A new synthetic approach towards isoquinobenzazepinone and isoindolinobenzazepinone using acid-mediated cyclisation and Heck reaction

Article abstract of DOI:10.1016/j.tet.2008.10.044

Six-membered ring cyclisation of N-ethylbenzazepinone, prepared from the condensation of benzazepinone with phenethyl iodide under basic conditions, smoothly provided the corresponding product, isoquino[1,2-b][3]benzazepinone, under acid-mediated conditions. On the other hand, the attempted direct five-membered ring cyclisation using the acid-mediated conditions failed to give the 7,5 fused ring isoindolinobenzazepinone from N-benzylbenzazepinone, but the 7,6 fused ring product was instead obtained. However, five-membered ring cyclisation of N-benzylbenzazepinone could be effected efficiently by employing the Heck reaction followed by catalytic hydrogenation to furnish the desired isoindolinobenzazepinone.

Full text of DOI:10.1016/j.tet.2008.10.044

Tetrahedron 65 (2009) 351–356
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A new synthetic approach towards isoquinobenzazepinone and
isoindolinobenzazepinone using acid-mediated cyclisation and Heck reaction
,
,c,
Wong Phakhodee a b, Poonsakdi Ploypradith a, Poolsak Sahakitpichan a, Somsak Ruchirawat a
*
a Laboratory of Medicinal Chemistry, Chulabhorn Research Institute and Chulabhorn Graduate Institute, Vipavadee Rangsit Highway, Bangkok 10210, Thailand
b Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
c Programme on Research and Development of Synthetic Drugs, Institute of Science and Technology for Research and Development, Mahidol University, Salaya Campus, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
Six-membered ring cyclisation of N-ethylbenzazepinone, prepared from the condensation of benzaze-
pinone with phenethyl iodide under basic conditions, smoothly provided the corresponding product,
isoquino[1,2-b][3]benzazepinone, under acid-mediated conditions. On the other hand, the attempted
direct five-membered ring cyclisation using the acid-mediated conditions failed to give the 7,5 fused ring
isoindolinobenzazepinone from N-benzylbenzazepinone, but the 7,6 fused ring product was instead
obtained. However, five-membered ring cyclisation of N-benzylbenzazepinone could be effected effi-
ciently by employing the Heck reaction followed by catalytic hydrogenation to furnish the desired
isoindolinobenzazepinone.
Received 22 February 2008
Received in revised form
30 September 2008
Accepted 16 October 2008
Available online 1 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
OMe
O
MeO
O
O
O
N
Lennoxamine 1 is the prominent representative of the iso-
indolobenzazepine alkaloids and it was isolated from the Chilean
plant Berberis darwinii Hook.1 Despite its lack of important bi-
ological activities reported in the literature, its unique structural
feature of the five- and seven-membered ring system fused with
the aromatic moieties renders this molecule an attractive and
synthetically challenging target. C-Homoprotoberberine is struc-
turally related to lennoxamine containing the unique framework
of the six- and seven-membered ring joined with the respective
aromatic parts. Hediamine 2, the prototype of C-homo-
N
OMe
OMe
2
1
O
O
Figure 1. Structures of lennoxamine 1 and hediamine 2.
in the lennoxamine on the five-membered ring of the indoline
unit (Fig. 1).
protoberberine, has been recently isolated from
a natural
Significantly, it was found that the benzazepinone ring played
a crucial role for bradycardic activity from the structure–activity
relationships study.17 In addition, some C-homoprotoberberines
exhibited significant cytotoxicity against some human breast car-
cinoma cell lines.16
As shown retrosynthetically in Scheme 1, we now wish to
report the total synthesis of both isoindolinobenzazepinone 9a,
via Heck reaction,18 (n¼1, forming a five-membered ring) and
C-homoprotoberberine 9b via acid-mediated cyclisation19 (n¼2,
forming a six-membered ring) from the common synthon ben-
zazepinone 4. We envisioned that N-alkylbenzazepinones 8 and
6 could serve as the key intermediates for 9a and 9b, re-
spectively, since both compounds could be formed by the cor-
source.2
Lennoxamine has been the target of many synthetic en-
3–14
deavours
including our own work15 employing a wide va-
riety of approaches. C-Homoprotoberberine could be obtained
from phenylethyl phenylacetamide by tin(IV) chloride-promoted
reaction with oxalyl chloride.16 While the C-homoproto-
berberine and lennoxamine both share a fused tetracyclic sys-
tem, their frameworks differ in the sizes of the fused lactam
rings (seven-five in lennoxamine versus seven-six in C-homo-
protoberberine). The lactam carbonyl group in the C-homo-
protoberberine resides on the benzazepine moiety whereas that
responding N-alkylation reactions of benzazepinone
4 with
derivatives of either phenethyl iodide 5 or benzyl bromide 7.
