The astounding chemistry of a 2-amino-1,2-dihydroisoquinoline derivative

Article abstract of DOI:10.1002/1522-2675(20000906)83:9<2363::AID-HLCA2363>3.0.CO;2-4

The cycloadducts of isoquinolinium N-phenyl imide 2 with C=C bonds are derivatives of 2-amino-1,2-dihydroisoquinoline. Their Nβ-vinylphenylhydrazine system is amenable to an acid-catalyzed [3,3]-sigmatropic shift; the formation of pentacyclic aminals is exemplified by 6 → 8. The dimethyl maleate adduct 11, C₂₁H₂₀N₂O₄, is exceptional by being converted on treatment with acid to bright-yellow crystals, C₂₄H₂₂N₂O₆ (additional C₃H₂O₂). X-Ray crystal-structure analysis and NMR spectra reveal structure 13, and mechanistic studies indicated an initial β-elimination at the N-N bond of 11 to yield 18; this step is followed by a retro-Mannich-type cleavage that gives methyl isoquinoline-1-acetate (14) and methyl 2-(phenylimino)acetate (15), according to the sequence C₂₁H₂₀N₂O₄ (11) → 18 → C₁₂H₁₁NO₂ (14)+C₉H₉NO₂ (15). In the second act of the drama, electrophilic attack by 15-H⁺ on the ene-hydrazine group of a second molecule of 11 furnishes 13 by a polystep intramolecular redox reaction. All rate constants must be fine-tuned in this reaction cascade to give 13 in yields of up to 78% with an overall stoichiometry: 2 C₂₁H₂₀N₂O₄ (11) → C₂₄H₂₂N₂O₆ (13) + C₁₂H₁₁NO₂ (14) + aniline. Interception and model experiments confirmed the above pathway. A by-product, C₃₃H₃₁N₃O₆ (62), arises from an acid-catalyzed dimerization of 11 and subsequent elimination of 15.

Full text of DOI:10.1002/1522-2675(20000906)83:9<2363::AID-HLCA2363>3.0.CO;2-4

Helvetica Chimica Acta ±Vol. 83 (2000)
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The Astounding Chemistry of a 2-Amino-1,2-dihydroisoquinoline
Derivative1)
by Toni Durst, Jürgen A. Finke, Rolf Huisgen*, and Robert Temme
Institut für Organische Chemie der Universität München, Butenandtstr. 5 ±13 (Haus F), D-81377 München
Dedicated to Professor Albert Eschenmoser on the occasion of his 75th birthday
The cycloadducts of isoquinolinium N-phenyl imide 2 with CˆC bonds are derivatives of 2-amino-1,2-
dihydroisoquinoline. Their Nb-vinylphenylhydrazine system is amenable to an acid-catalyzed [3,3]-sigmatropic
shift; the formation of pentacyclic aminals is exemplified by 6 ! 8. The dimethyl maleate adduct 11, C21H20N2O4,
is exceptional by being converted on treatment with acid to bright-yellow crystals, C24H22N2O6 (additional
C3H2O2). X-Ray crystal-structure analysis and NMR spectra reveal structure 13, and mechanistic studies
indicated an initial b-elimination at the NÀN bond of 11 to yield 18; this step is followed by a retro-Mannich-
type cleavage that gives methyl isoquinoline-1-acetate (14) and methyl 2-(phenylimino)acetate (15), according
to the sequence C21H20N2O4 (11) ! 18 ! C12H11NO2 (14) ‡ C9H9NO2 (15). In the second act of the drama,
‡
electrophilic attack by 15-H on the ene-hydrazine group of a second molecule of 11 furnishes 13 by a polystep
intramolecular redox reaction. All rate constants must be fine-tuned in this reaction cascade to give 13 in yields
of up to 78% with an overall stoichiometry: 2 C21H20N2O4 (11) ! C24H22N2O6 (13) ‡ C12H11NO2 (14) ‡ aniline.
Interception and model experiments confirmed the above pathway. A by-product, C33H31N3O6 (62), arises from
an acid-catalyzed dimerization of 11 and subsequent elimination of 15.
1. Introduction. ±ꢀIsoquinoline N-aryl imidesꢁ of type 2 can be regarded as
azomethine imines [2][3] that undergo in situ 1,3-dipolar cycloadditions to CˆC bonds
to furnish N-aryltetrahydropyrazolo[5,1-a]isoquinolines; e.g., the reaction of N-phenyl
imide 2 with dimethyl fumarate furnished the trans-diesters 4 and 52) in the ratio of
85 :15 [4] (Scheme 1).
The adduct structures contain the bond systems of an Nb-vinylphenylhydrazine,
which was subjected to a hydrazo rearrangement known as Fischerꢁs indole synthesis
[5] (for a review, see [6]). Treatment of 2 with acid afforded the pentacyclic aminal 8
[7]. In formula 6, i.e., protonated 4, the thicker bonds help one to recognize the initial
[3,3]-sigmatropic shift (Scheme 2). The final indolization, 8 ! 9, does not take place
because the gain in aromaticity cannot outweigh the increased ring strain; an (E,Z)-1,3-
cyclooctadiene system is incorporated in the tetracyclic indole 9.
This hydrazo rearrangement was observed for numerous cycloadducts of 2, formed
with a,b-unsaturated carboxylates and nitriles [7], with acetylenic carboxylates [8],
enamines [9], and even ethylene [7]. Some cycloadducts undergo rearrangement in
neutral media. Special precautions are often required to isolate the initial cycloadducts.
1
)
)
1,3-Dipolar Cycloadditions, Part 118; Part 117: [1].
2
A representation was arbitrarily chosen, in which HÀC(10b) appears on the b-side; this hydrogen becomes
HbÀC(5) of 8.

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Scheme 1
Scheme 2
The deep-red 1,3-dipole 2 is not isolable. When generated by slow addition of Et3N
to a solution of 1, the triethylammonium chloride formed can catalyze the rearrange-
ment of the cycloadduct. The adduct with CS2, 3, is a neutral source of 2. The light-
yellow crystals of 3 dissolve to give a solution with a deep-red color, showing a rapidly
established dissociation equilibrium [10].
The cycloaddition of 2 with dimethyl maleate proceeded with retention of
dipolarophile configuration, suggesting a concerted pathway [11]. The two crystalline
cis-diesters 10 and 11 were obtained in the ratio of 10 :90, and their structures were
1
assigned on the basis of H-NMR data (Scheme 3) [4]. The hydrazo rearrangement of
the minor adduct 10 slowly afforded aminal 12 quantitatively, even in the absence of
acid [7].

Helvetica Chimica Acta ±Vol. 83 (2000)
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Scheme 3
2. Results and Discussion. ±2.1. Exceptional Behavior ofthe Major Cycloadduct of
Dimethyl Maleate. ꢀThere are no general reactionsꢁ (R. B. Woodward) [12]. It came as a
surprise that the major adduct 11, on treatment with acid, followed a fundamentally
different pathway. The bright-yellow crystalline product had the molecular formula
C24H22N2O6, i.e., C3H2O2 more than 11 (C21H20N2O4). Since addition of dimethyl
maleate during the acid treatment did not increase the yield of the C24 compound, the
additional three C-atoms cannot come from the maleate, a conceivable equilibrium
partner. When HCl was passed through the solution of 11 in CH2Cl2/MeOH at 08, yields
of up to 78% of the C24 compound were isolated, based on the participation of two C21
molecules (for a preliminary communication based on a lecture, see [13]).
Karle et al. established structure 13 for the yellow compound by X-ray analysis [14].
The 1H-NMR spectrum shows three different ester Me groups, and the signal at lowest
frequency (s, 3.57 ppm) corresponds to the CH2 group of the acetate side chain; this
CH2 group is subject to H/D exchange with MeOD/MeONa. The allylic HÀC(2) of 13
is deshielded by N(3) and an ester group: the singlet for this proton appears at
5.09 ppm. One aromatic H-atom resonates at 10.02 ppm as a dd and is ascribed to
HÀC(10); its high frequency suggests near-coplanarity with the MeOCO group [15]
and a small distance to the carbonyl O-atom.
The visible absorption at 420 nm (CHCl3, e 7600) is responsible for the deep-yellow
color of 13. The mass spectrum confirmed the molecular mass; the base peak was [M À
‡
‡
‡
CO2CH3] , and peaks corresponding to [M À 2 CO2CH3] and [M À 3 CO2CH3] were
also observed. The low-frequency CˆO vibration (1677 cmÀ1) comes from the
enamine-b-carboxylate.
Yields for the conversion 11 ! 13 by the procedure described above fluctuated. The
use of defined HCl concentrations did, however, improve the reproducibility of the
reaction. Entries 2 ± 5 of Table 1 list variations in acidity and the ratio of CH2Cl2/

