Photocycloaddition of phthalimide anion to alkenes - A highly efficient, convergent method for [2]benzazepine synthesis

Article abstract of DOI:10.1002/1099-0690(200206)2002:12<1903::AID-EJOC1903>3.0.CO;2-P

The excited state of phthalimide anion adds to cyclic, acyclic and aryl-conjugated alkenes in an efficient and regioselective manner to form [2]benzazepine-1,5-diones, substituted at positions 3 and/or 4. The reaction is independent of the ionization pote

Full text of DOI:10.1002/1099-0690(200206)2002:12<1903::AID-EJOC1903>3.0.CO;2-P

FULL PAPER
Photocycloaddition of Phthalimide Anion to Alkenes ؊ A Highly Efficient,
Convergent Method for [2]Benzazepine Synthesis
[a]
[a]
[a]
´
´
´
´
Rafael Suau,* Cristobal Sanchez-Sanchez, Rafael Garcıa-Segura, and
[a]
´
Ezequiel Perez-Inestrosa
Keywords: Alkaloids / Nitrogen heterocycles / Photochemistry / Photocycloaddition / Ring-expansion
The excited state of phthalimide anion adds to cyclic, acyclic
and aryl-conjugated alkenes in an efficient and regioselec-
tive manner to form [2]benzazepine-1,5-diones, substituted
at positions 3 and/or 4. The reaction is independent of the
ionization potential of the alkene. This process contrasts with
the related reactions of N-methylphthalimide or phthalimide,
alkenes have oxidation potentials Ͼ ca. 2 V. Photocycloaddi-
tion of the phthalimide anion with indene serves as a concise
method to prepare the basic skeleton found in members of
the ribasine alkaloid family.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
which are limited by the requirement that the participating 2002)
Introduction
substrates, and the other the expansion of smaller
rings.[10Ϫ17] A combination of both approaches has been
used for the photochemical synthesis of [2]benzazepine-1,5-
diones. Several photochemical approaches starting with
suitably substituted N-alkylphthalimides and silylalkyl ana-
logues, involving a hydroxyazetidine intermediate that op-
ens to give the expanded benzazepinedione ring, have been
developed.[18Ϫ23] These photoprocesses follow various path-
ways that include Norrish type II or sequential SET desilyl-
ation reactions followed by Yang cyclization,[24Ϫ27] ω-hy-
drogen abstraction/elimination,[28,29] single-electron transfer
(SET) together with proton transfer[30,31] and SET followed
by decarboxylative photocyclization.[32]
The [2]benzazepine skeleton is a common structural fea-
ture found in a variety of naturally occurring and synthetic
bioactive compounds. Examples are found in the ribasine-
type alkaloids, which possess an indanobenzazepine struc-
ture,[1] and the galanthamine class of Amarillidaceae alkal-
oids, which have a spiro-linked benzazepine structure.[2]
Galanthamine, the parent compound in the latter family,
and its synthetic analogues are cholinesterase inhibitors
and are currently undergoing testing in Alzheimer’s disease
therapy.[3] Other biologically prominent examples include
fused pyrimido[5,4-d][2]benzazepines, which exhibit promis-
ing antitumor activity,[4] the conformationally restricted
amino acids derived from 4-amino-1,3,4,5-tetrahy-
dro[2]benzazepine-3-one, used in the synthesis of pep-
tides,[5] and 1-aryl[2]benzazepinones, which are active on
the central nervous system.[6,7]
A more convergent approach is provided by the intermol-
ecular photocycloaddition of alkenes to the C(O)ϪN bond
of N-methylphthalimide (NMP). The reaction has been
extensively investigated over the last two decades and is
known to occur in a regio- and stereoselective manner, from
the singlet excited state of the phthalimide and through an
oriented exciplex[33] (Scheme 1). However, S1 in NMP is
competitively deactivated by SET from alkenes. The ion-
radical pair, produced in this way, can undergo back-elec-
tron-transfer, thus quenching the excited state, or give re-
ductive photoaddition to the carbonyl group. In the pres-
ence of nucleophilic solvents (alcohols), radical-cation trap-
ping precedes radical coupling.[34,35] In some cases, intersys-
tem crossing (isc) competes and alkenes add to the NMP
triplet at the aromatic ring to give the [4ϩ2] photocycload-
dition products,[36Ϫ38] provided that the triplet energy of the
alkene is higher than that of the imide.
Two major approaches to the synthesis of [2]benzazepine
heterocycles have been employed.[8,9] One involves the intra-
molecular cyclization of appropriately substituted aromatic
A major drawback of the intermolecular σ2ϩπ2 photo-
cycloaddition approach for the synthesis of [2]benzazepines
is its lack of universality, owing to competitive electron-
transfer quenching by alkenes. For phthalimide and its N-
[a]
´
´
Dpto. Quımica Organica, Facultad de Ciencias, Universidad
´
de Malaga,
´
Campus Teatinos s/n, 29071 Malaga, Spain
Fax: (internat.) ϩ 34-95/213-1941
E-mail: suau@uma.es
Eur. J. Org. Chem. 2002, 1903Ϫ1911  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0612Ϫ1903 $ 20.00ϩ.50/0
1903

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R. Suau, C. Sanchez-Sanchez, R. Garcıa-Segura, E. Perez-Inestrosa
FULL PAPER
of phthalimide (PHT-H) and cyclohexene in a 7:1 aceto-
nitrile/water mixture, containing sufficient quantities of
NaOH to maintain a pH of ca. 10. Irradiation of this solu-
tion (Ͼ 90% conversion) afforded an 84% yield of a mixture
of cis (1c) and trans (1t) cycloadducts, in addition to 9%
of a diastereomeric mixture of the allylic adducts 2a and
2b (Scheme 2).[42]
Scheme 2
The reduced value of the coupling constant (J4a,11a
ϭ
Scheme 1
2.7 Hz) substantiated the cis stereochemistry of adduct 1c,
while that in 1t (J4a,11a ϭ 11.8 Hz) was consistent with a
trans configuration. From previous results from studies of
the photocycloaddition of alkenes to phthalimides, it was
assumed that the configuration of the alkene was retained
in this reaction. As a result, formation of the trans isomer
had to be due to base-catalysed isomerization of the initially
formed cis isomer 1c. In fact, a methanol solution of 1c
was almost quantitatively converted into 1t upon treatment
with NaOH.
In order to prevent the secondary epimerization reaction,
the base concentration used in the photoreaction was re-
duced by making [PHT-H] Ͼ [HOϪ]. Remarkable differ-
ences were observed as a result of this change. Namely, the
overall yield of 1 (1c ϩ 1t) was reduced to 46%, that of the
allylic photoadducts 2a and 2b was slightly increased, and
a new compound, N-cyclohexylphthalimide (3), was ob-
tained. The formation of 3 is formally the result of photo-
addition of phthalimide to the alkene double bond, a pro-
cess previously described as the photophthalimidation of
cyclohexene (Scheme 3).[43]
alkyl derivatives, with a singlet excited state energy of 80
kcal/mol and a reduction potential of Ϫ1.46 V,[39] thermo-
dynamically allowed SET occurs when the oxidation poten-
tial of the alkene is less than ca. 2.1 V. Kubo[35] and Maz-
zocchi[34] showed that, while 1-substituted, and 1,1- and
1,2-disubstituted alkenes photoreacted with NMP to give
the corresponding [2]benzazepine-1,5-diones, reactions of
this type did not take place with cyclic (cyclopentene, cyclo-
hexene), trisubstituted (2-methyl-2-butene) or tetrasubsti-
tuted (2,3-dimethyl-2-butene) alkenes.
The electron transfer process can be made endergonic by
lowering the reduction potential of the phthalimide. Ac-
cordingly, we predicted that the phthalimide anion, while
retaining [2ϩ2] photocycloaddition reactivity, would not
participate in photoinduced SET with alkenes. In this pa-
per, we describe an investigation focussing on the photo-
chemical behaviour of the phthalimide anion in the pres-
ence of alkenes. The results of this study demonstrated that
the phthalimide anion underwent efficient, regiocontrolled
[2ϩ2] photocycloaddition to a wide variety of alkenes, inde-
pendently of the ionization potential, and that the process
served as a concise method for the synthesis of [2]benzazep-
ines substituted at positions 3 and/or 4.