Both N-alkylbenzazepinones 6 and 8 share the common synthon
in benzazepinone 4.
* Corresponding author. Tel.: þ66 2 574 0601; fax: þ66 2 574 2027.
E-mail address: somsak@cri.or.th (S. Ruchirawat).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.044

352
W. Phakhodee et al. / Tetrahedron 65 (2009) 351–356
O
O
O
MeO
MeO
MeO
MeO
MeO
Acid-mediated
cyclization
Heck
reaction
N
N
N
n
MeO
I
OMe
OMe
8
OMe
6
OMe
MeO
OMe
9a, n = 1: Isoindolinobenzazepinone
9b, n = 2: Isoquino[1, 2-b][3]benzazepinone
N -Alkylation
N-Alkylation
O
O
MeO
MeO
MeO
MeO
I
MeO
MeO
O
MeO
MeO
MeO
MeO
Br
OMe
OMe
NH
NH
HN
I
5
4
3
4
7
Scheme 1. Retrosynthetic strategies of isoindolinobenzazepinone 9a and isoquino[1,2-b][3]benzazepinone 9b via a common intermediate benzazepinone 4.
2. Results and discussion
O
O
acid
MeO
MeO
MeO
MeO
conditions
N
N
Our synthesis commenced with the preparation of the starting
material benzazepinone17 4 from the acid-mediated cyclisation of
acetal amide 3. Cyclisation of acetal amide 3 with HCl/AcOH gave
benzazepinone 4 in 75% yield. The cyclisation could also be ac-
complished by H2SO4/AcOH or HCO2H, albeit in lower yield of 45%
and 40%, respectively.
see Table 1
6
9b
MeO
OMe
MeO
OMe
Scheme 3. Acid-mediated cyclisation of N-alkylbenzazepinone 6.
N-Alkylation of benzazepinone 4 using sodium hydride as a base
in DMF at 0 ꢀC for 30 min, followed by the addition of 3,4-dime-
thoxyphenethyl iodide 5 was first employed. However, our initial
attempt to carry out the reaction using sodium hydride did not
proceed to give the desired product 6, but rather gave 3,4-dime-
thoxystyrene from the elimination reaction of 5 and recovered
starting material benzazepinone 4. Potassium tert-butoxide has
been used as base in the N-alkylation reactions in polar solvents
(DMF or DMSO).17 Thus, treatment of benzazepinone 4 with
1.5 equiv of potassium tert-butoxide in DMF at 0 ꢀC for 30 min,
followed by the addition of 3,4-dimethoxyphenethyliodide 5 fur-
nished, after purification, N-alkylbenzazepinone 6 in 77% yield as
shown in Scheme 2. From this experiment, it was apparent that
bulky base was critical for this N-alkylation reaction. Similar
treatment of benzazepinone 4 with potassium tert-butoxide in
DMF at 0 ꢀC followed by the addition of 3,4-dimethoxybenzyl
chloride gave N-alkylbenzazepinone 10 in 86% yield (Scheme 3).
After the key intermediate N-alkylbenzazepinones 6 and 10
were prepared, the acid-mediated cyclisation to convert N-alkyl-
benzazepinone 6 to isoquino[1,2-b][3]benzazepinone 9b was ex-
with AcOH resulted in better yields of the product (entries 1–6
compared with entries 7–12). However, the best results were
obtained when formic acid, a weaker acid, was employed, fur-
nishing the desired isoquino[1,2-b][3]benzazepinone product 9b in
72–85% yields and in much shorter reaction times (1–2 h).
Our attempts to induce an acid-mediated cyclisation of
N-alkylbenzazepinone 10, using the mixed acid systems (HCl or
H2SO4 and AcOH) or refluxed formic acid failed to produce the
desired product 9a. However upon treating with triflic acid in
refluxed dichloromethane for 2 h, 10 underwent an extremely
smooth cyclisation to the tetracyclic ring system 11 via a 7,6 an-
nulation in 64% yield (Scheme 4).
