZ8.7, 1.5 Hz, 1H, H-60); 13C NMR (CDCl3) d
108.6 (C-3), 113.9 (C-20), 114.5 (C-7), 121.7 (C-60), 121.8
(ArC–H), 123.1 (C-4), 124.1 (ArC–H), 125.0 (ArC–H),
125.6 (C-40), 128.9 (ArC–H), 130.7 (C-3a), 132.6 (ArC–H),
135.4 (C-7a), 135.5 (C-10), 149.2 (CO); CI-MS m/z 315
([MCH; 79Br]C, 100%), 317 ([MCH; 81Br]C, 99%);
HRCI-MS m/z calcd for [MCH]C C15H12N2O79Br:
315.0133, found: 315.0091.
4.3.1. N-(2-Bromophenyl)-N-methyl-1H-indole-1-carb-
oxamide (7a). NaH (60% dispersion in mineral oil,
13 mg, 0.33 mmol) was reacted with a solution of 6a
(94 mg, 0.30 mmol) and methyl iodide (38 mL, 0.60 mmol)
to give 7a (73 mg, 76%) as a white solid; mp 136–137 8C;
1
IR (KBr) nmax: 1688 (C]O) cmK1; H NMR (CDCl3) d
3.42 (s, 3H, CH3), 6.25 (dd, JZ3.3, 0.9 Hz, 1H, H-3), 6.79
(d, JZ3.9 Hz, 1H, H-2), 7.08–7.13 (m, 2H, H-5 and H-50),
7.15–7.25 (m, 2H, H-30 and H-40), 7.32 (td, JZ7.8, 1.2 Hz,
1H, H-6), 7.46 (dd, JZ7.8, 0.6 Hz, 1H, H-4), 7.61 (dd, JZ
7.8, 1.8 Hz, 1H, H-60), 8.11 (dd, JZ7.2, 0.6 Hz, 1H, H-7);
13C NMR (CDCl3) d 39.0 (CH3), 106.5 (C-3), 114.9 (C-7),
120.8 (C-4), 122.30(C-20), 122.5 (C-5), 124.1 (C-6), 125.9
(C-2), 129.1 (C-3 ), 129.3 (C-40), 129.36 (C-500), 129.4
(C-3a), 134.4 (C-60), 136.6 (C-7a), 143.6 (C-1 ), 154.1
(CO); CI-MS m/z 329 ([MCH; 79Br]C, 100%), 331 ([MC
H; 81Br]C, 97%); HRCI-MS m/z calcd for [MCH]C
C16H14N2O79Br: 329.0289, found: 329.0283.
4.2.2. N-(2-Bromophenyl)-5-methoxy-1H-indole-1-car-
boxamide (6b). Following the general procedure, NaH
(0.18 g, 4.49 mmol) was reacted with a solution of 5b
(0.60 g, 4.08 mmol) and 2-bromophenyl isocyanate
(0.64 mL, 5.22 mmol) to give 6b (0.80 g, 56%) as white
1
needles; mp 117–118 8C; H NMR (CDCl3) d 3.82 (s, 3H,
OCH3), 6.67 (dd, JZ3.6, 0.9 Hz, 1H, H-3), 7.02 (dd, JZ9.0,
2.4 Hz, 1H, H-6), 7.04 (td, JZ7.8, 2.4 Hz, 1H, H-40), 7.10
(d, JZ3.0 Hz, 1H, H-4), 7.40 (td, JZ8.7, 1.5 Hz, 1H, H-50),
7.58 (d, JZ3.9 Hz, 1H, H-2), 7.60 (dd, JZ8.4, 1.2 Hz, 1H,
H-30), 7.95 (br s, 1H, NH), 8.14 (d, JZ9.0 Hz, 1H, H-7),
8.35 (dd, JZ8.1, 1.5 Hz, 1H, H-60); 13C NMR (CDCl3) d
55.7 (OCH3), 103.8 (C-4), 108.2 (C-3), 113.6 (C-20), 113.7
(C-6), 115.1 (C-7), 121.5 (C-60), 124.3 (C-2), 125.3 (C-400),
128.7 (C-50), 130.3 (C-3a), 131.3 (C-7a), 132.4 (C-3 ),
135.3 (C-10), 148.7 (COCH3), 156.0 (CO); CI-MS m/z 345
([MCH; 79Br]C, 100%), 347 ([MCH; 81Br]C, 99%);
HRCI-MS m/z calcd for [MCH]C C16H14N2O281Br:
347.0218, found: 347.0204.
4.3.2. N-(2-Bromophenyl)-5-methoxy-N-methyl-1H-
indole-1-carboxamide (7b). NaH (60% dispersion in
mineral oil, 34 mg, 0.70 mmol) was reacted with a solution
of 6b (0.22 g, 0.64 mmol) and methyl iodide (0.10 mL,
1.60 mmol) to give 7b (0.20, 88%) as a white solid; mp
1
130–132 8C; IR (KBr) nmax: 1685 (C]O) cmK1; H NMR
(CDCl3) d 3.39 (s, 3H, NCH3), 3.80 (s, 3H, OCH3), 6.18 (dd,
JZ3.6, 0.6 Hz, 1H, H-3), 6.74 (d, JZ3.6 Hz, 1H, H-2), 6.92
(s, 1H, H-4), 6.93 (dd, JZ8.4, 2.4 Hz, 1H, H-6), 7.07–7.12
(m, 2H, H-40 and H-50), 7.19 (dd, JZ6.9, 1.2 Hz, 1H, H-30),
7.60 (dd, JZ7.8, 1.8 Hz, 1H, H-60), 8.00 (dd, JZ8.7,
0.6 Hz, 1H, H-7); 13C NMR (CDCl3) d 39.0 (CH3), 55.9
(OCH3), 103.1 (C-4), 106.4 (C-3), 113.3 (C-6), 115.7 (C-7),
4.2.3. N-(2-Bromophenyl)-5-fluoro-1H-indole-1-carbox-
amide (6c). Following the general procedure, NaH (0.39 g,
8.14 mmol) was reacted with a solution of 5c (1.0 g,
7.40 mmol) and 2-bromophenyl isocyanate (1.20 mL,

J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 5489–5498
5493
122.3 (C-20), 126.5 (C-2), 129.1, 129.2 (C-40 or C-50), 129.4
(C-300), 130.1 (C-3a), 131.4 (C-7a), 134.4 (C-60), 143.7
(C-1 ), 154.1 (COCH3), 155.9 (CO); CI-MS m/z 359
([MCH; 79Br]C, 100%), 361 ([MCH; 81Br]C, 95%);
HRCI-MS m/z calcd for [MCH]C C17H15N2O279Br:
359.0395, found: 359.0391.
4.4.2. N-Benzyl-N-(2-bromophenyl)-5-methoxy-1H-
indole-1-carboxamide (8b). A suspension of NaH (ca.
50% dispersion in mineral oil, 44 mg, 0.91 mmol) was
reacted with a solution of 6b (0.24 g, 0.70 mmol), tert-
butylammonium iodide (3.5 mg) and benzyl bromide
(0.13 mL, 1.05 mmol) to give 8b (0.25 g, 81%) as a while
1
solid; mp 117–118 8C; H NMR (500 MHz, CDCl3) d 3.79
(s, 3H, CH3), 4.66 (br s, 1H, CHH), 5.34 (br s, 1H, CHH),
6.08 (dd, JZ3.5 Hz, 1H, H-3), 6.69–6.71 (m, 2H, H-2 and
Ar), 6.82 (s, 1H, H-4), 06.83 (dd, JZ9.0, 2.5 Hz, 1H, H-60)0,
6.95–6.98 (m, 2H, H-5 and Ar), 7.17–7.19 (m, 3H, H-3 ,
H-500 and Ar), 7.24 (dd, JZ6.5, 2.5 Hz, 2H, H-200 and H-600),
7.46 (dd, JZ6.5, 2.5 Hz, 1H, H-60), 7.94 (d, JZ9.0 Hz, 1H,
H-7); 13C NMR (125 MHz, CDCl3) d 54.0 (CH2), 55.6
(CH3), 102.8 (C-4), 106.1 (C-3), 113.0 (C-6), 115.6 (C-7),
122.6 (C-20), 126.1 (C-2), 127.7 (ArC–H), 128.3 (C-300 and
C-500), 128.4, 128.8, 129.3 (all ArC–H), 129.8 (C-3a), 130.3
(C-200 and C-600), 131.3 (C-7a), 134.0 (C-60), 136.2 (C-100),
141.3 (C-10), 153.5 (CO), 155.6 (COCH3); CI-MS m/z 335
([MCH; 79Br]C, 100%), 337 ([MCH; 81Br]C, 95%);
HRCI-MS m/z calcd for [MCH]C C23H20N2O281Br:
437.0688, found: 437.0669.