Results and Discussion
In an earlier effort,[40] photochemical reactions were per-
formed by irradiation (1 h) of solutions of sodium phthali-
mide in methanol or tert-butyl alcohol, containing a ca. ten-
fold excess of cyclohexene. The [2ϩ2] photocycloaddition
products 1c and 1t were formed under these conditions in
Scheme 3
The dependence of the nature of the photoreaction on
low yields (20 and 35% yield, respectively). In fact, the ma- base concentration is interesting. We found that photoreac-
jor photoreactions occurring under these conditions in- tions of phthalimide, at [PHT-H] ഠ [HOϪ], with cyclopen-
volved the solvents.[41]
tene, tetramethylethylene and 2-ethyl-1-butene, three alkenes
We have found that participation of the solvent in these that are known not to give benzazepinediones with phthalim-
photochemical reactions can be avoided by use of solutions ide or N-methylphthalimide,[34,35] gave the respective photo-
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Eur. J. Org. Chem. 2002, 1903Ϫ1911

A Highly Efficient, Convergent Method for [2]Benzazepine Synthesis
FULL PAPER
cycloaddition products 4, 6 and 8 in good yields. The reac- cyclohexene (78 mmol) in acetonitrile/water (3:1) for
tions were all fast (30 min irradiation resulted in conver- 25 min. This gave a 89% yield of adduct 1 (1c ϩ 1t) at 90%
sions of Ͼ 80%), and the yields in the photocycloaddition conversion. Under identical conditions and with similar ir-
products ranged from 67 to 80% (Scheme 4).[44] For cyclo- radiation times, photoadducts 4 and 6 were obtained in 86%
pentene and tetramethylethylene, the allylic adducts 5a, 5b and 84% yields (at 80% and 85% conversions), respectively.
and 7 were also generated. However, the reaction behaviour
The observed formation of 3 (Scheme 3) suggests that an
of the asymmetric 2-ethyl-1-butene, although highly re- alternate mechanism might be responsible for the photo-
gioselective, was more complex since the benzazepinedione cycloaddition process. Specifically, the excited state of N-
product 8 experienced secondary photochemistry by a ra- cyclohexylphthalimide is known to undergo the Norrish
ther efficient γ-hydrogen abstraction pathway to form a 1,4- type II reaction followed by Yang cyclization to produce
biradical, which underwent β-cleavage (9) or Yang cycliza- the azetidine (I), which opens to yield the benzazepinedione
tion (10).[45]
1 (Scheme 5).[25] However, this possibility can be discarded
since no fluorescence was detected at NaOH concentrations
Ͻ 1:10 relative to that of phthalimide. Also, the [2ϩ2]
photocycloaddition was nearly completely suppressed,
while formation of 3 became dominant under these condi-
tions. Moreover, cyclization of N-cyclohexylphthalimide
was found to be roughly 40 times slower than the [2ϩ2]
photocycloaddition of phthalimide anion.
Scheme 5
Photoreactions with alkenylbenzenes (styrene and styrene
derivatives) were more complicated (Scheme 6 and Table 1).
These processes were much slower, since the alkene concen-
tration had to be kept low to prevent competitive absorp-
tion of light. Owing to the need for long irradiation times,
photoreactions were initially performed at low NaOH con-
centration to exclude thermal reaction with phthalimide. In
all cases, the reactions were found to be regioselective, fa-
vouring products with the aromatic substituent at position
4 of the benzodiazepine ring system. Photoaddition of
trans-β-methylstyrene yielded a mixture of cis (12c) and
trans (12t) isomers in a ca. 1:1 ratio. The trans adduct 16t
was the major product formed in the photoreaction of
trans-stilbene, while isosafrole yielded only the trans ad-
duct 15.[51]
Scheme 4
The electronic absorption spectra of phthalimide in polar
solvents, such as methanol or an acetonitrile/water mixture,
are very similar. The longest-wavelength absorption max-
ima occur at λmax ϭ 290 nm and are ascribed to a π-π*
transition.[46] The addition of NaOH to an acetonitrile/
water solution of phthalimide resulted in a red shift in the
electronic absorption spectrum to λmax ϭ 330 nm. This ba-
thochromic shift is related to a new absorption band
ascribed to the phthalimide anion (in equilibrium with its
protonated form). Phthalimide[39,47] and N-alkylphthalim-
ides[48,49] are poorly fluorescent species. In contrast, the
phthalimide anion exhibits a significant fluorescence emis-
sion at 440 nm,[50] the maximum emission intensity being
reached at a phthalimide/NaOH ratio of 2:3 in an acetonitr-
ile/water solution (Φf ϭ 2.10Ϫ2). This emission decays
mono-exponentially with a lifetime of 4 ns, and its excita-
tion spectrum reproduces the absorption spectrum. Inter-
estingly, the fluorescence of the phthalimide anion was ef-
fectively quenched by addition of cyclohexene (the fluores-
cence intensity was halved upon addition of 12 equiv. of
cyclohexene). This result suggests the involvement of the
first singlet excited state of phthalimide anion in the photo-
cycloaddition processes described above.
Scheme 6
These findings resulted in the design of optimal photoad-
As would be expected, use of a higher PHT-H/NaOH
dition reaction conditions, involving irradiation of a solu- ratio (1:1.5) and a 400-W medium-pressure mercury lamp
tion of phthalimide (6.8 mmol), NaOH (10.2 mmol) and resulted in increased photocycloaddition yields (90% for
Eur. J. Org. Chem. 2002, 1903Ϫ1911
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R. Suau, C. Sanchez-Sanchez, R. Garcıa-Segura, E. Perez-Inestrosa
FULL PAPER
Table 1. Irradiation of PHT-H/NaOH in the presence of alkenylbenzenes
Alkenylbenzene
Alkene/PHT-H
[mmol]
Irradiation
time [h][a]
Conversion [%]
[2ϩ2] Cycloadduct
(yield [%])
Styrene
2.6
2
5
2.2
2
1
2
5
1
2
5
4
78
40
91
74
28
20
11 (58)
12 (47)
13 (41)
14 (41)
15 (51)
16 (78)
trans-β-Methylstyrene
α-Methylstyrene
p-Methoxystyrene
Isosafrole
trans-Stilbene
[a]
All irradiations were carried out at a 3.4:1 PHT-H/NaOH ratio.
styrene, 72% for trans-β-methylstyrene and 68% for α- The value of the coupling constant J4b,11a indicated that
methylstyrene at 92%, 88% and 93% conversion, respect- 18 had a trans ring fusion stereochemistry. This is the first
ively).
instance in which both regioisomeric adducts have been
An example of particular interest was the photocycload- produced in the phthalimide anion photocycloaddition re-
dition of PHT-H to indene, a reaction that might provide actions.
a direct entry to the indeno[2,1-c][2]benzazepine skeleton
present in members of the ribasine-type alkaloid family.
Conclusion
Their synthesis by photocyclization of N-(2-indanyl)phthal-
imide or photocycloaddition of phthalimide and substituted
phthalimides and indenes proved unsuccessful. However, ir-
radiation of a solution of PHT-H/NaOH and indene
(1:1.5:1.3 equiv. ratio) for 4 h (62% conversion) followed by
chromatographic separation gave adduct 17a as the major
product, in 43% yield (Scheme 7).
The results presented above demonstrate that the phthali-
mide anion undergoes high-yielding photoaddition reac-
tions with a wide variety of alkenes and that this process
serves as a concise method for the synthesis of [2]benzazep-
ine-1,5-diones. The efficiency of the reaction is independent
of the ionization potential of the alkene, a likely result of
the low reduction potential of the reactive PHTϪ singlet
excited state. The results of quenching of the fluorescence
of the phthalimide anion by alkene can be used to design
reaction conditions that optimize the photocycloaddition
yields.
