A free radical cyclization approach to indolo-benzodiazocine derivatives

Article abstract of DOI:10.1016/j.tet.2004.11.007

A versatile route to indolo[2,1-d][1,5]benzodiazocine derivatives has been developed based on a free radical cyclization approach from 1-substituted indole derivatives with appropriately positioned haloacetamide functionalities. Fair yields of the indole- and dihydroindole-fused eight-membered ring derivatives were obtained from N-substituted iodo- and bromoacetamide precursors. Synthetic and mechanistic aspects of the regiospecific cyclization are discussed.

Full text of DOI:10.1016/j.tet.2004.11.007

Tetrahedron 61 (2005) 941–953
A free radical cyclization approach to
indolo-benzodiazocine derivatives
*
John B. Bremner and Waya Sengpracha
Institute for Biomolecular Science and Department of Chemistry, University of Wollongong, NSW 2522, Australia
Received 30 July 2004; revised 11 October 2004; accepted 5 November 2004
Available online 8 December 2004
Abstract—A versatile route to indolo[2,1-d][1,5]benzodiazocine derivatives has been developed based on a free radical cyclization
approach from 1-substituted indole derivatives with appropriately positioned haloacetamide functionalities. Fair yields of the indole- and
dihydroindole-fused eight-membered ring derivatives were obtained from N-substituted iodo- and bromoacetamide precursors. Synthetic and
mechanistic aspects of the regiospecific cyclization are discussed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
In an effort to develop a viable regioselective route to
indolo-benzodiazocinone derivatives, thermal radical
cyclizations via an 8-exo-trig process of precursor 1-indolyl
haloacetamides, using tributyltin hydride, have been
investigated and the results are reported in this paper.
Free radical cyclization is now a useful and well established
methodology in heterocyclic synthesis.1,2 The more suc-
cessful intramolecular radical cyclizations proceed to form
five-membered rings,3–5 and these are more general than
those forming six-membered6 or seven-membered7,8 rings.
However, cyclization leading to indole fused eight-
membered rings is less well investigated.
2. Results and discussion
The indolyl substrates required for the radical cyclizations
were prepared starting from the 1-substituted indole
derivatives 4–6.9 Then, N-alkylation with the appropriate
alkyl halides, benzyl halides or reductive amination,
followed by acylation of the resulting amines 7–13
with the acyl halides, gave the corresponding halo-
acetamides 14–16. Reaction of the chloroacetamides
14a–h with sodium iodide in acetonitrile gave the
iodoacetamides 15a–h (Scheme 1). The iodoacetamide 15i
was prepared by direct alkylation of the chloroacetamide
14i with methyl iodide in DMF after amide anion formation
(Scheme 2).
As part of a wider program to identify structurally novel
antibacterial compounds with, hopefully, new modes of
action to combat resistance problems, we became interested
in the indolo[2,1-d][1,5]benzodiazocinones 1–3, with an
indole fused eight-membered ring system. Previous studies
in our laboratory had revealed that this system could be
accessed in low yields, together with indolo-benzodiazoni-
nones and pyrrolo-indoloquinazolinones, by the photolysis
of chloroacetamides.9
Free radical cyclization reactions of the haloacetamides
14–16 were then induced using a 40 mM solution of
tributyltin hydride (Bu3SnH) in the presence of azobisiso-
butyronitrile (AIBN) in various solvents at reflux.
A slow addition of tributyltin hydride to a boiling toluene
solution of the haloacetamides gave the indole fused eight-
membered ring compounds 17–18 in fair yields, and also the
simple reduced compounds 19 (Scheme 1, Table 1).
Dehydrogenation of 18a was achieved in a separate
aromatization reaction with Pd/C in boiling toluene to
Keywords: Fused benzodiazocines; Indoles; Radical cyclization; eight-
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 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.007

942
J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 941–953
Scheme 1. (a) (i) K2CO3, (ii) R0X, THF; (b) (i) R0CHO, 5 M HCl-MeOH, (ii) NaBH3CN, MeOH; (c) (i) K2CO3, 5 8C, DCM (ii) ClCH2COCl, r.t., 16 h.; (d) (i)
NaH (ii) ClCH2COCl, THF, r.t., 16 h.; (e) (i) NaH (ii) BrCH2COCl, THF, r.t., 16 h.; (f) Bu3SnH, AIBN, boiling solvents; (g) Pd/C, toluene, heat.
Scheme 2. (a) (i) NaH, (ii) MeI, DMF.
give 17a in 50% yield. In the 1H NMR spectra of the fused
benzodiazocinones 17, the H-8 proton appeared as a singlet
signal at about d 6.28–6.37, which was clearly separated
from other signals. In contrast, the signal attributed to the
H-8 protons in compounds of type 18 appeared as a
multiplet around d 2.40–2.50 due to coupling with H-7a. In
the H NMR of the acetamides 19, a diagnostic singlet
signal integrating for three protons was apparent at around d
1.80.
An increase in the cyclization product yields was generally
observed as the steric bulk of the substituent group R0 on the
haloacetamide nitrogen was increased.10,11 When the
haloacetamides with R0ZH (Entries 1 and 3, Table 1)
were reacted, the products 19 of simple reduction were
obtained.
1
However, when a sufficiently large group (R0) was
employed as a substituent on the amide nitrogen, the

J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 941–953
943
Table 1. Radical cyclization of haloacetamides 14–16 using Bu3SnH/AIBN in boiling toluene
R0
Entry
Substate
R
X
mmol
Yield (%)
17
18
19
1
2
3
4
5
6
7
8
14a
14b
15a
15b
15c
15d
15e
15f
15g
15i
16a
16b
H
H
H
H
H
H
H
OMe
OMe
F
H
OMe
H
Me
H
Me
Cl
Cl
I
I
I
I
I
I
I
0.16
0.20
0.21
0.13
0.33
0.08
0.07
0.19
0.12
0.14
0.10
0.12
—
—
—
20
13
25
22
50
25
35
54
24
—
—
—
60
11
43
26a
—
—
—
20b
—
82
83
85
20
7
CH2C6H4-p-OMe
CH2Ph
CH(CH3)Ph
Me
CH2Ph
Me
10
20
!1
17
9
10
11
12
I
Br
Br
CH2Ph
Me
33
a Mixture of 18d:19d in a ratio of ca. 1:1 (determined by 1H NMR).
b Mixture of 18c:19c in a ratio of ca. 2:1 (determined by 1H NMR).
cyclization products were formed with iodo or bromo-
acetamide groups (e.g., entries 8 and 11, Table 1). Ishibashi
et al.5 also observed halogen-dependant differences in
radical cyclization versus radical reduction with other
N-benzylhaloacetamides. In their case, the chloroacetamide
afforded cyclization from the cisoid amide rotamer, while
the iodoacetamide gave predominately the non-cyclized
reduction product from the favoured transoid rotamer.
Clearly amide conformational preferences will also be
influenced by the nature of both the N-substituents and with
the N,N-disubstituted amides 15b–g, the very bulky
indolylmethyl substituent, together with the methyl or
benzylic substituent, would induce a preference for the
cisoid rotamer of type B (Scheme 3) for the iodoacetamides.
Scheme 3. Proposed cyclization mechanism.

944
J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 941–953
Table 2. Radical cyclization of haloacetamides using Bu3SnH/AIBN in various solvents
Entry
Substrate
Solvent
Yield (%)
17
18
19
1
15b
15d
15d
15d
15d
15g
15g
15h
Mesitylene
Toluene
Xylenes
Mesitylene
(CH3)3CC6H5
Mesitylene
Toluene
44
25
57
70
46
29
25
23
—
43
—
—
—
—
—
—
—
10
—
—
9
—
!1
15
2a
3
4
5
6
7a
8
Mesitylene
a From Table 1.
A temperature-dependence study of the cyclization revealed
increasing yields with higher boiling point solvents
(Table 2).
much discussion, but it now seems likely that two possible
pathways include hydrogen abstraction by the (CH3)2C%CN
radical, plus reaction with AIBN.13 In this connection, it is
of interest to note that in one larger scale reaction involving
15d, some of the radical trapped adduct 20 was isolated.
Cyclizations in high boiling point solvents, for example,
xylenes and mesitylene, increased yields of the benzo-
diazocinones 17 and neither the dihydroindole fused
products 18 nor the acetamides 19 were isolated when
15b or 15d was the substrate (Table 2). No products from
radical attack on the aromatic hydrocarbon solvents were
seen.12 The increased yield of cyclization products and the
diminished formation of reduced, uncyclized by-products in
high boiling point aromatic solvents suggests that the amide
rotamer (B) required for cyclization after radical formation
is increased in concentration in the equilibrium at higher
temperatures relative to rotamer A.5 Also, with radical
attack on the heteroaromatic ring likely to be slow,4 the
increased temperature would be favourable for this reaction.
With a view to ultimately providing access to other
N-substituted indolo[2,1-d][1,5]benzodiazocine-6-ones, a
chemoselective means of removal of the N-benzyl group
in 17c was investigated. Debenzylation of 17c was
performed using sodium in liquid ammonia14 to afford 1
in 35% yield (Scheme 4). There was no unreacted 17c, but
some unidentified baseline material was observed in the
PTLC of the reaction mixture. Selective addition of a
solvated electron was expected at the less-electron rich
aromatic ring of the benzyl-protecting group. However, the
reaction time was crucial to ensure a reasonable yield of
the product. The most suitable time for the cleavage of the
benzyl protecting group, and not the eight-membered ring,
was 6–8 min.
3. Conclusions
It has been shown that, in contrast to photo-initiated
reactions, an indole-fused eight-membered ring system
can be accessed in fair yield by a thermal free radical
cyclization route from 1-substituted indoles. This route has
the potential for synthesis of a range of analogues and
substituted derivatives.
4. Experimental
4.1. General
A 8-exo-trig addition of the amidylmethyl radical would
give the dihydroindole radical (C) and then an oxidation
step to give the products 17 (Scheme 3); the exact details of
this latter step in other cyclizations has been the subject of
Melting points were determined using a Reichert hot-stage
Scheme 4. (a) Na, liq. NH3, THF.

