A convenient synthesis of papaverine analogs via photocyclization of N-acyl-α-dehydroarylalaninamide derivatives

Article abstract of DOI:10.3987/COM-06-10710

Photochemical cyclizations of (Z)-N-(substituted phenylacetyl)-α-dehydro(3,4-dimethoxyphenyl)alaninamides in methanol were found to proceed regioselectively giving papaverine analogs in satisfactory yields, irrespective of the substituent introduced. MM2

Full text of DOI:10.3987/COM-06-10710

HETEROCYCLES, Vol. 68, No. 5, 2006
993
HETEROCYCLES, Vol. 68, No. 5, 2006, pp. 993 - 1006. © The Japan Institute of Heterocyclic Chemistry
Received, 23rd February, 2006, Accepted, 20th March, 2006, Published online, 24th March, 2006. COM-06-10710
A CONVENIENT SYNTHESIS OF PAPAVERINE ANALOGS VIA
PHOTOCYCLIZATION
AMIDE DERIVATIVES
OF
N-ACYL-α-DEHYDROARYLALANIN-
Hideki Hoshina, Kei Maekawa, Kaori Kobayashi, Tetsutaro Igarashi, and
Tadamitsu Sakurai*
Department of Applied Chemistry, Faculty of Engineering, Kanagawa University,
Kanagawa-ku, Yokohama 221-8686, Japan
Abstract–Photochemical cyclizations of (Z)-N-(substituted phenylacetyl)-α-
dehydro(3,4-dimethoxyphenyl)alaninamides in methanol were found to proceed
regioselectively giving papaverine analogs in satisfactory yields, irrespective of the
substituent introduced. MM2 and PM5 calculations revealed that steric hindrance
of the methoxy group introduced at the meta-position on the styryl benzene ring is
responsible for the regioselective photocyclization observed.
Photochemistry has continued to contribute to the development of efficient and selective transformations of
organic materials into pharmaceutically important heterocyclic compounds.1 It is well-known that
numerous biomolecules and natural products contain various types of heterocyclic rings as their principal
constituents. We have been interested in exploring the excited-state reactivities of α-dehydroamino acid
derivatives, one of the main constituents of some antibiotics,2 as well as in demonstrating the synthetic utility
of these photochemical reactions. Taking into account that α-dehydroamino acid-derived products may
possess high biological activities, we embarked on a systematic study regarding photochemical reactivities
of aryl-substituted α-dehydroalanine derivatives and discovered novel photocyclization reactions forming
pharmaceutically useful products.3,4 One of the important findings is that the photocyclization of substituted
(Z)-N-acetyl-α-dehydrophenylalaninamides in methanol and acetonitrile constitutes a useful method for
constructing the isoquinoline skeleton.3 Very recently, we found that the introduction of a methoxy group
at the meta-position on the styryl benzene ring accomplishes regioselective photocyclization to give
6-methoxyisoquinoline derivative in a reasonable yield without forming any 8-methoxy derivative.5 These
findings stimulated us to photochemically synthesize analogs of papaverine, one of the isoquinoline
alkaloids, as an extension of our study on the photocyclization of N-acyl-α- dehydroamino acid derivatives.
A careful literature survey demonstrates that although there are many synthetic routes to papaverine and its
analogs, no convenient photochemical route to these analogs is known.6 Thus, it is of significance to
develop a photochemical method for synthesizing papaverine analogs. To this end we designed and
synthesized (Z)-N-(substituted phenylacetyl)-α-dehydro(3,4-dimethoxyphenyl)alaninamides [(Z)-1a–g],
hoping to establish a new route to analogs of pharmaceutically important papaverine.

