Studies on (1S)-N-(1-phenylethyl)phthalimide: Synthesis of both chiral spiro indane and benzazepine derivatives

Article abstract of DOI:10.3987/com-02-s(m)43

Chiral spiro indane and benzazepine compounds in isoindolinone series were prepared easily by π-cationic cyclization of the N-acyliminium ions (5-9) or the acylium ion (17) precursors with trifluoroacetic acid or aluminum trichloride, respectively. The stereochemistry and the ratio of diastereomeric mixtures observed during these process were also discussed.

Full text of DOI:10.3987/com-02-s(m)43

HETEROCYCLES, Vol. 58, 2002, pp. 449-456, Received, 8th April, 2002
STUDIES ON (1S)-N-(1-PHENYLETHYL)PHTHALIMIDE: SYNTHESIS OF
BOTH CHIRAL SPIRO INDANE AND BENZAZEPINE DERIVATIVES
Abderrahim Chihab-Eddine,a Adam Daïch,b* Abderrahim Jilale,a and Bernard
Decroixb
aLaboratory of Bio-Organic Chemistry, Department of Chemistry, Faculty of Sciences,
University of Ibnou Zohr, B.P 28/S, Agadir, Morocco
bLaboratory of Chemistry, URCOM, EA 3221, Faculty of Sciences and Techniques,
University of Le Havre, 25 rue Philippe Lebon, BP 540, 76058 Le Havre Cedex, France.
Adam.daich@univ-lehavre.fr
Abstract – Chiral spiro indane and benzazepine compounds in isoindolinone
series were prepared easily by π-cationic cyclization of the N-acyliminium ions
(5-9) or the acylium ion (17) precursors with trifluoroacetic acid or aluminum
trichloride, respectively. The stereochemistry and the ratio of diastereomeric
mixtures observed during these process were also discussed.
Introduction
N-Acyliminium ions have been shown to be highly important species in organic synthesis.1 Also, for
stereoselective syntheses of aza-compounds and aza-containing natural products, application of N-
acyliminium cation intermediates in the crucial carbon-carbon bond formation in an intermolecular and
intramolecular manner is well established.1,2
O
O
O
O
N
N
N
N
S
n( )
R
O
O
HO
Ph
1
2 (R=Me, Et)
3
4 (n=1,2)
As an extension of our work in this field, allied with our interest in the development of synthetic
approaches to diversely chiral heterocyclic compounds containing isoindolinone or pyrrolidinone
moieties, we have recently reported the preparation of chiral aza-analogues of senkyunolide-E (2) in three
steps from phthalimide derivative (1) by successive organolithium addition, Meyer-Schuster
rearrangement and Grignard reaction.3 More recently, we focused our interest on the synthesis of chiral

pyrroloisothiochroman (4, n=1) and pyrrolobenzo[d]thiepine (4, n=2),4 starting from the maleimide
synthon (3) by sulfurization, regioselective reduction followed by π-cationic cyclization, to apply to these
original molecules an exhaustive pharmaceutical investigation. In this paper, we wish to report full our
studies concerning the reactivity of (1S)-N-(1-phenylethyl)phthalimide (1) towards nucleophiles followed
by subsequent cyclization of the resulting hydroxylactams and carboxylic acids derivatives.
Result and discussion
As highlighted in Scheme 1, the enantiopure substrate (1) described earlier by us3 was subjected to
reduction and carbophilic addition in order to study the influence of the steric and electronic effects in
both reduction-addition and further cyclization steps.
