Palladium-catalyzed intramolecular C-H amidation: Synthesis and biological activities of indolobenzazocin-8-ones

Article abstract of DOI:10.1016/j.tet.2012.10.011

The synthesis of multi ring-fused indolobenzazocinone derivatives, an antimitotic agent, has been carried out using palladium-catalyzed C-H activation/intramolecular amidation of benzo[d]azocinones, which were synthesized by the ring annulations of dihydroisoquinolines and azlactone in refluxing acetonitrile. The target compounds, indolobenzazocin-8-one derivatives, were evaluated for their cytotoxicity against the cancer cell lines HUCCA-1, A549, HepG2, and MOLT-3. The results showed that an unsubstituted indolobenzazocin-8-one 1e exhibited very good activities in the nanomolar IC₅₀ value range (HepG2 and MOLT-3).

Full text of DOI:10.1016/j.tet.2012.10.011

Tetrahedron 68 (2012) 10293e10301
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed intramolecular CeH amidation: synthesis and biological
activities of indolobenzazocin-8-ones
,
b
,
,b
Sasiwadee Boonya-udtayan a, Meredith Eno b, Somsak Ruchirawat a c, Chulabhorn Mahidol a
,
,b,c,
Nopporn Thasana a
*
a Program on Chemical Biology, Chulabhorn Graduate Institute, Laksi, Bangkok 10210, Thailand
b Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand
c Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, Bangkok, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 June 2012
Received in revised form 13 September 2012
Accepted 2 October 2012
Available online 9 October 2012
The synthesis of multi ring-fused indolobenzazocinone derivatives, an antimitotic agent, has been carried
out using palladium-catalyzed CeH activation/intramolecular amidation of benzo[d]azocinones, which
were synthesized by the ring annulations of dihydroisoquinolines and azlactone in refluxing acetonitrile.
The target compounds, indolobenzazocin-8-one derivatives, were evaluated for their cytotoxicity against
the cancer cell lines HUCCA-1, A549, HepG2, and MOLT-3. The results showed that an unsubstituted
indolobenzazocin-8-one 1e exhibited very good activities in the nanomolar IC50 value range (HepG2 and
MOLT-3).
Keywords:
Indolobenzazocinone
Benzo[d]azocinone
Pd-catalyzed CeH activation
Amidation
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Antitumor agent
1. Introduction
categorized as antimitotic agents.7 This methodology involved
Suzuki coupling and lactamization steps. They also synthesized
Benzazocinone belongs to a class of alkaloid displaying a wide
range of biological activities including hepatoprotective activity
against chemical toxin and antiamnesia as well as acting as in-
hibitors of tubulin polymerization.1 Recently our group reported
a facile and convenient protocol based on ring annulations of
dihydroisoquinoline with azlactone to synthesize benzo[d]azocin-
4-ones 1.2 This protocol served as a useful template for the syn-
thesis of eight-membered ring molecules. In our continuing in-
terest concerning the application of this protocol, we focused our
attention to the synthesis of indolobenzazocinone analogues from
benzo[d]azocin-4-one derivatives. Indolobenzazocinone 2c is
closely related to some natural products and other biologically
active compounds, such as indolobenzazepinones (with C5
substituted group) 3, an antimitotic agent,3 latonduine 4, a cyto-
toxic agent,4 and their regioisomers, paullones 5, which act as
cyclin-dependent kinase inhibitors (Fig. 1).5
compounds with different substitution pattern 3b at C5 position by
using the application of an isocyanide-based multicomponent re-
actions (MCRs).3
In 2007, Joseph reported the synthesis of indolobenzazepinones
2b using the intramolecular Heck reaction.6 Similarly, Dodd
revealed that the C5-alkylated indolobenzazepinones (3a) showed
high cytotoxicity against various cancer cell lines and were
* Corresponding author. E-mail address: nopporn@cri.or.th (N. Thasana).
Fig. 1. Indolobenzazepinone derivatives and some related natural compounds.
0040-4020/$ e see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.011

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S. Boonya-udtayan et al. / Tetrahedron 68 (2012) 10293e10301
Recently, Joseph and colleagues reported the synthesis and SAR
studies involving six-, seven-, eight- and nine-membered ring de-
rivatives of indolobenzazepinones. The result showed that almost
all of them exhibited good potency in both cell-based and target-
based assays, especially, 5,6,7,9-tetrahydro-8H-indolo[2,3-e][3]
benzazocin-8-one 2c.8 Moreover, the molecular modeling of indo-
lobenzazepinones was also studied in comparison with tubulin
polymerization inhibitor colchicine.8 To accomplish these target
indolobenzazocinones 6, we have elaborated not only the con-
densation of various dihydroisoquinolines with azlactone but also
investigated the CeN bond formation involving palladium-
catalyzed intramolecular CeH amidation as depicted in Scheme 1.
Table 1
Synthesis of 5-amido-8,9-dimethoxy-6-aryl-2,3-dihydrobenzo[d]azocin-4-ones 1a
Entry
1
Dihydroisoquinolines 7
Products 1
Yield [%]
MeO
MeO
MeO
NH
N
1a, 74a
MeO
O
7a
O
HN
Ph
MeO
MeO
MeO
NH
N
O
MeO
O
2
3
7b
1b, 39a
HN
Ph
OMe
OMe
OMe
MeO
MeO
MeO
MeO
NH
N
MeO
O
O
7c
HN
1c, 40a
Ph
OMe
MeO
MeO
MeO
MeO
MeO
NH
N
O
MeO
O
4
5
7d
1d, 48a
HN
Ph
Scheme 1. Retrosynthetic plan for the synthesis of indolobenzazocin-8-one
derivatives.
MeO
OMe
OMe
NH
During the past decade, Pd-catalyzed CeH activation9 has
played a significant role in construction of the desired CeC, CeO,
CeS, CeX bond formation and particularly the formation of CeN
bond, as pioneered by Buchwald and co-workers.10 The advantage
of this approach is the support of green chemistry because reducing
the number of steps as well as improving atom economy led to an
increase in overall efficiency.11 Accordingly, Pd-catalyzed CeN bond
formation has attracted attention from many research groups.9,10,12
Herein, this chemistry was used as the first time application to
establish biologically active indolobenzazocinone derivatives.
N
7e
1e, 37a
O
O
HN
Ph
BnO
MeO
BnO
NH
N
O
MeO
O
6
7f
1f, 40b
HN
Ph
OMe
OMe
MeO
MeO
BnO
MeO
NH
N
BnO
7
8
7g
1g, 37b
O
O
2. Results and discussion
HN
Ph
OMe
Ten analogues of dihydroisoquinolines 7aej were first in-
vestigated to expand our developed protocol.2,13 Various dihy-
droisoquinolines 7 were prepared from different arylethylamines
and various benzoic acids and nicotinic acid to generate amides
followed by BischlereNapieralski reaction.2 Only dihy-
droisoquinoline 7e was prepared using the Movassaghi’s method.14
Azlactone 8 was obtained from hippuric acid, as previously re-
ported.2,15 With both key starting materials in hand, we studied the
ring annulations of dihydroisoquinolines 7aej with azlactone 8 in
refluxing acetonitrile under dry conditions to afford compounds
1aei in moderate yields (30e74%) as shown in Table 1.
Notably, beta-lactam intermediate 9j was isolated in 45% yield
(Table 1, entry 10).16 This supported our previously proposed
mechanism that beta-lactams are intermediates in the formation of
benzo[d]azocinones.2 Furthermore, the isolation of beta-lactam 9j
shed some lights on the mechanism of ring expansion. Possible
pathway might involve ring expansion via the carbocation 10 and
the carbocation must be stabilized by both adjacent phenyl groups.
In the case of beta-lactam 9j ring expansion was not possible
BnO
N
MeO
7h
1h, 30a
OMe
OMe
BnO
BnO
MeO
NH
N
9
7i
1i, 58a
9j, 45a
MeO
O
O
HN
Ph
N
N
MeO
10
7j
N
MeO
Br
a
Products were purified by crystallization.
b
Products were purified by column chromatography.

S. Boonya-udtayan et al. / Tetrahedron 68 (2012) 10293e10301
10295
Table 2
because the ortho bromo substituent would interfere with the
Pd-catalyzed CeH activationa
stability of carbocation via steric inhibition to resonance owing to
the loss of co-planarity as shown in Scheme 2. Under refluxing
toluene, a higher boiling point solvent, compound 9j underwent
retro-ring annulation reaction and imine 7j was isolated.
