Synthesis of the dibenzopyrrocoline alkaloid skeleton: indolo[2,1-a]isoquinolines and related analogues

Article abstract of DOI:10.1016/j.tet.2006.12.063

The indolo[2,1-a]isoquinoline and pyrrolo[2,1-a]isoquinoline nuclei have been synthesized from N-benzylindole or ethyl 1H-indol-1-ylacetate and N-benzylpyrrole precursors, respectively. Firstly, at C-2 of either the indole or pyrrole nucleus, aromatic rin

Full text of DOI:10.1016/j.tet.2006.12.063

Tetrahedron 63 (2007) 2263–2274
Synthesis of the dibenzopyrrocoline alkaloid skeleton: indolo-
[2,1-a]isoquinolines and related analogues
y
€
Angelique N. C. Lotter, Rakhi Pathak, Thato S. Sello, Manuel A. Fernandes,
*
Willem A. L. van Otterlo and Charles B. de Koning
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, 2050 Johannesburg, South Africa
Received 4 October 2006; revised 11 December 2006; accepted 21 December 2006
Available online 27 December 2006
Abstract—The indolo[2,1-a]isoquinoline and pyrrolo[2,1-a]isoquinoline nuclei have been synthesized from N-benzylindole or ethyl 1H-
indol-1-ylacetate and N-benzylpyrrole precursors, respectively. Firstly, at C-2 of either the indole or pyrrole nucleus, aromatic rings contain-
ing a carbonyl substituent ortho to the newly formed biaryl axis were introduced using the Suzuki–Miyaura coupling reaction. Thereafter,
under basic conditions the nucleophile that formed at the acidic methylene protons of the N-benzylindole, ethyl 1H-indol-1-ylacetate or
N-benzylpyrrole intermediate reacted with the internal aromatic carbonyl to yield (after the expulsion of water) the title compounds. For
example, exposure of ethyl 2-(2-(2-formylphenyl)-1H-indol-1-yl)acetate to potassium tert-butoxide resulted in the formation of ethyl
indolo[2,1-a]isoquinoline-6-carboxylate.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
such as 3 exhibit strong binding affinities for the estrogen
receptor of MDA-MB 231 and MCF-7 mammary tumour
cell lines.6 It has also been reported that hydroxy-substituted
indolo[2,1-a]isoquinolines bind to the colchicine binding
site and inhibit the polymerization of tubulin.6
The dibenzopyrrocoline alkaloids contain an indole ring
fused to the isoquinoline moiety where they share a common
nitrogen atom.
For example, the natural products cryptaustoline 1 and cryp-
towoline 2 (Fig. 1) isolated from the bark of Cryptocarya
bowie fit into this category.1 These types of alkaloids have
been reported to possess antileukemic,2 tubulin polymeriza-
tion inhibitory3 and antitumour activities.4,5 Related syn-
thetic acetoxy-substituted 5,6-dihydro[2,1-a]isoquinolines
Related compounds containing a hexahydropyrrolo[2,1-a]-
isoquinoline such as compounds 4 and 5, lacking the
additional fused benzene ring, have been reported to be
potential candidates for the treatment of depression (Fig. 2).
Studies show that they inhibit the neuronal uptake of dop-
amine (DA), norepinephrine (NE) and serotonin (5 HT).7,8
I_
MeO
HO
OMe
OMe
I_
N
Me
+N
Me
+
O
O
Cl
HO
OMe
1, Cryptaustoline
2, Cryptowoline
N
N
H
H
4
5
AcO
N
Figure 2. Examples of biologically active pyrrolo[2,1-a]isoquinolines.
OAc
3
A number of different strategies have been utilized to syn-
thesize both the indolo[2,1-a]isoquinolines and the pyr-
rolo[2,1-a]isoquinolines. Shown in Scheme 1 are some of
the general methods used for the formation of the final
ring of the indolo[2,1-a]isoquinolines nucleus. A common
initial disconnection is between the isoquinoline nitrogen
and the benzene ring, which ultimately forms part of the
Figure 1. Examples of biologically active indolo[2,1-a]isoquinolines.
Keywords: Indolo[2,1-c]isoquinolines; Isatin; Indole; Pyrrole; Suzuki–
Miyaura coupling reaction; Potassium tert-butoxide.
* Corresponding author. E-mail: dekoning@chem.wits.ac.za
y
For correspondence regarding X-ray crystallography: manuel@hobbes.
gh.wits.ac.za.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.063

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A. N. C. Lo€tter et al. / Tetrahedron 63 (2007) 2263–2274
indole nucleus. This bond in the syntheses has then been
formed by base-, radical- and benzyne-mediated ring clo-
sures or by palladium-catalyzed methods [see Scheme 1,
(i), (ii), (iii) or (iv)]. However, as shown in Scheme 1 other
approaches have been successfully used for the assembly
of this nucleus.
benzotriazole methodology. Reaction of 8 with diethyl acet-
ylene dicarboxylate, in the presence of triethylamine gave
the compound of interest, pyrrolo[2,1-a]isoquinoline 10.
The reaction is postulated to occur by way of intermediate 9.
In this paper, we wish to report a novel synthesis of both the
indolo[2,1-a]isoquinolines and pyrrolo[2,1-a]isoquinolines
with the ultimate aim of synthesizing the indolo[2,1-a]iso-
quinoline skeleton of cryptaustoline 1 and cryptowoline 2.
One of the key steps in our synthesis is that the final ring
forming reaction (as shown in the retrosynthesis) involves
a novel disconnection at the C-5 and C-6 of the indolo-
[2,1-a]isoquinoline or pyrrolo[2,1-a]isoquinoline nucleus
(i.e., Fig. 3, 11012). Aspects of this work have been
reported in a communication.21
R
R
O
R
N
H
O
O
N
X
R
O
O
Ph
R
H2N
(iv)
(vi)
(i)
(vii)
(ii), (iii) or (iv)
R
N
R1
R
1 R
COR
N
R
5
R1
6
(viii), (ix)
CO2Me
N
(x)
R1=COPh for (iv)
I
R=Ph or CO2Et
R1=H or Me
12
MeO
MeO
11
R
R
N
Figure 3. Retrosynthesis.
H2N
2. Results and discussion
Scheme 1. (i) X¼Br, K2CO3, DMF, reflux, 3 days9 or (ii) X¼Br, AIBN,
Bu3SnH6,10 or (iii) X¼Cl, n-BuLi, THF, ꢀ100 ꢁC, 98%;11 (iv) Pd catalysis;
e.g., 8% Pd2(dba)3, 16% SIPr, NaOtBu, PhMe;12 (v) MeNO2, rt, 2 days,
72%;13 (vi) TFA/CH2Cl2, 18 h, 53%; (vii) BH3/THF;14 (viii) CuI, DMF,
reflux, 2 h, (ix) p-TsOH, CH2Cl2;15 (x) dicumylperoxide, chlorobenzene,
heat, 69–85%.16
While working on the synthesis of benzo- and naphtho-fused
carbazoles,22 we had reason to synthesize the substituted N-
benzyl-protected indole 1323 from the Boc-protected indole
14 (Scheme 3). Reaction of 14 with n-BuLi and trimethyl
borate followed by work-up with aqueous acid afforded bo-
ronic acid 15. Dihydronaphthalene 16 was then reacted with
boronic acid 15 in the presence of catalytic Pd(PPh3)4 under
The pyrrolo[2,1-a]isoquinoline skeleton can be obtained by
using, for example, acid-catalyzed reactions. Cyclization of
6 in the presence of polyphosphoric acid gave 7 as a mixture
of cis and trans diastereomers (Scheme 2).7
Br
CHO
F3C
CF3
F3C
16
B(OH)2
(i)
(ii)
N
N
CF3
(i)
Boc
Boc
14
15
N
OH
N
H
N
Boc
N
6
H
7
(iii)
CHO
CHO
17a
17b
(ii)
N+
N+
Ph
Cl
Bt
Bt
9
8
N
(v)
(iv)
CHO
N
13
Ph
Ph
EtO2C
CO2Et
10
N
N
Scheme 2. (i) PPA, heat, 47%; (ii) EtCO2C^CCO2Et, Et3N, MeCN, 67%.
18b
18a
As also shown in Scheme 2, 1,3-dipolar cycloadditions have
been used quite extensively to construct this skeleton (Elwan
et al.,17 Hershenson,18 Anderson et al.2 and Zhao et al.19).
For example, Katritzky et al.20 has described the regioselec-
tive synthesis of pyrrolo[2,1-a]isoquinolines using his
Scheme 3. Reagents and conditions: (i) (a) n-BuLi, THF, ꢀ78 ꢁC, (b)
B(OMe)3, THF, ꢀ78 ꢁC, (c) H3O+, extract into Et2O; (ii) 10% Pd(PPh3)4,
aq Na2CO3/DME (Et2O removed by bubbling N2 through reaction mixture),
96% (two steps); (iii) AlCl3, CH2Cl2, rt, 2 h, 100%; (iv) BnBr, 50% aq
NaOH, DMF, 53%; (v) KOtBu, DMF, hn, 80 ꢁC, 18a: 0%, 18b: 65%.

A. N. C. Lo€tter et al. / Tetrahedron 63 (2007) 2263–2274
2265
Suzuki–Miyaura coupling reaction conditions to afford the
desired coupled product 17a.16 In addition to the peaks at
d 1.29 and 2.10 due to the Boc group and the aromatic
methyl group, respectively, the H NMR spectrum of com-
1
pound 17a also showed evidence for the presence of the
methylene protons (d 2.72–3.01) and the aldehyde group at
d 9.70. The HRMS showed a molecular ion peak at m/z
387.1834 (C25H25NO3 requires 387.1830). The compound
was crystalline and gave good quality crystals suitable for
X-ray crystallography, after recrystallization from an
EtOAc/hexane solution.24 The X-ray crystal structure of
17a is shown in Figure 4. It is clear from the X-ray crystal
structure that the steric crowding due to the Boc, methyl
and aldehyde groups forces the molecule to adopt a solid
state structure that minimizes steric interactions.
Figure 5. ORTEP diagram of 14-methyl-8-phenylbenzo[h]indolo[2,1-a]-
isoquinoline 18b (ellipsoids at 50% probability).
In light of this result, we decided to test the generality of this
reaction by synthesizing a number of indole and pyrrole
analogues. An obvious extension to this methodology would
be to exchange the functional groups of the substrates re-
quired for the coupling reaction. Therefore, bromoindole
20 was synthesized using published chemistry from com-
mercially available 3-methylindole 19.28 Suzuki–Miyaura
coupling of 20 with the commercially available boronic
acid 21 gave the desired precursor 22 on which the ring
Figure 4. ORTEP diagram of tert-butyl-2-(2-formyl-3,4-dihydro-1-naph-
thalenyl)-3-methyl-1H-indole-1-carboxylate 17a (ellipsoids at 50% proba-
bility).
1
forming reaction was attempted (Scheme 4). The H NMR
spectrum of 22 provided evidence for the identity of the
product as there were two methyl groups at d 1.83 and
2.17. In addition to this, two doublets corresponding to the
non-equivalent methylene protons of the benzyl group at
d 5.04 and 5.24 were also evident. In the 13C NMR spectrum
the peak at d 202.8 due to the carbonyl group also suggested
the formation of the expected product. Exposure of 22 to
KOtBu in DMF afforded the ring-closed alcohols 23a and
23b as diastereoisomers (w1:3 ratio). The IR spectra of the
two separated diastereoisomers showed stretching bands at
Exposure of 17a to the Lewis acid AlCl3 yielded the interme-
diate deprotected indole 17b. The 1H NMR spectrum of the
product showed a broad peak at d 7.99 due the NH proton,
thus indicating that the desired product had been formed.
In addition, the peaks due to the methyl protons of the Boc
group were no longer present in the spectrum. Treatment
of the intermediate with benzyl bromide gave the required
benzyl-protected 13. In the 1H NMR spectrum of this prod-
uct the broad peak due to the NH proton was no longer
evident. Instead, two doublets due to the non-equivalent
methylene protons of the benzyl group were now observed
at d 4.75 and 5.23.
21
(HO)2B
O
Br
Utilizing the reaction conditions25,26 developed for the
formation of aromatic rings (KOtBu, hn, DMF, 80 ꢁC), we
treated 13 using this procedure. However, none of the
expected naphtho[a]carbazole 18a was isolated, and isoqui-
noline 18b was obtained instead. Subjecting substrate 13 to
the same reaction conditions as described before but without
the light source resulted in the formation of the identical
product 18b in a similar yield. Therefore, the base is ab-
stracting an N-benzyl proton of 13 and the resulting anion
is condensing with the electrophilic aldehyde to afford the
fused isoquinoline 18b after aromatization of the putative
dihydronaphthalene intermediate.
(i)
(ii)
N
H
N
Bn
19
20
Ph
H
N
HO
O
Bn
N
+
(iii)
( )
23a
22
5
Ph
Ph
HO
6
N
H
N
(iv)
24
11
( )
23b
The structure of the product 18b was confirmed by X-ray
crystallography.27 X-ray crystallography shows that 18b is
not flat as seen from selected bond angles in the crystal struc-
ture (Fig. 5).
Scheme 4. Reagents and conditions: (i) (a) NBS, CCl4, 3 h, 98%; (b) aq
NaOH, BnBr, 66%; (ii) 10% Pd(PPh3)4, aq Na2CO3/DME, 64%; (iii)
KOtBu, DMF, 80 ꢁC, 23a: 26%, 23b: 74%; (iv) 23b, 15 mol % TsOH,
CH2Cl2, rt, 24 h, 79%.