Me
O
O
H
Scheme 1
R1
O
N
N
N
+
HO
HO
H
OH
H
5A Maj
5B Min
I
5.5/4.5
1
(6A) R =Me, 57%
NaBH MeOH
4
Maj
Min
1
O
(7A) R =Ph, 100%
Me
H
O
I
1
(8A) R =Bn, 55%
O
1
N
1
(9A) R =Ph(CH ) , 56%
N
S
1) R -MgX
2 2
2) H O
Me
H
2
O
HO
R1
O
N
II
1
R1-MgX CH Cl
Felkin-Ahn model
TS-(I)
2
2
II
O
O
N
N
+
1
(6B) R =Me, 43%
1
(7B) R =Ph, 0%
1
R1
HO
OH
R
1
(8B) R =Bn, 45%
1
(9B) R =Ph(CH ) , 44%
6-9A Maj
6-9B Min
2 2
Actually, reduction of the carbonyl group of the imide function was carried out with large excess of
sodium borohydride in dry methanol at –5-0°C. The reaction was accomplished in 30 min, by regular
addition of an ethanolic hydrochloric acid solution according to our precedent report,5 and afforded in
92% yield a 5.5/4.5 mixture of two diastereomers. These products were separated by fractional
crystallization (FC) or preparative TLC (hexane/ether : 1/9) and were assigned as 5A and 5B,
respectively. On the other hand, the addition of Grignard reagents (R1-MgX with R1-X = Me-I, Ph-Cl,
PhCH2-Br, Ph(CH2)2-Br) onto imide (1) give after aqueous hydrolysis6 α-hydroxy lactams (6-9) with
moderate to good yields (65-88%). It is worth mentioning that when the reaction was hydrolyzed by an
aqueous acidic solution, other significant competing process like the dehydration of hydroxy lactam into
enamide for example took place giving a complex mixture of inseparable products.
Interestingly, the results highlighted in Scheme 1 show that the reaction proceeded with moderate to high
diastereoselectivity depending on the R1 group in the Grignard reagent. These facts could be rationalized
by assuming that reduction and carbophilic addition reactions proceeded probably through Felkin-Ahn

like model as in the transition state TS-(I) (Scheme 1) in which the steric hindrance of the methylbenzyl
group induces a diastereofacial discrimination during the approach of the incoming nucleophile.
Consequently, exclusive nucleophilic addition product (7A) (88%) was obtained with phenylmagnesium
chloride, whereas methylmagnesium iodide, benzylmagnesium bromide and phenylethylmagnesium
bromide gave α-hydroxy lactams (6) (86%), (8) (65%) and (9) (67%) which showed respectively a
5.7/4.3, 5.5/4.5 and 5.6/4.4 mixture of two diastereomers inseparable by column chromatography. These
observations were comparable with our previously reported study in chiral succinimide series.4
Taking into account that the products (5-9) could give access to endocyclic N-acyliminium ion
intermediate (10) (Scheme 2) precursors of isoindoloisoindolinone core (11) as an attractive target, they
were subjected to the general π-cationic cyclization condition (trifluoroacetic acid, room temperature).7
Under these conditions, 5-7A,B were recovered unreacted accompanied in the case of 5A,B and 6A,B
with some epimerization in the favor of the major isomer (A). Interestingly, under harsher acid conditions
(neat TFA at reflux) 7A led to the expected cycle (12) in 18% yield accompanied with some
resinification of the starting material. This product which shows a cis-relationship between methyl and
phenyl groups is similar to that obtained (racemic form) earlier as a major diastereomer (16%) from the
corresponding racemate 3-hydroxy-3-phenyl-2-(1-phenylethyl)isoindolin-1-one.8
Similarly, 8A,B led to only the stable enamide compound (13) (84%) resulting from the dehydration of
the hydroxy lactams (8A,B). However, the application of this process to 9A,B provided a cyclized spiro
lactam instead of the expected isoindoloisoindolinone (11) (R=-(CH2)2-Ph), as the single diastereomer
(14) (63%). Alternatively, the dehydrated phenylethylidenephthalimidine product (15), homologous of
the enamide (13), was obtained as a 5.6/4.4 (Z/E) mixture, inseparable by chromatography, in 78% yield
when an hydrochloric acid solution (6M) was used as a proton source.
Scheme 2
O
O
O
O
7
9
N6
TFA X
TFA
O
+
N
N
S
N
rt
Reflux
5
10
R
OH
R
R
1
10
3
5-9 A,B
11 (R=H, Me)
reflux
12 (5S, 11bR)
TFA
TFA rt
6M HCl
rt
O
N
O
Me
H
O
2'
1
O
S
S
N
N
1'
O
+
2
N
3
4
4
H
H
Ph
15 (Z/E:5.6/4.4)
TS-(II)
13 (E)
14 (1'S, 3S)
1
Evidence of the Z/E geometry of olefin part in enamides (13 and 15) was performed from the H NMR
spectral data. For benzylidene (13) for example, the lone alkene proton appears at δ=5.86 ppm while the
aromatic proton H4 appears as a doublet at δ=6.40 ppm. The shielding effect of the latter proton is

comparable to the one observed for related stereoisomers.9 Based on these values we assert that the
benzylidene side chain in 13 has a s-cis conformation and E configuration. Finally, under same
considerations, the Z and E stereomers of the phenylethylidene (15) were unambiguously assigned.