Entry Pd(II)
Re-oxidant
(equiv)
Temp (ꢀC) Time (h) Yield [%] SM [%]
12a 6a
b
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Cu(OAc)2 (1)/
AgOCOCF3 (2)
Cu(OAc)2 (3)/
AgOCOCF3 (6)
Cu(OAc)2 (3)/ 100
AgOCOCF3 (6)
50
24
144
24
21
37
13
42
54
72
71
60
71
d
d
33
d
26
12
7
67
d
d
20
d
d
4
Pd(OAc)2
Pd(OAc)2
50
Pd(OCOCF3)2 Cu(OAc)2 (3)/
AgOCOCF3 (6)
Pd(OCOCF3)2 Cu(OAc)2 (3)/
AgOCOCF3 (6)
Pd(OCOCF3)2 Cu(OAc)2 (3)/
AgOCOCF3 (6)
50
50
80
80
80
80
24
44
20
PdCl2
Cu(OAc)2 (3)/
AgOCOCF3 (6)
16
Scheme 2. Proposed mechanism for the formation of compounds 1 and 9.
PdCl2(PPh3)2 Cu(OAc)2 (3)/
AgOCOCF3 (6)
Pd2(dba)3
16
8
19
19
Moreover, the presence of electron-donating group R1 of dihy-
droisoquinoline 7 may facilitate the ring expansion step but it is not
an absolute requirement since we could prepare unsubstituted
benzo[d]azocinone 1e in moderate yield (Table 1, entry 5).
Benzo[d]azocinones 1aei thus obtained were further in-
vestigated as precursors for the indolobenzazocinones 6.
Palladium-catalyzed CeH activation chemistry and hydrolysis were
studied with the aim to form the CeN bond followed by deben-
zoylation. We began to study the formation of the CeN bond by
screening the catalytic system using benzo[d]azocinone 1a as the
substrate.
Cu(OAc)2 (3)/
AgOCOCF3 (6)
16
8
10
11
12
13
14
Pd(OCOCF3)2 Cu(OAc)2 (3)
Pd(OCOCF3)2 AgOCOCF3 (3)
Pd(OCOCF3)2 Cu(OAc)2 (1)
Pd(OCOCF3)2 Cu(OAc)2 (0.3) 80
Pd(OCOCF3)2 Cu(OAc)2 (0.1) 80
80
80
80
54
54
5
42
89
68
17
73
68
21
7
d
d
64
d
d
72
2
6
d
a
All reactions were performed with 0.3 equiv of palladium catalyst in 0.05 M
DMSO under argon atmosphere except entries 10e14, the reactions were done
under O2 atmosphere.
b
Pd(OAc)2 (0.1 equiv) was required. SM¼Starting material.
12. The debenzoylated product 6a, which is sometimes, obtained in
low yield, likely to be formed via simple benzoyl cleavage as
depicted.
Hiroya12b and co-workers reported the synthesis of indazole
derivatives using the palladium-catalyzed CeH activation and CeN
bond formation. We initially attempted to modify Hiroya’s con-
ditions using 0.1 equiv of Pd(OAc)2, 1.0 equiv of Cu(OAc)2, and
2.0 equiv of AgOCOCF3 in 0.05 M DMSO at 50 ꢀC under argon at-
mosphere and obtained the desired indolobenzazocinone 12a in
21% yield (Table 2, entry 1). Increasing the amount of catalyst and
longer reaction time gave no significant increase in the yield of
product 12a (Table 2, entry 2). A mixture of indolobenzazocinone
12a and hydrolyzed product 6a was obtained when the reaction
temperature was increased to 100 ꢀC (Table 2, entry 3). When the
palladium catalyst was changed to Pd(OCOCF3)2 more promising
results were obtained (Table 2, entries 4e5). Increasing the re-
action temperature to 80 ꢀC gave a better yield in a shorter re-
action time (Table 2, entry 6). We then optimized the reaction
condition by screening other palladium catalysts and achieved the
target product in the range of 60e71% yield (Table 2, entries 7e9).
We also studied the re-oxidant and the use of atmospheric oxygen
for oxidation, as reported by Buchwald.10 Interestingly, using an
oxygen atmosphere could eliminate the use of AgOCOCF3 and gave
the product in 68% yield (Table 2, entry 10) while using only
AgOCOCF3 without co-oxidant Cu(OAc)2 under an O2 atmosphere
gave a very poor yield of 12a (Table 2, entry 11). The catalytic
amount of co-oxidant was also studied and found that 0.3 equiv of
Cu(OAc)2 was enough to mediate the reaction whereas 0.1 equiv of
Cu(OAc)2 was insufficient to complete the reaction (Table 2, en-
tries 12e14).
Scheme 3. Proposed mechanism for the formation of 12a and 6a.
With effective conditions for the synthesis of indolobenzazoci-
none 1a, we then directed our attention to the synthesis of a small
library of indolobenzazocinone analogues using Pd(OCOCF3)2 as the
catalyst and Cu(OAc)2 as the re-oxidant under the oxygen atmo-
sphere. An increased amount of Cu(OAc)2 was necessary for the
The postulated reaction pathway of Pd-catalyzed CeH amida-
tion for benzo[d]azocinones cores is depicted in Scheme 3.12b The
amide nitrogen atom could complex to Pd(OCOCF3)2 and release
trifluoroacetic acid (TFA) followed by the formation of palladacycle
15. Subsequent reductive elimination could generate the product

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S. Boonya-udtayan et al. / Tetrahedron 68 (2012) 10293e10301
higher oxygenated analogues 1bei in the context of decreasing
reaction time and obtaining optimal yield (Table 3). In addition, in
some cases, increasing the amount of palladium catalyst to
0.5 equiv was required to obtain higher yield (Table 3, entry 7). We
reasoned that the steric hindrance makes it difficult to incorporate
the palladium species in the six-membered palladacycle complexes
as shown in the postulated mechanism (Scheme 3).
With the success of Pd(II)-catalyzed CeH amidation of com-
pounds 1, we then turned our attention to find a way to effect the
transformation of compounds 1 to indolobenzazocinones 6 in one
pot. To effect such transformation, 4 N NaOH in H2O was added to
the crude products to hydrolyze the amide group to give com-
pounds 6 in moderate to good yields as shown in Table 4.
Table 4
Pd-catalyzed CeH activation and hydrolysisa
Table 3
Pd-catalyzed CeH activationa
Entry
1
SM
Cu(OAc)2 (equiv)
0.3
Time (h)
22
Products
Yield [%] 6
a, 83
Entry SM
Cu(OAc)2 Time (h)
(equiv)
Products
Yield [%]
1a
12 (R¼Bz) 6 (R¼H)
1
1a
0.3
42
a, 68
a, 6
2
3
1b
1c
0.6
0.6
20
22
b, 60
c, 60
2
3
4
5
6
7
8
1bd
1b
0.3
0.6
0.3
0.6
0.6
1
50
40
50
16
40
47
18
b, 25
b, 59
c, 31
c, 88
d, 14
d, 21
e, 91
b, 5
b, 6
d
1cd
1c
4
1db
1
40
d, 10
c, 7
d, 5
d, 7
d
1dd
1db,d
1e
5
6
1e
1f
0.6
0.6
42
15
e, 66
f, 67
0.6
9
1f
0.6
0.6
15
23
f, 49
f, 9
7
8
1g
1h
0.6
0.6
20
22
g, 54
h, 54
10
1g
g, 50
g, 3
11
12
1i
1i
0.6
1
20
20
d
d
NAc
NAc
d
d
a
All reactions were performed with 0.3 equiv Pd(OCOCF3)2 in 0.05 M DMSO at
80 ꢀC under O2 atmosphere and were monitored by TLC.
a
All reactions were performed with 0.3 equiv Pd(OCOCF3)2 in 0.05 M DMSO at
80 ꢀC under O2 atmosphere and were monitored by TLC.
b
Pd(OCOCF3)2 (0.5 equiv) was required.
b
Pd(OCOCF3)2 (0.5 equiv) was required.
Complex mixture of products were detected.
Starting materials were recovered as follows entry 2 (33%), entry 4 (39%), entry 6
c
d
Compounds 6feh required an additional step involving deben-
zylation in order to furnish indolobenzazocinone derivatives
16feh. The hydrogenolysis of compounds 6feh was conducted
using palladium on activated charcoal in ethyl acetate at 75 psi in
the Parr apparatus at room temperature to give the debenzylated
products 16feh in moderate to good yield (54e84%, Scheme 4).
Interestingly, all 1H NMR spectra of indolobenzazocinone de-
rivatives 6 and 16 showed the absence of two sets of methylene
protons at room temperature (Fig. 2, bottom). By decreasing the
operating temperature to ꢁ20 ꢀC, 1H NMR spectra of four methy-
lene protons appeared separately in the range of 2.6e4.0 ppm
(44%), and entry 7 (6%). SM¼Starting material.
