Substituent effects in the ring-chain tautomerism of 4-aryl-1,3,4,6,7,11b- hexahydro-2H-pyrimido[6,1-a]isoquinolines

Article abstract of DOI:10.1016/j.tet.2005.03.067

By condensation of 1-(2′-aminoethyl)-1,2,3,4-tetrahydroisoquinoline derivatives with substituted benzaldehydes, 1,6-unsubstituted and diastereomers of 1-methyl- or 6-methyl-substituted 4-aryl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrimido[6,1-a]isoquinolines were prepared. The ring-chain tautomeric equilibria of most of these compounds in CDCl₃ at 300 K were found to be shifted nearly totally towards either the cyclic or the open tautomeric forms, while the (6R*,11bR*)-6-methyl substituted compounds proved to be three-component tautomeric mixtures, the equilibria of which could be characterized by a Hammett-type equation. The conformational equilibria of the cyclic forms turned out to be strongly influenced by the 1- and 6-methyl substituents and the configurations of the substituted carbons (C-1 or C-6 and C-4) relative to C-11b.

Full text of DOI:10.1016/j.tet.2005.03.067

Tetrahedron 61 (2005) 5287–5295
Substituent effects in the ring-chain tautomerism of
4-aryl-1,3,4,6,7,11b-hexahydro-2H-pyrimido[6,1-a]isoquinolines
*
´ ´ ´ ´ ´ ´ ´
¨ ¨
Zita Zalan, Anasztazia Hetenyi, Laszlo Lazar and Ferenc Fulop
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, POB 121, Hungary
Received 1 February 2005; revised 2 March 2005; accepted 18 March 2005
Available online 11 April 2005
´ ´
Dedicated to Professor Alajos Kalman on the occasion of his 70th birthday
Abstract—By condensation of 1-(20-aminoethyl)-1,2,3,4-tetrahydroisoquinoline derivatives with substituted benzaldehydes, 1,6-
unsubstituted and diastereomers of 1-methyl- or 6-methyl-substituted 4-aryl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrimido[6,1-a]
isoquinolines were prepared. The ring-chain tautomeric equilibria of most of these compounds in CDCl3 at 300 K were found to be shifted
nearly totally towards either the cyclic or the open tautomeric forms, while the (6R*,11bR*)-6-methyl substituted compounds proved to be
three-component tautomeric mixtures, the equilibria of which could be characterized by a Hammett-type equation. The conformational
equilibria of the cyclic forms turned out to be strongly influenced by the 1- and 6-methyl substituents and the configurations of the substituted
carbons (C-1 or C-6 and C-4) relative to C-11b.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
hexahydropyrimidines,5–7 1,2,3,4-tetrahydro quina zolines,6,8
perhydroquinazolines9 and 3-arylhexahydroimidazo[5,1-a]-
and -[1,5-b]isoquinolines10 led to the conclusion that, simi-
larly to their 1,3-O,N analogues, the ring-chain tautomeric
equilibria of these compounds could likewise be character-
ized by Eq. 1. Complex 1,3-N,N heterocyclic tautomeric
mixtures containing regioisomeric open and/or diastereo-
meric cyclic forms could also be characterized by Eq. 1.7,9,10
For N-substituted 2-aryl-1,3-N,N heterocycles, the tauto-
meric process and the values of r and log KXZH in Eq. 1
were found to be dependent on the steric and electronic
characters of the substituent on the nitrogen. In contrast with
the 1,3-O,N analogues, the value of r did not prove to be
characteristic of the 1,3-N,N ring system.2
Ring-chain tautomerism, the reversible intramolecular
addition of a hydroxy, mercapto or amino group to a
C]N double bond, is a characteristic phenomenon for
saturated, N-unsubstituted, five- and six-membered 1,3-X,N
heterocycles (XZO, S, NR). It is often exploited advanta-
geously in different areas of organic synthesis, and also in
physical, medicinal and peptide chemistry.1,2
Substituent effects influencing the ring-chain tautomeric
process have been studied thoroughly in recent decades. For
the tautomeric equilibria of oxazolidines and tetrahydro-
1,3-oxazines bearing a substituted phenyl group at position
2, in both the liquid and the gas phase, a linear Hammett-
type correlation was found between the log K (KZ[ring]/
[chain]) values of the equilibria and the electronic character
(sC) of the substituents X on the 2-phenyl group (Eq. 1).
The value of r in Eq. 1 was found to be characteristic of the
ring system and dependent on the temperature and the
nature of the solvent.1,2
As a continuation of our previous studies on the ring-chain
tautomerism of five- and six-membered 1,3-N,N hetero-
cycles2 and stereochemical investigations on 1,2,3,4-tetra-
hydro isoquinoline-condensed 1,3- and 1,2,3-heterocycles,11
our primary present aim was to determine the influence of
the substituents and the relative configuration of the sub-
stituted carbon atoms on the ring-chain tautomeric character
and the conformation of 4-aryl-1,3,4,6,7,11b-hexahydro-
2H-pyrimido[6,1-a]isoquinolines. In the knowledge of the
significant substituent effects on both the ring-chain
tautomeric and conformational equilibria of saturated 1,3-
heterocycles,2,12 a further aim was to study the conse-
quences of methyl substitution at positions 1 and 6 of the
hexahydropyrimido[6,1-a]isoquinoline ring system.
log KX Z rsC Clog KXZH
(1)
Recent studies on 2-aryl-substituted imidazolidines,3,4
Keywords: Diamines; Isoquinolines; Hexahydropyrimidines; Ring-chain
tautomerism; Conformation.
Corresponding author. Tel.: C36 62 545564; fax: C36 62 545705;
e-mail: fulop@pharm.u-szeged.hu
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.067

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5288
2. Results and discussion
was obtained by applying a procedure analogous to that
used for the synthesis of 2b. In the NaBH4 reduction of
dihydroisoquinoline 6, obtained in two steps from N-
protected b-alanine and a-methylhomoveratrylamine (4), a
12:1 mixture of tetrahydroisoquinoline isomers (1R*,3S*)-
7a and (1R*,3R*)-7b was formed, from which 7a was
obtained by crystallization and was converted into the pure
(1R*,3S*) diamine diastereomer 8 by removal of the Cbz
group (Scheme 2). The cis selectivity of the reduction can be
rationalized by the steric effect of the 3-methyl group, which
directs the hydride attack to the sterically less hindered side,
resulting in 7a as the main product.16–18 The relative
configuration (1R*,3S*) of 8 was deduced from the NOE
data on H-1 and H-3.
