Synthesis of isoindolobenzazepine alkaloids based on radical reactions or Pd(0)-catalyzed reactions

Article abstract of DOI:10.1021/jo900311g

(Chemical Equation Presented) Methods for synthesis of a ring system characteristic of isoindolobenzazepine alkaloids were studied. Synthesis of lennoxamine and a formal synthesis of chelenine were accomplished in a short route via radical or Pd(0)-cataly

Full text of DOI:10.1021/jo900311g

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Synthesis of Isoindolobenzazepine Alkaloids Based on Radical Reactions
or Pd(0)-Catalyzed Reactions
Yu Onozaki, Nobuhito Kurono,† Hisanori Senboku,† Masao Tokuda, and
Kazuhiko Orito*
Laboratory of Organic Synthesis, Division of Molecular Chemistry, Graduate School of Engineering,
Hokkaido University, Sapporo 060-8628, Japan. †Present address: Division of Chemical Process Engineering.
orito@eng.hokudai.ac.jp
Received February 11, 2009
Methods for synthesis of a ring system characteristic of isoindolobenzazepine alkaloids were studied.
Synthesis of lennoxamine and a formal synthesis of chelenine were accomplished in a short route
via radical or Pd(0)-catalyzed cyclization as the key step. An altenative approach based on a
radical migration of a cyano group or Pd(0)-catalyzed carbonylation was also developed for both
alkaloids.
Introduction
f7 at the final stage of the synthesis. Conversion of dehydro-
lennoxamine (3) into chilenine3d and lennoxamine2e,3g has
been achieved (Scheme 1). We were interested in the synthetic
routes via a ring-closure at e, f, or g, which leads to the
isoindolinone ring formation, and examined the validity
of the methodologies based on Pd-catalyzed cyclizations
Lennoxamine (1) and chilenine (2)1 occur together with
some isoquinoline alkaloids in nature.1 The ring system,
isoindolo[1,2-b][3]benzazepine, has been completed by cycli-
zation that forms a C-C or C-N bond at a,2 b,3 c,4 d,5 e,6 or
(1) (a) Shamma, M. The Alkaloids; Academic Press: New York, 1972; p 408.
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5486 J. Org. Chem. 2009, 74, 5486–5495
Published on Web 05/21/2009
DOI: 10.1021/jo900311g
r
2009 American Chemical Society

Onozaki et al.
JOCArticle
SCHEME 1. Isoindolobenzazepine Alkaloids
SCHEME 2. Preparation of Tetrahydro-3H-3-benzazepine 7a
involving Heck reaction8 or Mori-Ban carbonylation,9,10 or
aryl radical reactions11 using 3-benzazepines with a haloaryl
group as the substrates.
Results and Discussion
Preparation and reactions of 3-benzazepine intermediates
8 and 10 are first examined on the basis of the reported
method.12 3-Benzazepin-2-one 6a was prepared via primary-
amino acid 5a from 4a in a low yield of 30% but was
smoothly reduced with LiAlH4 to tetrahydro-3H-3-benza-
zepine 7a in good yield. Introduction of a p-methoxybenzyl
group on the nitrogen atom improved the yield for the
intramolecular condensation (5b f 6b) to 87%, although
reaction steps for the benzylation and debenzylation were
required to give 7a (Scheme 2).
3H-3-benzazepine 8 in 95% yield. A radical cyclization via a
1,5-hydrogen atom migration13 followed by aninsertion of the
generated R-acylamino radical6c to an internal phenyl group
for the conversion of 8 to lennoxamine 1 [8 f i f ii f 1] was
unsuccessful, and only debrominated reactant 9 was formed in
94% yield. Attempts at conversion of 8 into its dehydro-
derivative 10 by dehydrogenation with DDQ or Pd-C or
similar functionalization at C-1 by other methods, including
NBS/(PhCOO)2 or hν, or CrO3 oxidation were unsuccessful.
Another route to dihydro-3H-3-benzazepine 10 was ex-
amined. N-Alkylation of phenethylamine 1114 with BrCH2-
(OMe)2 (K2CO3, in DMF at 80 °C) produced acetal 12
almost quantitatively, as shown in Scheme 4. Successive N-
benzoylation with 6-bromo-2,3-dimethoxybenzoyl chlori-
de2b (Py in C6H6, rt) gave benzamide 13 (61%). An attempt
As shown in Scheme 3, benzapine 7a was then treated with
6-bromo-2,3-dimethoxybenzoyl chloride2b to give 3-benzoyl-
(8) For reviews on the Pd-catalyzed Heck reaction, see: (a) Beletskaya,
I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009–3066. (b) Whitcombe,
N J.; Hii, K. K. (M.); Gibson, S. E. Tetrahedron 2001, 57, 7440–7476.
(c) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176–4211.
(d) Dyker, G. Handbook of Organopalladium Chemistry for Organic Synth-
esis; Wiley: New Yori, 2002; Vol. 1, pp 1255-1282. (e) Dounay, A. B.; Overman,
L. E. Chem. Rev. 2003, 103, 2945–2963. (f) For recent references, see:Berthiol,
F.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2003, 44, 1221–1225.
(9) (a) Mori, M.; Chiba, K.; Ban, Y. J. Org. Chem. 1978, 43, 1684–1687.
(b) Mori, M.; Chiba, K.; Inotsume, N.; Ban, M. Heterocycles 1979, 12, 921–
924.
(10) (a) Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V. Carbonylation,
Direct Synthesis of Carbonyl Compound; Plenum Press: New York, 1991; pp
191-204. (b) Tsuji, J. Palladium Reagents and Catalysts, Innovation in
Organic Synthesis; John Willey & Sons: Chichester, U.K., 1995; pp 188-209.
(c) Tkatchenko, I. In Comprehensive Organometallic Chemistry; Wilkinson, G.,
Stone, F. G. A., Abel, E. W., Eds.; Pergamon Press: Oxford, UK, 1982; Vol. 8, pp
101-223.
(11) For reviews on aryl radical cyclization, see: (a) Ikeda, M.; Sato, T.;
Ishibashi, H. Rev. Heteroatom Chem. 1998, 18, 169–198. (b) Banik, B. K.
Curr. Org. Chem. 1999, 3, 469–496. (c) Murphy, J. A. Pure Appl. Chem. 2000,
72, 1327–1334. (d) Ishibasi, H. Chem. Rec. 2006, 6, 23–31. (e) For recent
references, see: Zhou, A.; Niogu, M. N.; Pittman, C. U. Jr. Tetrahedron 2006, 62,
4093–4102.
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R. H.; Rodrigo, R. J. Heterocycl. Chem. 1980, 417–423.
5c
to induce cyclization of 13 by a method using AcCl-ZnCl2
resulted in recovery of the corresponding aldehyde. Cour-
ture’s conditions with H2SO4-AcOH (5:3 v/v)5e caused
decomposition of the substrate to give a complex mixture.
The effect of reduction in the amount of H2SO4 was at-
tempted. The use of a 1:3 v/v H2SO4-AcOH solution yielded
the desired 10 in 45% yield, together with a significant
amount of the aldehyde. Addition of MgSO4, Ac2O, or MS
did not improve the reaction, but the addition of a small
amount of MeOH (half volume of H2SO4), which was
expected to reproduce the acetal group, markedly improved
the low cyclization efficiency to 82% yield of 10 in two steps.
In addition, treatment of acetal 12 with H2SO4-AcOH
(1:4 v/v) at 40 °C produced dihydroazepine 14 in 77% yield,
but its N-acylation with 6-bromo-2,3-dimethoxybenzoyl
chloride failed to give 10, and a complex mixture was
obtained.
(13) For formation of 1-oxoisoindolines by a 1,5-hydrogen atom transfer
by aryl radicals generated from o-halobenzamides followed by cyclization of
the resulting R-amidoyl radical, see: (a) Snieckus, V.; Cuevas, J.-C.; Sloan,
C. P.; Liu, H.; Curran, D. P. J. Am. Chem. Soc. 1990, 112, 896–898.
(b) Curran, D. P.; Liu, H. J. Chem. Soc., Perkin Trans. 1 1994, 1377–1393.
(c) Beckwith, A. L. J.; Storey, J. M. D. J. Chem. Soc., Chem. Commun. 1995,
977–978. (d) Ikeda, M.; Kugo, Y.; Sato, T. J. Chem. Soc., Perkin Trans. 1
1996, 1819–1824.
(14) Dallacker, F.; Bernabei, D.; Katzke, R.; Benders, P.-H. Chem. Ber.
1971, 104, 2517–2525.
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SCHEME 3. Attempts at Conversion of 8 to Lennoxamine (1)
SCHEME 4. Preparation of 10 and Synthesis of 1 and Dehy-
drolennoxamine (3)
To examine the e-bond formation, radical cyclization of
dihydro-3H-3-benzazepine 10 to lennoxamine 1 was examined.