2266
A. N. C. Lo€tter et al. / Tetrahedron 63 (2007) 2263–2274
3417 and 3447 cmꢀ1, respectively, for 23a and 23b, indicat-
ing the presence of the alcohol functional groups. The major
diastereoisomer was shown to be 23b by NOE spectroscopy.
Exposure of 23b to 15 mol % TsOH afforded the dibenzo-
pyrrocoline 24 in very good yield. The HRMS for this com-
pound showed a molecular ion peak at m/z 321.1517
(C24H19N requires 321.1516).
of the desired indole 34b. Suzuki–Miyaura coupling of both
34a and 34b with benzaldehyde boronic acid 35 afforded
good yields of the desired products 36a and 36b. Subjecting
36a to KOtBu in DMF for 1 min gave the desired ring-closed
alcohols 37a and 37b as a mixture of diastereoisomers.
Unfortunately, exposure of 37a and 37b to p-TsOH did not
give the desired aromatic compound 38 but a complex mix-
ture of uncharacterizable products. However, subjecting 36b
to the same conditions afforded the targeted product 39 in
good yield.
In summary, at this stage as far as the synthesis of crypta-
ustoline 1 and cryptowoline 2 nuclei was concerned, we had
synthesized compound 24, which possesses additional
methyl substituents at C-5 and C-11 as well as a phenyl sub-
stituent at C-6. The next phase of this project was to adapt
our methodology to assemble the basic nucleus of 1 and 2.
O
O
Cl
Cl
O
(i)
(ii)
O
O
N
N
N
H
R
R
30
Logically, we thought that the best way to tackle this
problem using our methodology was to commence with
the known Boc-protected indole boronic acid 25. Using
Suzuki–Miyaura coupling methodology we hoped to access
27. The next step would be the removal of the Boc protecting
group and this would be replaced by a benzyl substituent to
yield 29a. However, as the phenyl at C-6 of 24 is derived
from the benzyl we thought that this could be replaced by
a methylene ester to give 29b. This would then result in
the formation of the ester derivative of 24. In other words,
the phenyl substituent at C-6 of 24 would be substituted by
CO2Et. This should be easier to remove by decarboxylation
than the phenyl substituent. Both 27a and 27b were easy to
synthesize using standard methodology from 25 and 26 but
the removal of the Boc group to give 28 proved to be prob-
lematic (Scheme 5). After considerable experimentation by
using a variety of methods (e.g., NaOMe in MeOH29) none
of the desired product 28b was obtained and therefore, we
needed to modify our synthesis.
31a, R=Bn
31b, R=CH2CO2Et
32a, R=Bn
32b, R=CH2CO2Et
(iii)
(iv)
O
(v)
Br
N
R
N
R
35
CHO
33a, R=Bn
34a, R=Bn
B(OH)2
33b, R=CH2CO2Et
34b, R=CH2CO2Et
HO
Ph
CHO
R
N
(vii)
(vi)
N
X
R=Bn
37a, Syn
37b, Anti
36a, R=Bn
36b, R=CH2CO2Et
R=CH2CO2Et
(viii)
Ph
N
CO2Et
N
38
39
Scheme 6. Reagents and conditions: (i) BnBr or BrCH2CO2Et, CaH2, DMF,
100 ꢁC, 31a: 89%, 31b: 100%; (ii) PCl5, benzene, 25 ꢁC, 32a: 81%, 32b:
65%; (iii) Zn, AcOH, rt, 33a: 76%, 33b: 100%; (iv) POBr3, CH2Cl2, imid-
azole, reflux, 34a: 55%; POBr3, CH2Cl2, reflux, 34b: 50%; (v) 10%
Pd(PPh3)4, aq Na2CO3/DME, 36a: 92%, 36b: 77%; (vi) KOtBu, DMF,
80 ꢁC, 76%; (vii) 15 mol % TsOH, CH2Cl2, rt, 24 h; (viii) KOtBu, DMF,
80 ꢁC, 59%.
COR
Boc
COR
N
(i)
Br
B(OH)2
26a, R=H
26b, R=Me
N
Boc
27a, R=H
27b, R=Me
25
COMe
R
COMe
N
H
N
(ii)
As a next step, we thought it would be useful to see if the
same type of chemistry could be done on pyrrole derivatives
to assemble pyrroloisoquinolines.
X
R=Me
29a, R=Bn
29b, R=CH2CO2Et
28b
The synthesis of the required bromopyrrole 40 was achieved
using literature procedures.34,35 Coupling this compound
under Suzuki–Miyaura conditions with either the boronic
acid 21 or the aldehyde equivalent 35 resulted in the forma-
tion of both desired precursors 41a (R¼Me) and 41b (R¼H).
The 1H NMR spectrum of 41a showed two singlets at d 1.83
and 4.91 corresponding to the ketone methyl substituent
and methylene protons of the benzyl group, respectively.
The HRMS of 41a showed a molecular ion peak at m/z
339.1623 corresponding to the expected product
(C24H21NO requires 339.1623). Subjecting 41a to KOtBu
in DMF afforded a diastereomeric mixture of alcohols 42a
and 42b (ratio w1:2.5). The major product 42b was dehy-
drated under acidic conditions to give the desired product
43a. In the same manner when 41b was treated with KOtBu,
43b was produced, presumably by way of the intermediate
alcohol (Scheme 7).
Scheme 5. Reagents and conditions: (i) 27a, R¼H, 10% Pd(PPh3)4, aq
Na2CO3/DME, 63%; 27b, R¼Me, 85%; (ii) NaOMe, MeOH.
Initially, attempts were made to N-benzylate oxindole but
this proved fruitless as a result of N- and C-3 alkylation.
Isatin 30 was thus treated with both benzyl bromide and ethyl
bromacetate in separate reactions in the presence of CaH2
to provide both 31a and 31b.30 Exposure of 31a and 31b
to PCl5 provided 32a and 32b (Scheme 6). Separate reac-
tions of 32a and 32b with Zn in AcOH31 afforded the desired
oxindoles 33a and 33b on which we attempted the formation
of the desired 2-bromoindoles 34a and 34b. After consider-
able experimentation, we found that treatment of 33a with
POBr3 and imidazole32 in CH2Cl2 gave a mediocre yield
(55%) of the required bromide 34a. In a similar fashion
33b was treated with POBr3 in CH2Cl233 to give a 50% yield