A high degree of the stereocontrol observed in the synthesis of the spiro indene (14) could be rationalized
in terms of a Felkin-Ahn like transition state (Scheme 2). In fact, in the TS-(II) the π-system attack the
iminium cation from the upper side of the phenyl group at the α-position of the stereocenter to produce
the adduct (14) as a single diastereomer. These results were in accordance with N-acyliminium ion
cyclizations onto π-aromatics,4 oxygen atom10,11 or olefins. Some relevant examples of the latter process
have been reviewed recently by Speckamp.1,2 The relative stereochemistry of 14 was also confirmed by
its 1H-NMR spectral characteristics which were identical to the one obtained in a racemate form (SS and
RR) as a major isomer by Bahajaj et al.11 From these considerations, we can infer the (1’S, 3S) absolute
configuration for the spiro indane (14) ([α]D= +121° (c 0.5 M, CH2Cl2)).
Scheme 3
O
O
O
O
7
9
6
AlCl3
0°C to rt
5
1) Ph3P=CHCO2Et,
toluene, reflux
2) K2CO3, EtOH
H2O, reflux
SOCl2
reflux
N
N
N
N
3
11
H
OH
11b
13
HO2C
16A,B
1
ClOC
17A,B
O
18A (5S, 11bS)
5A and/or 5B
Our next concern was the cyclization of acetic acid derivative (16) by Friedel-Crafts reaction. Thus, the
conversion of diastereopure α-hydroxy lactam (5A or 5B) or a diastereomeric mixture of 5A,B to acetic
acid derivative (16) was accomplished by applying the elegant tandem Wittig type condensation/alkaline
hydrolysis, followed with an acidic treatment.12 At this stage, it is important to note that this reaction
occurred with good diastereoselectivity. Actually, the acids (16) are isolated as white crystalline materials
in 68% yield and showed a 84/16 mixture of two diastereomers. A tentative of separation by FC have not
give satisfactory results but led only to an enriched 92/8 diastereomeric mixture of 16A,B. This mixture
was then treated with thionyl chloride in dichloromethane at reflux and the resulting acid chloride 17
under π-cationic cyclization using aluminum trichloride (99.99%) as catalyst gave the expected ketone
(18) (68%) in an equivalent diasteromeric ratio. This mixture was chromatographed without success but
pure diastereomer (18A) ([α]D= +67° (c 0.3 M, CH2Cl2)) was obtained by recrystallization from ethanol.
Because the difficulty encountered in our course to obtain good monocrystals during the recrystallization
of 18A, its stereochemistry cannot be determined by X-Ray analysis. However, the absolute
configuration of the new chiral center at the H11b-position for ketone (18A) was determined by NOE
experiments. In fact, when the angular proton H11b (dd at δ= 5.10 ppm) was irradiated a significant NOE
affect was detected for the proton H5 (q at δ= 5.87 ppm). These results prove clearly the cis orientation of
H11b and H5 as shown in Scheme 3. This indicates also that the isoindolobenzoazepinone (18A) have a (5S,
11bS) configuration.

Conclusion: In summary, we have demonstrated in this paper that (1S)-N-(1-phenylethyl)phthalimide (1)
substrate constitutes an excellent precursor into both chiral spiro indane and benzazepine in isoindolinone
series using N-acyliminium ion and acylium ion cyclizations, respectively.