Funk has already reported the conversion affording 1 in 58%
yield under standard conditions using a catalytic amount of
AIBN (0.15 mol equiv),6b and a radical cyclization of o-bromo-
benzylamine derivative was also reported by Hanaoka.6a The use
of excess AIBN (3.0 mol equiv) together with Bu3SnH (1.5 mol
equiv) in boiling benzene for 8 h produced 1 in 73% yield
together with the debrominated reactant (15) (24%). The use of
a smaller amount of AIBN (1 mol equiv) resulted in the
formation of a larger amount of 15 (>30%). An alternative
procedure utilizing AIBN (4 mol equiv) and AllylSnBu3 (4 mol
equiv) resulted in complete suppression of the debromination,
but the cyclization proceeded slowly to give a 1:1 mixture of the
unchanged reactant 10 and 1 even after 4 days.
cyclization via trans-elimination of HPdBr15b-g to give 3 in
DMF (entry 3) or better in toluene (92% isolated yield)
(entry 4 in Table 1). In view of the previous conversion of 3
into lennoxamine (1)2e,3g and chilenine (2),3d this constitutes
a formal synthesis of these alkaloids, providing a new
example for Heck cyclization versus radical cyclization.18
The previously reported one-pot method with EtONa in
EtOH affords 1-cyano-2-phenyl-3-benzazepines in low yield
of about 30%.19 Therefore, according to the aforementioned
procedure for the preparation of 4b, trifluoroacetamide 4a
was first treated with bromobenzaldehyde 16a20 and K2CO3
in MeOH-H2O (1:1) in the presence of 3 A molecular sieves
On the other hand, Heck cyclization15a of 10 with Pd-
(OAc)2 (20 mol %) and PPh3 (40 mol %) in the presence of
K2CO3 (10 mol equiv) heated in boiling toluene for 24 h gave
dehydrolennoxamine (3) in 94% isolated yield, as shown in
entry 1 (Table 1). Tertiary amine (Et3N) used instead of
K2CO3 was not effective at all (entry 2).16 The use of Bu4NCl
(2 mol equiv)17 instead of PPh3 resulted in exclusive Heck
(15) (a) Ikeda, M.; El Bialy, S. A. A.; Yakura, T. Heterocycles 1999, 51,
1957–1970. (b) Grigg, R.; Sridharan, V.; Stevenson, P.; Sukirthalingam, S.;
Worakun, T. Tetrahedron 1990, 46, 4003–4018. (c) Comins, D. L.; Joseph,
S. P.; Zhang, Y. Tetrahedron Lett. 1996, 37, 793–796. (d) Garcı
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a, A.;
(18) For Heck vs. radical cyclizations, see: (a) Sundberg, R. J.; Cherney,
R. J. J. Org. Chem. 1990, 55, 6028–6037. (b) Ishibashi, H.; Ito, K.; Tabuchi,
M.; Ikeda, M. Heterocycles 1991, 32, 1279–1282. (c) Kraus, G. A.; Kim, H.
Synth. Commun. 1993, 23, 55–64. (d) Mohanakrishnan, A. K.; Srinivasan,
P. C. Tetrahedron Lett. 1996, 37, 2659–2662. (e) Cossy, J.; Peglion, J.-L.;
Dpardo, D. G. Tetrahedron Lett. 1998, 39, 2965–2968. (f) Frey, D. A.; Duan,
C.; Ghiviriga, I.; Hudlicky, T. Collect. Czech. Chem. Commun. 2000, 65, 561–
569. (g) Denieul, M.-P.; Laursen, B.; Hhhazell, R.; Skrydstrup, T. J. Org.
Chem. 2000, 65, 6052–6060. (h) Kundig, P.; Ratni, H.; Crousse, B.;
Bernardinelli, G. J. Org. Chem. 2001, 66, 1852–1860.
Rodrı
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2001, 42, 1903–1905. (e) Lauthens, M.; Fang, Y.-Q. Org. Lett. 2003, 5,
3679–3682. (f) Ackermann, A.; Kaspar, L. T.; Gschrei, C. J. Chem. Commun.
2004, 2824–2825. (g) Wada, Y.; Nishida, N.; Kurono, N.; Ohkuma, T.; Orito,
K. Eur. J. Org. Chem. 2007, 4320–4327.
(16) (a) Plevyak, J. E.; Dickerson, J. K.; Heck, R. F. J. Org. Chem. 1979,
44, 4078–4080. (b) Andersson, C.-M.; Hallberg, A. J. Org. Chem. 1989, 54,
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2360.
5488 J. Org. Chem. Vol. 74, No. 15, 2009

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TABLE 1. Heck Cyclization of Dihydro-3H-3-benzazepine 10
entry
solvent
catalyst (mol %)/ligand (mol %)
base (mol equiv)
additive (mol equiv)
10:3
yield of 3 (%)
1
2
3
4
toluenea
toluenea
DMFb
Pd(OAc)2 (20)/PPh3 (40)
Pd(OAc)2 (20)/PPh3 (40)
Pd(OAc)2 (20)
K2CO3 (10)
Et3N (3)
K2CO3 (10)
K2CO3 (10)
0:100
94
100:0
15:85
0:100
Bu4NCl (2)
Bu4NCl (2)
toluenea
Pd(OAc)2 (20)
92
aRefluxed under argon for 24 h. bHeated at 90 °C under argon for 24 h.
SCHEME 5. Synthesis of 3 via Pd-Catalyzed Carbonylation
16b (73%), which was similarly subjected to condensation
with 4a to give imine 18b (95%).
A combination of EtONa (1.1 equiv) with an ethanolic solvent
such as EtOH, THF-EtOH (entries 1 and 2 in Table 2), or
dioxane-EtOH (entry 3) did not give good results for the
conversion of imine 18a to 3-benzazepine 19a. The use of a 3-
fold greater amount of the base resulted in the better formation
of the desired azepine 19a (entry 4). When a more basic alkoxide,
t-BuONa, was used in THF-t-BuOH, the cyclization proceeded
smoothly, and 80% of 19a was formed after 3 h (entry 5). It was
isolated almost quantitatively in the best isolated yield of 95%
after 6 h (entry 6). Thus,18b was also heated with t-BuONa (1.1
equiv) in THF-t-BuOH (2:1) for 6 h to afford benzazepine 19b
(85% in two steps).
As shown in Scheme 5, Pd(0)-catalyzed carbonylation of
iodobenzazepine 19b [CO (1 atm), Pd(OAc)2 (20 mol %),
PPh3 (40 mol %), K2CO3 (2 mol equiv)] in boiling toluene
(12 h) produced cyanolennoxamine 20a in 97% yield. Under the
same conditions, bromobenzazepine 19a failed to produce 20a,
but its 40,50-dimethoxy derivative 19c underwent carbonylation
to give 20b (42%), which is a regioisomer to 20a. To generate a
vicinal ketol system such as that in 2, 20a was subjected to
oxidative decyanation with Bu4NI (10 equiv) by treatment in a
refluxing 50% NaOH-CHCl3 solution under oxygen for 2
days.23 However, neither 2 nor other oxygenated compounds
were formed, and unsaturated cyanolennoxamine 21a was
instead obtained in 75% yield. The use of Bu4NBr in place of
Bu4NI resulted in complete recovery of 20a. Further attempts at
dioxygenation of an unsaturated system in 21a by using a dual-
oxygenation reagent, such as dimethyldioxirane,3d,24 OsO4,3d,25
H2O2,26 t-BuOOH,26 or KMnO4,27 have so far been unsuccess-
ful. For instance, treatment of 21a with H2O2 in the presence of
Bu4NF26 afforded amide 21b in 48% yield. The cyano group of
20a was quantitatively removed in a boiling t-BuOH-THF (3:2)
solution containing t-BuONa (1.5 equiv), and the aforemen-
tioned synthetic precursor 3 of lennoxamine (1) or chilenine (2)
was obtained. Execution of this two-step procedure on 19b in one
pot resulted in the formation of 3 in 96% yield.
(23) (a) Donetti, A.; Boniardi, O.; Ezhaya, A. Synthesis 1980, 1009–1011.
(b) Hatzigrigoriou, E.; Wartski, L. Bull. Soc. Chem. Fr. 1983, II-313–II-316.
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(27) Ogino, T.; Mochizuki, K. Chem. Lett. 1979, 443–445.
at rt for 12 h, to afford imine 18a (97%), as shown in
Scheme 5. An attempt to prepare iodobenzaldehyde 16b by
direct treatment of bromide 16a with CuI/KI/TMEDA,21
LDA/I2, or NIS failed. A halogen exchange on ethylene
acetal 17 (99%) with BuLi and NIS,22 followed by deaceta-
lization with 2 N HCl solution, produced iodobenzaldehyde
(28) For radical 1,4-migration of a cyano group, see: (a) Kalvoda, J. Helv.