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Table 1. Acid Reactions ofCycloadduct 11 in CH2Cl2 /MeOH (conditions: 2 h 208; acid: CF3CO2H in Entry 1,
HCl in Entries 2 ± 9)
Entry
Adduct 11
Acid [n]
Vol-% MeOH
Products [mmol]
[mmol]
[m]
13
14
Aniline
18
C33H31N3O6
1
2
3
4
5
6
7
8
9
2.74
2.74
2.74
2.74
13.70
2.74
2.74
2.74
2.74
0.14
0.14
0.14
0.14
0.06
0.14
0.14
0.14
0.14
0.45
0.55
0.27
0.14
0.02
0.55
0.55
0.55
0.55
0
10
5
0.99
0.56
0.62
0.43
±
0.53
0.58
0.52
0.59
0.48
0.47
0.55
0.66
0.73
1.07
1.05
0.22
3
a
a
0.5
25
50
75
100
)
)
6.68
0.09
0.41
0.52
0.21
0.32
0.26
a
a
)
)
)
)
a
a
0.37
0.35
a) No workup by distillation.
MeOH; with 0.27n HCl the yield reached 45%. With CF3COOH (0.45n) in CH2Cl2,
72% of 13 was isolated (Entry 1, Table 1).
Aniline and methyl isoquinoline-1-acetate (14) were identified as side-products. To
avoid ambiguity, yields in Table 1 are given in mmol rather than in percentages. Based
on the consumption of 2 equiv. of 11, 77% of aniline and 40% of 14 were isolated by
distillation (Entry 3).
Exper. 6 ± 9 in Table 1 were conducted in solvents with higher MeOH contents. An
additional crystalline product, C33H31N3O6, was observed, and its structure and mode of
formation will be discussed in Sect. 2.8.
The high rate of the polystep sequence to give 13 is astonishing; under standard
conditions (0.4n HCl in CH2Cl2/MeOH 3 :1, 208), 33% of 13 was detected after 5 min,
and yields of 41 and 47% were obtained after reaction times of 20 and 120 min,
respectively.
The structure of 13 did not per se suggest a formation pathway, and a number of
questions arise regarding this aspect: how is the methyl-acetate group transferred to a
second molecule of 11, and how are two H-atoms removed from C(1) and C(10b) of 11?
2.2. Key Experiments in the Mechanistic Elucidation. The breakthrough in this
respect came from the reaction of 11 with 0.9n HCl in the presence of 2,4-
dinitrophenylhydrazine (2,4-DNPH). Compound 13 was not formed, but 59% of the
hydrazone 16 of methyl glyoxylate precipitated. Aniline and 14 were further products
(Scheme 4).
Scheme 4

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Cycloadduct 11 appears to undergo fragmentation into 14 and methyl 2-(phenyl-
imino)acetate (15) upon treatment with acid. It will be established in Sect. 2.5 that
protonated 15 is indeed the reagent that introduces the acetate side chain into 11; in the
presence of 2,4-DNPH, 15 is intercepted by conversion to 16.
Another key experiment led to the elucidation of an intermediate in the
aforementioned fragmentation. When a dilute solution of 11 in CH2Cl2 was treated
1
with less than ꢂ3 equiv. of HCl, an isomer of 11 (49%) was obtained instead of the
yellow compound 13 (Entry 5, Table 1). The IR NH absorption and the formation of
hydantoin 19 with PhNCO revealed the presence of a sec-amino group. The UV
spectrum was closely related to that of 1-methylisoquinoline, thus establishing the
open-chain dimethyl 2-anilino-3-(isoquinolin-1-yl)succinate (18) and indicating a b-
elimination at the NÀN bond via the protonated species 17 (Scheme 5).
Scheme 5
When 18 was treated with a stronger acid, 14 and aniline were isolated, but
compound 13 was not formed; nevertheless, 18 is the precursor of imino-acetate 15.
Acid cleavage of 18 in the presence of 2,4-DNPH afforded 76% of the hydrazone 16, as
well as 14 (66%) and aniline (77%). The acid-catalyzed process, 18 ! 14 ‡ 15,
resembles a retro-Mannich reaction. The configuration of 18 will reveal further insights
into the processes that occur (Sect. 2.4).
Numerous cycloadducts of 2 undergo the hydrazo rearrangement in acidic medium,
as mentioned above. Previously, we encountered an acid-catalyzed b-elimination only
for the cycloadducts of 2 with (E)-cyclooctene and (E,Z)-cycloocta-1,5-diene [16],
represented by 20 ! 21 (Scheme 6). Treatment with AcOH at room temperature or
adsorption onto silica gel proved sufficient to induce the ring-opening of 20.
Presumably, the trans-annulation of the eight- and five-membered rings in 21 generates
strain in the transition state of the [3,3]-sigmatropic rearrangement.
Scheme 6
2.3. Tautomerism ofMethyl Isoquinoline-1-acetate (14). Several groups (ours included)
have reported on the methyl and ethyl isoquinoline-1-acetates [17][18]. However, two
special features remained unnoticed: the facile H/D exchange of the CH2 protons of 14
in neutral MeOD and the yellow color of its solution (lmax 394 nm, e ˆ 402, EtOH).

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The reaction of 14 with MeI and subsequent deprotonation with NH3 provided the
deep-yellow N-methyl enamine 23, which shows a long-wavelength absorption at
394 nm (e ˆ 12600, EtOH). If equal extinction coefficients are assumed for 22 and 23,
then 14 is in equilibrium with 3.2% of enamine 22.
Enamine-methylenimine tautomerism has been described for heteroaromatic
compounds, e.g., quinoline-2-methyl ketones and related compounds (for a review,
see [19]). Basicity studies led Jones and Katritzky to estimate an enamine content of
10À6 m for ethyl pyridine-2-acetate [20].
‡
The mass spectrum of 14 deserves brief consideration. The molecular ion M
appears with an intensity of 57%, and the peak at m/z 143, which corresponds to [M À
‡
C2H2O2] , is the base peak instead of that at m/z 142 for the usual loss of CO2CH3. At
our request, Schwarz3) established two metastable radical cations (m/z 201, 171) as
precursors and proposed the fragmentation 24 ! 25 (Scheme 7). The basic N-atom
promotes the initial H migration to give 24. In the mass spectrum of methyl
‡
naphthalene-1-acetate, a carbocyclic analog, [M À CO2CH3] appears as the base peak,
since favored distonic ions like 24 and 25 cannot be formed.
Scheme 7
2.4. The Role ofDimethyl 2-Anilino-3-(isoquinolin-1-yl)succinate (18). The ring-
opened compound 18 has two stereogenic centers, and the erythro structure is expected
to be formed from cis-diester 11. To our surprise, the isolated sharp-melting compound
18 was a 4 :1 mixture of erythro- and threo-forms, the assignment being unknown. The
analytical HPLC displayed two peaks, but the preparative separation was unsuccessful.
The HÀC(2), HÀC(3), and NH signals of the major component appear in the
1H-NMR spectrum as an AMX pattern, which was simplified to AM by adding D2O.
The minor stereoisomer showed an A2 spectrum for HÀC(2) and HÀC(3) after N-
deuteration. The 13C-NMR spectrum of 18 displayed a double set of signals.
Solutions of 18 are colorless, demonstrating the absence of an enamine tautomer, a
situation in contrast to the equilibrium of 14 with 22. H/D Exchange of HÀC(2) and
HÀC(3) was not observed, when 18 was refluxed in MeOD; the diastereoisomer ratio
remained 4 :1. However, treatment with MeONa/MeOD gave [3,N-2H2]-18.
In the hope of separating the diastereoisomers, the dimethyl-maleate adducts 26
and 27 were subjected to the same treatment with 0.3 equiv. of HCl. According to NMR
spectra, the p-toluidino compound 28 was obtained as 62 :38 mixture of diaster-
eoisomers. The N-(4-chlorophenyl) derivative 29 was homogeneous, but in all three
cases, 18, 28, and 29, the NMR data were insufficient for an erythro/threo-assignment.
3
)
We express our deep gratitude to Prof. Helmut Schwarz, Technical University, Berlin, for his fine MS study.

Helvetica Chimica Acta ±Vol. 83 (2000)
2369
‡
‡
The mass spectrum of 18 showed both imino-acetate 15 (25%) and 24 (i.e., 14 ,
32%) as products of a McLafferty reaction; the base peak corresponds to [15 À
‡
‡
CO2CH3] , which is probably a nitrilium ion HCꢀN ÀPh. The mass spectra of 28,
29, and [2H2]-18 helped to establish various fragmentation pathways.
Surprisingly, 14 and 15 reacted slowly in benzene to give again the sec-amine 18. The
lability of the synthetic specimen of 15 [21] may be responsible for the low yield (26%);
the reaction of the butyl ester 30 with 14 furnished 67% of 31 (Scheme 8). The
nucleophilic enamine tautomer 22 is the logical partner for the reaction with the
electrophilic imino-acetate 15; the cyclic electron shift indicates an ene reaction, the
CˆN bond being the enophile. Additions of enamines to imines or iminium salts have
been reported [22] (for a review, see [23]).
Scheme 8
There is probably an equilibrium, 22 ‡ 15 with 18, in which the addition direction is
favored. In acidic media, protonation of 22 and/or reaction of 15 with alcohol, H2O etc.
might well take place via dissociation.
Both the reaction of 14 (via 22) with 15 and the treatment of 11 with 0.3 equiv. of
‡
HCl, i.e., the buffer system of 11 ‡ 11-H , led to the same 4 :1 erythro/threo-mixture of
the sec-amine 18. It is assumed that the dissociation-association equilibrium is already
established during the acid treatment of 11. The reaction of butyl ester 30 with 14 (via
22) provided 31 as a liquid 1:1 erythro/threo-mixture.
2.5. Introduction ofthe Acetate Group into Adduct 11. Ene-hydrazines like 11
harbor a nucleophilic b-C-atom, as do enamines. Whereas the electrophilic attack of 15
on enamine 22 takes place in a neutral medium, the reaction at C(6) of 11 (no longer an
‡
ene reaction) requires the stronger electrophilic reagent 15-H (Scheme 9).
Acid treatment of 18 produced 14 ‡ 15 (see Sect. 2.2), but not the yellow compound
‡
13. However, 18 can transfer 15-H to the maleate adduct 11. Equimolar amounts of 11
and 18 were converted, by treatment with 0.4n HCl at room temperature, to 13 in 60%
yield, based on a 1:1 stoichiometry; the side products, 14 and aniline, were also isolated.
In the presence of CF3COOH, butyl 2-(phenylimino)acetate (30) reacted with 11 to
afford the yellow C27 compound 32 in 75% yield; the trimethyl ester 13 was not found to