EXPERIMENTAL
Melting points are uncorrected. The IR spectra of solids (potassium bromide) were recorded on a Perkin
1
13
Elmer FTIR paragon 1000 spectrophotometer. The H and C NMR spectra were recorded on a Bruker
AC-200 (200 MHz) instrument in deuteriochloroform solution unless otherwise noted and chemical shifts
(δ) are expressed in ppm relative to internal TMS. Ascending thin layer chromatography was performed
on precoated plates of silica gel 60 F 254 (Merck) and the spots visualized using an ultraviolet lamp or
iodine vapor. E. Merck silica gel 60 F (70-300 mesh) was used for column chromatography. Optical
rotations were measured with a Perkin Elmer 251 polarimeter in a 10 cm cell at 20°C. The elemental
analyses were carried out by the microanalysis laboratory of INSA at Rouen, F 76130 Mt. St. Aignan,
France. MS spectral measurements were recorded on a MS 902 S spectrometer.
(1’S, 3R and 1’S, 3S)-2,3-Dihydro-3-hydroxy-2-(1’-phenylethyl)-1H-isoindol-1-ones (5A,B). To a
mixture of (1’S)-N-(1-phenylethyl)phthalimide (1) (1.26 g, 5 mmol) in dry methanol (40 mL) at –5-0°C
was added sodium borohydride (0.94 g, 25 mmol) by portions (5 min). To this mixture was added 5 drops
of ethanolic hydrochloric acid solution at regular intervals of 10 min. The reaction was monitored by
TLC using CH2Cl2 as eluent. After the end of the reaction (30 min), the excess of sodium borohydride
was decomposed by careful addition of cold water (15 mL) and 10 % hydrochloric acid until pH=4.
Sodium hydrogen carbonate was added and the solvent was evaporated. The residue was triturated with
water and brine and the solid was separated by filtration, washed with water and dried. The resulting
solid was separated by fractional crystallization or preparative TLC by using a mixture of hexane/ether
(1/9) to furnish pure α-hydroxy lactams (5A and 5B) in a 5.5/4.5 ratio and 92% yield.
1
Major isomer (5A): mp 118.5°C; [α]D=+51° (c 0.8 M, CH2Cl2); IR: 3279 (OH), 1682 (C=O) cm-1; H-
NMR: δ 1.82 (d, J=6.0 Hz, 3H, CH3), 2.79 (s, 1H, OH), 5.34 (q, J=6.0 Hz, 1H, N-CH), 5.91 (s, 1H, O-
CH), 7.23-7.69 (m, 9H, Haromatic); MS (EI, 70 eV) m/z: 253 (M+); Anal. Calcd for C16H15NO2: C, 75.87; H,
5.97; N, 5.53. Found: C, 75.85; H, 5.66; N, 5.35.
1
Minor isomer (5B): mp 165°C; [α]D=-71° (c 0.9 M, CH2Cl2); IR: 3265 (OH), 1689 (C=O) cm-1; H-
NMR: δ 1.78 (d, J=6.0 Hz, 3H, CH3), 3.33 (s, 1H, OH), 5.49 (s, 1H, O-CH), 5.55 (q, J=6.0 Hz, 1H, N-
CH), 7.23-7.54 (m, 9H, Haromatic); MS (EI, 70 eV) m/z: 253 (M+); Anal. Calcd for C16H15NO2: C, 75.87 ;
H, 5.97 ; N, 5.53. Found: C, 75.80 ; H, 5.72 ; N, 5.41.
General procedure for synthesis of α-hydroxy lactams (6-9A,B) by Grignard reaction. To a well
stirred and cold solution (0°C) of (1’S)-N-(1-phenylethyl)phthalimide (1) (1.26 g, 5 mmol) in anhydrous
CH2Cl2 or ether (30 mL) was added slowly and dropwise 6 mmol of a commercially available Grignard
reagent (R1-MgX with R1=Me, Ph and Bn) or a freshly prepared Ph(CH2)2MgBr. After 1 h of reaction at
0°C, the reaction was allowed to stir for an additional 3 h at rt. After water hydrolysis (40 mL) under

stirring, the solution was passed through celite. After separation, the organic layer was washed with water,
brine, dried over magnesium sulfate and concentrated in vacuo. Recrystallization of the reaction residue
from a mixture of ether/hexane gave hydroxy lactams (6-9A,B) in a range of 65-88% yields.