4.3.3. N-(2-Bromophenyl)-5-fluoro-N-methyl-1H-indole-
1-carboxamide (7c). NaH (60% dispersion in mineral oil,
40 mg, 0.83 mmol) was reacted with a solution of 6c
(0.25 g, 0.75 mmol) and methyl iodide (0.12 mL,
1.88 mmol) to give 7c (0.18 g, 69%) as a white solid; mp
1
133–134 8C; IR (KBr) nmax: 1689 (C]O) cmK1; H NMR
(CDCl3) d 3.42 (s, 3H, CH3), 6.22 (dd, JZ3.6, 0.6 Hz, 1H,
H-3), 6.83 (d, JZ3.3 Hz, 1H, H-2), 7.04 (td, JZ9.0, 2.7 Hz,
1H, H-60), 7.09–7.16 (m, 3H, Ar), 7.24 (td, 0JZ6.9, 1.5 Hz,
1H, H-5 ), 7.61 (td, JZ7.5, 0.6 Hz, 1H, H-6 ), 8.06 (dd, JZ
8.7, 4.2 Hz, 1H, H-7); 13C NMR (CDCl3) d 39.1 (CH3),
106.1 (d, JZ23.6 Hz, 13C–19F, C6–F), 106.3 (d, JZ3.9 Hz,
13C–19F, C3–F), 112.4 (d, JZ25.2 Hz, 13C–19F, C4–F),
13
115.9 (d, JZ9.2 Hz, C–19F, C7–F), 122.4 (C-20), 127.5
(C-2), 129.1, 129.4, 129.45 (all ArC–H), 130.1 (d, JZ
10.30Hz, 13C–19F, C3a–F), 133.0 (C-7a), 134.5 (C-60), 143.4
(C-1 ), 155.8 (d, JZ286.3 Hz, 13C–19F, C5–F), 160.9 (CO);
CI-MS m/z 347 ([MCH; 79Br]C, 100%), 349 ([MCH;
81Br]C, 95%); HRCI-MS m/z calcd for [MCH]C
C16H13N2O2F79Br: 347.0195, found: 347.0194.
4.4.3. N-Benzyl-N-(2-bromophenyl)-5-fluoro-1H-indole-
1-carboxamide (8c). A suspension of NaH (ca. 50%
dispersion in mineral oil, 44 mg, 0.91 mmol) was reacted
with a solution of 6c (0.23 g, 0.70 mmol), tert-butylammo-
nium iodide (3.5 mg) and benzyl bromide (0.13 mL,
1.05 mmol) to give 8c (0.27 g, 91%) as a while solid; mp
116–118 8C; 1H NMR (CDCl3) d 4.64 (br s, 1H, CHH), 5.36
(br s, 1H, CHH), 6.14 (d, JZ3.6 Hz, 1H, H-3), 6.77 (m, 1H,
H-30), 6.80 (d, JZ3.6 Hz, 1H, H-2), 6.94–7.06 (m, 4H, Ar),
7.20–7.25 (m, 3H, H-300, H-500 and Ar), 7.29–7.32 (m, 2H,
H-200 and H-600), 7.50 (m, 1H, H-60), 8.05 (d, JZ9.0, 4.5 Hz,
1H, H-7); 13C NMR (CDCl3) d 54.4 (CH2), 106.11 (d, JZ
20.0 Hz, 13C–19F, C6–F), 106.3 (C-3), 112.1 (d, JZ25.2 Hz,
13C–019F, C4–F), 116.1 (d, JZ9.2 Hz, 13C–19F, C7–F), 113.0
4.4. General procedure for the N-benzylation of the
ureas (6a–c)
To a suspension of NaH (ca. 50% dispersion in mineral oil,
1.3 equiv) in dry DMF (10 mL) at 0 8C was added a solution
of the urea 6a–c (1.0 equiv) in DMF (30 mL) followed by
addition of a catalytic amount of tert-butylammonium
iodide. After 30 min, a solution of benzyl bromide
(1.5 equiv) in DMF (20 mL) was added and the reaction
mixture was stirred for 16 h at rt. The DMF was then
evaporated, DCM (20 mL) was added to the residue and the
solution washed with water several times. The DCM phase
was dried, concentrated and subjected to flash column
chromatography (silica gel, 10% EtOAc/pet. spirit).
00
(C-2 ), 127.4 (C-2), 128.2 (ArC–H), 128.7 (C-300 and C-5 ),
00
129.0 (ArC–H), 129.4 (ArC–H), 129.7 (C-200 and C-6 ),
130.1 (d, JZ9.8 Hz, 130 C–19F, C3a–F), 130.6 (ArC–H),
133.2 (C-7a), 134.4 (C-6 ), 136.4 (C-100), 154.0 (C-10), 159.9
(d, JZ285.0 Hz 13C–19F, C5–F), 171.8 (CO); CI-MS m/z
423 ([MCH; 79Br]C, 100%), 425 ([MCH; 81Br]C, 95%);
HREI-MS m/z calcd for [M]C C22H16N2OF81Br: 424.0410,
found: 424.0415.
4.4.1. N-Benzyl-N-(2-bromophenyl)-1H-indole-1-carb-
oxamide (8a). A suspension of NaH (ca. 50% dispersion
in mineral oil, 88 mg, 1.80 mmol) was reacted with a
solution of 6a (0.44 g, 1.40 mmol), tert-butylammonium
iodide (7 mg) and benzyl bromide (0.26 mL, 2.10 mmol) to
give 8a (0.35 g, 62%) as a while solid; mp 109–111 8C; 1H
NMR (CDCl3) d 4.63 (br s, 1H, CHH), 5.38 (br s, 1H, CHH),
6.21 (d, JZ3.9 Hz, 1H, H-3), 6.74 (m, 1H, H-30), 6.80 (d,
JZ3.6 Hz, 1H, H-2), 7.00–7.04 (m, 2H, H-40 and H-50),
7.14 (td, JZ7.5, 0.6 Hz, 1H, H-5), 7.20–7.27 (m, 3H, H-6,
H-300 and H-500), 7.30–7.34 (m, 3H, H-200, H-400 and0H-600),
7.42 (dd, JZ7.5, 0.3 Hz, 1H, H-4), 7.53 (m, 1H, H-6 ), 8.11
(d, JZ8.4 Hz, 1H, H-7); 13C NMR (CDCl3) d 54.3 (CH2),
106.5 (C-3), 115.1 (C-7), 120.9 (C-4), 122.6 (C-5), 123.0
(C-20), 124.1 (C-6), 125.9 (C-2), 128.1 (C-400), 128.7 (C-300
and C-500), 128.9, 129.3 (C-40 and C-50), 129.4 (C-3a), 129.7
(C-200 and 0C0 -600), 130.7 (C-30), 134.4 (C-60), 136.5 (C-7a),
136.8 (C-1 ), 141.4 (C-10), 153.9 (CO); EI-MS m/z 404 ([M;
79Br]C, 49%), 406 ([M; 81Br]C, 52%); HREI-MS m/z calcd
for [M]C C22H17N2O79Br: 404.0524, found: 404.0525.
4.5. Palladium cyclisation procedure
A mixture of the urea 7–8 (1 equiv), palladium acetate
(Pd(OAc)2) (0.33 equiv), triphenylphosphine (P(Ph)3)
(0.2 equiv), tert-butylammonium bromide (Bu4NBr)
(1 equiv) and K2CO3 (2 equiv) in dry DMF (13 mL) was
heated at 120 8C under an Ar atmosphere for 3 h. After
cooling, the DMF was evaporated, and then DCM (15 mL)
was added and washed with water several times. The DCM
layer was washed with brine, dried, evaporated and
subjected to flash column chromography (silica gel, 9:1
pet. spirit/EtOAc).
4.5.1. 5-Methylindolo[1,2-c]quinazolin-6(5H)-one (9a).