J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 941–953
945
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 in CDCl3 and referenced to TMS (proton) and
the chloroform mid-line (77 ppm) (carbon). Chemical shifts
are reported in parts per million (d). 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 layer chromatography were 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.
Compounds 4–6, 14a and 14i were prepared following the
methods reported previously.9 1H and 13C NMR spectra for
cyclized and uncyclized derivatives were assigned using the
numbering systems illustrated on 17 and 19 (Scheme 1).
8.1 Hz, 1H, H-7), 7.67 (d, JZ7.5 Hz, 1H, H-4); 13C NMR
(CDCl3) d 31.0 (CH3), 47.7 (CH2), 102.2 (C-3), 109.7 (C-7),
110.6 (!2), 117.5, 120.0 (ArC), 121.1 (C-10), 121.3, 122.0,
127.4, 129.8 (C-3a and ArC), 136.5 (C-7a), 147.5 (C–N);
CI-MS m/z 237 ([MCH]C, 97%); HREI-MS m/z calcd for
[M]C C16H16N2: 236.1313, found: 236.1309.
4.2.2. 1-[(2-N-(40-Methoxybenzyl)aminophenyl)methyl]-
1H-indole (8). Following procedure A, treatment of 4
(0.13 g, 0.59 mmol) in dry DMF (20 mL) with K2CO3
(82 mg, 0.59 mmol) and 4-methoxybenzyl bromide (0.12 g,
0.59 mmol) gave 8 (0.14 g, 71%) as a yellow solid; mp 105–
106 8C; IR (KBr) nmax: 3425 (NH) cmK1; 1H NMR (CDCl3)
d 3.86 (br s, 1H, NH), 3.88 (s, 3H, CH3), 4.26 (s, 2H,
NHCH2), 5.26 (s, 2H, CH2), 6.63 (d, JZ3.3 Hz, 1H, H-3),
6.77–6.83 (m, 2H, Ar), 6.87 (d, JZ8.7 Hz, 2H, Ar), 7.22–
7.26 (m, 6H, Ar), 7.32 (t, JZ9.0 Hz, 1H, Ar), 7.43 (dd, JZ
7.5, 1.2 Hz, 1H, H-7), 7.76 (dd, JZ7.5, 1.8 Hz, 1H, H-4);
13C NMR (CDCl3) d 47.4 (NHCH2), 47.7 (CH2), 55.3
(CH3), 102.0 (C-3), 109.3, 111.2, 113.8, 117.3, 119.6, 120.6
(C-10), 121.0, 121.7, 127.2, 128.3, 128.7 (C-3a0), 129.2,
129.4, 130.6 (C-7a), 136.2 (C-100), 146.0 (C-2 ), 158.5
(COCH3); CI-MS m/z 343 ([MCH]C, 100%); HREI-MS
m/z calcd for [M]C C23H22N2O: 342.1732, found:
342.1731.
4.2. General procedures for the preparation of
N-substituted amines (7–13)
Procedure A. To a stirred solution of amines (4–6,
1.0 equiv) in dry DMF under a nitrogen atmosphere was
added anhydrous potassium carbonate (K2CO3) (1.0 equiv)
and the suspension was stirred at 0–5 8C for 5 min. The
appropriate alkyl halide (1.0–1.5 equiv) was then added and
the reaction mixture stirred at r.t. overnight. Solvent was
then removed under reduced pressure. DCM (20 mL) was
added to the residue and the mixture was washed with water
(4!20 mL). The organic extracts was dried, concentrated,
and chromatographed on a column by elution with 1:1
DCM/hexane.
4.2.3. 1-[(2-N-Benzylaminophenyl)methyl]-1H-indole
(9). Following procedure B, treatment of 4 (0.30 g,
1.35 mmol) with 5 M HCl–MeOH (90 mL, 0.45 mmol),
benzaldehyde (0.14 mL, 1.35 mmol) and NaBH3CN
(85 mg, 1.35 mmol) gave 9 (0.28 g, 66%) as a yellow
1
solid; mp 89–91 8C; IR (KBr) nmax: 3432 (NH) cmK1; H
NMR (CDCl3) d 3.93 (br s, 1H, NH), 4.32 (s, 2H, NHCH2),
5.20 (s, 2H, CH2), 6.65 (dd, JZ3.3, 0.6 Hz, 1H, H-3), 6.76
(d, JZ8.1 Hz, 1H, H-30), 6.83 (td, JZ7.5, 1.2 Hz, 1H, Ar),
7.07–7.11 (m, with prominent d, JZ3.3 Hz, 2H, H-2 and
Ar), 7.18–7.38 (m, 8H, Ar), 7.44 (dd, JZ7.2, 1.5 Hz, 1H,
H-7), 7.78 (dd, JZ7.5, 0.9 Hz, 1H, H-4); 13C NMR (CDCl3)
d 48.0 (NHCH2), 48.3 (CH2), 102.5 (C-3), 109.8, 111.7,
120.1, 121.0 (C-10), 121.5, 122.2, 127.4, 127.6, 128.9, 129.2
(C-3a), 129.7, 129.8, 136.6 (C-7a), 139.1 (C-100), 146.3
(C-20); CI-MS m/z 313 ([MCH]C, 100%); HREI-MS m/z
calcd for [M]C C22H20N2: 312.1625, found: 312.1621.
Procedure B. To a solution of amine 4 (1.0 equiv) in
˚
absolute methanol (10 mL) with molecular sieves 3 A was
added 5 M HCl–MeOH (0.33 equiv), followed by the
appropriate aldehyde (0.25 or 1 equiv) and NaBH3CN (0.1
or 1.0 equiv). The reaction mixture was stirred at r.t. for
20 h. The mixture was filtered and the filtrate was
evaporated to dryness. Water (20 mL) was added and the
mixture extracted with DCM (20 mL). The aqueous layer
was brought to pHO10 with solid KOH and extracted with
DCM (3!20 mL). The organic extracts were combined and
washed with brine (15 mL), dried, concentrated, and
chromatographed by elution with 1:1 DCM/hexane.
4.2.4. 1-{[2-N-(10-Phenylethyl)aminophenyl]methyl}-1H-
indole (10). Following procedure B, treatment of 4 (0.30 g,
1.42 mmol), with 5 M HCl–MeOH (0.1 mL, 0.50 mmol),
acetophenone (40 mL, 0.34 mmol), and NaBH3CN (10 mg,
0.14 mmol) gave 10 (82 mg, 74%) as an off-white solid; mp
86–88 8C; IR (KBr) nmax: 3425 (NH) cmK1 1H NMR
;
The following compounds were prepared by one of these
general procedures.
(CDCl3) d 1.11 (d, JZ6.6 Hz, 3H,CH3), 3.47 (br s, 1H, NH),
4.33 (q, JZ6.6 Hz, 1H, CH), 5.20 (s, 2H, CH2), 6.37 (d, JZ
8.1 Hz, 1H, Ar), 6.57 (d, JZ3.3 Hz, 1H, H-3), 6.64 (t, JZ
7.5 Hz, 1H, Ar), 6.93–6.95 (m, 2H, Ar), 7.00–7.10 (m, 3H,
H-2 and Ar), 7.11–7.23 (m, 5H, Ar), 7.42 (d, JZ8.1 Hz, 1H,
Ar), 7.66 (d, JZ7.5 Hz, 1H, Ar); 13C NMR (CDCl3) d 25.4
(CH3), 48.6 (CH2), 53.2 (CH), 102.7 (C-3), 109.7, 112.6,
117.3, 120.1, 120.8 (C-10), 121.6, 122.2, 125.8, 127.1,
127.6, 128.8, 129.1 (C-3a), 129.6, 130.1, 136.6 (C-7a),
144.9 (C-100), 145.8 (C-20); CI-MS m/z 327 ([MCH]C,
100%); HRCI-MS m/z calcd for [MCH]C C23H23N2:
317.1861, found: 327.1850.
4.2.1. 1-[(2-N-Methylaminophenyl)methyl]-1H-indole
(7). Following procedure A, treatment of 4 (0.16 g,
0.71 mmol) in dry DMF (20 mL) with K2CO3 (98 mg,
0.71 mmol) and methyl iodide (66 mL, 1.07 mmol) gave 7
(83 mg, 50%) as a colourless solid, mp 52–53 8C; IR (KBr)
nmax: 3430 (NH), 2815 (N–CH3) cmK1: 1H NMR (CDCl3) d
2.77 (s, 3H, CH3), 3.51 (br s, 1H, NH), 5.15 (s, 2H, CH2),
6.53 (d, JZ3.6 Hz, 1H, H-3), 6.70 (d, JZ8.1 Hz, 1H, H-30),
6.75 (d, JZ7.5 Hz, 1H, Ar), 6.99 (m, JZ8.4 Hz, 2H, H-2
and Ar), 7.13–7.33 (m, 3H, H-20, H-5 and H-6), 7.42 (d, JZ

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J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 941–953
4.2.5. 1-[(2-N-Methylaminophenyl)methyl]-5-methoxy-
1H-indole (11). Following procedure A, treatment of 5
(0.39 g, 1.54 mmol) with K2CO3 (0.21 g, 1.54 mmol) and
methyl iodide (0.1 mL, 1.69 mmol) gave 11 (0.29 g, 71%)
as a yellow solid; mp 59–60 8C; IR (KBr) nmax: 3429 (NH),
2815 (N–CH3) cmK1; 1H NMR d 2.74 (s, 3H, CH3), 3.48 (br
s, 1H, NH), 3.84 (s, 3H, OCH3), 5.06 (s, 2H, CH2), 6.42 (d,
JZ3.6 Hz, 1H, H-3), 6.66–6.73 (m, 2H, Ar), 6.86 (dd, JZ
8.6, 2.1 Hz, 1H, H-7), 6.92–6.94 (m with prominent d, JZ
3.3 Hz, 2H, H-2 and Ar), 7.11 (d, JZ2.1 Hz, 1H, H-4),
7.22–7.30 (m, 2H, Ar); 13C NMR (CDCl3) d 31.0 (CH3),
48.1 (CH2), 56.2 (OCH3), 101.8, 102.9 (C-3), 110.5, 110.6,
112.3 (!3), 117.6, 120.7 (C-10), 128.2 (C-2), 129.5 (C-3a),
129.7, 131.9 (C-7a), 147.5 (C–N), 154.4 (COCH3); CI-MS
m/z 267 ([MCH]C, 100%); HRCI-MS m/z calcd for [MC
H]C C17H18N2O: 267.1497, found: 267.1490.
to r.t. with stirring overnight. Distilled water (15 mL) was
added to the reaction mixture and the aqueous layer was
extracted with DCM (3!20 mL). The combined organic
extract was dried, then concentrated and the residue
chromatographed on a column by elution with DCM.
Procedure D. To a stirred suspension of sodium hydride
(NaH) (ca. 50% in mineral oil, 1.1 equiv) in dry THF (5 mL)
was added a solution of 8–10 or 12–13 (1.0 equiv) in dry
THF (20 mL) under a nitrogen atmosphere and the solution
was stirred at r.t. for 30 min. Chloroacetyl chloride
(2.5 equiv) in THF (5 mL) was added to the solution and
the reaction mixture was stirred at r.t. overnight. Solvent
was then removed under reduced pressure. DCM (15 mL)
was added to the residue and the mixture was washed with
water (3!15 mL). The organic layer was dried, and the
solvent then evaporated in vacuo to give a yellow residue.
The residue was purified by flash column chromatography
with DCM as eluent.
4.2.6. 1-[(2-N-Benzylaminophenyl)methyl]-5-methoxy-
1H-indole (12). Following procedure A, treatment of 5
(1.00 g, 4.00 mmol) with K2CO3 (0.58 g, 4.17 mmol) and
benzyl bromide (0.50 mL, 4.17 mmol) gave 12 (0.80 g,
4.3.1. N-[(2-(10-1H-Indolyl)methyl]phenyl]-N-methyl
chloroacetamide (14b). Following procedure C, treatment
of 7 (83 mg, 0.35 mmol) with K2CO3 (0.18 g, 1.30 mmol) in
dry DCM (5 mL), and chloroacetyl chloride (70 mL,
0.88 mmol) gave 14b (63 mg, 57%) as colourless solid;
mp 89–92 8C; IR (KBr) nmax: 2852 (N–CH3), 1658 (C]O),
58%) as a yellow solid; mp 108–110 8C; IR (KBr) nmax
:
3428 (NH) cmK1; 1H NMR (CDCl3) d 3.86 (s, 3H, OCH3),
4.23 (s, 2H, NHCH2), 5.17 (s, 2H, CH2), 6.48 (d, JZ3.3 Hz,
1H, H-3), 6.65 (d, JZ8.4 Hz, 1H, H-30), 6.73 (t, JZ7.5 Hz,
1H, Ar), 6.81 (dd, JZ8.7, 2.4 Hz, 1H, H-6), 6.98–7.02 (m,
2H, H-2 and Ar), 7.07–7.11 (m, 3H, Ar), 7.18–7.30 (m, 6H,
Ar); 13C NMR (CDCl3) d 48.1 (NHCH2), 48.2 (CH2), 56.1
(CH3), 101.9 (C-3), 103.0 (C-4), 110.4, 111.6, 112.2, 117.7,
120.8 (C-10), 127.4, 128.1, 128.8, 129.6, 129.8, 131.8
(C-7a), 139.0 (C-100), 146.2 (C-20), 154.4 (COCH3); CI-MS
m/z 343 ([MCH]C, 100%); HREI-MS m/z calcd for [M]C
C23H22N2O: 342.1732, found: 342.1731.
1
796 (C–Cl) cmK1; H NMR (CDCl3) d 3.24 (s, 3H, CH3),
3.56 (d, JZ12.6 Hz, 1H, CHHCl), 3.66 (d, JZ12.6 Hz, 1H,
CHHCl), 5.29 (d, JZ5.7 Hz, 2H, CH2), 6.59 (d, JZ3.3 Hz,
1H, H-3), 6.99 (d, JZ7.5 Hz, 1H, Ar), 7.06 (d, JZ3.0 Hz,
1H, H-2), 7.11–7.39 (m, 4H, Ar), 7.36 (m, 1H, H-6), 7.67 (d,
JZ7.8 Hz, 1H, H-4); 13C NMR (CDCl3) d 37.5 (CH3), 41.3
(CH2Cl), 46.7 (CH2), 102.7 (C-3), 109.6 (C-7), 119.9, 121.2
(C-10), 122.0 (C-30), 125.1 (C-2), 127.0 (C-3a), 127.4,
128.8, 128.9, 129.2, 130.4, 134.1 (C-7a), 136.4 (C-20), 164.6
(CO); CI-MS m/z 313 ([MCH]C, 100%), HRCI-MS m/z
calcd for [MCH]C C18H18N2O35Cl: 313.1108, found:
313.1111.
4.2.7. 1-[(2-N-Benzylaminophenyl)methyl]-5-fluoro-1H-
indole (13). Following procedure A, treatment of 6 (1.00 g,
4.12 mmol) with K2CO3 (0.57 g, 4.12 mmol) and benzyl
bromide (0.49 mL, 4.12 mmol) gave 13 (0.65 g, 48%) as
colourless needles; mp 189–191 8C; IR (KBr) nmax: 3430
(NH) cmK1; 1H NMR (CDCl3) d 4.24 (s, 2H, NHCH2), 5.19
(s, 2H, CH2), 6.50 (d, JZ3.3 Hz, 1H, H-3), 6.71 (d, JZ
8.1 Hz, 1H, Ar), 6.77 (t, JZ7.5 Hz, 1H, Ar), 6.90 (td, JZ
9.0, 2.7 Hz, 1H, H-6), 7.00 (dd, JZ7.5, 1.5 Hz, 1H, Ar),
7.05–7.10 (m with prominent d, JZ3.3 Hz, 2H, H-2 and
Ar), 7.16–7.27 (m, 6H, Ar), 7.30 (dd, JZ9.6, 2.4 Hz, 1H,
H-7); 13C NMR (CDCl3) d 48.2 (NHCH2), 48.3 (CH2),
102.3 (d, JZ4.9 Hz, 13C–19F, C3–F), 106.1 (d, JZ23.2 Hz,
13C–19F, C6–F), 110.9 (d, JZ10.3 Hz, 13C–19F, C7–F),
110.8 (d, JZ27.8 Hz, 13C–19F, C4–F), 117.0, 118.1, 120.9
(C-10), 127.5, 128.8, 129.15, 129.23, 129.5 (d, JZ16.3 Hz,
13C–19F, C2a–F), 129.8, 133.1 (C-7a), 138.6 (C-10), 146.0
(C-20), 158.2 (d, JZ233.1 Hz, 13C–19F, C5–F); CI-MS m/z
331 ([MCH]C, 100%); HREI-MS m/z calcd for [M]C
C22H19N2F: 330.1532, found: 330.1533.
4.3.2. N-[(2-(10-1H-Indolyl)methyl]phenyl]-N-(400-meth-
oxylbenzyl)chloroacetamide (14c). Following procedure
D, NaH (27 mg ca. 50% in mineral oil, 0.57 mmol) was
reacted with a solution of 8 (0.18 g, 0.52 mmol) and
chloroacetyl chloride (0.11 mL, 1.42 mmol) to give 14c
1
(0.20 g, 93%) as a yellow solid; mp 82–84 8C; H NMR
(CDCl3) d 3.51 (d, JZ12.6 Hz, 1H, CHHCl), 3.62 (d, JZ
12.6 Hz, 1H, CHHCl), 3.75 (s, 3H, OCH3), 4.55 (d, JZ
13.8 Hz, 1H, CONCHH), 4.78 (d, JZ16.8 Hz, 1H, CHH),
4.95 (d, JZ13.8 Hz, 1H, CONCHH), 5.08 (d, JZ16.8 Hz,
1H, CHH), 6.51 (d, JZ3.3 Hz, 1H, H-3), 6.77–6.80 (m with
prominent d, JZ8.7 Hz, 3H, H-30, H-300, and H-500), 6.84–
6.88 (m with prominent d, JZ3.0 Hz, 2H, H-2 and H-60),
7.00 (d, JZ8.1 Hz, 1H, Ar), 7.07 (t, JZ7.2 Hz, 1H, H-50)0,
7.09–7.12 (m with prominent d, JZ8.7 Hz, 3H, H-6, H-2 ,
and H-600), 7.17–7.24 (m, 2H, Ar), 7.59 (d, JZ7.5 Hz, 1H,
H-4); 13C NMR (CDCl3) d 41.8 (CH2Cl), 46.6 (CH2), 53.8
(CONCH2), 55.6 (CH3), 102.7 (C-3), 109.6, 114.3, 120.8,
121.4, 122.3, 128.2, 128.3, 128.8 (C-3a), 129.3, 129.4,
129.9, 130.1, 131.3, 135.9 (C-10), 136.4 (C-7a), 138.4
(C-20), 159.7 (COCH3), 166.8 (CO); CI-MS m/z 419 ([MC
H; 35Cl]C, 100%), 421 ([MCH; 37Cl]C, 35%); HRCI-MS
m/z calcd for [MCH]C C25H24N2O237Cl: 421.1497, found:
421.1498.
4.3. General procedures for the preparation of chloro-
acetamides (14b–d, 14f–h)
Procedure C A mixture of 7 or 11 (1.0 equiv) and anhydrous
potassium carbonate (K2CO3) (3.7 equiv) in dry DCM was
cooled to 0–5 8C and chloroacetyl chloride (2.5 equiv) was
added. Stirring was continued with cooling for a further
30 min and the reaction mixture was then allowed to warm

