An efficient approach to isoindolo[2,1-b][2]benzazepines via intramolecular [4+2] cycloaddition of maleic anhydride to 4-α-furyl-4-N-benzylaminobut- 1-enes

Article abstract of DOI:10.1016/j.tet.2004.07.008

Acylation of 4-α-furyl-4-N-benzylaminobut-1-enes with maleic anhydride gave 4-oxo-3-aza-10-oxatricyclo[5.2.1.0^1,5]dec-8-ene-6- carboxylic acid via amide formation followed by intramolecular Diels-Alder reaction of furan (IMDAF). The cycloaddition proceeded under mild reaction conditions (25°C) and provided only the exo-adduct in quantitative yield. Treatment of this compound with PPA gave isoindolo[2,1-b][2]benzazepine derivatives via ring opening, aromatization and intramolecular electrophilic alkylation. In order to extend the scope of the reaction sequence, 7-oxo-5,11b,12,13-tetrahydro-7H-isoindolo[2,1-b][2]benzazepine-8-carboxylic acids were further transformed into useful synthetic intermediates. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.07.008

Tetrahedron 60 (2004) 8455–8463
An efficient approach to isoindolo[2,1-b][2]benzazepines via
intramolecular [4C2] cycloaddition of maleic anhydride to
4-a-furyl-4-N-benzylaminobut-1-enes
a
b
a
Fedor I. Zubkov,a, Ekaterina V. Boltukhina, Konstantin F. Turchin and Alexey V. Varlamov
*
aOrganic Chemistry Department of Russian Peoples’ Friendship University, 6, Miklukho-Maklayia St., Moscow 117198, Russian Federation
bCenter of Drugs Chemistry-All-Russian Institute for Chemical and Pharmaceutical Research, 7, Zubovskaya St., Moscow 119815, Russian
Federation
Received 2 January 2004; revised 9 June 2004; accepted 1 July 2004
Abstract—Acylation of 4-a-furyl-4-N-benzylaminobut-1-enes with maleic anhydride gave 4-oxo-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-
ene-6-carboxylic acid via amide formation followed by intramolecular Diels–Alder reaction of furan (IMDAF). The cycloaddition proceeded
under mild reaction conditions (25 8C) and provided only the exo-adduct in quantitative yield. Treatment of this compound with PPA gave
isoindolo[2,1-b][2]benzazepine derivatives via ring opening, aromatization and intramolecular electrophilic alkylation. In order to extend the
scope of the reaction sequence, 7-oxo-5,11b,12,13-tetrahydro-7H-isoindolo[2,1-b][2]benzazepine-8-carboxylic acids were further
transformed into useful synthetic intermediates.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
a]quinolines from 4-a-furyl-4-N-arylaminobut-1-ens
(homoallylamines) using an intramolecular Diels–Alder
reaction of furan as the key transformation. As part of our
continuing effort to investigate the reactivity of homo-
allylfuryl amines,5 we extended this approach to prepare
various polycyclic nitrogen heterocycles. In this paper we
describe a three-step protocol for the synthesis of 7-
oxotetrahydroisoindolo[2,1-b][2]benzazepine-8-carboxylic
acids 5a-e from readily available 4-a-furyl-4-N-benzylami-
nobut-1-enes 3a-e (Scheme 2).
Compounds with the isoindolo[2,1-b][2]benzazepine core
are known to have important biological activities.1,2 For
example, 5,11b,12,13-tetrahydro-3-[1-oxo-3[1-(phenyl-
methyl)-4-piperidinyl]propyl]-7H-isoindolo[2,1-b][2]ben-
zazepine-7-one (A) and 12-diethylaminomethyl-5H-
isoindolo[2,1-b][2]benzazepine-7,13-dione (B) are known
to have AChE-inhibiting activity1a and a protective effect
against nitrogen-induced hypoxia2 respectively (Scheme 1).
Although compounds with the isoindolo[2,1-b][2]benzaze-
pine moiety show interesting biological properties, to the
best of our knowledge, only two synthetic routes to
isoindolo[2,1-b][2]benzazepines have been reported in the
literature. The first route is based on the intramolecular
Friedel–Crafts acylation of 2,3-dihydro-3-oxo-2-(phenyl-
methyl)-1H-isoindol-1-acetic acids2 whereas the second one
utilized the p-cyclization of N-acyliminium ions generated
from N-alkenyl-3-hydroxyisoindolin-1-ones.3 Both
approaches involve many steps and yielded the desired
products in moderate yields. Recently,4 we reported a
synthetic approach to substituted oxoisoindolo[2,1-
2. Results and discussion
The starting 4-N-benzylaminobut-1-enes 3a-e were readily
obtained by a two-step one-pot procedure.5c Condensation
of benzylamines 1 with furaldehydes 2 gave the intermedi-
ate imines, which were immediately treated with
Keywords: Homoallylamines; Isoindolobenz-2-azepines; Intramolecular
Diels–Alder reaction; IMDAF; Intramolecular electrophilic alkylation.
* Corresponding author. Tel.: C7-95-3355798; fax: C7-95-9550779;
e-mail: fzubkov@sci.pfu.edu.ru
Scheme 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.008

8456
F. I. Zubkov et al. / Tetrahedron 60 (2004) 8455–8463
Scheme 2.
methallylmagnesium chloride to provide the desired amines
3a-e in good overall yields (Scheme 2). It is noteworthy that
the a-methylbenzylamine derivative 3c was isolated as a
1:1.1 mixture of diastereoisomers with (R*,R*)- and (R*,S*)-
oriented methallyl and CH3 (R1) groups.
Having successfully isolated compounds 4a-e in high
yields, we then proceeded to study the acid promoted ring
opening/ ring forming sequence. Treatment of epoxyisoin-
dolines 4a-e with excess polyphosphoric acid (PPA) at
90 8C for 40 min smoothly promoted a 1,7-oxygen bridge
opening/ aromatization/ intramolecular electrophilic cycli-
zation sequence to give the isoindolobenzazepine car-
boxylic acids 5a-e in 30–75% yields (Scheme 2).
Treatment of compound 4a with H3PO4 at 60 8C gave a
mixture of the cyclized compound 5a and the uncyclized
double bond migration product 6 (w1:2). Isolation of
intermediate 6 shows that the reaction sequence involves an
initial cleavage of the 1,7-oxygen bridge followed by
aromatization to give 6. Electrophilic cyclization of pure
isoindolone 6 under the action of PPA at 90 8C proceeds via
formation of the thermodynamically stable tertiary carbo-
cation and yields isoindolobenzazepine 5a in 83% yield.
The reaction of homoallylamines 3a-e with maleic anhy-
dride6 proceeded smoothly (toluene, rt, 2–3 days) to give the
corresponding 3-benzyl-2-methallyl-3-aza-10-oxatricyclo
[5.2.1.01,5]dec-8-ene-6-carboxylic acids 4a-e as a w1:1
mixture of isomers at C-2. The products are formed via an
initial N-acylation followed by the IMDA cycloaddition
reaction sequence. The IMDA cycloaddition reaction was
highly stereoselective and furnished only the exo-cycload-
ducts 4a-e. Under the acylation reaction conditions, amine
3c with two stereogenic centers gave a 1:5:10 mixture of
exo-isomers, determined from the 1H NMR spectrum of the
crude product. No additional experiment was carried out to
establish the relative stereochemistry of compound 4c. The
exo-configuration of Diels–Alder adducts 4a,c-e (R2ZH)
Compounds 5a,b,d,e exist in the form of one conformer
with the pseudo-axial orientation of 11b-H, as evidenced by
1H NMR spectroscopic data. In particular, the vicinal
coupling constant values J11b,12A(ax)Z12.0–14.0 Hz and
J11b,12B(eq)Z2.5–2.9 Hz unambiguously prove the pseudo-
axial orientation of 11b-H. Although heating isomeric
mixtures of compound 4c (R1ZMe) with PPA could lead
to a mixture of two stereoisomers of compound 5c (cis- and
trans-configurations of the methyl group at C-5 and the
proton at C-11b), to our surprise, acid 5c was isolated as a
single cis-isomer with the pseudo-equatorial orientation of
the 5-CH3 group and the pseudo-axial of the 11b proton.
3
was confirmed by comparing the J6-H,7-H value of
compounds 4a,c-e with the analogous bridged systems
3
reported in the literature.7 The reported J6-H,7-H value for
6-H in molecules with an endo-orientation is !1 Hz
whereas, the J6-H,7-H value for 6-H in molecules with an
3
exo-orientation is around 3 Hz. So the observed coupling
constants for compounds 4a,c-e (3J6-H,7-HZ0–0.8 Hz)
unambiguously proves the endo-orientation of 6-H (and
5-H correspondingly). The stereochemistry of adducts 4b
(R2ZMe) can be surmised by analogy with compounds
4a,c-e. We were unable to separate the isomer mixtures due
to the insoluble nature of compound 4 in commonly used
solvents.