Chim. Acta, 1968, 51, 267-277; Kalvoda, J. Chem. Commun. 1970, 1002-1003.
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TABLE 2. Cyclization of Imine 18a to 3-Benzazepine 19aa
entry
base (equiv)
solvents
temp, °C
time, h
18a:19ab
yield of 19a, %
1
2
3
4
5
6
EtONa (1.1)
EtONa (1.1)
EtONa (1.1)
EtONa (3.0)
tBuONa (1.1)
tBuONa (1.1)
THF/EtOH (2:1)
THF/EtOH (2:1)
dioxane/EtOH (2:1)
THF/EtOH (2:1)
THF/tBuOH (2:1)
THF/tBuOH (2:1)
reflux
50
50
50
50
3
20
3
3
3
4:1
a complex mixture
1: 1
1:2
1:4
0:10
50
6
95
aReactions were carried out under argon. bDetermined by 1H NMR analysis.
SCHEME 6. Radical 1,4-Cyano Migration of 3-Benzazepines 19 and Synthesis of 1
To obtain 3-benzazepine 22a, a 1,4-cyano migration via a
5-exo radical cyclization onto the halogenated aryl carbon
was examined (Scheme 6).28 When iodide 19b in a 0.02 M
boiling benzene solution was treated with AIBN (1.5 equiv)
and Bu3SnH (2 equiv) for 12 h, only deiodination occurred
in 50% conversion to give 24a (entry 1 in Table 3). Replace-
ment of the solvent with boiling toluene afforded an un-
saturated cyano migrated product 23a over 24a in a ratio of
2:1 from both iodide 19b and bromide 19a (entries 2 and 4).
Reaction in boiling xylene gave a complex mixture (entry 3).
Similar treatments of N-Me derivatives (19bMe and
19aMe) of 19b and 19a in boiling toluene produced a
saturated cyano migration product, 2-(2-cyanophenyl)-
3H-3-benzazepine 22b and dehalogenated reactant 24b in
a 1:1 ratio in a dark brown reaction mixture, respectively
(entries 5 and 6). In entries 7 and 8, the amount of the
5490 J. Org. Chem. Vol. 74, No. 15, 2009

Onozaki et al.
JOCArticle
TABLE 3. Radical 1,4-Cyano Migration of 3-Benzazepines 19a
entry
substrate
R
X
AIBN/Bu3SnH, mol equiv
concn, M
solvent
NMR mol ratio 19:22:23:24
yield
1b
2b
3b
4b
19b
19b
19b
19a
H
I
I
I
Br
1.5/2.0
1.5/2.0
1.5/2.0
1.5/2.0
0.02
0.02
0.02
0.02
benzene
toluene
xylene
1:0:0:1
0:0:2:1
a complex mixture
0:0:2:1
24a (40%)
23a (65%)
H
H
H
toluene
23a (63%)
5b
6b
19bMe
19aMe
Me
Me
I
Br
1.5/2.0
1.5/2.0
0.02
0.02
toluene
toluene
0:1:0:1
0:1:0:1
22b (28%)
22b (30%)
24b (27%)
22a (40%)d
22a (51%)d
22a (57%)d
22a (44%)d
23c (85%)
7c
19a
19a
19a
19a
19c
H
H
H
H
H
Br
Br
Br
Br
Br
0.5/2.0
0.1/2.0
0.5/2.0
0.1/2.0
1.5/2.0
0.02
0.02
0.01
0.01
0.02
toluene
toluene
toluene
toluene
toluene
0:2:0.1:1
0:3:0:1
0:4:0.2:1
1.5:3:0.3:1
0:0:15:1
8c
9c
10c
11b
aAll reactions were carried out in an appropriate boiling solvent under Ar. bThe reaction was carried out with 0.05 mmol of each substrate in a solvent
(2.5 mL). cThe reaction was carried out with 1 mmol of 19a. dIsolated as an HBr salt.
SCHEME 7. Radical 1,4-Cyano Migration of 3-Benzazepines 19
radical initiator AIBN in the reaction of bromide 19a was
reduced to 0.5 or 0.1 molar equiv, the 0.5 molar equiv giving
the desired product 22a together with a small amount of its
1,2-unsaturated derivative 23a and the 0.1 molar equiv
giving a greater amount of 22a without forming 23a. The
use of 0.5 molar equiv of AIBN in a diluted system (0.01 M
toluene solution, entry 9) resulted in more efficient 1,4-
cyano migration (>80%) to produce 2-(2-cyanophenyl)-
3H-3-benzazepine 22a in 57% isolated yield accompanied
by its 1,2-unsaturated derivative 23a and debrominated
reactant 24a in a ratio of 4:0.2:1 (entry 9). In another diluted
system containing 0.1 molar equiv of AIBN (entry 10) some
of the reactant remained unchanged. Successive treatment
of 22a with 1 N NaOH solution in boiling isoPrOH (1:5 vol %)
for 24 h produced lennoxamine (1) in 70% yield. A one-pot
procedure for these conversions gave 1 in a better yield
(54%). Thus, the first natural product synthesis through a
cyano migration28 was accomplished. In addition, bromide
19c gave an unsaturated cyano migration product 23c,
together with a small amount of 24a in a ratio of 15:1, in
85% isolated yield (entry 11) under the same conditions as
those in entry 2.
Scheme 7 shows processes for radical cyano migration
followed by abstraction of a hydrogen atom. In the radical
reaction of 19b, which has an NH group, a greater amount of
AIBN causes a hydrogen abstraction at the C2 position by a
generated isobutyronitrile radical after cyano migration to
form a double bond in an unsaturated azepine 23a. In
contrast, in the case of its N-Me derivatives, 19aMe and
19bMe, the attack of the isobutyronitrile radical to the C-2
hydrogen is blocked with a barricade of an N-Me group, and
an unsaturated azepine depicted as 23b was not formed. The
radical at C-1 abstracts a hydrogen atom from Bu3SnH to
give a saturated azepine 22b, as shown in entries 5 and 6.
Moreover, the cyano migration proceeded more slowly with
a sterically hindered aryl radical generated from the 20-halo-
30,40-dimethoxyphenyl group in 19a or 19b compared with
that from the 20-halo-40,50-dimethoxy group in 19c, and the
hindered aryl radical tended to abstract a hydrogen atom
intermolecularly from Bu3SnH to give 24a or 24b. This is the
reason why 19c gave the cyano migration product (23c) in
greater amount. Thus, the desired compound 22a was more
efficiently formed in a diluted solution of 19a in order to
suppress an intermolecular hydrogen abstraction of the C-20
J. Org. Chem. Vol. 74, No. 15, 2009 5491

Onozaki et al.
JOCArticle
aryl radical from Bu3SnH to 24a and an intermolecular
hydrogen abstraction at C-2 by an isobutyronitrile radical
to 23a.
In summary, methods for synthesis of a ring system
characteristic of isoindolobenzazepine alkaloids were studied.
Synthesis of lennoxamine and a formal synthesis of chelenine
were accomplished in a short route via radical or Pd(0)-
catalyzed cyclization as the key step. An alternative access
based on a radical migration of a cyano group also led to the
synthesis of lennoxamine.
dried (Na2SO4). The solvent was evaporated to give amide 13
(290 mg, 61%) as a light brown oil. This was dissol-
ved in a mixture of MeOH (0.5 mL) and acetic acid (3 mL)
and cooled to 0 °C. After concd H2SO4 (1.0 mL) was added
dropwise, the mixture was stirred at rt for 24 h and poured
slowly into concd NH4OH (15 mL). The mixture was extracted
with CH2Cl2 (3ꢀ15 mL). The combined extracts were washed
with water (3ꢀ20 mL), dried (Na2SO4), and concentrated to give
an oil (281 mg), which was purified by preparative TLC on silica
gel developed with 1% MeOHCH2Cl2. A main band with Rf 0.6
gave 3-benzazepine 10 (186 mg, 85% in 2 steps) as a colorless oil:
1
IR (Nujol) νmax 1661, 1636, 1505 cm-1; H NMR (270 MHz,
CDCl3) δ 2.96-3.13 (m, 2H), 3.62, 4.11 (2:1, each t, J=5.0,
4.0 Hz, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 4.01-4.36 (m, 1H), 5.40,
5.80 (2:1, each d, J=10.6, 2:1, 1H), 5.92 (s, 2H), 6.20, 7.42 (2:1,
each d, J=10.6 Hz, 1H), 6.50, 6.61, 6.64, 6.71 (1:2:2:1, each s,
2H), 6.83, 6.85 (2:1. each d, J=8.9 Hz, 1H), 7.30, 7.36 (2:1, each
s, 1H); EI-MS m/z (rel intensity) 433 (M+, 29), 431 (M+, 30),
243 (100). HRMS calcd for C20H18BrNO5 431.0396, found
431.0382.