Experimental Section
General Remarks: Melting points were determined with a Gallenk-
amp instrument and are given uncorrected. IR spectra were re-
corded with a PerkinϪElmer 883 spectrophotometer and a Bruker
FT-IR Equinox 55 spectrometer equipped with a Specac Golden
Gate ATR accessory. Absorption spectra were recorded with an
HP 8452A Diode Array Spectrophotometer. Emission spectra were
obtained with a JASCO FP-750 Spectrofluorimeter interfaced to a
Spectra Manager (v. 1.30.00) data station. Fluorescence quantum
yields were determined by comparison with 0.1  quinine sulfate
in 0.05  sulfuric acid as reference, by using the Demas method.[52]
Fluorescence decay measurements were performed with an Aminco
SLM 48000S spectrofluorimeter equipped with a 450-W xenon
Scheme 7
The spectroscopic properties of 17a were consistent with
those expected for a [2ϩ2] photoadduct. However, its mo-
lecular composition of C17H13NO3, consistent with a mo-
lecular ion peak at m/z ϭ 279, suggested that it contained
an additional oxygen atom. A lowfield quaternary carbon
1
signal at δ ϭ 93.8 ppm and the H NMR pattern (dd upon
addition of D2O) for the hydrogen atom α to the nitrogen
atom suggested that the isolated product had a quaternary lamp, a Hamamatsu R928 photomultiplier tube detector and a
Pockel cell electro-optic modulator. Fluorescence lifetime deter-
minations were performed by use of multifrequency modulated ex-
citation beams and a glycogen scattering solution as reference.
Phase and modulation measurements used the ‘‘100-average’’
mode, in which each measurement was the average of 100 sam-
plings, automatically conducted by the instrument circuitry over a
period of approximately 25 s. Low-resolution MS (EI and CI) was
recorded with an HP-MS 5988A spectrometer operating at 70 eV,
and high-resolution MS was performed with a Kratos MS 50 TC
mass spectrometer. NMR spectra were recorded with a Bruker WP-
benzylic position vicinal to the ketone carbonyl group.
Thus, the hydroxylated product 17a was fully consistent
with this data. A second product, diastereoisomer 17b
(10%), was also isolated. We believe that hydroxylation of
the initial adduct took place during chromatographic sep-
aration. It should be noted that this position also contains
hydroxy functionality in the ribasine alkaloids. A third ad-
duct, 18 (7%), was also isolated, its regiochemistry inferred
1
from the H NMR splitting exhibited by 4b-H, which was
coupled to the NH proton and to the bridged 11a-H atom. 200 SY instrument, at 200 MHz for 1H and 50.3 MHz for 13C.
1906
Eur. J. Org. Chem. 2002, 1903Ϫ1911

A Highly Efficient, Convergent Method for [2]Benzazepine Synthesis
FULL PAPER
Chemical shifts are given relative to the residual signal of solvent,
δH ϭ 7.24 ppm and δC ϭ 77.0 ppm for deuteriochloroform. TLC
analyses were performed on silica gel 60 F 256 plates, and column
chromatography was carried out on silica gel 60 (70Ϫ230 mesh).
Organic solutions were dried with MgSO4. Solutions were irradi-
H), 2.60 (s, 1 H, OH), 2.00Ϫ0.80 (m, 6 H, 3 ϫ CH2) ppm. 13C
NMR (CDCl3): δ ϭ 170.0 (C-1), 148.5 (C-3a), 131.0 (C-7a), 133.0,
131.9, 129.5, 125.0 (C-5, C-6, C-7, C-4), 123.5, 122.1 (C-2Ј, C-3Ј),
89.6 (C-3), 42.5 (C-1Ј), 24.5, 23.9, 21.0 (CH2) ppm. EIMS: m/z ϭ
229 (4) [M]ϩ, 212 (7), 148 (100). CIMS (CH4): m/z ϭ 230 (100) [M
ated at room temperature in a 250-mL immersion well photore- ϩ H]ϩ, 213 (31), 212 (33). C14H15NO2 (229.28): calcd. C 73.34, H
actor (Pyrex) equipped with a 125-W medium-pressure mercury
lamp (unless otherwise stated). A stream of nitrogen was passed
through the medium during irradiation. Yields given are based on
consumed phthalimide.
6.59, N 6.11; found C 73.25, H 6.83, N 5.95.
3-(2-Cyclohexenyl)-2,3-dihydro-3-hydroxy-1H-isoindol-1-one (2b):
White crystals. M.p. 154Ϫ156 °C (CHCl3). IR (KBr): ν˜ ϭ 3376,
1
3198, 1678 cmϪ1. H NMR (CDCl3): δ ϭ 7.75Ϫ7.40 (m, 4 H, Ar-
H), 6.50 (s, 1 H, NH), 5.59Ϫ5.40 (m, 2 H, 2Ј-H, 3Ј-H), 2.90 (m, 1
H, 1Ј-H), 3.19 (s, 1H, OH), 2.10Ϫ0.90 (m, 6 H, 3 ϫ CH2) ppm.
13C NMR (CDCl3): δ ϭ 169.3 (C-1), 147.9 (C-3a), 131.3 (C-7a),
132.1, 130.1, 129.0, 125.2 (C-5, C-6, C-7, C-4), 123.0, 122.5 (C-2Ј,
C-3Ј), 89.5 (C-3), 43.5 (C-1Ј), 24.5, 23.5, 21.3 (CH2) ppm. EIMS:
m/z ϭ 212 (3) [Mϩ Ϫ 17], 148 (100). CIMS (CH4): m/z ϭ 230 (100)
[M ϩ H]ϩ, 100], 213 (26), 212 (42). C14H15NO2 (229.28): calcd. C
73.34, H 6.59, N 6.11; found C 73.28, H 6.31, N 5.96.
Irradiation of Sodium Phthalimide/Cyclohexene in Methanol: So-
dium phthalimide (2 g, 11.8 mmol) was dissolved in MeOH
(200 mL), a large excess of cyclohexene (12 mL) was added, and
the clear solution was irradiated for 1 h. Most of the solvent was
removed, and the crude reaction mixture was taken up in water
(50 mL) and extracted with CHCl3. The organic layer was dried,
the solvent was removed, and the residue was column-chromato-
graphed (silica gel; hexane/EtOAc from 2:1 to 1:1) to afford un-
changed phthalimide (810 mg) and adduct 1c (289 mg, 20%).
At [PHT-H]/[NaOH] ؍ 1:0.3: A solution of phthalimide (1 g,
6.8 mmol), NaOH (2 mL of a 1  solution) and cyclohexene (1 mL,
8.6 mmol) in 140 mL of acetonitrile and 20 mL of water was irradi-
ated for 1/2 h. Workup of the reaction mixture was carried out
as above and provided unchanged phthalimide (220 mg, 22%), 1c
(549 mg, 46%), 2a ϩ 2b (137 mg, 12%) and 3 (297 mg, 25%).
cis-3,4,4a,11a-Tetrahydro-1H-dibenzo[b,e]azepine-6,11(2H,5H)-
dione (1c): White crystals. M.p. 210Ϫ212 °C (EtOAc). IR (KBr):
1
ν˜ ϭ 3188, 1656 cmϪ1. H NMR (CDCl3): δ ϭ 7.92 (dd, J ϭ 5.8,
2.8 Hz, 1 H, 10-H), 7.88Ϫ7.54 (m, 3 H, 7-H, 8-H, 9-H), 6.83 (br.
d, J ϭ 3.8 Hz, 1 H, NH), 4.25 (m, 1 H, 4a-H), 2.56 (ddd, J ϭ 11.8,
4.0, 2.7 Hz, 1 H, 11a-H), 2.36Ϫ1.33 (m, 8 H, 4 ϫ CH2) ppm. 13C
NMR (CDCl3): δ ϭ 204.0 (C-11), 169.9 (C-6), 137.4 (C-10a), 131.8
(C-6a), 132.1, 131.9, 129.5, 128.0 (C-7, C-8, C-9, C-10), 55.8 (C-
4a), 47.9 (C-11a), 29.4, 25.1, 22.6, 20.1 (CH2) ppm. EIMS: m/z ϭ
229 (27) [M]ϩ, 201 (19), 186 (11), 148 (100). C14H15NO2 (229.28):
calcd. C 73.34, H 6.59, N 6.11; found C 73.48, H 6.57, N 5.93.
N-Cyclohexylphthalimide (3): White crystals. M.p. 169Ϫ171 °C
(CH3OH) (ref.[53] 168.5Ϫ171 °C).
Irradiation of PHT-H/NaOH with Other Alkenes: The homogen-
eous solution consisting of phthalimide (1 g, 6.8 mmol), NaOH
(8 mL of a 1  solution), 140 mL of acetonitrile, 20 mL of water
and the alkene was irradiated for 30 min. Workup was as above,
and chromatography gave the following results.
Irradiation of Sodium Phthalimide/Cyclohexene in tert-Butyl Alco-
hol: The irradiation (1 h) and the workup were carried out as in
methanol. On column chromatography of the reaction mixture, un-
changed phthalimide was recovered (650 mg) together with the ad-
duct 1c (593 mg, 35%).