J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 941–953
947
4.3.3. N-[(2-(10-1H-Indolyl)methyl]phenyl]-N-benzyl-
chloroacetamide (14d). Following procedure D, NaH
CHHCl), 3.83 (s, 3H, OCH3), 5.23 (d, JZ5.1 Hz, 2H,
CH2), 6.84 (d, JZ3.6 Hz, 1H, C-3), 6.83 (dd, JZ9.0,
2.4 Hz, 1H, Ar), 6.87 (d, JZ7.5 Hz, 1H, Ar), 7.02 (d, JZ
3.0 Hz, 1H, H-2), 7.05–7.10 (m with prominent d, JZ
2.4 Hz, 2H, Ar), 7.20 (dd, JZ7.5, 1.2 Hz, 1H, Ar), 7.28–
7.39 (m, 2H, Ar); 13C NMR (CDCl3) d 37.5 (CH3), 41.2
(CH2Cl), 47.1 (CH2), 56.1 (OCH3), 102.3 (C-3), 103.0,
110.4, 1120.6, 128.9, 129.0, 129.3 (C-3a), 129.7, 129.9,
131.6 (C-1 ), 135.2 (C-7a), 140.6 (C-20), 154.4 (COCH3),
166.8 (CO); CI-MS m/z 343 ([MCH]C, 100%); HRCI-MS
m/z calcd for [MCH]C C19H20N2O235Cl: 343.1213, found:
343.1208.
(70 mg, 1.76 mmol) was reacted with 9 (0.50 g,
1.60 mmol) and chloroacetyl chloride (0.32 mL,
4.00 mmol) to give 14d (0.50 g, 81%) as a yellow solid;
1
mp 148–149 8C; H NMR (CDCl3) d 3.56 (d, JZ12.9 Hz,
1H, CHHCl), 3.66 (d, JZ13.2 Hz, 1H, CHHCl), 4.65 (d,
JZ13.8 Hz, 1H, CONCHH), 4.80 (d, JZ16.8 Hz, 1H,
CHH), 5.04 (d, JZ13.8 Hz, 1H, CONCHH), 5.12 (d, JZ
16.8 Hz, 1H, CHH), 6.54 (d, JZ3.0 Hz, 1H, H-3), 6.78 (m,
1H, Ar), 6.85 (d, JZ3.0 Hz, 1H, H-2), 6.93 (m, 1H, Ar),
7.04 (d, JZ7.8 Hz, 1H, H-7), 7.13 (td, JZ7.2, 1.5 Hz, 1H,
H-5), 7.22 (td, JZ6.9, 0.9 Hz, 1H, H-6), 7.22–7.28 (m, 4H,
Ar), 7.30–7.36 (m, 3H, Ar), 7.64 (dd, JZ7.5, 0.9 Hz, 1H,
H-4); 13C NMR (CDCl3) d 41.3 (CH2Cl), 46.3 (CH2), 53.3
(CONCH2), 102.5 (C-3), 109.3 (C-7), 119.5 (C-5), 121.2
(C-4), 122.1 (C-6), 127.9 (C-2), 128.3, 128.5 (C-3a), 128.8,
129.0, 129.2, 129.7, 129.8, 129.9, 135.7 (C-10), 136.0
(C-7a), 136.2 (C-100), 138.3 (C-20), 166.5 (CO); CI-MS m/z
389 ([MCH]C, 100%); HREI-MS m/z calcd for [M]C
C24H21N2O35Cl: 388.1342, found 388.1334.
4.3.6. N-{2-[10-(5-Methoxy-1H-indolyl)methyl]phenyl}-
N-benzylchloroacetamide (14g). Following procedure D,
compound 12 (0.20 g, 0.58 mmol), NaH (23 mg,
0.64 mmol) and chloroacetyl chloride (0.12 mL,
1.45 mmol) were reacted to give 14g (0.14 g, 58%) as a
yellow solid; mp 166–169 8C; 1H NMR (CDCl3) d 3.54 (d,
JZ12.9 Hz, 1H, CHHCl), 3.64 (d, JZ12.9 Hz, 1H,
CHHCl), 3.83 (s, 3H, OCH3), 4.62 (d, JZ13.5 Hz, 1H,
CONCHH), 4.78 (d, JZ16.5 Hz, 1H, CHH), 5.04 (d, JZ
13.8 Hz, 1H, CONCHH), 5.08 (d, JZ16.5 Hz, 1H, CHH),
6.46 (d, JZ2.4 Hz, 1H, H-3), 6.79–6.84 (m, 3H, Ar), 6.90–
6.93 (m, 2H, Ar), 7.08 (d, JZ2.4 Hz, 1H, H-4), 7.21–7.33
(m, 7H, Ar); 13C NMR (CDCl3) d 41.6 (CH2Cl), 46.8 (CH2),
53.5 (CONCH2), 56.0 (CH3), 102.2 (C-3), 110.3, 112.6,
128.5, 128.7, 128.9, 129.2 (C-3a), 129.3, 129.5, 129.9,
130.0, 130.1, 131.7 (C-10), 136.0 (C-7a), 136.3 (C-100),
138.6 (C-20), 154.5 (COCH3), 166.7 (CO); CI-MS m/z 419
([MCH; 35Cl]C, 100%); HRCI-MS m/z calcd for [MCH]C
C25H24N2O325Cl: 419.1526, found: 419.1506.
4.3.4.
N-[(2-(10-1H-Indolyl)methyl]phenyl]-N-(100-
phenylethyl)chloroacetamide (14e). A mixture of 10
(87 mg, 0.27 mmol), triethylamine (56 mL, 0.41 mmol),
and 4-dimethylaminopyridine (3.3 mg, 0.03 mmol) in dry
DCM (10 mL) was stirred at 0 8C. To this solution was
added a solution of chloroacetyl chloride (60 mL,
0.54 mmol) in dry DCM (2 mL) and the mixture was stirred
at r.t. for 1 h. The reaction mixture was washed with brine
and the organic layer was dried and concentrated. The
residue was subjected to flash column chromatography
(hexane–dichloromethane, 1:1) to give 14e (36 mg, 33%) as
a colourless solid; mp 90–92 8C; 1H NMR (CDCl3, rotamer
ratio of ca 2:1*, *Zminor rotamer) d 1.58* (d, JZ7.2 Hz,
1H, CH3) 1.64 (d, JZ7.2 Hz, 2H, CH3), 3.53 (d, JZ
13.2 Hz, 1H, CHHCl), 3.63 (d, JZ13.2 Hz, 1H, CHHCl),
3.73 (d, JZ17.4 Hz, 0.7H, CHH), 4.63 (d, JZ17.4 Hz,
0.7H, CHH), 5.31* (d, JZ17.1 Hz, 0.3H, CHH), 5.37* (d,
JZ17.1 Hz, 0.3H, CHH), 6.22* (q, JZ7.2 Hz, 0.3H, CH),
6.30 (q, JZ7.2 Hz, 0.7H, CH), 6.40 (d, JZ7.8 Hz, 0.7H,
H-30), 6.50 (d, JZ3.3 Hz, 0.7H, H-3), 6.51 (d, JZ3.0 Hz,
0.7H, H-2), 6.60* (d, JZ3.3 Hz, 0.3H, H-3), 6.78 (d, JZ
7.8 Hz, 1H, Ar), 7.02–7.04* (m, 0.6H, H-2 and Ar), 7.06–
7.16 (m,0 3.4H, H-200, H-600 and Ar), 7.22 (td,00JZ7.5, 1.5 Hz,
1H, H-4 and H-40*), 7.27–7.36 (m, 5H, H-3 , H-500 and Ar),
7.39–7.43 (m, 1H, H-7 and H-7*), 7.58 (dd, JZ8.1, 2.1 Hz,
0.7H, H-4), 7.67* (d, JZ7.8 Hz, 0.3H, H-4); 13C NMR
(CDCl3) d 19.4 (CH3), 42.3 (CH2Cl), 46.0 (CH2), 55.7 (CH),
102.5 (C-3), 109.4, 119.9 (C-5), 121.2 (C-4), 122.1, 128.0
(C-2), 128.4 (C-30), 128.05 (C-3a), 128.6, 128.9, 129.5,
130.2, 131.4, 134.9 (C-1 ), 136.5 (C-7a), 138.3 (C-100),
139.1 (C–N), 166.3 (CO); CI-MS m/z 403 ([MCH]C,
100%); HRCI-MS m/z calcd for [MCH]C C25H24N2O35Cl:
403.1577, found: 403.1559.
4.3.7. N-{2-[10-(5-Fluoro-1H-indolyl)methyl]phenyl}-N-
benzylchloroacetamide (14h). Following procedure D,
compound 13 (0.14 g, 0.42 mmol), NaH (18 mg,
0.46 mmol) and chloroacetyl chloride (84 mL, 1.05 mmol)
were reacted to give 14h (0.13 g, 76%) as a yellow solid; mp
1
135–136 8C; H NMR (CDCl3) d 3.55 (d, JZ12.6 Hz, 1H,
CHHCl), 3.67 (d, JZ12.9 Hz, 1H, CHHCl), 4.64 (d, JZ
13.8 Hz, 1H, CONCHH), 4.79 (d, JZ16.8 Hz, 1H, CHH),
5.02 (d, JZ13.8 Hz, 1H, CONCHH), 5.11 (d, JZ16.5 Hz,
1H, CHH), 6.50 (d, JZ3.3 Hz, 1H, H-3), 6.79 (ddd, JZ9.3,
8.1, 2.7 Hz, 1H, Ar), 6.90 (d, JZ3.3 Hz, 1H, H-2), 6.91–
6.97 (m, 3H, Ar), 7.22–7.34 (m, 8H, Ar); 13C NMR (CDCl3)
d 41.5 (CH2Cl), 46.8 (CH2), 53.6 (CONCH2), 102.7 (d, JZ
4.6 Hz, 13C–19F, C-3), 106.2 (d, JZ23.0 Hz, 13C–19F, C-6),
110.2 (d, JZ9.8 Hz, 13C–19F, C-7), 110.7 (d, JZ26 Hz,
13C–19F, C-4), 128.6, 129.0, 129.2, 0129.3, 129.5 (C-3a),
129.7, 129.8, 130.0, 130.2, 133.1 (C-1 ), 135.7 (C-7a), 136.2
(C-100), 138.6 (C-20), 158.2 (d, JZ223.6 Hz, 13C–19F, C5–
F), 166.9 (CO); CI-MS m/z 407 ([MCH]C, 100%); HRCI-
MS m/z calcd for [MCH]C C24H21N2O35ClF: 407.1326,
found: 407.1319.
4.4. Genernal procedure for the preparation of iodo-
acetamides (15a–h)
4.3.5. N-{2-[10-(5-Methoxy-1H-indolyl)methyl]phenyl}-
N-methylchloroacetamide (14f). Following procedure C,
treatment of 11 (0.29 g, 1.09 mmol) with K2CO3 (0.56 g,
4.03 mmol) and chloroacetyl chloride (0.22 mL,
2.73 mmol) gave 14f (0.22 g, 58%) as a yellow solid; mp
A solution of 14a–h (1.0 equiv) in acetronitrile containing
sodium iodide (NaI) (10.0 equiv) was heated at reflux for
2 h. The solution was cooled and water (10 mL) was added.
The solution was then extracted with EtOAc (3!20 mL).
The organic extracts were combined, dried, concentrated,
1
71–73 8C; H NMR (CDCl3) d 3.21 (s, 3H, CH3), 3.52 (d,
JZ12.6 Hz, 1H, CHHCl), 3.62 (d, JZ12.6 Hz, 1H,