Moreover, we found that steric effect played an important role
in the regioselectivity. Only the regioselective products were ob-
tained from unsymmetrical materials 1b,c and 1f,g, which were
confirmed by spectroscopic data. Unfortunately, the pyridine de-
rivative 1i gave no reaction even after increasing the amount of
Pd(OCOCF3)2 or Cu(OAc)2 (Table 3, entries 11e12). This could be due
to the complexation of pyridine nitrogen with the transition metal
rendering the catalyst inactive.17

S. Boonya-udtayan et al. / Tetrahedron 68 (2012) 10293e10301
10297
The results showed that unsubstituted indolobenzazocin-8-one
6e showed the highest IC50 values for all cancer cell lines tested as
compared to other substituted compounds. Compound 6e exhibi-
ted hepatoblastoma HepG2 in the lower micromolar range
(IC50¼0.46
mM) and T-lymphoblast (acute lymphoblastic leukemia)
MOLT-3 in nanomolar range (IC50¼9 nM) (Table 5, entry 5). The
presence of either methoxy or hydroxy groups at the C-4, C-5 or C-6
position of the indole ring and C-8 or C-9 of benzoazocinone ring
led to decreasing cytotoxic activity or becoming inactive, whereas
the presence of C-7 methoxy group of the indole ring in compound
6d led to modest cytotoxicity in both MOLT-3 and HepG2
Scheme 4. Debenzylation.
(IC50¼3.98e11.04
mM) (Table 5, entry 4). This study provided crucial
information about the role of the oxygenated substitution on
indolobenzazocin-8-one core skeleton in support of the previous
reports by Dodd and Joseph groups.8
3. Conclusion
In summary, we have reported the synthesis and biological ac-
tivities of indolobenzazocin-8-ones using ring annulations of vari-
ous dihydroisoquinolines with azlactone and Pd-catalyzed CeH
amidation. The method we have developed and reported here
should be applicable to the synthesis of other biologically active
indolobenzazocin-8-ones in just two steps and also capable of
constructing a wide range of related compounds with different
substitution patterns. Indolobenzazocin-8-one 6e exhibited very
good activities in the nanomolar IC50 value range as compared to
the oxygenated substitution on this core system. This study also
delineated the structureeactivity relationship studies involving
substitution patterns of the indolobenzazocin-8-ones.
Fig. 2. Selected 1H NMR spectra of compound 6a at ꢁ20 ꢀC (top) and 1H NMR spectra
of compound 6a at room temperature (bottom).
(Fig. 2, top). This phenomenon possibly resulted from the restricted
rotation of the secondary cyclic amide in this indolobenzazocin-8-
one system.18
4. Experimental section
4.1. General methods
As reported by Joseph and co-workers, indolobenzazocin-8-one
6e showed the most potent antiproliferative activity inhibiting cell
growth in several cancer cell lines in the nanomolar IC50 value
range.6 Our synthetic indolobenzazocinones 6aed and 16feh were
evaluated for cytotoxicity as compared with unsubstituted com-
pound 6e as cytotoxic agents on a panel of four human tumor cell
lines; cholangiocarcinoma HUCCA-1, lung carcinoma A549, hep-
atoblastoma HepG2, and T-lymphoblast (acute lymphoblastic leu-
kemia) MOLT-3 using MTT and XTT assays depending on the cell-
line types as shown in Table 5.
Melting points were measured with a Thermo Fisher Scientific
IA920 digital melting point apparatus and reported without cor-
rection. 1H Nuclear magnetic resonance (1H NMR) spectra were
recorded on Varion Germini2000, Bruker AV-300, and Bruker AV-
400 NMR instruments at 200, 300, and 400 MHz, respectively, us-
ing deuterochloroform as solvents with tetramethylsilane as an
internal standard. 13C Nuclear magnetic resonance (13C NMR)
spectra were recorded on Varion Germini2000, Bruker AV-300, and
Bruker AV-400 NMR instruments at 50, 75, and 100 MHz, re-
spectively, using deuterochloroform with tetramethylsilane as an
internal standard and dimethylsulfoxide-d6 for some compound.
FTIR spectra were obtained on the Spectrum One FTIR spectrome-
ter, Perkin Elmer System with the universal ATR (UATR) accessory.
Mass spectra were performed with an AEI-MS-902. High-resolution
mass spectra were performed with a MicroTOFLC, Bruker Daltonics.
Column chromatography was carried out using Fluka aluminum
oxide (type 507 C neutral; 100e125 mesh) and Merck silica gel
(70e230 mesh ASTM). Thin layer chromatography (TLC) and pre-
parative thin layer chromatography (PTLC) were carried out on
silica gel (E. Merck PF 254). All reagents were purified and dried
according to the standard procedures. Solvents were removed by
Table 5
Biological activities of synthetic indolobenzazocinone derivatives 6aee and 16feh
in MTT and XTT assaysa
Entry
Compounds
IC50 (mM)
HuCCA-1b,f
A549c,f
HepG2d,f
MOLT-3e,g
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
16f
16g
16h
Inactive
83.8
Inactive
Inactive
48.1
Inactive
71.0
Inactive
Inactive
12.6
96.23
39.8
122.1
11.04
0.46
69.80
84.79
99.65
29.8
44.50
17.12
71.7
3.98
0.009
26.6
102.8
66.4
Inactive
Inactive
ND
Inactive
124.26
ND
80.8
€
using Eyela Aspirator A-2S and Buchi Rotavapor R110. All products
25.98
0.047
ND
were evacuated by a Christ Freeze Dryer Unit Alpha l/6, to remove
the last traces of solvents.
Etoposide
Doxorubicin
10
0.83
0.63
0.57
ND¼Not determined.
a
4.2. General procedure for the preparation of benzo[d]azo-
cin-4-ones (1)
DMSO solution (10 mg/mL).
HuCCA-1: cholangiocarcinoma.
A549: lung carcinoma.
b
c
d
e
f
HepG2: hepatoblastoma.
MOLT-3: T-lymphoblast (acute lymphoblastic leukemia).
MTT assay.
XTT assay.
A solution of azlactone 8 (1 equiv) and 3,4-dihydroisoquinolines
7aej (1 equiv) in acetonitrile (6 mL/mmol of starting material) was
heated at reflux for 2 h. The resulting reaction was allowed cool to
g

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S. Boonya-udtayan et al. / Tetrahedron 68 (2012) 10293e10301
room temperature and was then concentrated under reduced
pressure. The crude product was further purified by re-
crystallization to furnish the desired product (37e74%).
(100), 91 (45), 77 (25). TOF-HRMS calcd for C33H31N2O5: 535.2228;
found 535.2226.
4.2.6. 5-Amido-6-(30-methoxylphenyl)-8-benzyloxy-9-methoxy-1,2-
dihydrobenzo[d]azocin-4-one (1g). Yellow amorphous (0.51 g, 37%
yield). Rf 0.53 (90% EtOAc/Hexane, two times). Mp: 212 ꢀC. IR
4.2.1. 5-Amido-6-(30-methoxylphenyl)-8,9-dimethoxy-1,2-dihydro-
benzo[d]azocin-4-one (1b). Pale yellow solid (1.15 g, 39% yield). Rf
0.33 (90% EtOAc/Hexane, two times). Mp: 191.2 ꢀC. IR (UATR): nmax
(UATR): nmax 3233, 1652, 1603, 1473 cmꢁ1 1H NMR (300 MHz,
.
3231, 1655, 1653 cmꢁ1. 1H NMR (200 MHz, CDCl3):
d
2.88e2.96 (m,
CDCl3): d 2.73e2.83 (m, 1H), 3.25e3.34 (m, 2H), 3.63 (s, 3H), 3.76 (s,
1H), 3.36e3.48 (m, 2H), 3.86e4.07 (m, 1H), 3.72 (s, 3H), 3.76 (s, 3H),
3H), 3.92e3.99 (m, 1H), 4.88 (q, J¼12.0 Hz, 2H), 6.06 (s, 1H), 6.60 (s,
3.87 (s, 3H), 4.06 (m, 1H), 5.99 (s, 1H), 6.63 (s, 1H), 6.68 (s, 1H),
2H), 6.67 (s, 1H), 6.71e6.79 (m, 2H), 7.15e7.39 (m, 9H), 7.59 (d,
6.83e6.96 (m, 3H). 13C NMR (50 MHz, CDCl3):
d
32.5, 41.7, 55.2, 55.9
J¼7.8 Hz, 2H), 8.37 (s, 1H). 13C NMR (75 MHz, CDCl3):
d 32.5, 41.5,
(2C), 112.1, 113.0, 113.5, 114.0, 120.2, 127.2 (2C), 128.6 (2C), 129.2
(2C), 130.3 (2C), 131.1, 132.0, 132.8, 139.6, 147.6, 148.8, 160.2, 164.5,
169.2; EI-MS: m/z (%) 458 (Mþ, 12), 298 (23), 105 (100); TOF-HRMS
calcd for C27H27N2O5: 459.1915; found 459.1925.