With Cyclopentene (56 mmol): Unchanged phthalimide (255 mg,
25%), 4c (494 mg, 45%), 4t (384 mg, 35%), 5a (61 mg, 6%), 5b
(58 mg, 5%).
cis-1,2,3,3a,4,10a-Hexahydrocyclopenta[c][2]benzazepine-5,10-dione
(4c): White crystals. M.p. 210Ϫ211 °C (EtOAc) (ref.[25] 210Ϫ212
°C). IR (KBr): ν˜ ϭ 3248, 1697, 1650 cmϪ1. 1H NMR (CDCl3): δ ϭ
7.90 (m, 1 H, 9-H), 7.69Ϫ7.35 (m, 3 H, 6-H, 7-H, 8-H), 6.65 (br.
d, J ϭ 2.6 Hz, 1 H, NH), 4.25 (m, 1 H, 3a-H), 3.12 (dt, J ϭ 4.8,
9.3 Hz, 1 H, 10a-H), 2.40Ϫ1.70 (m, 6 H, 3 ϫ CH2) ppm. 13C NMR
(CDCl3): δ ϭ 204.0 (C-10), 171.1 (C-5), 139.7 (C-9a), 131.3 (C-5a),
131.9, 131.5, 129.6, 126.6 (C-6, C-7, C-8, C-9), 62.1 (C-3a), 53.6
(C-10a), 32.7, 24.1, 22.5 (CH2) ppm. EIMS: m/z ϭ 215 (7) [M]ϩ,
172 (35), 148 (100). CIMS (CH4): m/z ϭ 216 (100) [M ϩ H]ϩ, 199
(50), 198 (46). C13H13NO2 (215.25): calcd. C 72.53, H 6.09, N 6.51;
found C 72.51, H 6.07, N 6.31.
Irradiation of PHT-H/NaOH/Cyclohexene
At pH ഠ 10: An NaOH solution (1 ) was added to a solution of
phthalimide (1 g, 6.8 mmol) and cyclohexene (5 mL, 75 mmol) in
acetonitrile/water (7:1) until pH ഠ 10 was reached. The resulting
homogeneous solution was irradiated for 30 min and neutralized
with dilute HCl, and the solvent was removed. On column chroma-
tography of the reaction mixture, unchanged phthalimide (92 mg,
9%) and the following four compounds were isolated: 1c (228 mg,
17%), 1t (924 mg, 67%), 2a (69 mg, 5%) and 2b (58 mg, 4%).
trans-3,4,4a,11a-Tetrahydro-1H-dibenzo[b,e]azepine-6,11(2H,5H)-
dione (1t): White crystals. M.p. 203Ϫ205 °C (EtOAc). IR (KBr):
1
ν˜ ϭ 3189, 1655 cmϪ1. H NMR (CDCl3): δ ϭ 7.91 (dd, J ϭ 6.5,
trans-1,2,3,3a,4,10a-Hexahydrocyclopenta[c][2]benzazepine-5,10-
dione (4t): White crystals. M.p. 202Ϫ203 °C (EtOAc). IR (KBr):
2.1 Hz, 1 H, 10-H), 7.69Ϫ7.50 (m, 3 H, 7-H, 8-H, 9-H), 6.98 (br.
d, J ϭ 4.7 Hz, 1 H, NH), 3.48 (m, 1 H, 4a-H), 2.65 (dt, J ϭ 11.8,
4.0 Hz, 1 H, 11a-H), 2.2Ϫ1.1 (m, 8 H, 4 ϫ CH2) ppm. 13C NMR
(CDCl3): δ ϭ 206.6 (C-11), 169.9 (C-6), 137.4 (C-10a), 131.8 (C-
6a), 132.3, 131.1, 131.8, 128.1 (C-7, C-8, C-9, C-10), 60.2 (C-4a),
52.1 (C-11a), 30.6, 29.5, 24.8, 24.5 (CH2) ppm. EIMS: m/z ϭ 229
(52) [M]ϩ, 201 (23), 186 (16), 148 (100). C14H15NO2 (229.28): calcd.
C 73.34, H 6.59, N 6.11; found C 73.79, H 6.54, N 6.11.
1
ν˜ ϭ 3250, 1696, 1650 cmϪ1. H NMR (CDCl3): δ ϭ 8.10 (m, 2 H,
6-H, 9-H), 7.65 (m, 2 H, 7-H, 8-H), 6.89 (br. d, 1 H, NH), 3.90 (m,
1 H, 3a-H), 3.12 (m, 1 H, 10a-H-), 2.40Ϫ1.65 (m, 6 H, 3 ϫ CH2)
ppm. 13C NMR (CDCl3): δ ϭ 200.7 (C-10), 169.5 (C-5), 134.4 (C-
9a), 131.5 (C-5a), 133.2, 131.6, 131.6, 129.3 (C-6 to C-9), 61.0 (C-
3a), 53.9 (C-10a), 31.9, 26.6, 22.1 (CH2) ppm. EIMS: m/z ϭ 215
(10) [M]ϩ, 172 (47), 148 (100). m/z (CI, CH4) 216 (100) [M ϩ H]ϩ.
C13H13NO2 (215.25): calcd. C 72.53, H 6.09, N 6.51; found C
72.22, H 6.10, N 6.53.
3-(2-Cyclohexenyl)-2,3-dihydro-3-hydroxy-1H-isoindol-1-one (2a):
White crystals. M.p.158Ϫ159 °C (CHCl3). IR (KBr): ν˜ ϭ 3380,
1
3191, 1680 cmϪ1. H NMR (CDCl3): δ ϭ 7.80Ϫ7.45 (m, 4 H, Ar-
3-(2-Cyclopentenyl)-2,3-dihydro-3-hydroxy-1H-isoindol-1-one (5a):
H), 6.15 (s, 1 H, NH), 6.01 (m, 2 H, 2Ј-H, 3Ј-H), 3.00 (m, 1 H, 1Ј- White crystals. M.p. 158Ϫ159 °C (CHCl3). IR (neat): ν˜ ϭ 3392,
Eur. J. Org. Chem. 2002, 1903Ϫ1911 1907

´
´
´
´
R. Suau, C. Sanchez-Sanchez, R. Garcıa-Segura, E. Perez-Inestrosa
FULL PAPER
3189, 1677 cmϪ1. H NMR (CDCl3): δ ϭ 7.70Ϫ7.40 (m, 4 H, Ar- 4-Ethyl-3,4-dihydro-1H-2-benzazepine-1,5(2H)-dione (9): White
1
H), 6.35 (br. d, 1 H, NH), 6.05 (m, 2 H, 2Ј-H, 3Ј-H), 3.75 (s, 1H, crystals. M.p. 109Ϫ110 °C (EtOAc). IR (KBr): ν˜ ϭ 3208, 1686,
1
OH), 3.55 (m, 1H, 1Ј-H), 2.40Ϫ1.00 (m, 4H, 2 ϫ CH2) ppm. 13C 1657 cmϪ1. H NMR (CDCl3): δ ϭ 8.15 (br. t, J ϭ 5.6 Hz, 1 H,
NMR (CDCl3): δ ϭ 169.4 (C-1), 148.1 (C-3a), 130.7 (C-7a), 135.5,
132.9, 129.5, 129.2 (C-4 to C-7), 123.4, 121.9 (C-2Ј, C-3Ј), 89.9 (C- 2.81 (m, 1 H, 4-H), 1.75 (m, 2 H, CH2), 1.00 (t, J ϭ 7.5 Hz, 3 H,
3), 52.8 (C-1Ј), 32.3, 24.4 (CH2) ppm. EIMS: m/z ϭ 197 (1) [Mϩ CH3) ppm. 13C NMR (CDCl3): δ ϭ 206.0 (C-5), 171.5 (C-1), 137.1
NH), 7.90 (m, 1 H, 6-H), 7.60 (m, 3 H, Ar-H), 3.45 (m, 2 H, 3-H),
Ϫ 18], 151 (24), 130 (89), 148 (100). CIMS (CH4): m/z ϭ 216 (100) (C-5a), 131.5 (C-9a), 132.2, 131.9, 129.5, 128.0 (C-6, C-7, C-8, C-
[M ϩ H]ϩ, 199 (50), 198 (46). C13H13NO2 (215.25): calcd. C 72.53, 9), 56.8 (C-4), 41.2 (C-3), 23.1 (CH2), 11.3 (CH3) ppm. EIMS:
H 6.09, N 6.51; found C 72.24, H 6.04, N 6.31.
m/z ϭ 203 (1) [M]ϩ, 174 (3), 148 (100). CIMS (CH4): m/z ϭ 204
(100) [M ϩ H]ϩ, 175 (21). C12H13NO2 (213.24): calcd. C 70.92, H
6.45, N 6.89; found C 71.18, H 6.10, N 6.36.