Experimental Section
3-(6-Bromo-2,3-dimethoxybenzoyl)-7,8-(methylenedioxy)-1,2,
4,5-tetrahydro-3H-3-benzazepine (8). To a stirred solution of 7a
(442 mg, 2.31 mmol) and pyridine (1.5 mL) in benzene (10 mL)
at rt was dropwise added 6-bromo-2,3-dimethoxybenzoyl chlor-
ide2b,15g (700 mg, 2.5 mmol) {freshly prepared from 6-bro-
mo-2,3-dimethoxybenzoic acid [prepared by bromination of
2,3-dimethoxybenzoic acid with 1,3-dibromo-5,5-dimethylhy-
dantoin, mp 81-83 °C (benzene-hexane), 1H NMR δ 3.88 (s,
3H), 3.93 (s, 3H), 6.86 (d, J=8.6 Hz, 1H), 7.28 (d, J=8.6 Hz,
1H)] and excess SOCl2} in benzene (10 mL). The mixture was
stirred for 12 h and then washed with aq 2 N HCl (3ꢀ25 mL), aq
2 N NaOH (3 ꢀ 25 mL), and water (3 ꢀ 50 mL), then dried
(Na2SO4). The solvent was evaporated, and the residue was
crystallized from benzene -hexane to give 8 (963 mg, 95%),
mp 201-203 °C, as dark gray crystals: IR (Nujol) νmax 1628,
Preparation of 7,8-Methylenedioxy-4,5-dihydro-3H-3-benza-
zepine (14) and an Attempt To Obtain Its N-Benzoyl Derivative
10. To a stirred solution of acetal 12 (127 mg, 0.5 mmol) in
AcOH (2 mL) was added concd H2SO4 (0.5 mL). The mixture
was warmed at 40 °C for 15 h, then poured slowly into concd
NH4OH solution (10 mL). The mixture was extracted with
CH2Cl2 (3ꢀ10 mL). The combined extracts were washed with
water (3 ꢀ 10 mL), dried (Na2SO4), and concentrated to give
enamine 14 as an oil (73 mg, 77%); IR (Nujol) νmax 3310, 1628,
1502 cm-1; 1H NMR (270 MHz, CDCl3) δ 2.39-2.97 (m, 2H),
3.42-3.47 (m, 1H), 3.91 (br s, 1H), 4.95 (d, J=9.9 Hz, 1H), 5.87
(s, 2H), 6.11 (dd, J=9.9, 5.9 Hz, 1H), 6.50 (s, 1H), 6.56 (s, 1H);
EI-MS (rel intensity) 189 (M+, 100). HRMS calcd for
C20H18BrNO5 189.0790, found 189.0783. This was dissolved
in benzene (2 mL) containing pyridine (0.5 mL) and treated
with 6-bromo-2,3-dimethoxybenzoyl chloride2b,15g (137 mg,
0.49 mmol) in benzene (1 mL) at rt for 12 h. The reaction
mixture was diluted with Et2O (15 mL), washed with water (3ꢀ
10 mL) and aq 2 N NaOH (3ꢀ10 mL), and dried (Na2SO4). The
solvent was evaporated to give an oil (127 mg), 1H NMR
spectrum of which showed mainly the presence of 6-bromo-
2,3-dimethoxybenzoic acid but not the desired amide 10.
Radical Cyclization of 10: Synthesis of Lennoxamine (1). A
solution of 10 (30 mg, 0.07 mmol), AIBN (36 mg, 0.21 mmol),
and Bu3SnH (30 mg, 2.3 mmol) in dry benzene (12 mL) under
nitrogen was refluxed with stirring for 8 h. The solvent was
evaporated. The residue was dissolved in CH3CN (10 mL) and
washed with hexane (3 ꢀ 20 mL). The CH3CN layer was
separated and concentrated to give an oil (35 mg), which was
purified by preparative TLC on silica gel developed with 3%
MeOH-CH2Cl2. A main band with Rf 0.6 was crystallized from
MeOH to give lennoxamine (1) (18 mg, 73%), mp 229-230 °C
(lit.1e mp 225 °C; lit.2c mp 223-225 °C; lit.6b mp 223-226 °C;
lit.3j mp 226-227 °C; lit.5h 226-228 °C; lit.6c mp 227-228 °C;
lit.5c,7a mp 228-229 °C; lit.2d mp 229-230 °C; lit.5f mp 235-
235.5 °C), as colorless crystals. A band with Rf 0.8 gave the
debrominated reactant 15 (6 mg, 24%) as a pale yellow oil: IR
(neat) νmax 2938, 2240, 1659 cm-1; 1H NMR (270 MHz, CDCl3)
δ 2.94-3.03 (m, 2H), 3.70-4.33 (m, 2H), 3.85 (s, 3H), 3.90 and
3.91 (2:1, each s, 3H), 5.36 and 5.75 (2:1, each d, J=10.6 Hz, 1H),
5.92 (s, 2H), 6.29 and 7.43 (2:1, each d, J=10.6 Hz, 1H), 6.51,
6.60, 6.64, 6.71 (1:2:2:1, each s, 2H), 6.83-6.88 (m, 1H), 6.98
(dd, J = 8.3, 1.7, 1H), 7.09-7.16 (m, 1H); EI-MS m/z (rel
intensity) 353 (M+, 1), 91 (31). HRMS calcd for C20H17NO5
353.1263, found 353.1260.
1
1490 cm-1; H NMR (270 MHz, CDCl3) δ 2.83 (dd, J=6.3,
3.0 Hz, 2H), 2.95 (t, J=4.6 Hz, 2H), 3.33 (dd, J=6.3, 4.6 Hz,
2H), 3.87 (s, 3H), 3.88 (s, 3H), 3.70-4.10 (m, 2H), 5.91 (s, 2H),
6.54 (s, 1H), 6.68 (s, 1H), 6.80, 7.26 (AB type, J=8.6 Hz, each
1H); 13C NMR (67.8 MHz, CDCl3) δ 37.0, 37.3, 44.5, 49.7, 56.0,
61.7, 100.9, 109.2, 11.1, 110.2, 113.6, 128.2, 133.4, 133.7, 134.4,
145.6, 145.8, 152.2, 165.5, 183.7; EI-MS m/z (rel intensity) 435
(M+, 31), 433 (M+, 32), 354 (68), 243 (100). Anal. Calcd for
C20H20BrNO5: C, 55.31; H, 4.64; Br, 18.40; N, 3.23. Found: C,
55.56; H, 4.79; Br, 18.43; N, 3.15.
Treatment of 8 with Bu3SnH and AIBN. A stirred solution of 8
(30.4 mg, 0.07 mmol), AIBN (11.5 mg, 0.07 mmol), and Bu3SnH
(40.7 mg, 0.14 mmol) in toluene (2 mL) was heated at reflux for
4 h. The reaction mixture was concentrated. The residue was
dissolved in CH3CN (10 mL), then washed with hexane (3ꢀ20
mL). Evaporation of CH3CN afforded an oil (34 mg), which was
subjected to preparative TLC with 3% MeOHCH2Cl2. A band
with Rf 0.6 afforded 9 as colorless crystals (21 mg, 94%), mp
151-152 °C (Et2O) (lit.6c mp 151-152 °C).
Preparation of 3-(6-Bromo-2,3-dimethoxybenzoyl)-7,8-(meth-
ylenedioxy)-1,2-dihydro-3H-3-benzazepine (10). A mixture of
phenethylamine 11 (2.48 g, 15 mmol), bromoacetaldehyde
dimethylacetal (2.53 g, 15 mmol), and K2CO3 (10.3 g, 75 mmol)
in DMF (50 mL) was stirred at 80 °C for 12 h. The mixture was
poured into water (80 mL), then extracted with ether (3 ꢀ
40 mL). The combined extracts were washed with saturated
brine (5 ꢀ 50 mL), dried (MgSO4), and concentrated to give
acetal 12 (3.83 g, 99%) as a colorless oil: IR (Nujol) νmax 3328,
1609, 1502 cm-1; 1H NMR (270 MHz, CDCl3) δ 2.75, 2.85 (each
t, J=5.6 Hz, each 2H), 3.37 (s, 6H), 4.45 (t, J=5.6 Hz, 1H), 5.92
(s, 2H), 6.64 (dd, J=7.9, 1.7 Hz, 1H), 6.69 (d, J=1.7 Hz, 1H),
6.73 (d, J=7.9 Hz, 1H); EI-MS m/z (rel intensity) 253 (M+, 7),
190 (15), 149 (55), 118 (100). HRMS calcd for C13H19NO4
253.1314, found 253.1316. To a stirred suspension of 12 (128
mg, 0.5 mmol), Et3N (91 mg, 0.9 mmol), and anhydrous MgSO4
(100 mg) in CH2Cl2 (7 mL) at rt was added dropwise 6-bromo-
2,3-dimethoxybenzoyl chloride2b,15g (0.24 g, 0.6 mmol) in
CH2Cl2 (5 mL). The mixture was stirred for 12 h, and then
washed with water (3ꢀ50 mL) and aq 2 N NaOH (3ꢀ25 mL) and
Heck Cyclization of Benzazepine 10: Synthesis of Dehydrolennox-
amine (3). A stirred mixture of benzazepine 10 (15 mg, 0.035 mmol),
Pd(OAc)2 (1.6 mg, 0.007 mmol), PPh3 (3.7 mg, 0.014 mmol), and
5492 J. Org. Chem. Vol. 74, No. 15, 2009

Onozaki et al.