2.1. Synthesis
For the synthesis of the target hexahydropyrimido[6,1-a]
isoquinolines, the appropriate 1-(20-aminoethyl)-1,2,3,4-
tetrahydroisoquinolines bearing 0 a methyl substituent at
either position 3 or position 1 of the side-chain were
required. The usual methods applied earlier for the synthesis
of 1-aminoalkyl-1,2,3,4-tetrahydroisoquinolines involve
reduction of the corresponding isoquinolines bearing
nitrogen-containing functional groups (nitrile, carboxamide
or nitro) in the side-chain and procedures based on the
Bischler–Napieralski or Pictet–Spengler ring-closures,
using the appropriate N-protected amino acids or amino
aldehydes,13 both of which were utilized in the preparation
of the 10- or 3-methyl-substituted tetrahydroisoquinoline
diamines.
The (1R*,3R*) diamine diastereomer 11 was prepared by
LiAlH4 reduction of (1R*,3R*)-6,7-dimethoxy-3-methyl-
1,2,3,4-tetrahydroisoquinoline-1-acetamide (10), which was
obtained in a highly diastereoselective two-step pro-
cedure16,17 (monoethyl malonate addition and subsequent
amidation) from 3-methyl-6,7-dimethoxy-3,4-dihydroiso-
quinoline (9) (Scheme 3).
The unsubstituted diamine 2a was obtained by the catalytic
hydrogenation of 6,7-dimethoxy-1,2,3,4-tetrahydro-1-iso-
quinolylacetonitrile (1)14 (Scheme 1). The 10-methyl-
substituted tetrahydroisoquinoline diamine diastereomers
(2b,c) were prepared via a highly diastereoselective, four-
step process, starting from 3-benzyloxycarbonylamino-2-
methyl-N-[2-(3,4-dimethoxyphenyl)ethyl]propanamide (3).
The formation of either the (1R*,10S*) (2b) or the
(1R*,10R*) isomer (2c) as major product was found to be
dependent on the sequence of reduction and deprotection
steps applied.15
Condensations of diamines 2a–c, 8 and 11 with equivalent
amounts of p-nitro- and p-(dimethylamino)benzaldehyde
resulted in model hexahydropyrimido[6,1-a]isoquinoline
compounds 12–16 mainly as crystalline products (Scheme 4).
In the knowledge of the strong influence of the electronic
effects of the aromatic substituents on the ring-chain tauto-
meric behaviour of 1,3-X,N heterocyclic compounds,1,2
aromatic aldehydes were chosen according to their opposite
electronic character, which favour the predominance of
either the cyclic (in the case of p-NO2) or the open (in the
case of p-NMe2) form.
The 3-methyl-substituted tetrahydroisoquinoline diamine
diastereomers (8 and 11) were prepared using different
synthetic pathways. (1R*,3S*)-1-(20-aminoethyl)-6,7-
dimethoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline (8)
Scheme 1. Reagents and conditions: (i) see Ref. 14 (1/2a); (ii) see Ref. 15 (3/2b,c).
Scheme 2. Reagents and conditions: (i) ClCOOEt, N-Cbz-b-alanine, toluene, K10 8C, 6, 5 min, 84%; (ii) POCl3, CHCl3, 6, 3 h, 78%; (iii) NaBH4, MeOH,
0 8C, 3 h, then rt, 3 h, 7a:7bZ12:1, 82% (7a); (iv) 1. 33% HBr in AcOH, rt, 30 min, 2. NaOH, 74%.

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5289
Scheme 3. Reagents and conditions: (i) see Ref. 17; (ii) LiAlH4, THF, reflux, 7 h, 82%.
Scheme 4. Reagents and conditions: (i) XC6H4CHO, MeOH, rt, 1 h, 43–100%. (For the meanings of R1–R4 and X, see Table 1).
2.2. Ring-chain tautomerism
(X-phenyl)-substituted derivatives was prepared, with
substituent X exhibiting different electronic characters
(16a–g). In consequence of the very similar NMR spectro-
scopic characteristics of 16a–g, the relative configurations
of the major (B) and minor (C) ring-closed tautomers were
determined only for 16a. The proportion of the minor cyclic
form (C) was found to be decreased to below the limit of
detection in the event of strongly electron-donating 4-aryl
substituents (p-OMe and p-NMe2).
Quantitative studies on the ring-chain tautomeric equilibria
of 2-aryl-substituted 1,3-X,N heterocycles (XZO, S, NR)
are based on the integration of the well-separated X-CHAr-N
(ring) and N]CHAr (chain) proton singlets in the 1H NMR
spectra.1,2 The proportions of the chain (A) and diastereo-
meric ring forms (B and C) of the tautomeric equilibria of
1
12–16 were determined by this method (Table 1). The H
NMR (CDCl3, 300 K) spectroscopic data on the 1-
unsubstituted and 1-methyl-substituted model compounds
(12–14) revealed that, independently of the electronic
character of the aromatic substituents and the presence of
the methyl group at position 1, their tautomeric equilibria
were shifted totally towards the cyclic forms (B and C). The
NOESY spectra unequivocally showed that the major ring
forms in the tautomeric equilibria of 12–14 contain H-4 and
H-11b in the cis position (B). The proportion of the minor
cyclic tautomer, possessing H-4 and H-11b in the trans
position (C), was found to be increased in (1R*,11bR*)-1-
methylhexahydropyrimido[6,1-a]isoquinoline 14.
Data on 16a and 16g were chosen to illustrate the 1H NMR
spectra of this type of prepared tautomeric compound (see
Section 4). 4-Aryl substituents did not change the sequence
of the chemical shifts of the characteristic N–CHAr–N and
N]CHAr protons. The configuration of the azomethine
double bond was found to be E, according to the NOE
interaction observed between H-2 and N]CH.
When Eq. 1 was applied to the log KX values (KXZ[ring]/
[chain]) of 16a–g, good linear correlations were obtained
versus the Hammett–Brown parameter sC of the substituent
X on the 4-phenyl group, for both the cis-chain (B#A) and
the trans-chain (C#A) equilibria (Fig. 1 and Table 2).
The 6-methyl substitution caused a dramatic change in the
tautomeric ratios. For (6S*,11bR*)-6-methyl-substituted
hexahydropyrimido[6,1-a]isoquinolines 15, the tautomeric
equilibrium was found to be shifted entirely towards the
open tautomer (A), even in 15a, which bears an electron-
withdrawing p-nitro substituent on the aromatic ring.