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Helvetica Chimica Acta ±Vol. 83 (2000)
Scheme 9
be present alongside the butyl dimethyl ester 32. In the absence of 30, compound 11
alone was converted to 13 (72%, based on 2 equiv. of 11; see Sect. 2.1) under the same
‡
conditions. Thus, the reaction of 11 with 30-H must be faster than its acid degradation.
Methyl or butyl glyoxylate, 33 and 34, respectively, activated by HCl, were likewise
capable of converting 11 to 13 (50%) and 32 (63%), respectively (cf. Table 2). The 1-
[(methoxycarbonyl)methylidene]piperidinium chloride (35) was prepared by Gross et
al. [24] and employed for aminoalkylations; a couple of enamines were among the
reactants [25] (for reviews on aminoalkylations with iminium salts, see [26]). The rapid
interaction of 35 and 11 can be visually followed by the deepening yellow color, and
76% of 13 was isolated.
Scheme 10
A new mechanistic problem arises: the oxidation state of an aldehyde in reagents
15, 30, and 33 ± 35 is changed to that of an arylacetate in 13 and 32. The HÀC(1) and

Helvetica Chimica Acta ±Vol. 83 (2000)
2371
HÀC(10b) of the pyrazolidine ring in 11 are involved in an intramolecular redox
process. Based on precedents (see below), a series of acid-base reactions with
‡
elimination of aniline is proposed. The addition of the electrophilic 15-H to C(6) of 11
produces iminium ion 36 (Scheme 10). By de- and reprotonation, HÀC(6) is formally
transferred to the anilino group in 37. The loss of aniline affords the a,b-unsaturated
iminium ion 38, and deprotonation at C(10b) benefits from establishing the
isoquinolinium resonance. A formal proton transfer from C(1) of 39 to the carbanionic
side chain furnishes 13. The electron flow from the lower to the upper part of the
molecule demonstrates the redox process.
The reaction depicted in Scheme 11 found precedence in the fine experiments
described by Dyke and co-workers [27]. 1,2-Dihydro-2-methylisoquinoline (40) is
attacked by glyoxylic acid and HCl, and the subsequent redox reaction, with loss of
H2O, yields the isoquinolinium salt 41. A nice variation of this reaction has been
described by Minter and Re [28].
Scheme 11
2.6. Model Reactions with Varying Reagents. Further electrophilic reagents are
successful in attacking C(6) of adduct 11 as long as they exceed the rate of the b-
elimination 11 ! 18. 4-Nitrobenzaldehyde, catalyzed by CF3CO2H, converted 11 to the
deep-yellow nitrobenzyl compound 44 (47%; Table 2). Benzaldehyde failed to react,
but N-benzylidenemethylamine furnished 45, albeit in poor yield.
All cycloadducts of 2 are ene-hydrazines; we reported cycloadditions of dimethyl
acetylenedicarboxylate or mesitonitrile (ˆ2,4,6-trimethylbenzonitrile) N-oxide to the
electron-rich C(5)ˆC(6) bond of 4 and 11 [4]. Electrophilic substitution of the

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Helvetica Chimica Acta ±Vol. 83 (2000)
Table 2. Reactions ofCycloadducts with Electrophilic Reagents (conditions: 208, 2 ± 3 h; A: 0.4 ±1.1n HCl in
CH2Cl2/MeOH; B: 0.5n CF3CO2H in CH2Cl2; C: in CH2Cl2)
Cycloadduct
Electrophilic
reagent
Conditions
Product
Formula
Yield [%]
M.p. [8C]
‡
11
11
11
11
11
11
11
11
4
4
4
42
18 (via 15 )
30-H
A
B
C
C
A
A
B
B
A
C
A
C
13
32
32
13
13
32
44
45
13
13
32
46
47
48
60
75
49
76
50
61
47
26
26
46
16
24
44
67
182 ±184
128 ±129
128 ±129
182 ±184
182 ±184
128 ±129
185 ±186
152 ±153
182 ±184
182 ±184
128 ±129
122 ±124
154 ±155
82 ±83
‡
30 ‡ MeI
35
33
34
4-NO2ÀC6H4CHˆO
PhCHˆNMe
‡
18 (via 15-H )
35
34
35
35
43
C
‡
N-Methylpyrrole
18 (via 15-H )
AcOH
dimethyl fumarate adduct 4 at C(6) will occur only when it is faster than the hydrazo
rearrangement leading to 8. Indeed, reaction of 4 with iminium salt 35 afforded the C24
compound 13 (Table 2); both 11 and 4 yielded 13 since the stereocenters C(1) and
C(10b) were lost in the process.
In contrast to the reaction of 11, the substitution of 4 at C(6) by 4-nitrobenzaldehyde
and HCl failed; 87% of the Fischer product 8 was isolated instead. Clearly, the [3,3]-
sigmatropic shift, 6 ! 7, is more rapid than the cascade reaction 11 ! 13 in an acidic
medium. It is assumed that the hydrazo rearrangement of 11 is sterically hindered.
The acrylonitrile adduct 43 is also amenable to the Fischer reaction [7]. Never-
theless, 43 was converted to the yellow nitrile 47 (44%) with iminium salt 35 in CH2Cl2;
the only protic acid present is the piperidinium chloride formed during the process. In
its nucleophilic reactivity at C(2), N-methylpyrrole resembles a dienamine, and the
‡
substitution at C(2) by 15-H gave 48.
2.7. Competing Reactions and Selectivity Problems. Two pathways are open to our
tetrahydro-3-phenylpyrazolo[5,1-a]isoquinolines in acidic media: the [3,3]-sigmatropic
reaction that initiates the Fischer reaction, and the b-elimination that is the first-step in
the conversion 11 ! 13. The origin of both reactions is the weakness of the NÀN bond.
Is the polystep sequence 11 ! 13 unique, and which structural features are responsible?
Adducts 4 and 11 are C(1) epimers. Only N(3)-protonation cis to HÀC(10b), i.e.,
on the ꢀundersideꢁ of the perspective formula 49, offers the close proximity of the N-
phenyl and dihydroisoquinoline required for the [3,3]-sigmatropic shift. It is assumed
‡
that two vicinal ester groups in 49b (11-H ) impede the approach of the ortho position
‡
of Ph and C(6), whereas one ester group ꢀaboveꢁ (2a-CO2Me) in 49a (4-H ) is still
tolerated. The hindrance by 1a-CO2Me in 49b can be ascribed to a buttressing effect.
The presence of two ester groups ꢀbelowꢁ in 49 leads to less hindrance; indeed, the
minor maleate adduct 10 enters the [3,3]-sigmatropic rearrangement, even without acid
(see Introduction).
Closely related to maleate adduct 11 is 42, which is the major regioisomer in the
cycloaddition of 2 to methyl cis-3-cyanoacrylate [4]; it is the 1a-CO2Me group of 11

Helvetica Chimica Acta ±Vol. 83 (2000)
2373
that is replaced by 1a-CN. Treatment of 42 with CF3CO2H rendered aniline (13%) and
isoquinoline-1-acetonitrile (50, 12%), but neither 46 nor the Fischer aminal were
isolated. A more successful reaction was that of 42 with HCl in MeOH in the presence
of 2,4-DNPH, which furnished hydrazone 16 (30%), aniline (58%), and 50 (53%), a
process that is still less clean than the conversion of 11 (see Sect. 2.2). The ꢀfine-tuningꢁ
in the polystep sequence appears to be disturbed. On the other hand, the reaction of 42
with iminium salt 35 provided the yellow compound 46 (24%; Table 2).
We reported recently on the cycloaddition of pyridinium N-phenylimide with
dimethyl maleate; adduct 51 smoothly underwent the hydrazo rearrangement to give a
tetracyclic aminal [29]. In the framework of structure 49b, removal of the fused benzo
ring reduces steric hindrance and allows the [3,3]-sigmatropic shift to proceed.
The replacement of the 2-CO2Me group in structure 49b by an H-atom should
likewise relieve the hindrance, and this was confirmed experimentally. We treated
adducts 52 ± 54, described in [4], with HCl and isolated aminals 55 ± 57. The structures
established by 1H-NMR spectra are in agreement with a previously reported
investigation [7].
2.8. Structure ofthe Side-Product C 33H31N3O6 and its Mode ofFormation . The
reaction of 11 with HCl in CH2Cl2/MeOH gave rise to C33H31N3O6 (see Sect. 2.1). The
molecular formula was established by elemental analysis and mass determination.
Based on the stoichiometry
2 C21H20N2O4 (11) ! C33H31N3O4 (62) ‡ C9H9NO2 (15),
the yield of the C33 compound reached 23% (Table 1). A probable pathway will be
discussed before the spectroscopic evidence is presented.
1,2-Dihydroisoquinoline derivatives show a propensity for dimerization [30][31].
On refluxing the hydrochloride of 58 in MeOH, Brown and Dyke obtained the bis-
‡
hydrochloride of 59 (75%) [30]. The electrophilic iminium ion 58-H attacks the
nucleophilic C(4) of 58, and subsequent deprotonation gives rise to 59 (Scheme 12).