948
J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 941–953
1
and chromatographed on a column by elution with DCM.
The following compounds were prepared by this method.
solid; mp 101–103 8C; H NMR (CDCl3) d 3.31 (d, JZ
9.9 Hz, 1H, CHHI), 3.46 (d, JZ9.6 Hz, 1H, CHHI), 4.62 (d,
JZ13.8 Hz, 1H, CONCHH), 4.85 (d, JZ16.8 Hz, 1H,
CHH), 5.04 (d, JZ14.1 Hz, 1H, CONCHH), 5.18 (d, JZ
16.5 Hz, 1H, CHH), 6.55 (d, JZ3.3 Hz, 1H, H-3), 6.79 (dd,
JZ7.5, 2.7 Hz, 1H, Ar), 6.88 (d, JZ3.3 Hz, 1H, H-2), 7.03
(d, JZ6.9 Hz, 1H, Ar), 7.06 (d, JZ7.5 Hz, 1H, H-7), 7.11
(td, JZ6.6, 0.9 Hz, 1H, H-5), 7.18 (td, JZ7.5, 1.2 Hz, 1H,
H-6), 7.22–7.28 (m, 4H, Ar), 7.30–7.36 (m, 3H, Ar), 7.64
(dd, JZ7.8, 1.2 Hz, 1H, H-4); 13C NMR (CDCl3) d K2.2
(CH2I), 46.8 (CH2), 53.7 (CONCH2), 102.7 (C-3), 109.6,
120.6, 121.4, 122.2, 128.1 (C-2), 128.4, 128.8 (C-3a), 128.9,
129.2, 129.3, 129.7, 129.8, 129.9, 135.6 (C-10), 136.4
(C-7a), 136.5 (C-100), 139.3 (C-20), 168.1 (CO); CI-MS m/z
480 ([MCH]C, 100%); HRCI-MS m/z calcd for [MCH]C
C24H21N2OI: 480.0690, found: 480.0689.
4.4.1. N-[(2-(10-1H-Indoly)methyl]phenyl]-N-iodoaceta-
mide (15a). Treatment of 14a (73 mg, 0.24 mmol) with
NaI (0.37 g, 2.48 mmol) in refluxing acetronitrile (5 mL)
gave 15a (83 mg, 87%) as a colourless crystalline solid; mp
101–103 8C; IR (KBr) nmax: 2853 (N–CH3), 1659
1
(C]O) cmK1; H NMR (CDCl3) d 3.53 (s, 2H, CH2I),
5.27 (s, 2H, CH2), 6.58 (d, JZ3.3 Hz, 1H, H-3), 7.03 (br d,
JZ3.3 Hz, 2H, H-2 and Ar), 7.12–7.26 (m, 3H, Ar), 7.29–
7.32 (m, 2H, Ar and NH), 7.53 (br d, JZ7.5 Hz, 2H, H-6
and Ar), 7.67 (d, JZ7.2 Hz, 1H, H-4); 13C NMR (CDCl3) d
K2.8 (CH2I), 47.5 (CH2), 102.9 (C-3), 109.8 (C-7), 120.3,
121.5, 122.4, 125.3, 127.1, 127.9, 129.0, 129.2, 131.0,
134.8, 136.5 (C-20), 166.4 (CO); EI-MS m/z 390 ([M]C,
75%), 264 ([MKI]C, 100%); HREI-MS m/z calcd. for
[M]C C17H15N2OI: 390.0229, found: 390.0233.
4.4.5.
N-[(2-(10-1H-Indolyl)methyl]phenyl]-N-(100-
phenylethyl)iodoacetamide (15e). Treatment of 14e
(36 mg, 0.09 mmol) with NaI (0.14 g, 0.95 mmol) in
refluxing acetonitrile (2 mL) gave 15e (37 mg, 82%) as a
yellow solid; mp 60–61 8C; 1H NMR (CDCl3, rotamer ratio
of ca. 2:1*) d 1.55* (d, JZ7.2 Hz, 1H, CH3), 1.62 (d, JZ
6.9 Hz, 2H, CH3), 3.24 (d, JZ9.9 Hz, 1H, CHHI), 3.44 (d,
JZ9.6 Hz, 1H, CHHI), 3.80 (d, JZ17.1 Hz, 0.7H, CHH),
4.69 (d, JZ17.1 Hz, 0.7H, CHH), 5.30* (d, JZ16.8 Hz,
0.3H, CHH), 5.39* (d, JZ16.8 Hz, 0.3H, CHH), 6.204–6.29
(m, 1H, CH and CH*), 6.39 (d, JZ7.8 Hz, 0.7H, H-3 ), 6.45
(dd, JZ3.0, 0.9 Hz, 0.7H, H-3), 6.52–6.54 (m with
pominent d, JZ3.3 Hz, 1H, H-2 and H-30*), 6.60 (d, JZ
3.3 Hz, 0.3H, H-3*), 6.78 (d, JZ8.1 Hz, 1H, Ar), 7.03–7.21
(m, 4H, H-5, H-200, H-600 and Ar), 7.20–7.21 (m, 1H, H-40
and Ar), 7.27–7.42 (m, 5H, H-7, H-300, H-500 and Ar), 7.57
(dd, JZ7.5, 1.5 Hz, 0.7H, H-4), 7.69 (d, JZ7.5 Hz, 0.3H,
H-4*); 13C NMR (CDCl3) d K1.3 (CH2I), K0.8* (CH2I),
17.4* (CH3), 19.1 (CH3), 46.2 (CH2), 47.1* (CH2), 55.2*
(CH), 55.7 (CH), 102.5 (C-3), 103.0* (C-3), 109.5, 119.9,
120.2*, 121.2, 121.5*, 122.0, 122.4*, 128.1, 128.2, 128.3,
128.5, 128.7, 128.8 (C-3a), 128.87, 128.9, 129.5, 129.8*,
130.1, 130.7*, 131.0, 135.6 (C-10), 136.4* (ArC), 136.5
(C-7a), 136.66* (ArC), 136.7* (ArC), 138.0 (C-100), 139.2
(C-20), 141.3* (C-2), 167.9 (CO), 171.3* (CO); CI-MS m/z
495 ([MCH]C, 100%); HRCI-MS m/z calcd for [MCH]C
C25H24N2OI: 495.0933, found: 495.0926.
4.4.2. N-[(2-(10-1H-Indolyl)methyl]phenyl]-N-methyl-
iodoacetamide (15b). Treatment of 14b (0.10 g,
0.32 mmol) with NaI (0.50 g, 3.32 mmol) in refluxing
acetonitrile (5 mL) gave 15b (0.12 g, 93%) as a yellow
solid; mp 53–54 8C; 1H NMR (CDCl3) d 3.21 (s, 3H, CH3),
3.30 (d, JZ10.2 Hz, 1H, CHHI), 3.45 (d, JZ9.6 Hz, 1H,
CHHI), 5.25 (d, JZ16.5 Hz, 1H, CHH), 5.37 (d, JZ
16.5 Hz, 1H, CHH) 6.58 (d, JZ2.7 Hz, 1H, H-3), 6.96 (d,
JZ8.4 Hz, 1H, Ar), 7.09 (d, JZ3.0 Hz, 1H, H-2). 7.11–7.39
(m, 6H, ArH), 7.66 (d, JZ7.5 Hz, 1H, H-4); 13C NMR
(CDCl3) d K2.9 (CH2I), 37.7 (CH3), 47.0 (CH2), 102.7
(C-3), 109.7 (C-7), 120.1, 121.4, 122.3, 128.3, 128.5, 128.6
(C-3a), 128.9, 129.6, 129.8, 134.9 (C-10), 136.4 (C-7a),
141.3 (C-20), 168.3 (CO); CI-MS m/z 405 ([MCH]C,
100%); HREI-MS m/z calcd for [M]C C18H17N2OI:
404.0386, found: 404.0396.
4.4.3. N-[(2-(10-1H-Indolyl)methyl]phenyl]-N-(400-meth-
oxybenzyl)iodoacetamide (15c). Treatment of 14c
(0.20 g, 0.48 mmol) with NaI (0.76 g, 5.04 mmol) in
refluxing acetonitrile (10 mL) gave 15c (0.17 g, 70%) as a
yellow solid; mp 64–65 8C; 1H NMR (CDCl3) d 3.20 (d, JZ
9.6 Hz, 1H, CHHI), 3.35 (d, JZ9.9 Hz, 1H, CHHI), 3.72 (s,
3H, OCH3), 4.51 (d, JZ13.8 Hz, 1H, CONCHH), 4.77 (d,
JZ16.8 Hz, 1H, CHH), 4.87 (d, JZ14.1 Hz, 1H,
CONCHH), 5.10 (d, JZ16.8 Hz, 1H, CHH), 6.47 (dd, JZ
3.3, 0.9 Hz, 1H, H-3), 6.70 (dd, JZ8.1, 2.400Hz, 1H, H-30),
6.76 (dd, JZ9.0, 2.4 Hz, 2H, H-300 and H-5 ), 6.82 0(d, JZ
3.0 Hz, 1H, H-2), 6.95 (dd, JZ9.0, 2.4 Hz, 1H, H-6 ), 6.98
(d, JZ8.4 Hz, 1H, Ar), 7.04 (td, JZ6.9, 1.2 Hz, 1H, H-50)0,
7.05–7.12 (m with prominent d, JZ8.7 Hz, 3H, H-6, H-2 ,
and H-600), 7.14–7.23 (m, 2H, Ar), 7.56 (dd, JZ7.5, 0.9 Hz,
1H, H-4); 13C NMR (CDCl3) d K2.0 (CH2I), 46.8 (CH2),
53.1 (CONCH2), 55.6 (CH3), 102.7 (C-3), 109.7, 114.3,
120.1, 121.4, 122.2, 128.2, 128.5, 128.7 (C-3a), 129.03,
129.8, 131.2, 135.6 (C-100), 136.5 (C-7a), 139.2 (C-2 ),
159.7 (COCH3), 168.0 (CO); CI-MS m/z 511 ([MCH]C,
13%); HREI-MS m/z calcd for [M]C C25H23N2O2I:
510.0804, found: 510.0810.
4.4.6. N-{2-[10-(5-Methoxy-1H-indolyl)methyl]phenyl}-
N-methyliodoacetamide (15f). Treatment of 14f (0.21 g,
0.63 mmol) with NaI (0.99 g, 6.61 mmol) in refluxing
acetonitrile (10 mL) gave 15f (0.17 g, 70%) as a yellow
solid; mp 75–77 8C; 1H NMR (CDCl3) d 3.18 (s, 3H, CH3),
3.27 (d, JZ9.9 Hz, 1H, CHHI), 3.42 (d, JZ10.2 Hz, 1H,
CHHI), 3.83 (s, 3H, OCH3), 5.26 (d, JZ16.2 Hz, 1H, CHH),
5.37 (d, JZ16.5 Hz, 1H, CHH), 6.48 (d, JZ3.3 Hz, 1H,
H-3), 6.83 (dd, JZ8.7, 2.7 Hz, 1H, Ar), 6.93 (dd, JZ7.2,
2.1 Hz, 1H, Ar), 7.05 (d, JZ3.0 Hz, 1H, H-2), 7.08–7.11
(m, 2H, Ar), 7.23 (td, JZ8.4, 1.5 Hz, 1H, Ar), 7.35 (d, JZ
8.7 Hz, 1H, Ar), 7.38 (d, JZ9.3 Hz, 1H, H-4); 13C NMR
(CDCl3) d K2.7 (CH2I), 37.7 (CH3), 47.2 (CH2), 56.1
(OCH3), 102.3 (C-3), 103.0, 110.5, 112.6, 128.5, 128.9,
129.6, 129.8, 131.7 (C-10), 135.0 (C-7a), 141.3 (C-20), 154.4
(COCH3), 168.3 (CO); CI-MS m/z 435 ([MCH]C, 100%);
HREI-MS m/z calcd for [M]C C19H19N2O2I: 434.0491,
found: 434.0476.
4.4.4. N-[(2-(10-1H-Indolyl)methyl]phenyl]-N-benzyl-
iodoacetamide (15d). Treatment of 14d (0.50 g,
1.29 mmol) with NaI (1.90 g, 12.9 mmol) in refluxing
acetonitrile (25 mL) gave 15d (0.52 g, 96%) as a yellow