55.1, 55.9, 71.0, 112.6, 113.4, 113.8, 115.8, 120.2, 127.2 (5C), 127.6,
128.3 (3C), 128.5 (2C), 129.7, 130.2, 130.9, 132.0, 132.7, 136.8, 139.4,
146.6, 149.3, 160.0, 164.6, 169.4. EI-MS: m/z (%) 535 (MþHþ, 4), 534
(Mþ, 13), 374 (12), 105 (100), 91 (56), 77 (26). TOF-HRMS calcd for
C33H31N2O5: 535.2228; found 535.2211.
4.2.2. 5-Amido-6-(30,40-dimethoxylphenyl)-8,9-dimethoxy-1,2-
dihydrobenzo[d]azocin-4-one (1c). Pale yellow solid (1.84 g, 40%
yield). Rf 0.25 (90% EtOAc/Hexane, two times). Mp: 214 ꢀC. IR
4.2.7. 5-Amido-6-(20,30-dimethoxylphenyl)-9-benzyloxy-8-methoxy-
1,2-dihydrobenzo[d]azocin-4-one (1h). Yellow amorphous (0.33 g,
30% yield). Rf 0.43 (100% EtOAc). IR (UATR): nmax 3231, 1654,
(UATR): nmax 3320, 3227, 1652, 1649 cmꢁ1 1H NMR (200 MHz,
.
CDCl3):
d
2.87e2.98 (m, 1H), 3.39e3.48 (m, 2H), 3.72 (s, 3H), 3.80 (s,
1471 cmꢁ1 1H NMR (300 MHz, CDCl3):
. d 2.82e2.88 (m, 1H),
3H), 3.87 (s, 6H), 3.93e4.05 (m, 1H), 6.08 (br s, 1H), 6.63 (s, 1H), 6.69
3.33e3.48 (m, 2H), 3.69 (s, 3H), 3.89 (s, 3H), 3.96 (s, 3H), 4.10e4.16
(m, 1H), 5.13 (s, 2H), 5.96 (br s, 1H), 6.49 (s, 1H), 6.75 (s, 1H),
6.86e6.99 (m, 2H), 7.29e7.47 (m, 9H), 7.81 (d, J¼9.6 Hz, 2H), 9.34
(s,1H), 6.84 (s,1H), 6.89 (s, 2H) 7.35e7.72 (m, 5H), 8.54 (br s,1H). 13C
NMR (50 MHz, CDCl3): d 32.4, 41.7, 55.8, 55.9 (2C), 56.0, 111.2, 111.6,
112.0, 113.0, 121.0, 127.1 (3C), 127.8, 128.5, 128.5, 128.9, 129.2, 130.6,
131.4, 132.0, 132.8, 147.5, 148.7, 149.3, 164.5, 169.5. EI-MS: m/z (%)
488 (Mþ, 1), 105 (77), 77 (44), 69 (26), 57 (26). TOF-HRMS calcd for
C28H29N2O6: 489.2020; found 489.1994.
(br s, 1H). 13C NMR (75 MHz, CDCl3):
d 32.2, 41.3, 55.7, 55.9, 61.9,
70.9, 111.9, 114.0, 114.8, 122.5, 124.7, 127.2 (3C), 127.7 (2C), 128.3
(3C), 128.4 (2C), 129.6, 129.7, 131.8, 132.2, 132.3, 132.8, 136.8, 145.1,
147.9, 148.0, 153.1, 164.9, 169.5. EI-MS: m/z (%) 564 (Mþ, 2), 105
(100), 91 (47), 77 (23). TOF-HRMS calcd for C34H33N2O6: 565.2333;
found 565.2351.
4.2.3. 5-Amido-6-(30,50-dimethoxylphenyl)-8,9-dimethoxy-1,2-
dihydrobenzo[d]azocin-4-one (1d). Pale yellow solid (0.64 g, 48%
yield). Rf 0.33 (90% EtOAc/Hexane, two times). Mp: 214 ꢀC. IR
4.2.8. 5-Amido-6-(30-pyridyl)-9-benzyloxy-8-methoxy-1,2-dihydro-
benzo[d]azocin-4-one (1i). Pale yellow solid (0.29 g, 58% yield). Rf
0.20 (90% EtOAc/Hexane, two times). Mp: 200 ꢀC. IR (UATR): nmax
(UATR): nmax 3336, 3233, 1654, 1602 cmꢁ1 1H NMR (200 MHz,
.
CDCl3): d 2.85e2.95 (m, 1H), 3.31e3.50 (m, 2H), 3.73 (s, 3H), 3.77 (s,
3H), 3.88 (s, 3H), 3.96e4.10 (m, 1H), 6.15 (br s, 1H), 6.41 (d, J¼2.2 Hz,
3328, 3221, 1654 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 2.81e2.89 (m,
1H), 6.48 (d, J¼2.2 Hz, 2H), 6.61 (s, 1H), 6.70 (s, 1H), 7.37e7.51 (m,
1H), 3.26e3.53 (m, 2H), 3.72 (s, 3H), 4.01e4.16 (m, 1H), 5.14 (s, 2H),
5.95 (br s, 1H, NH), 6.61 (s, 1H), 6.73 (s, 1H), 7.23e7.52 (m, 8H),
7.57e7.69 (m, 3H), 8.32 (s, 1H), 8.50 (d, J¼3.9 Hz, 1H), 8.70 (s, 1H).
3H), 7.71 (dd, J¼8.6, 2.8 Hz, 2H). 13C NMR (50 MHz, CDCl3):
d 32.3,
41.5, 55.3 (2C), 55.8, 55.8, 99.9, 106.1 (2C), 112.0, 112.8, 127.1 (3C),
128.5 (2C), 129.1, 130.9, 132.0 (2C), 132.7, 140.1, 147.5, 148.8, 161.4
(2C), 164.6, 169.4. EI-MS: m/z (%) 489 (MþHþ, 1), 488 (Mþ, 3) 328
(10), 105 (100), 77 (35). TOF-HRMS calcd for C28H29N2O6: 489.2020;
found 489.2042.
13C NMR (75 MHz, CDCl3):
d 32.2, 42.1, 56.1, 71.1, 113.5, 114.8, 123.9,
127.2, 127.3 (4C), 128.0 (2C) 128.6 (2C), 128.7 (2C), 129.3, 129.4,
130.9, 132.3, 132.7, 136.1, 136.9, 148.5, 148.6, 149.0, 149.2, 165.1,
169.3. EI-MS: m/z (%) 506 (Mþ, 0), 105 (100), 91 (53), 77 (34). TOF-
HRMS calcd for C31H28N3O4: 506.2074; found 506.2071.
4.2.4. 5-Amido-6-phenyl-1,2-dihydrobenzo[d]azocin-4-one
(1e).
Pale yellow solid (51.2 mg, 58% yield). Rf 0.51 (90% EtOAc/Hexane,
4.2.9. 1-Amido-9b-(20-bromophenyl)-7,8-dimethoxy-1,4,5,9b-tetra-
hydro-2H-azeto[2,1-a]isoquinolin-2-one (9j). White solid (1.22 g,
45% yield). Rf 0.48 (90% EtOAc/Hexane). Mp: 157 ꢀC. IR (UATR): nmax
two times). Mp: 222 ꢀC. IR (UATR): nmax 3235, 1651 cmꢁ1. 1H NMR
(400 MHz, CDCl3):
5.77 (br s, 1H), 7.12e7.69 (m, 14H), 8.30 (s, 1H). 13C NMR (100 MHz,
CDCl3): 32.8, 41.5, 126.8, 127.3 (2C), 128.2 (3C), 128.3, 128.7 (3C),
d 3.00 (m, 1H), 3.37e3.53 (m, 2H), 4.13 (m, 1H),
1684, 1247 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 2.52e2.79 (m, 2H),
d
3.59e3.65 (m, 2H), 3.92 (s, 1H), 4.08 (s, 1H), 5.85 (d, J¼8.4 Hz, 1H),
129.1, 129.3, 129.4 (2C), 130.1, 132.2, 132.7, 136.8, 138.2, 139.1, 164.7,
169.2. EI-MS: m/z (%) 369 (MþHþ, 4), 368 (Mþ, 15), 219 (30), 208
(41), 105 (100), 77 (28); TOF-HRMS calcd for C24H21N2O2: 369.1598;
found 369.1600.