Treatment of 7a (50 mg, 0.15 mmol), Pd(OAc)2 (12 mg,
0.05 mmol), P(Ph)3 (8 mg, 0.03 mmol), Bu4NBr (49 mg,
0.15 mmol) and K2CO3 (42 mg, 0.30 mmol) gave 9a

5494
J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 5489–5498
(31 mg, 87%) as white needles; mp 181–183 8C; IR (KBr)
nmax: 1677 (C]O) cmK1; 1H NMR (CDCl3) d 3.71 (s, 3H,
CH3), 7.03 (d, JZ0.6 Hz, 1H, H-12), 7.22 (td, JZ8.1,
0.9 Hz, 1H, H-3), 7.24 (td, JZ7.5, 0.9 Hz, 1H, H-10), 7.35–
7.46 (m, 3H, H-2, H-9, H-10), 7.68 (ddd, JZ6.0, 2.1,
0.9 Hz, 1H, H-1), 7.92 (dd, JZ8.1, 1.8 Hz, 1H, H-4), 8.69
(ddd, JZ5.7, 2.7, 0.9 Hz, 1H, H-8); 13C NMR (CDCl3) d
30.4 (CH3), 98.3 (C-12), 114.5 (C-8), 115.6 (C-12b), 116.5
(C-11), 120.3 (C-9), 123.3, 123.7, 123.9 (all ArC–H), 124.0
(C-1), 129.4 (C-3), 130.1 (C-12a), 133.3 (C-11a), 134.6
(C-4a), 135.8 (C-7a), 148.2 (CO); CI-MS m/z 249 ([MC
H]C, 100%); HRCI-MS m/z calcd for [MCH]C
C16H13N2O: 249.1028, found: 249.1021.
115.5 (C-9), 115.9 (C-12b), 116.7 (C-8), 120.3 (C-11),
123.5, 123.9, 124.10 (all ArC–H), 124.12 (C-4), 126.7 (C-20
and C-60), 127.7 (ArC–H), 129.1 (C-30 and C-50), 129.4
(ArC–H), 130.2 (C-11a), 133.4 (C-12a), 134.7 (C-4a), 135.2
(C-7a), 136.5 (C-10), 148.6 (CO); EI-MS m/z 324 ([M]C,
50%); HREI-MS m/z calcd for [M]C C22H16N2O: 324.1263,
found: 324.1261.
4.5.5. 5-Benzyl-10-methoxyindolo[1,2-c]quinazolin-
6(5H)-one (10b). Treatment of 8b (0.25 g, 0.57 mmol),
Pd(OAc)2 (52 mg, 0.23 mmol), P(Ph)3 (39 mg, 0.15 mmol),
Bu4NBr (0.24 g, 0.73 mmol) and K2CO3 (0.20 g,
1.48 mmol) gave compound 10b (0.18 g, 89%) as a while
1
solid; mp 214–215 8C; H NMR (CDCl3) d 3.91 (s, 3H,
4.5.2. 10-Methoxy-5-methylindolo[1,2-c]quinazolin-
6(5H)-one (9b). Treatment of 7b (0.15 g, 0.42 mmol),
Pd(OAc)2 (40 mg, 0.18 mmol), P(Ph)3 (22 mg, 0.08 mmol),
Bu4NBr (0.14 g, 0.42 mmol) and K2CO3 (0.12 g,
0.84 mmol) gave the title compound 9b (65 mg, 55%); mp
CH3), 5.52 (s, 2H, CH2), 7.02 (dd, JZ9.0, 2.7 Hz, 1H, H-9),
7.03 (s, 1H, H-12), 7.14 (s, 1H, H-11), 7.15 (t, JZ9.3 Hz,
1H, H-3), 7.02–7.33 (m, 7H, Ar), 7.94 (dd, JZ7.8, 1.2 Hz,
1H, H-4), 8.61 (d, JZ9.0 Hz, 1H, H-8); 13C NMR (CDCl3)
d 47.0 (CH2), 55.9 (CH3), 98.3 (C-12), 102.3 (C-8), 113.1
(C-11), 115.5 (C-9), 115.7 (C-12b), 117.4, 123.4, 124.0
(all ArC–H), 126.7 (C-20 and C-60), 127.7 (ArC–H), 129.1
(C-30and C-50), 129.3 (ArC–H), 129.5 (C-11a), 131.2
(C-12a), 134.0 (C-4a), 135.1 (C-7a), 136.5 (C-10), 148.0
(CO), 157.0 (COCH3); CI-MS m/z 355 ([MCH]C, 100%);
HREI-MS m/z calcd for [M]C C23H18N2O2: 354.1368,
found: 354.1386.
1
146–147 8C; H NMR (CDCl3) d 3.73 (s, 3H, NCH3), 3.90
(s, 3H, OCH3), 6.99 (s, 1H, H-12), 7.00 (dd, JZ9.0, 2.7 Hz,
1H, H-9), 7.12 (d, JZ2.7 Hz, 1H, H-11), 7.22–7.28 (m, 2H,
H-1 and H-3), 7.44 (td, JZ7.5, 1.5 Hz, 1H, H-2), 7.94 (dd,
JZ7.8, 1.5 Hz, 1H, H-4), 8.57 (d, JZ9.3 Hz, 1H, H-8); 13C
NMR (CDCl3) d 30.4 (CH3), 55.8 (OCH3), 98.1 (C-12),
102.2 (C-8), 113.0 (C-11), 114.5 (C-9), 115.5 (C-12b),
117.3, 123.3, 123.9 (all ArC–H), 129.4 (C-12a), 131.0
(C-11a), 133.9 (C-4a), 135.8 (C-7a), 148.2 (CO), 156.8
(COCH3); CI-MS m/z 279 ([MCH]C, 100%); HRCI-MS
m/z calcd for [MCH]C C17H15N2O2: 279.1134, found:
279.1122.
4.5.6. 5-Benzyl-10-fluoroindolo[1,2-c]quinazolin-6(5H)-
one (10c). Treatment of 8c (0.27 g, 0.64 mmol), Pd(OAc)2
(58 mg, 0.26 mmol), P(Ph)3 (45 mg, 0.0917 mmol),
Bu4NBr (0.26 g, 0.82 mmol) and K2CO3 (0.22 g,
1.66 mmol) gave the title compound 10c (0.15 g, 69%) as
a white solid; mp 185–186 8C; 1H NMR (CDCl3) d 5.45 (s,
2H, CH2), 6.97 (s, 1H, H-12), 7.03 (td, JZ9.0, 2.4 Hz, 1H,
H-9), 7.07 (d, JZ8.1 Hz, 1H, H-1), 7.15 (t, JZ8.1 Hz, 1H,
H-3), 7.18–7.28 (m, 7H, Ar), 7.87 (d, JZ7.5 Hz, 1H, H-4),
8.59 (dd, JZ9.0, 5.1 Hz, 1H, H-8); 13C NMR (CDCl3), d
47.1 (CH2), 98.2 (d, JZ4.6 Hz, 13C–19F, C12–F), 105.5 (d,
JZ23.8 Hz, 13C–19F, C11–F), 111.8 (d, JZ25.2 Hz,
13C–19F, C9–F), 115.4 (C-12b), 115.6 (C-4), 117.8 (d, JZ
9.4 Hz, 13C–19F, C8–F), 123.6 (ArC–H), 124.2 (ArC–H),
126.7 (C-20 and C-60), 127.8 (ArC–H), 129.2 (C-30 and
C-50), 129.8 (ArC–H), 131.1 (C-11a), 131.2 (C-12a), 134.9
(C-4a), 135.2 (C-7a), 136.3 (C-10), 148.4 (CO), 160.2 (d,
JZ238.5 Hz, 13C–19F, C10–F); CI-MS m/z 343 ([MCH]C,
100%); HRCI-MS m/z calcd for [MCH]C C22H16N2OF:
343.1247, found: 343.1249.
4.5.3. 10-Fluoro-5-methylindolo[1,2-c]quinazolin-6(5H)-
one (9c). Treatment of 7c (0.10 g, 0.29 mmol), Pd(OAc)2
(24 mg, 0.10 mmol), P(Ph)3 (16 mg, 0.06 mmol), Bu4NBr
(49 mg, 0.15 mmol), and K2CO3 (42 mg, 0.30 mmol) gave
compound 9c (59 mg, 76%) as offwhite needles; mp 188–
189 8C; 1H NMR (CDCl3) d 3.66 (s, 3H, CH3), 6.89 (s, 1H,
H-12), 7.05 (td, JZ9.0, 2.7 Hz, 1H, H-9), 7.16 (d, JZ
8.7 Hz, 1H, H-1), 7.19–7.25 (m, 2H, H-2 and H-11), 7.41
(ddd, JZ8.1, 7.5, 1.2 Hz, 1H, H-3), 7.84 (dd, JZ7.8,
1.2 Hz, 1H, H-4), 8.57 (dd, JZ9.0, 5.1 Hz, 1H, H-8); 13C
NMR (CDCl3) d 30.4 (CH3), 97.8 (d, JZ4.3 Hz, 13C–19F,
C12–F), 105.3 (d, JZ23.8 Hz, 13C–19F, C11–F), 111.6
(d, JZ25.2 Hz, 13C–19F, C9–F), 114.5 (C-4), 115.0 (C-12b),
117.5 (d, JZ9.4 Hz, 13C–19F, C8–F), 123.7 (C-2), 124.0
(C-3), 129.7 (C-1), 130.8 (C-11a), 131.0 (C-12a), 134.7
(C-4a), 135.8 (C-7a), 147.8 (CO), 160.0 (d, JZ238.5 Hz,
13C–19F, C10–F); CI-MS m/z 267 ([MCH]C, 100%);
HRCI-MS m/z calcd for [MCH]C C17H12N2OF:
267.0934, found: 267.0926.