J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 941–953
949
4.4.7. N-{2-[10-(5-Methoxy-1H-indolyl)methyl]phenyl}-
N-benzyliodoacetamide (15g). Treatment of 14g (62 mg,
0.15 mmol) with NaI (0.22 g, 1.50 mmol) in refluxing
acetonitrile (3 mL) gave 15g (55 mg, 73%) as a yellow
solid; mp 59–61 8C; 1H NMR (CDCl3) d 3.28 (d, JZ9.6 Hz,
1H, CHHI), 3.43 (d, JZ9.9 Hz, 1H, CHHI), 3.84 (s, 3H,
OCH3), 4.60 (d, JZ13.8 Hz, 1H, CONCHH), 4.81 (d, JZ
16.8 Hz, 1H, CHH), 5.02 (d, JZ13.8 Hz, 1H, CONCHH),
5.12 (d, JZ16.8 Hz, 1H, CHH), 6.46 (dd, JZ3.3, 0.9 Hz,
1H, H-3), 6.78–6.81 (m, 2H, Ar), 6.83–6.86 (m, 2H, H-2 and
Ar), 6.93 (dd, JZ9.0, 0.6 Hz, 1H, H-30), 7.05 (ddd, JZ9.0,
6.6, 2.4 Hz, 1H, Ar), 7.09 (d, JZ2.4 Hz, 1H, H-4), 7.27–
7.29 (m, 4H, Ar), 7.33–7.36 (m, 2H, Ar); 13C NMR (CDCl3)
d K2.5 (CH2I), 46.9 (CH2), 53.5 (CONCH2), 56.0 (OCH3),
102.2 (C-3), 102.9, 110.4, 112.5, 128.4, 128.6 (C-3a), 128.7,
128.9, 129.2, 129.4, 129.7, 129.8, 0129.9, 131.8 (C-10), 135.7
(C-7a), 136.5 (C-100), 139.4 (C-2 ), 154.5 (COCH3), 168.2
(CO); CI-MS m/z 511 ([MCH]C, 100%); HRCI-MS m/z
calcd for [MCH]C C25H24N2O2I: 511.0883, found:
511.0868.
(CH3), 47.2 (CH2), 102.7 (d, JZ4.6 Hz, C13–F19, C3–F),
106.2 (d, JZ23.5 Hz, C13–F19, C6–F), 110.3 (d, JZ9.5 Hz,
C13–F19, C7–F), 110.8 (d, JZ26 Hz, C13–F19, C4–F), 128.7,
129.2 (d, JZ10.4 Hz, C13–F19, C3a–F), 129.6, 129.808,
129.93, 130.0, 133.1 (C-7a), 134.6 (C-100), 141.4 (C-2 ),
158.7 (d, JZ225.0 Hz, C13–F19, C5–F), 168.4 (CO); CI-MS
m/z 423 ([MCH]C, 43%); HRCI-MS m/z calcd for [MC
H]C C18H17N2OFI: 423.0369, found: 423.0336.
4.4.10. N-[(2-(10-1H-Indolyl)methyl]phenyl]-N-benzyl-
bromoacetamide (16a). By a procedure similar to that for
15i, treatment of 9 (0.11 g, 0.34 mmol) with NaH (18 mg,
0.38 mmol) and bromoacetyl chloride (0.10 mL, 0.85 ml) in
dry DMF (20 mL) gave 16a, after purification by column
chromatography (1:1 DCM/hexane), (0.10 g, 68%) as a
1
yellow solid; mp 99–101 8C; H NMR (CDCl3) d 3.43 (d,
JZ1.8 Hz, 2H, CH2Br), 4.62 (d, JZ13.8 Hz, 1H,
CONCHH), 4.34 (d, JZ16.8 Hz, 1H, CHH), 5.06 (d, JZ
13.8 Hz, CONCHH), 5.17 (d, JZ16.8 Hz, 1H, CHH), 6.55
(dd, JZ3.3, 0.9 Hz, 1H, H-3), 6.81 (m, 1H, Ar), 6.87 (d, JZ
3.3 Hz, 1H, H-2), 6.98 (m, 1H, Ar), 7.07 (dd, JZ6.9, 0.9 Hz,
1H, H-7), 7.12 (ddd, JZ8.4, 7.2, 1.2 Hz, 1H, H-5), 7.18 (td,
JZ8.5, 1.2 Hz, 1H, H-6), 7.23–7.28 (m, 4H, Ar), 7.30–7.35
(m, 3H, Ar), 7.64 (dd, JZ8.0, 1.2 Hz, 1H, H-4); 13C NMR
(CDCl3) d 27.0 (CH2Br), 46.7 (CH2), 53.6 (CONCH2),
102.7 (C-3), 109.3 (C-7), 120.1, 121.4, 122.3, 128.1, 128.4,
128.8 (C-3a), 129.0, 129.3, 129.4, 129.9, 130.1, 135.7
(ArC), 136.3 (ArC), 136.4 (C-20), 138.9 (C-12a), 166.8
(CO); CI-MS m/z 433 ([MCH]C, 90%); HREI-MS m/z
calcd for [M]C C24H21N2O79Br: 432.0837, found:
432.0851.
4.4.8. N-{2-[10-(5-Fluoro-1H-indolyl)methyl]phenyl}-N-
benzyliodoacetamide (15h). Treatment of 14h (74 mg,
0.18 mmol) with NaI (0.27 g, 1.80 mmol) in acetonitrile
(4 mL) gave 15h (77 mg, 89%) as a yellow solid; mp 53–
54 8C; 1H NMR (CDCl3) d 3.28 (d, JZ9.9 Hz, 1H, CHHI),
3.42 (d, JZ9.0 Hz, 1H, CHHI), 4.64 (d, JZ13.8 Hz, 1H,
CONCHH), 4.82 (d, JZ16.8 Hz, 1H, CHH), 4.98 (d, JZ
13.8 Hz, 1H, CONCHH), 5.15 (d, JZ16.8 Hz, 1H, CHH),
6.49 (d, JZ3.3 Hz, 1H, H-3), 6.77 (dd, JZ7.5, 2.7 Hz, 1H,
Ar), 6.90–6.93 (m with prominent d, JZ3.0 Hz, 3H, H-2
and Ar), 7.05 (dd, JZ8.9, 2.7 Hz, 1H, Ar), 7.22–7.33 (m,
8H, Ar); 13C NMR (CDCl3) d K2.6 (CH2I), 47.0 (CH2),
53.6 (CONCH2), 102.6 (d, JZ5.2 Hz, 13C–19F, C3–F),
106.1 (d, JZ22.9 Hz, 13C–19F, C6–F), 110.3 (d, JZ9.8 Hz,
13C–19F, C7–F), 110.7 (d, JZ26.3 Hz, 13C–19F, C4–F),
128.5, 129.0, 129.2, 129.6, 129.79, 129.83, 129.88, 129.9,
130.5 (C-3a), 133.1 (C-10), 135.4 (C-7a), 136.5 (C-100),
139.4 (C-20), 158.2 (d, JZ223.7 Hz, 13C–19F, C5–F), 168.2
(CO); CI-MS m/z 499 ([MCH]C, 46%); HREI-MS m/z
calcd for [M]C C24H20N2OFI: 498.0604, found: 498.0600.
4.4.11. N-{2-[10-(5-methoxy-1H-indolyl)methyl]phenyl}-
N-methylbromoacetamide (16b). A mixture of 11 (0.11 g,
0.41 mmol) and anhydrous K2CO3 (0.20 g, 1.50 mmol) in
dry DCM (5 mL) was cooled to 0–5 8C and bromoacetyl
chloride (80 mL, 1.03 mmol) in DCM (3 mL) was added.
Stirring was continued at 0–5 8C for a further 30 min and the
reaction mixture was then allowed to warm to r.t. with
stirring overnight. Distilled water (20 mL) was added to the
reaction mixture and the aqueous layer was extracted with
DCM (3!20 mL). The combined organic extracts were
dried, and concentrated to yield a yellow solid. The crude
solid was subjected to flash column chromatography (DCM)
to give 16b (83 mg, 54%) as yellow crystals; mp 58–59 8C;
1H NMR (CDCl3) d 3.21 (s, 3H, CH3), 3.53 (d, JZ12.6 Hz,
1H, CHHBr), 3.63 (d, JZ12.6 Hz, 1H, CHHBr), 3.84 (s,
3H, OCH3), 5.25 (d, JZ5.4 Hz, 2H, CH2), 6.49 (dd, JZ3.0,
0.6 Hz, 1H, H-3), 6.83 (dd, JZ9.0, 2.4 Hz, 1H, Ar), 6.97
(dd, JZ7.8, 2.1 Hz, 1H, Ar), 7.02–7.10 (m, 2H, H-2 and
Ar), 7.20–7.40 (m, 4H, Ar); 13C NMR (CDCl3) d 26.4
(CH2Br), 37.5 (CH3), 47.1 (CH2), 56.1 (OCH3), 102.3 (C-3),
103.2, 110.5, 112.6, 128.9, 129.3 (C-3a), 129.7, 129.8,
129.9, 131.6 (ArC), 135.2 (C-7a), 140.6 (C-20), 154.4
(COCH3), 166.8 (CO); CI-MS m/z 387 ([MCH]C, 13%);
HREI-MS m/z calcd for [M]C C19H19N2O279Br: 386.0630,
found: 386.0624.
4.4.9. N-{2-[10-(5-Fluoro-1H-indoly)methyl]phenyl}-N-
methyliodoacetamide (15i). To a suspension of NaH
(18.2 mg of ca. 50% dispersion in mineral oil, 0.38 mmol)
in dry DMF (5 mL) under nitrogen was cooled to 0–5 8C and
a solution of 14i (0.11 g, 0.35 mmol) in DMF (15 mL) was
added dropwise and the mixture was stirred for 30 min at r.t.
A solution of methyl iodide (54 mL, 0.87 mmol) in DMF
(2 mL) was added and the reaction mixture was stirred at r.t.
for a further 16 h. The solvent was evaporated, DCM
(20 mL) was added and washed with water (3!15 mL),
dried, and evaporated. The crude product was subjected to
flash column chromatography (DCM) to give 15i (76 mg,
1
66%) as a yellow solid; mp 74–76 8C; H NMR (CDCl3) d
3.17 (s, 3H, CH3), 3.29 (d, JZ9.9 Hz, 1H, CHHI), 3.43 (d,
JZ10.2 Hz, 1H, CHHI), 5.29 (d, JZ16.5 Hz, 1H, CHH),
5.39 (d, JZ16.5 Hz, 1H, CHH), 6.53 (dd, JZ3.9, 0.9 Hz,
1H, H-3), 6.91 (dd, JZ9.3, 2.7 Hz, 1H, H-4), 6.95 (dd, JZ
7.8, 2.1 Hz, 1H, H-30), 7.12 (d, JZ3.3 Hz, 1H, H-2), 7.15
(dd, JZ7.2, 2.4 Hz, 1H, H-7), 7.29 (ddd, JZ9.6, 7.2,
2.4 Hz, 1H, H-6), 7.32 (dd, JZ7.8, 1.5 Hz, 1H, H-60), 7.36–
7.44 (m, 2H, Ar); 13C NMR (CDCl3) d K3.2 (CH2I), 37.6
4.5. General procedure for radical cyclization
A solution of tributyltin hydride (Bu3SnH) (2.0 equiv) and
AIBN (1.0 equiv) in an appropriate solvent (40 mM) was
added dropwise to the solution of the haloacetamide (14–16,