6.74 (s, 1H), 7.04e7.22 (m, 4H), 7.33e7.53 (m, 5H), 7.62 (dd, J¼7.8,
1.5 Hz, 1H), 7.93 (s, 1H, NH). 13C NMR (75 MHz, CDCl3):
d 26.5, 39.6,
56.0, 56.4, 66.6, 111.5, 111.6, 121.6, 126.7 (2C), 127.2 (2C), 127.7, 128.6
(2C), 129.8, 131.3, 131.9, 132.1, 133.4, 135.4 (2C), 147.8, 148.7, 166.3,
167.6. EI-MS: m/z (%) 506 (Mþ, 0), 508 (Mþ2Hþ, 0), 348 (7), 346
(27), 105 (100), 77 (63). TOF-HRMS calcd for C26H24BrN2O4:
507.0914; found 507.0928.
4.2.5. 5-Amido-6-(30-methoxylphenyl)-9-benzyloxy-8-methoxy-1,2-
dihydrobenzo[d]azocin-4-one (1f). Yellow amorphous (0.92 g, 40%
yield). Rf 0.58 (90% EtOAc/Hexane, two times). Mp: 214 ꢀC. IR
(UATR): nmax 3227, 1655, 1508, 1473 cmꢁ1
.
1H NMR (300 MHz,
4.3. General procedure for the preparation of N-benzoy-
lindolobenzazocinones (12aeg)
CDCl3): d 2.68e2.78 (m, 1H), 3.18e3.36 (m, 2H), 3.65 (s, 3H), 3.68 (s,
3H), 3.92e3.96 (m, 1H), 5.05 (s, 2H), 5.82 (br s, 1H), 6.57 (s, 1H), 6.62
(s, 1H), 6.75 (s, 1H), 6.77 (d, J¼9.0 Hz, 2H), 6.88 (d, J¼7.5 Hz, 1H),
7.20e7.43 (m, 9H), 7.58 (s, 1H), 7.59 (d, J¼7.8 Hz, 1H). 13C NMR
In a round bottle flask, mixture of benzo[d]azocinone 1, Pd(O-
COCF3)2 (0.3e0.5 equiv), Cu(OAc)2 (0.3e1 equiv) was evacuated
and refilled with Ar. Under argon atmosphere, DMSO (0.05 M) was
added via syringe and flask was again evacuated and refilled with
O2. The reaction mixture was then stirred at 70e80 ꢀC. The reaction
was monitored via TLC until completion. After being cooled to room
(75 MHz, CDCl3):
d 32.4, 41.7, 55.3, 56.1, 71.1, 113.5, 113.6, 114.0,
114.7, 120.3, 127.3 (4C), 127.9, 128.4, 128.6 (3C), 128.7 (2C), 129.2,
130.5, 131.7, 132.2, 132.8, 137.0, 139.6, 148.1, 148.3, 160.3, 164.6,
169.3. EI-MS: m/z (%) 535 (MþHþ, 3), 534 (Mþ, 9), 388 (24), 105

S. Boonya-udtayan et al. / Tetrahedron 68 (2012) 10293e10301
10299
temperature, the reaction mixture was filtered through Celite and
then extracted with EtOAc. Combined organic layer was washed
with water and dried over Na2SO4. The solvent was evaporated and
the residue was purified by PTLC (80%EtOAc/Hexane) to give
products 12.
(100 MHz, CDCl3):
d
32.8, 44.9, 114.7, 121.3,123.6, 126.6, 126.9, 127.6,
128.3 (3C), 128.5, 129.3 (2C), 129.6, 130.2, 131.5, 132.2, 132.8, 135.8,
137.4, 138.4, 165.1, 168.6. EI-MS: m/z (%) 368 (Mþ2Hþ, 6), 367
(MþHþ, 22), 366 (Mþ, 79), 105 (100), 77 (27). HRMS (microTOF) m/z
calcd for C24H19N2O2 (MþH)þ: 367.1441; found: 367.1435.
4.3.1. 9-Benzoyl-(2,3-dimethoxyl)-5,6,7,9-tetrahydroindolo[2,3-e][3]
benzazocin-8-one (12a). White solid (26.1 mg, 68% yield). Rf 0.43
(100% EtOAc). Mp: 255 ꢀC. IR (UATR): nmax 1687, 1647 cmꢁ1. 1H NMR
(200 MHz, CDCl3): 2.80e2.90 (m,1H), 3.24e3.51 (m, 2H), 3.70e3.80
(m, 1H), 3.90 (s, 3H), 3.96 (s, 3H), 5.78 (br s, 1H), 6.88 (s, 1H), 7.10 (s,
1H), 7.27e7.68 (m, 6H), 7.79e7.86 (m, 3H). 13C NMR (50 MHz,
4.3.6. 9-Benzoyl-(3-benzyloxyl-2,12-dimethoxyl)-5,6,7,9-tetrahydro-
indolo[2,3-e][3]benzazocin-8-one (12f). Yellow amorphous (50 mg,
49% yield). Rf 0.55 (100% EtOAc). IR (UATR): nmax 3660, 1683, 1647,
1513 cmꢁ1 1H NMR (300 MHz, CDCl3):
. d 2.63e2.67 (m, 1H),
3.06e3.32 (m, 2H), 3.58e3.60 (m, 1H), 3.71 (s, 3H), 3.79 (s, 3H), 5.11
(s, 2H), 5.82 (br s, 1H), 6.81 (s, 1H), 6.91 (d, J¼9.0 Hz, 1H), 6.96 (s,
1H), 7.01 (s, 1H), 7.20e7.46 (m, 8H), 7.63e7.69 (m, 3H). 13C NMR
CDCl3):
d 32.6, 45.0, 56.0, 56.1, 112.4, 113.1, 114.7, 121.2, 123.7, 123.8,
124.3, 126.6, 127.7, 128.3 (2C), 129.3 (2C), 129.8, 131.2, 132.7, 135.8,
138.4, 147.8, 149.0, 165.1, 168.6. EI-MS: m/z (%) 427 (MþHþ, 15), 426
(Mþ, 47), 304 (31), 293 (10),105 (100), 77 (55). HRMS (microTOF) m/
z calcd for C26H23N2O4 (MþHþ): 427.1652; found: 427.1651.
(75 MHz, CDCl3): d 32.6, 44.9, 55.7, 56.3, 71.1, 102.9, 113.5, 115.1,
115.9, 116.0, 123.6, 124.9, 127.4 (2C), 128.0 (2C), 128.4 (2C), 128.6,
128.7 (2C), 129.3, 129.9, 131.8, 132.7, 133.3, 135.9, 136.9, 148.3, 148.5,
156.7, 165.2, 168.5. EI-MS: m/z (%) 532 (Mþ, 0.3), 270 (100), 166 (96),
105 (11), 91 (61), 77 (21). HRMS (microTOF) m/z calcd for
C33H29N2O5 (MþH)þ: 533.2071; found: 533.2077.
4.3.2. 9-Benzoyl-(2,3,12-trimethoxyl)-5,6,7,9-tetrahydroindolo[2,3-e]
[3]benzazocin-8-one (12b). White solid (43.7 mg, 59%). Rf 0.45
(100% EtOAc). Mp: 262 ꢀC. IR (UATR): nmax 3333,1683,1646 cmꢁ1. 1H
4.3.7. 9-Benzoyl-(2-benzyloxyl-3,12-dimethoxyl)-5,6,7,9-tetrahydro-
NMR (400 MHz, CDCl3):
d
2.81e2.87 (m, 1H), 3.25e3.34 (m, 1H),
indolo[2,3-e][3]benzazocin-8-one
(87.8 mg, 50% yield); Rf 0.38 (100% EtOAc). IR (UATR): nmax 3327,
1684, 1646, 1514 cmꢁ1. 1H NMR (300 MHz, CDCl3):
2.78e2.85 (m,
(12g). Yellow
amorphous
3.39e3.47 (m, 1H), 3.74e3.80 (m, 1H), 3.81 (s, 3H), 3.89 (s, 3H), 3.95
(s, 3H), 5.63 (br s, 1H), 6.88 (s, 1H), 7.01 (dd, J¼9.1, 2.6 Hz, 1H), 7.05
(d, J¼2.4 Hz, 1H), 7.09 (s, 1H), 7.46e7.60 (m, 3H), 7.73 (d, J¼9.1 Hz,
d
1H), 3.25e3.43 (m, 2H), 3.57e3.72 (m, 1H), 3.70 (s, 3H), 3.95 (s, 3H),
5.15 (q, J¼12.6 Hz, 2H), 6.11 (br s, 1H), 6.79 (d, J¼2.4 Hz, 1H), 6.90 (s,
1H), 6.96 (dd, J¼9.0, 2.4 Hz, 1H), 7.11 (s, 1H), 7.25e7.56 (m, 8H), 7.69
(d, J¼9.0 Hz, 1H), 7.78 (d, J¼7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3):
1H), 7.81 (d, J¼7.0 Hz, 2H). 13C NMR (100 MHz, CDCl3):
d 32.6, 44.9,
55.7, 56.0, 56.1, 102.8, 112.5, 112.9, 115.8, 116.0, 123.7, 124.4, 128.3,
128.3, 128.5, 129.3 (2C), 129.8, 131.7, 132.6, 133.3, 136.0, 147.9, 149.1,
156.6, 165.0, 168.4. EI-MS: m/z (%) 457 (MþHþ, 311), 456 (Mþ, 38),
352 (7), 105 (100), 77 (31). HRMS (microTOF) m/z calcd for
C27H25N2O5 (MþH)þ: 457.1758; found: 457.1758.