The data in Table 2 show that both the slope (r) and the
intercept (log KXZH) of the regression line were strongly
influenced by the relative configuration of C-4 and C-11b. A
comparison of the intercepts in Table 2, which indicate the
stability of the given cyclic form,1,2 indicates, that the
attached tetrahydroisoquinoline ring makes both cyclic
forms of 16 more stable than the corresponding monocyclic
analogue 2-aryl-1-isopropylhexahydropyrimidine (17B).
The difference in the values of r for the cis-chain
(16B#16A) and trans-chain (16C#16A) equilibria,
which reflects the difference in the sensitivities of the
The tautomeric ratios determined for (6R*,11bR*) 6-
methyl-substituted 4-(p-nitrophenyl)- (16a) and 4-[p-
(dimethylamino)phenyl]hexahydropyrimido[6,1-a]isoquino-
line (16g) suggested that the ring-chain equilibrium of this
model compound was sensitive to the electronic effects of
the 4-aryl substituents (Table 1). Accordingly, a full set of 4-

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Z. Zalan et al. / Tetrahedron 61 (2005) 5287–5295
5290
Table 1. Proportions (%) of tautomeric forms (A, B and C) in tautomeric equilibria for compounds 12–16 (CDCl3, 300 K)
Comp.
R1
R2
R3
R4
X
sC
A
B
C
12a
12b
13a
13b
14a
14b
15a
15b
16a
16b
16c
16d
16e
16f
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
pNO2
pNMe2
pNO2
pNMe2
pNO2
pNMe2
pNO2
pNMe2
pNO2
mBr
pBr
H
pMe
pOMe
pNMe2
0.79
K1.7
0.79
K1.7
0.79
K1.7
0.79
K1.7
0.79
0.405
0.15
0
K0.311
K0.778
K1.7
0
0
0
0
0
0
100
100
10.7
17.6
24.1
31.4
40.8
54.9
79.4
92.6
100
100
100
65.4
81.3
0
7.4
0
0
0
34.6
18.7
0
0
0
74.7
75.4
69.2
64.9
57.2
45.1
20.6
14.6
7.0
6.7
3.7
2.0
0
16g
0
containing trans-connected rings B/C, than that in 16C,
Z
with a predominant cis1 conformation (nNKs*C-Ar
K167.9 and 37.3).
The substantial increase in the proportions of the open
tautomers for the equilibria of 15 and 16, as compared with
the tautomeric ratios for 12–14, can be rationalized by the
increased steric hindrance of the N-substituent caused by the
6-methyl group. Earlier data on the ring-chain tautomeric
equilibria of 1,3-N,N-heterocycles indicated that the pro-
portion of the ring-closed form decreases with increasing
bulkiness of the N-substituent.2
2.3. Conformations
Figure 1. Plots of log KX for 16B (B) and 16C (!) versus Hammett–
Brown parameter sC
.
The stereostructure of tetrahydroisoquinoline-fused six-
membered saturated heterocycles can be described by a
conformational equilibrium of cis1–trans–cis2 type. In the
trans structure, the B/C hetero rings are trans-connected,
with H-11b and the N-5 lone pair trans-diaxial. In the two
other configurations, the hetero rings are cis-connected,
where in the cis1 conformation C-1 is in the inside, while in
the cis2 conformation C-1 is in the outside position (Fig. 2).19
The conformational equilibria of 1-, 2- and 4-substituted
saturated 1,3-oxazino[4,3-a]-,11 1,2,3-oxathiazino[4,3-a]-20
and 1,3,2-oxazaphosphorino [4,3-a]isoquinolines21 and
1,3,2-diazaphosphorino[6,1-a]isoquinolines15 have been
thoroughly studied, but fewer data are available on the
analogous hexahydropyrimido[6,1-a]isoquinolines. A slight
predominance of the conformer with trans-connected B/C
reactions to electron supply or withdrawal, was found to be
considerable higher (DrZ0.94) than that observed for the
ring-chain tautomeric equilibria of the analogous 3-aryl-
hexahydroimidazo[5,1-a]isoquinolines (DrZ0.04).2,10 The
different values of r for the cis-chain (16B#16A) and
trans-chain (16C#16A) equilibria can probably be
rationalized by the different hyperconjugative (anomeric)
effects10 in 16B and 16C, possessing different predominant
B/C ring connections (see Section 2.3). The polarization
along all the single bonds associated with C-4 changes the
extent of the orbital overlaps between the nitrogen lone pairs
and the antibonding orbitals. Because of the dihedral angles
between the interacting orbitals (nNKs*C-ArZK66.9 and
67.9), the hyperconjugative effect is higher in 16B,
Table 2. Linear regression data on compounds 16 and 2-aryl-1-isopropylhexahydropyrimidines (17)
Equilibrium
No. of points
Slopea (r)
Intercepta
Correlation coefficient
16A#16B
16A#16C
17A#17Bb
7
5
6
0.36(5)
1.30(9)
0.77(3)
0.57(6)
K0.88(6)
K1.04(4)
0.995
0.982
0.985
a Standard deviations are given in parentheses.
b Data from Ref. 6.

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5291
trans B/C ring junction with an axial aromatic substituent.
The NOESY cross-peaks for the (6R*,11bR*)-6-methyl-
substituted C-4 epimeric model compounds (16aB and
16aC) could be characterized by different B/C ring
junctions: trans for 16aB (NOESY cross-peaks: H-11b-H-
2ax, H-11b-H-4 and H-4-Me-6ax), and equatorial and cis1
for 16aC (NOESY cross-peaks: H-11b–H-2ax, H-4–Me-6ax)
with an axial 4-(p-nitrophenyl) substituent.
The structures of the C-4 epimers of 14a and 16a were
confirmed by molecular modelling. The conformational
protocol comprised a stochastic search, using the Merck
Molecular Force Field (MMFF94). Figure 3 depicts the
typical minimum-energy molecular structures for 14aB and
14aC and for 16aB and 16aC. The steric hindrance between
H-11 and the 1-methyl group (for 14aB), or between the
6-methyl and 4-(p-nitrophenyl) groups (for 16aC), makes
the predominant conformation with trans-arranged B/C
rings unfavourable and shifts the conformational equili-
brium towards the cis1 structure.