4.6. General procedure for preparation of the
chloroacetamides (13a–c)
Compounds 9–10 were heated at reflux in 25% NaOH and
EtOH for 24 h. or until no starting material was observed
(determined by TLC; silica gel, 10% EtOAc/pet. spirit). The
EtOH was then evaporated and water (15 mL) was added
and extracted with DCM (3!15 mL). The organic layer
was separated, dried and concentrated to give a blue solid.
The solid was dried on a high pressure vacuum pump for
2–3 h and then K2CO3 (3.6 equiv) and dry THF (10 mL)
were added. The reaction mixture was stirred at 0–5 8C
under a N2 atmosphere for 30 min and a solution of
chloroacetyl chloride (2.5 equiv) in THF (3 mL) was then
added and the mixture stirred overnight at rt. The THF was
4.5.4. 5-Benzylindolo[1,2-c]quinazolin-6(5H)-one (10a).
Treatment of 8a (0.30 g, 0.74 mmol), Pd(OAc)2 (66 mg,
0.30 mmol), P(Ph)3 (52 mg, 0.20 mmol), Bu4NBr (0.31 g,
0.95 mmol), and K2CO3 (0.27 g, 1.92 mmol) gave 10a
(0.16 g, 66%) as a white solid; mp 141–143 8C; IR (KBr)
1
nmax: 1685 (C]O) cmK1; H NMR (500 MHz, CDCl3) d
5.54 (s, 2H, CH2), 7.12–7.16 (m, 2H, H-12 and H-9), 7.22
(td, JZ7.5 Hz, 1H, H-10), 7.26–7.34 (m, 6H, Ar), 7.39–7.41
(m, 2H, Ar), 7.72 (dd, JZ7.5, 2.1 Hz, 1H, H-11), 7.98 (d,
JZ7.5 Hz, 1H, H-4), 8.74 (dd, JZ8.0, 1.5 Hz, 1H, H-8);
13C NMR (125 MHz, CDCl3) d 47.0 (CH2), 98.6 (C-12),

J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 5489–5498
5495
evaporated to dryness and DCM (20 mL) was then added.
The reaction mixture was washed with water (3!10 mL)
and the DCM layer was separated, dried and concentrated.
The residue was subjected to preparative thin layer
chromatography (silica gel, 10% EtOAc/pet. spirit) to
isolate the chloroacetamide products.
d 37.3 (CH3), 41.9 (CH2Cl), 103.3 (d, JZ4.6 Hz, 13C–19F,
C3–F), 105.9 (d, JZ23.5 Hz, 13C–19F, C4–F), 111.9 (d,
JZ26.3 Hz, 13C–19F, C6–F), 112.2 (d, JZ9.5 Hz, 13C–19F,
C7–F), 129.2 (d, JZ10.4 Hz, 13C–19F, C3a–F), 1290.5
(C-60), 129.6, 129.7, 129.8 (all ArC–H), 130.2 (C-1 ),
133.7 (C-2), 135.0 (C-7a), 139.2 (C-20), 158.4 (d, JZ
234.2 Hz, 13C–19F, C5–F), 167.2 (CO); CI-MS m/z 317
([MCH; 35Cl]C, 100%); HREI-MS m/z calcd for [M]C
C17H14N2OF35Cl: 316.0779, found: 316.0778.
4.6.1. N-(2-(1H-Indol-2-yl)phenyl)-N-methylchloro aceta-
mide (13a). A mixture of 9a (26 mg, 0.10 mmol), 25%
NaOH (6 mL) and EtOH (10 mL) was heated at reflux for
24 h. After work up, the crude solid product was then
reacted with K2CO3 (50 mg, 0.43 mmol) and chloroacetyl
chloride (23 mL, 0.30 mmol) to give the title compound 13a
(21 mg, 70%) as a yellow solid; mp 84–86 8C; IR (KBr)
nmax: 3310 (NH), 1655 (C]O), 747 (C–Cl) cmK1; 1H NMR
(CDCl3) d 3.16 (s, 3H, CH3), 3.81 (d, JZ12.6 Hz, 1H,
CHHCl), 3.87 (d, JZ14.1 Hz, 1H, CHHCl), 6.56 (s, 1H,
H-3), 7.08 (t, JZ7.8 Hz, 1H, H-5), 7.18–7.59 (m, 2H, Ar),
7.30–7.39 (m, 2H, Ar), 7.45 (t, JZ7.8 Hz, 1H, H-500), 7.58
(d, JZ7.8 Hz, 1H, H-4), 7.69 (d, JZ8.1 Hz, 1H, H-6 ), 8.37
(br s, 1H, NH); 13C NMR (CDCl3) d 37.2 (CH3), 41.9
(CH2Cl), 103.6 (C-3), 111.3 (C-7), 120.8 (C-5), 121.3 (C-4),
123.5 (C-6), 129.0 (C-3a), 129.35, 129.4, 129.65, 129.7
(all ArC–H), 132.0 (C-10), 133.5 (C-2), 135.0 (C-7a), 140.0
(C-20), 167.3 (CO); CI-MS m/z 299 ([MCH; 35Cl]C,
100%); HRCI-MS m/z calcd for [MCH]C
C17H16N2O325Cl: 299.0951, found: 299.0945.
4.6.4. N-(2-(1H-Indol-2-yl)phenyl)-N-benzylchloro
acetamide (14a). A mixture of 10a (0.14 g, 0.10 mmol),
25% NaOH (27 mL) and EtOH (40 mL) was heated at reflux
for 24 h. After work up, the crude solid product was then
reacted with K2CO3 (0.23 g, 1.7 mmol) and chloroacetyl
chloride (96 mL, 1.20 mmol) to give the chloroacetamide
14a (0.20 g, 79%) as a yellow solid; mp 139–141 8C; IR
(KBr) nmax: 3311 (NH), 1638 (C]O), 745 (C–Cl) cmK1; 1H
NMR (CDCl3) d 3.74 (d, JZ13.5 Hz, 1H, CHHCl), 3.87 (d,
JZ13.2 Hz, 1H, CHHCl), 4.58 (d, JZ14.1 Hz, 1H, CHH),
5.17 (d, JZ13.8 Hz, 1H, CHH), 6.69 0(d, JZ2.4 Hz, 1H,
H-3), 7.03 (dd, JZ8.1, 1.2 Hz, 1H, H-3 ), 7.12 (m, 2H, Ar),
7.19 (m, 2H, Ar), 7.25 (m, 2H, Ar), 7.31 (m, 3H, Ar), 7.46
(td, JZ7.8, 1.5 Hz, 1H, H-50), 7.61 (dd, JZ7.5, 0.9 Hz, 1H,
H-4), 7.71 (dd, JZ7.8, 1.2 Hz, 1H, H-60), 7.86 (br s, 1H,
NH); 13C NMR (CDCl3) d 42.4 (CH2Cl), 53.7 (CH2), 103.6
(C-3), 111.4 (C-7), 120.6 (C-4), 121.1 (C-6), 123.3 (C-5),
128.5 (C-30), 128.6 (C-3a), 129.0 (C-200 and C-600), 129.1
(ArC–H), 129.6 (C-3000 and C-500), 129.9 (ArC–H), 130.1
(ArC–H), 131.0 (C-1 ), 133.6 (C-2), 136.2 (C-7a), 136.8
(C-20), 137.2 (C-100), 166.8 (CO); CI-MS m/z 375 ([MCH;
35Cl]C, 11%); HRCI-MS m/z calcd for [MCH]C
C23H20N2O35Cl: 375.1264, found: 375.1267.