The cis-structure of compound 5c was confirmed by NOE.
The NOE values (h) indicated an increase of Hi signal

F. I. Zubkov et al. / Tetrahedron 60 (2004) 8455–8463
8457
intensity when Hj signal was saturated (hHi{Hj}, %). The
values of h11b-H{5-H}Z9.5%, on one hand, and h5-H{11b-
H}Z5%, on the other hand, proved that 11b-H and 5-H
were situated on the one side of the benz-2-azepine ring
plane.
single compound in 73% yield. The structure of compound 7
was confirmed by 1H NMR spectroscopy, based on the
multiplicities of proton signals of the nitro substituted
benzene ring, and NOE values for the same protons. High
NOE values were measured for the doublet signal d 7.69
(JorthoZ8.9 Hz, NOEZ13%) with 13-CH3 saturation (d
1.50), and for the doublet signal d 8.30 (JmetaZ2.7 Hz,
NOEZ18%) with 5-HA saturation (d 5.37) thus proving 1
and 4 position of the above mentioned aromatic protons, and
3 nitro substituent position.9
The carboxylic acids 5a-e are crystalline with high melting
points and insoluble in most of the commonly used organic
solvents. The low (w30%) yield of cyclization products 5b
and 5c is explained by considerable resinification of reaction
mixtures and losses during recrystallization from the
i-PrOH–DMF mixture. Probably, the second (minor)
trans-isomer of 5c could be lost at the purification stage
of the reaction mixture.
Heating acid 5a in PhNO2 smoothly oxidized the ring to
give compound 9. Heating compound 5a with thionyl
chloride in benzene gave the unexpected ring oxidized acid
chloride 8. We suppose, that the dehydrogenation occurs
due to an oxidative action of SOCl2 itself or products of its
decomposition (SO2, Cl2). Several examples of similar
dehydrogenation exist in the literature,10 but in all cases the
oxidation was carried out under basic conditions (pyridine,
picoline). The structure of the acid chloride 8 was confirmed
by 1H and 13C NMR spectra and by conversion into
compound 9 by hydrolysis of acid chloride 8 with NaOH.
The amide 10 and ester 11 were prepared from the acid
chloride 8 and acid 5a, respectively, in moderate yields. The
reduction of 5a with 8 mol equiv. lithium aluminum hydride
in boiling THF gave alcohol 12 (Scheme 3).
Having developed an efficient simple synthetic route for the
isoindolo[2,1-b][2]benzazepine system, we turned our
attention to further functionalize the system to make the
reaction sequence synthetically useful. Accordingly, com-
pound 5a was chosen as the test substrate and subjected to
various reaction conditions and the results are shown in
Scheme 3.
As far as we know there is only one example of the aromatic
electrophilic substitution of 7-oxoisoindolo[2,1-b][2]benza-
zepines.8 The authors regioselectively acylated isoindolo-
benzazepines at the C-3 position with AcCl/AlCl3 in boiling
dichloroethane. Unfortunately, our attempts to acylate the
isoindolobenzazepine carboxylic acid 5a with excess Ac2O/
AlCl3 in dichloromethane (or AcCl/AlCl3 in dichloroethane
or nitrobenzene) using the published procedure8 met with
failure.
In conclusion, this paper describes a simple and efficient
synthetic approach to isoindolo[2,1-b][2]benzazepine-8-
carboxylic acids. The synthetic route involves intramole-
cular Diels–Alder cycloaddition of 4-a-furyl-4-N-benzyla-
minobut-1-enes with maleic anhydride followed by PPA
acid-promoted intramolecular seven-membered ring for-
mation sequence. This two-step synthetic sequence is very
efficient and yielded the tetracyclic compounds in high
Treatment of 5a with potassium nitrate and concentrated
sulfuric acid afforded the 3-nitro substituted azepine 7 as a
Scheme 3.

8458
F. I. Zubkov et al. / Tetrahedron 60 (2004) 8455–8463
yields. Further functionalization of the acid was also
examined. Considering the mild reaction conditions, and
stereochemical control associated with the IMDA cycload-
dition/ acid promoted cyclization reaction sequence, we
believe that this methodology could be of use in organic
synthesis for the preparation of polycyclic drug- and natural
product-like molecules.
3.1.2. 2-Methyl-4-(2-(5-methylfuryl))-4-N-benzylamino-
but-1-ene (3b). Yield 34%; bp 158–159 8C/3 mm Hg; IR
3310 (NH), and 1640 (C]C) cmK1; EI-MS (70 eV) m/z
(rel. intensity): [MK55 (–CH2C(Me)]CH2)]C 200 (57),
91 (100), 77 (8), 65 (15), 51 (10), 39 (20); 1H NMR (CDCl3,
200 MHz) d 1.60 (s, 3H, Me-2), 1.73 (brs, 1H, NH), 2.29
(brs, 3H, Me-50), 2.41 (dd, 1H, H-3B, JZ5.5, 13.8 Hz), 2.51
(dd, 1H, H-3A, JZ8.9, 13.8 Hz), 3.57 (d, 1H, NCHAHB, JZ
13.4 Hz), 3.77 (dd, 1H, H-4, JZ8.9, 5.5 Hz), 3.80 (d, 1H,
NCHAHB, JZ13.4 Hz), 4.76 (brs, 1H, H-1), 4.80 (brs, 1H,
H-1), 5.89 (dq, 1H, H-40, JZ3.0, 1.0 Hz), 6.06 (d, 1H, H-30,
JZ3.0 Hz), 7.17–7.37 (m, 5H, Ph–H). Anal. Calcd for
C17H21NO: C, 80.00; H, 8.24; N, 5.49. Found: C, 80.00; H,
8.22; N, 5.47.
3. Experimental
All reagents were purchased from Acros Chemical Co. All
solvents were used without further purification. Melting
points were determined using a Fisher–Johns melting point
apparatus and are uncorrected. IR spectra were obtained on
a UR-20 spectrometer in KBr pellets for solid or in thin film
3.1.3. 2-Methyl-4-N-(a-methylbenzyl)-4-(2-furyl)amino-
but-1-ene (3c). Mixture of two diastereoisomers in the ratio
w1:1.1, yield 79%; bp 150–155 8C/7 mm Hg; n2D0 1.5274;
IR 3305 (NH), and 1645 (C]C) cmK1; EI-MS (70 eV) m/z
(rel. intensity): [MK55 (–CH2C(Me)]CH2)]C 200 (51),
105 (100), 96 (90), 79 (28), 77 (33), 55 (15), 41 (14), 39
(21); 1H NMR (CDCl3, 200 MHz) maj isomer d 1.33 (d, 3H,
MeCHN, JZ6.5 Hz), 1.62 (s, 3H, Me-2), 1.68 (brs, 1H,
NH), 2.43 (dd, 1H, H-3B, JZ13.7, 7.1 Hz), 2.52 (dd, 1H, H-
3A, JZ13.7, 7.1 Hz), 3.74 (q, 1H, MeCHN, JZ6.5 Hz),
3.90 (t, 1H, H-4, JZ7.1 Hz), 4.68 (m, 1H, H-1), 4.75 (m,
1H, 0H-1), 6.06 (brd, 1H, H-30, JZ3.0, 0.80Hz), 6.22 (dd, 1H,
H-4 , JZ3.0, 1.8 Hz), 7.29 (dd, 1H, H-5 , JZ1.8, 0.8 Hz),
7.16–7.31 (m, 5H, Ph–H). 13C NMR (CDCl3, 100.6 MHz) d
156.61 (C-20), 145.74 (Cqu.-Ph), 142.2 (C-50), 140.9 (C-2),
126.40 (2C, ortho-Ph), 128.10 (2C, meta-Ph), 126.58 (para-
Ph), 113.0 (C-1), 109.7 (C-30), 105.9 (C-40), 55.1 (CHMe),
52.2 (C-4), 43.0 (C-3), 22.8 (CHMe), 22.1 (Me-2); min
isomer d 1.29 (d, 3H, MeCHNH, JZ6.7 Hz), 1.45 (s, 3H,
Me-2), 1.68 (brs, 1H, NH), 2.31 (dd, 1H, H-3B, JZ13.5,
5.4 Hz), 2.45 (dd, 1H, H-3A, JZ13.5, 9.1 Hz), 3.52 (dd, 1H,
H-4, JZ9.1, 5.4 Hz), 3.59 (q, 1H, MeCHN, JZ6.7 Hz),
4.72 (m, 1H, H-1), 4.78 (m, 1H, H-01), 6.06 (brd, 1H, H-30,
JZ3.0, 0.7 Hz), 6.29 (dd, 1H, H-4 , JZ3.0, 1.7 Hz), 7.36
(dd, 1H, H-50, JZ1.7, 0.7 Hz), 7.16–7.31 (m, 5H, Ph-H).