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HETEROCYCLES, Vol. 68, No. 5, 2006
3
O
1
2
1
2
O
NHR
O
R
R
O
N
R
N
H
R
3
R NH
2
MeO
MeO
MeO
MeO
(Z)-1a–g
OMe
OMe
N
1a
1b
1c
1d
H
1e
Cl
1f
Cl
H
1g
F
OMe
OMe
1
R :
OMe OMe OMe
OMe OMe
Bu CH Ph Bu
2
R :
H
H
Cl
H
3
R :
Bu
Bu
Bu
Bu
Papaverine
2
Scheme 1
The starting (Z)-isomers were prepared in high yields (>80%) by the ring opening reactions of (Z)-2-
(substituted benzyl)-4-(methoxy-substituted benzylidene)-5(4H)-oxazolones with butylamine [for (Z)-
1a,c–g] or benzylamine [for (Z)-1b] in the presence of triethylamine (Scheme 1).7 The synthesis of these
oxazolones was achieved by the Knoevenagel-type condensation and ring closure reactions between
methoxy-substituted benzaldehydes and N-(substituted phenylacetyl)glycines,7 though their yields were not
so high (20–27%). After a nitrogen purged methanol solution of (Z)-1a (1.0×10–3 mol dm–3) was
irradiated with Pyrex-filtered light (>280 nm) from a 400 W high pressure Hg lamp for 360 min at room
temperature, the product mixture obtained was subjected to column or preparative thin layer chromatography
over silica gel (ethyl acetate-chloroform), which allowed us to isolate papaverine analog (2a, 46%) as shown
in Scheme 2. In addition, (E)-1a could be isolated in 33% yield from the mixture obtained by the 60 min
irradiation of the same solution. The structures of (E)-1a and 2a were determined based on their
1
spectroscopic and physical properties. A H NMR spectral analysis of the product mixture showed that
there is formation of trans-1-azetine [trans-3a; δ= 4.37 and 5.45 ppm, J= 6.7 Hz (azetine ring-proton
signals)] and cis-3a [δ= 4.82 and 5.69 ppm, J= 10.4 Hz (azetine ring-proton signals)], as predicted from the
previous studies (Scheme 2).3 However, any attempts to isolate these azetine derivatives were unsuccessful,
probably because of the much lower stability of 3a as compared to that of 1-azetines previously isolated.
O
NHBu
O
N
MeO
MeO
NHBu
N
h!
MeO
MeO
(Z)-1a
(E)-1a
OMe
MeO
OMe
OMe
2a
3a (trans and cis)
Scheme 2
Since the photocyclization of (Z)-1a accompanies side reactions to some extent, the sum of composition for

HETEROCYCLES, Vol. 68, No. 5, 2006
995
(Z)-1a, (E)-1a, 2a, and 3a was regarded as 100% for estimating the compositions of these compounds
1
based on the area ratio of given H NMR signals (Table 1). The photocyclization of (Z)-1a in methanol
gave the same product distribution as that derived from the cyclization of substituted N-acetyl-α-
dehydrophenylalaninamides, thus allowing us to discuss the rate of the isomerization relative to the rate of
the cyclization on the basis of the same reaction scheme as that previously proposed (Scheme 3).3 The
result obtained for (Z)-1a demonstrates the rapid production of (E)-1a and the subsequent increase in a
composition for 2a and 3a with the decrease of (Z)- and (E)-isomer compositions. In addition, the use of
(E)-1a (1.0×10–3 mol dm–3) as the starting isomer gave almost the same isomer composition as that derived
from (Z)-1a at the early stage of the reaction (Table 1), confirming that the rate of the photoisomerization
(Path A in Scheme 3) is much faster than that of the subsequent photocyclization process (Path B). The
Table 1. Relation between irradiation time and composition (%) of each
compound obtained by the irradiation of (Z)-1a and (E)-1a in methanol
Irradiation time (min)
Compound
0
30
60
90
120
240
360
3.5
38.6
(38.0)a)
53.5
36.2
34.1
18.4
(Z)-1a
(E)-1a
2a
100
(0)a) (38.9)a)
39.6
50.2
8.0
46.4
12.5
4.4
25.9
38.0
12.0
5.7
4.3
63.9
19.6
8.7
0
57.3
(54.5)a)
(100)a) (58.0)a)
1.8
(0)a) (1.5)a)
0.8
(0)a) (1.0)a)
0.5
(0)a) (0.6)a)
4.6
0
(4.0)a)
2.0
(2.0)a)
3.2
trans-3a
cis-3a
0
1.3
(1.5)a)
2.4
2.6
0
a) Composition obtained by the irradiation of (E)-1a.
data in Table 1 also show that selectivity for 2a [defined as the product-composition ratio, namely, 2/(2 + 3)]
is in the range of 60–70% and comparable to that (69%) for isoquinoline derivative generated by the
irradiation of N-acetyl-α-dehydro(4-methoxyphenyl)alaninamide in methanol.3 This finding strongly
suggests that the methoxy-substituted phenylacetyl carbonyl in the excited-state (Z)- and (E)-isomers
1
possesses the reactivity comparable to that of the acetyl carbonyl. A careful analysis of the H NMR
spectrum recorded after 360 min irradiation revealed negligible formation of 7,8-dimethoxyisoquinoline
derivative. In order to confirm whether the methoxy group introduced at the 3-position on the styryl benzene
ring exerts a large steric effect on the cyclization proceeding at the 2-position, conformational energy of the
(Z)-isomer was minimized by MM2 and PM5 calculations (Figure 1).8 An examination of the energy-
minimized conformation revealed that the 3-methoxy methyl group is directed toward the hydrogen atom
attached to the 2-position and, hence, the cyclization process taking place at this position experiences a