Under the mixed acid systems (HCl or H2SO4 in AcOH) or
refluxed formic acid, 10 did not provide the product 9a presumably
due to the angle strain present for the unfavoured anti-Baldwin 5-
endo-trig cyclisation20 of the resulting iminium Pictet–Spengler-
plored. Table
1 summarises the results of our investigation
Table 1
employing different acidic conditions. It is apparent that longer
reaction time or changing HCl to H2SO4 in the mixed acid system
Effect of acids and reaction time on the cyclisation of N-alkylbenzazepinone 6 to
homoprotoberberine 9b
Entry
Acid
Temperature
Time (h)
Yielda (%)
O
O
1
2
3
4
5
6
7
8
HCl/AcOHb
HCl/AcOHb
HCl/AcOHb
HCl/AcOHb
HCl/AcOHb
HCl/AcOHb
H2SO4/AcOHc
H2SO4/AcOHc
H2SO4/AcOHc
H2SO4/AcOHc
H2SO4/AcOHc
H2SO4/AcOHc
HCO2H
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
Reflux
Reflux
2
4
6
41
46
48
52
54
68
46
62
70
75
76
80
72
85
MeO
MeO
MeO
MeO
i
N
NH
77%
8
4
6
10
17
2
4
6
MeO
OMe
O
O
N
9
MeO
MeO
MeO
MeO
10
11
12
13
14
8
ii
NH
10
17
1
86%
OMe
OMe
4
10
HCO2H
2
a
Isolated yield after chromatography on silica gel.
All reactions were performed with HCl/AcOH (1:1).
b
c
Scheme 2. Reagents and conditions: (i) (a) ButOK (1.5 equiv), DMF, 0 ꢀC, (b) 5; (ii) (a)
All reactions were performed with H2SO4/AcOH (1:5).11
ButOK (1.5 equiv), DMF, 0 ꢀC, (b) 3,4-dimethoxybenzyl chloride.

W. Phakhodee et al. / Tetrahedron 65 (2009) 351–356
353
O
O
O
O
MeO
MeO
MeO
MeO
MeO
MeO
MeO
(i)
(i)
N
NH
N
N
MeO
4
I
OMe
OMe
9a
10
(ii)
8
OMe
OMe
OMe
OMe
OMe
(ii)
O
MeO
MeO
O
N
O
N
MeO
MeO
MeO
MeO
(iii)
N
11
OMe
9a
15
OMe
OMe
OMe
OMe
Scheme 4. Reagents and conditions: (i) HCl/AcOH or H2SO4; (ii) triflic acid (4 equiv),
Scheme 6. Reagents and conditions: (i) (a) ButOK, DMF, 0 ꢀC, (b) 7, 96%; (ii) Pd(OAc)2,
CH2Cl2, reflux, 2 h, 64%.
K2CO3, Bu4NBr, DMF, 110 ꢀC, 7 h, 91%; (iii) H2/Pd/C, 83%.
type intermediate 12. On the other hand, as shown in Scheme 5, the
isolation of 11 under strong acid condition suggests that the initial
step in the conversion of 10 to 11 involves the intermediacy of the
corresponding para-quinone methide 13, which underwent the
favoured 6-exo-trig cyclisation.21 Similarly, compound 9b could be
formed from the corresponding benzazepinone 6 via intermediacy
of the iminium ion 14 undergoing the favoured 6-endo-trig
cyclisation.22
N-alkylbenzazepinone 8 with Pd(OAc)2 in DMF containing K2CO3
(2 equiv) and Bu4NþBrꢁ (1 equiv) at 110 ꢀC for 2 h provided the de-
sired tetracyclic ring structure of dehydroisoindolinobenzazepinone
15 in 91% yield. Subsequent palladium-catalysed hydrogenation of
the dehydroisoindolinobenzazepinone 15 readily furnished the
corresponding isoindolinobenzazepinone 9a in 83% yield.
