Stereoselectivity of cyclisations via N-acyliminium ions to form pyrido[2′,3′:3,4]pyrrolo[2,1-a]isoindole, -isoquinoline and -benz[c]azepine ring systems

Article abstract of DOI:10.1039/b009316p

Pyrido[2′,3′:3,4]pyrrolo[2,1-a]isoindole, -isoquinoline and -benz[c]azepine derivatives are obtained by heating in polyphosphoric acid (PPA) appropriate hydroxy lactam precursors derived from pyridine-2,3-dicarboximides. The stereoselectivity of ring closure is rationalised by considering the development of A(1,3) strain in the cyclisation step from N-acyliminium ion intermediates.

Full text of DOI:10.1039/b009316p

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Stereoselectivity of cyclisations via N-acyliminium ions to form
pyrido[2Ј,3Ј:3,4]pyrrolo[2,1-a]isoindole, -isoquinoline and
-benz[c]azepine ring systems
1
Abood A. Bahajaj, John M. Vernon* and Giles D. Wilson
Department of Chemistry, University of York, Heslington, York, UK YO10 5DD
Received (in Cambridge, UK) 20th November 2000, Accepted 3rd May 2001
First published as an Advance Article on the web 30th May 2001
Pyrido[2Ј,3Ј:3,4]pyrrolo[2,1-a]isoindole, -isoquinoline and -benz[c]azepine derivatives are obtained by heating in
polyphosphoric acid (PPA) appropriate hydroxy lactam precursors derived from pyridine-2,3-dicarboximides. The
stereoselectivity of ring closure is rationalised by considering the development of A(1,3) strain in the cyclisation step
from N-acyliminium ion intermediates.
expected product(s) 8.6 We have described the preparation of a
Introduction
series of spiro lactams related to 10.7 In this paper, we return
Cyclisations via N-acyliminium ions provide access to many
to the possibility of formation of fused heterocyclic products
fused heterocyclic systems1 and have been widely applied in the
related to 8 and to the stereoselectivity of cyclisation.
synthesis of alkaloids.2 A variety of 5- and 6-endo-cyclisations
conform to the general type 1 (X = CH or N), in which the
Results and discussion
The only difference between structures 3 and 4 is the α-methyl
group in the N-substituent in 4, which becomes part of the
styryl group in 9 and then part of the indane ring in 10.6 Our
first strategy to block the rearrangement pathway and thus
hopefully to force the alternative cyclisation to 8 was to replace
this α-methyl group by phenyl in the N-benzhydryl hydroxy
lactam 5. Maryanoff and co-workers have described 6-endo-
cyclisations of N-acyliminium ions containing 1,2-diphenyl-
ethyl or 2,2-diphenylethyl N-substituents.8 However, no
identifiable cyclised products were obtainable from 5 by heating
in trifluoroacetic acid (TFA) or in PPA, possibly because the
benzhydryl group is too easily lost from the N-acyliminium ion
intermediate.
Our second strategy was to activate the ring position for the
required 5-endo-cyclisation to structure 8 by a m-methoxy sub-
stituent in the side chain phenyl group. Accordingly, we pre-
pared the hydroxy lactams 14 and 15 by Grignard addition to
the corresponding imides 11 and 12 (Scheme 2). Addition to the
pyridine-2,3-dicarboximide 11 occurred regioselectively at the
more reactive 7-carbonyl group, as shown previously.5 With a
π-nucleophile is an aromatic ring attached to nitrogen through
one or two carbon atoms.3–5 In particular, N-benzyl hydroxy
chiral N-substituent and a second stereogenic centre at C-7,
lactams 2 and 3 on heating in polyphosphoric acid (PPA)
undergo cyclisation via N-acyliminium ion intermediates to
give the fused tetracyclic products 6 and 7, respectively.3,5 In
contrast, hydroxy lactam 4 containing the N-(1-phenylethyl)
group reacts quite differently, with an extraordinary rearrange-
ment via the styrene intermediate 9 to give a 3 : 1 mixture of
diastereoisomeric spiro lactams 10 (Scheme 1) instead of the
each of these products 14 and 15 was a mixture of two diastereo-
isomers, inseparable by chromatography. This is unimportant
because the N-acyliminium ion intermediate in the ensuing
cyclisation step is planar at C-7.
Hydroxy lactam 15, and likewise 16 (obtained in the same
way from imide 13), were accompanied by the corresponding
open chain ketoamides 20 and 21, respectively,9 from which
they were incompletely separated by chromatography or
1
recrystallisation. For example, the H NMR spectrum of 15
included additional signals for CH (δ 4.98, quintet) coupled to
both NH (δ 6.32, doublet) and CH3 (δ 1.32, doublet) and for
OCH3 (δ 3.77, singlet). Corresponding 13C NMR signals were
seen for CH, two CH and ketone C᎐O of 20. Fortunately,
᎐
3
separation was unnecessary, as either hydroxy lactam or
ketoamide structure can be the precursor for formation of the
same N-acyliminium ion intermediate in acidic conditions.
Heating hydroxy lactam 14 in PPA at 100 ЊC gave a 74% yield
of a 4 : 1 mixture of two diastereoisomeric products 17a,b
Scheme 1
1446
J. Chem. Soc., Perkin Trans. 1, 2001, 1446–1451
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b009316p

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Fig.
1
ORTEP drawing of structure 17a with crystallographic
numbering scheme (hydrogen atoms omitted).
outcome of N-acyliminium ion cyclisation to six-membered
rings. For reaction of 14, cyclisation to 17 proceeds via struc-
ture 22: A(1,3) strain between the C-methyl and carbonyl
groups in 22b determines the preference for the cis-stereo-
chemistry 22a. The fused tetracyclic structure and cis-stereo-
chemistry of the major product 17a were confirmed by
single-crystal X-ray diffraction (Fig. 1).