A. N. C. Lo€tter et al. / Tetrahedron 63 (2007) 2263–2274
2267
R = Me, 21 or H, 35;
from sodium/benzophenone, dichloromethane and di-
methylformamide were distilled from calcium hydride and
toluene and benzene were distilled from sodium. Potassium
tert-butoxide was sublimed prior to use.
R
R
O
Bn
N
Br
(HO)2B
(i)
O
N
Bn
40
41a; R=Me
41b; R=H
4.2. Crystal structure data and refinement
HO
HO
Intensity data were collected on a Bruker SMART 1K CCD
area detector diffractometer with graphite monochromated
Mo Ka radiation (50 kV, 30 mA). The collection method in-
volved u-scans of width 0.3ꢁ. Data reduction was carried out
using the program SAINT+. The crystal structure was solved
by direct methods using SHELXTL. Non-hydrogen atoms
were first refined isotropically followed by anisotropic re-
finement by full matrix least-squares calculations based on
F2 using SHELXTL. Hydrogen atoms were first located in
the difference map, then positioned geometrically and al-
lowed to ride on their respective parent atoms. Diagrams
and publication material were generated using SHELXTL
and PLATON.
Ph
H
Ph
H
R=Me
(ii)
and
(iv)
N
N
( )
42a
( )
42b
R
R=H
Ph
R=Me
(iii)
N
43a; R=Me
43b; R=H
Scheme 7. Reagents and conditions: (i) 10% Pd(PPh3)4, aq Na2CO3/DME,
41a: 82%, 41b: 52%; (ii) KOtBu, DMF, hn, 80 ꢁC, 42a: 56%, 42b: 23%; (iii)
R¼Me, 15 mol % TsOH, CH2Cl2, rt, 24 h, 43a: 74%; (iv) R¼H, KOtBu,
DMF, 80 ꢁC, 43b: 68%.
4.2.1. tert-Butyl-2-(2-formyl-3,4-dihydro-1-naphthal-
enyl)-3-methyl-1H-indole-1-carboxylate 17a. A solution
of 1-bromo-3,4-dihydronaphthalene-2-carbaldehyde 16
(0.20 g, 0.84 mmol) in DME (4 cm3) was deoxygenated
by passing nitrogen through the mixture for 5 min. The solu-
tion was then added to Pd(PPh3)4 (10 mol %, 0.096 g,
0.08 mmol) and stirred under an atmosphere of N2 for 10 min
at rt. A solution of 1-(tert-butoxycarbonyl)-3-methyl-1H-
indol-2-ylboronic acid 15 (0.346 g, 1.27 mmol) in ethanol
(1.5 cm3) was deoxygenated and added to the reaction mix-
ture. The mixture was stirred for further 10 min. A deoxy-
genated 2 M aq Na2CO3 solution (3.6 cm3, 7.12 mmol) was
then added to the reaction mixture, which was stirred at rt
for further 5 min before being heated at reflux for 2 days.
The mixture was cooled to rt and quenched with H2O
(20 cm3) after which the organic material was extracted
with CH2Cl2 (3ꢂ30 cm3) and the solvent was evaporated
under reduced pressure. The crude product was subjected to
column chromatography (5–10% EtOAc/hexane) to afford
the product, tert-butyl-2-(2-formyl-3,4-dihydro-1-naphthal-
enyl)-3-methyl-1H-indole-1-carboxylate 17a as a yellow
3. Conclusion
In conclusion, we have been able to synthesize both indolo-
and pyrrolo[2,1-a]isoquinoline including the dibenzopyrro-
coline skeleton, starting from simple N-benzylated indoles
or pyrroles.
We are presently using this methodology to assemble the
desired cryptaustoline nucleus with the correct oxygenation
pattern.
4. Experimental
4.1. General
The H and 13C NMR spectra were recorded on a Bruker
AVANCE 300 (300.13 MHz) and chemical shifts are re-
ported in parts per million (ppm) with TMS as the internal
1
1
standard in H NMR spectrum and using d 77.00 (CDCl3)
as reference peak in 13C NMR spectrum. Spectra were re-
corded in deuterated chloroform (CDCl3) unless otherwise
specified. CH-correlated, NOE, NOESY and DEPT spectra
were run on some samples for the complete assignments of
signals. IR spectra were recorded on a Bruker IFS-25 Fourier
transform spectrometer or on a Bruker Vector-22 Fourier
transform spectrometer. The infra-red signals are reported
in wavenumbers (n/cmꢀ1). For liquid samples NaCl plates
were used to run the IR spectrum while KBr pellets were
made for solid samples. High-resolution mass spectra
(HRMS) were recorded on a VG70 MS (Mass Spectrum
CC Pyramid data system) or on a VG70 SEQ (VG 11-250J
or Marc II data systems). The melting points were deter-
mined on a Reichert hot-stage microscope and are uncor-
rected. For silica gel chromatography Macherey–Nagel
Kieselgel 60 (particle size 0.063–2.00 mm) was used.
Aluminium-backed Macherey–Nagel ALUGRAM Sil
G/UV254 was used for thin layer chromatography (TLC).
All the solvents used for reactions and chromatography
were distilled prior to use according to the standard proce-
dures. Tetrahydrofuran and diethylether were distilled
solid (0.313 g, 96%): mp 141–142 ꢁC; nmax (CHCl3)/cmꢀ1
:
1725 and 1660 (C]O) and 1559 (ArC]C); 1H NMR
(300 MHz, C0DCl3, Me4Si) 1.29 (9H, s, Boc), 2.10 (3H, s,
ArCH3), 2.72–2.82 (2H, m, CH2), 2.96–3.00 (2H, m, CH2),
6.78 (1H, d, J¼7.8 Hz, ArH), 7.08–7.11 (1H, m, ArH),
7.25–7.45 (4H, m, 4ꢂArH), 7.57 (1H, d, J¼7.4 Hz, ArH),
8.29 (1H, d, J¼8.3 Hz, ArH) and 9.70 (1H, s, CHO); 13C
NMR (75 MHz, CDCl3) 9.3 (ArCH3), 20.2 (CH2), 27.1
(CH2), 27.8 (Boc), 83.9 [C(CH3)3], 115.7 (CH), 119.1 (CH),
120.7 (C), 123.0 (CH), 125.4 (CH), 126.7 (CH), 126.9 (CH),
128.0 (CH), 129.8 (C), 130.2 (CH), 134.5 (C), 135.5 (C),
136.5 (C), 137.8 (C), 146.5 (C), 149.5 (NC]O) and 192.0
(CHO); MS m/z (EI): 387 (M+, 47%), 287 (83), 273 (30),
272 (100), 269 (32), 258 (50) and 241 (16); HRMS calcd
for C25H25NO3: 387.1830, found: 387.1834.
4.2.2. 1-(3-Methyl-1H-indol-3-yl)-3,4-dihydro-2-naph-
thalenecarbaldehyde 17b. AlCl3 (0.152 g, 0.34 mmol)
was added to a solution of 17a (0.133 g, 0.34 mmol) in dry
CH2Cl2 (5 cm3) under an N2 atmosphere in portions at
0 ꢁC. The suspension was vigorously stirred at rt for 2 h.

2268
A. N. C. Lo€tter et al. / Tetrahedron 63 (2007) 2263–2274
After completion of the reaction, it was neutralized with aq
NaHCO3 solution and the product was extracted with EtOAc
(3ꢂ30 cm3). The organic phase was separated, dried
(MgSO4), filtered and the solvent was removed in vacuo
to afford the crude product. The product was then purified
by column chromatography (5% EtOAc/hexane) to afford
1-(3-methyl-1H-indol-3-yl)-3,4-dihydro-2-naphthalenecar-
baldehyde 17b as a reddish brown solid (0.098 g, quantita-
tive): mp 150–152 ꢁC; nmax (CHCl3)/cmꢀ1: 1638 (C]O),
1601 and 1566 (ArC]C); 1H NMR (300 MHz, CDCl3,
Me4Si) 2.22 (3H, s, ArCH3), 2.55–2.92 (4H, m, 2ꢂCH2),
6.92 (1H, d, J¼7.7 Hz, ArH), 7.11–7.38 (6H, m, 6ꢂArH),
7.65 (1H, d, J¼7.7 Hz, ArH), 7.99 (1H, s, NH) and 9.66
(1H, s, CHO); 13C NMR (75 MHz, CDCl3) 9.3 (ArCH3),
20.5 (CH2), 27.4 (CH2), 110.7 (CH), 115.1 (C), 119.2
(CH), 119.9 (CH), 123.2 (CH), 127.0 (CH), 127.2 (C),
128.0 (CH), 128.1 (CH), 128.4 (C), 130.5 (CH), 133.9 (C),
136.1 (C), 137.2 (C), 138.5 (C), 144.8 (C) and 193.3
(CHO); MS m/z (EI): 287 (M+, 100%), 272 (86), 269 (32),
258 (73) and 244 (19); HRMS calcd for C20H17NO:
287.1313, found: 287.1310.
the product, 14-methyl-8-phenylbenzo[h]indolo[2,1-a]iso-
quinoline 18b (0.076 g, 65%) as a yellow solid: mp 96–
98 ꢁC; nmax (CHCl3)/cmꢀ1: 1663 (C]O), 1594 and 1551
1
(ArC]C); H NMR (300 MHz, CDCl3, Me4Si) 2.55 (3H,
s, ArCH3), 6.53 (1H, s, ArH), 6.58 (1H, d, J¼8.6 Hz,
ArH), 6.95–7.00 (1H, m, ArH), 7.29–7.34 (1H, m, ArH),
7.52–7.65 (8H, m, 8ꢂArH), 7.81 (1H, d, J¼8.0 Hz, ArH),
7.90 (1H, d, J¼8.4 Hz, ArH), 7.94 (1H, d, J¼7.9 Hz, ArH)
and 8.32 (1H, d, J¼8.3 Hz, ArH); 13C NMR (75 MHz,
CDCl3) 14.5 (ArCH3), 108.2 (C), 111.3 (CH), 114.0 (CH),
118.3 (CH), 120.8 (CH), 121.7 (CH), 124.1 (CH), 125.1
(CH), 125.5 (CH), 127.9 (2ꢂCH), 128.3 (CH), 128.9
(2ꢂCH), 128.9 (C), 129.0 (2ꢂCH), 129.2 (CH), 129.7 (C),
131.2 (C), 131.6 (C), 132.9 (C), 137.0 (C) and 139.1 (C)
(two quaternary carbons missing); MS m/z (EI): 358
(36%), 357 (M+, 100), 356 (54), 354 (21), 278 (11) and
171 (11); HRMS calcd for C27H19N: 357.1518, found:
357.1517.
4.2.5. 1-[2-(1-Benzyl-3-methyl-1H-indol-2-yl)phenyl]-1-
ethanone 22. A solution of 1-benzyl-2-bromo-3-methyl-
1H-indole21 (0.470 g, 1.58 mmol) in DME (10 cm3) was
deoxygenated by passing nitrogen through the mixture for
5 min. The solution was then added to Pd(PPh3)4
(10 mol %, 0.194 g, 0.16 mmol) and stirred under an atmo-
sphere of N2 for 10 min at rt. A solution of 2-acetylphenyl-
boronic acid 21 (0.388 g, 2.40 mmol) in ethanol (3.75 cm3)
was deoxygenated and added to the reaction mixture. The
mixture was stirred for further 10 min. A deoxygenated
2 M aq Na2CO3 solution (6.7 cm3, 13.2 mmol) was then
added to the reaction mixture, which was stirred at rt for fur-
ther 5 min before being heated at reflux for 2 days. The mix-
ture was cooled to rt and quenched with water (20 cm3) after
which the organic material was extracted with CH2Cl2
(3ꢂ30 cm3) and the solvent was evaporated under reduced
pressure. The crude product was subjected to column chro-
matography (5–10% EtOAc/hexane) to afford the product,
1-[2-(1-benzyl-3-methyl-1H-indol-2-yl)phenyl]-1-ethanone
22 as a yellow oil (0.343 g, 64%): nmax (film)/cmꢀ1: 3059,
1684 (C]O), 1598 (ArC]C) and 742; 1H NMR
(300 MHz, CDCl3, Me4Si) 1.83 (3H, s, ArCH3), 2.17 (3H,
s, ArCOCH3), 5.01 (1H, d, J¼16.5 Hz, PhCH), 5.24 (1H,
d, J¼16.5 Hz, PhCH), 6.81–6.85 (2H, br m, 2ꢂArH),
7.14–7.28 (7H, m, 7ꢂArH), 7.42–7.50 (2H, m, 2ꢂArH)
and 7.61–7.63 (1H, m, ArH), 7.68–7.71 (1H, m, ArH); 13C
NMR (75 MHz, CDCl3) 9.1 (ArCH3), 28.7 (ArCOCH3),
47.5 (CH2), 110.2 (CH), 110.8 (C), 119.1 (CH), 119.6
(CH), 122.4 (CH), 126.4 (2ꢂCH), 127.2 (CH), 128.2
(CH), 128.5 (2ꢂCH), 128.6 (C), 128.7 (CH), 130.1 (C),
130.8 (CH), 132.2 (CH), 135.4 (C), 136.9 (C), 137.8 (C),
142.0 (C) and 202.8 (C]O); MS m/z (EI): 339 (M+, 91%),
248 (33), 232 (25), 204 (31) and 91 (100); HRMS calcd
for C24H21NO: 339.1623, found: 339.1623.
4.2.3. 1-(1-Benzyl-3-methyl-1H-indol-2-yl)-3,4-dihydro-
2-naphthalenecarbaldehyde 13. 2-Naphthalenecarbalde-
hyde 17b (0.10 g, 0.35 mmol) was dissolved in dry THF
(6 cm3) and mixed with 50% aq NaOH (1.5 g in 3 cm3
H2O). Benzyl bromide (0.082 cm3, 0.70 mmol) was added
over 20 min and the mixture was treated with a catalytic
amount of the phase transfer catalyst, (n-Bu)4NBr (0.02 g).
The reaction mixture was stirred vigorously for 1.5 h. The
reaction mixture was then extracted with EtOAc (3ꢂ
30 cm3). The combined organic extracts were washed with
brine, dried (MgSO4) and the solvent was removed under
reduced pressure. The crude product was then purified by
column chromatography (5–20% EtOAc/hexane) to give
1-(1-benzyl-3-methyl-1H-indol-2-yl)-3,4-dihydro-2-naph-
thalenecarbaldehyde 13 as a brown oil (0.068 g, 52%): nmax
1
(film)/cmꢀ1: 1663 (C]O) and 1603 (ArC]C); H NMR
(300 MHz, CDCl3, Me4Si) 2.20 (3H, s, ArCH3), 2.42–2.52
[1H, m, C(H)H], 2.74–2.91 (3H, m, C(H)H, CH2), 4.75
(1H, d, J¼16.3 Hz, PhCH), 5.23 (1H, d, J¼16.3 Hz,
PhCH), 6.75 (1H, d, J¼7.6 Hz, ArH), 6.81–6.83 (2H, m,
2ꢂArH), 7.05–7.19 (4H, m, 4ꢂArH), 7.22–7.36 (5H, m,
5ꢂArH), 7.67 (1H, d, J¼7.7 Hz, ArH) and 9.39 (1H, s,
CHO); 13C NMR (75 MHz, CDCl3) 9.2 (ArCH3), 20.1
(CH2), 27.2 (CH2), 48.0 (NCH2Ph), 109.8 (CH), 114.6 (C),
119.2 (CH), 119.6 (CH), 122.8 (CH), 126.4 (2ꢂCH),
127.0 (CH), 127.3 (CH), 127.5 (CH), 127.9 (CH), 128.1
(C), 128.5 (2ꢂCH), 129.6 (C), 130.4 (CH), 133.7 (C),
137.5 (C), 137.7 (C), 137.9 (C), 138.0 (C), 143.8 (C) and
192.6 (CHO); MS m/z (EI): 377 (M+, 28%), 286 (100),
256 (7) and 91 (23); HRMS calcd for C27H23NO:
377.1779, found: 377.1780.
4.2.4. 14-Methyl-8-phenylbenzo[h]indolo[2,1-a]isoquino-
line 18b. KOtBu (0.119 g, 1.06 mmol) was added to 13
(0.105 g, 0.33 mmol) dissolved in dry DMF (10 cm3) and
heated under N2 at 80 ꢁC for 10 min. The reaction mixture
was quenched with H2O (50 cm3) and the organic material
was extracted into Et2O (3ꢂ50 cm3). The combined organic
layers were dried (MgSO4) and filtered. The solvent was
then evaporated in vacuo and the residue was subjected to
column chromatography (5–20% EtOAc/hexane) to afford
4.2.6. 5,12-Dimethyl-6-phenyl-5,6-dihydroindolo[2,1-
a]isoquin-5-ols 23a and 23b. KOtBu (0.082 g, 1.27 mmol)
was added to 22 (0.062 g, 0.32 mmol) dissolved in dry
DMF (6 cm3) and heated under N2 at 80 ꢁC for 10 min. The
reaction mixture was quenched by adding H2O (50 cm3) and
then the organic material was extracted with Et2O
(3ꢂ50 cm3). The combined organic layers were dried over
MgSO4 and filtered. The organic solvent was then evaporated
in vacuo and subjected to column chromatography (5–20%