As a result of the undesirable acid-mediated cyclisation of 10 to
11, we now envisioned that the desired compound 9a could be more
readily prepared from the N-alkylbenzazepinone 8 via Heck re-
action. We decided to investigate the use of Heck reaction of
N-alkylbenzazepinone 8. Compound 8 was synthesised by the cor-
responding alkylation reaction of benzazepinone 4 with potassium
tert-butoxide and 2-iodo-3,4-dimethoxybenzyl bromide 723 as
outlined in Scheme 6. Firstly, we examined the use of Pd(0) in the
Heck reaction of N-alkylbenzazepinone 8 to form the dehy-
droisoindolinobenzazepinone 15. Initially, conditions employing
Pd(PPh3)4, Et3N in DMF at 110 ꢀC for 24 h was explored for the Heck
reaction of benzazepinone 8. Unfortunately, the reaction did not
provide the desired product 15. We then attempted to use Pd(II) in
the presence of Bu4NþBrꢁ as an additive.6,24 Treatment of
3. Conclusion
Isoindolinobenzazepinone 9a and isoquino[1,2-b][3]benzazepi-
none 9b were successfully synthesised in three and two steps from
benzazepinone 4 with either benzyl bromide 7 or phenethyl iodide 5
in 74% and 66% overall yields, respectively. The key step for 9a was
the Heck reaction that produced dehydroisoindolinobenzazepinone
15 in 91% yield, which, upon catalytic hydrogenation, furnished
isoindolinobenzazepinone 9a. On the other hand, acid-mediated
cyclisation reaction of N-alkylbenzazepinone 6 proceeded to pro-
vide homoprotoberberine 9b in 85% yield. Both benzazepinone al-
kaloids were synthesised from the same key intermediate 4, and
both phenethyl iodide 5 and benzyl bromide 7 were easily prepared
from commercially available starting materials.
O
O
MeO
MeO
N
N
MeO
MeO
OMe
6
10
OMe
MeO
H
OMe
OMe
H
H
O
O
O
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
OMe
OMe
OMe
12
14
MeO
13
OMe
5-endo-trig (unfavoured)
O
6-exo-trig (favoured)
6-endo-trig (favoured)
O
N
O
N
MeO
MeO
MeO
MeO
MeO
MeO
N
9b
9a
11
OMe
OMe
OMe
OMe
MeO
OMe
Scheme 5. Proposed mechanism for tetracycles 9b and 11.

354
W. Phakhodee et al. / Tetrahedron 65 (2009) 351–356
4. Experimental
stirred at this temperature for 30 min. To the reaction mixture was
slowly added phenethyl iodide 5, benzyl bromide 7 or 3,4-dime-
thoxybenzyl chloride as a solution in DMF (5 mL) and then the
resulting mixture was stirred at room temperature for 2 h. The
reaction mixture was poured on crushed ice containing NH4Cl
(50 mL). The aqueous phase was extracted with EtOAc, washed
with water, dried (Na2SO4), filtered and concentrated under re-
duced pressure to give the crude product, which was further pu-
rified by column chromatography on silica (40% EtOAc/hexane), to
provide the corresponding product N-alkylbenzazepinones.
4.1. General
Melting points were determined on a Electrothermal 9100 ap-
paratus and are uncorrected. 1H and 13C NMR spectra were recor-
ded on a Bruker DPX-300 using deuterochloroform and dimethyl
sulfoxide-d6 as solvents. IR spectra were run on a Perkin Elmer
system 2000 FT-IR and JASCO A-302 spectrometers. Mass spectra
were recorded on a Finnigan INCOS 50 and Bruker Daltonics
(microTOF). Elemental analyses were performed on Perkin Elmer
Elemental Analyzer 2400 CHN. Column and preparative thin layer
chromatographic purifications were carried out using silica gel (70–
230 mesh ASTM) and on a silica gel E. Merck PF254, respectively.
When 7,8-dimethoxy-1,3-dihydro-2H-benzazepinone 4 (1.00 g,
4.56 mmol), potassium tert-butoxide (0.77 g, 6.84 mmol), and
phenethyl iodide 5 (2.62 g, 6.84 mmol) were reacted, 3-[2-(3,4-
dimethoxyphenyl)ethyl]-7,8-dimethoxy-1,3-dihydrobenzo-[d]aza-
pin-2-one 6 (1.35 g, 3.51 mmol, 77%) was obtained as a viscous oil.
4.2. 7,8-Dimethoxy-1,3-dihydro-2H-benzazepin-2-one (4)
IR (KBr) nmax 1651, 1516, 1465 cmꢁ1 1H NMR (CDCl3, 300 MHz):
;
d
2.76 (t, J¼7.2 Hz, 2H, CH2CH2N), 3.43 (s, 2H, CH2CO), 3.73 (s, 3H,
Oxalyl chloride (3.25 mL, 38.4 mmol) was added slowly to
a stirred solution of homoveratric acid (5.00 g, 25.5 mmol) and N,N-
dimethylformamide (3 drops) in benzene (20 mL). The reaction
mixture was stirred at room temperature for 1 h and then con-
centrated under reduced pressure to give the crude acid chloride.