Scheme 2 Reagents and conditions: (i) PhMgBr; (ii) PPA, 100 ЊC or
AlCl3, DCE, Ϫ7 ЊC.
Starting from the same pyridine-2,3-dicarboximide 11 and
adding p-anisyl Grignard reagent, then heating in PPA, we
obtained the fused tetracyclic products 23a,b in 6 : 1 ratio. The
p-anisyl group would be expected to stabilise the intermediate
N-acyliminium ion (cf. 1, R = p-anisyl) and thereby to increase
the diastereoselectivity of cyclisation.
Analogous cyclisations were also achievable in the phthal-
imide series, starting from phthalimides 12 and 13 via hydroxy
lactams 15 and 16 (Scheme 1). The mixture of diastereo-
isomeric products 18a,b was obtained by heating 15 in PPA or
in TFA and in similar yield and product ratio as for 17a,b.
Again 18a,b were inseparable by chromatography, and the
major component was the cis-isomer 18a with the doublet
resonance for CH3 at higher field (δ 1.34 vs. 2.01 for 18b). The
m-methoxy substituent in 14 and 15 is not, after all, essential to
obtain cyclisation in the required manner (cf. 1). Although
reactions of hydroxy lactam 16 in PPA or TFA were unsuccess-
ful, treatment of 16 with AlCl3 in 1,2-dichloroethane at Ϫ7 ЊC
led to the formation of cyclised products 19a,b in 20% yield
and 4 : 1 ratio in favour of the cis-isomer 19a. This result is
consistent with the formation of 6 from 2,3 but it is in surprising
contrast to the behaviour of 4 in PPA.6 In spite of the lower
yield of fused products 19a,b from 16, no spiro by-product
analagous to 10 was detected. The presence of the pyridine
nitrogen atom in 4 apparently is responsible for the rearrange-
ment via 9 to 10, but the mechanism of this reaction is still
partly unexplained.
(from the 1H NMR spectrum), which was inseparable by
chromatography. The same result was obtained by heating 14
for 3 days in refluxing TFA. After trials with different binary
solvent systems, we succeeded in isolating a pure sample of the
major product by fractional crystallisation. When this was
reheated to 100 ЊC in PPA, it was recoverable unchanged, with
no equilibration with the minor diastereoisomer, showing that
the product ratio is kinetically determined.
NMR spectra provided compelling evidence that the
products had the structure 17a,b and not spiro structures
analogous to 10. In particular, the presence of an extra peak for
unprotonated carbon in the aromatic region (not present in the
Further to those 5-endo-cyclisations, which are disfavoured
by Baldwin’s rules, it seemed worthwhile to examine the possi-
bility of 6- and 7-endo-cyclisations in related systems and their
stereoselectivity. There are, of course, many precedents for
N-acyliminium ion cyclisations to six-membered rings and
several examples of cyclisation to seven-membered rings.12
Accordingly, we prepared the imides 24 and 25 and from them
the hydroxy lactams 26 and 27 (Scheme 3), which are side chain
homologues of 4.
Treatment of 26 with hot PPA afforded a mixture of cyclised
products 28a,b in 87% yield and 3 : 1 ratio (from the 13C NMR
spectrum); reaction in TFA at reflux gave the same products in
89% yield. Assignment of cis-stereochemistry 28a to the major
isomer is consistent with earlier results11 and with a kinetic
preference for cyclisation via an intermediate, in which the
methyl group occupies an axial position in relation to the
1
13C NMR spectrum of 14), the splitting pattern of H reson-
ances for the MeO-substituted benzene ring, and the doublet
and quartet signals for CH3CH (in contrast to the ABX system
for ring CH2CH in the spiro structure 10)6 are consistent
with structure 17a,b. In the 1H NMR spectra the CH3 and CH
signals were at δ 1.44 and 5.45 for the major isomer, but at δ 2.05
and 4.95 for the minor isomer. If the higher field position
in each case is ascribed to shielding by the phenyl group at
C-11b,10 then the major isomer has the cis-stereochemistry 17a.
The kinetic preference for formation of the cis-isomer can be
rationalised in accordance with studies by Hart11 concerning
the effect of substituents α to nitrogen on the stereochemical
J. Chem. Soc., Perkin Trans. 1, 2001, 1446–1451
1447

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General procedure for preparation of N-substituted pyridine-2,3-
dicarboximides
Pyridine-2,3-dicarboxylic anhydride was freshly prepared by
heating pyridine-2,3-dicarboxylic acid in acetic anhydride
under reflux for 2.5 h, then evaporating to dryness. An equi-
molar amount of the required amine was added, dissolved in
dry THF, and the solution heated under reflux for 2 h. The
solvent was evaporated and replaced by acetic anhydride. The
mixture was heated again under reflux for 3 h, concentrated by
removal of most of the solvent, cooled and poured into ice–
water. The resulting solid was crushed, filtered, thoroughly
washed with water, dried and recrystallised from toluene–light
petroleum.
6-[1-(3-Methoxyphenyl)ethyl]-5H-pyrrolo[3,4-b]pyridine-
5,7(6H)-dione 11. Obtained from pyridine-2,3-dicarboxylic acid
(9.0 g) and 1-(m-methoxyphenyl)ethylamine (8.2 g). Yield 7.3 g
(48%), mp 80–81 ЊC (HREIMS Found Mϩ 282.1005.