950
J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 941–953
1.0 equiv) in boiling solvent (22 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 r.t. for 2–3 h. The organic
layer was separated, dried, concentrated and column
chromatographed (DCM eluent).
AIBN (23 mg, 0.14 mmol) and Bu3SnH (75 mL,
0.28 mmol). The crude material was chromatographed
(DCM) to give 18a (17 mg, 44%).
4.5.3. Cyclization of 15c. Compound 15c (0.17 g,
0.33 mmol) in toluene (5 mL) was treated with AIBN
(37 mg, 0.23 mmol) and Bu3SnH (0.12 mL, 0.46 mmol).
The first fraction from column gave 5,14-dihydro-5-(40-
methoxybenzyl)indolo[2,1-d][1,5]benzodiazo cin-6-one
17b (16 mg, 13%) as a yellow solid; mp 213–215 8C
(DCM); 1H NMR (CDCl3) d 3.42 (dd, JZ14.1, 1.2 Hz, 1H,
CHH-7), 3.68 (d, JZ14.1 Hz, 1H, CHH-7), 3.76 (s, 3H,
OCH3), 4.10 (d, JZ13.8 Hz, 1H, CHH-14), 4.50 (d, JZ
13.8 Hz, 1H, CONCHH), 4.93 (d, JZ13.8 Hz, 1H, CHH-
14), 5.52 (d, JZ13.8 Hz, 1H, CONCHH), 6.35 (s, 1H, H-8),
6.74 (d, JZ8.7 Hz, 2H, H-30 and H-50)0, 7.06 (t, 0JZ7.5 Hz,
1H, H-10), 7.11 (d, JZ8.7 Hz, 2H, H-2 and H-6 ), 7.18 (td,
JZ7.2, 0.6 Hz, 1H, H-11), 7.30–7.40 (m, 4H, Ar), 7.46 (dd,
JZ7.2, 1.5 Hz, 1H, Ar), 7.51 (d, JZ7.8 Hz, 1H, H-9); 13C
NMR (CDCl3) d 36.6 (CH2-7), 44.8 (CH2-14), 52.2
(CONCH2), 55.5 (OCH3), 103.5 (C-8), 108.7, 114.0,
119.8, 120.5, 121.5, 126.0, 128.0 (ArC), 128.5 (ArC),
129.0, 130.4, 130.90, 132.8 (ArC), 133.1 (ArC), 137.5
(C-12a), 142.8 (C-1 ), 159.3 (COCH3), 168.2 (CO); CI-
MS m/z 383 ([MCH]C, 100%); HRES-MS m/z calcd for
[MCH]C C25H23N2O2: 383.1763, found: 383.1760.
The following radical cyclizations were performed by this
method.
4.5.1. Cyclization of 15b. Compound 15b (54 mg,
0.13 mmol) in toluene (5 mL) was treated with AIBN
(21 mg, 0.13 mmol) and Bu3SnH (70 mL, 0.26 mmol). The
first fraction from the column gave 5,14-dihydro-5-methyl-
indolo[2,1-d][1,5]benzodiazocin-6-one 17a, (20 mg, 20%)
as a yellow solid; mp 211–212 8C (DCM); IR (KBr) nmax
:
1
2852 (N–CH3), 1660 (C]O) cmK1; H NMR (CDCl3) d
3.436 (s, 3H, CH3), 3.447 (d, JZ13.8 Hz, 1H, CHH-7), 3.67
(d, JZ13.8 Hz, 1H, CHH-7), 4.75 (d, JZ14.1 Hz, 1H,
CHH-14), 5.36 (d, JZ13.8 Hz, 1H, CHH-14), 6.37 (s, 1H,
H-8), 7.10 (t, JZ7.5 Hz, 1H, H-10), 7.23 (td, JZ8,1 Hz,
1H, Ar), 7.38 (d, JZ7.2 Hz, 1H, Ar), 7.46–7.56 (m, 5H, Ar);
13C NMR (CDCl3) d 36.2 (CH2-7), 36.7 (CH3), 45.2 (CH2-
14), 103.6 (C-8), 108.7, 119.9, 120.6, 121.7, 125.5, 128.0
(C-8a), 129.0, 130.6, 131.8 (C-7a), 132.2, 133.0 (C-14a),
136.8 (C-12a), 144.7 (C-4a), 168.9 (CO); CI-MS m/z 277
([MCH]C, 100%); HRCI-MS m/z calcd for [MCH]C
C18H17N2O: 277.1341, found: 277.1341.
The second fraction gave 5,7a,8,14-tetrahydro-5-(40-
methoxybenzyl)indolo[2,1-d][1,5]benzodiazocin-6-one
18b (13 mg, 11%) as a yellow solid; mp 107–109 8C
1
The second fraction gave 5,7a,8,14-tetrahydro-5-methyl
indolo[2,1-d][1,5]benzodiazocin-6-one 18a, (80 mg, 60%)
as a yellow solid; mp 129–130 8C (DCM); 1H NMR
(CDCl3) d 2.39–2.50 (m, 2H, CH2-8), 2.60 (dd, JZ15.9,
9.0 Hz, 1H, CHH-7), 3.29 (dd, JZ15.9, 9.0 Hz, 1H, CHH-
7), 3.38 (s, 3H, CH3), 3.84 (d, JZ14.7 Hz, 1H, CHH-14),
4.08 (qd, JZ8.1, 1.2 Hz, 1H, H-7a), 4.55 (d, JZ15.0, 1H,
CHH-14), 6.58 (t, JZ7.5 Hz, 1H, H-10), 6.68 (d, JZ7.8 Hz,
1H, H-12), 6.99 (d, JZ7.2 Hz, 1H, Ar), 7.06 (m, 2H, Ar),
7.22–7.39 (m, 3H, Ar), 7.52 (d, JZ7.2 Hz, 1H, H-9); 13C
NMR (CDCl3) d 36.8 (CH2-7), 38.0 (CH3), 42.7 0 (CH2-8),
45.8 (CH2-14), 62.4 (CH), 105.1 (C-12), 116.9, 124.8,
126.0, 127.6, 127.7 (C-8a), 128.3, 129.2, 131.6, 135.3
(ArC), 142.4 (ArC), 149.5 (C-4a), 172.1 (CO); CI-MS m/z
279 ([MCH]C, 100%); HREI-MS m/z calcd for [M]C
C18H18N2O: 278.1419, found: 278.1413.
(DCM); H NMR (CDCl3) d 2.39–2.51 (m, 2H, CH2-8),
2.56 (dd, JZ15.6, 8.4 Hz, 1H, CHH-7), 3.20–3.29 (m with
prominent d, JZ14.1 Hz, 2H, CHH-7 and CONCHH), 3.76
(d, JZ1.2 Hz, 3H, OCH3), 4.01 (q, JZ8.4 Hz, 1H, H-7a),
4.14 (d, JZ15.0 Hz, 1H, CONCHH), 4.38 (d, JZ14.1 Hz,
1H, CHH-14), 5.51 (d, JZ13.8 Hz, 1H, CHH-14), 6.51–
6.56 (m with prominent d, 0JZ6.9 Hz, 2H, Ar), 6.75 (d, JZ
7.8 Hz, 2H, H-30 and H-5 ), 6.95 (d, JZ7.5 Hz, 1H, Ar),
7.04 (t, JZ8.4 Hz, 1H, Ar), 7.07 (d, JZ7.8 Hz, 2H, H-20
and H-60), 7.22–7.35 (m, 3H, Ar), 7.39 (d, JZ7.5 Hz, 1H,
H-9); 13C NMR (CDCl3) d 36.7 (CH2-7), 42.6 (CH2-8), 45.6
(CH2-14), 53.1 (CONCH2), 55.5 (OCH3), 62.8 (CH), 105.0,
113.9, 116.7, 124.7, 126.7, 127.5, 127.7 (ArC), 128.4, 128.9
(ArC), 129.0, 130.7, 131.3, 136.7 (ArC), 140.4 (ArC), 154.7
(COCH3), 171.5 (CO); CI-MS m/z 385 ([MCH]C, 100%);
HRES-MS m/z calcd for [MCH]C C25H25N2O2: 385.1910,
found: 385.1916.
The third fraction gave N-[(2-(10-1H-indolyl)methyl)
phenyl]-N-methylacetamide 19a, (20 mg, 20%); mp 58–
59 8C; H NMR (CDCl3) d 1.78 (s, 3H, COCH3), 3.20 (s,
The third fraction gave N-[(2-(10-1H-indolyl)methyl)-
phenyl]-N-(400-methoxybenzyl)acetamide 19b (9 mg, 7%)
as a yellow solid; mp 58–60 8C (DCM); 1H NMR (CDCl3) d
1.81 (s, 3H, CH3), 3.79 (s, 3H, OCH3), 4.75 (d, JZ15.9 Hz,
2H, CHH and CONCHH), 4.84 (d, JZ13.8 Hz, 1H, CHH),
5.03 (d, JZ17.2 Hz, 1H, CONCHH), 6.53 (dd, JZ3.0,
1.5 Hz, 1H, H-3), 6.65 (d, JZ7.8 Hz, 1H, H-300), 6.83 (0m
with prominent dd, JZ8.7, 2.4 Hz, 3H, H-2, H-3 and0H-5 ),
6.95 (t, JZ8.7 Hz, 1H, H-50), 7.08–7.17 (m, 3H, H-2 , H-60
and Ar), 7.20–7.23 (m, 2H, Ar), 7.42–7.52 (m, 2H, Ar), 7.63
(d, JZ6.9 Hz, 1H, H-4); 13C NMR (CDCl3) d 22.5 (CH3),
47.4 (CH2), 52.1 (CONCH2), 55.5 (OCH3), 102.5 (C-3),
109.5, 114.2, 111.9, 121.3, 122.1, 128.3, 128.5, 129.02,
129.7, 130.9, 131.3, 132.4 (ArC), 135.9 (ArC), 137.6 (C-1 ),
140.3 (C-4a), 159.6 (COCH3), 168.2 (CO); CI-MS m/z 385
1
3H, NCH3), 5.26 (s, 2H, CH2-8), 6.58 (d, JZ3.0 Hz, 1H,
H-3), 6.90 (d, JZ7.5 Hz, 1H, Ar), 7.07 (dd, JZ3.0, 0.6 Hz,
1H, H-2), 7.11–7.20 (m, 4H, Ar), 7.25 (t, JZ7.5 Hz, 1H,
Ar), 7.35 (t, JZ7.5 Hz, 1H, Ar), 7.66 (dd, JZ7.8, 1.2 Hz,
1H, Ar); 13C NMR (CDCl3) d 22.2 (COCH3), 36.6 (NCH3),
46.6 (CH2-8), 102.6, 109.7, 120.1, 121.2, 122.0, 128.2,
128.4, 129.0, 129.4, 135.0 (ArC), 136.3 (ArC), 140.1 (C-20),
171.7 (CO); CI-MS m/z 279 ([MCH]C, 100%); HRCI-MS
m/z calcd for [MCH]C C18H19N2O: 279.1497, found:
279.1499.
4.5.2. Cyclization of 15b in mesitylene. Compound 15b
(56 mg, 0.14 mmol) in mesitylene (5 mL) was treated with