Figure 2. Possible steric structures of 1,3,4,6,7,11b-hexahydro-2H-
pyrimido[6,1-a]isoquinolines.
rings was found for the conformational equilibrium of the
3-methyl-substituted parent compound in CDCl3.22
Conformational analysis of the prepared hexahydropyri-
mido[6,1-a]isoquinolines was performed only for the 4-(p-
nitrophenyl)-substituted derivatives, which contain the
cyclic tautomers in the highest proportions. To determine
the mode of connection of the B/C rings 1H NMR
spectroscopic methods were used, since the geometries of
the B/C ring connections of cis1 or cis2 or trans type produce
different patterns of cross-peaks derived from the 1,3-
diaxial protons in the NOESY spectra. While the stereo-
structure of the major cyclic forms (B) of the prepared
model compounds could be determined in each case (12a–
14a and 16a), the relatively low abundance of the minor
cyclic form (C) meant that its conformational analysis could
be performed only for 14a.
3. Conclusions
Both the ring-chain tautomeric and conformational equili-
bria of 4-aryl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-
pyrimido[6,1-a]isoquinolines proved to be sensitive to the
effects of the methyl substituents at position 1 or 6 and the
configurations of the substituted carbons (C-1 or C-6
and C-4) relative to C-11b. For the 1,6-unsubstituted parent
compound 12, NMR spectroscopic investigations revealed
the predominance of the ring form B (cis H-4 and H-11b)
with a trans B/C anellated conformation in CDCl3 at 300 K.
(1R*,11bR*)-1-Methyl substitution (14) caused changes in
the ratios of the C-4 epimeric ring-closed tautomers (B and
C). 6-Methyl substitution resulted in dramatic decreases in
the ratios of the ring-closed forms, leading either to a total
shift of the equilibrium towards the open forms (A) for
the 6S*,11bR* isomers (15) or to the existence of three-
component tautomeric equilibria for the 6R*,11bR*
compounds (16), which could be characterized by a
For 12aB and 13aB, the NOESY spectra showed H-11b–H-
6ax, H-11b–H-4, and H-4–H-6ax NOE cross-peaks, which
are typical for a B/C trans-arranged ring junction with an
equatorial aromatic substituent. For 14aB, however, the
NOESY spectrum revealed H-1–H-6ax, H-11b–H-2ax and
H-11b–H-4 NOE cross-peaks, which unequivocally proved
the cis1 connection of the B/C rings. For 14aC, the NOESY
cross-peaks for H-11b with H-2ax, H-6ax and the ortho
protons of the 4-(p-nitrophenyl) substituents pointed to a
Figure 3. Typical minimum-energy structures for 14aB and 14aC and for 16aB and 16aC.

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5292
Hammett-type equation. For 14a and 16a, steric hindrance
between the substituents resulted in different predominant
conformations (cis1 for 14aB and 16aC; trans for 14aC and
16aB) for the C-4 epimeric ring forms (B and C).
NH), 6.66–6.71 (2H, m, C6H3), 6.77 (1H, d, JZ8.2 Hz,
C6H3), 7.28–7.38 (5H, m, C6H5); MS m/z 400 [MC1]C.
4.1.2. 1-[20-(Benzyloxycarbonylamino)ethyl]-3-methyl-
6,7-dimethoxy-3,4-dihydroisoquinoline (6). To a stirred
solution of the propanamide (2, 16.02 g, 0.04 mol) in dry
CHCl3 (300 mL), POCl3 (18.40 g, 0.12 mol) was added.
The mixture was heated under reflux for 3 h, and then
evaporated in vacuo. The oily residue was dissolved in
water (250 mL) under gentle warming, and the solution was
cooled and extracted with EtOAc (2!75 mL). The aqueous
phase was made alkaline with 25% NaOH solution with
cooling, and extracted with CHCl3 (4!150 mL). The com-
bined organic extracts were dried (Na2SO4) and evaporated
to give a crystalline product, which was filtered off and
washed with Et2O. This crude product was used in the next
step without further purification.
4. Experimental
4.1. General
1
The H NMR spectra were recorded in CDCl3 or in D2O
solutions at 300 K on a Bruker AVANCE DRX 400
spectrometer at 400.13 MHz (1H NMR) and at
100.03 MHz (13C NMR). Chemical shifts are given in d
(ppm) relative to TMS (CDCl3) or to DSS (D2O) as internal
standards; multiplicites were recorded as s (singlet), bs
(broad singlet), d (doublet), dd (double doublet), ddd
(double double doublet), dt (double triplet), t (triplet), q
(quartet) and m (multiplet). In the cases of 12–16, the
solutions were left to stand at ambient temperature for 1 day
Compound 6. Yield: 11.98 g (78%). An analytical sample
of 6 was recrystallized from MeOH to give beige needles,
mp 128–130 8C; [found: C, 68.91; H, 6.87; N, 7.48.
C22H26N2O4 requires C, 69.09; H, 6.85; N, 7.32%]; nmax
1
for the equilibria to be established before the H NMR
1
3192, 2956, 1701, 1517, 1280 cmK1; H NMR d (CDCl3)
spectra were run. IR spectra were run in KBr discs on a
Perkin–Elmer Paragon 1000 PC FT-IR spectrometer con-
trolled by GRAMS Analyst for PE 1000 3.01A software.
Mass spectra were recorded on a Finnigan MAT 95S
instrument, using electron impact ionization. Melting points
were recorded on a Kofler hot-plate microscope apparatus
and are uncorrected.
1.33 (3H, d, JZ6.8 Hz, CH3), 2.38 (1H, dd, JZ15.6,
12.3 Hz, 4-CH2), 2.65 (1H, dd, JZ15.6, 5.4 Hz, 4-CH2),
2.77–2.96 (2H, m, 10-CH2), 3.49–3.67 (3H, m, 3-CH, 20-
CH2), 3.91 (6H, s, 2!OCH3), 5.09 (2H, s, OCH2), 5.70 (1H,
bs, NH), 6.66 (1H, s, C6H2), 7.01 (1H, s, C6H2), 7.27–7.38
(5H, m, C6H5); MS m/z 382 [MC1]C.
Compounds 2a–c,14,15 423 and 1017 were prepared accord-
ing to known procedures.
4.1.3. (1R*,3S*)-1-[20-(Benzyloxycarbonylamino)ethyl]-
3-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
(7a). To a stirred and ice-cooled solution of dihydroiso-
quinoline 6 (11.47 g, 30 mmol) in MeOH (250 mL), NaBH4
(3.40 g, 90 mmol) was added in small portions. The
resulting mixture was stirred for 3 h with ice-water bath
cooling and for 3 h without, and then evaporated in vacuo.