To a mixture of aminoacetaldehyde dimethyl acetal (2.75 mL,
25.5 mmol) in CH2Cl2 (50 mL) and Na2CO3 (5.40 g, 25.5 mmol) in
water (15 mL) was added the solution of acid chloride in CH2Cl2
(15 mL). The reaction mixture was stirred at room temperature for
2 h. Water (50 mL) was added and the two phases were separated.
The aqueous layer was extracted with CH2Cl2 (3ꢂ10 mL). The
combined organic extracts were washed with water, dried
(Na2SO4), filtered and concentrated to give the crude acetal amide
3, which was used in the next step without further purification.
When HCl/AcOH was utilised, the crude acetal amide 3 was
dissolved in glacial AcOH (15 mL) and concd HCl (15 mL) was then
added dropwise. The reaction mixture was allowed to stir at room
temperature for 17 h. The reaction mixture was then poured into
a mixture of ice and water, stirred for 30 min, filtered and washed
with water. Benzazepinone 4 (4.16 g, 19.1 mmol, 75%) was obtained
as a white solid.
OCH3), 3.76 (t, J¼7.2 Hz, 2H, CH2CH2N), 3.85 (s, 3H, OCH3), 3.90 (s,
3H, OCH3), 3.92 (s, 3H, OCH3), 6.01 (d, J¼9.1 Hz, 1H, CH]CHN), 6.21
(d, J¼9.1 Hz, 1H, CH]CHN), 6.56 (d, J¼1.7 Hz, 1H, ArH), 6.62 (dd,
J¼8.1, 1.7 Hz, 1H, ArH), 6.68 (s, 1H, ArH), 6.71 (d, J¼8.1 Hz, 1H, ArH),
6.80 (s, 1H, ArH); 13C NMR (CDCl3, 75 MHz):
d 34.3, 43.2, 50.3, 55.6,
55.8, 55.9, 109.4, 111.1, 112.1, 116.7, 120.7, 124.6, 126.4, 128.6, 131.1,
147.5, 147.9, 148.7, 149.8, 167.5; LRMS (EI) m/z (rel intensity) 385
(Mþþ2, 10), 384 (MþHþ, 44), 383 (Mþ, 100), 219 (87), 176 (29);
HRMS (TOF) calcd for C22H26NO5[MþH]þ 384.1805, found:
384.1810.
When 7,8-dimethoxy-1,3-dihydro-2H-benzazepinone 4 (0.20 g,
0.91 mmol), potassium tert-butoxide (0.15 g, 1.37 mmol), and bro-
momethyl-2-iodo-4,5-dimethoxybenzene
7 (0.49 g, 1.37 mmol)
were reacted, 3-(2-iodo-4,5-dimethoxybenzyl)-7,8-dimethoxy-1,3-
dihydrobenzo[d]-azepin-2-one 8 (0.45 g, 0.89 mmol, 98%) was
obtained as a white solid. Mp 150–151 ꢀC; IR (KBr) nmax 1670, 1507,
867 cmꢁ1; 1H NMR (CDCl3, 300 MHz):
d 3.18 (s, 3H, OCH3), 3.48 (s,
2H, CH2CO), 3.73 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.84 (s, 3H,
OCH3), 4.64 (s, 2H, CH2N), 5.96 (s, 1H, ArH), 6.12 (d, J¼9.0 Hz, 1H,
CH]CHN), 6.34 (d, J¼9.0 Hz, 1H, CH]CHN), 6.66 (s, 1H, ArH), 6.79
(s, 1H, ArH), 7.10 (s, 1H, ArH); 13C NMR (CDCl3, 75 MHz):
d 42.8, 54.9,
When H2SO4/AcOH was used, the crude acetal amide 3 was
dissolved in glacial AcOH (20 mL) and concd H2SO4 (4 mL) was then
added dropwise. The reaction mixture was allowed to stir at room
temperature for 17 h. The reaction mixture was then poured into
a mixture of ice and water, stirred for 30 min, filtered and washed
with water. Benzazepinone 4 (2.53 g,11.5 mmol, 45%) was obtained.
When HCO2H was used, the crude acetal amide 3 was refluxed in
HCO2H (20 mL) for 4 h. The reaction mixture was poured into water
containing crushed ice and the aqueous phase was then extracted
with CH2Cl2 (3ꢂ15 mL). The combined organic solution was washed
with water, dried (Na2SO4), filtered and concentrated under reduced
pressure to give a yellow solid, which was recrystallised in ethyl
acetate to give benzazepinone 4 (2.24 g, 10.2 mmol, 40%).