C16H14N2O3 requires M 282.1004); IR (Nujol) νmax/cmϪ1 1715
(C᎐O); 1H NMR (270 MHz) δ 1.94 (3H, d, J 7.3 Hz, CH ), 3.79
(3H, s, OCH3), 5.60 (1H, q, J 7.3 Hz, CHCH3), 6.80–7.28 (4H,
m, ArH), 7.59 (1H, dd, J 5.1 and 7.5 Hz, H-3), 8.11 (1H, dd,
J 1.5 and 7.5 Hz, H-4) and 8.95 (1H, dd, J 1.5 and 5.1 Hz, H-2);
13C NMR (67.5 MHz) δ 17.6 (CH3), 50.0 (CH), 55.2 (CH3),
113.2 (CH), 113.4 (CH), 119.8 (CH), 127.2 (C), 127.4 (CH),
129.6 (CH), 131.1 (CH), 141.4 (C), 151.4 (C), 155.2 (CH), 159.7
(C), 166.0 (C) and 166.1 (C); MS m/z 282 (Mϩ, 100%), 267 (16),
254 (25), 239 (37), 184 (30) and 78 (46).
Scheme 3 Reagent and conditions: (i) PhMgBr; (ii) PPA, 100 ЊC.
᎐
3
newly formed six-membered ring, thereby minimising A(1,3)
interaction with the carbonyl group.
The corresponding cyclisation of hydroxy lactam 27 in hot
PPA gave the fused azepines 29a,b in only 19% yield and 3 : 2
ratio. Both the lower yield and lower stereoselectivity are
attributable to greater conformational freedom for the longer
side chain and for formation of a seven-membered ring. As
before, the major product is the cis-isomer 29a, with the CH3
doublet resonance (δ 0.54) at higher field than for the
trans-isomer 29b (δ 1.33).
6-(1-Phenylpropan-2-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-
dione 24. Obtained from pyridine-2,3-dicarboxylic acid (6.0 g)
and 1-phenylpropan-2-ylamine (5.0 g). Yield 7.0 g (70%), mp
94–95 ЊC (HREIMS Found: Mϩ 266.1055. C16H14N2O2 requires
Experimental
M 266.1055); IR (CHCl3) νmax/cmϪ1 1720 (C᎐O); 1H NMR (90
IR Spectra were recorded for Nujol mulls or for solutions
in chloroform (Pye-Unicam SP3-2000 or Perkin-Elmer 1420
spectrophotometers) and calibrated with polystyrene. 1H NMR
Spectra were recorded at 90 (JEOL FX90Q) or 270 MHz
(JEOL EX 270) and 13C NMR spectra at 22.5 or 67.5 MHz (on
the same instruments) for solutions in deuteriochloroform,
unless stated otherwise, and with tetramethylsilane as internal
standard. Assignments of 13C NMR signals were facilitated by
recording DEPT spectra. In NMR spectra of diastereoisomeric
mixtures, resonances attributed to the minor diastereoisomers
are shown in brackets { }. Mass spectra were obtained by elec-
tron impact (EI) at 70 eV (VG Autospec). Chromatography
was performed on MN-silica gel 60. Tetrahydrofuran (THF)
was dried before use. Light petroleum refers to the fraction of
bp 60–80 ЊC.
1-Phenylethylamine was prepared by a Leuckart reaction
from acetophenone and ammonium formate.13 Using the same
procedure, 1-(3-methoxyphenyl)ethylamine14 was prepared
from m-methoxyacetophenone, 1-phenylpropan-2-ylamine15
(benzedrine) from phenylacetone, and 4-phenylbutan-2-yl-
amine16 from 4-phenylbutan-2-one; all these amines had bp in
agreement with literature values and NMR and mass spectra
consistent with their structures.
᎐
MHz) δ 1.55 (3H, d, J 7.0 Hz, CH3), 3.11 (1H, dd, J 7.0 and 13.7
Hz, PhCHa), 3.36 (1H, dd, J 9.2 and 13.7 Hz, PhCHb), 4.76
(1H, m, CH), 7.16 (5H, s, C6H5), 7.55 (1H, dd, J 4.8 and 7.7 Hz,
H-3), 8.11 (1H, dd, J 1.5 and 7.5 Hz, H-4) and 8.95 (1H, dd,
J 1.5 and 5.1 Hz, H-2); 13C NMR (22.5 MHz) δ 18.2 (CH3), 39.6
(CH2), 48.9 (CH), 126.5 (CH), 126.7 (CH), 127.2 (CH), 128.3
(C), 128.7 (CH), 130.8 (CH), 137.9 (C), 151.1 (C), 154.9 (CH),
165.9 (C) and 166.1 (C); MS m/z 282 (Mϩ, 100%), 267 (16), 254
(25), 239 (37), 184 (30) and 78 (46).
6-(4-Phenylbutan-2-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-
dione 25. Obtained from pyridine-2,3-dicarboxylic acid (1.4 g)
and 4-phenylbutan-2-ylamine (1.4 g). The crude product was
purified by chromatography on silica, with ethyl acetate–chloro-
form (1 : 4 v/v) as eluent. Yield 2.1 g (82%), mp 91–92 ЊC
(HREIMS Found: Mϩ 280.1216. C17H16N2O2 requires M
280.1212); 1H NMR (270 MHz) δ 1.51 (3H, d, J 6.9 Hz, CH3),
2.05 (1H, m) and 2.48–2.75 (3H, m, 2 × CH2), 4.47 (1H, m,
NCHCH3), 6.96–7.16 (5H, m, ArH), 7.57 (1H, dd, J 5.0 and 7.6
Hz, H-3), 8.06 (1H, dd, J 1.3 and 7.6 Hz, H-4) and 8.92 (1H, dd,
J 1.3 and 5.0 Hz, H-2); 13C NMR (67.5 MHz) δ 19.0 (CH3), 33.4
(CH2), 34.5 (CH2), 47.9 (CH), 125.7 (CH), 127.0 (C), 127.2
(CH), 128.3 (2 × CH), 130.9 (CH), 140.8 (C), 151.4 (C), 155.0
(CH), 166.3 (C) and 166.4 (C); MS m/z 280 (Mϩ, 27%), 176
(100), 149 (27), 131 (26), 117 (25), 91 (34) and 79 (40).