4.6.2. N-(2-(5-Methoxy-1H-indol-2-yl)phenyl)-N-methyl
chloroacetamide (13b). A mixture of 9b (35 mg,
0.14 mmol), 25% NaOH (10 mL) and EtOH (25 mL) was
heated at reflux for 48 h. After work up, the crude solid
product was then reacted with K2CO3 (0.10 g, 0.74 mmol)
and chloroacetyl chloride (42 mL, 0.53 mmol) to give the
title compound 13b (29 mg, 64%) as a yellow solid; mp
88–89 8C; IR (KBr) nmax: 3314 (NH), 1653 (C]O), 763
(C–Cl) cmK1; 1H NMR (CDCl3) d 3.23 (s, 3H, NCH3), 3.86
(s, 3H, OCH3), 3.89 (d, JZ5.1 Hz, 2H, CH2Cl), 6.40 (d, JZ
1.2 Hz, 1H, H-3), 6.90 (dd, JZ8.7, 2.4 Hz, 1H, H-6), 7.08
(d, JZ2.1 Hz, 1H, H-4), 7.30 (d, JZ8.70Hz, 2H, H-7
and H-30), 7.41 0(td, JZ8.1, 0.9 Hz, 1H, H-4 ), 7.49 (t, JZ
7.8 Hz, 1H, H-5 ), 7.73 (d, JZ7.8 Hz, 1H, H-60), 8.32 (br s,
1H, NH); 13C NMR (CDCl3), d 37.3 (CH3), 41.9 (CH2Cl),
55.8 (OCH3), 102.2 (C-3), 103.2 (C-4), 112.3 (C-6), 113.9
(C-7), 128.4 (C-30), 129.1 (C-3a), 129.4, 129.7, 129.8
(all ArC–H), 130.7 (C-10), 132.0 (C-2), 135.0 (C-7a), 139.0
(C-20), 155.0 (COCH3), 167.0 (CO); CI-MS m/z 329
([MCH; 35Cl]C, 32%); HRCI-MS m/z calcd for
[MCH]C C18H18N2O237Cl: 331.1027, found: 331.1032.
4.6.5. N-(2-(5-Methoxy-1H-indol-2-yl)phenyl)-N-benzyl-
chloroacetamide (14b). A mixture of 10b (0.12 g,
0.22 mmol), 25% NaOH (30 mL) and EtOH (40 mL) was
heated at reflux for 48 h. After work up, the solid product
was then reacted with K2CO3 (0.11 g, 0.79 mmol) and
chloroacetyl chloride (71 mL, 0.55 mmol) to give the title
compound 14b (97 mg, 71%) as a yellow solid; mp 109–
111 8C; IR (KBr) nmax: 3297 (NH), 1655 (C]O), 736
(C–Cl) cmK1; 1H NMR (CDCl3) d 3.75 (d, JZ13.5 Hz, 1H,
CHHCl), 3.84 (s, 3H, CH3), 3.88 (d, JZ13.8 Hz, 1H,
CHHCl), 4.44 (d, JZ13.8 Hz, 1H, CHH), 5.26 (d, JZ
14.1 Hz, 1H, CHH), 6.61 (dd, JZ2.1, 0.9 Hz, 1H, H-3), 6.85
(dd,0JZ9.0, 2.4 Hz, 1H, H-6), 6.97 (dd, JZ8.1, 1.5 Hz, 1H,
H-3 ), 7.06 (d, JZ2.4 Hz, 1H, H-4), 7.13 (d, JZ8.7 Hz, 1H,
H-7), 7.21–7.32 (m, 6H, Ar), 7.42 (td, JZ7.5, 1.2 Hz, 1H,
H-50), 7.73 (dd, JZ7.8, 1.3 Hz, 1H, H-60), 8.17 (br s, 1H,
NH); 13C NMR (CDCl3) d 42.5 (CH2Cl), 53.4 (CH2), 56.0
(OCH3), 102.2 (C-3), 103.2 (C-4), 112.3 (C-6), 114.0 (C-7),
128.5 (ArC–H), 128.9 (ArC–H), 129.0 (C-200 and C-600),
129.2 (C-3a), 129.6 (A0rC–H), 129.8 (ArC–H), 129.9 (C-300
and C-500), 130.7 (0C-6 ), 130.9 (C-10), 132.2 (C-2), 134.1
(C-7a), 136.3 (C-2 ), 137.0 (C-100), 154.7 (COCH3), 167.0
(CO); CI-MS m/z 405 ([MCH; 35Cl]C, 100%); HREI-MS
m/z calcd for [M]C C24H21N2O327Cl: 406.1262, found:
406.1208.
4.6.3. N-(2-(5-Fluoro-1H-indol-2-yl)phenyl)-N-methyl
chloroacetamide (13c). A mixture of 9c (50 mg,
0.19 mmol), 25% NaOH (10 mL) and EtOH (25 mL) was
heated at reflux for 24 h. After work up, the solid product
was then reacted with K2CO3 (0.10 g, 0.74 mmol) and
chloroacetyl chloride (42 mL, 0.53 mmol) to give the
title compound 13c (46 mg, 79%) as a yellow solid; mp
175–176 8C; IR (KBr) nmax: 3315 (NH), 1654 (C]O), 764
1
(C–Cl) cmK1; H NMR (CDCl3) d 3.21 (s, 3H, NCH3),
3.84 (d, JZ12.9 Hz, 1H, CHHCl), 3.91 (d, JZ12.9 Hz, 1H,
CHHCl), 6.64 (d, JZ2.1 Hz, 1H, H-3), 6.95 (td, JZ9.3,
2.4 Hz, 1H, H-6), 7.23–7.35 (m, 3H, Ar), 7.40–7.51 (m, 2H,
Ar), 7.76 (dd, JZ7.5, 1.5 Hz, 1H, H-60); 13C NMR (CDCl3)
4.6.6. N-(2-(5-Fluoro-1H-indol-2-yl)phenyl)-N-benzyl
chloroacetamide (14c). A mixture of 10c (0.13 g,
0.38 mmol), 25% NaOH (30 mL) and EtOH (40 mL) was

5496
J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 5489–5498
heated at reflux for 24 h. After work up, the solid product
was then reacted with K2CO3 (0.19 g, 1.37 mmol) and
chloroacetyl chloride (76 mL, 0.53 mmol) to give the title
compound 14c (90 mg, 82%) as a yellow solid; mp 202–
203 8C; 1H NMR (CDCl3) d 3.70 (d, JZ13.2 Hz, 1H,
CHHCl), 3.82 (d, JZ13.2 Hz, 1H, CHHCl), 4.64 (d, JZ
14.1 Hz, 1H, CHH), 5.07 (d, JZ13.8 Hz, 1H, CHH), 6.60
(d, JZ1.8 Hz, 1H, H-3), 6.91 (td, JZ9.0, 2.4 Hz, 1H, H-6),
7.04–7.08 (m, 2H, H-4 and Ar), 7.19–7.31 (m, 6H, Ar), 7.34
(td, 0JZ7.8, 1.8 Hz, 1H, H-40), 7.44 (td, JZ7.2, 0.9 Hz, 1H,
H-5 ), 7.68 (dd, JZ7.8, 1.5 Hz, 1H, H-60), 7.77 (br s, 1H,
NH); 13C NMR (CDCl3) d 42.3 (CH2Cl), 53.8 (CH2), 103.6
(d, JZ4.8 Hz, 13C–19F, C3–F), 105.7 (d, JZ23.5 Hz,
13C–19F, C4–F), 111.8 (d, JZ26.3 Hz, 13C–19F, C6–F),
112.2 (d, JZ9.8 Hz, 13C–19F, C7–F), 128.7 (ArC–H), 129.2
6.62 (d, JZ2.4 Hz, 1H, H-3), 6.84 (dd, JZ9.0, 2.4 Hz, 1H,
H-6), 7.03–7.13 (m, 3H, Ar), 7.24–7.32 (m, 6H, Ar), 7.42
(t, JZ7.5 Hz, 1H, H-50), 7.71 (dd, JZ7.8, 1.5 Hz, 1H,
H-60), 8.05 (br s, 1H, NH); 13C NMR (CDCl3) d K1.5
(CH2I), 53.5 (CH2), 56.0 (OCH3), 102.3 (C-3), 103.3 (C-4),
112.3 (C-60)0, 113.9 (0C0 -7), 128.4 (ArC–H), 128.8 (ArC–H),
129.0 (C-2 and C-6 ), 129.2 (C-3a), 129.5 (ArC–H), 129.7
(ArC–H), 129.8 (C-300 and C-500), 130.4 (ArC–H), 130.8
(C-1000), 132.2 (C-2), 134.3 (C-7a), 136.5 (C-20), 138.0
(C-1 ), 154.7 (COCH3), 168.5 (CO); CI-MS m/z 497 ([MC
H]C, 14%); HREI-MS m/z calcd for [M]C C24H21N2O2I:
496.0648, found: 496.0643.