13C NMR (CDCl3, 100.6 MHz) d 156.56 (C-20), 145.23
(Cqu.-Ph), 142.1 (C-50), 141.2 (C-2), 126.48 (2C, ortho-Ph),
128.18 (2C, meta-Ph), 126.7 (para-Ph), 113.2 (C-1), 109.6
(C-30), 106.2 (C-40), 55.0 (CHMe), 51.0 (C-4), 43.9 (C-3),
24.5 (CHMe), 21.6 (Me-2); Anal. Calcd for C17H21NO: C,
80.00; H, 8.24; N, 5.49. Found: C, 80.02; H, 8.25; N, 5.50.
1
for oils. H NMR spectra were recorded on a Bruker WP-
200 or WH-400 spectrometers for solutions (2%) in
deuteriochloroform or DMSO-D6 at 30 8C and using TMS
as internal standard. Chemical shifts are reported in ppm
units, and coupling constants (J) are quoted in Hz.
Abbreviations of coupling patterns: s (singlet), d (doublet),
t (triplet), dd (doublet of doublets), ddd (doublet doublet of
doublets), ddt (doublet doublet of triplets), m (multiplet).
Mass spectra were obtained by electron impact at 70 eV on a
Varian MAT-112 spectrometer or Finnegan MAT95XL
chromatomass spectrometer. The purity of the obtained
substances and the composition of the reaction mixtures
were controlled by TLC silufol UV254 plates.
3.1. 4-(2-Furyl)-4-N-benzylaminobut-1-enes 3. Typical
procedure
The freshly obtained5c,9 aldimine (0.30 mol) was added
slowly drop-wise at reflux to a stirred solution of
methallylmagnesium chloride, prepared from methallyl
chloride (41 mL, 0.45 mol) and magnesium turnings
(22.0 g, 0.90 mol) in mixture THF–ether (1:1, 300 mL).
After the addition of the Schiff base the reaction mixture
was stirred for one hour at room temperature. The cooled
reaction mixture was taken up in saturated aqueous NH4Cl
solution (300 mL) under ice cooling and extracted with
ether (3!100 mL). The organic layer was dried MgSO4 and
concentrated. The residue was distilled in vacuo to give the
products 3 as colourless oils.
3.1.1. 2-Methyl-4-(2-furyl)-4-N-benzylaminobut-1-ene
(3a). Yield 83%; bp 158–160 8C/7 mm Hg; n2D0 1.5350; IR
3320 (NH), and 1640 (C]C) cmK1; EI-MS (70 eV) m/z
(rel. intensity): MC 241 (1), 186 (50), 91 (100), 77 (32), 55
(9), 51 (16), 39 (22); 1H NMR (CDCl3, 200 MHz) d 1.60 (s,
3H, Me-2), 1.72 (brs, 1H, NH), 2.35–2.60 (m, 2H, H-3),
3.56 (d, 1H, NCHAHB, JZ13.4 Hz), 3.77 (d, 1H, NCHAHB,
JZ13.4 Hz), 3.85 (dd, 1H, H-4, JZ8.2, 6.4 Hz), 4.73 (brs,
1H, H-1), 4.79 (brs, 1H, H-1), 6.18 (dd, 1H, H-30, JZ3.1,
0.9 Hz), 6.31 (dd, 1H, H-40, JZ3.1, 1.8), 7.15–7.35 (m, 5H,
Ph-H), 7.36 (dd, 1H, H-50, JZ1.8, 0.9). 13C NMR (CDCl3,
100.6 MHz) d 156.4 (C-20), 142.2 (Cqu.-Ph), 141.4 (C-50),
140.2 (C-2), 128.23 (2C, orto-Ph), 128.100 (2C, meta-Ph),
126.8 (para-Ph), 113.29 (C-1), 109.8 (C-3 ), 106.4 (C-40),
53.0 (C-4), 51.1 (CH2N), 43.5 (C-3), 21.8 (Me-2). Anal.
Calcd for C16H19NO: C, 79.67; H, 7.88; N, 5.81. Found: C,
79.69; H, 7.86; N, 5.81.
3.1.4. 2-Methyl-4-N-(4-methylbenzyl)-4-(2-furyl)amino-
but-1-ene (3d). Yield 75%; bp 147–148 8C/2 mm Hg; nD22
1.5315; IR 3320 (NH), and 1645 (C]C) cmK1; EI-MS
(70 eV) m/z (rel. intensity): [MK55 (–CH2C(Me)]CH2)]C
200 (31), 105 (100), 95 (18), 94 (13), 91 (22), 79 (21), 77
1
(26), 65 (11), 39 (35); H NMR (CDCl3, 400 MHz) d 1.61
(s, 3H, Me-2), 1.78 (brs, 1H, NH), 2.34 (s, 3H, Me-Ar), 2.43
(dd, 1H, H-3B, JZ13.7, 5.7 Hz), 2.53 (ddd, 1H, H-3A, JZ
13.7, 8.7, 0.7 Hz), 3.52 (d, 1H, NCHAHB, JZ13.0 Hz), 3.76
(d, 1H, NCHAHB, JZ13.0 Hz), 3.85 (dd, 1H, H-4, JZ8.7,
5.7 Hz), 4.75 (d, 10H, H-1, JZ0.7 Hz), 4.80 (brs, 1H, H-1),
6.20 (brd, 1H, H-3 , JZ3.0 Hz), 6.34 (dd,01H, H-40, JZ3.0,
1.7 Hz), 7.13 (BB0, 2H, H-Ar), 7.16 (AA , 2H, H-Ar), 7.39
(dd, 1H, H-50, JZ1.7, 0.7 Hz). 13C NMR (CDCl3,
100.6 MHz) d 156.3 (C-20), 142.0 (Cqu.–C6H4Me), 141.2
(C-50), 137.0 (Cqu.–C6H4Me), 136.1 (C-2), 128.8 (2C,

F. I. Zubkov et al. / Tetrahedron 60 (2004) 8455–8463
8459
ortho-C6H4Me), 127.9 (2C, meta-C6H4Me), 113.1 (C-1),
109.7 (C-30), 102.2 (C-40), 50.7 (CH2N), 52.8 (C-4), 43.3
(C-3), 20.9 (C6H4Me), 22.7 (Me-2); Anal. Calcd for
C17H21NO: C, 80.00; H, 8.24; N, 5.49. Found: C, 80.00;
H, 8.28; N, 5.52.
Ratio of isomers A/B w1:2; yield 89%; mp 174.5–175 8C;
IR 1730 (COOH), and 1650 (N–C]O) cmK1; EI-MS
(70 eV) m/z (rel. intensity): MC 353 (10), 309 (3), 298
(53), 262 (23), 254 (6), 208 (10), 149 (15), 131 (5), 106 (10),
99 (20), 91 (100), 65 (18), 55 (13); 1H NMR (CDCl3,
400 MHz) isomer A d 1.69 (s, 6H, Me-20 and Me-7), 2.31
(dd, 1H, H-30A, JZ15.3, 8.7 Hz), 2.50 (dd, 1H, H-30B, JZ
15.3, 5.2 Hz), 2.83 (d, 1H, H-6, JZ8.7 Hz), 3.09 (d, 1H,
H-5, JZ8.7 Hz), 3.96 (dd, 1H, H-2, JZ8.7, 5.2 Hz), 4.11 (d,
1H, CHAHBN, JZ15.6 Hz), 4.82 (brs, 1H, H-10), 4.91 (brs,
1H, H-10), 5.10 (d, 1H, CHAHBN, JZ15.6 Hz), 6.12 (d, 1H,
H-8, JZ5.7 Hz), 6.54 (d, 1H, H-9, JZ5.7 Hz), 7.20–7.35
(m, 5H, H-Ph), 9.38 (brs, 1H, COOH); 0isomer B d 1.69 (s,
6H, Me-20 and Me-7), 2.50 (m, 2H, H-3 ), 2.82 (d, 1H, H-6,
JZ8.6), 2.93 (d, 1H, H-5, JZ8.6 Hz), 3.98 (m, 1H, H-3),
4.15 (d, 1H, CHAHBN, JZ15.6 Hz), 4.71 (brs, 1H, H-10),
4.80 (brs, 1H, H-10), 5.01 (d, 1H, CHAHBN, JZ15.6 Hz),
6.06 (d, 1H, H-8, JZ5.6 Hz), 6.33 (d, 1H, H-9, JZ5.6 Hz),
7.20–7.35 (m, 5H, H-Ph), 9.38 (brs, 1H, COOH). Anal.
Calcd for C21H23NO4: C, 71.39; H, 6.50; N, 3.97. Found: C,
71.39; H, 6.51; N, 3.98.