d
32.6, 45.0, 55.8, 56.1, 71.1, 102.9, 113.0, 115.2, 115.7, 116.0, 123.6,
124.3, 127.2 (3C), 128.0 (2C), 128.4, 128.7 (3C), 129.3, 130.5, 131.7,
132.7, 133.2, 136.0, 137.0, 147.1, 149.7, 156.7, 165.3, 168.5. EI-MS: m/z
(%) 534 (Mþ2Hþ, 2), 533 (MþHþ, 9), 532 (Mþ, 30), 105 (100), 77
(33). HRMS (microTOF) m/z calcd for C33H29N2O5 (MþH)þ:
533.2071; found: 533.2071.
4.3.3. 9-Benzoyl-(2,3,11,12-tetramethoxyl)-5,6,7,9-tetrahydro indolo
[2,3-e][3]benzazocin-8-one (12c). White solid (64.1 mg, 88% yield).
Rf 0.38 (100% EtOAc). Mp: 258 ꢀC. IR (UATR): nmax 3328, 1681,
1644 cmꢁ1 1H NMR (300 MHz, CDCl3):
. d 2.81e2.87 (m, 1H),
3.20e3.33 (m, 1H), 3.45e3.56 (m, 1H), 3.70e3.75 (m, 1H), 3.89 (s,
6H), 3.92 (s, 3H), 3.96 (s, 3H), 5.41 (br s,1H), 6.89 (s,1H), 7.02 (s, 1H),
7.09 (s, 1H), 7.48e7.59 (m, 3H), 7.62 (s, 1H), 7.82 (d, J¼6.9 Hz, 2H).
4.4. General procedure for the preparation of in-
dolobenzazociones (6aeh)
13C NMR (75 MHz, CDCl3):
d 32.5, 45.3, 56.0, 56.1 (3C), 97.8, 101.6,
112.2, 112.7, 120.0, 124.4, 124.6, 128.2 (2C), 129.1 (2C), 129.6, 130.0,
132.4, 133.6, 136.4, 147.5, 147.8, 149.0, 150.1, 165.0, 168.8. EI-MS: m/z
(%) 488 (Mþ2Hþ, 4), 487 (MþHþ, 19), 486 (Mþ, 63), 364 (12), 105
(100), 77 (17). HRMS (microTOF) m/z calcd for C28H26N2O6 (MþH)þ:
487.1864; found: 487.1870.
In a round bottle flask, mixture of benzo[d]azocinone 1, Pd(O-
COCF3)2 (0.3e0.5 equiv), CuOAc2 (0.3e1 equiv) was evacuated and
refilled with Ar. Under argon atmosphere, DMSO (0.05 M) was
added via syringe and the flask was again evacuated and refilled
with O2. The reaction mixture was then stirred at 70e80 ꢀC. The
reaction was monitored via TLC until completion. After being
cooled to room temperature, the reaction mixture was filtered
through Celite and washed with EtOAc. The resulting solution was
evaporated to give a brown solution in DMSO, which was added
with 4 M NaOH/H2O. Reaction mixture was stirred at room tem-
perature for 5 min and was then added with water and extracted
with EtOAc three times. An organic layer was washed with water
three times was then with brine. The organic layer was evaporated
to give brown oil, which further purified by PTLC (80% EtOAc/
Hexane) to give products 6 (10e83%).
4.3.4. 9-Benzoyl-(2,3,10,12-tetramethoxyl)-5,6,7,9-tetrahydroindolo
[2,3-e][3]benzazocin-8-one (12d). White solid (18.6 mg, 21% yield).
Rf 0.48 (100% EtOAc). Mp: 236 ꢀC; IR (UATR): nmax 3333, 1703, 1648,
1516 cmꢁ1 1H NMR (400 MHz, CDCl3):
. d 2.72e2.78 (m, 1H),
3.21e3.33 (m, 2H), 3.34 (s, 3H), 3.72 (s, 3H), 3.84 (s, 3H), 3.86e3.90
(m, 1H), 3.88 (s, 3H), 5.59 (br s, 1H), 6.32 (d, J¼2.1 Hz, 1H), 6.58 (d,
J¼2.1 Hz, 1H), 6.78 (s, 1H), 7.06 (s, 1H), 7.35 (d, J¼7.4 Hz, 1H), 7.37 (d,
J¼7.8 Hz, 1H), 7.48 (dd, J¼7.4, 7.4 Hz, 1H), 7.77 (d, J¼7.1 Hz, 2H). 13C
NMR (100 MHz, CDCl3): d 33.0, 44.7, 55.1, 55.7, 56.0, 56.1, 93.7, 98.5,
109.5, 111.6, 112.9, 113.4, 121.4, 124.9, 128.1 (2C), 129.0, 129.6, 129.7
(2C), 132.2, 132.7, 136.0, 147.8, 156.9, 165.8, 169.4 (1C not observed).
EI-MS: m/z (%) 487 (MþHþ, 30), 486 (Mþ, 100), 381 (2), 105 (11), 77
(3). HRMS (microTOF) m/z calcd for C28H26N2O6 (MþH)þ: 487.1864;
found: 487.1871.
4.4.1. (2,3-Dimethoxyl)-5,6,7,9-tetrahydroindolo[2,3-e][3] benzazo-
cin-8-one (6a). White solid (25 mg, 83% yield). Rf 0.35 (100%
EtOAc). Mp: 256 ꢀC. IR (UATR): nmax 3273, 2953 cmꢁ1 1H NMR
.
(400 MHz, CDCl3, at ꢁ20 ꢀC):
d 2.77e2.81 (m, 1H), 3.31e3.39 (m,
1H), 3.51e3.57 (m, 1H), 3.91 (s, 3H), 3.92e3.97 (m, 1H), 3.99 (s, 3H),
6.21 (br s, 1H), 6.91 (s, 1H), 7.11 (s, 1H), 7.19 (ddd, J¼8.0, 7.2, 0.6 Hz,
1H), 7.34 (ddd, J¼8.0, 7.3, 0.8 Hz, 1H), 7.49 (d, J¼8.3 Hz), 7.70 (d,
4.3.5. 9-Benzoyl-5,6,7,9-tetrahydroindolo[2,3-e][3]benzazocin-8-one
(12e). White solid (52.9 mg, 91% yield). Rf 0.43 (100% EtOAc). Mp:
223 ꢀC; IR (UATR): nmax 1690, 1651 cmꢁ1. 1H NMR (400 MHz, CDCl3):
J¼8.1 Hz, 1H), 10.16 (s, 1H). 13C NMR (100 MHz, CDCl3):
d 31.9, 48.6,
d
2.85e2.90 (m, 1H), 3.20e3.30 (m, 1H), 3.37e3.45 (m, 1H)
56.0, 56.1, 111.9, 112.0, 113.3, 118.0, 120.7, 121.2, 124.9, 125.8, 126.8,
3.69e3.74 (m, 1H), 5.91 (br s, 1H), 7.28e7.80 (m, 13H). 13C NMR
128.3. 129.9, 136.8, 147.8, 148.5, 167.5. EI-MS: m/z (%) 323 (MþHþ),

10300
S. Boonya-udtayan et al. / Tetrahedron 68 (2012) 10293e10301
322 (Mþ, 61), 293 (25), 278 (24), 250 (13), 69 (100). HRMS
(microTOF): m/z calcd for C19H19N2O3: 323.1390; found: 323.1389.
126.6, 128.3 (3C), 128.8 (2C), 129.9, 130.5, 132.2, 137.7, 147.3, 147.9,
154.5, 166.6; EI-MS: m/z (%) 429 (MþHþ, 7), 428 (Mþ, 29), 281 (14),
280 (30), 105 (11), 91 (100), 77 (6). HRMS (microTOF) m/z calcd for
C26H25N2O4 (MþH)þ: 429.1809; found: 429.1815.