N-(1-Phenylethyl)phthalimide 13 was prepared as described
in ref. 7. The same procedure using phthalic anhydride (4.4 g, 30
mmol) and 1-(m-methoxyphenyl)ethylamine (4.5 g, 30 mmol)
afforded N-[1-(3-methoxyphenyl)ethyl]phthalimide 12 (5.8 g,
69%), mp 61–62 ЊC (from toluene–light petroleum) (HREIMS
General procedure to prepare hydroxy lactams
Found: Mϩ 281.1044. C17H15NO3 requires M 281.1052); IR
The Grignard reagent was prepared from bromobenzene and
magnesium in dry THF under nitrogen; reaction was completed
by heating under reflux for 1–2 h. The Grignard solution was
cooled to 0 ЊC and the imide dissolved in dry THF was added
rapidly with stirring: an excess of the Grignard reagent was
employed (typically 4 : 1 mole ratio to imide). The mixture was
stirred at 0 ЊC for 3–4 h, then poured into saturated aqueous
NH4Cl solution and extracted thrice with chloroform. The
combined extracts were washed with water, dried (MgSO4),
1
(Nujol) νmax/cmϪ1 1770 and 1700 (C᎐O); H NMR (90 MHz)
᎐
δ 1.91 (3H, d, J 7.3 Hz, CHCH3), 3.78 (3H, s, OCH3), 5.53 (1H,
q, J 7.3 Hz, CHCH3), 6.79 (1H, ddd, J 1.5, 2.6 and 7.7 Hz,
ArH), 7.04–7.33 (3H, m, ArH) and 7.59–7.85 (4H, m, ArH); 13
C
NMR (22.5 MHz) δ 17.5 (CH3), 48.8 (CH), 54.8 (CH3), 112.2
(CH), 112.7 (CH), 118.7 (CH), 122.9 (CH), 129.4 (CH), 131.2
(CH), 134.3 (C), 142.2 (C), 159.2 (C) and 167.6 (C); MS m/z 281
(Mϩ, 100%), 266 (67), 130 (40), 105 (16) and 77 (15).
1448
J. Chem. Soc., Perkin Trans. 1, 2001, 1446–1451

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filtered and the filtrate evaporated to dryness. The crude
product was purified by chromatography on silica, eluting with
ethyl acetate–chloroform (1 : 4 v/v).
136.8 and {137.1} (C), {139.3} and 139.7 (C), {152.6} and
153.0 (CH), 165.7 (C) and 166.3 (C); MS m/z 344 (Mϩ, 0.2%),
253 (M Ϫ CH2Ph, 25) and 210 (100).
7-Hydroxy-6-[1-(3-methoxyphenyl)ethyl]-7-phenyl-6,7-
7-Hydroxy-6-(4-phenylbutan-2-yl)-6,7-dihydro-5H-pyrrolo-
[3,4-b]pyridin-5-one 27. Obtained from imide 25 (1.0 g, 3.57
mmol) and Grignard reagent from bromobenzene (2.26 g, 14.4
mmol) and magnesium 0.35 g. Yield 0.92 g (72%), mp 192–
195 ЊC (from toluene–light petroleum) (HREIMS Found: Mϩ,
dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 14. Obtained from
imide 11 (1.0 g, 3.55 mmol) and Grignard reagent from
bromobenzene (2.20 g, 14.0 mmol) and magnesium (0.34 g).
Yield 1.2 g (94%), mp 160–162 ЊC (from toluene–light petrol-
eum) (Found: C, 73.3; H, 5.7; N, 7.7. C22H20N2O3 requires C,
1
358.1685. C23H22N2O2 requires M, 358.1681); H NMR (270
1
73.3; H, 5.6; N, 7.8%); H NMR (90 MHz) δ 1.58 and {1.70}
MHz) δ 1.16 and 1.41 (3H, d, J 6.9 Hz, CH3), 1.84–2.29 (2H, m,
CH2Ph), 2.31–2.46 and 2.50–2.71 (2H, m, CHCH2), 3.47 and
3.49 (1H, overlapping sext., J 7.2 Hz, CHCH3), 5.00 and 5.07
(1H, s, OH), 6.85 (1H, dd, J 1.5 and 7.8 Hz, ArH), 7.05–7.42
(10H, m, ArH), 8.02 (1H, dd, J 1.3 and 7.6 Hz, H-4) and 8.42
(1H, dd, J 1.3 and 4.9 Hz, H-2); 13C NMR (67.5 MHz) δ 17.8
and 18.6 (CH3), 33.0 and 33.4 (CH2), 35.2 and 36.0 (CH2), 48.9
and 49.5 (CH), 91.2 and 91.5 (C), 124.4 (CH), 125.6 and 125.7
(CH), 126.0 and 126.1 (C), 126.6 (2 × CH), 128.1 and 128.2
(CH), 128.3 (2 × CH), 128.5 (CH) 128.7 (CH), 129.0 (CH),
131.8 (CH), 137.3 and 137.5 (C), 141.3 and 141.9 (C), 152.6
(CH), 165.2 and 165.4 (C), 166.3 and 166.4 (C); MS m/z 358
(Mϩ, 9%), 253 (23), 211 (73), 210 (100), 182 (14), 154 (21),
91 (17) and 77 (18).