The residue was dissolved in 5% HCl (250 mL), and the
solution was made alkaline with 20% NaOH while cooled,
and then extracted with CHCl3 (4!150 mL). The combined
organic extracts were dried (Na2SO4) and evaporated in
vacuo to give an oily product, containing diastereomers 7a
and 7b in a 12:1 ratio. The oil crystallized on treatment with
n-hexane. The crystalline product, which was filtered off
and washed with n-hexane, proved to be diastereomerically
pure 7a. The crude crystalline product was used in the next
step without further purification.
4.1.1. 3-Benzyloxycarbonylamino-N-[1-methyl-2-(3,4-
dimethoxyphenyl)ethyl]propanamide (5). To a stirred
and ice-salt bath-cooled solution of N-benzyloxycarbonyl-
b-alanine (11.16 g, 0.05 mol) and triethylamine (5.06 g,
0.05 mol) in anhydrous toluene (150 mL), ethyl chloroform-
ate (5.43 g, 0.05 mol) was added dropwise at a rate low
enough to keep the internal temperature below K10 8C.
After 5 min, a solution of 1-methyl-2-(3,4-dimethoxy-
phenyl)ethylamine (4) (9.76 g, 0.05 mol) in CH2Cl2
(60 mL) was added dropwise, the internal temperature
being kept below 0 8C. When the addition was complete, the
reaction mixture was heated under reflux for 5 min. The
mixture was allowed to cool down to room temperature and
CHCl3 (300 mL) was added. The mixture was next washed
with saturated NaHCO3 solution (3!75 mL) and water
(2!75 mL), and then dried (Na2SO4), and the solvent was
removed in vacuo to give a crude oily (2) product, which
crystallized on treatment with Et2O. The crystals were
filtered off, washed with Et2O and recrystallized from
EtOAc.
Compound 7a. Yield: 9.46 g (82%). An analytical sample of
7a was recrystallized from Et2O to give a white solid, mp
69–72 8C; [found: C, 67.80; H, 6.97; N, 7.59. C22H28N2O4
requires C, 68.73; H, 7.34; N, 7.29%]; nmax 3346, 1687,
1
1532, 1247, 1094 cmK1; H NMR d (CDCl3) 1.19 (3H, d,
JZ6.0 Hz, CH3), 1.82–1.92 (1H, m, 10-CH2), 2.04–2.14
(1H, m, 10-CH2), 2.45 (1H, dd, JZ15.5, 10.7 Hz, 4-CH2),
2.56 (1H, dd, JZ15.5, 2.9 Hz, 4-CH2), 2.85–2.95 (1H, m,
20-CH2), 3.26–3.35 (2H, m, 3-CH, 20-CH2), 3.80 (6H, s, 2!
OCH3), 4.13–4.19 (1H, m, 1-CH), 5.05 (2H, s, OCH2), 6.13
(1H, bs, NH), 6.52 (1H, s, C6H2), 6.61 (1H, s, C6H2), 7.23–
7.35 (5H, m, C6H5); MS m/z 384 [MC1]C.
Compound 5. A white solid; yield: 16.75 g (84%); mp 107–
108 8C; [found: C, 65.76; H, 6.98; N, 7.05. C22H28N2O5
requires C, 65.98; H, 7.05; N, 6.99%]; nmax 3335, 1690,
1
1636, 1542, 1262 cmK1; H NMR d (CDCl3) 1.10 (3H, d,
JZ6.6 Hz, CH3), 2.28–2.41 (2H, m, COCH2), 2.60 (1H, dd,
JZ13.6, 7.4 Hz, ArCH2), 2.76 (1H, dd, JZ13.6, 5.9 Hz,
ArCH2), 3.44 (2H, q, JZ6.0 Hz, NCH2), 3.83 (3H, s,
OCH3), 3.85 (3H, s, OCH3), 4.15–4.27 (m, 1H, NCH), 5.09
(2H, s, OCH2), 5.38 (1H, bs, NH), 5.45 (1H, d, JZ6.8 Hz,
4.1.4.
dimethoxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide
(1R*,3S*)-1-(20-Aminoethyl)-3-methyl-6,7-

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5293
(8$2HBr). A mixture of compound 7a (7.69 g, 20 mmol)
and 33% HBr in AcOH (25 mL) was heated gently in a flask
equipped with a CaCl2 tube, with occasional shaking, until
all of the substance had dissolved. The bubbling solution
was left to stand at ambient temperature for 30 min, and
Et2O (25 mL) was then added. The yellow crystals of the
dihydrobromide of 8 which formed were filtered off, washed
with a mixture of MeOH and Et2O, dried and recrystallized
from 90% MeOH–Et2O.
temperature for 1 h. The solvent was then evaporated off
and the oily product crystallized on treatment with Et2O or
n-hexane. The crystalline products (12a,b, 13a,b, 14a,b,
15a,b and 16a,c,d,e,g) were filtered off and recrystallized.
In the cases of 16b and 16f, the evaporation was repeated
after the addition of toluene (10 mL), and the oily products
(obtained in nearly quantitative yields) were dried in a
vacuum desiccator for 24 h. The NMR spectrum proved that
the purity of these compounds was O95%.
Compound 8$2HBr. White crystals; yield: 6.10 g (74%); mp
250–252 8C; [found: C, 40.97; H, 5.76, N, 6.89.
C14H24Br2N2O2 requires C, 40.80, H, 5.87; N, 6.80%];
nmax 3410, 1613, 1522, 1256, 1009 cmK1; 1H NMR d (D2O)
1.57 (3H, d, JZ6.6 Hz, CH3), 2.48–2.72 (2H, m, 10-CH2),
2.96–3.10 (2H, m, 4-CH2), 3.20–3.37 (2H, m, 20-CH2),
3.57–3.68 (1H, m, 3-CH), 3.90 (3H, s, OCH3), 3.93 (3H, s,
OCH3), 4.81–4.85 (1H, m, 1-CH), 6.94 (1H, s, C6H2), 6.96
(1H, s, C6H2); MS m/z 250 [MC1]C.
In consequence of the small relative concentrations, only the
characteristic N–CHAr–N and N]CHAr protons are listed
for the detectable minor tautomericforms of12a,b, 13a,b, 14b
and 15a,b; a full NMR characterization is given for 12aB,
13aB, 14aB, 14aC and 15aA. Withregardtothe similarities in
1
the H NMR data for 16a–g, the full spectra of the major
tautomers are described only for two representatives of this set
of compounds (16aB and 16gA). The protons of the open form
(A) are numbered according to the corresponding protons of
the 1,3,4,6,7,11b-hexahydro-2H-[6,1-a]isoquinoline ring
forms (B and C).