(1’S, 3R and 1’S, 3S)-2,3-Dihydro-3-hydroxy-3-methyl-2-(1’-phenylethyl)-1H-isoindol-1-ones
(6A,B). This compound was prepared in a yield of 86% as a 5.7/4.3 ratio of two diastereomers, mp 69-
1
73°C (mixture); IR: 3256 (OH), 1682 (C=O) cm-1; H NMR (Major): δ 1.79 (d, J = 7.5 Hz, 3H, CH3),
3.92 (s, 3H, CH3), 4.15 (s, 1H, OH), 4.91 (q, J = 7.5 Hz, 1H, CH), 7.10-7.18 (m, 3H, Haromatic), 7.21-7.61
(m, 6H, Haromatic); MS (EI, 70 eV) m/z: 249 (M+-H2O); Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41; N,
5.24. Found: C, 76.19; H, 6.22; N, 5.18.
(1’S,
3S)-2,3-Dihydro-3-hydroxy-3-phenyl-2-(1’-phenylethyl)-1H-isoindol-1-one
(7A).
This
compound was prepared in a yield of 88% as a single diastereomer, mp 138°C; [α]D=+19° (c 0.7 M,
1
CH2Cl2); IR: 3218 (OH), 1687 (C=O); H-NMR: δ 1.88 (d, J=7.4 Hz, 3H, CH3), 4,75 (q, J=7.4 Hz, 1H,
N-CH), 6.78-7.60 (m, 14H, Haromatic); MS (EI, 70 eV) m/z: 329 (M+); Anal. Calcd for C22H19NO2: C,
80.22; H, 5.81; N, 4.25. Found: C, 80.09; H, 5.72; N, 4.16.
(1’S, 3R and 1’S, 3S)-2,3-Dihydro-3-benzyl-3-hydroxy-2-(1’-phenylethyl)-1H-isoindol-1-ones (8A,B).
This compound was prepared in a yield of 65% as a 5.5/4.5 mixture of two diastereomers, mp 126-129°C
(mixture); IR: 3279 (OH), 1656 (C=O); 1H-NMR (Major): δ 1.84 (d, J=8.0 Hz, 3H, CH3), 2.56 (d, J=13.4
Hz, 1H, Ph-CH2), 2.77 (s, 1H, OH), 3.41 (d, J=13.4 Hz, 1H, Ph-CH2), 4.98 (q, J=8.0 Hz, 1H, N-CH),
6.49-7.54 (m, 14H, Haromatic); MS (EI, 70 eV) m/z: 325 (M+-H2O); Anal. Calcd for C23H21NO2: C, 80.44;
H, 6.16; N, 4.08. Found: C, 80.09; H, 6.06; N, 4.00.
(1’S, 3R and 1’S, 3S)-2,3-Dihydro-3-hydroxy-3-(2-phenylethyl)-2-(1’-phenylethyl)-1H-isoindol-1-
ones (9A,B). This compound was obtained in a yield of 67% as a 5.6/4.4 ratio of two diastereomers, mp
135-137°C; IR: 3283 (OH), 1664 (C=O); 1H-NMR (Major): δ 1.84 (d, J=7.0 Hz, 3H, CH3), 2.13-2.24 (m,
4H, Ph-CH2-CH2), 4.78 (q, J=7.0 Hz, N-CH), 6.80-7.60 (m, 14H, Haromatic); MS (EI, 70 eV) m/z: 339
(M+-H2O); Anal. Calcd for C24H23NO2: C, 80.64; H, 6.48; N, 3.92. Found: C, 80.39; H, 6.32; N, 3.89.
General procedure for treatment of hydroxylactams (7-9A,B) with neat TFA or HCl 6M. A solution
of hydroxy lactams (7-9A,B) (10 mmol) in 15 mL of trifluoroacetic acid (or 6M aqueous HCl (25 mL) for
synthesis of olefin (15)) was stirred over night at rt (or reflux) (the reaction was monitored by TLC). The
solution was concentrated in vacuo, diluted with CH2Cl2, washed successively with a saturated sodium
hydrogen carbonate solution, then with water and was dried over magnesium sulfate and filtered. The
solution was concentrated under reduced pressure and the residue was recrystallized or chromatographed
to furnish 12, 13, 14 or 15.
(5S,
11bR)-5,11b-Dihydro-5-methyl-11b-phenyl-7H-isoindolo[1,2-a]isoindol-7-one
(12).