J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 941–953
951
([MCH]C, 100%); HRES-MS m/z calcd for [MCH]C
C25H25N2O2: 385.1910, found: 385.1916.
4.5.5. Cyclization of 15d in larger scale. Compound 15d
(0.30 g, 0.68 mmol) in toluene (45 mL) was treated with
AIBN (0.12 g, 0.72 mmol) and Bu3SnH (0.39 mL,
1.44 mmol). The crude material was chromatographed to
give 17c (26 mg, 12%), 18c (42.8 mg, 19%), 19c (70 mg,
32%). A further product from the chromatographic
separation was compound 20 (10 mg, 4%), obtained as a
yellow solid; mp 76–77 8C; IR (KBr) nmax: 1650
4.5.4. Cyclization of 15d. Compound 15d (38 mg,
0.08 mmol) in toluene (5 mL) was treated with AIBN
(13 mg, 0.08 mmol) and Bu3SnH (43 mL, 0.16 mmol) The
first fraction from the column gave 5-benzyl-5,14-dihydro-
indolo[2,1-d][1,5]benzodiazocin-6-one 17c (8 mg, 25%) as
a yellow solid; mp 154–155 8C (DCM); IR (KBr) nmax: 1661
1
(C]O) cmK1; H NMR (CDCl3) d 1.23 (s, 3H,CH3), 1.49
(C]O) cmK1 1H NMR (CDCl3) d 3.45 (dd, JZ13.8,
;
(s, 3H, CH3), 2.21 (d, JZ12.3 Hz, 1H, CHH-7), 2.58 (dd,
JZ12.3, 10.5 Hz, 1H, CHH-7), 3.01 (d, JZ3.3 Hz, 1H,
H-8), 3.43 (d, JZ15.6 Hz, 1H, CHH-14), 3.96 (dd, JZ10.5,
3.6 Hz, 1H, H-7a), 4.24 (d, JZ15.6 Hz, 1H, CHH-14), 4.56
(d, JZ13.5 Hz, 1H, CONCHH), 5.44 (d, JZ13.5 Hz, 1H,
CONCHH), 6.58 (t, JZ7.2 Hz, 1H, H-10), 6.65 (d, JZ
8.1 Hz, 1H, H-12), 7.12–7.20 (m, 3H, H-2, H-11 and Ar),
7.22–7.29 (m, 5H, Ar), 7.30–7.34 (m, 2H, H-9 and Ar), 7.47
(d, JZ7.5 Hz, 1H, H-1); 13C NMR (CDCl3) d 21.9 (CH3),
24.5 (CH3), 36.7 (CCN), 44.2 (CH2-7), 44.3 (CH2-14), 53.6
(CONCH2), 56.1 (C-8), 63.5 (C-7a), 106.8 (C-7), 116.8
(C-5), 124.7 (CN), 125.4 (C-8a), 126.2 (C-4), 126.6, 128.0,
128.1, 128.7 (all ArCH), 129.2 (C-11), 129.37, 129.4 (all
ArCH), 132.0 (C-1), 135.3 (C-14a), 136.6 (C-10), 140.7
(C-4a), 149.1 (C-12a), 171.1 (CO); CI-MS m/z 422 ([MC
H]C, 100%); HREI-MS m/z calcd for [M]C C28H27N3O:
421.2154, found: 421.2160.
1.5 Hz, 1H, CHH-7), 3.71 (d, JZ13.8 Hz, 1H, CHH-7), 4.13
(d, JZ14.1 Hz, 1H, CONCHH), 4.62 (d, JZ13.8 Hz, 1H,
CHH-14), 4.93 (d, JZ13.8 Hz, 1H, CONCHH), 5.53 (d, JZ
14.1 Hz, 1H, CHH-14), 6.37 (s, 1H, H-8), 7.07 (t, JZ7.8,
1.2 Hz, 1H, H-10), 7.16–7.25 (m, 7H, Ar), 7.34 (d, JZ
7.8 Hz, 1H, Ar), 7.38–7.42 (m, 2H, Ar), 7.46 (dd, JZ8.1,
1.8 Hz, 1H, Ar), 7.52 (d, JZ7.8 Hz, 1H, H-9); 13C NMR
(CDCl3) d 36.6 (CH2-7), 44.8 (CH2-14), 52.8 (CONCH2),
103.6 (C-8), 108.7, 119.8, 120.5, 121.5, 125.9, 128.0 (C-8a),
128.2, 128.8, 129.0, 129.6, 130.5, 132.1, 132.7 (C-7a),
133.0 (C-14a), 136.3 (C-12a), 137.5 (C-10), 142.8 (C-4a),
168.4 (CO); CI-MS m/z 353 ([MCH]C, 100%); HREI-MS
m/z calcd for [M]C C24H20N2O: 352.1576, found:
352.1565.
The second fraction gave 5-benzyl-5,7a,8,14-tetrahydro-
indolo[2,1-d][1,5]benzodiazocin-6-one 18c (12 mg, 43%)
4.5.6. Cyclization of 15d in xylene. Compound 15d
(52 mg, 0.11 mmol) in xylene (5 mL) was treated with
AIBN (18 mg, 0.11 mmol) and Bu3SnH (59 mL,
0.22 mmol). The crude material was chromatographed to
give 17c (22 mg, 57%).
as a yellow solid; mp 141–144 8C (DCM); IR (KBr) nmax
:
1647 (C]O) cmK1; 1H NMR (CDCl3) d 2.41–2.52 (m, 2H,
CH2-8), 2.57 (dd, JZ15.9, 9.3 Hz, 1H, CHH-7), 3.22–3.30
(m with prominent d, JZ15.3 Hz, 2H, CHH-7 and
CONCHH), 4.02 (qd, JZ9.0, 1.2 Hz, 1H, H-7a), 4.14 (d,
JZ15.0 Hz, 1H, CONCHH), 4.50 (d, JZ14.1 Hz, 1H,
CHH-14), 5.51 (d, JZ14.1 Hz, 1H, CHH-14), 6.51–6.56
(m, 2H, Ar), 6.95 (d, JZ6.9 Hz, 1H, Ar), 7.04 (t, JZ7.8 Hz,
1H, Ar), 7.14–7.19 (m, 2H, Ar), 7.22–7.27 (m, 5H, Ar), 7.30
(dd, JZ9.0, 1.8 Hz, 1H, Ar), 7.40 (dd, JZ9.0, 2.4 Hz, 1H,
H-9); 13C NMR (CDCl3) d 36.6 (CH2-7), 42.5 (CH2-8), 45.5
(CH2-14), 53.7 (CONCH2), 62.7 (CH), 105.0, 116.8, 124.8,
126.7, 127.6, 127.7 (C-8a), 128.0, 128.5, 128.7, 129.1,
129.4, 131.4 (ArC), 136.7 (ArC), 136.8 (C-10), 149.6 (C-4a),
171.1 (CO); CI-MS m/z 355 ([MCH]C, 100%); HREI-MS
m/z calcd for [M]C C24H22N2O: 354.1732, found:
354.1718.
4.5.7. Cyclization of 15d in mesitylene. Compound 15d
(51 mg, 0.11 mmol) in mesitylene (5 mL) was treated with
AIBN (18 mg, 0.11 mmol) and Bu3SnH (59 mL,
0.22 mmol). The crude material was chromatographed to
give 17c (27 mg, 70%).
4.5.8. Cyclization of 15d in tert-butylbenzene. Compound
15d (55 mg, 0.12 mmol) in tert-butylbenzene (5 mL) was
treated with AIBN (20 mg, 0.11 mmol) and Bu3SnH (65 mL,
0.22 mmol). The crude material was chromatographed to
give 17c (19 mg, 46%) and 19c (4 mg, 9%).
The third fraction gave N-[(2-(10-1H-Indolyl)methyl)-
phenyl]-N-benzylacetamide 19c (3 mg, 10%) as a yellow
solid; mp 158–159 8C (DCM); IR (KBr) nmax: 1676 (C]O),
4.5.9. Cyclization of 15e in toluene. Compound 15e
(37 mg, 0.07 mmol) in toluene (5 mL) was treated with
AIBN (12 mg, 0.07 mmol) and Bu3SnH (40 mL,
0.15 mmol). The first fraction gave 5,14-dihydro-5-(10-
phenylethyl)indolo[2,1-d][1,5]benzodiazocin-6-one 17d
(6 mg, 22%) as a yellow solid; mp 157–159 8C (DCM);
1H NMR (CDCl3, rotamer ratio 52:48*) d 1.56 (d, JZ
7.2 Hz, 1.6H, CHCH3), 1.78* (d, JZ7.5 Hz, 1.4 Hz,
CHCH3), 3.33* (d, JZ13.8 Hz, 0.5H, CHH-7), 3.38 (d,
JZ12.3 Hz, 0.5H, CHH-7), 3.66* (d, JZ13.5 Hz, 0.5H,
CHH-7), 3.72 (d, JZ14.1 Hz, 0.5H, CHH-7), 3.73* (d, JZ
13.8 Hz, 0.5H, CHH-14), 4.64* (d, JZ13.8 Hz, 0.5H, CHH-
14), 4.88 (d, JZ13.8 Hz, 0.5H, CHH-14), 5.37 (d, JZ
13.5 Hz, 0.5H, CHH-14), 6.32* (br s, 0.5H, CHCH3), 6.32*
(s, JZ0.5 Hz, H-8), 6.35 (s, JZ0.5 Hz, H-8), 6.38 (br s,
0.5H, CHCH3), 6.54 (d, JZ8.1 Hz, 0.5H, H-4), 7.02–7.56
(m, 12.5H, Ar); 13C NMR (CDCl3) d 16.4 (CH3), 19.0*
(CH3), 36.9 (CH2-7), 44.3* (CH2-14), 45.2 (CH2-14), 52.8*
1
1358 (CO–CH3) cmK1; H NMR (CDCl3) d 1.83 (s, 3H,
CH3), 4.74 (d, JZ16.8 Hz, 1H, CONCHH), 4.80 (d, JZ
14.1 Hz, 1H, CHH), 4.92 (d, JZ14.1 Hz, 1H, CHH), 5.04
(d, JZ16.8 Hz, 1H, CONCHH), 6.53 (dd, JZ3.3, 0.9 Hz,
1H, H-3), 6.65 (d, JZ7.8 Hz, 1H, H-30), 6.79 (d, JZ3.3 Hz,
1H, H-2), 6.94–6.99 (m, 2H, Ar), 7.11 (td, JZ7.2, 1.2 Hz,
1H, Ar), 7.15–7.16 (m, 2H, H-5 and H-10), 7.21 (td, JZ8.4,
1.8 Hz, 1H, H-11), 7.24–7.29 (m, 3H, Ar), 7.30–7.35 (m,
2H, Ar), 7.64 (ddd, JZ7.2, 1.8, 0.6 Hz, 1H, H-4); 13C NMR
(CDCl3) d 22.6 (CH3), 46.4 (CH2), 52.7 (CONCH2), 102.5
(C-3), 109.6, 120.0, 121.3, 122.1, 128.4, 128.5, 128.8
(C-3a), 128.9, 129.2, 129.7, 129.8, 135.9 (C-10), 136.5
(C-7a), 137.2 (C-100), 140.3 (C-20), 170.6 (CO); CI-MS m/z
355 ([MCH]C, 100%); HREI-MS m/z calcd for [M]C
C24H22N2O: 354.1732, found: 354.1732.