3-(2-Cyclopentenyl)-2,3-dihydro-3-hydroxy-1H-isoindol-1-one (5b):
White crystals. M.p. 156Ϫ158 °C (CHCl3). IR (neat): ν˜ ϭ 3396,
3191, 1676 cmϪ1 1H NMR (CDCl3): δ ϭ 7.60 (m, 4 H, Ar-H),
.
cis- and trans-2a-Ethyl-1,2,2a,3,4,9b-hexahydro-9b-hydroxy-5H-
cyclobuta[d][2]benzazepin-5-one (10): White crystals. M.p. 180Ϫ184
5.85 (m, 1 H, 2Ј-H), 5.50 (m, 1 H, 3Ј-H), 4.35 (s, 1 H, OH), 3.50
(m, 1 H, 1Ј-H), 2.35Ϫ1.50 (m, 4 H, 2 ϫ CH2) ppm. 13C NMR
(CDCl3): δ ϭ 169.3 (C-1), 147.3 (C-3a), 131.1 (C-7a), 134.8, 132.5,
129.5, 129.2 (C-4 to C-7), 123.3, 122.9 (C-2Ј, C-3Ј), 89.7 (C-3), 54.1
(C-1Ј), 32.1, 24.4 (CH2) ppm. EIMS: m/z ϭ 197 (2) [Mϩ Ϫ 18],
151 (19), 130 (89), 148 (100). CIMS (CH4): m/z ϭ 216 (100) [M ϩ
H]ϩ, 199 (44), 198 (48). C13H13NO2 (215.25): calcd. C 72.53, H
6.09, N 6.51; found C 72.25, H 6.01, N 6.32.
1
°C (EtOAc). IR (KBr): ν˜ ϭ 3311, 1636 cmϪ1. H NMR (CDCl3):
δ ϭ 7.85Ϫ7.36 (m, 8 H, Ar-H), 7.25 (br. t, J ϭ 5.7 Hz, 1 H, NH),
6.84 (br. t, J ϭ 5.7 Hz, 1 H, NH), 3.10Ϫ1.20 (m, 16 H, 8 ϫ CH2),
0.94 (t, J ϭ 7.5 Hz, 3 H, CH3), 0.73 (t, J ϭ 7.5 Hz, 3 H, CH3)
ppm. 13C NMR (CDCl3): δ ϭ 173.8, 172.8 (C-5), 142.9, 142.2 (C-
9a), 132.8, 131.2 (C-5a), 131.1, 130.7, 130.4, 129.6, 128.2, 127.1,
126.2, 124.2 (C-6, C-7, C-8, C-9), 78.6, 78.3 (C-9b), 56.6, 53.5 (C-
2a), 45.9, 45.6 (C-3), 35.5, 30.7, 25.6, 25.5, 21.5, 20.9 (CH2), 7.9,
7.4 (CH3) ppm. EIMS: m/z ϭ 231 (5) [M]ϩ, 203 (15), 174 (100),
160 (25), 130 (29). C14H17NO2 (231.29): calcd. C 72.70, H 7.41, N
6.06; found C 72.38, H 7.41, N 6.04.
With Tetramethylethylene (17 mmol): Unchanged phthalimide
(90 mg, 9%), 6 (1.10 g, 73%), 7 (195 mg, 12%).
3,4-Dihydro-3,3,4,4-tetramethyl-1H-2-benzazepine-1,5(2H)-dione
(6): White crystals. M.p. 157Ϫ158 °C (EtOH) (ref.[44] 165 °C). IR
Improved Formation of Benzazepinediones 1, 4 and 6: Reactions
were conducted with phthalimide (1 g, 6.8 mmol), NaOH (10.2 mL
of a 1  solution) [phthalimide/sodium hydroxide in 1:1.5 ratio],
140 mL of acetonitrile, 20 mL of water and excess alkene. After
25 min of irradiation, most of the phthalimide had reacted (TLC).
The solvent and excess alkenes were removed under vacuum (the
reaction mixtures with cyclohexene and cyclopentene were stirred
in the dark for 30 min to allow equilibration of the benzazepine-
dione isomers before solvent removal). The residues were taken up
in chloroform, the solutions were washed with water, and the or-
ganic layer was concentrated to dryness to give solids that were
crystallized directly. With cyclohexene (11 equiv. excess): 1.25 g of
1t (89% at 90% conversion).With cyclopentene (8 equiv. excess):
1.01 g of 4t (86% at 80% conversion).With tetramethylethylene (2.5
equiv. excess): 1.12 g of 6 (84% at 85% conversion).
1
(KBr): ν˜ ϭ 3216, 1648 cmϪ1. H NMR (CDCl3): δ ϭ 8.12 (m, 1
H, 6-H), 7.90 (m, 1 H, 9-H), 7.60 (m, 2 H, 7-H, 8-H), 6.80 (br. d,
1 H, NH), 1.28 (s, 6 H, 2 ϫ CH3), 1.30 (s, 6 H, 2 ϫ CH3) ppm.
13C NMR (CDCl3): δ ϭ 204.8 (C-5), 168.5 (C-1), 135.5 (C-5a),
131.5 (C-9a), 132.4, 132.0, 130.8, 129.6 (C-6, C-7, C-8, C-9), 55.8
(C-3), 54.7 (C-4), 26.1, 22.2 (CH3) ppm. EIMS: m/z ϭ 174 (60),
159 (100). CIMS (CH4): m/z ϭ 232 (100) [M ϩ H]ϩ. C14H17NO2
(231.29): calcd. C 72.70, H 7.41, N 6.06; found C 72.69, H 7.41,
N 6.15.
2,3-Dihydro-3-(2,3-dimethyl-2-butenyl)-3-hydroxy-1H-isoindol-1-one
(7): White crystals. M.p. 155Ϫ156 °C (CH2Cl2). IR (KBr): ν˜ ϭ
3339, 3224, 1677 cmϪ1 1H NMR (CDCl3): δ ϭ 7.60Ϫ7.30 (m, 4
.
H, Ar-H), 6.95 (br. d, 1 H, NH), 3.90 (s, 1 H, OH), 2.90 (d, J ϭ
13.9 Hz, 1 H, 1Ј-H), 2.65 (d, J ϭ 13.9 Hz, 1 H, 1Ј-H), 1.70 (s, 3 H,
CH3), 1.65 (s, 3 H, CH3), 1.57 (s, 3 H, CH3) ppm. 13C NMR
(CDCl3): δ ϭ 168.8 (C-1), 149.1 (C-3a), 130.4 (C-7a), 132.5, 129.4,
123.3 122.2 (C-4 to C-7), 130.2, 122.5 (C-2Ј, C-3Ј), 88.6 (C-3), 43.1
Irradiation of PHT-H/NaOH/Alkenylbenzenes: The homogeneous
solution consisting of phthalimide (1 g, 6.8 mmol), NaOH (2 mL
of a 1  solution), 140 mL of acetonitrile, 25 mL of water and
the alkenylbenzene was irradiated for the stated time. The reaction
medium was neutralised (dilute HCl) and most of the acetonitrile
was removed under vacuum. The residue was supplemented with
20 mL of a 1  NaOH solution and H2O (20 mL), and extracted
with CH2Cl2. The organic layer was dried and concentrated in va-
cuo. The residue was applied to a column chromatography (silica
gel) rinsing with hexane to remove excess of alkenylbenzene, ad-
ducts being eluted with hexane/EtOAc (from 2:1 to 1:1). The aque-
ous phase was acidified and extracted with Et2O, removal of the
solvent leaving a fraction consisting of unchanged phthalimide.
(C-1Ј), 21.2, 20.8, 20.6 (CH3) ppm. EIMS: m/z ϭ 213 (7) [Mϩ
Ϫ
18], 185 (15), 148 (100). CIMS (CH4): m/z ϭ 232 (100) [M ϩ H]ϩ,
214 (38). C14H17NO2 (231.29): calcd. C 72.70, H 7.41, N 6.06;
found C 72.94, H 7.35, N 5.98.