4.1.5.
(1R*,3R*)-l-(20-Aminoethyl)-3-methyl-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride
(11$2HCl). To a stirred and cooled suspension of LiAlH4
(3.42 g, 90 mmol) in dry THF (120 mL), (1R*,3R*)-6,7-
dimethoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline-1-aceta-
mide (10)17 (7.93 g, 30 mmol) was added in small portions. The
mixture was stirred and refluxed for 4 h and then cooled, and the
excess of LiAlH4 was decomposed by the addition of a mixture
of water (6.8 mL) and THF (30 mL). The inorganic salts were
filteredoff andwashedwithEtOAc(3!50 mL). The combined
organic filtrate and washings were dried (Na2SO4) and
evaporated under reduced pressure to give an oily product,
which was converted to the crystalline dihydrochloride of 11 by
treatment of its solution in MeOH with an excess of 22%
ethanolic HCl and Et2O. The crystalline dihydrochloride of 11
was filtered off, dried and recrystallized from MeOH–H2O–
Et2O.
4.2.1. Compound 12a. Beige crystals; yield: 0.83 g (75%);
mp: 150–151 8C (iPr2O–EtOAc); [found: C, 65.25; H, 6.13;
N, 11.48. C20H23N3O4 requires C, 65.03; H, 6.28; N,
11.37%]; nmax 2910, 1520, 1224, 1099, 745 cmK1 1H
;
NMR d (CDCl3) 1.77 (1H, dd, JZ4.3, 12.6 Hz, H-1), 2.18–
2.30 (2H, m, H-1, H-6), 2.54 (1H, dt, JZ3.8, 16.1 Hz, H-7),
2.66–2.74 (1H, m, H-6), 2.88 (1H, dd, JZ2.8, 16.1 Hz, H-7),
3.37 (1H, ddd, JZ1.3, 4.0, 13.4 Hz, H-2), 3.70 (1H, d, JZ
10.6 Hz, H-11b), 3.86 (3H, s, OCH3), 3.87 (3H, s, OCH3),
4.40 (1H, s, H-4), 6.58 (1H, s, H-8), 6.71 (1H, s, H-11),
7.68–7.74 (2H, m, Ar), 8.22–8.26 (2H, m, Ar), 13C NMR d
(CDCl3) 29.5, 32.4, 46.4, 46.6, 56.6, 56.8, 62.8, 81.1, 108.8,
112.2, 124.7, 127.4, 128.9, 130.6, 148.4 (3!), 149.9
(tautomeric form B); 4.92 (1H, s, 4-H) (tautomeric form
C); MS m/z 369 [MC1]C.
Compound 11$2HCl. A white solid, yield: 4.37 g (45%); mp
240–245 8C; [found: C, 51.97; H, 7.56, N, 8.74.
C14H24Cl2N2O2 requires C, 52.02, H, 7.48; N, 8.67%]; nmax
3157, 1618, 1521, 1259, 1117 cmK1; 1H NMR d (D2O) 1.54
(3H, d, JZ6.3 Hz, CH3), 2.43–2.49 (2H, m, 10-CH2), 2.88
(1H, dd, JZ10.0, 17.5 Hz, 4-CH2), 3.24–3.35 (3H, m, 20-CH2,
4-CH2), 3.90 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.94–3.98
(1H, m, 3-CH), 4.75 (1H, t, JZ6.5 Hz, 1-CH), 6.90 (1H, s,
C6H2), 6.97 (1H, s, C6H2); MS m/z 250 [MC1]C.
4.2.2. Compound 12b. Beige crystals; yield: 0.62 g (56%);
mp: 100–103 8C (iPr2O); [found: C, 72.21; H, 8.02; N,
11.31. C22H29N3O2 requires C, 71.90; H, 7.95; N, 11.43%];
nmax 2938, 1610, 1517, 1253, 820 cmK1 1H NMR d
;
(CDCl3) 4.15 (N–CHAr–N) (tautomeric form B); MS m/z
367 [MC1]C.
4.2.3. Compound 13a. Orange-yellow crystals; yield:
0.49 g (43%); mp: 86–90 8C (n-hexane); [found: C, 66.02;
H, 6.45; N, 10.88. C21H25N3O4 requires C, 65.78; H, 6.57;
1
N, 10.96%]; nmax 2964, 1519, 1343, 1133, 861 cmK1; H
Pure diamine bases 8 and 11 were obtained from the above
dihydrohalides by alkaline treatment (20% NaOH), extrac-
tion (CH2Cl2) and evaporation under reduced pressure. The
free bases were dried in a vacuum desiccator for 24 h before
further transformations.
NMR d (CDCl3) 1.02 (3H, d, JZ6.8 Hz, CH3), 2.12 (1H,
ddd, JZ3.3, 11.8 Hz, H-6), 2.31–2.43 (2H, m, H-1, H-7),
2.54–2.61 (1H, m, H-6), 2.83–2.93 (1H, m, H-7), 3.10 (1H,
dd, JZ1.3, 13.6 Hz, H-2), 3.28 (1H, dd, JZ3.3, 13.6 Hz,
H-2), 3.72 (1H, s, H-11b), 3.86 (3H, s, OCH3), 3.87 (3H, s,
OCH3), 4.22 (1H, s, H-4), 6.56 (1H, s, H-8), 6.69 (1H, s,
H-11), 7.68–7.74 (2H, m, Ar), 8.22–8.28 (2H, m, Ar), 13C
NMR d (CDCl3) 12.6, 29.5, 32.7, 48.3, 52.5, 56.5, 56.8,
66.4, 82.1, 108.4, 112.0, 124.8, 128.7, 129.3, 148.0 (2!),
148.5, 150.6 (tautomeric form B); 4.87 (H-4) (tautomeric
form C); MS m/z 383 [MC1]C.
4.2. General procedure for the preparation of 4-Aryl-
9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-
pyrimido[6,1-a]isoquinolines (12–16)
To a solution of the corresponding tetrahydroisoquinoline
diamine (2a–c, 8 and 11) (3 mmol) in absolute MeOH
(25 mL), an equivalent amount of aromatic aldehyde was
added (for liquid aldehydes, a freshly distilled sample was
used), and the mixture was allowed to stand at ambient
4.2.4. Compound 13b. Pale-yellow crystals; yield: 0.80 g
(70%); mp: 129–131 8C (n-hexane); [found: C, 72.26; H,

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5294
1
8.30; N, 10.89. C23H31N3O2 requires C, 72.41; H, 8.19; N,
11.01%]; nmax 2904, 1611, 1249, 1131, 820 cmK1; 1H NMR
d (CDCl3) 4.00 (N–CHAr–N) (tautomeric form B); MS m/z
381 [MC1]C.