3.1.5. 2-Methyl-4-N-(4-methoxybenzyl)-4-(2-furyl)ami-
nobut-1-ene (3e). Yield 71%; bp 162 8C/2 mm Hg; nD22
1.5381; IR 3310 (NH), and 1645 (C]C) cmK1; EI-MS
(70 eV) m/z (rel. intensity): [MK55 (–CH2C(Me)]CH2)]C
216 (28), 121 (100), 91 (11), 77 (18), 65 (8), 55 (7), 39 (12);
1H NMR (CDCl3, 400 MHz) d 1.61 (brs, 3H, Me-2), 1.81
(brs, 1H, NH), 2.43 (brdd, 1H, H-3B, JZ13.7, 5.9 Hz), 2.52
(dd, 1H, H-3A, JZ13.7, 8.7 Hz), 3.50 (d, 1H, NCHAHB, JZ
13.1 Hz), 3.73 (d, 1H, NCHAHB, JZ13.1 Hz), 3.79 (s, 3H,
OMe), 3.84 (dd, 1H, H-4, JZ8.7, 5.9 Hz), 4.74 (m, 1H, H-
1), 4.80 (m, 1H, H-1), 6.20 (dd, 1H, H-30, JZ3.2, 0.8 Hz),
6.33 (dd, 01H, H-40, JZ3.2, 1.8 Hz), 6.850 (BB0, 2H, H-Ar),
7.18 (AA , 2H, H-Ar), 7.39 (dd, 1H, H-5 , JZ1.8, 0.8 Hz).
13C NMR (CDCl3, 100.6 MHz) d 158.5 (Cqu.–C6H4OMe),
156.4 (C-20), 142.1 (Cqu.–C6H4OMe), 141.3 (C-50), 132.2
(C-2), 129.2 (2C, ortho-C6H4OMe), 113.6 (2C, meta-
C6H4OMe), 113.2 (C-1), 109.7 (C-30), 106.3 (C-40), 55.0
(MeO), 50.5 (CH2N), 52.8 (C-4), 43.4 (C-3), 21.8 (Me-2);
Anal. Calcd for C17H21NO2: C, 75.28; H, 7.75; N, 5.49.
Found: C, 75.29; H, 7.72; N, 5.19.
3.2.3. 2-Methallyl-4-oxo-3-(a-phenylethyl)-10-oxa-3-
azatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (4c).
Ratio of isomers A/B/C w10:5:1; yield 73%; mp 212–
215 8C; IR 1730 (COOH), and 1660 (N–C]O) cmK1; EI-
MS (70 eV) m/z (rel. intensity): MC 353 (2), 298 (6), 186
(10), 120 (14), 105 (100), 96 (28), 91 (36), 77 (18), 65 (12),
51 (6), 39 (10); 1H NMR (CDCl3, 200 MHz) isomer A (maj)
d 1.58 (brs, 3H, Me-20), 1.63 (d, 3H, MeCH, JZ7.3 Hz),
1.90–2.15 (m, 2H, H-30), 2.83 (d, 1H, H-6, JZ9.2 Hz), 2.99
(d, 1H, H-5, JZ9.2 Hz), 0 4.19 (dd, 1H, H-2, JZ10.1,
4.0 Hz), 4.70 (brs, 1H, H-1 ), 4.84 (brs, 1H, H-10), 5.28 (d,
1H, H-7, JZ1.5 Hz), 5.35 (q, 1H, CHMe, JZ7.3 Hz), 6.37
(dd, 1H, H-8, JZ5.8, 1.5 Hz), 6.46 (d, 1H, H-9, JZ5.8v),
7.15–7.50 (m, 5H, H-Ph). Anal. Calcd for C21H23NO4: C,
71.39; H, 6.50; N, 3.97. Found: C, 71.41; H, 6.48; N, 3.97.
3.2. 4-Oxo-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene-6-
carboxylic acids (4). Typical procedure
Corresponding amine 3 (0.1 mol) was dissolved in 150 mL
of toluene and an equimolar amount of maleic anhydride
(0.1 mol, 9.8 g) was added in one portion. Reaction mixture
was stirred for 30–60 h at room temperature and then
crystalline product was filtered off, washed with toluene
(2!100 mL), ether (2!80 mL) and dried at 100 8C to give
desired products 4 as white solids.
3.2.1. 3-Benzyl-2-methallyl-4-oxo-10-oxa-3-azatricy-
clo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (4a). Ratio of
isomers A/B w1:1.6; yield 95%; mp 169–170 8C; IR 1710
(COOH), and 1640 (N–C]O) cmK1; EI-MS (70 eV) m/z
(rel. intensity): MC 339 (2), 284 (10), 204 (8), 194 (7), 120
3.2.4. 3-(4-Methylbenzyl)-2-methallyl-4-oxo-10-oxa-3-
azatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (4d).
Ratio of isomers A/B w 1:1.2; yield 92%; mp 109.5–
111 8C; IR 1720 (COOH), and 1665 (N–C]O) cmK1
;
EI-MS (70 eV) m/z (rel. intensity): MC 353 (9), 218 (36),
194 (17), 120 (33), 105 (100), 99 (15), 91 (10), 77 (16), 65
(7), 55 (9), 39 (9); 1H NMR (DMSO-D6, 400 MHz) isomer
A d 1.560 (s, 3H, Me-20), 2.26 (s, 3H, Me-Ar), 2.36–2.52 (m,
2H, H-3 ), 2.49 (d, 1H, H-6, JZ9.1 Hz), 2.99 (d, 1H, H-5,
JZ9.1 Hz), 4.16 (dd, 1H, H-2, JZ10.1, 4.5 H0z), 4.59 (d,
1H, CHAHBN, JZ15.3 Hz), 4.63 (m, 1H, H-1 ), 4.71 (m,
1H, H-10), 4.80 (d, 1H, CHAHBN, JZ15.3 Hz), 5.01 (d, 1H,
H-7, JZ1.7 Hz), 6.29 (dd, 1H, H-8, JZ5.8, 1.7 Hz), 6.43 (d,
1H, H-9, JZ5.8 Hz), 7.07–7.15 (m, 4H, H-Ar); isomer B d
1.67 (s, 3H, Me-20), 2.14 (dd, 1H, H-30A, JZ13.9, 9.0 Hz),
2.25 (s, 3H, Me-Ar), 2.40 (m, 1H, H-30B), 2.49 (d, 1H, H-6,
JZ9.1 Hz), 2.82 (d, 1H, H-5, JZ9.1 Hz), 3.68 (dd, 1H, H-2,
JZ9.0, 5.5 Hz), 3.99 (d, 1H, CHAHBN, JZ15.4 Hz), 4.19
(d, 1H, CHAHBN, JZ15.4 Hz), 4.77 (m, 1H, H-10), 4.85 (m,
1H, H-10), 4.97 (d, 1H, H-7, JZ1.7 Hz), 6.39 (dd, 1H, H-8,
JZ5.8, 1.7 Hz), 6.54 (d, 1H, H-9, JZ5.8 Hz), 7.07–7.15
(m, 4H, H-Ar). 13C NMR (DMSO-D6, 65 8C, 100.6 MHz)
isomer A d 173.5, 172.5, 140.5, 135.6, 132.2, 127.0, 56.1,
44.3, 38.1, 22.5, 158.9, 133.7, 128.8, 92.1, 90.6, 81.5, 81.4,
55.1, 50.7, 49.3, 45.9. Isomer B d 173.6, 173.1, 139.8, 136.4,
1
(6), 99 (12), 91 (100), 78 (16), 65 (16), 51 (8), 39 (10); H
NMR (CDCl3, 200 MHz) isomer A d 1.71 (s, 3H, Me-20),
2.40–2.55 (m, 2H, H-30), 2.83 (d, 1H, H-6, JZ9.2 Hz), 3.04
(d, 1H, H-5, JZ9.2 Hz), 3.95 (dd, 1H, H-2, JZ8.2, 5.5 Hz),
4.08 (d, 1H, CHAHBN, JZ15.0 Hz), 4.82 (brs, 1H, H-10),
4.92 (brs, 1H, H-10), 5.09 (d, 1H, CHAHBN, JZ15.0 Hz),
5.25 (d, 1H, H-7, JZ1.5 Hz), 6.35 (dd, 1H, H-8, JZ5.8,
1.5 Hz), 6.48 (d, 1H, H-9, JZ5.8 Hz), 7.15–7.45 (m, 5H, H-
Ph), 11.03 (brs, 1H, COOH); isomer B d 1.71 (s, 3H, Me-20),
2.40–2.55 (m, 2H, H-30), 2.83 (d, 1H, H-6, JZ9.2 Hz), 2.89
(d, 1H, H-7, JZ9.2 Hz), 4.10 (dd, 1H, H-3, JZ8.1, 6.6 Hz),
4.19 (d, 1H, CHAHBN, JZ15.0 Hz), 4.71 (brs, 1H, H-10),
4.82 (brs, 1H, H-10), 4.95 (d, 1H, CHAHBN, JZ15.0 Hz),
5.29 (s, 1H, H-7), 6.28 (s, 2H, H-8 and H-9), 7.15–7.45 (m,
5?, H-Ph), and 11.03 (brs, 1H, COOH). Anal. Calcd for
C20H21NO4: C, 74.80; H, 6.20; N, 4.13. Found: C, 74.80; H,
6.21; N, 4.10.