A. N. C. Lo€tter et al. / Tetrahedron 63 (2007) 2263–2274
2269
EtOAc/hexane) to afford firstly the product 23b (0.046 g,
74%) as a yellow solid: mp 61–63 ꢁC; nmax (CHCl3)/cmꢀ1
butyl 1H-indole-1-carboxylate (2.00 g, 9.20 mmol) was
added to the dropping funnel. The solution was lowered
to ꢀ78 ꢁC and n-butyl lithium (7.9 cm3, 11.04 mmol,
1.2 equiv) was added drop wise, over 5 min. The solution
was warmed to 0 ꢁC over 30 min and then recooled to
ꢀ78 ꢁC. The solution in the dropping funnel was now added
drop wise to the flask and the resulting mixturewas stirred for
1.5 h at ꢀ78 ꢁC. B(OMe)3 (5.16 cm3, 46.00 mmol, 5 equiv)
was added and the solution was stirred at ꢀ78 ꢁC for further
30 min before allowing to warm up to rt. Water (150 cm3)
was added, the solution was acidified using a 1 M HCl solu-
tion and then extracted with Et2O (3ꢂ100 cm3). The organic
layers were combined, washed with brine and dried over an-
hydrous MgSO4. The solvent was removed, in vacuo, until
approximately 15 cm3 remained. Cold hexane was added,
which resulted in 1-(tert-butoxycarbonyl)-1H-indol-2-yl-2-
boronic acid 25,26,36 precipitating as a white solid (1.57 g,
65%). The solid 25 was obtained by filtration, dried overnight
:
3417 (OH), 1603, 1575 and 1555 (ArC]C); 1H NMR
(300 MHz, CDCl3, Me4Si) 1.63 (3H, s, ArCH3), 2.54 (1H,
s, OH), 2.72 (3H, s, CH3), 5.51 (1H, s, CH), 6.93–6.97 (2H,
m, 2ꢂArH), 7.06–7.17 (5H, m, 5ꢂArH), 7.23–7.30 (2H, m,
2ꢂArH), 7.43–7.53 (2H, m, 2ꢂArH), 7.62 (1H, d, J¼
7.3 Hz, ArH) and 8.03 (1H, d, J¼7.8 Hz, ArH); 13C NMR
(75 MHz, CDCl3) 11.0 (ArCH3), 23.7 (CH3), 67.3 (CH),
72.7 (C–OH), 108.5 (C), 109.2 (CH), 119.0 (CH), 119.6
(CH), 122.6 (CH), 125.7 (CH), 125.8 (CH), 127.2 (CH),
127.5 (2ꢂCH), 127.8 (CH), 128.3 (2ꢂCH), 128.5 (C),
129.0 (CH), 129.4 (C), 129.8 (C), 135.4 (C), 136.0 (C) and
137.7 (C); MS m/z (EI): 340 (49%), 339 (M+, 100), 324
(38), 296 (26), 248 (33) and 216 (19); HRMS calcd for
C24H21NO: 339.1623, found: 339.1623.
The second product 23a was isolated as a yellow solid
(0.015 g, 26%): mp 123–126 ꢁC; nmax (solid)/cmꢀ1: 3447
(OH), 1602 and 1577 (ArC]C); 1H NMR (300 MHz,
CDCl3, Me4Si) 1.53 (3H, s, ArCH3), 2.15 (1H, s, OH), 2.71
(3H, s, CH3), 5.41 (1H, s, CH), 6.97–7.0 (2H, m, 2ꢂArH),
7.10–7.30 (7H, m, 7ꢂArH), 7.35–7.45 (1H, m, ArH), 7.54
(1H, d, J¼7.6 Hz, ArH), 7.62 (1H, d, J¼7.0 Hz, ArH) and
7.93 (1H, d, J¼7.7 Hz, ArH); 13C NMR (75 MHz, CDCl3)
10.7 (ArCH3), 29.7 (CH3), 60.4 (CH), 73.5 (C–OH), 108.3
(C), 108.8 (CH), 118.9 (CH), 119.6 (CH), 122.5 (CH),
124.5 (CH), 125.0 (CH), 127.4 (CH), 127.8 (CH), 128.0
(2ꢂCH), 128.2 (C), 128.3 (CH), 128.6 (2ꢂCH), 129.0 (C),
129.8 (C), 135.5 (C), 136.3 (C) and 139.0 (C); MS m/z
(EI): 340 (M+, 27%), 339 (100), 324 (20), 296 (15) and
248 (17); HRMS calcd for C24H21NO: 339.1623, found:
339.1624.
1
under N2 and stored in a refrigerator. H NMR (300 MHz,
CDCl3, Me4Si) 1.74 (9H, s, 9ꢂCH3), 7.25 (1H, t,
J¼7.4 Hz, ArH), 7.35 (1H, m, ArH), 7.50 (1H, s, 3-H),
7.54 (2H, s, 2ꢂOH), 7.60 (1H, d, J¼7.6 Hz, ArH) and 8.02
(1H, d, J¼8.4 Hz, ArH).
4.2.9. tert-Butyl 2-(2-formylphenyl)-1H-indole-1-carbox-
ylate 27a. Pd(PPh3)4 (0.53 g, 0.46 mmol, 10 mol %) was
added to a flame dried round bottom flask equipped with
a condenser and dropping funnel. Boronic acid 25 (1.80 g,
6.89 mmol, 1.5 equiv), 2-bromobenzaldehyde (0.85 g,
4.60 mmol) and DME (12.65 cm3) were combined in the
dropping funnel and degassed before adding to the flask. A
2 M Na2CO3 solution (2.44 g, 23.00 mmol) was added to
the dropping funnel, degassed and also added to the flask.
The dropping funnel was closed and the resulting mixture
was degassed once more before heating under reflux for
60 h. Water (50 cm3) was added to the reaction mixture
and the solution was extracted with EtOAc (3ꢂ50 cm3).
The organic layers were combined and dried over anhydrous
MgSO4. The organic solvent was removed in vacuo and the
residue was purified by column chromatography (2%
EtOAc/hexane) to afford tert-butyl 2-(2-formylphenyl)-1H-
indole-1-carboxylate 27a as a white solid (1.26 g, 85%): mp
127–128 ꢁC; nmax (film)/cmꢀ1: 1733 and 1698 (C]O) and
4.2.7. 5,12-Dimethyl-6-phenylindolo[2,1-a]isoquinoline
24. To a solution of 5,12-dimethyl-6-phenyl-5,6-dihydro-
indolo[2,1-a]isoquin-5-ol 23b (0.030 g, 0.09 mmol) in
CH2Cl2 (10 cm3) were added molecular sieves and pTSA
(15 mol %, 0.003 g, 0.005 mmol). The reaction mixture
was stirred at rt for 18 h. The reaction mixture was then fil-
tered, evaporated and subjected to column chromatography
(5–10% EtOAc/hexane) to afford the product, 5,12-di-
methyl-6-phenylindolo[2,1-a]isoquinoline 24 (0.022 g,
79%) as a yellow oil; nmax (film)/cmꢀ1: 1637 and 1599
1
1600 (ArC]C); H NMR (300 MHz, CDCl3, Me4Si) 1.24
1
(ArC]C); H NMR (300 MHz, CDCl3, Me4Si) 2.15 (3H,
(9H, s, Boc), 6.60 (1H, s, 3-H), 7.26–7.47 (3H, m,
3ꢂArH), 7.51–7.66 (3H, m, 3ꢂArH), 8.01 (1H, d, J¼
7.7 Hz, ArH), 8.28 (1H, d, J¼8.3 Hz, ArH) and 10.01 (1H,
s, CHO); 13C NMR (75 MHz, CDCl3) 27.5 (Boc), 83.9
[C(CH3)3], 112.6 (CH), 115.7 (CH), 120.6 (CH), 123.3
(CH), 124.9 (CH), 127.3 (CH), 128.5 (CH), 128.8 (C),
131.0 (CH), 133.1 (CH), 134.9 (C), 135.2 (C), 137.0 (C),
138.3 (C), 149.7 (NC]O) and 191.6 (PhC]O); MS m/z
(EI): 321 (M+, 16%), 221 (24), 193 (100), 165 (17), 57
(53) and 41 (13); HRMS C20H19NO3 requires: 321.1365,
found: 321.1323.
s, ArCH3), 2.89 (3H, s, ArCH3), 5.90 (1H, d, J¼8.7 Hz,
ArH), 6.77–6.80 (1H, m, ArH), 7.19 (1H, t, J¼7.5 Hz, ArH),
7.42–7.62 (7H, m, 7ꢂArH), 7.75–7.77 (2H, m, 2ꢂArH) and
8.50 (1H, d, J¼8.2 Hz, ArH); 13C NMR (75 MHz, CDCl3)
12.0 (ArCH3), 14.8 (ArCH3), 104.8 (C), 112.2 (C), 114.1
(CH), 117.8 (CH), 120.2 (CH), 120.7 (CH), 123.5 (CH),
124.6 (CH), 126.5 (2ꢂCH), 127.6 (C), 129.1 (CH), 129.4
(2ꢂCH), 130.0 (C), 130.1 (2ꢂCH), 130.8 (C), 131.2 (C),
135.4 (C) and 136.7 (C) (one quaternary C missing); MS
m/z (EI): 322 (M+, 27%), 321 (100), 320 (21) and 304 (6);
HRMS calcd for C24H19N: 321.1518, found: 321.1517.
4.2.10. tert-Butyl 2-(2-acetylphenyl)-1H-indole-1-carbox-
ylate 27b. Pd(PPh3)4 (0.53 g, 0.46 mmol, 10 mol %) was
added to a flame dried round bottom flask equipped with
a condenser and dropping funnel. Boronic acid 25 (1.80 g,
6.89 mmol, 1.5 equiv), 1-(2-bromophenyl)ethanone (0.92 g,
4.60 mmol) and DME (12.65 cm3) were combined in the
dropping funnel and degassed before adding to the flask.
4.2.8. 1-(tert-Butoxycarbonyl)-1H-indol-2-yl-2-boronic
acid 25. A flask equipped with a dropping funnel, rubber sep-
tum and N2 adaptor was flame dried. THF of 25 and 100 cm3
was added to the dropping funnel and round bottom flask, re-
spectively. Tetramethylpiperidine (2.04 cm3, 11.96 mmol,
1.3 equiv) was added to the flask using a syringe and tert-