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Scheme 12
The dimethyl maleate adduct 11 has several basic centers. The N(3)-protonated
species 17 undergoes b-elimination and initiates the cascade that produces 13. Iminium
‡
ion 60-H is the result of C(6)-protonation and should share with imino-acetate 15 the
capability of electrophilic substitution at C(6) of 11 (Scheme 13). The dimer 61 thus
formed is an analog of 59 and still contains the intact ene-hydrazine system of 11 in the
lower half. After N(3)-protonation, b-elimination at the NÀN bond can initiate the
same sequence of steps that converts 11 to 14 ‡ 15. Formally, the 1,2-dihydroisoquino-
line system of 11 has undergone a disproportionation, since we find isoquinoline and
tetrahydroisoquinoline rings in the lower and upper half of 62.
Scheme 13
The configuration of the pyrazolidine ring in 11 probably remained unchanged in
62. However, C(5) is a new stereogenic center created in the dimerization. Two
diastereoisomers of 62 are conceivable, but the isolated C33 compound is homogeneous.
The UV/VIS spectrum of 62 is strikingly similar to that of the tautomeric system of
methylisoquinoline-1-acetate (14) and enamine 22 (see Sect. 2.3). Comparison of the
extinction at 400 nm (EtOH) with that of 23 indicates the presence of 2.0% of an
enamine tautomer alongside 62. Both H-atoms of CH2ÀC(1') of 62 are exchanged with
neutral MeOD, demonstrating the mobility of the tautomeric equilibrium.
At first glance, the 1H-NMR spectrum (400 MHz) of 62 reveals only two ester Me
groups instead of three (Fig.). Tentatively, the MeO signal at 3.66 ppm is ascribed to
the 1'-CH2CO2Me group (3.65 ppm in the parent compound 14). The singlet at
3.32 ppm reaches only 56% of the height of the singlet at 3.66 ppm, and the third MeO
signal is in coalescence. Changing from 400 MHz to 60 MHz at 258 affects the spectrum

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2375
Figure. Sections ofthe 1H-NMR spectrum (400 MHz, CDCl3) ofproduct C 33H31N3O6 (62)
in a similar way as an increase in the temperature at constant field strength. In the 60-
MHz spectrum of 62 the MeO signals at 3.32 and 3.66 ppm have nearly the same height,
and the now well-defined singlet of the third MeO signal at 3.39 ppm stretches to half

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the height of the other two signals. Hindered rotation of the ester groups at C(1) and
C(2) appears to be responsible for the dynamic phenomenon.
The AB pattern at 4.18 and 4.34 ppm (the left branch overlapped), J ˆ 15.2 Hz,
disappears on deuteration and corresponds to the diastereotopic protons of
CH2ÀC(1'). The protons HÀC(1) (dd), HÀC(2) (d), and HÀC(10b) (d) of 62
resonate at somewhat higher frequencies than those of 11 [4].
When the 13C-NMR data of 62 are compared with those of 11 [32], isoquinoline,
and aniline [33], all the saturated and many aromatic C-atoms can be assigned. On
comparing the 100-MHz and 20-MHz 13C-NMR spectra, partial coalescences can be
observed; among others, the signals of C(6), C(5), and C(4') are involved, suggesting
hindered rotation about the C(4')ÀC(5) bond.
Our thanks are due to the Fonds der Chemischen Industrie, Frankfurt, for the support of the research
program. T. D. thanks the National Research Council ofCanada for a stipend. We are greatly indebted to Helmut
Huber for excellent NMR spectra, to Reinhard Seidl for the MS, and to Helmut Schulz for the elemental
analyses.
Experimental Part
1. General. TLC: Merck silica gel 60 PF254. HPLC: DuPont de Nemours 830, Zorbax-Sil column. Mol. mass:
Mechrolab vapor-phase osmometer. CC: Woelm silica gel (100 ±200 mesh), Fluka basic alumina. M.p.:
uncorrected. UV/VIS: Zeiss RPQ; lmax (log e), wavelength in nm. IR: Perkin-Elmer 125, KBr pellets, if not
otherwise stated; frequencies in cmÀ1. NMR: Varian A60, Bruker WP80 CW (1H: 80 MHz); Bruker WP80 DS
(13C: 20 MHz), and Varian XR 400S (1H: 400 MHz, 13C: 100 MHz); solvent CDCl3 (stored over dry K2CO3), if
not otherwise stated; J in Hz; chemical shifts, relative to TMS, were evaluated by first order except for AB;
multiplicities in 13C signals resulted from comparing H-decoupled and off-resonance spectra; DEPT for
100 MHz spectra. MS: AEI, Manchester, MS902 and Finnigan MAT90; EI spectra with 70 eV (if not stated
otherwise), m/z (%), intensities of 13C isotope peaks in % calc./found; HR: high resolution.
2. Dimethyl 2,3-Dihydro-6-[(methoxycarbonyl)methyl]-3-phenylpyrazolo[5,1-a]isoquinoline-1,2-dicarbox-
ylate (13). 2.1. Without Isolation of 11. Dimethyl maleate (4.40 g, 30.5 mmol) was added to the red soln. of the
CS2 adduct 3 (9.00 g, 30.4 mmol) [10] in CH2Cl2 (60 ml). After 30 min at r.t., the solvent was removed, and 10/11
was taken up in CH2Cl2 (80 ml) and MeOH (20 ml). A slow stream of HCl was passed through the soln. at 08 for
15 min. After 2 h at r.t. and concentration on the rotary evaporator, the oily residue was dissolved in CH2Cl2
(50 ml) and shaken with aq. 2n NH3. The brilliant-yellow org. phase was evaporated and portionwise subjected
to CC (basic alumina; AcOEt/benzene/petroleum ether 1:2 :1); the sensitivity of 13 to light required low light
levels for CC and later operations; the fast-moving yellow zone crystallized from acetone/benzene: 13 (5.21 g,
78% based on 2equiv. of 11 and 90 :10 ratio of 11/10 [4]).
2.2. Data of 13. M.p. 182 ±184 8. UV/VIS (CHCl3): 420 (3.88), 385 (sh, 3.81), 275 (4.09). IR: 690m, 758s,
767s, 782m, 926m, 1036s, 1095vs, 1167vs, 1206vs, 1288s, 1525vs (br.), 1600w, 1632m, 1677s, 1740vs, 2950m, 3070w.
1H-NMR (400 MHz): 3.57 (s, CH2ÀC(6)); 3.65, 3.69, 3.83 (3s, 3 MeO); 5.09 (s, HÀC(2)); 6.98 (s, HÀC(5)); 7.06
(dt, 2 arom. H); 7.19 (tt); 7.33 (tt, 2 arom. H); 7.52 (td); 7.53 (d, HÀC(7)); 7.64 (td); 10.02 (dd, broadened, J ˆ 7.6,
1.5, HÀC(10)). 13C-NMR (100 MHz, DEPT): 35.5 (CH2ÀC(6)); 50.5, 52.3, 52.6 (3 MeO); 76.7 (C(2)); 86.0
(C(1)); 109.9 (C(6)); 118.7 (C(2'/6')); 122.7 (C(4')); 129.6 (C(3'/5')); 125.3, 127.0, 128.5, 131.7, 132.2 (C(5),
C(7) ±C(10)); 123.7, 134.5, 147.0 (C(6a), C(10a), C(10b)); 151.3 (C(1 ')); 164.4, 171.16, 171.23 (3 CˆO). MS
‡
‡
(1758): 434 (2.5, [M , 13C 0.66/0.63]), 375 (100, [M À CO2Me] ; 13C 24.5/23.8, 13C2 2.9/3.4), 316 (3.7, [M À 2
‡
CO2Me] , C20H16N2O2 ; 13C 0.81/0.82), 283 (7), 257 (8, [M À 3 CO2Me]) , 256 (6), 255 (5), 163 (5), 104 (13,
‡
‡
‡
‡
‡
C7H6N , PhÀNꢀCH ; 13C 1.02/1.15), HR-MS: 77.0400 (10, C6H5 , calc. 77.0391). Anal. calc. for C24H22N2O6
(434.43): C 66.35, H 5.10, N 6.45; found: C 66.38, H 5.13, N 6.22.
2.3. Adduct 11 and CF3CO2H. Colorless crystalline 11 (1.00 g, 2.74 mmol) [4] in CH2Cl2 (20 ml) was treated
with CF3CO2H (0.70 ml, 9.1 mmol). After 2 h at r.t. and dilution with CH2Cl2 (20 ml), the acid was extracted
with 2n NH3, whereupon the color changed to yellow. The solvent was removed, and the residue was
recrystallized from acetone/pentane: 13 (430 mg, 72%). M.p. 182 ±184 8. Distillation of the mother liquor at 908
(bath)/0.01 Torr gave aniline (68 mg, 53%), identified as N,N'-diphenylthiourea (m.p. 153 ±154 8). At 1408/
10À3 Torr, methyl isoquinoline-1-acetate (14, see Sect. 4.2) was distilled. M.p. 47 ±48 8 (Et2O/pentane).