55.2, 55.98, 56.02, 56.1, 85.3, 109.4, 109.9, 111.2, 118.4, 121.4, 124.8,
126.3, 128.3, 131.2, 148.1, 148.5, 149.5, 150.0, 167.9; LRMS (EI) m/z
(rel intensity) 496 (MþHþ, 3), 495 (Mþ, 5), 369 (25), 368 (100), 277
(39). Anal. Calcd for C21H22NO5I: C, 50.92; H, 4.48; N, 2.83. Found: C,
50.94; H, 4.21; N, 2.40.
When 7,8-dimethoxy-1,3-dihydro-2H-benzazepinone 4 (1.00 g,
4.56 mmol), potassium tert-butoxide (0.77 g, 6.84 mmol), and 3,4-
dimethoxybenzyl chloride (1.28 g, 6.84 mmol) were reacted,
3-(3,4-dimethoxybenzyl)-7,8-dimethoxy-1,3-dihydrobenzo[d]aza-
pin-2-one 10 (1.43 g, 3.87 mmol, 86%) was obtained as a white
solid. Mp 61–63 ꢀC; IR (KBr) nmax 1667, 1518, 1460 cmꢁ1
;
1H NMR
3.53 (s, 2H, CH2CO), 3.66 (s, 3H, OCH3), 3.83 (s,
(CDCl3, 300 MHz):
d
3H, OCH3), 3.87 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 4.71 (s, 2H, CH2N),
6.20 (d, J¼9.1 Hz, 1H, CH]CHN), 6.36 (d, J¼9.1 Hz, 1H, CH]CHN),
6.54 (d, J¼1.7 Hz, 1H, ArH), 6.69 (dd, J¼8.1, 1.7 Hz, 1H, ArH), 6.72 (s,
1H, ArH), 6.77 (d, J¼8.1 Hz, 1H, ArH), 6.84 (s, 1H, ArH); 13C NMR
Benzazepinone 4 (white solid). Mp 236–238 ꢀC (lit.17 235–
237 ꢀC); IR (KBr) nmax 1667, 1634, 1514, 1414 cmꢁ1; 1H NMR (DMSO-
d6, 300 MHz):
d 3.27 (s, 2H, CH2CO), 3.73 (s, 3H, OCH3), 3.75 (s, 3H,
OCH3), 6.16 (dd, J¼9.2, 4.0 Hz,1H, CH]CHNH), 6.23 (d, J¼9.2 Hz,1H,
(CDCl3, 75 MHz): d 43.0, 50.3, 55.2, 55.4, 55.7, 55.9, 109.3, 110.3,
CH]CHNH), 6.83 (s, 1H, ArH), 6.84 (s, 1H, ArH), 9.45 (d, J¼4.0 Hz,
110.9, 111.1, 117.6, 119.5, 124.6, 126.3, 128.0, 129.4, 147.9, 148.1, 148.9,
149.8, 167.8; LRMS (EI) m/z (rel intensity) 370 (Mþþ1, 16), 369 (Mþ,
66), 151 (100); HRMS (FAB) calcd for C21H23NO5[MþH]þ 369.1576,
found: 369.1585.
1H, NH); 13C NMR (DMSO-d6, 75 MHz):
d 42.6, 55.56, 55.61, 110.3,
112.0, 114.4, 123.4, 124.2,127.2, 147.6, 149.1, 168.7; LRMS (EI) m/z (rel
intensity) 220 (MþHþ, 14), 219 (Mþ, 100), 176 (54); HRMS (TOF)
calcd for C12H14NO3[MþH]þ 220.0968, found: 220.0972.
4.4. 2,3,11,12-Tetramethoxy-5,9,14,14a-tetrahydro-6H-
benzo[4,5]azepino[2,1-a]isoquinolin-8-one (9b)
4.3. General procedure for the synthesis of N-
alkylbenzazepinones (6), (8) and (10)
When HCl/AcOH was used, 3-[2-(3,4-dimethoxoyphenyl)ethyl]-7,8-
dimethoxy-1,3-dihydrobenzo[d]azapin-2-one 6(0.50 g,1.30 mmol) was
dissolved in acetic acid (5 mL). To this mixture, concd HCl (5 mL) was
Benzazepinone 4 dissolved in DMF was slowly added into a so-
lution of potassium tert-butoxide in DMF (10 mL) at 0 ꢀC and then

W. Phakhodee et al. / Tetrahedron 65 (2009) 351–356
355
then slowly added dropwise and the entire reaction mixture was sub-
sequently stirred for different amounts of time (2, 4, 6, 8, 10 and 17 h).