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A. N. C. Lo€tter et al. / Tetrahedron 63 (2007) 2263–2274
A 2 M Na2CO3 solution (2.44 g, 23.00 mmol) was added to
the dropping funnel, degassed and then added to the flask.
The dropping funnel was closed and the resulting mixture
was degassed once more before heating under reflux for 3
days. Water (50 cm3) was added and the solution was ex-
tracted with EtOAc (3ꢂ50 cm3). The organic layers were
combined and dried over anhydrous MgSO4. The organic
solvent was removed in vacuo and the residue was purified
by column chromatography (2% EtOAc/hexane) to afford
tert-butyl 2-(2-acetylphenyl)-1H-indole-1-carboxylate 27b
as an orange-pink viscous oil that eventually solidified
(0.97 g, 63%): mp 91–92 ꢁC; nmax (film)/cmꢀ1: 1731 and
(CH), 129.0 (2ꢂCH), 129.3 (C), 131.8 (CH), 134.4 (C),
139.8 (C) and 169.2 (C]O).
4.2.13. 1-Benzylindolin-2-one 33a. 1-Benzyl-3,3-dichloro-
indolin-2-one 32a (3.00 g, 10.30 mmol) was dissolved in
AcOH (90 cm3). Activated Zn (10.00 g, 154.5 mmol,
15 equiv) was added over a 10 min period and the resulting
mixture was stirred for further 10 min at rt. The Zn was fil-
tered off and washed with AcOH and EtOAc. Most of the
solvent was removed in vacuo and concentrated. Solid
NaHCO3 was then added until effervescence ceased. The
solution was extracted with Et2O (3ꢂ50 cm3), the organic
layers were combined and the solvent was dried over anhy-
drous MgSO4. The solvent was removed in vacuo and the
resulting residue was purified by column chromatography
(20% EtOAc/hexane) to afford 1-benzylindolin-2-one 33a
as a white solid (1.75 g, 76%): mp 60–62 ꢁC (lit. mp 66.5–
67 ꢁC);39 1H NMR (300 MHz, CDCl3, Me4Si) 3.62 (2H, s,
PhCH2C]O), 4.91 (2H, s, PhCH2N), 6.72 (1H, d, J¼
7.8 Hz, ArH), 7.00 (1H, t, J¼7.5 Hz, ArH), 7.16 (1H, t,
J¼7.8 Hz, ArH), 7.21–7.34 (6H, m, 6ꢂArH); 13C NMR
(75 MHz, CDCl3) 35.7 (PhCH2C]O), 43.7 (PhCH2N),
109.0 (CH), 122.3 (CH), 124.3 (CH), 124.4 (C), 127.3
(2ꢂCH), 127.6 (CH), 127.8 (CH), 128.7 (2ꢂCH), 135.9
(C), 144.3 (C) and 175.1 (BnNC]O).
1
1688 (C]O) and 1598 (ArC]C); H NMR (300 MHz,
CDCl3, Me4Si) 1.29 (9H, s, Boc), 2.33 (3H, s, CH3C]O),
6.48 (1H, s, 3-H), 7.22–7.55 (6H, m, 6ꢂArH), 7.73 (1H, d,
J¼7.4 Hz, ArH) and 8.24 (1H, d, J¼8.3 Hz, ArH); 13C
NMR (75 MHz, CDCl3) 27.4 (Boc), 28.6 (CH3C]O),
83.2 [C(CH3)3], 110.3 (CH), 115.5 (CH), 120.3 (CH),
122.8 (CH), 124.3 (CH), 127.9 (CH), 128.0 (CH), 129.0
(C), 130.6 (CH), 130.8 (CH), 133.7 (C), 136.6 (C), 138.2
(C), 139.0 (C), 149.6 (NC]O) and 200.8 (PhC]O); MS
m/z (EI): 335 (M+, 30%), 235 (100), 220 (65), 165 (13), 57
(58), 41 (16) and 30 (12); HRMS C21H21NO3 requires:
335.1521, found: 335.1530.
4.2.11. 1-Benzylindoline-2,3-dione 31a. Isatin 30 (8.00 g,
54.00 mmol) and CaH2 (2.29 g, 54.00 mmol, 1 equiv) were
dissolved in DMF (27.00 cm3) in a round bottom flask.
The solution was stirred at 100 ꢁC for 1 h and then cooled
to 40 ꢁC so that benzyl bromide (7.10 cm3, 60.00 mmol,
1.1 equiv) could be added slowly. The resulting mixture
was heated to 100 ꢁC for 4 h and then allowed to cool to
rt. The solution was poured into an aqueous 0.5 M HCl solu-
tion (200 cm3) with vigorous stirring, which resulted in an
orange precipitate. The precipitate was filtered off and
washed with H2O. The crude product was further purified
by recrystallization (CH2Cl2/hexane) to afford 1-benzylin-
doline-2,3-dione 31a as orange needle-like crystals (11.44 g,
89%): mp 133–134 ꢁC (lit. mp 126–127 ꢁC);37 1H NMR
(300 MHz, CDCl3, Me4Si): dH (ppm) 4.94 (2H, s, PhCH2N),
6.78 (1H, d, J¼7.9 Hz, ArH), 7.09 (1H, t, J¼7.6 Hz, ArH),
7.25–7.38 (5H, m, 5ꢂArH), 7.48 (1H, dt, J¼1.2 and
7.8 Hz, ArH) and 7.61 (1H, d, J¼7.5 Hz, ArH); 13C NMR
(75 MHz, CDCl3): dC (ppm) 44.0 (PhCH2N), 110.0 (CH),
117.6 (C), 123.8 (CH), 125.3 (CH), 127.4 (2ꢂCH), 128.1
(CH), 129.0 (2ꢂCH), 134.5 (C), 138.3 (CH), 150.7 (C),
158.2 (BnNC]O) and 183.2 (C]O).
4.2.14. 1-Benzyl-2-bromo-1H-indole 34a. POBr3 (0.19 g,
0.68 mmol, 1.5 equiv) was added to a solution of 1-benzyl-
indolin-2-one 33a (0.10 g, 0.45 mmol) in dichloromethane
(10.00 cm3). The resulting mixture was stirred at reflux for
1 h. The solution was cooled to rt and imidazole (0.04 g,
0.54 mmol, 1.2 equiv) was added before refluxing for further
48 h. A 2 M NaHCO3 solution was added until the reaction
stopped and the solution was extracted with CH2Cl2 (3ꢂ
30 cm3). The organic layers were combined, washed with
brine and dried over anhydrous MgSO4 before removing
the solvent in vacuo. The resulting orange residue was puri-
fied by column chromatography (2% EtOAc/hexane) to
afford the brominated compound 34a as a white solid
(0.07 g, 88%) and starting material (0.02 g): mp 87–89 ꢁC;
nmax (film)/cmꢀ1: 1497, 1450, 737 and 722; 1H NMR
(300 MHz, CDCl3, Me4Si) 5.41 (2H, s, PhCH2N), 6.65
(1H, s, 3-H), 7.06–7.13 (4H, m, 4ꢂArH), 7.20–7.28 (4H,
m, 4ꢂArH) and 7.55 (1H, dd, J¼2.2 and 6.4 Hz, ArH);
13C NMR (75 MHz, CDCl3) 48.1 (PhCH2N), 104.5 (3-C),
109.0 (CH), 113.5 (C), 119.8 (CH), 120.3 (CH), 122.0
(CH), 126.4 (2ꢂCH), 127.5 (CH), 128.2 (C), 128.7
(2ꢂCH), 136.7 (C) and 137.0 (C); MS m/z (EI): 285 (M+,
42%), 204 (11), 91 (100), 65 (9); HRMS C15H12N79Br
requires: 285.0153, found: 285.0091.
4.2.12. 1-Benzyl-3,3-dichloroindolin-2-one 32a. Dione
31a (6.40 g, 27.00 mmol) was dissolved in benzene (70 cm3)
in a round bottom flask. Phosphorus pentachloride (12.80 g,
62.10 mmol, 2.3 equiv) was added and the solution was
warmed to 25 ꢁC for 24 h. The solvent was removed in vacuo
to obtain a yellow brown residue, which was further purified
by column chromatography (5% EtOAc/hexane) to afford
1-benzyl-3,3-dichloroindolin-2-one 32a as a light yellow
oil. On addition of ethanol 32a precipitated as a white solid
(6.37 g, 81%): mp 125–126 ꢁC (lit. mp 126–127 ꢁC);38 1H
NMR (300 MHz, CDCl3, Me4Si) 4.94 (2H, s, PhCH2N),
6.72 (1H, d, J¼7.9 Hz, ArH), 7.14 (1H, t, J¼7.6 Hz, ArH),
7.22–7.39 (6H, m, 6ꢂArH) and 7.64 (1H, d, J¼7.5 Hz,
ArH); 13C NMR (75 MHz, CDCl3) 44.5 (PhCH2N), 110.1
(ArCCl2), 124.2 (CH), 124.9 (CH), 127.1 (2ꢂCH), 128.1
4.2.15. 2-(1-Benzyl-1H-indol-2-yl)benzaldehyde 36a.
Pd(PPh3)4 (0.10 g, 0.087 mmol, 10 mol %) was added to
a 50 cm3 flame dried round bottom flask equipped with
a condenser and dropping funnel. Bromide 34a (0.25 g,
0.87 mmol), 2-formylphenylboronic acid 35 (0.15 g,
1.31 mmol) and DME (2.4 cm3) were combined in the drop-
ping funnel and degassed before adding to the flask. A 2 M
Na2CO3 solution (0.46 g, 4.35 mmol, 5 equiv) was added to
the dropping funnel, degassed and then added to the flask.
The dropping funnel was closed and the resulting mixture
was degassed once more before refluxing for 24 h. Water
(10 cm3) was added and the solution was extracted with