(tautomeric form A); H NMR d (CDCl3) 0.86 (3H, d, JZ
6.6 Hz, CH3), 1.70 (1H, ddd, JZ4.5, 12.8 Hz, H-1), 2.22
(1H, d, JZ15.6 Hz, H-7), 2.30–2.37 (1H, m, H-1), 2.89–
2.93 (1H, m, H-6), 3.02 (1H, ddd, JZ2.8, 13.4 Hz, H-2),
3.10 (1H, dd, JZ5.5, 15.6 Hz, H-7), 3.32 (1H, ddd, JZ1.5,
4.0, 13.4 Hz, H-2), 3.84–3.87 (7H, m, H-11b, 2!OCH3),
4.50 (1H, s, H-4), 6.55 (1H, s, H-8), 6.71 (1H, s, H-11),
7.65–7.71 (2H, m, Ar), 8.22–8.28 (2H, m, Ar) 13C NMR d
(CDCl3) 10.0, 34.2, 36.1, 45.3, 48.0, 55.5, 56.2, 56.4, 78.6,
108.2, 112.5, 124.6 (2!), 125.7, 129.0, 147.6, 149.6 (3!)
(tautomeric form B); 1H NMR d (CDCl3) 5.24, 13C NMR d
(CDCl3) 69.6 (tautomeric form C); MS m/z 383 [MC1]C.
4.2.5. Compound 14a. Yellow crystals; yield: 0.75 g
(65%); mp: 147–149 8C (EtOH); [found: C, 65.50; H,
6.38; N, 10.73. C21H25N3O4 requires C, 65.78; H, 6.57; N,
10.96%]; nmax 2910, 1513, 1350, 1123, 834 cmK1; 1H NMR
d (CDCl3) 0.99 (3H, d, JZ6.3 Hz, CH3), 1.99–2.13 (2H, m,
H-1), 2.37 (1H, dd, JZ7.3, 11.3 Hz, H-2), 2.64 (1H, dd, JZ
4.0, 16.1 Hz, H-7), 2.75–2.98 (2H, m, H-2, H-7), 3.06 (1H,
ddd, JZ4.3, 11.3 Hz, H-6), 3.36 (1H, dd, JZ4.3, 13.1 Hz,
H-2), 3.77–3.81 (1H, m, H-11b), 3.85 (3H, s, OCH3), 3.86
(3H, s, OCH3), 5.12 (1H, s, H-4), 6.62 (2H, s, H-8, H-11),
7.72–7.78 (2H, m, Ar), 8.17–8.24 (2H, m, Ar), 13C NMR d
(CDCl3) 17.4, 29.2, 29.8, 36.7, 54.9, 56.2 (2!), 67.2, 78.0,
112.1, 112.5, 123.8, 127.1, 128.4, 129.2, 146.5, 148.2 (3!)
4.2.10. Compound 16b. An orange foam; [found: C, 60.72;
H, 5.89; N, 6.78. C21H25BrN2O2 requires C, 60.44; H, 6.04;
N, 6.71%]; nmax 2829, 1508, 1250, 1018, 779 cmK1; H
1
NMR d (CDCl3) 8.21 (N]CHAr) (tautomeric form A); 4.27
(N–CHAr–N) (tautomeric form B); 4.99 (N–CHAr–N)
(tautomeric form C); MS m/z 416 [MC1]C.
1
(tautomeric form B); H NMR d (CDCl3) 0.85 (3H, d, JZ
6.6 Hz, CH3), 1.99–2.13 (1H, m, H-1), 2.50 (1H, dd, JZ
10.3, 13.9 Hz, H-6), 2.75–2.98 (3H, m, H-2, H-6, H-7),
3.08–3.16 (1H, m, H-7), 3.49 (1H, d, JZ9.6 Hz, H-11b),
3.60 (1H, ddd, JZ4.8, 10.8 Hz, H-2), 3.79 (3H, s, OCH3),
3.88 (3H, s, OCH3), 4.89 (1H, s, H-4), 6.46 (2H, s, H-8),
6.67 (2H, s, H-11), 7.92–7.98 (2H, m, Ar), 8.17–8.24 (2H,
m, Ar), 13C NMR d (CDCl3) 17.5, 28.9, 30.3, 45.7, 48.6,
56.4, 56.5, 59.7, 76.0, 112.1, 112.2, 124.0, 127.0, 128.7,
129.3, 147.8, 148.2, 148.4, 148.9 (tautomeric form C); MS
m/z 383 [MC1]C.
4.2.11. Compound 16c. A pale-yellow solid; yield: 0.90 g
(72%); mp: 113–116 8C (n-hexane–EtOAc); [found: C,
60.17; H, 5.89; N, 6.92. C21H25BrN2O2 requires C, 60.44;
H, 6.04; N, 6.71%]; nmax 2945, 1513, 1248, 1002, 737 cmK1
;
1H NMR d (CDCl3) 8.33 (N]CHAr) (tautomeric form A);
4.37 (N-CHAr-N) (tautomeric form B); 5.07 (N–CHAr–N)
(tautomeric form C); MS m/z 416 [MC1]C.
4.2.12. Compound 16d. Yellow crystals; yield: 0.77 g
(76%); mp: 88–91 8C (n-hexane–EtOAc); [found: C, 74.77;
H, 7.52; N, 8.40. C21H26N2O2 requires C, 74.52; H, 7.74; N,
8.28%]; nmax 2921, 1513, 1251, 1108, 794 cmK1; 1H NMR d
(CDCl3) 8.30 (N]CHAr) (tautomeric form A); 4.31 (N–
CHAr–N) (tautomeric form B); 4.97 (N–CHAr–N) (tauto-
meric form C); MS m/z 338 [MC1]C.
4.2.6. Compound 14b. White crystals; yield: 0.49 g (43%);
mp: 123–125 8C (iPr2O); [found: C, 72.08; H, 8.03; N,
10.81. C23H31N3O2 requires C, 72.41; H, 8.19; N, 11.01%];
nmax 2929, 1519, 1225, 1125, 812 cmK1 1H NMR d
;
(CDCl3) 4.99 (N–CHAr–N) (tautomeric form B); 4.70 (N–
CHAr–N) (tautomeric form C); MS m/z 381 [MC1]C.