JOCArticle
K2CO3 (48 mg, 0.35 mmol) in toluene (2 mL) was refluxed under
argon for 24 h. The reaction mixture was cooled to rt and filtered
through a Celite pad. The filtrate was concentrated. The residue
(18 mg) was purified by preparative TLC developed with 3%
MeOH-CH2Cl2. A main band with Rf 0.3 was crystallized from
MeOH to give 3 (12 mg, 94%) as yellow crystals, mp 210-211 °C
(lit.3j mp 208-209 °C; lit.2b mp 209-211 °C; lit.5f mp 213-214 °C).
Preparation of 2-Iodo-3,4-dimethoxybenzaldehyde (16b). A
mixture of 2-bromo-3,4-dimethoxybenzaldehyde (16a)20 (2.45 g,
10 mmol), ethylene glycol (5.68 mL, 0.1 mol), and concd H2SO4
(0.5 mL) in dry benzene (50 mL) was refluxed with a DeanStark
water separator under argon for 12 h. After cooling, the mixture
was diluted with Et2O (50 mL), washed with water (3ꢀ30 mL),
and dried (Na2SO4). The solvent was evaporated to give
[1,3]dioxolane 17 (2.93 g, >99%) as a crystalline solid. An anal-
ytical sample was prepared by recrystallization from benzene-
60.3, 62.1, 99.6, 101.3, 108.9, 110.2, 112.3, 118.2, 121.4, 124.5,
129.9, 131.5, 146.5, 147.6, 148.3, 154.6, 165.0; EI-MS m/z (rel
intensity) 478 (M+, 76), 304 (33), 177 (100). Anal. Calcd for
C20H19IN2O4: C, 50.22; H, 4.00; I, 26.53; N, 5.86. Found: C,
50.29; H, 4.03; I, 26.78; N, 5.78.
2-Cyanomethyl-N-(2-bromo-4,5-dimethoxybenzylidene)-4,
5-(methylenedioxy)phenethylamine (18c): colorless crystals
(93%), mp 109-110 °C (EtOH); IR (Nujol) νmax 2256,
1
1634, 1598, 1509 cm-1; H NMR (270 MHz, CDCl3) δ 2.94
(t, J=6.9 Hz, 2H), 3.72 (s, 2H), 3.84 (t, J=6.9 Hz, 2H), 3.91
(s, 3H), 3.94 (s, 3H), 5.96 (s, 2H), 6.76 (s, 1H), 6.84 (s, 1H),
6.98 (s, 1H), 7.48 (s, 1H), 8.37 (s, 1H); 13C NMR (67.8 MHz,
CDCl3) δ 21.4, 34.0, 56.1, 56.2, 62.1, 101.3, 109.0, 109.6,
110.3, 115.0, 116.7, 118.1, 121.3, 126.5, 131.5, 146.6, 147.7,
148.7, 151.7, 160.6; EI-MS m/z (rel intensity) 433 (M+, 49),
431 (M+, 50), 256 (31), 200 (44), 177 (100). Anal. Calcd for
1
hexane; mp 72-73 °C; IR (Nujol) νmax 1594, 1495 cm-1; H
C20H19BrN2O4: C, 55.70; H, 4.44; Br, 18.53; N, 6.50. Found:
C, 55.47; H, 4.59; Br, 18.70; N, 6.42.
NMR (270 MHz, CDCl3) δ 3.85 (s, 3H), 3.88 (s, 3H), 4.03-4.18
(m, 4H), 6.07 (s, 1H), 6.89 (d, J=8.9 Hz, 1H), 7.34 (d, J=8.9 Hz,
1H); EI-MS m/z (rel intensity) 290 (M+, 88), 289 [(M + H)+,
100], 288 (M+, 90), 257 (28), 243 (30), 216 (54). Anal. Calcd for
C11H13BrO4: C, 45.70; H, 4.53; Br, 27.64. Found: C, 45.81; H,
4.58; Br, 27.57. To a stirred solution of this dioxolane (4.34 g,
15 mmol) in dry THF (100 mL) under argon at -78 °C was added
dropwise n-BuLi (1.5 M hexane solution, 12 mL). After 20 min, a
solution of N-iodosuccinimide (4.39 g, 19.5 mmol) in dry THF
(100 mL) was added dropwise. The mixture was stirred at -78 °C
for 2 h, and then at rt for 3 h. The resulting mixture was quenched
with aq 2 N HCl (10 mL), stirred for 2 h, extracted with CH2Cl2
(3ꢀ30 mL), washed with saturated brine (3ꢀ30 mL), and dried
(Na2SO4). The solution was concentrated to dryness. The residue
(4.19 g) was subjected to column chromatography on silica gel
with CH2Cl2 as eluent to give iodide 16b (3.18 g, 73%) as a
crystalline solid. An analytical sample was prepared by recrystal-
2-(2-Bromo-3,4-dimethoxyphenyl)-1-cyano-7,8-(methylenedi-
oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine (19a): General Pro-
cedure. A solution of 18a (431 mg, 1.0 mmol) and t-BuONa
(105 mg, 1.1 mmol) in dry THF (30 mL) and dry t-BuOH
(15 mL) was refluxed under argon for 10 h. The cooled reaction
mixture was concentrated and dissolved in CH2Cl2 (20 mL),
washed with water (3ꢀ20 mL), dried (Na2SO4), and concen-
trated. The residue was crystallized from EtOH to give 3-ben-
zazepine 19a (409 mg, 95%) as colorless crystals, mp 208-
209 °C; IR (Nujol) νmax 1600, 1504 cm-1; 1H NMR (270 MHz,
CDCl3) δ 2.17 (br. s, 1H), 2.73 (dd, J=15.2, 5.6 Hz, 1H), 2.87 (t,
J=12.2 Hz, 1H), 3.42-3.55 (m, 2H), 3.87 (s, 3H), 3.90 (s, 3H),
3.94 (d, J=1.0 Hz, 1H), 4.34 (d, J=1.0 Hz, 1H), 5.97, 5.98 (each
d, J=1.3 Hz, each 1H), 6.68 (s, 1H), 6.70 (s, 1H), 6.96 (d, J=8.6
Hz, 1H), 7.51 (d, J=8.6 Hz, 1H); 13C NMR (67.8 MHz, CDCl3)
δ 37.5, 47.4, 48.9, 56.1, 60.5, 62.5, 101.4, 110.4, 111.1, 111.6,
117.7, 118.5, 122.4, 127.3, 133.5, 136.3, 136.0, 146.4, 147.4,
153.3; EI-MS m/z (rel intensity) 433 (M+, 22), 431 (M+, 24),
430 (92), 390 (12), 256 (50), 244 (100), 200 (95), 177 (94). Anal.
Calcd for C20H19BrN2O4: C, 55.70; H, 4.44; Br, 18.53; N, 6.50.
Found: C, 55.53; H, 4.31; Br, 18.72; N, 6.36.
lization from EtOH; mp 77-78 °C; IR (Nujol) 1677, 1579 cm-1
;
1H NMR (270 MHz, CDCl3) δ 3.87 (s, 3H), 3.96 (s, 3H), 6.97 (d,
J=8.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 10.02 (s, 1H); 13C NMR
(67.8 MHz, CDCl3) δ 56.2, 60.4, 100.3, 111.8, 127.4, 128.9, 148.7,
157.7, 194.9; EI-MS m/z (rel intensity) 292 (M+, 100), 277 (11),
248 (3). Anal. Calcd for C9H9BrO3: C, 44.11; H, 3.70; Br, 32.60.
Found: C, 44.04; H, 3.85; Br, 32.48.
1-Cyano-2-(2-iodo-3,4-dimethoxyphenyl)-7,8-(methylenedi-
oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine (19b): colorless crys-
tals (85% in two steps from 4 and 16b through 18b), mp 219-223
2-Cyanomethyl-N-(2-bromo-3,4-dimethoxybenzylidene)-4,
5-(methylenedioxy)phenethylamine (18a): General Procedure.
A mixture of trifluoroacatamide 4a (600 mg, 2.0 mmol),
2-bromo-3,4-dimethoxybenzaldehyde (16a) (490 mg, 2.0 mmol),
K2CO3 (1.38 g, 10 mmol), water (5 mL), and MeOH (15 mL) was
stirred at rt overnight. MeOH was then evaporated, and the
residue was treated with water (20 mL) and CH2Cl2 (20 mL).