4.7.3. N-(2-(5-Fluoro-1H-indol-2-yl)phenyl)-N-benzyl-
iodoacetamide (15c). Treatment 14c (90 mg, 0.31 mmol)
with NaI (0.46 g, 3.10 mmol) in acetonitrile (10 mL) at
reflux gave the title compound 15c (0.10 g, 68%) as a
yellow solid; mp 172–173 8C; IR (KBr) nmax: 3297 (NH),
00
00
(C-2 and C-6 ), 129.5 (ArC–H), 129.7 (ArC–H), 130.1
00
00
(C-3 and C-5 ), 130.1 (ArC–H), 130.6 (ArC–H), 130.8
0
(C-1 ), 133.4 (C-2), 135.4 (C-7a), 136.1 (C-20), 137.3
(C-100), 159.2 (d, JZ240.0 Hz, 13C–19F, C5–F), 166.9 (CO);
CI-MS m/z 393 ([MCH; 35Cl]C, 100%); HREI-MS m/z
calcd for [M]C C23H18N2OF35Cl: 392.1092, found:
392.1091.
1636 (C]O) cmK1 1H NMR (CDCl3) d 3.48 (d, JZ
;
10.2 Hz, 1H, CHHI), 3.53 (d, JZ10.2 Hz, 1H, CHHI), 4.62
(d, JZ14.1 Hz, 1H, CHH), 5.11 (d, JZ14.1 Hz, 1H, CHH),
6.63 (d, JZ2.1 Hz, 1H, H-3), 6.92 (td, JZ9.3, 2.7 Hz, 1H,
H-6), 7.09 (dd, JZ8.7, 4.5 Hz, 1H, H-7), 7.16 (dd, JZ7.8,
1.2 Hz, 1H, H-300), 7.21–7.33 (m, 6H, Ar), 7.36 (td, JZ7.5,
1.5 Hz, 1H, H-4 ), 7.46 (td, JZ7.8, 1.5 Hz, 1H, H-50), 7.70
(dd, JZ7.8, 1.5 Hz, 1H, H-60), 7.91 (br s, 1H, NH); 13C
NMR (CDCl3) d K1.8 (CH2I), 53.8 (CH2), 103.6 (d, JZ
5.2 Hz, 13C–19F, C3–F), 105.7 (d, JZ23.5 Hz, 13C–19F, C4–
F), 111.7 (d, JZ26.6 Hz, 13C–19F, C6–F), 112.1 (d, JZ
9.7 Hz, 13C–19F, C7–F), 128.6 (ArC–H), 129.0 (d, JZ
4.7. General procedure for the preparation of
iodoacetamides (15a–c)
A solution of 14a–c (1.0 equiv) in acetonitrile containing
sodium iodide (10 equiv) was heated at reflux for 2 h. The
solution was then cooled and water (10 mL) was added.
The solution was then extracted with EtOAc (3!20 mL).
The organic extracts were combined, dried, concentrated,
and chromatographed on a column by elution with DCM to
isolate the iodoacetamide products. The following com-
pounds were prepared by this method.
13
19
00
00
00
00
10.5 Hz, C– F, C3a–F), 129.1 (C-2 and C-6 ), 129.4
(ArC–H), 129.5 (ArC–H), 129.6 (C-3 and C-5 ), 130.2
(ArC–H), 130.3 (ArC–H), 130.6 0(0 C-10), 133.4 (C-2), 135.5
(C-7a), 136.3 (C-20), 138.1 (C-1 ), 158.4 (d, JZ221.1 Hz,
13C–19F, C5–F), 168.4 (CO); CI-MS m/z 485 ([MCH]C,
25%); HREI-MS m/z calcd for [M]C C23H18N2OFI:
484.0448, found: 484.0497.
4.7.1. N-(2-(1H-Indol-2-yl)phenyl)-N-benzyl iodoaceta-
mide (15a). Treatment of 14a (0.20 g, 0.53 mmol) with NaI
(0.78 g, 5.30 mmol) in acetonitrile (20 mL) at reflux gave
15a as a yellow solid (0.23 g, 92%); mp 168–169 8C; IR
4.8. General procedure for radical cyclisation
(KBr) nmax: 3312 (NH), 1637 (C]O) cmK1 1H NMR
;
(CDCl3) d 3.49 (d, JZ9.9 Hz, 1H, CHHI), 3.59 (d, JZ
10.2 Hz, 1H, CHHI), 4.54 (d, JZ13.8 Hz, 1H, CHH), 5.17
(d, JZ13.8 Hz, 1H, CHH), 6.69 (dd, JZ2.1, 0.6 Hz, 1H,
H-3), 7.12 (m, 2H, Ar), 7.20 (m, 2H, Ar), 7.25 (m, 2H, Ar),
7.32 (m, 4H, Ar), 7.44 (td, JZ8.7, 1.2 Hz, 1H, H-50), 7.61
(d, JZ7.8 Hz, 1H, H-4), 7.70 (dd, JZ7.8, 1.2 Hz, 1H, H-60),
7.94 (br s, 1H, NH); 13C NMR (CDCl3) d K1.9 (CH2I), 53.3
(CH2), 103.3 (C-3), 111.1 (C-7), 120.3 (C-4), 120.8 (C-6),
122.9 (C-5), 128.2 (C-30), 128.4 (C-3a), 128.7 (ArC–H),
128.8 (C-200 and C-600), 129.2 (ArC–H), 129.6 (C-300 and
C-500), 129.7 (ArC–H), 130.1 (ArC–H), 130.5 (C-10), 133.4
(C-2), 136.2 (C-7a), 136.6 (C-20), 137.8 (C-100), 168.1 (CO);
CI-MS m/z 467 ([MCH]C, 15%); HRCI-MS m/z calcd for
[MCH]C C23H20N2OI: 467.0620, found 467.0612.
A solution of tributyltin hydride (Bu3SnH) (2.0 equiv) and
AIBN (1.0 equiv) in an appropriate solvent (8 mM) was
added dropwise to a solution of the iodoacetamide (15a–c)
(1.0 equiv) in boiling solvent (14 mM) over 4 h, and the
mixture was then heated at reflux overnight. After removal
of the solvent in vacuo, diethyl ether (20 mL) and saturated
potassium fluoride solution (20 mL) were added and the
mixture was stirred vigorously at rt for 2–3 h. The organic
layer was separated, dried, concentrated and the residue
column chromatographed.
4.8.1. Radical cyclisation of 15a in toluene. Compound
15a (60 mg, 0.13 mmol) in toluene (9 mL) was treated with
Bu3SnH (70 mL, 0.26 mmol) and AIBN (21 mg, 0.13 mmol)
in toluene (33 mL). The crude material was chromato-
graphed (hexane/AcOEt, 70:30) to give 5-benzyl-7,12-
dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one 16a (11 mg,
4.7.2. N-(2-(5-Methoxy-1H-indol-2-yl)phenyl)-N-benzyl
iodoacetamide (15b). Treatment of 14b (97 mg,
0.24 mmol) with NaI (0.36 g, 2.40 mmol) in acetonitrile
(20 mL) at reflux gave 15b as a yellow solid (65 mg, 55%);
mp 138–139 8C; IR (KBr) nmax: 3311 (NH), 1637 (C]O)
cmK1; 1H NMR (CDCl3) d 3.50 (d, JZ9.9 Hz, 1H, CHHI),
3.56 (d, JZ10.2 Hz, 1H, CHHI), 3.84 (s, 3H, OCH3), 4.44
(d, JZ13.8 Hz, 1H, CHH), 5.24 (d, JZ13.8 Hz, 1H, CHH),
25%) as yellow needles; mp 214–216 8C; IR (KBr) nmax
;
:
3270 (NH), 1646 (C]O) cmK1 1H NMR (500 MHz,
DMSO-d6) d 3.37 (d, JZ13.5 Hz, 1H, CHH-7), 3.73 (d, JZ
14.0 Hz, 1H, CHH-7), 4.88 (d, JZ16.0 Hz, 1H, CHH),05.08
(d, JZ16.0 Hz, 1H, CHH), 6.76 (d, JZ7.0 Hz, 2H, H-2 and
H-60), 7.00 (m, 3H, H-30, H-40 and H-50), 7.11 (t, JZ8.0 Hz,

J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 5489–5498
5497
1H, H-9), 7.16 (t, JZ7.5 Hz, 1H, H-10), 7.21 (td, JZ8.0,
1.5 Hz, 1H, H-2), 7.27 (t, JZ7.5 Hz, 1H, H-3), 7.47 (m, 2H,
H-4 and H-11), 7.72 (d, JZ7.5 Hz, 1H, H-8), 7.75 (dd, JZ
8.0, 1.5 Hz, 1H, H-1), 11.62 (s, 1H, NH); 13C NMR
(125 MHz, DMSO-d6) d 35.3 (CH2-7), 53.2 (CH2), 110.1
(C-7a), 112.7 (C-11), 118.7 (C-8), 121.2 (C-10), 122.5
(C-9), 125.0 (C-4), 125.3 (C-7b), 126.7 (C-2), 126.8 (C-020
and C-60), 127.5 (C-3), 128.2 (C-1), 128.9 (C-30 and C-5 ),
130.2 (C-12b), 133.4 (C-12a), 137.0 (C-11a), 138.2 (C-4a),
138.5 (C-10), 169.4 (CO); CI-MS m/z 339 ([MCH]C,
100%); HRCI-MS m/z calcd for [MCH]C C23H19N2O:
339.1497, found: 339.1498.