A. N. C. Lo€tter et al. / Tetrahedron 63 (2007) 2263–2274
2271
EtOAc (3ꢂ20 cm3). The organic layers were combined and
dried over anhydrous MgSO4. The solvent was removed in
vacuo and the residue was purified by silica gel column chro-
matography (2% EtOAc/hexane) to afford 2-(1-benzyl-1H-
indol-2-yl)benzaldehyde 36a as a yellow, viscous oil
(0.25 g, 92%); nmax (CHCl3)/cmꢀ1: 1701 (C]O) and 1597
131.0 (C), 133.7 (C), 137.4 (C) and 137.8 (C); MS m/z
(EI): 311 (M+, 100%), 310 (20), 283 (18), 282 (47), 280
(14), 234 (18), 220 (42), 217 (14), 206 (42), 204 (31), 178
(16), 165 (19), 155 (15) and 91 (21); HRMS C22H17NO
requires: 311.1310, found: 311.1339.
1
(ArC]C); H NMR (300 MHz, CDCl3, Me4Si) 5.26 (2H,
4.2.17. Ethyl 2-(2,3-dioxoindolin-1-yl)acetate 31b. Isatin
30 (10.00 g, 68.00 mmol) and CaH2 (2.86 g, 68.00 mmol,
1 equiv) were dissolved in DMF (35.00 cm3) in a round bot-
tom flask. The solution was stirred at 100 ꢁC for 1 h and then
cooled to 40 ꢁC so that ethyl 2-bromoacetate (22.62 cm3,
204.00 mmol, 3 equiv) could be added slowly. The resulting
mixture was heated to 100 ꢁC for 4 h and then allowed to
cool to rt. The solution was poured into an aqueous 0.5 M
HCl solution (200 cm3) with vigorous stirring, which re-
sulted in a yellow precipitate. The precipitate was filtered
off and washed with H2O. The crude product was further
purified by recrystallization (CH2Cl2/hexane) to afford ethyl
2-(2,3-dioxoindolin-1-yl)acetate 31b as yellow crystals in
quantitative yield: mp 132–133 ꢁC (lit. mp 116–118 ꢁC);40
s, PhCH2N), 6.63 (1H, s, 3-H), 6.80–6.83 (2H, m,
2ꢂArH), 7.16–7.27 (5H, m, 5ꢂArH), 7.32 (1H, d, J¼
8.0 Hz, ArH), 7.40 (1H, dd, J¼1.2 and 7.4 Hz, ArH),
7.50–7.61 (2H, m, 2ꢂArH), 7.69 (1H, dd, J¼1.1 and 6.9 Hz,
ArH), 8.01 (1H, dd, J¼1.4 and 7.6 Hz, ArH) and 9.85 (1H, s,
CHO); 13C NMR (75 MHz, CDCl3) 47.6 (PhCH2N), 106.8
(3-C), 110.4 (CH), 120.5 (CH), 120.8 (CH), 122.7 (CH),
126.1 (2ꢂCH), 127.4 (CH), 127.5 (CH), 128.7 (2ꢂCH),
129.0 (CH), 131.4 (CH), 133.2 (CH), 135.4 (C), 135.5 (C),
135.8 (C), 137.4 (C), 137.8 (C) and 191.6 (C]O); MS m/z
(EI): 311 (M+, 33%), 283 (58), 282 (65), 221 (19), 220
(100), 206 (39), 182 (53), 181 (72), 180 (20), 153 (20), 152
(30), 91 (87), 86 (27), 84 (41), 76 (15), 57 (22), 43 (18);
HRMS C22H17NO requires: 311.1310, found: 311.1335.
1
nmax (CHCl3)/cmꢀ1: 1740 (C]O) and 1615 (ArC]C); H
NMR (300 MHz, CDCl3, Me4Si) 1.29 (3H, t, J¼7.1 Hz,
CH2CH3), 4.25 (2H, q, J¼7.1 Hz, CH2CH3), 4.49 (2H, s,
O]CCH2N), 6.79 (1H, d, J¼7.9 Hz, ArH), 7.16 (1H, t,
J¼7.5 Hz, ArH), 7.57–7.62 (1H, m, ArH) and 7.66 (1H, d,
J¼7.5 Hz, ArH); 13C NMR (75 MHz, CDCl3) 14.1 (CH3),
41.3 (O]CCH2N), 62.2 (CH3CH2), 110.1 (CH), 117.7
(C), 124.1 (CH), 125.6 (CH), 138.4 (CH), 150.3 (C), 158.0
(NC]O), 166.7 (OC]O) and 182.4 (PhC]O); MS m/z
(EI): 233 (M+, 35%), 132 (100), 77 (24) and 51 (9);
HRMS C12H11NO4 requires: 233.0688, found: 233.0675.
4.2.16. 5,6-Dihydro-6-phenylindolo[2,1-a]isoquinolin-
5-ols 37a and 37b. To a solution of 2-(1-benzyl-1H-indol-
2-yl)benzaldehyde 36a (0.20 g, 0.64 mmol) in DMF
(20 cm3) was added tBuOK (0.086 g, 0.77 mmol) and the re-
sulting mixture was stirred for 2 min at rt. The solution was
quenched with H2O (40 cm3) and the reaction mixture was
extracted with Et2O (3ꢂ40 cm3). After the organic layers
were combined and dried, the solvent was removed in vacuo.
The residue obtained was purified by column chromato-
graphy (2–5% EtOAc/hexane) to afford the syn- and anti-
diastereomer 37a and 37b as yellow-green resins in a 7:3
ratio (53% anti and 22% syn). anti-Diastereoisomer 37a:
nmax (film)/cmꢀ1: 3423 (OH) and 1605 (ArC]C); 1H
NMR (300 MHz, CDCl3, Me4Si) 1.66 (1H, d, J¼11.0 Hz,
OH), 5.38 (1H, dd, J¼7.0 and 11.0 Hz, PhCHOH), 5.71
(1H, d, J¼7.0 Hz, PhCHN), 6.85–6.82 (2H, m, 2ꢂArH),
6.92 (1H, s, 3-H), 6.97–7.05 (5H, m, 5ꢂArH), 7.11–7.21
(2H, m, 2ꢂArH), 7.29 (1H, t, J¼7.4 Hz, ArH), 7.38 (1H, d,
J¼7.8 Hz, ArH), 7.54 (1H, dd, J¼2.2 and 6.4 Hz, ArH) and
7.75 (1H, d, J¼7.6 Hz, ArH); 13C NMR (75 MHz, CDCl3):
59.5 (PhCHOH), 69.5 (PhCHN), 97.4 (CH), 109.4 (CH),
120.5 (CH), 120.8 (CH), 122.3 (CH), 123.9 (CH), 125.0
(CH), 127.3 (C), 127.9 (2ꢂCH), 128.0 (CH), 128.1 (CH),
128.4 (CH), 128.6 (2ꢂCH), 129.1 (C), 133.4 (C), 134.5
(C), 135.0 (C) and 136.4 (C); MS m/z (EI): 311 (M+,
100%), 310 (18), 283 (17), 282 (47), 280 (14), 234 (17),
220 (42), 206 (41), 204 (30), 178 (15), 165 (18), 155 (14)
and 91 (20); HRMS C22H17NO requires: 311.1310, found:
311.1302.
4.2.18. Ethyl 2-(3,3-dichloro-2-oxoindolin-1-yl)acetate
32b. Dione 31b (2.50 g, 10.70 mmol) was dissolved in
benzene (40 cm3) in a round bottom flask. PCl5 (5.00 g,
24.61 mmol, 2.3 equiv) was added and the solution was
warmed to 25 ꢁC for 24 h. The solvent was removed in vacuo
to obtain a light yellow residue, which was further purified
by column chromatography (hexane/2% EtOAc/hexane)
to afford ethyl 2-(3,3-dichloro-2-oxoindolin-1-yl)acetate
32b as a white solid (3.10 g, 100%): mp 115–116 ꢁC; nmax
(CHCl3)/cmꢀ1: 1746 (C]O), 1613 (ArC]C) and 670 (C–
Cl); 1H NMR (300 MHz, CDCl3, Me4Si) 1.26 (3H, t,
J¼7.1 Hz, CH2CH3), 4.23 (2H, q, J¼7.1 Hz, CH3CH2),
4.48 (2H, s, O]CCH2N), 6.77 (1H, d, J¼7.9 Hz, ArH),
7.19 (1H, t, J¼7.7 Hz, ArH), 7.39 (1H, dt, J¼1.0 and
7.8 Hz, ArH) and 7.66 (1H, d, J¼7.5 Hz, ArH); 13C NMR
(75 MHz, CDCl3) 14.0 (CH3), 41.8 (O]CCH2N), 62.1
(CH3CH2), 73.9 (CH), 109.1 (CCl2), 124.5 (CH), 125.0
(CH), 129.0 (C), 131.8 (CH), 139.4 (C), 166.4 (NC]O)
and 168.9 (OC]O); MS m/z (EI): 287 (M+, 39%), 254
(37), 252 (100), 216 (23), 214 (36), 188 (11), 186 (18),
173 (23), 151 (21) and 89 (18); HRMS C12H11NO35Cl2
requires: 287.0116, found: 287.0151.
syn-Diastereoisomer 37b: nmax (film)/cmꢀ1: 3364 (OH) and
1607 (ArC]C); H NMR (300 MHz, CDCl3, Me4Si) 2.18
1
(1H, br s, OH), 4.91 (1H, s, PhCHOH), 5.81 (1H, d,
J¼1.5 Hz, PhCHN), 6.72–6.69 (2H, m, 2ꢂArH), 6.97 (1H,
s, ArH), 7.00–7.09 (5H, m, 5ꢂArH), 7.12–7.18 (3H, m,
3ꢂArH), 7.29–7.35 (1H, m, ArH), 7.58–7.60 (1H, m,
ArH) and 7.79 (1H, d, J¼7.7 Hz, ArH); 13C NMR
(75 MHz, CDCl3) 62.0 (PhCHOH), 73.9 (PhCHN), 97.6
(CH), 109.6 (CH), 120.5 (CH), 120.9 (CH), 122.4 (CH),
124.4 (CH), 125.9 (2ꢂCH), 127.7 (CH), 128.0 (C), 128.1
(CH), 128.7 (2ꢂCH), 129.1 (C), 129.7 (CH), 129.9 (CH),
4.2.19. Ethyl 2-(2-oxoindolin-1-yl)acetate 33b. In a round
bottom flask, ethyl 2-(3,3-dichloro-2-oxoindolin-1-yl)ace-
tate 32b (0.15 g, 0.52 mmol) was dissolved in AcOH
(5 cm3). Activated Zn (0.50 g, 7.29 mmol, 14 equiv) was
added over a 10 min period and the resulting mixture was
stirred for further 5 min at rt. The Zn was filtered off and
washed with AcOH and EtOAc. Most of the solvent was re-
moved in vacuo and concentrated NaHCO3 was added until