4.2.13. Compound 16e. Yellow crystals; yield: 0.66 g
(62%); mp: 73–75 8C (n-hexane); [found: C, 75.12; H, 8.20;
N, 7.81. C22H28N2O2 requires C, 74.97; H, 8.01; N, 7.95%];
4.2.7. Compound 15a. A pale-beige solid; yield: 0.72 g
(63%); mp: 108–109 8C (n-hexane–Et2O); [found: C, 65.59;
H, 6.41; N, 11.10. C21H25N3O4 requires C, 65.78; H, 6.57;
nmax 2959, 1514, 1251, 1109, 780 cmK1 1H NMR d
;
1
N, 10.96%]; nmax 2860, 1517, 1350, 1219, 855 cmK1; H
(CDCl3) 8.35 (N]CHAr) (tautomeric form A); 4.37 (N–
CHAr–N) (tautomeric form B); 5.02 (N–CHAr–N) (tauto-
meric form C); MS m/z 352 [MC1]C.
NMR d (CDCl3) 1.24 (3H, d, JZ6.3 Hz, CH3), 2.03–2.14
(1H, m, H-1), 2.36–2.51 (2H, m, H-1, H-7), 2.62 (1H, dd,
JZ3.3, 15.9 Hz, H-7), 2.94–3.05 (1H, m, H-6), 3.75–3.92
(8H, m, 2!H-2, 2!OCH3), 4.27 (1H, d, JZ7.3 Hz, H-11b),
6.55 (1H, s, H-8), 6.71 (1H, s, H-11), 7.84–7.90 (2H, m, Ar),
8.24–8.30 (2H, m, Ar), 8.35 (1H, s, N]CHAr), 13C NMR d
(CDCl3) 23.1, 37.7, 38.4, 49.3, 55.7, 56.2, 56.5, 58.9, 108.9,
112.0, 124.3, 128.5, 129.1, 130.3, 142.0, 147.7, 159.4
(tautomeric form A); MS m/z 383 [MC1]C.
4.2.14. Compound 16f. A yellow oil; [found: C, 72.02; H,
7.51; N, 7.69. C22H28N2O3 requires C, 71.71; H, 7.66; N,
7.60%]; nmax 2936, 1606, 1248, 1032, 833 cmK1; 1H NMR d
(CDCl3) 8.21 (N]CHAr) (tautomeric form A); 4.25 (N–
CHAr–N) (tautomeric form B); MS m/z 368 [MC1]C.
4.2.15. Compound 16g. Yellow crystals; yield: 0.97 g
(85%); mp: 111–114 8C (n-hexane–EtOAc); [found: C,
72.68; H, 8.07; N, 10.86. C23H31N3O2 requires C, 72.41; H,
4.2.8. Compound 15b. A pale-beige solid; yield: 0.66 g
(58%); mp: 69–72 8C (n-hexane-Et2O); [found: C, 72.60; H,
8.27; N, 11.16. C23H31N3O2 requires C, 72.41; H, 8.19; N,
11.01%]; nmax 3581, 2904, 1610, 1219, 817 cmK1; 1H NMR
d (CDCl3) 8.12 (N]CHAr) (tautomeric form A); MS m/z
381 [MC1]C.
8.19; N, 11.01%]; nmax 2835, 1607, 1517, 1224, 1092 cmK1
;
1H NMR d (CDCl3) 1.18 (3H, d, JZ6.3 Hz, CH3), 1.94–
2.05 (1H, m, H-1), 2.08–2.08 (1H, m, H-1), 2.39 (1H, dd,
JZ10.3, 16.2 Hz, H-7), 2.66 (1H, dd, JZ3.8, 16.2 Hz, H-7),
3.01 (6H, s, N(CH3)2), 3.15–3.27 (1H, m, H-6), 3.69–3.79
(1H, m, H-2), 3.81–3.83 (7H, m, H-2, 2!OCH3), 4.11 (1H,
dd, JZ2.8, 10.3 Hz, H-11b), 6.53 (1H, s, H-8), 6.60 (1H, s,
H-11), 6.67–6.72 (2H, m, Ar), 7.69–7.64 (2H, m, Ar), 8.23
(N]CHAr), 13C NMR d (CDCl3) 23.0, 37.6, 38.4, 40.6,
42.9, 55.0, 56.2, 56.4, 60.1, 110.2, 111.9, 112.0, 112.5,
4.2.9. Compound 16a. Pale-yellow crystals; yield: 0.91 g
(79%); mp: 135–139 8C (n-hexane–EtOAc); [found: C,
65.96; H, 6.40; N, 11.09. C21H25N3O4 requires C, 65.78; H,
6.57; N, 10.96%]; nmax 2927, 1512, 1343, 1108, 999 cmK1
;
1H NMR d (CDCl3) 8.46, 13C NMR d (CDCl3) 159.3

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´ ´ ´ ´
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10. Hetenyi, A.; Martinek, T. A.; Lazar, L.; Zalan, Z.; Fu¨lop, F.
124.9, 127.2, 129.8, 131.9, 147.5, 147.6, 152.4, 161.6
(tautomeric form A); 4.29 (N–CHAr–N) (tautomeric form
B); MS m/z 381 [MC1]C.
J. Org. Chem. 2003, 68, 5705–5712.
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11. Heydenreich, M.; Koch, A.; Lazar, L.; Szatmari, I.; Sillanpaa,
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R.; Kleinpeter, E.; Fu¨lop, F. Tetrahedron 2003, 59, 1951–1959
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Acknowledgements
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12. Fu¨lop, F.; Bernath, G.; Pihlaja, K. Adv. Heterocycl. Chem.
1998, 69, 349–477.
The authors’ thanks are due to the Hungarian Research
Foundation (OTKA No. TS 040888 and T049407) for
financial support.
13. Schuster, H.; Kathawala, F. G. Isoquinolines Bearing Basic
Side Chains. In The Chemistry of Heterocyclic Compounds;
Coppola, G. M., Schuster, H. F., Eds.; Isoquinolines; Wiley:
New York, 1995; Vol. 38, pp 2–26; Part 3.
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14. Lazar, L.; Kivela, H.; Pihlaja, K.; Fulop, F. Tetrahedron Lett.
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2004, 45, 6199–6201.
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15. Zalan, Z.; Martinek, T.; Lazar, L.; Fu¨lop, F. Tetrahedron 2003,
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