After that, the reaction was quenched with water, neutralised with 25%
NH4OH and the aqueous phase extracted with CH2Cl2 (3ꢂ20 mL). The
combined organic layers were washed with water, brine, dried (Na2SO4),
filtered and the solvent evaporated under reduced pressure to give the
crude product ,which was purified by preparative TLC (60% EtOAc/
hexane) to give the desired isoquinolinobenzazepinone 9b. Similarly,
when H2SO4/AcOH was utilised, concd H2SO4 (1 mL) was employed
instead of concd HCl for 2, 4, 6, 8, 10 and 17 h. When formic acid was
used, compound 6 was refluxed in formic acid (10 mL) for 1 and 2 h.
From all cases, the desired product 9b was obtained from the crude
product by preparative TLC (60% EtOAc/hexanes) as a white solid (see
Table 1 for yields). Mp 185 ꢀC; IR (KBr) nmax 1645, 1521, 1448 cmꢁ1; 1H
CH2CO), 3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.91
(s, 3H, OCH3), 4.77 (s, 2H, CH2N), 6.54 (s, 1H, CH]C–N), 6.73 (s, 2H,
ArH), 6.77 (s, 1H, ArH), 7.02 (s, 1H, ArH); 13C NMR (CDCl3, 75 MHz):
d
43.7, 53.1, 55.97, 56.0, 56.2, 102.4, 104.2, 105.4, 109.8, 112.0, 121.7,
127.6,128.4,129.2,139.0,148.2,149.3,149.8,150.7,168.0;LRMS(EI)m/z
(relintensity)369 (Mþþ2,4), 368(MþHþ, 26), 367(Mþ,100), 353(15),
352 (60). Anal.Calcd forC21H21NO5: C, 68.65;H, 5.76;N, 3.81. Found:C,
68.51; H, 5.36; N, 3.52.
4.7. 2,3,10,11-Tetramethoxy-5,8,13,13a-tetrahydrobenzo-
[4,5]azepino[2,1-a]isoindol-7-one (9a)
To a stirred solution of dehydroindolinobenzazepinone 15
(0.05 g, 0.14 mmol) in CH2Cl2 containing AcOH (10 drops), 10% Pd
on charcoal (0.054 g) was added. The mixture was hydrogenated
with a hydrogen balloon at 1 atm by stirring at room temperature
for 20 h. Catalyst residue was removed by filtration and the residue
was washed with CH2Cl2. The organic layer was washed with water,
dried (Na2SO4), filtered and concentrated to give the crude product,
which was purified by preparative TLC (60% EtOAc/hexanes) to
provide isoindolinobenzazepinone 9a (0.042 g, 0.12 mmol, 83%) as
a white solid. Mp 264.0 ꢀC (decomposed); IR (KBr) nmax 1635, 1611,
NMR (CDCl3, 300 MHz):
d
2.85 (t, J¼6.0 Hz, 2H, CH2CH2N), 3.20 (dd,
J¼11.4, 3.5 Hz, 1H, CH2CHN), 3.27 (dd, J¼11.4, 3.5 Hz, 1H, CH2CHN), 3.44
(d, J¼15.0 Hz, 1H, CH2CO), 3.61 (dt, J¼13.0, 6.0 Hz,1H, CH2CH2N), 3.83 (s,
3H, OCH3), 3.87 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.03
(dt, J¼13.0, 6.0 Hz, 1H, CH2CH2N), 4.50 (d, J¼15.0 Hz, 1H, CH2CO), 5.43
(dd, J¼11.4, 3.5 Hz, 1H, CH2CHN), 6.57 (s, 1H, ArH), 6.66 (s, 1H, ArH), 6.70
(s,1H, ArH), 6.73 (s,1H, ArH); 13C NMR (CDCl3, 75 MHz):
d 28.1, 37.8, 41.0,
42.6, 54.2, 55.82, 55.85, 55.88, 56.04,109.6,111.2,113.1,114.0,123.0,127.3,
127.7, 147.2, 147.8, 147.9, 148.0, 171.8; LRMS (EI) m/z (rel intensity) 384
(MþHþ, 21), 383 (Mþ, 79), 355 (23), 192 (100), 190 (84). Anal. Calcd for
C22H25NO5: C, 68.91; H, 6.57; N, 3.65. Found: C, 68.88; H, 6.64; N, 3.49.