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2.4. Deuteration. A small amount of MeONa was added to 13 (150 mg, 0.35 mmol) in MeOD (5 ml). After
15 h at r.t., neutralization with aq. AcOH and extraction with CH2Cl2 furnished 108 mg, m.p. 181 ±183 8. The s of
1
2 H at 3.57 ppm was missing in the otherwise unchanged H-NMR spectrum.
2.5. Procedure with Defined HCl Concentrations (Entry 6 of Table 1). Methanolic HCl (2.3 ml, 4.8n) was
added to 11 (1.00 g, 2.74 mmol) in CH2Cl2 (15 ml) and MeOH (2.7 ml), corresponding to 0.55n HCl and 0.14m
11 in CH2Cl2/MeOH 3 :1 (v/v). After 2 h at r.t. and workup as described above, 13 (229 mg, 38%) crystallized
from acetone/pentane. M.p. 180 ±183 8. The solvent was removed, and the residue was dissolved in MeOH. At 58,
colorless crystals of 62 (117 mg, 15%) were obtained. M.p. 207 ±209 8. For further data, see Sect. 10. Distillation
of the mother liquor from a microflask afforded aniline (48 mg, 38%) and 14 (83 mg, 30%).
3. Acid Cleavage of 11 in the Presence of2,4-Dinitrophenylhydrazine . 2,4-DNPH (2.20 g, 11.1 mmol) was
briefly boiled with methanolic HCl (40 ml, 1.1n), filtered, and combined with 11 (2.00 g, 5.48 mmol) in CH2Cl2
(10 ml). In 2 d at À208, the orange methyl 2-(2,4-dinitrophenylhydrazono)acetate (16, 856 mg, 59%)
precipitated (leaflets from AcOEt). M.p. 164-1658. IR: 710m, 746m, 835m, 852m, 928m, 1108s, 1140s, 1323vs,
1345s, 1500s, 1577vs (NO2), 1622s, 1732vs (CˆN, CˆO), 3295s (NÀH). 1H-NMR: 3.91 (s, MeO); 7.09
(s, NˆCH); 9.13 (d, J ˆ 9.5, HÀC(6)); 9.35 (dd, J ˆ 9.5, 2.3, HÀC(5)); 10.16 (d, J ˆ 2.3, HÀC(3)). MS (1208):
‡
‡
268 (28, M ), 189 (10), 59 (14, [CO2Me] ), 43 (100). Anal. calc. for C9H8N4O6 (268.19): C 40.30, H 3.01,
N 20.89; found: C 40.59, H 2.84, N 20.89. A sample of 16 was prepared from methyl dimethoxyacetate and 2,4-
DNPH in methanolic H2SO4. M.p. 164 ±165 8; mixed m.p. without depression.
The mother liquor from the experiment with 11 was diluted with ice water, basified with 2n NH3 and
extracted with CH2Cl2. Distillation of the org. phase furnished aniline (205 mg, 40%) at 100 ±110 8 (bath)/
12 Torr and 14 (263 mg, 24%) at 170 ±180 8/10À2 Torr.
4. Methyl Isoquinoline-1-acetate (14). 4.1. Synthesis. 1-Methylisoquinoline (3.54 g, 24.7 mmol) in abs. THF
(20 ml) was treated under Ar at À788 with LDA (30 mmol) in Et2O (20 ml). The dark-red suspension was
stirred at À788 for 15 min, then methyl chloroformate (2.34 g, 24.8 mmol) was introduced dropwise. After
stirring for 30 min at r.t., H2O and benzene was added, the org. phase was extracted with 2n HCl, and worked up
with 2n NH3 and CH2Cl2. At 130 ±140 8 (Kugelrohr)/10À3 Torr, 14 (1.99 g, 40%) distilled as a light-yellow oil,
which solidified. M.p. 47 ±48 8 ([18]: 47 ±48 8), identical with the side-product of 13 (see Sect. 2.3).
4.2. Data of 14. UV/VIS (EtOH): ꢀtripletꢁ at 415 (2.46), 394 (2.60), 372 (2.46); 322 (3.56), 308 (3.46), 272
(3.69), 218 (4.71). IR: 750s, 797m, 806s, 1006m (br.), 1168s (br.), 1258s (br.), 1332s, 1388s, 1434s, 1560s, 1628s,
1739vs. 1H-NMR: 3.65 (s, MeO); 4.32 (s, CH2ÀC(1)); 7.47 ±8.21 ( m, 5 arom. H); 8.45 (d, J ˆ 5.2, HÀC(3));
‡
after dissolving in MeOD and evaporation, the CH2 signal had disappeared. MS (308): 201 (57, M , 24), 186 (5,
‡
‡
‡
[M À Me] ), 170 (16, [M À MeO] ), 143 (100, [M À C2H2O2] , 25), HR-MS: calc. 143.07349, found: 143.07343;
‡
‡
‡
142 (56, [M À CO2Me] ), 129 (13, C9H7N ), 128 (22), 115 (82), 89 (8), 59 (8, [CO2Me] ); a high-voltage scan of
m/z 143 established m/z 171 and 201 as metastable precursors. Anal. calc. for C12H11NO2 (201.22): C 71.62,
H 5.51, N 6.96; found: C 71.51, H 5.52, N 7.37.
Picrate of 14. From MeOH. M.p. 183 ±184 8 (dec.). Anal. calc. for C18H14N4O9 (430.32): C 50.24, H 3.28,
N 13.02; found: C 50.64, H 3.26, N 12.84.
4.3. Methyl 2-(1,2-Dihydro-2-methylisoquinolin-1-ylidene)acetate (23). Compound 14 (1.23 g, 6.11 mmol)
and MeI (1.85 g, 13.1 mmol) in benzene (3 ml) were reacted at 408 for 15 h. After cooling, the light-yellow 1-
[(methoxycarbonyl)methyl]-2-methylisoquinolinium iodide (1.88 g, 90%) was filtered. M.p. 183 ±184 8. Anal.
calc. for C13H14INO2 (343.16): C 45.50, H 4.11, N 4.08; found: C 45.29, H 4.15, N 3.89.
The N-methyl iodide (370 mg, 1.08 mmol), suspended in CH2Cl2 (10 ml), was shaken with 2n NH3 (10 ml),
whereby the org. phase became deep-yellow. Bulb-to-bulb distillation at 1108/10À3 Torr afforded 23 (227 mg,
98%) as a brilliant-yellow oil. UV/VIS (EtOH): 394 (4.09), 289 (4.00), 258 (sh, 3.74), 219 (4.48); the ꢀtripletꢁ fine
structure of the long-wave absorption is weaker than in tautomer 22, but recognizable, and the extinction of 23
at 394 nm is 31 times higher than that of the tautomeric mixture 15 > 22. 1H-NMR: 3.53 (br. s, MeN); 3.70
(s, MeO); 5.27 (s, HCˆC(1)); 6.28, 6.78 (2d, J ˆ 7.0, HÀC(4), HÀC( 3 )) ; 7.0 ±7.6 ( m, 4 arom. H). Anal. calc. for
C13H13NO2 (215.24): C 72.54, H 6.09, N 6.51; found: C 72.79, H 6.30, N 6.79.
5. Dimethyl 2-Anilino-3-(isoquinolin-1-yl)succinate (18). 5.1. By Acid-Catalyzed Ring Opening of 11.
Methanolic HCl (1.0 ml, 4n) was added to 11 (5.00 g, 13.7 mmol) in CH2Cl2 (200 ml); by this HCl concentration
29% of 11 was converted to the hydrochloride. After 2 h at r.t., the soln. was shaken with aq. NH3. The residue
of the yellow-brown org. phase crystallized from benzene: 18 (2.43 g, 49%) as colorless powder. M.p. 140 ±141 8.
Anal. HPLC with AcOEt/hexane 6 :1 at 40 bar and 1 ml/min showed two substances with tR of 22.5 and
23.5 min; no full separation at the basis. The 1H-NMR integrals of MeO groups indicate a 4 :1 mixture of
erythro- and threo-form; fractional crystallization and prep. HPLC failed to separate the stereoisomers.