The organic layer was washed with water (3 ꢀ 20 mL), dried
(Na2SO4), and concentrated. The residue was crystallized from
EtOH to give imine 18a (836 mg, 97%) as colorless crystals;
1
°C (EtOH); IR (Nujol) νmax 2236, 1587, 1504 cm-1; H NMR
(270 MHz, CDCl3) δ 2.13 (br. s, 1H), 2.74 (dd, J=15.2, 5.6 Hz,
1H), 2.88 (t, J=12.2 Hz, 1H), 3.48 (m, 2H), 3.85 (s, 3H), 3.89 (s,
3H), 3.91 (s, 1H), 4.24 (s, 1H), 5.97, 5.98 (each s, each 1H), 6.68
(s, 1H), 6.76 (s, 1H), 6.97 (d, J = 8.6 Hz, 1H), 7.51 (d,
J=8.6 Hz, 1H); 13C NMR (67.8 MHz, CDCl3) δ 37.5, 47.4,
48.9, 56.1, 60.3, 67.0, 98.4, 101.4, 110.8, 111.1, 112.6, 117.7,
123.1, 127.3, 136.4, 136.4, 146.0, 147.5, 148.7, 152.4; EI-MS m/z
(rel intensity) 478 (M+, 100), 438 (15), 304 (37), 256 (50), 215
(14), 177 (87). Anal. Calcd for C20H19IN2O4: C, 50.22; H, 4.00; I,
26.53; N, 5.86. Found: C, 50.18; H, 4.00; I, 26.47; N, 5.77.
2-(2-Bromo-4,5-dimethoxyphenyl)-1-cyano-7,8-(methylenedi-
oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine (19c): colorless crys-
tals (87% in two steps from 4 and 16c through 18c), mp 213-215 °C
1
mp 108-109 °C; IR (Nujol) νmax 1639, 1589 cm-1; H NMR
(270 MHz, CDCl3) δ 2.93 (t, J=6.6 Hz, 2H), 3.71 (s, 2H), 3.85 (s,
3H), 3.91(s, 3H), 3.85 (t, J=6.9 Hz, 2H), 5.96(s, 2H), 6.75 (s, 1H),
6.83 (s, 1H), 6.91 (d, J=8.9 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 8.42
(s, 1H); 13C NMR (67.8 MHz, CDCl3) δ 21.4, 33.9, 56.1, 60.5,
62.4, 101.3, 108.9, 110.2, 111.3, 118.2, 121.1, 121.4, 124.0, 127.5,
131.6, 146.0, 146.5, 147.6, 155.5, 160.6; EIMS m/z (rel intensity)
433 (M+, 14), 431 (M+, 15), 256 (37), 200 (50), 177 (100). Anal.
Calcd for C20H19BrN2O4: C, 55.70; H, 4.44; Br, 18.53; N, 6.50.
Found: C, 55.63; H, 4.57; Br, 18.28; N, 6.34.
(EtOH); IR (Nujol) νmax 1504 cm-1 1H NMR (270 MHz,
;
CDCl3) δ 2.0-2.2 (br, 1H), 2.75 (dd, J = 15.2, 5.6 Hz, 1H),
2.88 (t, J=12.2 Hz, 1H), 3.42-3.57 (m, 2H), 3.89 (s, 4H), 3.96 (s,
3H), 4.30 (s, 1H), 5.97, 5.98 (each d, J=2.0 Hz, each 1H), 6.67 (s,
1H), 6.69 (s, 1H), 7.04 (s, 1H), 7.39 (s, 1H); EI-MS m/z (rel
intensity) 433 (M+, 17), 431 (M+, 20), 430 (76), 390 (11), 256
(42), 244 (40), 200 (32), 177 (100). Anal. Calcd for C20H19Br-
N2O4: C, 55.70; H, 4.44; Br, 18.53; N, 6.50. Found: C, 55.67; H,
4.48; Br, 18.37; N, 6.41.
2-Cyanomethyl-N-(2-iodo-3,4-dimethoxybenzylidene)-4,5-(meth-
ylenedioxy)phenethylamine (18b): colorless crystals (99%), mp
128-130 °C (EtOH); IR (Nujol) νmax 1634, 1582, 1505 cm-1; 1H
NMR (270 MHz, CDCl3) δ 2.94 (t, J=6.6 Hz, 2H), 3.70 (s, 2H),
3.83 (s, 3H), 3.86 (t, J=6.9 Hz, 2H), 3.91 (s, 3H), 5.95 (s, 2H), 6.74
(s, 1H), 6.83 (s, 1H), 6.92 (d, J=8.9 Hz, 1H), 7.67 (d, J=8.9 Hz,
1H), 8.26 (s, 1H); 13C NMR (67.8 MHz, CDCl3) δ 21.4, 33.9, 56.0,
Preparation of 13-Cyannolenoxamine (20a): General Proce-
dure. A mixture of iodide 19b (954 mg, 2.0 mmol), PPh3 (210 mg,
0.80 mmol), Pd(OAc)2 (45 mg, 0.20 mmol), and K2CO3 (1.93 g,
J. Org. Chem. Vol. 74, No. 15, 2009 5493

Onozaki et al.
JOCArticle
14 mmol) in toluene (120 mL) was refluxed under CO for 12 h.
The precipitates were removed by filtration with a Celite pad,
and the filtrate was concentrated. The residue (1.49 g) was
chromatographed on silica gel with 3% MeOH-CH2Cl2 as
eluents to give a crude product. Crystallization from EtOAc-
hexane gave 20a (730 mg, 97%) as colorless crystals, mp 270-
3334, 2930, 1697, 1501 cm-1; 1H NMR (270 MHz, CDCl3) δ 2.95
(t, J=4.3 Hz, 2H), 3.54-3.66 (m, 2H), 3.87 (s, 3H), 3.97 (s, 3H),
5.98 (s, 2H), 6.15, 6.60 (each br s, each 1H), 6.63 (s, 1H), 7.01 (d,
J=8.6 Hz, 1H), 7.15 (s, 1H), 7.74 (d, J=8.6 Hz, 1H); EI-MS m/z
(rel intensity) 394 (M+, 100), 365 (19), 350 (40). Anal. Calcd for
C21H18N2O6: C, 63.96; H, 4.60; N, 7.10. Found: C, 63.69; H, 4.58;
N, 6.98.
272 °C; IR (Nujol) νmax 2242, 1693, 1504 cm-1 1H NMR
;
(270 MHz, CDCl3) δ 2.85 (dd, J=15.2, 4.3 Hz, 1H), 2.96 (t,
J=12.2 Hz, 1H), 3.34-3.45 (m, 1H), 3.93 (s, 3H), 4.12 (s, 3H),
4.22 (d, J=2.3 Hz, 1H), 4.53 (d, J=2.3 Hz, 1H), 4.80 (m, 1H),
6.00, 6.02 (each d, J=1.3 Hz, each 1H), 6.75 (s, 1H), 6.76 (s, 1H),
7.15, 7.19 (AB type, J = 8.3 Hz, each 1H); EI-MS m/z (rel
intensity) 378 (M+, 100), 338 (28), 205 (51), 192 (72). Anal.
Calcd for C21H18N2O5: C, 66.66; H, 4.79; N, 7.40. Found: C,
66.52; H, 4.75; N, 7.32.
2-(2-Bromo-3,4-dimethoxyphenyl)-1-cyano-3-methyl-7,8-(meth-
ylenedioxy)-1,2,4,5-tetrahydro-3H-3-benzazepine (19aMe): Gener-
al Procedure. A mixture of 19a (86 mg, 0.20 mmol) and CH3I
(0.12 mL, 2.0 mmol) in THF (3 mL) was refluxed for 8 h. The
resulting mixture was treated with 1.0 M aqueous K2CO3 solution
(10 mL), extracted with CH2Cl2 (3ꢀ10 mL), washed with water
(3ꢀ20 mL), dried (Na2SO4), and concentrated. The residue was
crystallized from CH2Cl2-EtOH-hexane to give 19aMe (71 mg,
95%) as colorless crystals, mp 212-213 °C (EtOH); IR (CHCl3)
13-Cyano-10,11-dimethoxy-5,6,12b,13-tetrahydro-8H-2,3-(meth-
ylenedioxy)isoindolo[1,2-b][3]benzazepin-8-one (20b). Bromide 19c
(22 mg, 0.05 mmol) on carbonylation under a similar manner for
24 h gave colorless crystals of 20b (8 mg, 42%), mp 276-278 °C
ν
max 2238, 1593, 1506 cm-1; 1H NMR (270 MHz, CDCl3) δ 2.14
(s, 3H), 2.42 (t, J=11.6 Hz, 1H), 2.80 (dd, J=15.8, 4.0 Hz, 1H),
3.37 (dd, J=12.9, 6.0 Hz, 1H), 3.49 (d, J=1.3 Hz, 1H), 3.61 (dd,
J=15.8, 10.6 Hz, 1H), 3.80 (d, J=1.3 Hz, 1H), 3.89 (s, 3H), 3.91 (s,
3H), 5.96, 5.99 (each d, J=1.3 Hz, each 1H), 6.66 (s, 1H), 6.67 (s,
1H), 6.99 (d, J=8.9 Hz, 1H), 7.64 (d, J=8.9 Hz, 1H); EI-MS m/z
(rel intensity) 446 (M+, 99), 444 (M+, 100), 404 (29), 270 (51), 229
(58). Anal. Calcd for C21H21BrN2O4: C, 56.64; H, 4.75; Br, 17.94;
N, 6.29. Found: C, 56.72; H, 4.79; Br, 17.78; N, 6.14.