(3H, d, J 7.2 Hz, CH3), {3.58} and 3.63 (3H, s, OCH3), 4.32 and
{4.45} (1H, s, OH) overlapping {4.40} and 4.61 (1H, q, J 7.2
Hz, CHCH3), 6.54–6.67 (2H, m, ArH ortho to OMe) and 7.00–
8.55 (10H, m, other ArH).
3-Hydroxy-2-[1-(3-methoxyphenyl)ethyl]-3-phenyl-2,3-di-
hydro-1H-isoindol-1-one 15. Obtained from imide 12 (1.0 g, 3.56
mmol) and Grignard reagent from bromobenzene (2.26 g, 14.4
mmol) and magnesium (0.35 g). Yield of crude product, which
also contains ketoamide 20, 1.19 g (93%); mp 137.5–139 ЊC of
15 (from ethyl acetate–light petroleum) (Found: C, 77.0; H, 6.1;
N, 3.9. C23H21NO3 requires C, 76.9; H, 5.9; N, 3.9%); 1H NMR
(90 MHz) δ 1.63 and {1.73} (3H, d, J 7.3 Hz, CH3), {3.61} and
3.69 (3H, s, OCH3), 3.79 and {3.92} (1H, s, OH), 4.45 and
{4.72} (1H, q, J 7.3 Hz, CHCH3) and 6.58–7.75 (13H, m, ArH);
13C NMR (22.5 MHz) δ 18.5 and {19.6} (CH3), 52.2 and {52.9}
(CH), 55.0 and {55.4} (CH3), 91.9 and {92.4} (C), 112.4, 112.8,
113.3, 113.9, 120.3, 120.5, 122.5, 123.1, 126.4, 126.7, 128.0,
128.2, 128.3, 128.6, 129.0, 129.3, 129.9, 131.2, 131.3, 132.4,
138.8, 144.1, 144.4, 148.5, 148.7, 158.9, 159.1 and 167.5; MS
m/z 359 (Mϩ, 2%), 210 (27), 209 (30), 151 (29), 150 (100), 105
(14) and 77 (19). Additional NMR signals due to the ketoamide
20: δH 1.31 (3H, d, J 7.2 Hz, CH3), 3.76 (3H, s, OCH3), 4.96
(1H, quintet, J 7.2 Hz, CHCH3) and 6.33 br (1H, d, J 7.2 Hz,
NH); δC 21.3 (CH3), 49.5 (CH), 55.3 (CH3), 112.3 (CH), 112.9
(CH), 118.6 (CH), 135.6 (C), 137.0 (C), 144.3 (C), 159.8 (C),
General procedure for cyclisations in PPA
The hydroxy lactam was dissolved in PPA and heated at 100–
125 ЊC. The hot solution was poured onto crushed ice and the
mixture extracted thrice with chloroform. The organic extract
was washed by shaking with NaHCO3 solution, then dried
(MgSO4), filtered, and the filtrate evaporated to dryness. The
residue was chromatographed on silica with ethyl acetate–
chloroform (1 : 4 v/v) as eluent.
General procedure for cyclisations in TFA
The hydroxy lactam was dissolved in TFA and the solution
heated under reflux. The mixture was cooled and poured in
small portions into an excess of saturated NaHCO3 solution.
This solution was extracted thrice with chloroform, the com-
bined extracts dried (MgSO4), filtered, and the filtrate evapor-
ated to dryness. The residue was chromatographed on silica
with ethyl acetate–chloroform (1 : 4 v/v) as eluent.
166.8 (amide C᎐O) and 197.8 (ketone C᎐O).
᎐
᎐
3-Hydroxy-2-(1-phenylethyl)-3-phenyl-2,3-dihydro-1H-
isoindol-1-one 16. Obtained from imide 13 (1.0 g, 3.98 mmol)
and Grignard reagent from bromobenzene (2.51 g, 16.0 mmol)
and magnesium (0.39 g). Yield of crude product, which also
contained ketoamide 21, 1.34 g (94%); mp 111–112 ЊC (from
toluene–light petroleum) (Found: C, 79.9; H, 6.0; N, 4.1.
C22H19NO2 requires C, 80.2; H, 5.8; N, 4.25%); IR (CHCl3)
9-Methoxy-7-methyl-11b-phenyl-7,11b-dihydro-5H-pyrido-
[2Ј,3Ј:3,4]pyrrolo[2,1-a]isoindol-5-ones 17a,b. Obtained from
hydroxy lactam 14 (0.47 g, 1.31 mmol) in PPA (32 g) heated at
100–110 ЊC for 1 h. Yield 0.33 g (74%), diastereoisomer ratio
17a : 17b 80 : 20 unchanged by chromatography and almost
unchanged after recrystallisation (toluene–light petroleum), mp
193–195 ЊC. A sample was dissolved in ethyl acetate and ether
added carefully to form an upper layer; the flask was stoppered
and left undisturbed while the layers mixed by diffusion and
crystals of the pure cis-isomer 17a separated, mp 205–206 ЊC
(Found: C, 77.5; H, 5.6; N, 8.0%; Mϩ, 342.1368. C22H18N2O2
requires C, 77.2; H, 5.3; N, 8.2%; M, 342.1368). IR(CHCl3)
νmax/cmϪ1 3370 (OH), 1690 and 1635 (C᎐O); 1H NMR (90
᎐
MHz) δ 1.67 (3H, d, J 6.9 Hz, CH3), 3.12 br (1H, s, OH), 4.49
(1H, q, J 6.9 Hz, CHCH3) and 7.08–7.80 (14H, m, ArH); MS
m/z Mϩ absent, 314 (M Ϫ Me, 1%), 313 (2), 298 (1), 210 (20),
209 (28) and 120 (100). Additional NMR signals due to the
ketoamide 21: δH 1.34 (3H, d, J 7.2 Hz, CH3), 5.02 (1H, quintet,
J 7.2 Hz, CHCH3) and 6.32 br (1H, d, J 7.2 Hz, NH); δC 166.6
(amide C᎐O) and 197.7 (ketone C᎐O).