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5.2. Data of 18. UV (EtOH): 322 (3.59), 308 (3.57), 282 (sh, 3.84), 218 (4.79); the range of 270 ±340 nm
closely resembles that of 1-methylisoquinoline. IR: 695m, 754s, 1230s (br.), 1275s (br.), 1502s, 1562w, 1603s,
1740vs (br.). IR (CCl4): 3410w (br., NÀH). 1H-NMR (400 MHz, C6D6): major isomer (ca. 80%): 3.24, 3.26 (2s,
2 MeO); AMX at 4.64 (d, slightly broadened, J(N,2) ˆ 10.3, NH); 5.54 (d, J(2,3) ˆ 7.8, HÀC(3)); 5.73 (dd, J ˆ
7.8, 10.3, HÀC(2)); 6.63 ±6.78 ( m, HÀC(2''/6''), HÀC(4'')); 7.00 ±7.36 (3 m, 6 arom. H of both isomers); 8.20
(m, HÀC(8')); 8.39 (d, J ˆ 7.3, HÀC(3')); with D2O the AMX spectrum simplifies to MX; minor isomer (ca.
20%): 3.21, 3.22 (2s, 2 MeO); 5.56 ±5.65 ( m, 3 H; with D2O ! A2 spectrum at 5.56 ppm); 7.89 (m, HÀC(8'));
8.31 (d, J ˆ 5.5, HÀC(3')). 1H-NMR (CDCl3): 3.58, 3.65 (2s, 2 MeO of major isomer); 3.52, 3.58 (2s, 2 MeO of
minor isomer). 13C-NMR (20 MHz; 28 lines visible of 38 expected, major/minor, where separated): 52.2, 52.4
(2q, 2 MeO); 50.9, 58.2/58.5 (3d, C(2), C(3)); 113.9/114.0, 118.5/118.3 (4d, C(2/6), C(4) of anilino); 120.0, 120.6,
124.2, 127.5, 127.7, 129.1, 130.9 (7d, 6 arom. CH); 141.4/141.3 (2d, C(3')); 129.0/127.2 (2s, C(8')); 136.5 (s, C(4a'));
‡
146.5/147.2 (2s, C(1) of anilino); 154.1/155.0 (2s, C(1')); 170.8, 172.4, 172.8 (3s, 2 CˆO). MS (808): 364 (1, M ),
‡
‡
‡
‡
271 (8, [M À PhNH2] ), 201 (32, C12H11NO2 , 24), 169 (13), 163 (25, C9H9NO2 , 15 ), 143 (50, 25), 115 (50), 104
‡
‡
‡
‡
(100, C7H6N , HCꢀNÀC6H5 ). HR-MS: 104.0495 (calc. 104.0499), 93 (27, C6H5NH2 ), 77 (87, C6H5 ). Anal. calc.
for C21H20N2O4 (364.39): C 69.22, H 5.53, N 7.69; found: C 69.41, H 5.66, N 7.72. Mol. mass: 365 (osmometr.,
C6H6, 378).
5.3. Mono-Deuteration of 18. Refluxing in MeOD (5 h) gave the N-deuterated compound with unchanged
diastereoisomer ratio. IR: 2510w (br., NÀD).
Bis-Deuteration. Compound 18 (0.56 mmol) and MeONa (0.11 mmol) in MeOD (3 ml) were refluxed for
2 h. Workup with D2O/CH2Cl2 afforded a red residue, which crystallized from benzene: colorless [2H2]-18. M.p.
133 ±136 8. 1H-NMR (80 MHz, C6D6): 3.21, 3.25 (2s, 4 MeO); 5.52, 5.69 (2 br. s, probably HÀC(2)); the MS
points to exchange at HÀC(3) and NH; the signal ratios suggest 55 :45 for the stereoisomers, further
‡
‡
clarification required. MS (1208): 271 (10, [M À C6H5ND2] ), 203 (25, C12D2H9NO2 , [2H2]-24), 202 (40 [2H2]-
‡
‡
‡
24), 163 (40, 15 ), 104 (100, C7H6N ), 95 (55, C6H5ND2 ), 94 (67, C6H5NHD).
5.4. Methyl a-(2,4-Dioxo-1,3-diphenylimidazolidin-5-yl)isoquinoline-1-acetate (19). Compound 18 and
PhNCO (1.34 mmol each) in CH2Cl2 (3 ml) reacted for 4 weeks at r.t.: colorless crystals of 19 (425 mg, 70%).
M.p. 224 ±225 8. IR: 642m, 693m, 754s, 762s, 827m, 1184s (br.), 1198s (br.), 1262s (br.), 1412vs, 1498s, 1562m,
1717vs, 1779m. 1H-NMR: 3.73 (s, MeO); 5.21, 5.64 (2d, J ˆ 5.0, HÀC(a), HÀC(5')); 6.9 ±7.8 ( m, 15 arom. H);
‡
‡
‡
8.39 (d, J ˆ 5.5, HÀC(3)). MS (2008): 451 (19, M ), 392 (100, [M À CO2Me] ), 104 (20, C7H6N ), 77 (15,
‡
C6H5 ). Anal. calc. for C27H21N3O4 (451.46): C 71.83, H 4.69, N 9.31; found: C 72.03, H 4.66,N 9.49.
5.5. Cleavage of 18 with 0.4n HCl. Compound 18 (500 mg, 1.37 mmol) in CH2Cl2 (15 ml) and MeOH (3 ml)
was reacted with methanolic HCl (2.0 ml, 4n) for 2 h at r.t.; workup with 2n NH3 and more CH2Cl2, and
distillation at 10À3 Torr furnished aniline (92 mg, 72%) and 14 (218 mg, 79%).
5.6. Treatment with HCl in the Presence of2,4-Dinitrophenylhydrazine . Compound 18 (1.37 mmol) was
added to 2,4-DNPH (1.37 mmol) in methanolic 4n HCl. After 30 min at r.t. and 15 h at 58, the yellow platelets of
16 (278 mg, 76%), m.p. 163 ±164 8, were filtered. The usual workup gave aniline (98 mg, 77%) and 14 (181 mg,
66%).
5.7. Preparation of 18 from 14 and Methyl 2-(Phenylimino)acetate (15). Compound 14 (1.17 g, 5.82 mmol)
and 15 (15 ml of 0.5m soln. in benzene [21]) were reacted for 5 d at r.t. and 4 h at 608. After washing with H2O
and evaporation, 18 (551 mg, 26%) crystallized from MeOH, m.p. 140 ±141 8; mixed m.p. and spectra showed the
identity with the product from 5.1.
5.8. Butyl 2-Anilino-3-(isoquinolin-1-yl)-3-(methoxycarbonyl)propionate (31). Butyl glyoxylate (34) [34]
was analogously converted to the less sensitive anil 30. Compound 30 (1.00 mmol) in benzene (1 ml) was added
to 14 (1.00 mmol) in benzene (10 ml) and refluxed for 3 h under Ar. CC (silica gel; AcOEt) furnished 31
(275 mg, 67%) as a colorless oil (erythro/threo ca. 1:1). IR (CCl4): 1501s, 1603s, 1737vs, 3400w (br., NÀH).
1H-NMR (80 MHz): 0.52 ±1.81 ( m,C3H7); 3.57, 3.62 (2s of equal height, 2 MeO); 3.8 ±4.1 ( m, 2 diastereotopic
CH2O); 5.11 ±6.10 ( m, 2 ABC); 6.51 ±8.15 ( m, 2  10 arom. H); 8.48 (d, J ˆ 6.0, 2  HÀC(3')). MS (1308): 406
‡
‡
‡
‡
(3, M ), 347 (6, [M À CO2Me] ), 337 (11), 313 (6, M À C6H5NH2] ), 309 (11), 221 (11), 205 (15) [C12H15NO2 ,
‡
‡
‡
30 ], 201 (44) [24], 169 (20), 143 (26) [25], 142 (20), 115 (22), 104 (68, C7H6N ), 93 (100, C6H5NH2 ), 77 (33,
C6H5 ). Anal. calc. for C24H26N2O4 (406.46): C 70.91, H 6.45, N 6.89; found: C 70.82, H 6.90, N 7.21.
‡
6. N-Aryl Analogs of 18. 6.1. Dimethyl (Æ)-[1a,2a,rel-10bb]-1,2,3,10b-Tetrahydro-3-p-tolylpyrazolo-
[5,1-a]isoquinoline-1,2-dicarboxylate (26). Aq. Na2CO3 was dropped into the stirred two-phase system of
N-(p-toluidino)isoquinolinium chloride [10] (5.00 g, 18.5 mmol) in H2O (25 ml) and dimethyl maleate (2.67 g,
18.5 mmol) in CH2Cl2 (30 ml), until the red color of the 1,3-dipole was no longer generated. Compound 26
(3.41 g, 49%) was isolated from the org. phase. M.p. 130 ±132 8 (Et2O/pentane). 1H-NMR: 2.32 (s, MeÀC(4'));