3.2.2. 3-Benzyl-7-methyl-2-methallyl-4-oxo-10-oxa-3-
azatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (4b).

8460
F. I. Zubkov et al. / Tetrahedron 60 (2004) 8455–8463
127.8, 114.4, 56.3, 43.7, 34.5, 22.8, 158.9, 133.7, 128.8,
92.1, 90.6, 81.5, 81.4, 55.1, 50.7, 49.3, 45.9. Anal. Calcd for
C21H23NO4: C, 71.39; H, 6.50; N, 3.97. Found: C, 71.41; H,
6.49; N, 3.95.
(q, Me-13). Anal. Calcd for C20H19NO3: C, 74.77; H, 5.92;
N, 4.36. Found: C, 74.78; H, 5.90; N, 4.37.
3.3.2. 9,13,13-Trimethyl-7-oxo-5,11b,12,13-tetrahydro-
7H-isoindolo[2,1-b][2]benzazepine-8-carboxylic acid
(5b). Yield 30%; mp 133.5–135 8C; IR 1710 (COOH),
and 1660 (N–C]O) cmK1; EI-MS (70 eV) m/z (rel.
intensity): MC 335 (1), 291 (100), 276 (25), 262 (5), 248
(25), 235 (5), 172 (113), 160 (13), 146 (34), 131 (30), 115
3.2.5. 3-(4-Methoxybenzyl)-2-methallyl-4-oxo-10-oxa-3-
azatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (4e).
Ratio of isomers A/B w1:3.1; yield 74%; mp 136.5–
139 8C; IR 1715 (COOH), and 1695 (N–C]O) cmK1; EI-
MS (70 eV) m/z (rel. intensity): MC 369 (4), 314 (3), 248
(11), 234 (38), 216 (20), 175 (10), 150 (8), 136 (29), 121
(100), 91 (4), 77 (4); 1H NMR (DMSO-D6, 400 MHz)
isomer A d 1.57 (s, 3H, Me-20), 2.150(dd, 1H, H-30A, JZ
13.1, 10.5 Hz), 2.39–2.56 (m, 1H, H-3 B), 2.47 (d, 1H, H-6,
JZ9.3 Hz), 2.81 (d, 1H, H-5, JZ9.3 Hz), 3.72 (s, 3H,
OMe), 4.15 (dd, 1H, H-2, JZ10.5, 4.1 Hz), 4.16 (d, 1H,
CHAHBN, JZ15.5 Hz), 4.58 (d, 1H, CHAHBN, JZ
15.5 Hz), 4.64 (brs, 1H, H-10), 4.72 (brs, 1H, H-10), 5.01
(d, 1H, H-7, JZ1.6 Hz), 6.29 (dd, 1H, H-8, JZ5.8, 1.6 Hz),
6.43 (d, 1H, H-9, JZ5.8 Hz), 6.86 (AB, 2H, 0H-Ar), 7.17
(AB, 2H, H-Ar); isomer B d 1.67 (s, 3H, Me-2 ), 2.39–2.56
(m, 2H, H-30), 2.47 (d, 1H, H-6, JZ9.3 Hz), 2.99 (d, 1H, H-
5, JZ9.3 Hz), 3.68 (dd, 1H, H-2, JZ8.5, 5.5 Hz), 3.71 (s,
3H, OMe), 3.98 (d, 1H, CHAHBN, JZ15.5 Hz), 4.79 (d, 1H,
CHAHBN, JZ15.5 Hz), 4.78 (brs, 1H, H-10), 4.97 (d, 1H, H-
7, JZ1.5 Hz), 6.86 (brs, 1H, H-10), 6.39 (dd, 1H, H-8, JZ
5.8, 1.5 Hz), 6.54 (d, 1H, H-9, JZ5.8 Hz), 6.83 (AB, 2H, H-
Ar), 7.17 (AB, 2H, H-Ar). Anal. Calcd for C21H23NO5: C,
68.29; H, 6.23; N, 3.79. Found: C, 68.31; H, 6.24; N, 3.82.
1
(40), 91 (63), 77 (16), 65 (13), 39 (13); H NMR (CDCl3,
400 MHz) d 1.53 (s, 3H, Me-13), 1.60 (dd, 1H, H-12A(ax),
JZ14.0, 12.2 Hz), 1.61 (s, 3H, Me-13), 2.25 (dd, 1H,
H-12B(eq), JZ14.0, 3.0 Hz), 2.42 (s, 3H, Me-9), 4.69 (d,
1H, H-5A, JZ15.6 Hz), 4.86 (dd, 1H, H-11b(ax), JZ3.0,
12.2 Hz), 5.31 (d, 1H, H-5B, JZ15.6 Hz), 7.16–7.42 (m,
6H, H-Ar), 7.63 (brs, 1H, COOH). 13C NMR (DMSO-D6,
100.6 MHz) d 166.0 (2C, COOH and C-7), 147.8, 144.1,
138.0, 137.2, 132.8, 132.0, 131.0, 128.2, 126.9, 126.7,
123.4, 122.6 (C-Ar), 59.2 (d, C-11b), 47.2 (t, C-5), 46.5 (t,
C-12), 38.1 (s, C-13), 32.9 (q, C-9), 21.3, 26.1 (q, Me-13).
Anal. Calcd for C21H21NO3: C, 75.11; H, 6.27; N, 4.18.
Found: C, 75.14; H, 6.25; N, 4.17.
3.3.3. 5,13,13-Trimethyl-7-oxo-5,11b,12,13-tetrahydro-
7H-isoindolo[2,1-b][2]benzazepine-8-carboxylic acid
(5c). Yield 31%; mp 209.5–211.5 8C; IR 1710 (COOH),
and 1680 (N–C]O) cmK1; EI-MS (70 eV) m/z (rel.
intensity): MC 335 (8), 320 (100), 289 (17), 276 (23), 138
(6), 129 (10), 115 (7), 103 (4), 91 (7), 81 (4), 44 (36), 28
(22); 1H NMR (CDCl3, 400 MHz) d 1.00 (brs, 3H, Me-13),
1.55 (s, 3H, Me-13), 1.81 (d, 3H, Me-5, JZ7.4 Hz), 2.17
(dd, 1H, H-12A, JZ14.7, 6.0 Hz), 2.70 (dd, 1H, H-12B, JZ
14.7, 6.0 Hz), 5.16 (t, 1H, H-11b, JZ6.0 Hz), 5.94 (q, 1H,
H-5, JZ7.4 Hz), 7.21–7.45 (m, 4H, H-Ar), 7.73–7.79 (m,
2H, H-Ar), 8.43 (dd, 1H, H-9, JZ7.4, 1.7 Hz), 15.80 (brs,
1H, COOH). 13C NMR (DMSO-D6, 50.3 MHz) d 168.2 and
165.3 (C]O), 147.4, 145.6, 138.8, 129.5, 129.0 (s, C-Ar),
133.4, 132.4, 130.5, 128.3, 127.5, 127.0, 126.0 (d, C-Ar),
57.2 (d, C-11b), 53.3 (d, C-5), 44.5 (s, C-13), 39.2 (t, C-12),
32.8, 31.9, 23.5 (q, Me-13 and Me-5). Calcd for
C21H21NO3: C, 75.11; H, 6.27; N, 4.18. Found: C, 75.11;
H, 6.28; N, 4.20.
3.3. 13,13-Dimethyl-7-oxoisoindolo[2,1-b][2]benz-
azepine-8-carboxylic acid (5). Typical procedure
A mixture of fine powdered adduct 4 (0.01 mol) and 40 mL
of PPA (prepared from 30 g of P2O5 and 30 mL of 85%
H3PO4) was stirred at 90 8C for 40 min (TLC control). Then
the reaction mixture was cooled and poured into 100 mL of
water. The obtained precipitate was filtered off washed with
cold water (5!80 mL), isopropanol (2!30 mL) and dried
in air. Then the crude product was purified by recrystalliza-
tion (i-PrOH–DMF) in case of 5a,c-e or on Al2O3 (1.5!
3 cm, chloroform) in case of 5b to give desired isoindolo-
benzazepines 5 as colorless crystals.
3.3.1. 13,13-Dimethyl-7-oxo-5,11b,12,13-tetrahydro-7H-
isoindolo[2,1-b][2]benzazepine-8-carboxylic acid (5a).