952
J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 941–953
(CH), 53.9 (CH), 103.2* (C-8), 103.3 (C-8), 108.4 (C-15),
119.4*, 119.6, 120.2*, 120.3. 121.1*, 121.3, 127.0* (C-4),
127.7, 128.0, 128.1, 128.2, 128.5, 129.0, 129.4, 130.8
(C-3a), 131.7*, 131.8, 132.8 (C-7a), 133.0* (C-14a), 133.2*
(C-7a), 134.2, (C-14a), 137.3* (C-12a), 138.9 (C-12a),
139.5 (C-10), 140.3* (C-10), 141.6 (C-4a), 145.5* (C-4a),
164.4 (CO), 168.4* (CO); CI-MS m/z 367 ([MCH]C,
100%); HRCI-MS m/z calcd for [MCH]C C25H23N2O:
367.1810, found: 367.1796.
6.99 (d, JZ2.4 Hz, 1H, H-9), 7.21–7.25 (m, 6H, Ar), 7.31–
7.50 (m, 4H, Ar); 13C NMR (CDCl3) d 36.4 (CH2-7), 44.9
(CH2-14), 52.7 (CONCH2), 56.1 (OCH3), 102.4 (C-8),
109.4, 111.6, 125.9, 128.2, 128.3 (C-8a), 128.8, 129.7,
129.6, 130.0, 130.5, 132.01, 132.7 (C-7a), 132.9 (C-14a),
133.5 (C-12a), 136.4 (C-1 ), 142.9 (C-4a), 154.3 (COCH3),
168.4 (CO); CI-MS m/z 383 ([MCH]C, 100%); HRCI-MS
m/z calcd for [MCH]C C25H23N2O2: 383.1760, found:
383.1766.
Further elution then gave a mixture of 18d and 19d (7 mg,
26%) in a ratio of ca. 1:1 (determined by 1H NMR
spectroscopy).
4.5.12. Cyclization of 15h. Compound 15h (77 mg,
0.16 mmol) in mesitylene (7 mL) was treated with AIBN
(25 mg, 0.16 mmol) and Bu3SnH (77 mL, 0.31 mmol) The
first fraction from the column gave 5-benzyl-10-fluoro-5,14-
dihydroindolo[2,1-d][1,5] benzodiazocin-6-one 17h
(14 mg, 23%) as a yellow solid; mp 115–116 8C (DCM);
4.5.10. Cyclization of 15f. Compound 15f (83 mg,
0.19 mmol) in toluene (5 mL) was treated with AIBN
(31 mg, 0.19 mmol) and Bu3SnH (0.12 mL, 0.38 mmol).
The crude material was chromatographed to give, in the first
fraction, 5,14-dihydro-10-methoxy-5-methylindolo[2,1-
d][1,5]benzodiazocin-6-one, 17e (30 mg, 50%) as a yellow
1
IR (KBr) nmax: 1663 (C]O) cmK1; H NMR (CDCl3) d
3.43 (dd, JZ13.8, 1.2 Hz, 1H, CHH-7), 3.69 (d, JZ
13.8 Hz, 1H, CHH-7), 4.13 (d, JZ14.1 Hz, 1H, CHH-14),
4.63 (d, JZ14.1 Hz, 1H, CONCHH), 4.86 (d, JZ13.8 Hz,
1H, CHH-14), 5.52 (d, JZ14.1 Hz, 1H, CONCHH), 6.31 (s,
1H, H-8), 6.90 (dd, JZ9.0, 2.7 Hz, 1H, Ar), 6.94 (dd, JZ
9.0, 2.4 Hz, 1H, H-9), 7.16 (dd, JZ9.6, 2.4 Hz, 1H, H-12),
7.19–7.27 (m, 5H, Ar), 7.31–7.40 (m, 3H, Ar), 7.47 (dd, JZ
6.6, 2.1 Hz, 1H, H-1); 13C NMR (CDCl3) d 36.4 (CH2-7),
45.0 (CH2-14), 52.6 (CONCH2), 105.5 (d, JZ4.6 Hz, C13–
F19, C8–F), 105.3 (d, JZ23.5 Hz, C13–F19, C11–F), 109.3
(d, JZ9.8 Hz, C13–F19, C12–F), 109.7 (d, JZ26.3 Hz, C13–
F19, C9–F), 126.0, 128.2, 129.2, 129.6, 130.1, 130.7, 132.1,
132.4 (ArC), 134.1 (ArC), 134.6 (ArC), 136.3 (C-10), 142.8
(C-4a), 158.7 (d, JZ238.6 Hz, C13–F19, C10–F), 168.2
(CO); CI-MS m/z 371 ([MCH]C, 100%); HRCI-MS m/z
calcd for [MCH]C C24H20N2O2F: 371.1560, found:
371.1552.
1
solid; mp 170–173 8C (DCM); H NMR (CDCl3) d 3.430
(dd, JZ13.8, 1.2 Hz, 1H, CHH-7), 3.434 (s, 3H, CH3), 3.63
(d, JZ13.5 Hz, 1H, CHH-7), 3.84 (s, 3H, OCH3), 4.74 (d,
JZ13.8 Hz, 1H, CHH-14), 5.27 (d, JZ13.8 Hz, 1H, CHH-
14), 6.30 (s, 1H, H-8), 6.90 (dd, JZ9.0, 2.4 Hz, 1H, H-4),
7.01 (d, JZ2.4 Hz, 1H, H-9), 7.35–7.39 (m, 3H, Ar), 7.45–
7.53 (m, 2H, Ar); 13C NMR (CDCl3) d 36.1 (CH2-7), 36.5
(NCH3), 45.3 (CH2-14), 56.1 (OCH3), 102.4 (C-8), 103.2
(C-9), 109.4, 111.7, 125.4, 128.4 (C-8a), 129.0, 130.6, 131.8
(C-7a), 132.2, 133.1 (C-14a), 133.5 (C-12a), 144.8 (C-4a),
154.3 (COCH3), 168.9 (CO); CI-MS m/z 307 ([MCH]C,
100%); HRCI-MS m/z calcd for [MCH]C C19H19N2O2:
307.1447, found: 307.1444.
Further elution then gave N-{2-[10-(50-methoxy-1H-
indolyl)methyl]phenyl}-N-methylacetamide 19e (11 mg,
20%) as a yellow solid; mp 151–153 8C (DCM); H NMR
Further elution then gave N-{2-[10(50-fluoro-1H-indolyl)-
methyl)phenyl]-N-benzylacetamide 19h (9 mg, 15%) as a
yellow solid; mp 63–64 8C (DCM); H NMR (CDCl3) d
1
1
(CDCl3) d 1.76 (s, 3H, CH3), 3.19 (s, 3H, NCH3), 3.84 (s,
3H, OCH3), 5.20 (s, 2H, CH2), 6.47 (d, JZ3.0 Hz, 1H, H-3),
6.80 (dd, JZ8.7, 2.1 Hz, 1H, Ar), 6.87 (d, JZ7.2 Hz, 1H,
Ar), 6.98–7.07 (m with prominent d, JZ3.6 Hz, 2H, H-2
and Ar), 7.08 (d, JZ2.1 Hz, 1H, H-4), 7.10 (d, JZ7.8 Hz,
1H, Ar), 7.23 (t, JZ8.7 Hz, 1H, Ar), 7.32 (dd, JZ7.2,
0.9 Hz, 1H, H-7); 13C NMR (CDCl3) d 22.2 (CH3), 36.5
(NCH3), 46.8 (CH2), 56.0 (OCH3), 102.0 (C-3), 103.0,
110.3, 112.5, 128.7, 129.1, 129.16, 129.24, 129.4, 129.7,
131.7 (ArC), 135.1 (ArC), 142.3 (C-20), 154.5 (COCH3),
170.9 (CO); CI-MS m/z 309 ([MCH]C, 87%); HREI-MS
m/z calcd for [M]C C19H20N2O2: 308.1525, found:
308.1524.
1.80 (d, 3H, CH3), 4.70 (d, JZ16.8 Hz, 1H, CONCHH),
4.84 (d, JZ5.1 Hz, 2H, CH2), 5.00 (d, JZ16.8 Hz, 1H,
CONCHH), 6.48 (dd, JZ2.7, 0.6 Hz, 1H, H-3), 6.63 (dd,
JZ7.5, 1.2 Hz, 1H, H-30), 6.79 (m with prominent d, JZ
3.3 Hz, 2H, H-2 and H-4), 6.88 (td, JZ9.0, 2.4 Hz, 1H,
H-6), 6.97 (dd, JZ7.8, 1.5 Hz, 1H, H-60), 7.20 (td, JZ7.5,
1.5 Hz, 1H, Ar), 7.23–7.28 (m, 5H, Ar), 7.29–7.34 (m, 3H,
Ar); 13C NMR (CDCl3) d 22.2 (CH3), 46.4 (CH2), 52.5
(CONCH2), 102.1 (d, JZ4.9 Hz, C13–F19, C3–F), 105.8 (d,
JZ11.6 Hz, C13–F19, C7–F), 109.9 (d, JZ9.8 Hz, C13–F19,
C6–F), 110.3 (d, JZ26.3 Hz, C13–F19, C4–F), 127.9, 128.2,
128.7, 128.9, 129.0, 129.2, 129.5, 129.67, 129.71, 135.4
(C-7a), 136.9 (C-100), 140.1 (C-20), 157.9 (d, JZ233.1 Hz,
C13–F19, C5–F), 170.3 (CO); CI-MS m/z 373 [MCH]C,
100%); HRCI-MS m/z calcd for [MCH]C C24H22N2O2F:
373.1716, found: 373.1704.
4.5.11. Cyclization of 15g. Compound 15g (55 mg,
0.11 mmol) in mesitylene (5 mL) was treated with AIBN
(18 mg, 0.11 mmol) and Bu3SnH (59 mL, 0.22 mmol). The
crude material was chromatographed to give 5-benzyl-5,14-
dihydro-10-methoxyindolo[2,1-d][1,5]benzodiazocin-6-one
17f (12 mg, 29%) as a yellow solid; mp 113–114 8C (DCM);
4.5.13. Cyclization of 15i. Compound 15i (60 mg,
0.14 mmol) in toluene (5 mL) was treated with AIBN
(23 mg, 0.14 mmol) and Bu3SnH (75 mL, 0.28 mmol) The
first column fraction gave 10-fluoro-5,14-dihydro-5-methyl-
indolo[2,1-d][1,5]benzodiazocin-6-one 17g (15 mg, 35%)
as a yellow solid; mp 200–202 8C (DCM); 1H NMR
(CDCl3) d 3.436 (s, 3H, CH3), 3.439 (d, JZ13.8 Hz, 1H,
CHH-7), 3.65 (d, JZ14.1 Hz, 1H, CHH-7), 4.76 (d,
1
IR (KBr) nmax: 1660 (C]O) cmK1; H NMR (CDCl3) d
3.42 (dd, JZ15, 1.2 Hz, 1H, CHH-7), 3.68 (d, JZ13.8 Hz,
1H, CHH-7), 3.82 (s, 3H, OCH3), 4.12 (s, JZ13.8 Hz, 1H,
CONCHH), 4.62 (d, JZ13.8 Hz, 1H, CHH-14), 4.85 (d, JZ
14.0 Hz, 1H, CONCHH), 5.51 (d, JZ13.8 Hz, 1H, CHH-
14), 6.28 (s, 1H, H-8), 6.84 (dd, JZ9.0, 2.4 Hz, 1H, H-4),

J. B. Bremner, W. Sengpracha / Tetrahedron 61 (2005) 941–953
953
JZ13.8 Hz, 1H, CHH-14), 5.29 (d, JZ13.8 Hz, 1H, CHH-
14), 6.33 (s, 1H, H-8), 6.97 (td, JZ9.0, 2.7 Hz, 1H, H-11),
7.18 (dd, JZ9.3, 2.4 Hz, 1H, H-9), 7.35–7.40 (m, 3H, Ar),
7.48 (dd, JZ7.5, 1.8 Hz, 1H, Ar), 7.51 (d, JZ7.2 Hz, 1H,
Ar); 13C NMR (CDCl3) d 36.2 (CH2-7), 36.7 (NCH3), 45.5
(CH2-14), 103.5 (d, JZ4.3 Hz, C13–F19, C8–F), 105.4 (d,
JZ23.2 Hz, C13–F19, C11–F), 109.3 (d, JZ9.5 Hz, C13–
F19, C12–F), 109.9 (d, JZ49.0 Hz, C13–F19, C9–F), 125.5,
128.2 (d, JZ10.1 Hz, C13–F19, C8a–F), 129.0, 130.7, 131.4
(C-7a), 132.1, 134.3 (C-14a), 134.6 (C-12a), 144.6 (C-4a),
158.0 (d, JZ232.7 Hz, C13–F19, C10–F), 168.6 (CO); CI-
MS m/z 295 ([MCH]C, 100%); HREI-MS m/z calcd for
[M]C C18H15N2OF: 294.1168, found: 294.1159.
0.09 mmol) in dry THF (2 mL) was added. The frozen
mixture was warmed to K60 8C and the reaction was stirred
for 20 min. Solid ammonium chloride was then added until
the colour dissipated, at which point the reaction was
allowed to warm to r.t. The residue was dissolved in ethyl
acetate (30 mL), extracted with water (20 mL), dried and
the organic layer concentrated to give a yellow residue. The
residue was purified using preparative thin layer chroma-
tography (1% MeOH/DCM) to give 1 (7.8 mg, 35%) as an
off white solid; mp 269–271 8C (lit.9 268–270 8C); IR (KBr)
1
nmax: 3415 (NH), 1655 (C]O) cmK1; H NMR (CDCl3) d
3.58 (s, 2H, CH2-7), 5.18 (s, 2H, CH2-14), 6.40 (s, 1H, H-8),
7.12 (td, JZ7.2, 0.9 Hz, 1H, Ar), 7.24–7.30 (m, 2H, Ar),
7.36–7.41 (m, 1H, Ar), 7.44 (dd, JZ7.5, 1.8 Hz, 1H, Ar),
7.48–7.58 (m, 3H, Ar), 7.73 (br s, 1H, NH); 13C NMR
(CDCl3) d 35.2 (CH2-14), 45.5 (CH2-7), 103.8 (C-8), 108.9,
120.1, 120.7, 121.8, 125.7, 128.1 (C-8a), 128.97, 129.02
(ArC), 130.4, 132.6, 138.3 (ArC), 144.0 (ArC), 170.7 (CO);
CI-MS m/z 263 ([MCH]C, 100%); HREI-MS m/z calcd for
[M]C C17H14N2O: 262.1106, found: 262.1104.
Further elution then gave N-{2-[10-(50-fluoro-1H-indolyl)-
methyl]phenyl}-N-methylacetamide 19g (7 mg, 17%) as a
yellow solid; mp 70–72 8C (DCM); H NMR (CDCl3) d
1
1.74 (s, 3H, CH3), 3.17 (s, 3H, NCH3), 5.23 (s, 2H, CH2),
6.52 (dd, JZ3.3, 0.9 Hz, 1H, H-3), 6.89–6.95 (m, 2H, Ar),
7.06 (dd, JZ9.3, 4.5 Hz, 1H, H-4), 7.09 (d, JZ3.0 Hz, 1H,
H-2), 7.18 (dd, JZ7.8, 1.5 Hz, 1H, Ar), 7.25–7.30 (m, 2H,
Ar), 7.36 (dd, JZ7.5, 1.5 Hz, 1H, Ar); 13C NMR (CDCl3) d
22.3 (CH3), 36.7 (NCH3), 47.1 (CH2), 102.5 (d, JZ4.6 Hz,
C13–F19, C3–F), 106.2 (d, JZ23.2 Hz, C13–F19, C6–F),
110.2 (d, JZ9.7 Hz, C13–F19, C7–F), 110.7 (d, JZ26.5 Hz,
C13–F19, C4–F), 128.8, 128.9, 129.1, 129.2, 129.5 (d, JZ
4.5 Hz, C13–F19, C3a–F), 129.9, 130.0, 133.0 (C-10), 134.6
(C-7a), 142.4 (C-20), 157.6 (d, JZ232.2 Hz, C13–F19, C5–
F), 170.7 (CO); CI-MS m/z 297 ([MCH]C, 100%); HREI-
MS m/z calcd for [M]C C18H17N2OF: 296.1325, found:
296.1320.
Acknowledgements
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.
References and notes
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mixture of 18c and 19c (7 mg, 20%) in a ratio of ca. 2:1
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