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3.13, 3.68 (2s, 2 MeO); 3.79 (dd, J ˆ 8.9, 7.3, HÀC(1)); 4.29 (d, J ˆ 8.9, HÀC(10b)); 4.78 (d, J ˆ 7.3, HÀC(2));
5.31, 6.38 (2d, J ˆ 8.0, HÀC(6), HÀC(5)); 6.68 ±7.26 ( m, 8 arom. H); assignments based on a previous study [4].
6.2. Dimethyl 3-(Isoquinolin-1-yl)-2-(p-toluidino)succinate (28). Compound 26 (1.03 g, 2.72 mmol) in
CH2Cl2 (40 ml) and methanolic HCl (0.2 ml, 4n) reacted 2 h at r.t.; workup with 2n NH3 gave 28 (440 mg, 43%).
M.p. 116 ±125 (Et 2O). Anal. HPLC (AcOEt/hexane 1:6, 50 bar, flow 1 ml/min) indicated two peaks of ca.
55 :45 ratio (tR 27.5, 28.5 min.); solubility was too low for prep. HPLC separation. The NMR spectra were taken
from another crystal fraction of 28 and showed a diastereoisomer ratio of 62 :38. IR: 749m, 827s, 998s, 1165s,
1202s, 1274s (br.), 1435s, 1522vs, 1562w, 1618s, 1735vs (br.), 3392w (sharp, NÀH). IR (CCl4): 3400w (br.,
NÀH). 1H-NMR (400 MHz; major/minor isomer, where separated): 2.191/2.198 (s, MeÀC(4'')); 3.57/3.54, 3.67/
3.62 (2s, 2 MeO); 4.40 (br. s, in coalescence, NH; disappears with D2O); 5.21, 5.25 (AB, J ˆ 7.2, HÀC(2),
HÀC(3), major); 5.17, 5.36 (br. AX, J ˆ 6.5, HÀC(2), HÀC(3), minor; signals get sharp with D2O, coupling
with NH stronger than for major isomer); 6.60, 6.92 (2m, AA'BB', C6H4); 7.56/7.57 (d, J ꢁ 6.1/5.6, HÀC(4'),
broadened by 4,8-coupling); 7.61/ ca. 7.60, 7.67 (2td, J ꢁ 8.2, 1.2, HÀC(7'), HÀC(6')); 7.81 (d, J ꢁ 8.1, HÀC(5'));
8.15/8.03 (d, J ˆ 8.1, HÀC(8')); 8.46/8.48 (d, J ˆ 6.1/5.6, HÀC(3')); NMR parameters of isoquinoline and N-
1
methyl-p-toluidine [33] helped the assignments of H- and 13C-NMR data. 13C-NMR (100 MHz, DEPT; major/
minor isomer): 20.38/20.40, MeÀC(4''); 52.26 (MeO); 52.52/52.56 (MeO); 52.36, 51.08 (C(3)); 58.67/59.13
(C(2)); 114.27/114.42 (C(2''/6'')); 120.66/120.71 (C(4')); 124.32/124.29, 127.59/127.63, 127.77/127.69 (C(5'), C(7'),
C(8')); 127.93/127.32, (C(8a')); 129.66/129.58 (C(3''/5'')); 130.07/130.04 (C(6')); 136.43/136.41 (C(4a')); 141.57/
141.40 (C(3')); 144.17/144.95 (C(4'')); 154.18/155.15 (C(1')); 170.91/170.97, 172.76/173.13 (2 CˆO). MS (18 eV,
‡
‡
‡
1008): 378 (0.5, M ), 271 (13, [M À C7H7NH2] ), 201 (77, 24), 177 (66, [C7H7NˆCHÀCO2Me] ), 143 (91,
‡
‡
‡
‡
C10H9N , 25), 142 (18), 118 (100, HCꢀNÀC7H7 ), 107 (91, C7H7NH2 ), 106 (52), 91 (24, C7H7 ). Anal. calc. for
C22H22N2O4 (378.41): C 69.82, H 5.86, N 7.40; found: C 69.76, H 5.86, N 7.55.
6.3. Dimethyl (Æ)-[1a,2a,rel-10bb]-3-(4-Chlorophenyl)-1,2,3,10b-tetrahydropyrazolo[5,1-a]isoquinoline-
1,2-dicarboxylate (27). Reaction of 2-(4-chloroanilino)isoquinolinium chloride [10] and dimethyl maleate, as
described for 26, furnished 27 (67%). M.p. 168 ±169 8 (MeOH). 1H-NMR (80 MHz): 3.19, 3.74 (2s, 2 MeO); 3.83
(dd, partially superposed, HÀC(1)); 4.26 (d, J ˆ 9.0, HÀC(10b)); 4.76 (d, J ˆ 6.8, HÀC(2)); 5.28, 6.31 (2d, J ˆ
7.9, HÀC(6), HÀC(5)); 7.4 ±6.8 ( m, 8 arom. H).
6.4. Dimethyl 2-(4-Chlorophenyl)-3-(isoquinolin-1-yl)succinate (29). Analogous to 6.2, 27 was converted to
29 (63%). M.p. 139 ±140 8 (MeOH). IR (CCl4): 1550s, 1568w, 1606m, 1741vs; 3415m (br., NÀH); with D2O
1
2540m (br., NÀD). H-NMR (90 MHz): 3.61, 3.68 (2s, 2 MeO); 4.63 (br. d, C of ABC, NH); 5.06 ±5.33 ( m, 6
lines visible, AB of ABC, HÀC(1), HÀC(2)); 6.50 ±6.67, 6.94 ±7.08 ( AA'BB', C6H4); 7.25 ±8.47 ( m, 6 arom. H);
with NÀD: 5.17, 5.28 (AB, J ˆ 7.5, HÀC(1), HÀC(2)). 13C-NMR (20 MHz): 52.1, 52.4 (2q, 2 MeO); 52.5, 58.3
(2d, C(2), C(3)); 115.0, 120.7, 124.1, 127.6, 127.8, 128.9, 130.1, 141.5 (8d, 10 arom. CH); 5s of arom. Cq at 123.1,
‡
‡
127.1, 136.4, 145.2, 153.9; 170.8, 172.5 (2s, 2 CˆO). MS (18 eV, 1508): 398 (1, M ), 339 (1.4, [M À CO2Me] ), 271
‡
‡
‡
(4, [M À ClC6H4NH2] ), 201 (100, 24), 197 (26, C9H8ClNO2 , p-Cl derivative of 15 ), 169 (18), 143 (48, [25]),
‡
‡
‡
‡
142 (29, [14 À CO2Me] ), 138 (59, [HCꢀNÀC6H4Cl] ), 127 (14, ClC6H4NH2 ), 111 (11, ClC6H4 ). Anal. calc.
for C21H19ClN2O4 (398.84): C 63.24, H 4.80, N 7.02; found: C 63.26, H 4.78, N 7.13.
7. Introduction ofAcetate Group into Adduct 11. 7.1. With 18 as Source ofImino-acetate 15. Compounds 11
and 18 (1.37 mmol each) in CH2Cl2 (15 ml) were mixed with methanolic HCl (5 ml, 1.6n). After 2 h at r.t.,
CH2Cl2 (20 ml) was added, and the acid was removed by shaking with 2n NH3. Compound 13 (354 mg, 60%)
crystallized from acetone/pentane, m.p. 182 ±184 8, 1H-NMR identified with the material from 2.1. Distillation at
10À3 Torr gave aniline (1.46 mmol) and 14 (1.12 mmol).
7.2. With Methyl Glyoxylate and HCl. Freshly prepared 33 [35] (2.43 g, 27.6 mmol) and 11 (1.00 g,
2.74 mmol) in CH2Cl2 (10 ml) were treated with methanolic 4n HCl (4 ml) for 2 h at r.t. under N2. Workup as
above furnished 13 (595 mg, 50%), m.p. 182 ±184 8.
7.3. With Butyl 2-(Phenylimino)acetate (30) and CF3COOH. Compound 30 in benzene (10 ml) was added
to 11 (5.48 mmol) and CF3CO2H (1.5 ml, 20.2 mmol) in CH2Cl2 (20 ml). After 2 h at r.t. under Ar, workup gave
dimethyl 6-[(butoxycarbonyl)methyl]-2,3-dihydro-3-phenylpyrazolo[5,1-a]isoquinoline-1,2-dicarboxylate (32,
1.96 g, 75%) as yellow crystals. M.p. 128 ±129 8 (from acetone/pentane). 1H-NMR (60 MHz): 0.61 ±1.21
(m, 7 H); 3.50 (s, CH2ÀC(6)); 3.58, 3.75 (2s, 2 MeO); 4.03 (t, J ˆ 6.5, CH2O); 5.08 (s, HÀC(2)); 6.90 ±7.68
(m, 8 arom. H). Anal. calc. for C27H28N2O6 (476.51): C 68.05, H 5.92, N 5.88; found: C 67.61, H 5.88, N 5.78.
Without acid catalysis, no 32 was found after 2 h at 258.
7.4. With Butyl Glyoxylate and HCl. Compound 34 (28 mmol) and 11 (2.74 mmol) in CH2Cl2 (10 ml), and
methanolic 4n HCl (4 ml) afforded 32 (1.72 mmol, 63%). M.p. 128 ±129 8.
7.5. With N-[(Methoxycarbonyl)methylidene]piperidinium Chloride. Compound 35 [24] is a colorless
hygroscopic powder, which was applied without purification. From 35 (1.90 g, 9.95 mmol) and 11 (5.48 mmol) in