Yield 75%; mp 255–257 8C; IR 1700 (COOH), and 1680
(N–C]O) cmK1; EI-MS (70 eV) m/z (rel. intensity): MC
321 (27), 306 (2), 278 (13), 277 (52), 276 (20), 275 (100),
131 (14), 115 (8), 103 (3), 91 (14), 77 (3); 1H NMR (DMSO-
D6, 400 MHz) d 1.42 (dd, 1H, H-12A(ax), JZ11.9,
14.0 Hz), 1.47 (s, 3H, Me-13), 1.57 (s, 3H, Me-13), 2.55
(dd, 1H, H-12B(eq), JZ3.4, 14.0 Hz), 4.97 (d, 1H, H-5A,
JZ15.5 Hz), 5.13 (d, 1H, H-5B, JZ15.5 Hz), 5.30 (dd, 1H,
H-11b, JZ3.4, 11.9 Hz), 7.21 (dd, 1H, H-1, JZ1.6, 7.5 Hz),
7.37 (dt, 1H, H-2, JZ1.1, 7.5 Hz), 7.37 (dt, 1H, H-3, JZ1.6,
7.5 Hz), 7.41 (dd, 1H, H-4, JZ1.1, 7.5 Hz), 7.82 (t, 1H, H-
10, JZ7.7), 7.99 (brd, 1H, H-11, JZ7.7 Hz), 8.12 (dd, 1H,
H-9, JZ7.7, 0.7 Hz), 9.03 (brs, 1H, COOH). 13C NMR
(DMSO-D6, 100.6 MHz) d 167.1 and 169.1 (s, C]O),
147.8, 147.2, 134.9, 128.1, 128.6 (s, C-Ar), 132.6, 131.9,
130.9, 128.3, 127.0, 126.62, 126.56 (d, C-Ar), 60.6 (d, C-
11b), 46.8 (t, C-5), 45.6 (t, C-12), 37.5 (s, C-13), 32.3, 25.5
3.3.4. 2,13,13-Trimethyl-7-oxo-5,11b,12,13-tetrahydro-
7H-isoindolo[2,1-b][2]benzazepine-8-carboxylic acid
(5d). Yield 48%; mp 219–221 8C; IR 1705 (COOH), and
1695 (N-C]O) cmK1; EI-MS (70 eV) m/z (rel. intensity):
M
C 335 (23), 291 (22), 289 (100), 207 (1), 159 (3), 144 (5),
129 (7), 115 (5), 91 (3), 77 (2); 1H NMR (DMSO-D6,
400 MHz) d 1.37 (dd, 1H, H-12A(ax), JZ13.5, 11.7 Hz),
1.46 (s, 3H, Me-13), 1.55 (s, 3H, Me-13), 2.26 (s, 3H, Me-
2), 2.53 (dd, 1H, H-12B(eq), JZ2.6, 13.5 Hz), 4.91 (d, 1H,
H-5A, JZ15.4 Hz), 5.08 (d, 1H, H-5B, JZ15.4 Hz), 5.28
(dd, 1H, H-11b(ax), JZ2.6, 11.7 Hz), 7.00 (brd, 1H, H-3,
JZ7.4 Hz), 7.19 (brs, 1H, H-1), 7.24 (d, 1H, H-4, JZ
7.4 Hz), 7.81 (t, 1H, H-10, JZ7.6 Hz), 7.99 (d, 1?, H-11,
JZ7.6 Hz), 8.12 (d, 1?, H-9, JZ7.6 Hz). 13C NMR
(DMSO-D6, 50.3 MHz) d 167.6 and 165.5 (C]O), 148.4,
147.6, 137.9, 133.9, 132.9, 132.5, 132.1, 129.1, 128.7,
128.4, 127.2, 126.6, 60.3, 48.6, 47.3, 38.0, 32.8, 26.0, 21.7.
Anal. Calcd for C21H21NO3: C, 75.11; H, 6.27; N, 4.18.
Found: C, 75.12; H, 6.29; N, 4.18.

F. I. Zubkov et al. / Tetrahedron 60 (2004) 8455–8463
8461
3.3.5. 2-Methoxy-13,13-trimethyl-7-oxo-5,11b,12,13-tet-
rahydro-7H-isoindolo[2,1-b][2]benzazepine-8-car-
boxylic acid (5e). Yield 48%; mp 197–198?; IR 1705
(COOH), and 1695 (N-CZO) cmK1; EI-MS (70 eV) m/z
(rel. intensity): MC 351 (15), 334 (4), 305 (100), 290 (2),
175 (4), 160 (5), 145 (4), 131 (3), 115 (3), 91 (4), 44 (7), 28
(5); 1H NMR (CDCl3, 400 MHz) d 1.61 (dd, 1H, H-12A(ax),
JZ14.3, 12.2), 1.55 (s, 3H, Me-13), 1.64 (s, 3H, Me-13),
2.32 (dd, 1H, H-12B(eq), JZ14.3, 3.3), 3.79 (s, 3H, OMe),
4.78 (d, 1H, H-5A, JZ15.4), 5.06 (dd, 1H, H-11b(ax), JZ
12.2, 3.3), 5.24 (d, 1H, H-5B, JZ15.4), 6.72 (dd, 1H, H-3,
JZ8.3, 2.6), 6.79 (d, 1H, H-1, JZ2.6), 7.31 (d, 1H, H-4, JZ
8.3), 7.65 (dd, 1H, H-11, JZ7.6, 1.1), 7.70 (t, 1?, H-10, JZ
7.6), 8.35 (dd, 1H, H-9, JZ7.6, 1.1). 13C NMR (DMSO-
D6KCDCl3, 75.4 MHz) d 172.4 and 170.1 (s, CZO), 164.3
(C-2), 153.8 (s), 152.8 (s), 137.7 (d), 137.6 (d), 137.3 (d),
133.9 (s), 133.6 (s), 132.20 (d), 132.16 (s), 119.2 (d), 115.1
(d), 65.9 (OMe), 60.2 (d, C-11b), 51.5 (t), 51.1 (t), 44.9 (s),
37.5 (q), 30.5 (q). Anal. Calcd. for C21H21NO4: C, 71.79; H,
5.98; N, 3.99. Found: C, 71.81; H, 5.99; N, 4.01.
(DMSO-D6, 400 MHz) d 1.51 (s, 3H, Me-13), 1.52 (dd, 1H,
H-12A(ax), JZ14.3, 11.0 Hz), 1.62 (s, 3H, Me-13), 2.62
(dd, 1H, H-12B(eq), JZ14.3, 3.5 Hz), 5.05 (d, 1H, H-5A,
JZ15.9 Hz), 5.34 (dd, 1H, H-11b(ax), JZ11.0, 3.5 Hz),
5.37 (d, 1H, H-5B, JZ15.9 Hz), 7.69 (d, 1H, H-1, JZ
8.9 Hz), 7.83 (t, 1H, H-10, JZ7.6 Hz), 8.00 (d, 1H, H-11,
JZ7.6), 8.12 (d, 1H, H-9, JZ7.6 Hz), 8.13 (dd, 1H, H-2,
JZ2.7, 8.9 Hz), 8.30 (d, 1H, H-4, JZ2.7 Hz). 13C NMR
(DMSO-D6, 100.6 MHz) d 25.1, 32.3 (q, Me-13), 38.5 (s,
C-13), 46.1 (t, C-5), 44.8 (t, C-12), 60.4 (d, C-11b), 123.0 (d,
C-2), 125.1 (d, C-4), 127.0 (d, C-11), 128.7 (d, C-1), 131.9
(d, C-9), 132.8 (d, C-10), 128.0, 128.8, 137.0, 145.6, 147.7,
155.3 (all s, 6C-Aryl), 165.0 (COOH), 167.4 (C-7). Anal.
Calcd for C20H18N2O5: C, 65.57; H, 4.92; N, 7.65. Found:
C, 65.59; H, 4.92; N, 7.67.
3.3.8. Chloroanhydride of 5,13-dihydro-13,13-dimethyl-
7-oxo-7H-isoindolo[2,1-b][2]benzazepine-8-carboxylic
acid (8). Four molar equivalents of thionylchloride
(1.79 mL, 25 mmol) were added to a suspension of acid
5a (2.0 g, 6.23 mmol) in 50 mL of benzene. Then the
reaction mixture was refluxed for 6 h. The precipitate
formed on cooling of the reaction mixture was filtered off.