4.4.2. (2,3,12-Trimethoxyl)-5,6,7,9-tetrahydroindolo[2,3-e][3]benza-
zocin-8-one (6b). White solid (39.8 mg, 60% yield). Rf 0.33 (100%
EtOAc). Mp: 206 ꢀC. IR (UATR): nmax 3330, 3329, 1652 cmꢁ1. 1H NMR
4.4.7. (2-Benzyloxyl-3,12-dimethoxyl)-5,6,7,9-tetrahydroindolo[2,3-
(400 MHz, CDCl3, at ꢁ20 ꢀC):
d
2.75e2.78 (m, 1H), 3.27e3.35 (m,
e][3]benzazocin-8-one (6g). Yellow amorphous (185.1 mg, 53%
1H), 3.47e3.53 (m, 1H), 3.79 (s, 3H), 3.90 (s, 3H), 3.93 (m, 1H), 3.96
(s, 3H), 6.82 (s, 1H), 6.86 (s, 1H), 6.94 (dd, J¼8.8, 1.9 Hz, 1H), 7.04 (s,
1H), 7.09 (s, 1H), 7.35 (d, J¼8.8 Hz, 1H), 10.86 (s, 1H). 13C NMR
yield). Rf 0.35 (100% EtOAc). IR (UATR): nmax 3297, 2925, 1706 cmꢁ1
.
1H NMR (400 MHz, CDCl3, at ꢁ20 ꢀC): 2.64e2.68 (m, 1H), 3.16e3.24
(m, 1H), 3.37e3.43 (m, 1H), 3.51 (s, 3H), 3.79e3.83 (m, 1H), 3.89 (s,
3H), 5.09 (q, J¼12.7 Hz, 2H), 6.61 (br s, 1H), 6.68 (d, J¼1.9 Hz, 1H),
6.81 (s, 1H), 6.83 (dd, J¼8.8, 2.4 Hz, 1H), 7.01 (s, 1H), 7.23e7.37 (m,
(100 MHz, CDCl3):
d 32, 48.3, 55.6, 56.0, 56.1, 100.6, 111.5, 112.5,
113.4, 116.1, 117.5, 125.7, 126.6, 128.5, 129.6, 132.3, 147.3, 147.9, 154.4,
168.2. EI-MS: m/z (%) 353 (MþHþ, 21), 352 (Mþ, 100), 323 (55), 308
(44). HRMS (microTOF) m/z calcd for C20H20N2O4 (MþH)þ:
353.1496 found: 353.1497.
5H). 13C NMR (100 MHz, CDCl3):
d 32.1, 48.3, 55.8, 56.2, 71.1, 101.7,
112.7, 112.9, 115.6, 116.1, 117.4, 126.1, 126.9, 127.1 (2C), 127.8, 128.5
(2C), 128.8, 130.5, 132.3, 137.1, 147.1, 149.1, 154.9, 167.7. EI-MS: m/z
(%) 429 (MþHþ, 18), 428 (Mþ, 68), 337 (12), 281 (31), 250 (12), 105
(7), 91 (100), 65 (11). HRMS (microTOF) m/z calcd for C26H25N2O4
(MþH)þ: 429.1808; found: 429.1818.
4.4.3. (2,3,11,12-Tetramethoxyl)-5,6,7,9-tetrahydroindolo[2,3-e][3]
benzazocin-8-one (6c). Yellow amorphous (27.5 mg, 60% yield). Rf
0.33 (100% EtOAc). IR (UATR): nmax 3273, 1628, 1540, 1514 cmꢁ1. 1H
NMR (400 MHz, CDCl3, at ꢁ20 ꢀC):
d
2.77 (d, J¼14.1 Hz,1H), 3.34 (td,
4.4.8. (3-Benzyloxyl-2,12,13-trimethoxyl)-5,6,7,9-tetrahydro indolo
[2,3-e][3]benzazocin-8-one (6h). Yellow amorphous (143.5 mg, 54%
yield). Rf 0.42 (100% EtOAc). IR (UATR): nmax 3277, 1632, 1509, cm1.
1H NMR (400 MHz, CDCl3, at ꢁ20 ꢀC): 2.71e2.74 (m, 1H), 3.26 (s,
3H), 3.31e3.40 (m, 2H), 3.84e3.87 (m, 1H), 3.90 (s, 3H), 3.92 (s, 3H),
5.24 (s, 2H), 5.98 (br s,1H), 6.84 (s,1H), 7.10 (d, J¼8.9 Hz,1H), 7.19 (d,
J¼8.0 Hz, 1H), 7.20 (s, 1H), 7.36e7.53 (m, 5H), 9.82 (br s, 1H). 13C
J¼12.9, 4.5 Hz, 1H), 3.54 (t, J¼12.6 Hz, 1H), 3.78 (s, 3H), 3.85 (s, 3H),
3.91 (s, 3H), 3.91 (m, 1H), 4.00 (s, 3H), 6.57 (br s, 1H), 6.90 (s, 1H),
6.91 (s, 1H), 7.00 (s, 1H), 7.10 (s, 1H), 11.1 (br s, 1H). 13C NMR
(100 MHz, CDCl3): d 32.0, 49.0, 56.0, 56.0, 56, 56.1, 93.9, 100.3, 111.3,
112.1, 118.4, 119.0, 126.0, 126.5, 129.8, 132.2, 145.6, 147.3, 147.9, 149.1,
168.4. EI-MS: m/z (%) 383 (MþHþ, 23), 382 (Mþ, 100), 367 (30), 353
(35), 338 (23), 57 (55). HRMS (microTOF) m/z calcd for C21H23N2O5
(MþH)þ: 383.16015; found: 383.1591.
NMR (100 MHz, CDCl3):
d 31.8, 48.2, 56.1, 58.1, 60.9, 71.4, 107.1,
113.6, 114.5, 116.2, 120.6, 122.6, 124.7, 126.8, 127.4 (2C), 127.8, 128.4
(2C), 128.5, 128.9, 129.5, 133.9, 145.9, 147.5, 147.9, 167.1. EI-MS: m/z
(%) 459 (MþHþ, 8), 428 (Mþ, 26), 368 (19), 367 (81), 105 (20), 91
(100), 77 (8). HRMS (microTOF) m/z calcd for C27H27N2O5 (MþH)þ:
459.1915; found: 459.1906.
4.4.4. (2,3,10,12-Tetramethoxyl)-5,6,7,9-tetrahydroindolo[2,3-e][3]
benzazocin-8-one (6d). Pale yellow solid (14.1 mg, 10% yield). Rf
0.35 (100% EtOAc). Mp: 243 ꢀC. IR (UATR): nmax 3284, 1628, 1517,
1455 cmꢁ1
.
1H NMR (400 MHz, CDCl3, at ꢁ20 ꢀC):
d 2.71 (d,
J¼14.2 Hz, 1H), 3.25 (td, J¼13.3, 4.6 Hz, 1H), 3.27 (t, J¼12.4 Hz, 1H),
3.72 (s, 3H), 3.83 (s, 3H), 3.85 (m, 1H), 3.86 (s, 3H), 3.90 (s, 3H), 6.18
(s,1H), 6.37 (d, J¼1.2 Hz,1H), 6.55 (d, J¼0.8 Hz,1H), 6.82 (s,1H), 7.02
4.5. General procedure for the synthesis of in-
dolobenzazecinones 16feh
(s, 1H), 9.59 (s, 1H). 13C NMR (100 MHz, CDCl3):
d
31.7, 48.3, 55.5,
A solution of 6feh (1 equiv) in EtOAc (60 mL/mmol) was placed
in a high pressure Parr apparatus at room temperature. To this
solution was added palladium on activated charcoal (ca. 100 mg).
The resulting mixture was hydrogenated (75 psi) until all starting
material was consumed (normally 16 h) as indicated by TLC. The
mixture was then filtered through a plug of Celite and concentrated
under reduced pressure to give a white solid. The crude material
was further purified by recrystallization (PTLC) to give the desired
product.
55.6, 55.8, 55.9, 91.8, 96.5, 111.2, 112.1, 117.6, 123.1, 125.6, 126.7,
128.0, 129.6, 146.9, 147.1, 147.7, 155.2, 167.3. EI-MS: m/z (%) 383
(MþHþ, 18), 382 (Mþ, 96), 353 (28), 83 (42), 57 (100), 55 (86). HRMS
(microTOF) m/z calcd for C21H23N2O5 (MþH)þ: 383.1601 found:
383.1600.
4.4.5. 5,6,7,9-Tetrahydro-8H-indolo[2,3-e][3]benzazocin-8-one
(6e). Pale yellow solid (7.5 mg, 66% yield). Rf 0.48 (100% EtOAc).