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Helvetica Chimica Acta ±Vol. 83 (2000)
CH2Cl2 (20 ml), a deep-yellow soln. was obtained within 5 min. After 24 h at r.t., workup provided 13 (1.80 g,
76%). M.p. 182 ±184 8.
8. Variation ofReactants . The data of Table 2 are supplemented by spectra and elemental analyses.
8.1. Dimethyl 2,3-Dihydro-6-(4-nitrobenzyl)-3-phenylpyrazolo[5,1-a]isoquinoline-1,2-dicarboxylate (44).
IR: 1094s, 1200s (br., CÀO); 1345s, 1521vs (br., NO2); 1678s, 1744s. 1H-NMR: 3.63, 3.83 (2s, 2 MeO); 4.00
(s, CH2ÀC(6)); 5.08 (s, HÀC(2)). Anal. calc. for C28H23N3O6 (497.49): C 67.60, H 4.66, N 8.45; found: C 67.70,
H 4.66, N 8.30.
8.2. Dimethyl 6-Benzyl-2,3-dihyro-3-phenylpyrazolo[5,1-a]isoquinoline-1,2-dicarboxylate (45). 1H-NMR:
3.61, 3.78 (2s, 2 MeO); 3.98 (s, CH2ÀC(6)); 5.08 (s, HÀC(2)). Anal. calc. for C28H24N2O4 (452.49): C 74.32,
H 5.35, N 6.19; found: C 74.28, H 5.41, N 6.32.
8.3. Methyl 1-Cyano-2,3-dihydro-6-[(methoxycarbonyl)methyl]-3-phenylpyrazolo[5,1-a]isoquinoline-2-
carboxylate (46). IR: 698m, 764s, 772s, 1170s (br.), 1205s (br.), 1496s, 1558vs, 1634s, 1740vs, 1756s, 2185s.
1H-NMR: 3.45 (s, CH2ÀC(6)); 3.58, 3.76 (2s, 2 MeO); 4.80 (s, HÀC(2)). Anal. calc. for C23H19N3O4 (401.41):
C 68.82, H 4.77, N 10.47; found: C 68.65, H 5.00, N 10.41.
8.4. Methyl 1-Cyano-2,3-dihydro-3-phenylpyrazolo[5,1-a]isoquinoline-6-acetate (47). 1H-NMR: 3.47
(s, CH2ÀC(6)); 3.65 (s, MeO); 4.62 (s, CH2(2)). Anal. calc. for C21H17N3O2 (343.37): C 73.45, H 4.99, N 12.24;
found: C 73.63, H 5.13, N 12.25.
8.5. Methyl a-Anilino-2-methylpyrrole-2-acetate (48). Compound 18 (5.48 mmol), N-methylpyrrole
(10 ml), and AcOH (2 ml) were reacted for 3 h at r.t.; workup with aq. NH3/CH2Cl2 and distillation gave 48
(903 mg, 67%) as a light-yellow oil, which crystallized from Et2O/pentane. M.p. 82 ±83 8. IR: 695m, 712s, 758s,
1
972m, 1120m, 1216s, 1501s, 1604s, 1741vs (br.). H-NMR (80 MHz): 3.48 (s, MeN); 3.60 (s, MeO); 4.42 (br. s,
NH); 5.07 (s, HÀC(a)); 5.9 ±7.2 ( m, 8 arom. H). 13C-NMR: 33.7 (q, MeN); 52.3 (q, MeO); 53.9 (d, C(a)); 107.1,
108.2 (2d, C(3), C(4)); 113.3 (d, C(2'/6')); 118.5 (d, C(4')); 123.5 (d, C(5)); 127.4 (s, C(2)); 129.2 (d, C(3'/5'));
146.3 (s, C(1')); 171.8 (s, CˆO); assignments on the basis of pyrrole and N-methylaniline [33]. MS (508): 244
‡
‡
‡
‡
(32, M ), 185 (100, [M À CO2Me] ), 152 (100, [M À C6H5NH] ), 104 (16, [HCꢀNÀC6H5] ), 92 (22,
‡
‡
C6H5NH ), 82 (25), 77 (15, C6H5 ). Anal. calc. for C14H16N2O2 (244.28): C 68.83, H 6.60, N 11.47; found: C 68.73,
H 6.72, N 11.31.
9. Competing Reactions ofCycloadducts with Acid. 9.1. Adduct 42 ofMethyl ( Z)-3-Cyanoacrylate. a)
Compound 42 [4] (6.03 mmol) and CF3CO2H (2.0 ml, 27 mmol) in CH2Cl2 (40 ml) were reacted 2 h at r.t. Bulb-
to-bulb distillation afforded aniline (13%) and, at 1708/10À3 Torr, isoquinoline-1-acetonitrile (50, 12%).
‡
1H-NMR: 4.29 (s, CH2ÀC(1)); 6.5 ±8.05 ( m, 5 arom. H); 8.43 (d, J ˆ 5.5, HÀC(3)). MS (408): 168 (100, M ),
‡
‡
129 (12, C9H7N ), 128 (25, C9H6N ). The picrate of 50 crystallized from EtOH. M.p. 127 ±129 8. Anal. calc. for
C17H11N5O7 (397.30): C 51.39, H 2.79, N 17.63; found: C 51.97, H 2.88, N 17.72.
b) 2,4-DNPH (550 mg, 2.78 mmol) and 42 (907 mg, 2.74 mmol) were reacted in methanolic 1.8n HCl
(45 ml); after 12 h at 48, hydrazone 16 (217 mg, 30%) was filtered. The mother liquor was worked up, and
distillation provided aniline (147 mg, 58%) and 50 (246 mg, 53%).
9.2. Adduct 52 ofMethyl Acrylate . Compound 52 [4] (500 mg, 1.63 mmol) in CH2Cl2 (5 ml) and methanolic
2.7n HCl (2 ml), 2 h at r.t., yielded methyl (Æ)-(6ab,11bb,13a,rel-5b)-6,6a,7,11b-tetrahydro-5,7-ethano-5H-
indolo[2,3-c]isoquinoline-13-carboxylate (55, 49%). Colorless crystals. M.p. 134 ±135 8 (Et2O). IR: 744s, 770m,
1
778m, 800m, 1173s, 1212s, 1473s, 1726vs, 3315m, 3335m (sharp, NÀH). H-NMR: 2.57 (br. s, NH; disappears
with D2O); 2.33 ±3.77 ( m, CH2(12), HÀC(13)); 3.53 (s, MeO); 4.02, 4.87 (2d, J ˆ 5.8, HÀC(11b), HÀC(6a));
4.65 (d, J ˆ 3.8, HÀC(5)); 6.73 ±7.71 ( m, 8 arom. H). Anal. calc. for C19H18N2O2 (306.35): C 74.49, H 5.92,
N 9.15; found: C 74.61, H 5.81, N 8.99.
9.3. Adduct 53 ofMethyl Methacrylate . Compound 53 [4] (3.12 mmol) was analogously treated with HCl
and gave 56 (13a-methyl-55; 2.18 mmol, 70%). M.p. 159 ±160 8 (Et2O). 1H-NMR (60 MHz): 1.58
(s, MeÀC(13)); 2.73 (br. s, NH); 3.09 (s, MeO); 3.15, 3.20 (AB, J ˆ 12.0, CH2(12)); 4.00, 5.03 (2d, J ˆ 6.3,
HÀC(11b), HÀC(6a)); 4.10 (s, HÀC(5)); 6.7 ±7.6 ( m, 8 arom. H). Anal. calc. for C20H20N2O2 (320.38): C 74.97,
H 6.29, N 8.74; found: C 74.66, H 6.51, N 8.72.
9.4. Adduct 54 ofMethyl 2-Chloroacrylate . Treatment of 54 with HCl as described above furnished aminal
57 (83%). M.p. 1268 (Et2O/pentane). IR: 747s, 752s, 1243s, 1263s, 1464m, 1605w, 1748vs, 3340w (sharp, NÀH).
1H-NMR (80 MHz): 3.10, 3.67 (AB, J ˆ 13.5, left branch split by J(12,6a) ˆ 1.5, CH2(12)); 3.52 (s, NH, MeO);
4.02, 4.90 (AB, J ˆ 5.8, HÀC(11b), HÀC(6a)); 4.53 (br. s, HÀC(5)); 6.35 ±7.63 ( m, 8 arom. H). Anal. calc. for
C19H17ClN2O2 (340.80): C 66.96, H 5.03, N 8.22; found: C 66.96, H 5.09, N 8.13.
10. Dimethyl (Æ)-(1a,2a,rel-10bb)-1,2,3,5,6,10b-Hexahydro-5-{1-[(methoxycarbonyl)methyl]isoquinolin-4-
yl}-3-phenylpyrazolo[5,1-a]isoquinoline-1,2-dicarboxylate (62). Entry 6 of Table 1 was described in Sect. 2.5,
and Entry 7 gave the highest yield of 62 (23%). UV/VIS (EtOH): ꢀtripletꢁ at 424 (2.28), 400 (2.40), 380 (2.32),

Helvetica Chimica Acta ±Vol. 83 (2000)
2381
328 (3.83), 313 (3.76), 289 (sh., 3.84), 279 (3.88); the three long-wave absorptions resemble those of 14. IR
(CHCl3): 1174s, 1378m, 1440m, 1489s, 1603s, 1732vs, 1766s. 1H-NMR (400 MHz; Fig.): 3.11 (dd, J ˆ 16.7, 3.8,
HAÀC(6); HBÀC(6) at 3.32 is superimposed); 3.32 (br. s, MeO; superimposed by ca. 3.37 ppm, MeO in
coalescence); 3.66 (s, MeO); 4.18, 4.34 (2d, left branch overlapped by HÀC(1), Jgem ˆ 15.2, diastereotopic
CH2ÀC(1'); disappear with D2O); 4.32 (dd, J ˆ 10.7, 9.1, HÀC(1)); 4.65 (d, J ˆ 10.7, HÀC(10b)); 5.04 (d, J ˆ 9.1,
HÀC(2)); 6.02 (m, not resolved, HÀC(5)?); 6.86 (m, 1 arom. H); 7.08 ±7.25 ( m, 8 arom. H); 7.59,7.72, 8.08, 8.25
1
(4m, 4 arom. H); 8.82 (br. s, probably HÀC(3')). H-NMR (60 MHz): 3.32, 3.39, 3.66 (3s, 3 MeO). 13C-NMR
(100 MHz)4): 39.5* (t, C(6)); 42.1 (t, CH2ÀC(1')); 51.8, 52.1, 52.4 (3q, 3 MeO); 53.8* (d, C(5)); 58.3 (d, C(1));
65.3 (d, C(10b)); 73.1 (d, C(2)); d of arom. CH: 115.2, 121.0, 125.7 (C6H5), 123.8*, 126.6, 127.54, 127.63 (2Â),
127.93, 129.5*, 140.8*; s of Cq: 127.0, 131.3, 132.4, 134.5, 134.9, 152.0, 152.5* (C(1'')); 171.0, 171.93, 172.00 (3s,
‡
‡
‡
3 CˆO); MS (2008): 565 (3, M ), 506 (3, [M À CO2Me] ), 271 (7), 269 (8), 151 (10), 144 (13, C6H8O4 , dimethyl
‡
‡
‡
‡
‡
fumarate ), 129 (10, C9H7N , isoquinoline ), 113 (60, C5H5O3 , MeO2CÀCHˆCHÀCꢀO ), 93 (100,
‡
‡
‡
C6H5NH2 ), 85 (20), 77 (13, C6H5 ), 59 (25, MeOÀCꢀO ). Anal. calc. for C33H31N3O6 (565.60): C 70.07,
H 5.52, N 7.43; found: C 69.87, H 5.62, N 7.56.
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4
)
*: Broad by coalescence at 100 MHz and less broad at 20 MHz.

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Helvetica Chimica Acta ±Vol. 83 (2000)
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Received May 29, 2000