2272
A. N. C. Lo€tter et al. / Tetrahedron 63 (2007) 2263–2274
effervescence stopped. The solution was extracted with Et2O
(3ꢂ20 cm3), the organic layers were combined and the
solvent was dried over anhydrous MgSO4. The solvent was
removed in vacuo and the resulting residue was purified by
column chromatography (2/5% EtOAc/hexane) to afford
ethyl 2-(2-oxoindolin-1-yl)acetate 33b as a white solid
in quantitative yield: mp 127–129 ꢁC (lit. mp 125–
127.5 ꢁC);41 nmax (CHCl3)/cmꢀ1: 1740 and 1715 (C]O)
viscous oil (0.21 g, 77%); nmax (film)/cmꢀ1: 1748 and
1693 (C]O) and 1600 (ArC]C); H NMR (300 MHz,
1
CDCl3, Me4Si) 1.15 (3H, t, J¼7.1 Hz, CH2CH3), 4.10 (2H,
q, J¼7.1 Hz, CH3CH2) 4.71 (2H, s, O]CCH2N), 6.63
(1H, s, 3-H), 7.18–7.33 (3H, m, 3ꢂArH), 7.51 (1H, d,
J¼7.6 Hz, ArH), 7.58–7.62 (1H, m, ArH), 7.65–7.70 (2H,
m, 2ꢂArH), 8.08 (1H, dd, J¼1.1 and 7.7 Hz, ArH) and
10.00 (1H, s, CHO); 13C NMR (75 MHz, CDCl3) 14.0
(CH3), 45.7 (O]CCH2N), 61.7 (CH3CH2), 107.1 (CH),
109.3 (CH), 120.9 (CH), 120.9 (CH), 121.0 (CH), 123.0
(CH), 127.9 (C), 129.2 (CH), 131.5 (CH), 133.3 (CH), 135.2
(C), 135.4 (C), 135.8 (C), 137.9 (C), 168.3 (OC]O) and
192.1 (CHO); MS m/z (EI): 307 (M+, 65%), 279 (33), 278
(39), 250 (24), 235 (13), 234 (47), 233 (25), 220 (19), 219
(23), 210 (12), 207 (20), 206 (54), 205 (43), 204 (47), 203
(15), 192 (13), 182 (36), 181 (100), 178 (20), 177 (14),
165 (19), 153 (31), 152 (49), 151 (23), 150 (16), 149 (56),
136 (24), 102 (12), 86 (34), 84 (45), 77 (19), 76 (23), 51
(10), 47 (12) and 29 (12); HRMS C19H17NO3 requires:
307.1208, found: 307.1200.
1
and 1615 (ArC]C); H NMR (300 MHz, CDCl3, Me4Si)
1.27 (3H, t, J¼7.1 Hz, CH2CH3), 3.60 (1H, s, PhCH2),
4.22 (2H, q, J¼7.1 Hz, CH3CH2), 4.47 (2H, s, O]
CCH2N), 6.70 (1H, d, J¼7.8 Hz, ArH), 7.03–7.05 (1H, m,
ArH) and 7.23–7.28 (2H, m, 2ꢂArH); 13C NMR (75 MHz,
CDCl3) 14.1 (CH3), 35.5 (PhCH2), 41.3 (O]CCH2N),
61.7 (CH3CH2), 108.1 (CH), 122.7 (CH), 124.2 (C), 124.5
(CH), 127.9 (CH), 143.8 (C), 167.6 (NC]O) and 174.9
(OC]O); MS m/z (EI): 219 (M+, 45%), 146 (49), 119
(11), 118 (100), 91 (39), 65 (14), 43 (12) and 21 (24);
HRMS C12H13NO3 requires: 219.0895, found: 219.0896.
4.2.20. Ethyl 2-(2-bromo-1H-indol-1-yl)acetate 34b.
POBr3 (0.60 g, 2.22 mmol, 1.2 equiv) was added to a solu-
tion of ethyl 2-(2-oxoindolin-1-yl)acetate 33b (0.40 g,
1.84 mmol) in dichloromethane (40 cm3). The resulting
mixture was stirred at reflux for 9 days. A 2 M NaHCO3 so-
lution was added until effervescence ceased and the solution
was extracted with CH2Cl2 (3ꢂ50 cm3). The organic layers
were combined, washed with brine and dried over anhydrous
MgSO4 before removing the solvent in vacuo. The resulting
purple residue was purified by column chromatography (2%
EtOAc/hexane) to afford the brominated compound 34b as
a white solid (0.25 g, 89%) and starting material (0.12 g):
4.2.22. Ethyl indolo[2,1-a]isoquinoline-6-carboxylate 39.
To a solution of ethyl 2-(2-(2-formylphenyl)-1H-indol-1-
yl)acetate 36b (0.15 g, 0.49 mmol) in DMF (15 cm3) was
t
added BuOK (0.006 g, 0.049 mmol, 10 mol %) at rt. The
resulting mixture was stirred for 2 min before it was
quenched with H2O (25 cm3) and then extracted with Et2O
(3ꢂ25 cm3). The organic layers were combined, dried over
MgSO4 and the solvent was removed in vacuo. The resulting
residue was purified by column chromatography (2%
EtOAc/hexane) to afford ethyl indolo[2,1-a]isoquinoline-
6-carboxylate 39 (0.083 g, 59%) as a yellow solid: mp
109–111 ꢁC; nmax (film)/cmꢀ1: 1724 (C]O) and 1601
1
mp 61–63 ꢁC; nmax (film)/cmꢀ1: 1737 (C]O); H NMR
1
(300 MHz, CDCl3, Me4Si) 1.23 (3H, t, J¼7.2 Hz,
CH3CH2), 4.19 (2H, q, J¼7.1 Hz, CH3CH2), 4.87 (2H, s,
O]CCH2N), 6.63 (1H, s, 3-H), 7.08–7.21 (3H, m,
3ꢂArH) and 7.53 (1H, d, J¼7.7 Hz, ArH); 13C NMR
(75 MHz, CDCl3) 14.1 (CH2CH3), 46.0 (O]CCH2N),
61.7 (CH3CH2), 105.1 (CH), 109.0 (CH), 113.4 (C), 120.0
(CH), 120.6 (CH), 122.2 (CH), 128.1 (C), 136.9 (C) and
167.9 (OC]O); MS m/z (EI): 281 (M+, 19%), 213 (15),
210 (35), 208 (36), 201 (35), 143 (12), 129 (19), 128 (10),
127 (18), 115 (66), 87 (15), 81 (41), 69 (14), 43 (21), 41
(100), 39 (13), 29 (42), 28 (18) and 27 (10); HRMS
C12H12NO279Br requires: 281.0051, found: 281.0052.
(ArC]C); H NMR (300 MHz, CDCl3, Me4Si) 1.41 (3H,
t, J¼7.1 Hz, CH3CH2), 4.51 (2H, q, J¼7.1 Hz, CH3CH2),
7.12 (1H, s, 3-H), 7.17–7.26 (3H, m, 3ꢂArH), 7.30–7.38
(1H, m, ArH), 7.44–7.53 (2H, m, 2ꢂArH), 7.61 (1H, d,
J¼8.2 Hz, ArH), 7.74 (1H, d, J¼7.6 Hz, ArH) and 8.07
(1H, d, J¼7.9 Hz, ArH); 13C NMR (75 MHz, CDCl3) 14.2
(CH3CH2), 62.2 (CH3CH2), 95.4 (CH), 113.8 (CH), 115.2
(CH), 120.7 (CH), 121.0 (CH), 122.2 (CH), 123.4 (CH),
126.9 (C), 127.3 (C), 127.7 (CH), 127.8 (CH), 128.8 (C),
129.2 (CH), 129.3 (C), 131.7 (C), 135.5 (C) and 164.1
(OC]O); MS m/z (EI): 289 (M+, 100%), 261 (67), 216
(19), 187 (5), 131 (7) and 108 (8); HRMS C19H15NO2 re-
quires: 289.1103, found: 289.1081.
4.2.21. Ethyl 2-[2-(2-formylphenyl)-1H-indol-1-yl]ace-
tate 36b. Pd(PPh3)4 (0.11 g, 0.089 mmol, 10 mol %) was
added to a flame dried round bottom flask equipped with
a condenser and dropping funnel. Bromide 34b (0.25 g,
0.89 mmol), 2-formylphenylboronic acid 35 (0.20 g,
1.14 mmol) and DME (2.6 cm3) were combined in the drop-
ping funnel and degassed before adding to the flask. A 2 M
Na2CO3 solution (0.47 g, 4.45 mmol, 5 equiv) was added to
the dropping funnel, degassed and then added to the flask.
The dropping funnel was closed and the resulting mixture
was degassed once more before refluxing for 10 min. Water
(10 cm3) was added and the solution was extracted with
EtOAc (3ꢂ20 cm3). The organic layers were combined
and dried over anhydrous MgSO4. The solvent was removed
in vacuo and the residue was purified by silica gel column
chromatography (2% EtOAc/hexane) to afford ethyl 2-(2-
(2-formylphenyl)-1H-indol-1-yl)acetate 36b as an orange
4.2.23. 1-[2-Benzyl-3-1H-pyrrol-2-ylphenyl]-1-ethanone
41a. A solution of 1-benzyl-2-bromo-1H-pyrrole 4035
(0.350 g, 1.48 mmol) in DME (4 cm3) was deoxygenated
by passing nitrogen through the mixture for 5 min. The solu-
tion was then added to Pd(PPh3)4 (10 mol %, 0.170 g,
0.15 mmol) and stirred under an atmosphere of N2 for
10 min at rt. A solution of 2-acetylphenylboronic acid
(0.365 g, 2.22 mmol) in EtOH (2.6 cm3) was deoxygenated
and added to the reaction mixture. The mixture was stirred
for further 10 min. A deoxygenated 2 M aq Na2CO3 solution
(6.3 cm3, 12.6 mmol) was then added to the reaction mix-
ture, which was stirred at rt for further 5 min before being
heated at reflux for 2 days. The mixture was cooled to rt
and quenched with H2O (20 cm3) after which the organic
material was extracted with CH2Cl2 (3ꢂ30 cm3) and the
solvent was evaporated under reduced pressure. The crude