1-Cyano-2-(2-iodo-3,4-dimethoxyphenyl)-3-methyl-7,8-(meth-
ylenedioxy)-1,2,4,5-tetrahydro-3H-3-benzazepine (19bMe): col-
orless crystals (96%), mp 213-215 °C (EtOH); IR (Nujol) νmax
2236, 1587, 1504 cm-1; 1H NMR (270 MHz, CDCl3) δ 2.13 (s,
3H), 2.43 (t, J=11.6 Hz, 1H), 2.78 (dd, J=15.8, 6.9 Hz, 1H), 3.37
(ddd, J=12.9, 6.9, 1.3 Hz, 1H), 3.63 (dd, J=15.8, 9.9 Hz, 1H),
3.76 (s, 2H), 3.87 (s, 3H), 3.91 (s, 3H), 5.97, 5.98 (d, J=1.3 Hz,
each 1H), 6.68 (s, 1H), 6.71 (s, 1H), 7.01 (d, J=8.6 Hz, 1H), 7.61
(d, J=8.6 Hz, 1H); EI-MS m/z (rel intensity) 492 (M+, 100), 452
(31), 365 (17), 318 (36), 277 (50). Anal. Calcd for C21H21IN2O4:
C, 51.23; H, 4.30; I, 25.78; N, 7.95. Found: C, 51.28; H, 4.28; I,
25.61; N, 8.00.
2-(2-Cyano-3,4-dimethoxyphenyl)-3-methyl-7,8-(methylene-
dioxy)-1,2,4,5-tetrahydro-3H-3-benzazepine (22b): General
Procedure for Radical 1,4-Cyano Migration (Entries 1-6 and
11 in Table 3). A stirred solution of bromide 19aMe (44 mg,
0.10 mmol), AIBN (24 mg, 0.15 mmol), and Bu3SnH (58 mg,
0.20 mmol) in dry toluene (6 mL) was refluxed for 12 h under
argon (entry 6). The resulting mixture was concentrated,
dissolved in CH3CN (10 mL), washed with hexane (3 ꢀ
20 mL), and concentrated. The residue was subjected to
preparative TLC on silica gel developed with 3% MeOH-
CH2Cl2 to show two bands at Rf 0.5 and 0.35 in a 1:1 ratio. A
mobile band with Rf 0.5 gave 22b (10 mg, 30%) as a light
brown oil; IR (CHCl3) νmax 2224, 1573, 1488, 1041 cm-1; 1H
NMR (270 MHz, CDCl3) δ 2.07 (s, 3H), 2.38-2.52 (m, 1H),
2.63 (d, J=14.9 Hz, 1H), 2.75 (dd, J=7.3, 14.9 Hz, 1H), 3.12-
3.28 (m, 3H), 3.51 (d, J=9.2, 1H), 3.90 (s, 3H), 4.03 (s, 3H),
5.90 (s, 2H), 6.58 (s, 1H), 6.63 (s, 1H), 7.11 (d, J=8.9 Hz, 1H),
7.24 (d, J=8.9 Hz, 1H); EI-MS m/z (rel intensity) 366 (M+,
100), 351 (23), 310 (49), 217 (37). HR-MS calcd for
1
(AcOEt-hexane); IR (CHCl3) νmax 2242, 1693, 1504 cm-1; H
NMR (270 MHz, CDCl3) δ 2.87-3.03 (m, 3H), 3.97 (s, 3H), 4.04
(s, 3H), 4.06 (d, J=7.9 Hz, 1H), 4.41 (d, J=7.9 Hz, 1H), 4.73-4.81
(m, 1H), 6.01, 6.03 (each d, J=1.0 Hz, each 1H), 6.75 (s, 1H), 7.30
(s, 1H), 7.33 (s, 1H), 7.49 (s, 1H); EI-MS m/z (rel intensity) 378
(M+, 100), 352 (31), 338 (23), 205 (98), 192 (87). Anal. Calcd for
C21H18N2O5: C, 66.66; H, 4.79; N, 7.40. Found: C, 66.45; H, 4.76;
N, 7.41.
Synthesis of 3 by Dehydrocyanation of 20a. A mixture of 20a
(38 mg, 0.1 mmol) and t-BuONa (15 mg, 0.15 mmol) in t-BuOH
(3 mL) and THF (2 mL) was refluxed under Ar for 1 h. The
cooled mixture was concentrated, then treated with CH2Cl2
(10 mL) and water (10 mL). The CH2Cl2 layer was washed with
water (10 mL), dried (Na2SO4), and concentrated to give 3 as a
solid (35 mg), which showed one spot (Rf 0.6) on silica gel TLC
developed with 3% MeOH-CH2Cl2. The reaction mixture
obtained from carbonylation of 19b (48 mg, 0.1 mmoL) fol-
lowed by the above-mentioned dehydrocyanation in one pot
was filtered through a Celite pad. The filtrate was subjected to
silica gel TLC (3% MeOH-CH2Cl2), and a band with Rf 0.6
gave 3 (34 mg, 96%) as colorless crystals, mp 208-209 °C
(MeOH).
13-Cyano-9,10-dimethoxy-5,6-dihydro-8H-2,3-(methylenedi-
oxy)isoindolo[1,2-b][3]benzazepin-8-one (21a). A mixture of 20a
(378 mg, 1.0 mmol), Bu4NI (3.69 g, 10 mmol), and 50 wt %
aqueous NaOH solution (5 mL) in CHCl3 (50 mL) was refluxed
under oxygen for 48 h. After cooling, Et2O (100 mL) was
added, and the mixture was washed with saturated brine (6ꢀ
50 mL), dried (MgSO4), and concentrated. The residue was
chromatographed on a silica gel column with 3% MeOH-
CH2Cl2 as eluents to give a crude product, which was crystal-
lized from CH2Cl2-hexane to give 21a (266 mg, 75%) as yellow
crystals, mp 280-281 °C; IR (Nujol) νmax 2202, 1712, 1578,
1
1511 cm-1; H NMR (270 MHz, CDCl3) δ 3.00 (dd, J=5.3,
4.3 Hz, 2H), 3.97 (s, 3H), 4.08 (s, 3H), 3.90-4.20 (br m, 2H),
6.02 (s, 2H), 6.66 (s, 1H), 7.17 (d, J=8.9 Hz, 1H), 7.36 (s, 1H),
8.57 (d, J=8.9 Hz, 1H); EI-MS m/z (rel intensity) 376 (M+,
100), 361 (38), 347 (22). Anal. Calcd for C21H16N2O5: C, 67.02;
H, 4.28; N, 7.44. Found: C, 66.88; H, 4.27; N, 7.51.
13-Carbamoyl-9,10-dimethoxy-5,6-dihydro-8H-2,3-(methylene-
dioxy)isoindolo[1,2-b][3]benzazepin-8-one (21b). A solution of 21a
(38 mg, 0.1 mmol), H2O2 (30 wt % solution in water, 0.34 mL),
and Bu4NF (1.0 M solution in THF, 3 mL) in DMSO (15 mL) was
stirred at rt for 3 h. The resulting mixture was diluted with Et2O
(30 mL) and washed with saturated brine (6 ꢀ 300 mL), dried
(MgSO4), and concentrated to give a crude product, which was
purified by preparative TLC on silica gel developed with 3%
MeOH-CH2Cl2. A main band with Rf 0.5 gave 21b (16 mg, 48%)
as yellow crystals, mp 245-250 °C (EtOH); IR (CHCl3) νmax
C
21H22N2O4 366.1579, found 366.1574. A less mobile band
with Rf 0.35 gave 24b, mp 175-178 °C (95% EtOH), as
colorless crystals (9 mg, 27%, Rf 0.35); IR (CHCl3) νmax
1
2242, 1603, 1590, 1517 cm-1; H NMR (400 MHz, CDCl3) δ
2.13 (s, 3H), 2.41 (t, J=11.7 Hz, 1H), 2.84 (dd, J=15.6, 6.8 Hz,
1H), 3.29 (br d, J=15.6 Hz, 1H), 3.55 (br s, 1H), 3.55 (br t, J=
12.7 Hz, 1H), 3.89, 3.90 (each s, each 3H), 3.93 (br s, 1H), 5.94,
5.96 (each d, J=1.5 Hz, each 1H), 6.55, 6.58 (each s, each 1H),
6.83 (d, J=7.8 Hz, 1H), 6.85 (dd, J=7.8, 2.0 Hz, 1H), 7.10 (br s,
1H); 13C NMR (100 MHz, CDCl3) δ 34.5, 46.3, 46.3,
55.9, 55.9, 57.2, 71.3, 101.3, 109.9, 110.0, 110.3, 118.9, 119.8,
127.0, 134.1, 135.4, 146.1, 147.6, 148.8, 149.2; EI-MS m/z
5494 J. Org. Chem. Vol. 74, No. 15, 2009

Onozaki et al.