᎐
᎐
7-Hydroxy-6-(phenylpropan-2-yl)-7-phenyl-6,7-dihydro-5H-
pyrrolo[3,4-b]pyridin-5-one 26. Obtained from imide 24 (1.0 g,
3.76 mmol) and Grignard reagent from bromobenzene (2.39 g,
15.2 mmol) and magnesium (0.37 g). Yield 1.31 g (100%),
mp 185–187 ЊC (from toluene–light petroleum) (Found: Mϩ,
νmax/cmϪ1 1720 (C᎐O); 1H NMR (90 MHz) δ 1.44 (3H, d, J 7.0
᎐
Hz, CH3), 3.77 (3H, s, OCH3), 5.44 (1H, q, J 7.0 Hz, H-7), 6.76
(1H, d, J 2.4 Hz, H-8), 6.92 (1H, dd, J 2.4 and 8.5 Hz, H-10),
7.20–7.50 (6H, m, other ArH), 7.90 (1H, d, J 8.5 Hz, H-11),
8.11 (1H, dd, J 1.5 and 7.7 Hz, H-4) and 8.70 (1H, dd, J 1.7 and
4.8 Hz, H-2); 13C NMR (22.5 MHz) δ 22.7 (CH3), 55.6 (CH3),
58.2 (CH), 108.3 (CH), 113.7 (CH), 123.6 (CH), 125.3 (CH),
125.5 (CH), 126.4 (2 × CH), 128.0 (CH), 128.5 (2 × CH), 130.0
(C), 133.0 (CH), 140.9 (C), 147.7 (C), 153.7 (CH), 160.7 (C),
169.5 (C) and 172.5 (C). In CDCl3 the resonance for quaternary
C-11b was masked by solvent signals, but in DMSO-d6 it was
seen at δ 81.7. MS m/z 342 (Mϩ, 42%), 327 (M Ϫ Me, 12), 266
(18) and 265 (M Ϫ Ph, 100). Hydroxy lactam 14 (0.34 g) was
dissolved in TFA (10 ml) and heated under reflux for 72 h. 17a,b
344.1531. C22H20N2O2 requires M, 344.1525); IR (CHCl3) νmax
/
cmϪ1 3400 (br, OH) and 1700 (C᎐O); 1H NMR (90 MHz) δ 1.22
᎐
and {1.38} (3H, d, J 6.8 Hz, CH3), 2.83 (1H, s, OH), 2.90–3.13
(2H, m, overlapping CHCH3 of two diastereoisomers), 3.30–
3.65 (2H, m, CH2), 7.08–7.40 (11H, m, ArH), 8.08 (1H, dd,
J 1.5 and 7.5 Hz, H-4) and 8.46 (1H, dd, J 1.5 and 4.8 Hz, H-2);
13C NMR (22.5 MHz) δ 17.7 and {17.9} (CH3), 40.4 and {40.7}
(CH2), {51.2} and 51.7 (CH), 90.9 and {91.7} (C), 124.3 (CH),
125.5 (CH), 126.1 (CH), 126.6 (2 × CH), 128.4 (2 × CH), 128.5
(2 × CH), 128.7 (CH), 129.1 (C), 129.3 (2 × CH), 131.5 (CH),
J. Chem. Soc., Perkin Trans. 1, 2001, 1446–1451
1449

View Article Online
(0.24 g, 74%) was obtained with the same diastereoisomer ratio
3.74 and 3.80 (each 3H, s, OCH3), 5.44 (1H, q, J 6.8 Hz,
as before and mp 193–195 ЊC after recrystallisation (toluene–
light petroleum). H NMR signals for trans isomer 17b: δ 2.05
(3H, d, J 7.0 Hz, CH3) and 4.95 (1H, q, Hz, H-7); signals for
OCH3 and aromatic H not resolved from corresponding signals
for 17a.
CHCH3), 6.75–6.96 (4H, m, ArH ortho to OCH3), 7.24–7.45
(3H, m, other ArH), 7.86 (1H, d, J 8.3 Hz, H-3), 8.07 (1H, dd, J
1.7 and 7.6 Hz, H-4) and 8.73 (1H, dd, J 1.6 and 4.9 Hz, H-2);
13C NMR (22.5 MHz) δ 16.7 (CH3), 55.2 (CH2), 55.5 (CH3),
58.1 (CH), 78.2 (C), 108.2 (C), 113.4 (CH), 113.8 (CH), 123.2
(CH), 125.1 (CH), 125.3 (CH), 127.2 (CH), 127.6 (CH), 130.5
(C), 132.1 (C), 132.6 (CH), 133.1 (C), 147.7 (C), 153.7 (CH),
159.1 (C), 160.5 (C), 169.7 (C) and 172.3 (C); MS m/z 372 (Mϩ,
20%), 265 (M Ϫ C6H4OMe, 32) and 91 (100).