1523, 1465, 1451, 1433 cmꢁ1; 1H NMR (CDCl3, 300 MHz):
d 3.02 (dd,
J¼16.9, 12.0 Hz, 1H, CH2CHN), 3.40 (d, J¼16.9 Hz, 1H, CH2CHN), 3.46
(d, J¼15.0 Hz, 1H, CH2CO), 3.82 (s, 3H, OCH3), 3.84 (s, 3H, OCH3),
3.91 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 4.31 (d, J¼15.0 Hz,1H, CH2CO),
4.69 (d, J¼15.4 Hz, 1H, CH2N), 4.85 (d, J¼15.4 Hz, 1H, CH2N), 5.53 (d,
J¼12.0 Hz, 1H, CH2CHN), 6.57 (s, 1H, ArH), 6.64 (s, 1H, ArH), 6.78 (s,
4.5. 2,3,10,11-Tetramethoxy-5,13-dihydro-8H-6,13-
methanodibenzo[c,f]azonin-7-one (11)
1H, ArH), 6.82 (s, 1H, ArH); 13C NMR (CDCl3, 75 MHz):
d 40.7, 43.0,
3-(3,4-Dimethoxybenzyl)-7,8-dimethoxy-1,3-dihydrobenzo
[d]azepin-2-one 10 (0.30 g, 0.81 mmol) was refluxed in triflic acid
(0.30 mL, 3.44 mmol) in CH2Cl2 (5 mL) for 2 h. At that time water
(20 mL) was added and then the mixture was extracted with CH2Cl2
(2ꢂ20 mL). The combined CH2Cl2 layers were washed with 10%
sodium carbonate and water, and dried (Na2SO4). After evaporation
of the solvent, the obtained solid was recrystallised from methanol/
diethyl ether and CH2Cl2 to give colourless needles of tetracycle 11
(0.18 g, 0.49 mmol) in 64% yield. Mp 306 ꢀC (decomposed); IR (KBr)
51.0, 55.81, 55.84, 56.04, 56.10, 61.4, 105.0, 105.7, 113.2, 114.0, 122.6,
126.8, 127.2, 132.0, 147.2, 147.8, 149.2, 149.6, 170.5; LRMS (EI) m/z
(rel intensity) 371 (Mþþ2, 2), 370 (MþHþ, 14), 369 (Mþ, 58), 178
(22), 177 (100), 165 (21). HRMS (TOF) Calcd for C21H24NO5[MþH]þ
370.1649, found: 370.1656.
Acknowledgements
nmax 1656, 1521, 1463 cmꢁ1 1H NMR (CDCl3, 300 MHz):
; d 3.42 (d,
We acknowledge the financial support from the Center for En-
vironmental Health, Toxicology and Management of Toxic Chem-
icals (ETM). One of us (W.P.) acknowledges partial financial support
from Center for Innovation in Chemistry: Postgraduate Education
and Research in Chemistry (CIC-PERCH).
J¼15.0 Hz, 1H, CH2N), 3.69 (dd, J¼14.5, 3.4 Hz, 1H, CHCH2N), 3.83 (s,
6H, 2ꢂOCH3), 3.90 (s, 3H, OCH3), 3.93 (d, J¼3.4 Hz, 1H, CHCH2N),
3.94 (s, 3H, OCH3), 4.07 (d, J¼15.8 Hz, 1H, CH2CO), 4.48 (d,
J¼15.0 Hz, 1H, CH2N), 4.57 (d, J¼14.5 Hz, 1H, CHCH2N), 5.38 (d,
J¼15.8 Hz,1H, CH2CO), 6.56 (s,1H, ArH), 6.60 (s,1H, ArH), 7.02 (s,1H,
ArH), 7.06 (s, 1H, ArH); 13C NMR (CDCl3, 75 MHz):
d 40.3, 42.3, 46.5,
References and notes
47.6, 55.84, 55.88, 55.94, 56.00, 109.2, 112.0, 113.8, 114.7, 122.9, 127.1,
129.6, 132.4, 147.5, 147.6, 147.7, 148.0, 174.9; LRMS (EI) m/z (rel in-
tensity) 370 (MþþHþ, 25), 369 (Mþ, 100), 340 (43), 309 (43), 281
(54). Anal. Calcd for C21H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C,
68.42; H, 6.52; N, 3.60.
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8
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d 3.46 (s, 2H,

356
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