Mp: 269 ꢀC. IR (UATR): nmax 3173, 1620 cmꢁ1 1H NMR (400 MHz,
.
CDCl3þCD3OD, at ꢁ20 ꢀC):
d
2.83 (d, J¼13.8 Hz,1H), 3.35 (td, J¼13.4,
4.5.1. (2,12-Dimethoxyl-3-hydroxyl)-5,6,7,9-tetrahydroindolo [2,3-e]
[3]benzazocin-8-one (16f). White solid (113.5 mg, 82% yield). Rf 0.40
(100% EtOAc). Mp: 238 ꢀC. IR (UATR): nmax 3280, 2929, 1652,
4.9 Hz, 1H), 3.47 (td, J¼12.7, 4.6 Hz, 1H), 3.93 (dd, J¼11.8 Hz, 1H),
6.12 (s, 1H), 7.15 (dd, J¼7.5, 7.5 Hz, 1H), 7.33 (dd, J¼7.8, 7.4 Hz, 1H),
7.37e7.42 (m, 3H), 7.47 (d, J¼8.2 Hz, 1H), 7.56 (d, J¼7.1 Hz, 1H), 7.66
1513 cmꢁ1
.
1H NMR (400 MHz, CDCl3þCD3OD, at ꢁ20 ꢀC):
d 2.65
(d, J¼8.1 Hz, 1H), 10.16 (s, 1H). 13C NMR (100 MHz, (CD3)2SO):
d
33.3,
(ddd, J¼14.4, 4.3, 4.3 Hz, 1H), 3.17 (td, J¼14.1, 4.9 Hz, 1H), 3.36 (td,
J¼12.4, 5.0 Hz, 1H), 3.73 (s, 3H), 3.80 (m, 1H), 3.80 (s, 1H), 6.47 (br s,
1H), 6.83 (s, 1H), 6.91 (dd, J¼8.9, 2.3 Hz, 1H), 6.96 (s, 1H), 6.98 (d,
J¼2.1 Hz, 1H), 7.31 (d, J¼8.9 Hz, 1H), 8.16 (br s, 1H). 13C NMR
45.8, 112.6, 115.3, 120.5, 120.5, 123.9, 126.3, 126.7, 127.5, 130.4, 130.5,
134.1, 137.1, 138.0, 166.6, 1C not observed. EI-MS: m/z (%) 263
(MþHþ, 14), 262 (Mþ, 97), 233 (57), 217 (21), 204 (100), 176 (24),
102 (14), 57 (42). HRMS (microTOF) m/z calcd for C17H15N2O
(MþH)þ: 263.1179; found: 263.1139.
(100 MHz, CDCl3þCD3OD):
d 31.4, 47.9, 55.4, 55.7,100.5,112.3,113.0,
115.2, 115.8, 117.5, 124.6, 126.2, 127.9, 129.9, 131.9, 144.7, 145.7, 154.1,
167.7. EI-MS: m/z (%) 339 (MþHþ, 18), 309 (53), 294 (22), 266 (30),
97 (16), 83 (15). HRMS (microTOF) m/z calcd for C19H19N2O4:
339.1339; found: 339.1343.
4.4.6. (3-Benzyloxyl-2,12-dimethoxyl)-5,6,7,9-tetrahydroindolo[2,3-
e][3]benzazocin-8-one (6f). Yellow amorphous (185.1 mg, 53%
yield). Rf 0.45 (100% EtOAc). IR (UATR): nmax 3282, 1652, 1515 cmꢁ1
.
1H NMR (400 MHz, CDCl3, at ꢁ20 ꢀC):
d
2.58 (d, J¼14.3 Hz, 1H), 3.16
4.5.2. (3,12-Dimethoxyl-2-hydroxyl)-5,6,7,9-tetrahydroindolo [2,3-e]
[3]benzazocin-8-one (16g). White solid (68.0 mg, 84% yield). Rf 0.30
(100% EtOAc). Mp: 217 ꢀC. IR (UATR): nmax 3282, 2928, 1623,
1512 cmꢁ1. 1H NMR (400 MHz, CDCl3þCD3OD, at ꢁ20 ꢀC): 2.69 (dt,
J¼14.3, 3.6 Hz, 1H), 3.21 (td, J¼12.7, 4.9 Hz, 1H), 3.40 (td, J¼12.5,
4.9 Hz, 1H), 3.73 (s, 3H), 3.80e3.83 (m, 1H), 3.89 (s, 3H), 6.39 (br s,
(td, J¼11.9, 4.5 Hz, 1H), 3.32 (t, J¼12.1 Hz, 1H), 3.70 (s, 3H),
3.76e3.83 (m, 1H), 3.80 (s, 3H), 5.12 (s, 2H), 6.70 (br s, 1H), 6.77 (s,
1H), 6.85 (dd, J¼8.9, 2.1 Hz, 1H), 6.96 (d, J¼1.6 Hz, 1H), 7.01 (s, 1H),
7.25e7.41 (m, 6H), 10.7 (s, 1H). 13C NMR (100 MHz, CDCl3):
d 33.1,
45.7, 55.7, 56.1, 70.6, 101.1, 113.5, 114.2, 114.9, 115.2, 115.7, 126.5,

S. Boonya-udtayan et al. / Tetrahedron 68 (2012) 10293e10301
10301
1H), 6.81 (s, 1H), 6.90 (dd, J¼8.9, 2.3 Hz, 1H), 6.98 (d, J¼2.0 Hz, 1H),
7.02 (s, 1H), 7.29 (d, J¼8.9 Hz, 1H), 8.01 (br s, 1H). 13C NMR
fellowship (CHE-0453126 for M.E.). Center of Excellence on Envi-
ronmental Health and Toxicology, Science & Technology Post-
graduate Education and Research Development Office (PERDO),
Ministry of Education is gratefully acknowledged. The authors are
thankful to Ms. Pagamas Intachote (Laboratory of Immunology),
Ms. Busakorn Saimanee and Ms. Suchada Siengsai (Integrated Re-
search Unit), Chulabhorn Research Institute for conducting the
cytotoxicity assays. The authors would also like to thank Ms. Cha-
trawadee Panwong and Ms. Jaruwan Joothamongkol, visiting stu-
dents from Prince of Songkla University, for assistance in the
preparation starting material.
(100 MHz, CDCl3þCD3OD):
d 31.6, 48.0, 55.5, 55.6, 100.6, 111.2,
112.8, 116.0, 116.0, 117.2, 125.8, 126.2, 127.9, 128.7, 131.9, 144.2, 146.3,
154.1, 168.5. EI-MS: m/z (%) 338 (Mþ, 8), 178 (18), 149 (19), 97 (22),
85 (16), 69 (81), 57 (100). HRMS (microTOF) m/z calcd for
C19H19N2O4: 339.1333; found: 339.1323.
4.5.3. (3-Hydroxyl-2,12,13-trimethoxyl)-5,6,7,9-tetrahydroindolo
[2,3-e][3]benzazocin-8-one (16h). White solid (77.0 mg, 54% yield).
Rf 0.43 (100% EtOAc). Mp: 248 ꢀC. IR (UATR): nmax 3280, 2929, 1623,
1508, 1455 cmꢁ1
.
1H NMR (400 MHz, CDCl3þCD3OD, at ꢁ20 ꢀC):
2.71e2.75 (m, 1H), 3.25 (s, 3H), 3.21e3.42 (m, 2H), 3.83e3.87 (m,
1H), 3.87 (s, 3H), 3.93 (s, 3H), 6.61 (br s, 1H), 6.83 (s, 1H), 7.10 (s, 1H),
7.11 (d, J¼8.4 Hz,1H), 7.22 (d, J¼8.8 Hz,1H), 8.10 (br s, 1H),10.6 (br s,
Supplementary data
Experimental procedures and spectral data for all new com-
pounds. Supplementary data related to this article can be found
online at http://dx.doi.org/10.1016/j.tet.2012.10.011.
1H). 13C NMR (100 MHz, CDCl3þCD3OD):
d 31.7, 47.6, 56.1, 58.1, 60.9,
107.4, 113.6, 114.3, 115.3, 116.5, 118.1, 120.3, 125.3, 129.6, 134.1, 143.3,
144.9, 145.0, 145.6, 167.6. EI-MS: m/z (%) 368 (Mþ, 10), 57 (100), 55
(60). HRMS (microTOF) m/z calcd for C20H21N2O5: 369.1445; found:
369.1455.
References and notes
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Acknowledgements
This work was supported in part by Thailand Research Fund
(RMU5380021 for N.T.), the award of the Royal Golden Jubilee
Scholarship (PHD/0028/2552 for S.B.) and NSF-REU research
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