This
compound was isolated after chromatography on silica gel column, using a mixture of ethyl acetate and
hexane (4/1) as eluent, as a single diastereomer (cis) in 18% yield, mp 142°C (lit.,8 mp 151-153°C for a
racemate); [α]D=+115° (c 0.5 M, CH2Cl2); MS (EI, 70 ev) m/z: 311 (M+); Anal. Calcd for C22H17NO: C,
84.86; H, 5.50; N, 4.50. Found: C, 84.67; H, 5.38; N, 4.36.

(1’S)-(E)-3-Benzylidene-2,3-dihydro-2-(1’-phenylethyl)-1H-isoindol-1-one (13). This compound was
isolated by recrystallization from ethanol in a yield of 84%, mp 243°C; [α]D=+98° (c 0.8 M, CH2Cl2); IR:
1715 (C=O), 1654 (C=C); 1H-NMR: δ 1.43 (d, J=8.0 Hz, 3H, CH3), 4.51 (q, J=8.0 Hz, 1H, N-CH), 5.86
13
(s, 1H, C=CH), 6.40 (d, J=6.4 Hz, 1H, H4), 6.80-7.80 (m, 13H, Haromatic); C-NMR: δ 18.1 (CH3), 42.2
(CH2), 123.2 (CH), 123.2 (CH), 126.5 (CH), 130.0 (CH), 130.2 (CH), 130.5 (CH), 130.8 (CH), 131.5
(CH), 136.5 (C), 137 .1 (C), 142.0 (C), 169.2 (CO); MS (EI, 70 ev) m/z: 325 (M+); Anal. Calcd for
C23H19NO: C, 84.90; H, 5.88; N, 4.30. Found: C, 84.77; H, 5.67; N, 4.10.
(1’S, 3S)-2-(1’-Phenylethyl)-spiro(indane-1,3-isoindol)-1-one (14). This compound was obtained by
recrystallization from ethanol in a yield of 63%, mp 202°C (lit.,8 mp 200-203°C for a racemate);
1
[α]D=+121° (c 0.5 M, CH2Cl2); IR: 1679 (C=O); H-NMR: δ 1.22 (d, J=6.7 Hz, 3H, CH3), 2.42-2.65 (m,
13
4H, CH2-CH2), 3.26 (q, J=6.7 Hz, 1H, N-CH), 6.80-7.80 (m, 13H, Haromatic); C-NMR: δ 18.1 (CH3),
35.5 (CH2), 43.0 (CH2), 59.5 (CH), 73.8 (C), 121.2 (CH), 122.4 (CH), 123.1 (CH), 123.2 (CH), 126.2
(CH), 127.0 (CH), 128.0 (CH), 128.1 (CH), 128.2 (CH), 128.3 (2CH), 130.0 (C), 131.2 (CH), 139.5 (C),
143.1 (C), 146.0 (C), 148.8 (C), 150.2 (C), 170.6 (CO); MS (EI, 70 ev) m/z: 339 (M+); Anal. Calcd for
C24H21NO: C, 84.92; H, 6.23; N, 4.12. Found: C, 84.70; H, 6.18; N, 4.58.
(1’S)-(Z+E)-2,3-Dihydro-3-phenylethylidene-2-(1’-phenylethyl)-1H-isoindol-1-ones
(15).
This
product was isolated after chromatography on silica gel column (CH2Cl2/hexane: 7/3) as a mixture of two
1
isomers (5.6/4.4: Z/E) in a yield of 78%, mp 115-119°C (mixture); IR: 1706 (C=O), 1651 (C=C); H-
NMR (Major): δ 1.39 (d, J= 8.2 Hz, 3H, CH3), 3.90 (d, 2H, J=7.8 Hz, CH2-CH=), 4.53 (q, J=8.2 Hz, 1H,
N-CH), 5.92 (t, 1H, J=7.8 Hz, C=CH-CH2) (5.41 ppm E isomer), 6.92-8.05 (m, 14H, Haromatic); MS (EI,
70 ev) m/z: 339 (M+); Anal. Calcd for C24H21NO: C, 84.92; H, 6.23; N, 4.12. Found: C, 84.59; H, 6.09; N,
4.08.