With 2-Ethyl-1-butene (16.4 mmol): Unchanged phthalimide
(151 mg, 15%), 8 (790 mg, 59%), 9 (50 mg, 4%), 10 (a 1:1 mixture
of the cis and trans isomers; 100 mg, 8%).
4,4-Diethyl-3,4-dihydro-1H-2-benzazepine-1,5(2H)-dione (8): White
crystals. M.p. 135Ϫ136 °C (EtOAc/hexane, 1:1). IR (KBr): ν˜ ϭ
3280, 1658, 1632 cmϪ1 1H NMR (CDCl3): δ ϭ 8.38 (br. t, J ϭ
.
With Styrene (17.4 mmol, 2 h): Unchanged phthalimide (230 mg,
23%), 11 (770 mg, 58%).
6.0 Hz, 1 H, NH), 7.87 (m, 1 H, 6-H), 7.55 (m, 3 H, Ar-H), 3.37
(d, J ϭ 6.0 Hz, 2 H, 3-H), 1.67 (m, 4 H, 2 ϫ CH2), 0.89 (t, J ϭ
7.5 Hz, 6 H, 2 ϫ CH3) ppm. 13C NMR (CDCl3): δ ϭ 208.2 (C-5), 3,4-Dihydro-4-phenyl-1H-2-benzazepine-1,5(2H)-dione (11): White
171.3 (C-1), 138.4 (C-5a), 131.0 (C-9a), 131.8, 131.6, 129.0, 127.7
crystals. M.p. 140Ϫ142°C (CHCl3/hexane) [ref.[35] 127Ϫ130 °C
1H NMR
(C-6, C-7, C-8, C-9), 58.3 (C-4), 45.1 (C-3), 25.6 (CH2), 7.8 (CH3) (hexane)]. IR (neat): ν˜ ϭ 3187, 1658, 1597 cmϪ1
.
ppm. EIMS: m/z ϭ 231 (2) [M]ϩ, 202 (27), 173 (43), 148 (100). (CDCl3): δ ϭ 7.97 (dd, J ϭ 2.0, 6.6 Hz, 1 H, 6-H), 7.75Ϫ7.12 (m,
CIMS (CH4): m/z ϭ 232 (100) [M ϩ H]ϩ, 214 (31), 203 (24). 8 H, Ar-H), 4.18 (dd, J ϭ 4.1, 9.9 Hz, 1 H, 4-H), 3.85 (ddd, J ϭ
C14H17NO2 (231.29): calcd. C 72.70, H 7.41, N 6.06; found C
72.84, H 7.81, N 6.11.
6.0, 9.9, 15.0 Hz, 1 H, 3ax-H), 3.65 (ddd, J ϭ 6.0, 4.1, 15.0 Hz, 1
H, 3eq-H) ppm. 13C NMR (CDCl3): δ ϭ 204.2 (C-5), 171.2 (C-1),
1908
Eur. J. Org. Chem. 2002, 1903Ϫ1911

A Highly Efficient, Convergent Method for [2]Benzazepine Synthesis
FULL PAPER
137.4 (C-1Ј), 137.2 (C-5a), 132.5, 132.2, 129.8, 128.5 (C-6, C-7, C-
H) ppm. 13C NMR (CDCl3): δ ϭ 204.7 (C-5), 171.3 (C-1), 158.9
8, C-9), 131.6 (C-9a), 129.1 (C-3Ј, C-5Ј), 128.0 (C-2Ј, C-6Ј), 127.8 (C-4Ј), 137.1 (C-5a), 132.4, 132.1, 129.6, 128.3 (C-6, C-7, C-8, C-
(C-4Ј), 61.9 (C-3), 44.2 (C-4) ppm. EIMS: m/z ϭ 251 (1) [M]ϩ, 222 9), 131.5 (C-9a), 129.4 (C-1Ј), 128.9 (C-2Ј, C-6Ј), 114.3 (C-3Ј, C-
(15), 165 (11), 104 (100). CIMS (CH4): m/z ϭ 252 (100) [M ϩ H]ϩ, 5Ј), 61.0 (C-3), 55.1 (OCH3), 44.1 (C-4) ppm. EIMS: m/z ϭ 281 (1)
223 (25). C16H13NO2 (251.28): calcd. C 76.48, H 5.21, N 5.57;
found C 76.70, H 5.17, N 5.50.
[M]ϩ, 252 (32), 237 (9), 134 (100). CIMS (CH4): m/z ϭ 282 (100)
[M ϩ H]ϩ, 253 (13). C17H15NO3 (281.31): calcd. C 72.58, H 5.37,
N 4.98; found C 72.23, H 5.40, N 4.82.
With trans-β-Methylstyrene (13.6 mmol, 5 h): Unchanged phthal-
imide (600 mg, 40%), 12c (175 mg, 24%), 12t (164 mg, 23%).
With Isosafrole (13.6 mmol, 5 h): Unchanged phthalimide (720 mg,
72%), 15 (300 mg, 51%).
cis-3,4-Dihydro-3-methyl-4-phenyl-1H-2-benzazepine-1,5(2H)-dione
(12c): White crystals. M.p. 152Ϫ154 °C (EtOAc). IR (neat): ν˜ ϭ
trans-4-(1,3-Benzodioxol-5-yl)-3,4-dihydro-1H-2-benzazepine-
1,5(2H)-dione (15): White crystals. M.p. 208Ϫ209 °C (EtOAc). IR
1
3178, 1657, 1599 cmϪ1. H NMR (CDCl3): δ ϭ 8.02 (m, 1 H, 6-
(neat): ν˜ ϭ 3189, 1661, 1597 cmϪ1 1H NMR (CDCl3): δ ϭ 7.94
.
H), 7.80Ϫ7.10 (m, 8 H, Ar-H), 5.75 (br. d, J ϭ 6.0 Hz, 1 H, NH),
4.52 (dq, J ϭ 6.0, 6.8, 2.6 Hz, 1 H, 3-H), 3.86 (d, J ϭ 2.6 Hz, 1 H,
4-H), 1.12 (d, J ϭ 6.8 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3):
δ ϭ 203.9 (C-5), 169.1 (C-1), 136.5 (C-5a), 135.1 (C-1Ј), 132.5,
131.7, 129.6, 128.4 (C-6, C-7, C-8,C-9), 127.5 (C-4Ј), 131.9 (C-9a),
130.3, 128.3 (C-2Ј, C-6Ј, C-3Ј, C-5Ј), 66.4 (C-3), 48.0 (C-4), 17.9
(CH3) ppm. EIMS: m/z ϭ 265 (1) [M]ϩ, 222 (100), 165 (25), 118
(42). CIMS (CH4): m/z ϭ 266 (100) [M ϩ H]ϩ, 223 (20).
C17H15NO2 (265.31): calcd. C 76.96, H 5.70, N 5.28; found C
76.76, H 5.76, N 5.19.
(dd, J ϭ 1.8, 7.1 Hz, 1 H, 6-H), 7.72Ϫ7.58 (m, 2 H, 7-H, 8-H),
7.35 (dd, J ϭ 1.8, 7.1 Hz, 1 H, 9-H), 6.77Ϫ6.54 (m, 3 H, Ar-H),
6.66 (br. s, 1 H, NH), 5.95 (s, 2 H, OCH2O), 4.08 (m, 1 H, 3-H),
3.75 (d, J ϭ 11.4 Hz, 1 H, 4-H), 1.17 (d, J ϭ 6.7 Hz, 3 H, CH3)
ppm. 13C NMR (CDCl3): δ ϭ 204.4 (C-5), 170.5 (C-1), 148.2, 147.3
(C-3aЈ, C-7aЈ), 137.8 (C-5a), 131.4 (C-9a), 130.9 (C-5Ј), 132.4,
132.1, 130.8, 129.4 (C-6, C-7, C-8, C-9), 121.3 (C-6Ј), 108.9, 107.9
(C-4Ј, C-7Ј), 101.2 (C-2Ј), 68.9 (C-3), 50.3 (C-4), 17.8 (CH3) ppm.