A. N. C. Lo€tter et al. / Tetrahedron 63 (2007) 2263–2274
2273
product was subjected to column chromatography (5–10%
EtOAc/hexane) to afford the product 1-[2-benzyl-3-1H-
pyrrol-2-ylphenyl]-1-ethanone 41a as a yellow oil (0.335 g,
82%); nmax (film)/cmꢀ1: 1682 (C]O), 1597 (ArC]C) and
709; 1H NMR (300 MHz, CDCl3, Me4Si) 1.86 (3H, s,
ArCOCH3), 4.91 (2H, s, CH2), 6.15–6.17 (1H, m, ArH),
6.24–6.26 (1H, m, ArH), 6.79–6.80 (1H, m, ArH), 6.88–
6.90 (2H, m, 2ꢂArH), 7.19–7.27 (4H, m, 4ꢂArH), 7.38–
7.42 (2H, m, 2ꢂArH) and 7.56–7.59 (1H, m, ArH); 13C
NMR (75 MHz, CDCl3) 28.9 (ArCOCH3), 50.9 (CH2),
108.8 (CH), 111.0 (CH), 122.8 (CH), 127.0 (2ꢂCH),
127.5 (CH), 127.8 (CH), 127.9 (CH), 128.2 (C), 128.5
(2ꢂCH), 130.6 (CH), 131.3 (CH), 131.7 (C), 137.8 (C),
141.8 (C) and 204.1 (C]O); MS m/z (EI): 275 (M+, 96%),
232 (49), 198 (45), 192 (20), 184 (63), 156 (60) and 91
(100); HRMS calcd for C19H17NO: 275.1310, found:
275.1320.
The mixture was then filtered, evaporated and subjected to
column chromatography (5–10% EtOAc/hexane) to afford
the product 6-methyl-5-phenylpyrrolo[2,1-a]isoquinoline
43a (0.014 g, 74%) as a pale yellow oil; nmax (film)/cmꢀ1
:
1655 and 1613 (ArC]C); 1H NMR (300 MHz, CDCl3,
Me4Si) 2.22 (3H, s, ArCH3), 6.56–6.58 (1H, m, ArH),
6.66–6.68 (1H, m, ArH), 6.99–7.01 (1H, m, ArH), 7.38–
7.58 (7H, m, 7ꢂArH), 7.75 (1H, d, J¼8.2 Hz, ArH) and
8.10 (1H, d, J¼7.8 Hz, ArH); 13C NMR (75 MHz, CDCl3)
14.8 (ArCH3), 99.8 (CH), 110.7 (CH), 114.1 (C), 114.8
(CH), 122.1 (CH), 124.0 (CH), 125.4 (CH), 126.0 (C),
127.0 (CH), 128.0 (C), 128.9 (CH), 129.2 (2ꢂCH), 130.1
(2ꢂCH), 133.5 (C) and 135.0 (2ꢂC); MS m/z (EI): 259
(M+, 28%), 257 (100), 256 (46), 254 (21), 241 (17) and
121 (8); HRMS calcd for C19H15N: 257.1205, found:
257.1205.
4.2.26. 2-(1-Benzyl-1H-pyrrol-2-yl)benzaldehyde 41b. A
solution of 1-benzyl-2-bromo-1H-pyrrole 40 (0.305 g,
1.29 mmol) in DME (6 cm3) was deoxygenated by passing
N2 through the mixture for 5 min. The solution was then
added to Pd(PPh3)4 (10 mol %, 0.146 g, 0.13 mmol) and
stirred under an atmosphere of N2 for 10 min at rt. A solution
of 2-formylphenylboronic acid (0.38 g, 1.9 mmol) in ethanol
(2.3 cm3) was deoxygenated and added to the reaction mix-
ture. The mixture was stirred for further 10 min. A deoxy-
genated 2 M aq Na2CO3 solution (5.4 cm3, 10.8 mmol)
was then added to the reaction mixture, which was stirred
at rt for further 5 min before being heated at reflux for 2
days. The reaction mixture was cooled to rt and quenched
with H2O (20 cm3) after which the organic material was
extracted with CH2Cl2 (3ꢂ30 cm3) and then the organic
solvent was evaporated under reduced pressure. The crude
product was subjected to column chromatography (5–10%
EtOAc/hexane) to afford the product 2-(1-benzyl-1H-pyr-
rol-2-yl)benzaldehyde as a yellow oil 41b (0.172 g, 52%);
4.2.24. 6-Methyl-5-phenyl-5,6-dihydropyrrolo[2,1-a]iso-
quin-6-ols 42a and 42b. KOtBu (0.164 g, 1.50 mmol) was
added to 1-[2-benzyl-3-1H-pyrrol-2-ylphenyl]-1-ethanone
41a (0.103 g, 0.37 mmol) dissolved in dry DMF (10 cm3)
and heated under N2 at 80 ꢁC. The reaction mixture was
quenched by adding H2O (50 cm3) and the organic material
was extracted with Et2O (3ꢂ50 cm3). The organic layer was
dried over MgSO4 and filtered. The organic solvent was then
evaporated in vacuo and the residue was subjected to column
chromatography (5–20% EtOAc/hexane) to afford firstly the
product 42a (0.056 g, 56%) as a yellow oil; nmax (film)/
1
cmꢀ1: 3401 (OH) and 1605 and 1580 (ArC]C); H NMR
(300 MHz, CDCl3, Me4Si) 1.50 (3H, s, CH3), 1.54 (1H, s,
OH), 5.15 (1H, s, CH), 6.24–6.26 (1H, m, ArH), 6.66–6.68
(2H, m, 2ꢂArH), 7.01–7.05 (2H, m, 2ꢂArH), 7.14–7.23
(4H, m, 4ꢂArH), 7.25–7.44 (2H, m, 2ꢂArH) and 7.66–
7.69 (1H, m, ArH); 13C NMR (75 MHz, CDCl3) 23.9
(CH3), 70.2 (CH), 73.0 (C), 104.8 (CH), 109.7 (CH), 121.9
(CH), 122.8 (CH), 124.9 (CH), 126.3 (CH), 127.9 (2ꢂCH),
128.2 (CH), 128.3 (C), 128.4 (2ꢂCH), 128.8 (CH), 134.1
(C) and 137.3 (2ꢂC); MS m/z (EI): 275 (M+, 100%), 274
(33), 232 (28), 198 (23) and 156 (36); HRMS calcd for
C19H17NO: 275.1310, found: 275.1311.
1
nmax (film)/cmꢀ1: 1693 (C]O) and 1599 (ArC]C); H
NMR (300 MHz, CDCl3, Me4Si) 5.00 (2H, s, CH2), 6.23–
6.32 (2H, m, 2ꢂArH), 6.81–6.88 (3H, m, 3ꢂArH), 7.18–
7.24 (3H, m, 3ꢂArH), 7.33 (1H, d, J¼6.9 Hz, ArH), 7.35–
7.46 (1H, m, ArH), 7.51–7.57 (1H, m, ArH), 7.93 (1H, dd,
J¼1.1 and 7.7 Hz, ArH) and 9.81 (1H, s, CHO); 13C NMR
(75 MHz, CDCl3) 51.1 (CH2), 108.5 (CH), 113.5 (CH),
123.6 (CH), 126.6 (2ꢂCH), 127.3 (CH), 127.6 (CH),
128.1 (CH), 128.6 (2ꢂCH and one C), 131.6 (CH), 133.2
(CH), 135.4 (C), 136.6 (C), 137.9 (C) and 192.3 (CHO);
MS m/z (EI): 261 (M+, 91%), 233 (37), 179 (25), 170 (97),
156 (54) and 91 (100); HRMS calcd for C18H15NO:
261.1154, found: 261.1154.
The second product 42b was also isolated as a yellow oil
(0.023 g, 23%); nmax (film)/cmꢀ1: 3448 (OH), 1605 and
1579 (ArC]C); H NMR (300 MHz, CDCl3, Me4Si) 1.58
1
(3H, s, CH3), 1.63 (1H, s, OH), 5.06 (1H, s, CH), 6.25–
6.26 (1H, m, ArH), 6.64–6.67 (2H, m, 2ꢂArH), 6.82–6.93
(2H, m, 2ꢂArH), 7.11–7.19 (4H, m, 4ꢂArH), 7.24–7.31
(1H, m, ArH), 7.43 (1H, d, J¼7.7 Hz, ArH) and 7.61 (1H,
d, J¼7.7 Hz, ArH); 13C NMR (75 MHz, CDCl3) 29.7
(CH3), 68.9 (CH), 73.4 (C), 104.5 (CH), 109.8 (CH), 121.5
(CH), 122.0 (CH), 124.2 (CH), 126.4 (CH), 127.5 (C),
127.7 (2ꢂCH), 127.9 (CH), 128.3 (CH), 128.6 (C), 128.6
(2ꢂCH), 136.4 (C) and 136.9 (C); MS m/z (EI): 275 (M+,
94%), 257 (37), 232 (31), 198 (28), 156 (48), 91 (47), 86
(85) and 84 (100); HRMS calcd for C19H17NO: 275.1310,
found: 275.1311.
4.2.27. 5-Phenylpyrrolo[2,1-a]isoquinoline 43b. KOtBu
(0.086 g, 0.76 mmol) was added to 2-(1-benzyl-1H-pyrrol-
2-yl)benzaldehyde 41b (0.050 g, 0.19 mmol) dissolved in
dry DMF (9 cm3) and heated under N2 at 80 ꢁC for
10 min. The reaction mixture was quenched with H2O
(50 cm3) and then extracted with Et2O (3ꢂ50 cm3). The or-
ganic layer was dried over MgSO4 and filtered. The organic
layers were then evaporated and subjected to column chro-
matography (5–20% EtOAc/hexane) to afford the product
5-phenylpyrrolo[2,1-a]isoquinoline 43b (0.032 g, 68%) as
a yellow oil; nmax (film)/cmꢀ1: 1635 and 1557 (ArC]C);
1H NMR (300 MHz, CDCl3, Me4Si) 6.68–6.70 (2H, m,
2ꢂArH), 7.04 (1H, m, ArH), 7.04–7.06 (1H, m, ArH),
4.2.25. 6-Methyl-5-phenylpyrrolo[2,1-a]isoquinoline 43a.
To a solution of 6-methyl-5-phenyl-5,6-dihydropyrrolo[2,1-
a]isoquin-6-ol 42b (0.020 g, 0.07 mmol) in CH2Cl2 (5 cm3)
were added molecular sieves and pTSA (15 mol %, 0.001 g,
0.004 mmol). The reaction mixture was stirred at rt for 18 h.

2274
A. N. C. Lo€tter et al. / Tetrahedron 63 (2007) 2263–2274
17. Elwan, N. M.; Abdelhadi, H. A.; Abdullah, T. A.; Hassaneen,
H. M. Tetrahedron 1996, 52, 3451.
18. Hershenson, F. M. J. Org. Chem. 1975, 40, 740.
19. Zhao, B.-X.; Yu, Y.; Eguchi, S. Tetrahedron 1996, 52, 12049.
20. Katritzky, A. R.; Qiu, G.; Yang, B.; He, H.-Y. J. Org. Chem.
1999, 64, 7618.
21. de Koning, C. B.; Michael, J. P.; Pathak, R.; van Otterlo,
W. A. L. Tetrahedron Lett. 2004, 45, 1117.
22. For example see: de Koning, C. B.; Michael, J. P.; Nhlapo, J.;
Pathak, R.; van Otterlo, W. A. L. Synlett 2003, 705.
23. The work in this paper is taken from the Ph.D. of R. Pathak,
University of the Witwatersrand, November 2004, the M.Sc.
7.31–7.36 (1H, m, ArH), 7.37–7.57 (5H, m, 5ꢂArH), 7.64–
7.67 (2H, m, 2ꢂArH) and 8.06 (1H, d, J¼8.0 Hz, ArH); 13C
NMR (75 MHz, CDCl3) 110.4 (CH), 111.4 (CH), 111.5
(CH), 114.1 (CH), 121.9 (CH), 125.5 (C), 125.6 (CH),
125.8 (C), 126.8 (CH), 127.2 (CH), 127.3 (C), 128.8
(2ꢂCH), 128.9 (2ꢂCH), 129.2 (CH), 135.3 (C) and 136.6
(C); MS m/z (EI): 243 (M+, 100%), 220 (21), 205 (63) and
170 (14); HRMS calcd for C18H13N: 243.1048, found:
243.1048.
Acknowledgements
€
of A. N. C. Lotter, April 2006 and the ongoing M.Sc. of T. S.
Sello, University of the Witwatersrand.
This work was supported by the National Research Founda-
tion (NRF, GUN 2053652), Pretoria, and the University of
the Witwatersrand (University Research Council). T.S.S.
thanks the NRF for a scarce skills bursary. We thank Prof.
J. P. Michael for many helpful discussions. Mr. R. Mampa
and Mr. T. van der Merwe are also thanked for providing
the NMR and MS spectroscopy services, respectively.
24. Crystal data for 17a: C21H17NO, M¼299.36, monoclinic,
˚
˚
˚
a¼13.5387(17) A, b¼8.8623(11) A, c¼13.8000(18) A, U¼
3
˚
1602.0(4) A , T¼293(2) K, space group P2(1)/n, Z¼4, m(Mo
Ka)¼0.076 mmꢀ1; 9101 reflections measured, 3140 unique
[R(int)¼0.0291], which were used in all calculations. Final R
indices [I>2s(I)], R1¼0.0705, wR(F2)¼0.2051. CCDC num-
ber: 612525.
25. de Koning, C. B.; Michael, J. P.; Rousseau, A. L. J. Chem. Soc.,
Perkin Trans. 1 2000, 787.
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