(1’S, 3R and 1’S, 3S)-2,3-Dihydro-2-(1’-phenylethyl)-1H-isoindol-1-one-3-acetic acids (16A,B). A
mixture of 5A and/or 5B (1.5 g, 5.9 mmol) and ethoxycarbonylmethylidenetriphenylphosphorane (2.48
g, 7.1 mmol) in 50 mL of toluene was refluxed for 12 h. After concentration, the residue was added to
ethanol (30 mL), potassium carbonate (0.92 g, 8.26 mmol) and water (10 mL). After 2 h of reflux, the
solution was concentrated in vacuo, dissolved in 50 mL of water and extracted with CH2Cl2 (2x30 mL).
The cold aqueous layer was acidified with 10% HCl to pH=2. The resulting precipitate was filtered off
then recrystallized from ethanol to give 16A,B as a 84/16 ratio of two diastereomers in 68% yield, mp
168°C; IR: 3433 (OH), 1724 (C=O), 1636 (C=C); 1H-NMR (Major): δ 1.79 (d, J=6.0 Hz, 3H, CH3), 2.13
(dd, J=16.6 and 4.1 Hz, 1H, CH2CO2H), 2.44 (dd, J= 16.6 and 4.1 Hz, 1H, CH2CO2H), 5.10 (dd, J= 9.4
and 4.1 Hz, 1H, CH2-CH), 5.50 (q, J=6.0 Hz, 1H, N-CH), 7.24-7.88 (m, 9H, Haromatic), 9.3 (s, 1H,
CO2H); 13C-NMR: δ 18.1 (CH3), 38.2 (CH2), 50.1 (CH), 56.2 (CH), 122.3 (CH), 124.5 (CH), 126.1 (CH),
127.5 (CH), 128.1 (CH), 129.1 (CH), 132.5 (CH), 138.5 (C), 140.1 (C), 147.2 (C), 168.0 (CO), 173.5
(CO); MS (EI, 70 ev) m/z: 295 (M+); Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C,
73.06; H, 5.66; N, 4.57.

(5S, 11bS)-5,7,11b,13-Tetrahydro-5-methylisoindolo[1,2-d]benzazepine-7,13(12H)-dione (18A). To a
stirred suspension of 16A,B (1.3 g, 4.4 mmol) in dry CH2Cl2 (25 mL) was treated slowly with freshly
distilled thionyl chloride (0.63 g, 5.28 mmol) and the mixture was heated under reflux for 2 h. After
cooling, the solution was concentrated in vacuo and the residue was dissolved in dry CH2Cl2 (35 mL).
The mixture was treated with aluminium trichloride (99.99%) (0.88 g, 6.6 mmol) over a period of 10 min
at -5-0°C. After 1 h of reaction at this temperature and 3 h at rt, the solution was poured onto cold water
and decanted. The aqueous layer was extracted with CH2Cl2 and the organic layers were washed with
water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the ketone (18) as a
96/4 ratio of two diastereomers (68%). The resulting solid after recrystallization from ethanol give pure
1
18A, mp 189°C; [α]D= +67° (c 0.3 M, CH2Cl2); IR: 1678 (C=O); H-NMR: δ 1.63 (d, J=8.0 Hz, 3H,
CH3), 2.92 (dd, J=8.0 and 12.0 Hz, CO-CH2), 3,54 (dd, J=6.0 and 12.0 Hz, CO-CH2), 5,10 (dd, J=6.0
and 8.0 Hz, 1H, CH2-CH), 5.87 (q, J=8.0 Hz, 1H, N-CH), 7.24-7.80 (m, 8H, Haromatic); 13C-NMR: δ 23.1
(CH3), 49.2 (CH2), 51.1 (CH), 55.0 (CH), 122.1 (CH), 125.2 (CH), 128.4 (CH), 129.1 (CH), 130.5 (CH),
132.0 (C), 133.5 (CH), 134.2 (CH), 138.0 (CH), 140.2 (C), 146.2 (C), 149.4 (C), 168.4 (CO), 202.2 (CO);
MS (EI, 70 ev) m/z: 277 (M+); Anal. Calcd for C18H15NO2: C, 77.96; H, 5.45; N, 5.05. Found: C, 77.75;
H, 5.38; N, 4.97.
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