EIMS: m/z ϭ 309 (2) [M]ϩ, 266 (100), 162 (29), 152 (17). CIMS
(CH4): m/z ϭ 310 (100) [M ϩ H]ϩ, 267 (10). C18H15NO4 (309.32):
calcd. C 69.88, H 4.89, N 4.48; found C 69.47, H 4.93, N 4.44.
trans-3,4-Dihydro-3-methyl-4-phenyl-1H-2-benzazepine-1,5(2H)-
dione (12t): White crystals. M.p. 207Ϫ208 °C (EtOAc). IR (neat):
1
ν˜ ϭ 3180, 1665, 1596 cmϪ1. H NMR (CDCl3): δ ϭ 8.00 (m, 1 H,
With trans-Stilbene (6.8 mmol, 4 h): Unchanged phthalimide
(800 mg, 80%), 16c (44 mg, 10%), 16t (288 mg, 68%).
6-H), 7.80Ϫ7.05 (m, 8 H, Ar-H), 6.11 (br. d, J ϭ 4.3 Hz, 1 H, NH),
4.22 (ddd, J ϭ 4.3, 6.5, 11.4 Hz, 1 H, 3-H), 3.85 (d, J ϭ 11.4 Hz,
1 H, 4-H), 1.15 (d, J ϭ 6.5 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3):
δ ϭ 204.5 (C-5), 170.4 (C-1), 137.8 (C-1Ј), 137.2 (C-5a), 132.2,
131.9, 129.3, 128.1 (C-6, C-7, C-8,C-9), 127.9 (C-4Ј), 131.6 (C-9a),
129.2, 127.8 (C-2Ј, C-6Ј, C-3Ј, C-5Ј), 69.5 (C-3), 50.2 (C-4), 17.7
(CH3) ppm. EIMS: m/z ϭ 265 (1) [M]ϩ, 222 (64), 165 (20), 118
(100). CIMS (CH4): m/z ϭ 266 (100) [M ϩ H]ϩ, 223 (9).
C17H15NO2 (265.31): calcd. C 76.96, H 5.70, N 5.28; found C
76.65, H 5.74, N 5.18.
cis-3,4-Dihydro-3,4-diphenyl-1H-2-benzazepine-1,5(2H)-dione (16c):
1
Syrup. IR (KBr): ν˜ ϭ 3207, 1657, 1596 cmϪ1. H NMR (CDCl3):
δ ϭ 8.10Ϫ6.60 (m, 14 H, Ar-H), 6.40 (br. d, J ϭ 6.5 Hz, 1 H, NH),
5.56 (dd, J ϭ 6.5, 2.5 Hz, 1 H, H-3), 4.09 (d, J ϭ 2.5 Hz, 1 H, H-
4) ppm. 13C NMR (CDCl3): δ ϭ 203.0 (C-5), 168.8 (C-1), 136.5,
136.4, 134.6, 133.2, 132.4, 131.0, 130.4, 129.2, 128.7, 128.4, 128.3,
127.6, 126.6, (aromatics), 67.8 (C-3), 57.6 (C-4) ppm. EIMS: m/z ϭ
222 (100), 179 (25), 165 (25). CIMS (CH4): m/z ϭ 328 (100) [M ϩ
H]ϩ, 222 (11). C22H17NO2 (327.38): calcd. C 80.70, H 5.24, N 4.28;
found C 80.37, H 5.09, N 4.32.
With α-Methylstyrene (34 mmol, 1 h): Unchanged phthalimide
(90 mg, 9%), 13 (668 mg, 41%).
trans-3,4-Dihydro-3,4-diphenyl-1H-2-benzazepine-1,5(2H)-dione
(16t): White crystals. M.p. 203Ϫ204 °C (EtOAc). IR (neat): ν˜ ϭ
3,4-Dihydro-4-methyl-4-phenyl-1H-2-benzazepine-1,5(2H)-dione
(13): White crystals. M.p. 149Ϫ150 °C (EtOAc); [ref.[35], 137.5Ϫ138
1
3185, 1663, 1595 cmϪ1. H NMR (CDCl3): δ ϭ 8.10Ϫ6.90 (m, 14
°C (hexane)]. IR (KBr): ν˜ ϭ 3205, 1683, 1669 cmϪ1 1H NMR
.
H, Ar-H), 6.30 (br. d, J ϭ 4.6 Hz, 1 H, NH), 5.56 (dd, J ϭ 11.7,
4.6 Hz, 1 H, 3-H), 4.09 (d, J ϭ 11.7 Hz, 1 H, 4-H) ppm. 13C NMR
(CDCl3): δ ϭ 204.0 (C-5), 169.5 (C-1), 137.8, 136.6, 136.3, 132.4,
132.1, 131.2, 129.7, 128.8, 128.7, 128.5, 128.2, 127.8, 127.6, 127.2
(aromatics), 68.7 (C-3), 59.5 (C-4) ppm. EIMS: m/z ϭ 222 (100),
179 (10), 165 (21). CIMS (CH4): m/z ϭ 328 (100) [M ϩ H]ϩ, 222
(14). C22H17NO2 (327.38): calcd. C 80.70, H 5.24, N 4.28; found C
80.32, H 5.07, N 4.23.
(CDCl3): δ ϭ 7.88 (dd, J ϭ 7.4, 2.0 Hz, 1 H, 6-H), 7.73 (br. t, 1
H, NH), 7.63 (dt, J ϭ 7.4, 2.0 Hz, 1 H, 7-H), 7.56 (dt, J ϭ 7.4,
2.0 Hz, 1 H, 8-H), 7.45 (dd, J ϭ 7.4, 2.0 Hz, 1 H, 9-H), 7.36Ϫ7.17
(m, 5 H, Ar-H), 3.89 (dd, J ϭ 16.0, 6.0 Hz, 1 H, 3-H), 3.48 (dd,
J ϭ 16.0, 6.0 Hz, 1 H, 3-H), 1.70 (s, 3 H, CH3) ppm. 13C NMR
(CDCl3): δ ϭ 207.1 (C-5), 171.2 (C-1), 140.8 (C-1Ј), 137.9 (C-5a),
132.1, 132.0 129.3 128.6 (C-6, C-7, C-8, C-9), 131.0 (C-9a), 128.8
(C-3Ј, C-5Ј), 127.5 (C-4Ј), 126.3 (C-2Ј, C-6Ј), 59.4 (C-3), 49.9 (C-
4), 21.8 (CH3) ppm. EIMS: m/z ϭ 265 (1) [M]ϩ, 236 (10), 118 (100).
CIMS (CH4): m/z ϭ 266 (100) [M ϩ H]ϩ, 237 (31). C17H15NO2
(265.31): calcd. C 76.96, H 5.70, N 5.28; found C 76.87, H 5.69,
N 5.19.
Improved Formation of Benzazepinediones 14, 15 and 16: A homo-
geneous solution of phthalimide (1 g, 6.8 mmol), NaOH (10.2 mL
of a 1  solution) [phthalimide/sodium hydroxide in a 1:1.5 ratio],
140 mL of acetonitrile, 20 mL of water and excess alkenylbenzene,
was irradiated (for the stated time) with a 400-W medium-pressure
mercury lamp with Pyrex-filtered light until most of the phthalim-
ide had reacted (TLC). The solvent and excess alkene were removed
under vacuum, the residue was taken up in chloroform, the solution
With p-Methoxystyrene (14.9 mmol, 2 h): Unchanged phthalimide
(260 mg, 26%), 14 (585 mg, 41%).
3,4-Dihydro-4-(4-methoxyphenyl)-1H-2-benzazepine-1,5(2H)-dione was washed with water, and the organic layer was concentrated to
(14): White crystals. M.p. 106Ϫ107 °C (EtOAc). IR (neat): ν˜ ϭ dryness to give a solid that was crystallized directly. With styrene
3191, 1656, 1596 cmϪ1. 1H NMR (CDCl3): δ ϭ 7.95 (d, J ϭ 7.3 Hz, (2.5 equiv. excess): 1.37 g of 11 (89% at 90% conversion). With
1 H, 6-H), 7.73Ϫ7.52 (m, 3 H, Ar-H), 7.05 (d, J ϭ 8.7 Hz, 2 H,
trans-β-methylstyrene (2 equiv. excess): 1.24 g of 12 (86% at 80%
2Ј-H, 6Ј-H), 6.86 (d, J ϭ 8.7 Hz, 2 H, 5Ј-H, 3Ј-H), 4.11 (dd, J ϭ conversion). With α-methylstyrene (2.5 equiv. excess): 1.29 g of 13
4.0, 9.9 Hz, 1 H, 4-H), 3.78 (s, 3 H, OCH3), 3.89Ϫ3.59 (m, 2 H, 3-
Eur. J. Org. Chem. 2002, 1903Ϫ1911
(84% at 85% conversion).