1
9-Methoxy-7-methyl-11b-phenyl-7,11b-dihydro-5H-isoindolo-
[1,2-a]isoindol-5-ones 18a,b. Obtained from hydroxy lactam 15
(0.56 g, 1.57 mmol) in PPA (35 g) heated at 100–110 ЊC for 1 h.
Yield 0.39 g (73%), diastereoisomer ratio 18a : 18b 80 : 20
unchanged by chromatography, mp 107–108 ЊC (from
toluene–light petroleum) (Found: C, 81.3; H, 5.9; N, 4.1%. Mϩ,
6-Methyl-12b-phenyl-5,12b-dihydropyrido[2Ј,3Ј:3,4]pyrrolo-
[2,1-a]isoquinolin-8(6H)-ones 28a,b. Obtained from hydroxy
lactam 26 (0.45 g, 1.31 mmol) in PPA (36 g) heated at 100–
110 ЊC. Yield 0.37 g (87%), diastereoisomer ratio 28a : 28b
75 : 25 after recrystallisation from toluene–light petroleum,
341.1436. C23H19NO2 requires C, 81.0; H, 5.6; N, 4.1%. M,
1
341.1416). IR (CHCl3) νmax/cmϪ1 1710 (C᎐O); H NMR (270
᎐
MHz) δ 1.34 and {2.02} (3H, d, J 7.0 Hz, CH3), 3.80 (3H, s,
OCH3), {4.80} and 5.39 (1H, q, J 7.0 Hz, H-7), 6.75 (1H, d,
J 2.2 Hz, H-8), 6.89 (1H, dd, J 2.4 and 8.2 Hz, H-10), 7.10–7.80
(10H, m, other ArH) and 7.83 (1H, d, J 7.3 Hz, ArH); 13C
NMR (22.5 MHz) δ 21.6 (CH3), 55.5 (CH3), 57.6 (CH), 78.1
(C), 108.3 (CH), 113.4 (CH), 122.5 (CH), 124.3 (CH), 124.7
(CH), 126.3 (2 × CH), 127.5 (CH), 128.3 (2 × CH), 129.0 (C),
131.2 (C), 131.5 (C), 132.9 (CH), 142.7 (C), 148.2 (C), 151.9
(C), 160.3 (C) and 174.3 (C); MS m/z 341 (Mϩ, 7%), 326
(M Ϫ Me, 4), 265 (19), 264 (M Ϫ Ph, 100) and 92 (29).
Hydroxy lactam 15 (0.54 g) was dissolved in TFA (15 ml) and
heated under reflux for 72 h. After chromatography, 18a,b (0.42
g, 82%) was obtained with the same diastereoisomer ratio as
before and mp 108–109 ЊC after recrystallisation (toluene–light
petroleum).
mp 215–217 ЊC (HREIMS Found: Mϩ, 326.1421. C22N18N2O
1
requires M, 326.1419). IR (CHCl3) νmax/cmϪ1 1690 (C᎐O); H
᎐
NMR (90 MHz) δ 1.51 (3H, d, J 6.3 Hz, CH3), 2.25–3.05 (2H,
m, CH2), 4.15–4.53 (1H, m, H-6), 7.08–7.55 (9H, m, ArH), 7.93–
8.36 (2H, m, H-9 and H-10) and 8.71 (1H, dd, J 1.6 and 4.9 Hz,
H-11); 13C NMR (22.5 MHz) δ 18.4 and {21.2} (CH3), {35.9}
and 36.1 (CH2), 47.2 and {47.7} (CH), 71.2 (C), 123.0, 123.2,
125.1, 126.0, 126.2, 126.5, 126.7, 127.7, 127.9, 128.1, 128.3,
128.6, 129.5, 131.8, 132.1, 135.0, 135.7, 135.9, 136.5, 139.5,
141.0, 152.3, 152.5, 166.6, 167.2 and 167.5; MS m/z 326 (Mϩ,
10%), 311 (M Ϫ Me, 11), 250 (18), 249 (M Ϫ Ph, 100) and
233 (19).
Hydroxy lactam 26 (0.31 g) was dissolved in TFA (9 ml) and
heated under reflux for 24 h. Work-up afforded 28a,b (0.26 g,
89%) with 1H and 13C NMR spectra and diastereoisomer ratio
the same as above.