The first, fraction gave 5-benzyl-11-methoxy-5H-
indolo[1,2-d][1,4]benzodiazepin-6(7H)-one 18 (12 mg,
30%) as a yellow solid, mp 153–154 8C; IR (KBr) nmax
:
1670 (C]O) cmK1; 1H NMR (500 MHz, CDCl3) d 3.88 (s,
3H, OCH3), 4.56 (d, JZ13.0 Hz, 1H, CHH), 4.97 (d, JZ
15.0 Hz, 1H, CHH), 5.01 (d, JZ16.0 Hz, 1H, CHH-7), 5.10
(d, JZ14.5 Hz, 1H, CHH-7), 6.69 (s, 1H, H-13), 6.95 (dd,
JZ9.0, 2.5 Hz, 1H, H-10), 7.00 (d, JZ7.5 Hz, 1H, H-4),
7.14 (d, 0JZ2.5 Hz, 1H, H-12), 7.16–7.20 (m, 2H, H-3, H-20
and H-60), 7.27 (td, JZ8.5, 1.5 Hz, 1H, H-2), 7.31–7.34 (m,
3H, H-3 , H-40 and H-50), 7.43 (d, JZ8.5 Hz, 1H, H-9), 7.65
(dd, JZ7.5, 1.5 Hz, 1H, H-1); 13C NMR (125 MHz, CDCl3)
d 47.7 (CH2), 52.6 (CH2-7), 55.9 (OCH3), 99.5 (C-13),
102.3 (C-12), 110.00 (C-9), 112.8 (C-10), 123.4 (C-40), 126.4
(C-2), 126.8 (C-2 and C-60), 127.1 (C-4), 127.2 (C-13b),
128.5 (C-30 and C-50), 128.7 (C-103a), 129.0 (C-3), 130.4
(C-1), 131.7 (C-12a), 136.8 (C-1 ), 137.5 (C-8a), 139.2
(C-4a), 154.6 (COCH3), 167.2 (CO); EI-MS m/z 368 ([H]C,
100%); HREI-MS m/z calcd for [M]C C24H20N2O2:
368.1525, found: 368.1529.
4.8.2. Radical cyclisation of 15a in de-gassed toluene.
Compound 15a (70 mg, 0.15 mmol) in boiling de-gassed
toluene (11 mL) under an Ar atmosphere was treated with
Bu3SnH (80 mL, 0.30 mmol) and AIBN (24 mg, 0.15 mmol)
in de-gassed toluene (38 mL). After work up, the residue
was chromatographed on silica gel (hexane/AcOEt, 70:30).
The first, fraction gave 1,2,3,4-tetrahydroquinolin-2-one-4-
spiro-20-indoline 17a (6.4 mg, 13%) and the second fraction
gave 16a (4 mg, 8%).
The second fraction gave 5-benzyl-7,12-dihydro-9-meth-
oxy-indolo[3,2-d][1]benzazepin-6(5H)-one 16b (10 mg,
25%) as an offwhite solid, mp 213–215 8C; IR (KBr) nmax
;
:
Compound 17a was obtained as a yellow solid, mp 89–
3300 (NH), 1647 (C]O) cmK1 1H NMR (500 MHz,
1
91 8C; IR (KBr) nmax: 3350 (NH), 1654 (C]O) cmK1; H
DMSO-d6) d 3.54 (br s, 2H, CH2-7), 3.08 (s, 3H, CH3), 5.08
(br s, 2H, CH2), 6.83 (dd, JZ8.5, 2.5 Hz, 1H, H-10), 6.90
(d, JZ6.5 Hz, 2H, H-20 and H-60), 7.10–7.15 (m, 3H, H-30,
H-40 and H-50), 7.21 (d, JZ2.5 Hz, H-8), 7.29 (t, JZ7.0 Hz,
1H, H-2), 7.32–7.36 (m, 2H, H-11 and H-3), 7.55 (d, JZ
8.5 Hz, 1H, H-4), 7.65 (dd, JZ7.5, 1.5 Hz, 1H, H-1), 11.57
(s, 1H, NH); 13C NMR (125 MHz, DMSO-d6) d 31.7
(CH2-7), 52.1 (CH2), 55.4 (OCH3), 99.7 (C-8), 109.7
(C-7a), 112.4 (C0-11), 112.8 (C-10), 124.2 (C-4), 125.1
(C-2), 126.3 (C-2 and C-60), 126.3 (C-7b), 126.4 (C-12b),
126.6 (C-40), 127.2 (C-1), 127.8 (C-3), 128.2 (C-30 and
C-50), 132.6 (C-11a), 133.0 (C-12a), 137.9 (C-10), 138.9
(C-4a), 153.6 (COCH3), 170.3 (CO); CI-MS m/z 369 ([MC
H]C, 100%); HREI-MS m/z calcd for [M]C C24H20N2O2:
368.1525, found: 368.1531.
(CDCl3) d 2.89 (d, JZ15.3 Hz, 1H, CHH-3), 3.03 (d, JZ
15.9 Hz, 1H, CHH-30), 3.09 (d,0 JZ15.6 Hz, 1H, CHH-3),
3.31 (d, JZ15.6 Hz, 1H, CHH-3 ), 3.95 (br s, 1H, NH), 5.13
(d, JZ16.2 Hz, 1H, CHH), 5.33 (d, JZ16.2 Hz, 1H, CHH),
6.70 (d, JZ8.1 Hz, 1H, H-70), 6.74 (t, JZ7.2 Hz, 1H, H-50),
6.95 (d, JZ8.1 Hz, 1H, H-8), 7.00 (t, JZ7.8 Hz, 1H, H-6),
7.04–7.11 (m, 2H, H-10 and H-12), 7.16 (td, JZ7.5, 1.2 Hz,
1H, H-7), 7.22–7.26 (m, 3H, H-20, H-40 and H-60), 7.30–7–
36 (m, 2H, H-30 and H-50), 7.54 (dd, JZ7.5, 0.1 Hz, 1H,
H-5); 13C NMR (CDCl3) d 42.4 (CH2-3), 44.8 (CH2), 46.3
(CH2-30), 63.7 (C-4 or C-20), 109.3 (C-70), 116.3 (C-50),
119.5 (C-8), 123.9 (C-6), 124.7 (C-7), 125.5 (C-5), 126.1
(C-30), 126.8 (C-20 and C-60), 127.5, 128.1, 128.8 (all ArC–
H), 129.0 (C-30 and C-50), 133.5 (C-4a), 137.0 (C-8a), 138.2
(C-10), 149.4 (C-7a), 168.9 (CO); EI-MS m/z 340 ([M]C,
100%); HRCI-MS m/z calcd for [MCH]C C23H21N2O:
341.1654, found: 341.1638.
4.8.6. Radical cyclisation of 15c. Compound 15c (50 mg,
0.10 mmol) in mesitylene (20 mL) was treated with Bu3SnH
(54 mL, 0.20 mmol) and AIBN (16 mg, 0.10 mmol) in
mesitylene (60 mL). The crude material was chomato-
graphed on silica gel (AcOEt/pet. spirit, 9:1) to give 5-
benzyl-9-fluoro-7,12-dihydro-indolo[3,2-d][1]benzazepin-
6(5H)-one 16c as off white needles (16 mg, 45%); mp 247–
4.8.3. Cylisation of 15a in toluene on a larger scale.
Compound 15a (0.17 g, 0.36 mmol) in toluene (25 mL) was
treated with Bu3SnH (0.20 mL, 0.73 mmol) and AIBN
(59 mg, 0.36 mmol) in toluene (92 mL). The crude product
was chromatographed (hexane/AcOEt, 70:30) to give the
spiro derivative 17a (12 mg, 10%) and some unidentified
compounds.