JOCArticle
(rel intensity) 366 (M+, 94), 192 (100), 178 (50), 151 (82). Anal.
Calcd for C21H22N2O4: C, 68.84; H, 6.05; N, 7.65. Found: C,
68.76; H, 5.98; N, 7.42.
each 1H), 6.73 (s, 1H), 6.74 (s, 1H), 7.23, 7.29 (AB type, J=8.3
Hz, each 1H); EI-MS m/z (rel intensity) 352 [(M - HBr)+,
100], 335 (53), 191 (87), 94 (53). Anal. Calcd for
1-Cyano-2-(3.4-dimethoxyphenyl)-7,8-(methylenedioxy)-1,2,
3,4-tetrahydro-3H-3-benzazepine (24a): colorless crystals (7 mg,
40%, Rf 0.2), mp 209-211 °C (95% EtOH), from 19b (24 mg,
0.05 mmol) (entry 1); IR (CHCl3) νmax 3320, 2232, 1606, 1593,
1519 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.20 (br s, 1H), 2.74
(dd, J=15.1, 5.4 Hz, 1H), 2.85 (t, J=12.2 Hz, 1H), 3.43 (ddd,
J=12.2, 5.4, 2.0 Hz, 1H), 3.52 (ddd, J=15.1, 12.2, 2.0 Hz, 1H),
3.89 (d, J=1.0 Hz, 1H), 3.93 (s, 3H and hiding 1H), 3.97 (s, 3H),
5.95, 5.97 (each d, J=1.5 Hz, each 1H), 6.59, 6.68 (each s, each
1H), 6.86 (d, J=8.3 Hz, 1H), 6.99 (dd, J=8.3, 2.0 Hz, 1H), 7.18
(d, J=2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 37.5, 48.9,
49.0, 56.0, 56.0, 65.1, 101.4, 109.3, 110.4, 111.2, 111.3, 118.4,
118.5, 127.8, 135.2, 136.2, 146.0, 147.5, 149.0, 149.3; EI-MS m/
z (rel intensity) 352 (M+, 57), 178 (100). Anal. Calcd for
C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found: C, 67.98; H,
5.54; N, 7.69.
C20H21BrN2O4: C, 55.44; H, 4.89; Br, 18.44; N, 6.47. Found:
C, 55.20; H, 4.89; Br, 18.76; N, 6.37. A mixture of 22a-HBr
(43 mg, 0.1 mmol) and K2CO3 (138 mg, 1 mmol) in MeOH (10
mL) was stirred at rt for 3 h. The resulting mixture was
concentrated, and the residue was dissolved in CH2Cl2,
washed with water (20 mL), dried (Na2SO4), and concen-
trated to give 22a (35 mg, >99%) as a pale brown oil; IR
1
(CHCl3) νmax 3398, 1678, 1630 cm-1; H NMR (270 MHz,
CDCl3) δ 2.84-3.09 (m, 5H), 3.92 (s, 3H), 4.04 (s, 3H), 4.39
(d, J=9.9 Hz, 1H), 5.01 (br d, J=12.2 Hz, 1H), 5.94, 5.95
(each d, J=1.3 Hz, each 1H), 6.72 (s, 1H), 6.75 (s, 1H), 7.10 (d,
J = 8.3 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H); EI-MS m/z (rel
intensity) 352 (M+, 100), 335 (26), 191 (96). HRMS calcd for
C
20H20N2O4 352.1424, found 352.1423.
2-(2-Cyano-4,5-dimethoxyphenyl)-7,8-(methylenedioxy)-4,5-
dihydro-3H-3-benzazepine (23c): dark yellow oil (16 mg, 85%,
Rf 0.2) from 19c (22 mg, 0.05 mmol) (entry 11); IR (CHCl3)
2-(2-Cyano-3.4-dimethoxyphenyl)-7,8-(methylenedioxy)-4,5-
dihydro-3H-3-benzazepine (23a): brown oil (11 mg, 65%, Rf
0.2) from 19b (25 mg, 0.05 mmol) (entry 2); IR (CHCl3) 3318,
1
2228, 1626, 1613, 1497 cm-1; H NMR (270 MHz, CDCl3) δ
3.08 (t, J=4.6 Hz, 2H), 3.99 (s, 3H), 4.03 (s, 3H), 3.85-4.30 (br
m, 2H), 5.96 (s, 2H), 6.14 (s, 1H), 6.67 (s, 1H), 6.80 (s, 1H), 7.11
(s, 1H), 7.14 (s, 1H); EI-MS m/z (rel intensity) 350 (M+, 100),
335 (99), 319 (16). HRMS calcd for C20H18N2O4 350.1266,
found 350.1289.
Preparation of 1 from 22a-HBr. 22a-HBr (78 mg, 0.2 mmol)
was dissolved in a solution of KOH (112 mg, 2 mmol) in
isoPrOH (5 mL) and H2O (1 mL) was refluxed for 24 h. The
reaction mixture was acidified with 2 N HCl (10 mL) and
extracted with CH2Cl2 (2ꢀ10 mL). The extracts were washed
with saturated brine (10 mL), dried (Na2SO4), and concen-
trated. The residue was crystallized from CH2Cl2-hexane to
give 1 (49 mg, 70%) as colorless crystals, mp 228-230 °C
(MeOH). A one-pot two-step procedure starting with 19a
(43 mg) gave 1 (20 mg) in 56% yield.
1
1625, 1500 cm-1; H NMR (270 MHz, CDCl3) δ 3.06 (t, J=
4.6 Hz, 2H), 3.93 (s, 3H), 4.02 (s, 3H), 3.80-4.30 (br m, 2H),
5.95 (s, 2H), 6.16 (s, 1H), 6.66 (s, 1H), 6.77 (s, 1H), 7.08 (d, J=
8.3 Hz, 1H), 7.38 (d, J=8.3 Hz, 1H); EI-MS m/z (rel intensity)
350 (M+, 96), 335 (100), 319 (12). HRMS calcd for C20H18N2-
O4 350.1266, found 350.1260.
2-(2-Cyano-3,4-dimethoxyphenyl)-7,8-(methylenedioxy)-1,2,
4,5-tetrahydro-3H-3-benzazepine (22a) and Its Hydrobromide
(22a-HBr): General Procedure for Radical 1,4-Cyano Migration
(Entries 7-9 in Table 3). A stirred solution of 19a (432 mg,
1.0 mmol), AIBN (82 mg, 0.50 mmol), and Bu3SnH (0.54 mL,
2.0 mmol) in dry toluene (100 mL) was refluxed under Ar for
12 h (entry 9). The solvent was evaporated to give an oil,
which showed a 4:0.2:1 ratio of 22a-HBr, 23a, and 24a in its
1H NMR spectrum, and was dissolved in CH3CN (30 mL),
washed with hexane (3 ꢀ 60 mL), and concentrated. The
residue was treated with CH2Cl2 to give 22a-HBr (246 mg,
57%) as yellow crystals, mp 220-225 °C dec; IR (CHCl3)
Supporting Information Available: Experimental proce-
1
dures for the preparation of benzazepine 7a, and copies of H
NMR spectra of every compound except 5a and 5b and 13C
NMR spectra of compounds 4a, 6b, 8, 16b, 18a, 18b, 18c, 19a,
19b, 24a, and 24b. This material is available free of charge via the
Internet at http://pubs.acs.org.
νmax 3398, 2244, 1679, 1609 cm-1 1H NMR (270 MHz,
;
CDCl3) δ 2.90 (dd, J = 15.1, 10.2 Hz, 1H), 3.07-3.20 (m,
3H), 3.35-3.41 (m, 1H), 3.96 (s, 3H), 4.15 (s, 3H), 4.63 (d, J=
10.2 Hz, 1H), 5.61 (br d, J=15.2 Hz, 1H), 5.96, 5.97 (each s,
J. Org. Chem. Vol. 74, No. 15, 2009 5495