The mother liquor was concentrated in vacuo and the
formed precipitate was filtered off. The crystalline fractions
were combined, washed with ether and recrystallized from
chloroform–DMF to give the desired product 8 as yellow
crystals. Yield 79%; mp 203–204 8C; IR 1700 (COCl), and
1668 (N–C]O and C]C) cmK1; EI-MS (70 eV) m/z (rel.
intensity): MC 339 (6), 337 (18), 322 (100), 294 (25), 286
(8), 259 (23), 230 (15), 192 (13), 164 (6), 151 (6), 143 (35),
129 (20), 115 (46), 101 (15), 83 (5), 78 (25), 63 (10), 51
(13), 36 (30); 1H NMR (DMSO-D6, 200 MHz) d 1.73 (s, 6H,
Me-13), 5.26 (s, 2H, H-5), 6.43 (s, 1H, H-12), 7.20–7.50 (m,
4H, H-1,2,3,4), 7.80 (t, 1H, H-10, JZ7.4 Hz), 8.01 (dd, 1H,
H-11, JZ7.4, 0.8 Hz), 8.20 (dd, 1H, H-9, JZ7.4, 0.8 Hz).
Anal. Calcd for C20H16NO2Cl: C, 71.11; H, 4.75; N, 4.15.
Found: C, 71.15; H, 4.74; N, 4.14.
3.3.6. 1-Oxo-2-benzyl-3-(20-methylpropenyl)-1,2-dihy-
dro-3H-isoindole-7-carboxylic acid (6). A mixture of
fine powdered adduct 4a (1.69 g, 5.0 mmol) and 25 mL of
H3PO4 (85%) was stirred at 60 8C for 40–60 min (TLC
control—before a disappearance of the initial compound
spot). Then the reaction mixture was cooled and poured into
100 mL of water. The obtained precipitate was filtered off
washed with cold water (5!80 mL) and dried. Then the
crude product was washed with isopropanol (6!30 mL)
and the solid fraction was discarded. The isopropanol
solution was concentrated in vacuo and the formed
precipitate was filtered off. The double recrystallization
(heptane–ethyl acetate) gave desired isoquinoline 6 as
colorless crystals, yield 13%; mp 149.5–150 8C; IR 1705
(COOH), and 1695 (N–C]O) cmK1; EI-MS (70 eV) m/z
(rel. intensity): MC 321 (43), 277 (100), 260 (4), 234 (4),
212 (6), 199 (14), 183 (4), 170 (9), 157 (4), 128 (8), 106 (7),
91 (49), 65 (5), 28 (8); 1H NMR (CDCl3, 400 MHz) d 1.75
(d, 3H, Me-10, JZ1.3 Hz), 1.86 (d, 3H, Me-20, JZ1.3 Hz),
4.18 (d, 1H, CHAHBN, JZ14.7 Hz), 4.80 (dt, 1H, H-30, JZ
10.0, 1.3 Hz), 5.18 (d, 1H, H-3, JZ10.0 Hz), 5.29 (d, 1H,
CHAHBN, JZ14.7 Hz), 7.25–7.35 (m, 5H, H-Ph), 7.46 (dd,
1H, H-4, JZ7.7, 0.8 Hz), 7.67 (t, 1H, H-5, JZ7.7 Hz), 8.36
(dd, 1H, H-6, JZ7.7, 0.8 Hz). Anal. Calcd for C20H19NO3:
C, 74.77; H, 5.92; N, 4.36. Found: C, 74.80; H, 5.94; N,
4.35.
3.3.9. 5,13-Dihydro-13,13-dimethyl-7-oxo-7H-isoin-
dolo[2,1-b][2]benzazepine-8-carboxylic acid (9). Pro-
cedure A. A mixture of chloroanhydride 8 (2.0 g,
5.93 mmol) and 10% solution of NaOH (30 mL) was stirred
at 80 8C for 30 min. Then the reaction mixture was poured
into 30 mL of water and acidified with 16% HCl to pH w7.
The obtained precipitate was filtered off, washed with water
(3!100 mL) and dried in air. Recrystallization from
i-PrOH–DMF gave the desired acid 9 as white crystals.
Yield 70%.
3.3.7. 3-Nitro-13,13-dimethyl-7-oxo-5,11b,12,13-tetrahy-
dro-7H-isoindolo[2,1-b][2]benzazepine-8-carboxylic
acid (7). Potassium nitrate (0.66 g, 6.5 mmol) was added in
portion to a stirred solution of 5a (2.00 g, 6.23 mmol) in
15 mL of sulfuric acid. Then the reaction mixture was
stirred at 40 8C for 30 min and poured into 50 mL of water.
The obtained precipitate was filtered off, washed with water
to pH w7 and dried in air. Then the crude product was
purified by recrystallization (i-PrOH–DMF) to give the
desired nitroderivative 7 as white crystals. Yield 73%; mp
240–242 8C; IR 1720 (COOH), 1690 (N–C]O), 1560 (NO2
s), and 1380 (NO2 as) cmK1; EI-MS (70 eV) m/z (rel.
intensity): MC 366 (3), 322 (100), 204 (20), 190 (5), 176
(5), 144 (8), 129 (28), 115 (33), 109 (68), 103 (15), 91 (18),
77 (18), 73 (41), 63 (10), 51 (9), 44 (83), 33 (18); 1H NMR
Procedure B. A mixture of 5a (2.0 g, 6.23 mmol) and
nitrobenzene (20 mL) was refluxed for 4 h. After that the
reaction mixture was concentrated in vacuo to half of its
volume and the formed crystals were filtered off, washed
with ether and dried in air. Then the crude product was
purified by recrystallization (i-PrOH–DMF) to give desired
dehydroderivative 9 as white crystals. Yield 64%; mp
285.5–287 8C; IR 1720 (COOH), and 1645 (N–C]O and
C]C) cmK1; EI-MS (70 eV) m/z (rel. intensity): MC 319
(18), 304 (100), 276 (30), 260 (5), 245 (5), 230 (8), 217 (10),
204 (8), 189 (5), 174 (8), 143 (5), 130 (20), 115 (50), 109
(20), 102 (50), 91 (13), 77 (13), 63 (15), 51 (9), 39 (15); 1H
NMR (DMSO-D6, 400 MHz) d 1.69 (s, 6H, Me-13), 5.21 (s,

8462
F. I. Zubkov et al. / Tetrahedron 60 (2004) 8455–8463
2H, H-5), 6.39 (s, 1H, H-12), 7.27 (dt, 1H, H-2, JZ1.2,
7.4 Hz), 7.35 (dt, 1H, H-3, JZ1.2, 7.4 Hz), 7.44 (dd, 1H,
H-1, JZ1.2, 7.4 Hz), 7.46 (dd, 1H, H-4, JZ1.2, 7.4 Hz),
7.78 (t, 1H, H-10, JZ7.7 Hz), 7.98 (dd, 1H, H-11, JZ0.8,
7.7 Hz), 8.20 (dd, 1H, H-9, JZ0.8, 7.7 Hz). Anal. Calcd for
C20H17NO3: C, 75.24; H, 5.33; N, 4.39. Found: C, 75.24; H,
5.36; N, 4.41.
molar equivalents of lithium aluminum hydride (0.90 g,
24.9 mmol) were added to a suspension of the acid 5a (1.0 g,
3.10 mmol) in 40 mL of THF. The resulting reaction
mixture was refluxed for 2 h. Then the excess LiAlH4 was
decomposed with water (50 mL). The obtained product was
extracted with chloroform (4!50 mL). The organic extract
was dried with MgSO4 and concentrated. The crude product
was recrystallized from hexane–ethyl acetate mixture to
give the desired benzylic alcohol 12 as colorless crystals.
Yield 46%; mp 146.5–148.5 8C; IR 3150 (OH) cmK1; EI-
MS (70 eV) m/z (rel. intensity): MC 293 (100), 278 (20),
250 (33), 237 (12), 218 (9), 202 (4), 174 (6), 161 (12), 146
(18), 131 (72), 91 (84), 77 (13), 55 (11), 39 (12); 1H NMR
(CDCl3, 400 MHz) d 1.47 (s, 3H, Me-13A), 1.50 (s, 3H, Me-
13B), 1.96–2.06 (m, CH2K12), 3.72 (brd, 1H, H-5B, JZ
12.9 Hz), 3.92 (brd, 1H, H-5A, JZ12.9 Hz), 3.96 (d, 1H, H-
7B, JZ14.0 Hz), 4.26 (m, CH2OH), 4.26 (d, 1H, H-7A, JZ
14.0 Hz), 4.26 (m, 1H, H-11b), 7.05 (brd, 1H, JZ7.2 Hz),
7.16–7.28 (m, 5H-Ar), 7.44 (brd, 1H, JZ7.7 Hz). 13C NMR
(DMSO-D6, 100.6 MHz) d 147.7, 145.1, 138.6, 137.4, 136.3
(s, C-Ar), 131.0, 127.3, 126.74, 126.68, 126.0, 125.1, 119.7
(d, C-Ar), 65.8 (d, C-11b), 61.3 (t), 58.4 (t), 57.0 (t), 44.9 (q,
C-13), 38.5 (C-12), 33.0, 28.2 (q, Me-13). Calcd for
C20H23NO: C, 81.91; H, 7.85; N, 4.78. Found: C, 81.93;
H, 7.86; N, 4.80.