248 8C; IR (KBr) nmax: 3277 (NH), 1641 (C]O) cmK1
;
1H NMR (CDCl3) d 3.50 (d, JZ13.5 Hz, 1H, CHH-7), 3.91
(d, JZ13.8 Hz, 1H, CHH-7), 5.05 (d, JZ15.6 Hz, 1H,
CHH), 5.14 (d, JZ15.4 Hz, 1H, CHH), 06.95 (td,0 JZ8.7,
2.4 Hz, 1H, H-10)0, 7.03–7.05 (m, 2H, H-2 and H-6 ), 7.15–
7.17 (m, 2H, H-3 and H-50), 7.23–7.27 (m, 2H, H-11 and
Ar), 7.30–7.39 (m, 2H, H-2 and Ar), 7.43–7.51 (m, 2H, H-8
and Ar), 7.83 (d, JZ7.2 Hz, 1H, H-1), 10.09 (s, 1H, NH);
13C NMR (CDCl3) d 35.6 (CH2-7), 54.6 (CH2), 103.9
(d, JZ24.1 Hz, 13C–19F, C8–F), 110.5 (d, JZ25.8 Hz,
13C–19F, C10–F), 111.1 (C-7a), 112.7 (d, JZ9.8 Hz,
13C–19F, C11–F), 124.4 (ArC–H), 125.7 (d, JZ10.0 Hz,
13C–019F, C7b–F), 126.4 (ArC–H), 126.5 (ArC–H), 126.8
(C-2 and C-60), 127.2 (C-40), 128.0 (C-1), 128.7 (C-30 and
C-50), 129.1 (C-12b), 129.8 (C-12a), 133.2 (C-11a), 137.6
4.8.4. Cycilzation of 15a in mesitylene. Compound 15a
(60 mg, 0.13 mmol) in mesitylene (9 mL) was treated with
Bu3SnH (70 mL, 0.26 mmol) and AIBN (21 mg, 0.13 mmol)
in mesitylene (30 mL). The crude product was chromato-
graphed (hexane/AcOEt, 70:30) to give compound 16a
(23 mg, 52%).
4.8.5. Radical cyclisation of 15b. Compound 15b (55 mg,
0.11 mmol) in mesitylene (20 mL) was treated with Bu3SnH
(59 mL, 0.22 mmol) and AIBN (18 mg, 0.11 mmol) in
mesitylene (60 mL). The crude material was chromato-
graphed on silica gel (AcOEt/pet. spirit, 9:1).

5498
J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 5489–5498
(C-10), 138.8 (C-4a), 159.0 (d, JZ230.6 Hz, 13C–19F,
C9–F), 169.4 (CO); CI-MS m/z 357 ([MCH]C, 100%);
HREI-MS m/z calcd for [M]C C23H17N2OF: 356.1325,
found: 356.1381.
References and notes
1. Zaharevitz, D. W.; Gussio, R.; Leost, M.; Senderowicz, A. M.;
Lahusen, T.; Kunick, C.; Meijer, L.; Sausville, E. A. Cancer
Res. 1999, 59, 2566–2569.
2. Schultz, C.; Link, A.; Leost, M.; Zaharevitz, D. W.; Gussio, R.;
Sausville, E. A.; Meijer, L.; Kunick, C. J. Org. Chem. 1999,
42, 2909–2919.
4.8.7. 7,12-Dihydro-indolo[3,2-d][1]benzazepin-6(5H)-
one 19 (RZH). Sodium metal (ca. 30 mg) was added to
dry THF (2 mL) under a N2 atmosphere and then the
mixture was frozen using a liquid N2 bath. Liquid ammonia
(condensed at K70 8C, ca. 7 mL) and a solution of 16a
(26 mg, 0.08 mmol) in dry THF (2 mL) was then added. The
frozen mixture was warmed to K60 8C and the reaction
mixture was stirred at this temperature for 10 min. Solid
ammonium chloride was then added until the colour
dissipated at which point the reaction was allowed to
warm to room temperature. The residue was dissolved in
ethyl acetate (30 mL), extracted with water (3!20 mL),
dried and concentrated to give a yellow residue. The residue
was purified using preparative thin layer chromatography
(silica gel, 1% MeOH/DCM) to give the title compound 19
(RZH) (8 mg, 40%) as a yellow solid; mp O272 8C (lit.17
3. Fisher, P. M.; Lane, D. P. Curr. Med. Chem. 2000, 7,
1213–1245.
4. Meijer, L.; Flajolet, M.; Greengard, P. Trends Pharmacol. Sci.
2004, 25, 471–480.
5. Kimball, S. D.; Webster, K. R. In Cell cycle kinases and
checkpoint regulation in cancer; Doherty, A. M., Ed.; Annual
reports in medicinal chemistry; Academic: New York, 2001;
Vol. 36, p 139.
6. Buolamwini, J. K. Curr. Pharm. Des. 2000, 6, 379–392.
7. Bremner, J. B.; Sengpracha, W. Tetrahedron 2005, 61,
941–953.
8. MacPhillamy, H. B.; Dziemain, R. L.; Lucas, R. A.; Kuehne,
M. E. J. Am. Chem. Soc. 1958, 80, 2172–2178.
9. Baudoin, O.; Cesario, M.; Guenard, D.; Gueritte, F. J. Org.
Chem. 2002, 67, 1199–1207.
O315 8C); IR (KBr) nmax: 3356 (NH), 1655 (C]O) cmK1
;
1H NMR (DMSO-d6) d 3.54 (s, 2H, CH2), 7.11 (ddd, JZ7.2,
6.9, 1.5 Hz, 1H, H-9), 7.16 (ddd, JZ7.5, 6.9, 1.5 Hz, 1H,
H-10), 7.23–7.29 (m, 3H, H-2, H-3 and H-4), 7.44 (dd, JZ
7.2, 1.5 Hz, 1H, H-11), 7.80 (d, JZ6.9 Hz, 1H, H-8), 7.85
(m, 1H, H-1), 10.08 (s, 1H, NH), 11.62 (br s, 1H, indole
NH); 13C NMR (CDCl3) d 35.7 (CH2), 109.7 (C-7a), 112.5
(C-11), 118.7 (C-8), 120.7 (C-9), 122.1 (C-10), 123.3 (ArC–
H), 124.8 (ArC–H), 125.9 (C-12b), 126.3 (ArC–H), 126.9
(C-7b), 128.2 (C-1), 132.2 (C-12a), 134.8 (C-4a), 136.9
(C-11a), 170.3 (CO); EI-MS m/z 248 ([M]C, 100%); HRCI-
MS m/z calcd for [MCH]C C16H13N2O: 249.1028, found:
249.1032.
10. Kunick, C.; Schultz, C.; Lemcke, T.; Zaharevitz, D. W.;
Gussio, R.; Jalluri, R. K.; Sausville, E. A.; Leost, M.; Meijer,
L. Bioorg. Med. Chem. Lett. 2000, 10, 567–569.
11. Wieking, K.; Knockaert, M.; Leost, M.; Zaharevitz, D.;
Meijer, L.; Kunick, C. Arch. Pharm. Med. Chem. 2002, 335,
311–317.
12. Kunick, C. Arch. Pharm. (Weinheim, Ger.) 1991, 324, 579–581.
13. A cyclic lactam related to 9 and 10, but made via an aza-Wittig
reaction with carbon dioxide, has been reported in Molina, P.;
Alajarin, M.; Vida, A. Tetrahedron 1990, 46, 1063–1078.
14. In a separate initial experiment involving N-benzylation of the
commercially available amine 2-(o-amino)phenylindole with
benzyl bromide, the amine 12a was obtained as a yellow solid
but it turned blue on contact with air.
15. Duncan, R. L.; Helsley, G. C.; Boswell, R. F. J. Heterocycl.
Chem. 1973, 10, 65–70.
Acknowledgements
16. Kyei, A. S.; Tchabanenko, K.; Baldwin, J. E.; Adlington, R. M.
Tetrahedron Lett. 2004, 45, 8931–8934.
We gratefully acknowledge support from the Institute for
Biomolecular Science, University of Wollongong and a
Royal Thai Government Scholarship (to W.S.) for this work.
17. Kunick, C. Arch. Pharm. (Weinheim, Ger.) 1992, 325,
297–299.