7-Methyl-11b-phenyl-7,11b-dihydro-5H-isoindolo[1,2-a]-
isoindol-5-ones 19a,b. Hydroxy lactam 16 (0.71 g, 2.16 mmol) in
1,2-dichloroethane (25 ml) was added slowly to a solution of
aluminium trichloride (1.15 g, 8.3 mmol) in 1,2-dichloroethane
(20 ml) cooled at Ϫ7 ЊC. The mixture was stirred at this tem-
perature for 4 h. It was then poured onto crushed ice and, after
addition of dilute sulfuric acid, extracted with chloroform
(2 × 20 ml). The combined extracts were dried (MgSO4) and
evaporated to dryness. The solid residue was chromatographed
on silica with ethyl acetate–chloroform (1 : 15 v/v) as eluent to
give 19a,b (0.13 g, 19%), in the ratio 80 : 20 after recrystallis-
ation from toluene–light petroleum, mp 151–153 ЊC (HREIMS
7-Methyl-13b-phenyl-5,6,7,13b-tetrahydro-9H-pyrido-
[2Ј,3Ј:3,4]pyrrolo[2,1-a]benz[c]azepin-9-ones 29a,b. Obtained
from hydroxy lactam 27 (0.60 g, 1.67 mmol) in PPA (32 g)
heated at 120–125 ЊC for 1 h. Yield 0.11 g (19%), diastereo-
isomer ratio 29a : 29b 60 : 40 after recrystallisation from
toluene–light petroleum, mp 170–172 ЊC (HREIMS Found: Mϩ,
340.1560. C23H20N2O requires M, 340.1576). 1H NMR (270
MHz) δ 0.54 and {1.33} (3H, d, J 6.9 Hz, CH3), 1.71–3.10 (4H,
m, 2 × CH2), {3.82–3.91} and 4.91–5.00 (1H, m, H-7), 6.85–
6.87 (2H, m, ArH), 7.10–7.41 (8H, m, ArH), {7.66–7.70} and
8.11–8.18 (1H, m, H-10), {8.48–8.53} and 8.70–8.75 (1H,
m, H-12); 13C NMR (67.5 MHz) δ {18.0} and 19.6 (CH3),
{31.5} and 32.8 (CH2), {32.4} and 33.5 (CH2), {48.1} and 50.3
(CH), 75.1 and {77.8} (C), 123.3 and {123.5} (CH), 125.1 (C),
125.3 and {126.5} (CH), {126.8} (C), 127.4 (CH), 128.1 (CH),
128.2 (CH), 128.3 (CH), 129.5 (CH), 131.0 (CH), 131.5 (CH),
131.6 (CH), 131.9 (CH) 132.4 (CH), 132.5 (CH), {135.6} and
136.1 (C), {138.8} and 141.3 (C), {142.3} and 142.6 (C),
{152.6} and 153.3 (CH), {166.9} and 167.1 (C) and {167.7} and
170.3 (C); MS m/z 340 (Mϩ, 41%), 326 (17), 325 (M Ϫ Me, 65),
264 (21), 263 (M Ϫ Ph, 100) and 221 (12).
1
Found: Mϩ, 311.1289. C22H17NO requires M, 311.1310). H
NMR (90 MHz) δ 1.35 and {2.03} (3H, d, J 7.0 Hz, CH3),
{4.83} and 5.44 (1H, q, J 7.0 Hz, H-7), and 7.26–7.87 (13H, m,
ArH); 13C NMR (22.5 MHz) δ {16.7} and 21.6 (CH3), {57.1}
and 57.6 (CH), C-11b signal masked by solvent peaks, {122.2}
and 122.7 (CH), 123.2 (CH), 123.9 (CH), {124.1} and 124.3
(CH), 126.0 (CH), 126.3 (CH), 127.2 (CH), 127.6 (CH), 128.4
(CH), 128.5 (CH), 131.6 (C), {132.4} and 133.0 (CH), 139.1
(C), 142.4 (C), 146.6 (C), 151.5 (C) and 174.3 (C); MS m/z 311
(Mϩ, 16%), 296 (34), 235 (18), 234 (M Ϫ Ph, 100) and 219 (16).
Starting material 16 (0.15 g, 21%) was recovered from later
fractions eluted with ethyl acetate–chloroform (1 : 4 v/v).
X-Ray analysis of 17a†
9-Methoxy-11b-(4-methoxyphenyl)-7-methyl-7,11b-dihydro-
5H-pyrido[2Ј,3Ј:3,4]pyrrolo[2,1-a]isoindol-5-ones 23a,b. Imide
11 (1.0 g, 3.55 mmol) was treated with the Grignard reagent
prepared from 4-methoxybromobenzene (2.85 g) and mag-
nesium (0.37 g) according to the general procedure. Yield 1.2 g
(87%) of a viscous oil, which was a mixture of hydroxy lactam
X-Ray analysis of 17a was carried out on a Rigaku AFC6S
four-circle diffractometer with graphite-monochromated
Mo-Kα radiation, λ = 0.710 70 Å, at 20 ЊC. 17a C22H18N2O2,
M = 382.38. The crystal was monoclinic, space group P21/c,
with unit cell a = 7.729(2), b = 11.983(3), c = 18.615(3) Å,
β = 93.13Њ, V = 1721.5(6) Å3, Z = 4, Dc = 1.321 g cmϪ3, µ = 0.86
cmϪ1. 1756 reflections collected in the range 5 < 2θ < 40Њ, of
which 1602 were independent (Rint 0.0538). Full matrix least-
squares refinement on F2 with 236 variable parameters for
1599 reflections with I > 2σ(I) gave final R1 = 0.0321 and
wR2 = 0.0781.
1
and ketoamide (from H and 13C NMR spectra). This crude
product (0.60 g) was heated with PPA (48 g) at 100–110 ЊC for
1 h. Work-up according to the general procedure afforded the
fused tetracyclic products 23a,b (0.36 g, 63%) in 85 : 15 ratio
(from 1H NMR spectrum), mp 180–182 ЊC (from toluene–light
petroleum) (Found: C, 74.2; H, 5.5; N, 7.6. C23H20N2O3 requires
C, 74.2; H, 5.4; N, 7.5%); IR (CHCl3) νmax/cmϪ1 1725w (C᎐O);
᎐
1H NMR (90 MHz) δ 1.44 and {2.03} (3H, d, J 6.8 Hz, CH3),
† CCDC reference number 154384.
1450
J. Chem. Soc., Perkin Trans. 1, 2001, 1446–1451

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7 A. A. Bahajaj and J. M. Vernon, J. Chem. Soc., Perkin Trans. 1,
1996, 1041.
Acknowledgements
A. A. B. was in receipt of a scholarship from the University of
Aden and of an ORS award.
8 B. E. Maryanoff and D. F. McComsey, Tetrahedron Lett., 1979,
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