1909

´
´
´
´
R. Suau, C. Sanchez-Sanchez, R. Garcıa-Segura, E. Perez-Inestrosa
FULL PAPER
´
Irradiation of PHT-H/NaOH/Indene: A solution of phthalimide
(1 g, 6.8 mmol), NaOH (10 mL of a 1  solution) and indene
(1 mL, 8.6 mmol) was irradiated for 4 h under a nitrogen stream.
The reaction medium was neutralized (HCl), the solvent was re-
moved, and the residue was column-chromatographed (silica gel;
hexane/EtAcO, 2:1). Three main fractions were collected; the first
one was unchanged PHT-H (400 mg, 2.6 mmol), followed by the
diastereomeric adducts 17a (480 mg, 43%) and 17b (113 mg, 10%),
and 18 (71 mg, 7%).
Universidad de Malaga) for access to the equipment used to meas-
ure the fluorescence lifetimes.
[1]
´
L. Ollero, L. Castedo, D. Domınguez, Tetrahedron 1999, 55,
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S. F. Martin, in The Alkaloids, Chemistry and Pharmacology
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[4]
5,5a,6,12a-Tetrahydro-12a-hydroxyindeno[2,1-c][2]benzazepine-7,12-
dione (17a): White crystals. M.p. 240Ϫ242 °C (EtOAc). IR (neat):
ν˜ ϭ 3315, 3283, 1664, 1600 cmϪ1. 1H NMR (CDCl3): δ ϭ 8.23 (m,
2 H, 8-H, 11-H), 7.60Ϫ7.00 (m, 6 H, Ar-H), 6.90 (br. d, J ϭ 5.0 Hz,
1 H, NH), 4.49 (s, 1 H, OH), 4.20 (ddd, J ϭ 5.0, 5.3, 11.4 Hz, 1
H, 5a-H), 3.35 (dd, J ϭ 17.0, 5.3 Hz, 1 H, 5eq-H), 2.90 (dd, J ϭ
17.0, 11.4 Hz, 1 H, 5ax-H) ppm. 13C NMR (CDCl3): δ ϭ 196.3
(C-12), 164.8 (C-7), 140.4, 135.8 130.1 (C-5a, C-9a, C-4a, C-11b),
134.8, 132.9, 129.4, 128.7, 128.3, 128.0, 127.5, 125.6 (C-1, C-2, C-
3, C-4, C-8, C-9, C-10, C-11), 74.7 (C-12a), 55.8 (C-5a), 34.7 (C-5)
ppm. EIMS: m/z ϭ 279 (18) [M]ϩ, 262 (19), 234 (9), 118 (100).
CIMS (CH4): m/z ϭ 280 (100) [M ϩ H]ϩ, 262 (74). C17H13NO3
(279.30): calcd. C 73.11, H 4.69, N 5.02; found C 73.20, H 4.61,
N 5.12.
[5]
[6]
[7]
´
[8]
[9]
[10]
´
´
2884Ϫ2886.
[11]
[12]
[13]
[14]
[15]
[16]
´
´
A. Garcıa, S. Paz, D. Domınguez, Tetrahedron Lett. 2001, 42,
665Ϫ667.
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5,5a,6,12a-Tetrahydro-12a-hydroxyindeno[2,1-c][2]benzazepine-7,12-
dione (17b): White crystals. M.p. 239Ϫ240 °C (EtOAc). IR (neat):
´
ν˜ ϭ 3299, 3262, 1633, 1594 cmϪ1 1H NMR (CDCl3): δ ϭ 7.94
.
(dd, J ϭ 7.0, 1.0 Hz, 1 H, 11-H), 7.60Ϫ6.90 (m, 7 H, Ar-H), 6.64
(br. d, J ϭ 7.4 Hz, 1 H, NH), 4.90 (s, 1 H, OH), 4.38 (ddd, J ϭ
7.4, 9.5, 9.8 Hz, 1 H, 5a-H), 3.37 (dd, J ϭ 16.4, 9.8 Hz, 1 H, 5eq-
H), 2.70 (dd, J ϭ 16.4, 9.5 Hz, 1 H, 5ax-H) ppm. 13C NMR
(CDCl3): δ ϭ 202.7 (C-12), 170.1 (C-7), 140.6 (C-4a, C-12b), 140.1
(C-11a), 136.2 (C-7a), 132.1 (C-9), 131.8 (C-10), 129.7, 129.2,
128.3, 127.6, 125.0, 123.9 (C-1, C-2, C-3, C-4, C-8, C-11), 93.8 (C-
12a), 61.3 (C-5a), 38.3 (C-5) ppm. EIMS: m/z ϭ 279 (3) [M]ϩ, 262
(6), 234 (3), 132 (100), 118 (74). CIMS (CH4): m/z ϭ 280 (100) [M
ϩ H]ϩ, 262 (69). C17H13NO3 (279.30): calcd. C 73.11, H 4.69, N
5.02; found C 73.28, H 4.58, N 5.14.
´
393Ϫ396.
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F. D. Lewis, G. D. Reddy, B. E. Cohen, Tetrahedron Lett.
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[19]
Y. Kanaoka, Acc. Chem. Res. 1978, 11, 407Ϫ413.
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[20]
[21]
4b,5,11a,12-Tetrahydroindeno[1,2-c][2]benzazepine-6,11-dione (18):
White crystals. M.p. 237Ϫ239 °C (EtOAc). IR (neat): ν˜ ϭ 3161,
1648, 1591 cmϪ1. 1H NMR (CDCl3): δ ϭ 8.25 (dd, J ϭ 2.0, 7.4 Hz,
1 H, 10-H), 8.18 (dd, J ϭ 1.8, 7.4 Hz, 1 H, 7-H), 7.4 (m, 6 H, Ar-
H), 6.78 (br. d, J ϭ 5.0 Hz, 1 H, NH), 5.20 (dd, J ϭ 10.0, 5.0 Hz,
1 H, 4b-H), 3.65 (ddd, J ϭ 10.2, 10.0, 8.6 Hz, 1 H, 11a-H), 3.45
(dd, J ϭ 16.2, 8.6 Hz, 1 H, 12-H), 3.25 (dd, J ϭ 16.2, 10.2 Hz, 1
H, 12-H) ppm. 13C NMR (CDCl3): δ ϭ 198.6 (C-11), 169.7 (C-6),
140.9 (C-12a, C-4a), 138.6 (C-10a), 134.0 (C-6a), 133.7 (C-8), 132.3
(C-9), 131.8, 129.3, 129.1, 127.6, 125.5, 122.6 (C-1, C-2, C-3, C-4,
C-7, C-10), 62.8 (C-4b), 57.2 (C-11a), 32.3 (C-12) ppm. EIMS:
m/z ϭ 263 (13) [M]ϩ, 246 (100), 148 (13). CIMS (CH4): m/z ϭ 264
(100) [M ϩ H]ϩ, 247 (10). HRMS for C17H13NO2 [Mϩ]: calcd.
263.0946; found 263.0941; for C17H12NO [Mϩ Ϫ 17]: calcd.
246.0919; found 246.0920. C17H13NO2 (263.31): calcd. C 77.54, H
4.98, N 5.32; found C 77.08, H 5.06, N 5.34.
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Acknowledgments
The authors wish to acknowledge financial support from the
Spanish DGES (project PB97-1077). Thanks are also due to Prof.
´
´
Domingo Domınguez (Universidad de Santiago de Compostela,
A. G. Griesbeck, A. Henz, W. Kramer, J. Lex, F. Nerowski, M.
Oelgemoller, K. Peters, E-M. Peters, Helv. Chim. Acta 1997,
80, 912Ϫ933.
Spain) for the NOE experiments and helpful discussions, and to
´
´
Prof. Francisco Garcıa Sanchez (Dept. Analytical Chemistry,
1910
Eur. J. Org. Chem. 2002, 1903Ϫ1911

A Highly Efficient, Convergent Method for [2]Benzazepine Synthesis
FULL PAPER
This type of allylic adducts is the only product formed upon
irradiation of N-methylphthalimide and cyclohexene in aceton-
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44, 1186Ϫ1188.
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Under these irradiation conditions, the photophthalimidation
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Received January 16, 2002
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The photochemistry of phthalimide anion with alcohols and
other hydrogen donors will be reported elsewhere.
[O02022]
Eur. J. Org. Chem. 2002, 1903Ϫ1911
1911