3.3.10. Morpholine amide of 5,13-dihydro-13,13-
dimethyl-7-oxo-7H-isoindolo[2,1-b][2]benzazepine-8-
carboxylic acid (10). A mixture of chloroanhydride 8
(0.75 g, 2.23 mmol) and 10 mL of morpholine was refluxed
for 4 h. Then the reaction mixture was cooling, poured into
30 mL of water and acidified with 15% hydrochloric acid.
The formed precipitate was filtered off, washed with water
(5!20 mL) and dried in air. The crude product was
recrystallized (i-PrOH–DMF) to give the desired amide 10
as slightly-yellow crystals. Yield 50%; mp 223–224 8C; IR
1700 and 1638 (N–C]O) cmK1; EI-MS (70 eV) m/z (rel.
intensity): MC 388 (55), 373 (100), 345 (30), 302 (15), 288
(20), 275 (28), 259 (48), 245 (15), 230 (20), 216 (20), 202
(15), 189 (9), 172 (11), 158 (13), 143 (45), 136 (8), 130 (29),
115 (35), 102 (15), 91 (15), 86 (35), 73 (21), 56 (19), 44
1
(28); H NMR (DMSO-D6, 200 MHz) d 1.74 (s, 3H, Me-
13), 1.76 (s, 3H, Me-13), 3.05–4.05 (m, 8H, H-morpholine),
5.16 (d, 1H, H-5A, JZ15.3 Hz), 5.26 (d, 1H, H-5B, JZ
15.3 Hz), 5.86 (s, 1H, H-12), 7.15–7.70 (m, 7H, H-Ar). 13C
NMR (DMSO-D6, 100.6 MHz) d 166.7 and 164.4 (s,
C]O), 147.5, 137.3, 134.3, 134.0, 133.3 (all s, C-Ar),
132.9, 131.6, 129.2, 127.7, 127.3, 126.1 (all d, C-Ar), 123.7
(s, C-11b), 120.7 (d), 118.0 (d, C-12), 66.4 (t, 2C), 47.4,
45.4, 42.3, 38.8 (s, C-13), 32.6 (q, 2C, Me-13). Anal. Calcd
for C24H24N2O3: C, 74.23; H, 6.19; N, 7.22. Found: C,
74.24; H, 6.20; N, 7.25.
Acknowledgements
The authors are grateful for the financial support by the
Russian Foundation for Basic Research (grant no. 04 03
32433). The authors would like to thank Dr. K. Paulvannan,
Sunesis Pharmaceuticals, Inc. for the useful discussion
during the preparation of this manuscript.
3.3.11. Methyl ether of 13,13-dimethyl-7-oxo-
5,11b,12,13-tetrahydro-7H-isoindolo[2,1-b][2]benz-
azepine-8-carboxylic acid (11). A mixture of acid 5a
(2.00 g, 6.23 mmol), 30 mL of dry methanol and 0.05 mL of
96% sulfuric acid was refluxed for 6 h. After the reaction
mixture was cooled, poured into water (80 mL) and
extracted with ethyl acetate (3!30 mL). The organic
phase was dried with MgSO4 and concentrated. The crude
product was recrystallized (hexane–ethyl acetate) to give
the desired ester 11 as white crystals. Yield 60%; mp 167–
169 8C; IR 1720 (O–C]O), and 1690 (N–C]O) cmK1; EI-
MS (70 eV) m/z (rel. intensity): MC 335 (35), 304 (6), 292
(5), 275 (100), 158 (11), 145 (6), 129 (15), 115 (18), 91 (28),
References and notes
1. (a) Ishihara, Y.; Doi, T.; Nagabukuro, H.; Ishichi Y.
Acetylcholinesterase-inhibiting amines for improving bladder
vesical excretory strength. Patent WO 2000018391, PCT Int.
Appl. 165 (published 06.04.2000). (b) Ishihara, Y.; Fujisawa,
Y.; Furuyama, N. Preparation of benzazepine hermogenics.
Patent WO 9846590, PCT Int. Appl. 399 (published
22.10.1998). (c) Goto, G.; Ishihara, Y.; Miyamoto, M.
Tetracyclic condensed heterocyclic compounds for the treat-
ment of senile dementia. Patent EP 655451, Eur. Pat. Appl. 53
(published 31.05.1995).
1
77 (8), 51 (2); H NMR (CDCl3, 400 MHz) d 1.54 (s, 3H,
Me-13), 1.60 (s, 3H, Me-13), 1.60 (dd, 1H, H-12A(ax), JZ
14.1, 12.0 Hz), 2.25 (dd, 1H, H-12B(eq), JZ3.0, 14.1 Hz),
3.98 (s, 3H, COOMe), 4.68 (d, 1H, H-5A, JZ15.5 Hz), 4.90
(dd, 1H, H-11b(ax), JZ3.0, 12.0 Hz), 5.28 (d, 1H, H-5B,
JZ15.5 Hz), 7.14–7.55 (m, 7H). 13C NMR (DMSO-D6,
100.6 MHz) d 169.1 and 165.1 (s, C]O), 148.1 (2C, s),
136.9, 130.6, 128.6 (s, C-Ar), 132.8, 131.6, 129.1, 127.8,
127.49, 127.55, 125.7 (d, C-Ar), 60.1 (d, C-11b), 53.6 (q,
OMe), 47.3 (t, C-5), 46.9 (s, C-13), 38.5 (t, C-12), 33.2, 26.3
(q, Me-13). Anal. Calcd for C21H21NO3: C, 75.11; H, 6.27;
N, 4.18. Found: C, 75.11; H, 6.28; N, 4.20.
2. Ishihara, Y.; Kiyota, Y.; Goto, G. Chem. Pharm. Bull. 1990,
38, 3024–3030.
¨
3. Daıch, A.; Marchalin, S.; Pigeon, P.; Decroix, B. Tetrahedron
Lett. 1998, 39, 9187–9190.
4. Varlamov, A. V.; Zubkov, F. I.; Boltukhina, E. V.; Sidorenko,
N. V.; Borisov, R. S. Tetrahedron Lett. 2003, 44, 3641–3643.
5. (a) Kouznetsov, V. V.; Palma, A. R.; Varlamov, A. V.
J. Heterocycl. Chem. 1998, 35, 761–785. (b) Puentes, C. O.;
Kouznetsov, V. V. J. Heterocycl. Chem. 2002, 39, 1–22. (c)
Varlamov, A. V.; Kouznetsov, V. V.; Zubkov, F. I.; Cherny-
shev, A. I.; Shurupova, O. V.; Vargas, L. M.; Palma, A. R.;
Castro, J. R.; Rosas-Romero, A. J. Synthesis 2002, 771–783.
(d) Varlamov, A. V.; Nikitina, E. V.; Zubkov, F. I.; Shurupova,
3.3.12. 5,11b,12,13-Tetrahydro-13,13-dimethyl-8-hydro-
xymethyl-7H-isoindolo[2,1-b][2] benzazepine (12). Eight

F. I. Zubkov et al. / Tetrahedron 60 (2004) 8455–8463
8463
O. V.; Chernyshev, A. I. Mendeleev Commun. 2002, 12,
32–33.
8. Ishihara, Y.; Tanaka, T.; Miwatashi, S.; Fujishima, A.; Goto,
G. J. Chem. Soc., Perkin Trans. 1 1994, 20, 2993–2999.
9. Varlamov, A. V.; Kouznetsov, V. V.; Zubkov, F. I.; Chernyshev,
A. I.; Alexandrov, G. G.; Palma, A. R.; Vargas, L.; Salas, S.
Synthesis 2001, 6, 849–854.
6. (a) Varlamov, A. V.; Sidorenko, N. V.; Zubkov, F. I.;
Chernyshev, A. I. Chem. Heterocycl. Compd. (Engl. transl.)
2002, 38, 490–491. (b) Zubkov, F. I.; Boltukhina, E. V.;
Krapivko, A. P.; Varlamov, A. V. Chem. Heterocycl. Compd.
(Engl. transl.) 2003, 39, 534–536. (c) Varlamov, A. V.;
Boltukhina, E. V.; Zubkov, F. I.; Sidorenko, N. V.; Chernyshev,
A. I.; Groudinin, D. G. Khim. Geterotsikl. Soedin. (Russ.) 2004,
1, 27–33.
10. (a) Csende, F.; Szabo, Z. Synth. Commun. 1993, 23,
2957–2964. (b) Kerwin, S. M.; Paul, A. G.; Heathcock, C. H.
J. Org. Chem. 1987, 52, 1686–1695. (c) Kobayashi, K.;
Tokimatsu, J.; Maeda, K.; Morikawa, O.; Konishi, H. J. Chem.
Soc., Perkin Trans. 1 1995, 3013–3016.
´
7. Bilovic, D. Croatica Chem. Acta 1968, 40, 15–22.