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HETEROCYCLES, Vol. 68, No. 5, 2006
3
3
CONHR
CONHR
N
H
NH
O
h!
1) H shift
Cyclization
(Z)-1a–g
(Z)-1a–g*
H
Path B
2) –H O
2
MeO
MeO
OMe
OMe
2
2
Path A
R
R
1
1
R
R
1
2
1
2
R
R
R
R
2a–g
Path A
H
N
O
N
3
3
CONHR
CONHR
h!
1) H abstraction
Cyclization
Path B
H
(E)-1a–g
(E)-1a–g*
2) –H O
2
MeO
MeO
OMe
OMe
( 3a–g )
Scheme 3
great steric hindrance of the methoxy group. Therefore, we were led to conclude that the 3-methoxy
substituent plays a decisive role in constructing the papaverine skeleton.
!
!
!
!
!
!
!
!
!
Table 2. Relation between irradiation time and
composition (%) of each compound obtained by
the irradiation of (Z)-1a in acetonitrile
"
#
!
"
!
Irradiation time (min)
Compound
!
#
!
!
!
1
0
30
60
90
120
!
!
6
!
2
100 69.7 66.0 62.5 57.3
0 30.3 32.0 33.4 35.2
!
(Z)-1a
(E)-1a
2a
"
!
!
!
!
3
"
5
!
!
!
0
0
0
0
0
0
2.0
0
3.5
0.6
0
6.3
1.2
0
"
4
"
!
trans-3a
cis-3a
!
!
!
!
0
!
Figure 1. Energy-minimized
conformation of (Z)-1a.
In Table 2 are shown solvent effects on the photoreactivity of 1a and the product composition. A
comparison of the data given in Tables 1 and 2 clearly indicates that the use of aprotic polar solvent,
acetonitrile, lowers the reactivity of each isomer in the excited state whereas the (Z)-isomer composition is
increased by a factor of about 2 at photostationary state in this solvent. It was previously found that
methanol is able to form a hydrogen bond to the amide carbonyl oxygen of N-acetyl-α-

HETEROCYCLES, Vol. 68, No. 5, 2006
997
dehydronaphthylalaninamide derivative in the ground and excited states.4 In addition to the fact that
methanol and acetonitrile have comparable polarities,9 this finding allowed us to propose that hydrogen-
bonding solvation of (Z)- and (E)-isomers in the excited state greatly affects not only the relative rate for
the isomerization but also the rate for the cyclization from a given isomer. Interestingly, the change in solvent
from methanol to acetonitrile resulted in an increase of the selectivity for 2a (64→84% at 120 min
irradiation) with a decrease of that for 3a (36→16%). However, on prolonged irradiation (>240 min) in
acetonitrile side reactions took place to an appreciable extent, making methanol better solvent for the reaction.
Table 3. Substituent effects on the composition of each compound obtained by the
irradiation of (Z)-1a in methanol and the selectivity of 2a
Composition (%)
Irradiation
time (min)
Selectivity
Compound
2
3a)
of 2 (%)
(Z)-1
(E)-1
1a
1b
1c
1d
1e
1f
60
360
60
38.6
3.5
53.5
4.3
4.6
63.9 (46)b)
2.6
3.3
28.3
2.0
69
67
70
66
81
68
75
39.9
4.3
55.5
5.7
360
60
60.7 (45)b)
29.3
3.1
36.7
0.7
55.0
0.9
5.2
68.6 (43)b)
3.7
240
60
29.8
3.3
36.9
3.0
56.1
4.0
360
60
61.5 (48)b)
31.5
1.7
34.8
2.7
59.7
3.6
3.8
75.6 (50)b)
2.9
360
60
18.1
1.0
36.5
3.2
59.6
4.2
360
60
62.6 (42)b)
30.0
1.9
1g
36.1
2.5
57.8
3.7
4.2
70.4 (46)b)
360
23.4
a) The sum of cis- and trans-isomers. b) Isolated yield (%).
In order to shed light on the scope and limitations of the photoinduced cyclization of (Z)-1a that provides a
new route to papaverine analog (2a), we investigated substituent effects on the composition of each
compound obtained at a given irradiation time. As demonstrated in Table 3, both the conversion of 1a
and the selectivity of 2a were only sightly affected by the replacement of two methoxy groups on the
benzene ring of the phenylacetyl moiety (R1 and R2) by two chlorine atoms (1e), as well as by the
introduction of benzyl group (R3) instead of butyl one (1b). A comparison of the data for 1c (R1= OMe,
R2= H, R3= Bu), 1d (R1= R2= H, R3= Bu), 1f (R1= Cl, R2= H, R3= Bu), and 1g (R1= F, R2= H, R3= Bu)
confirmed that the electron-donating methoxy group has a clear tendency to increase the conversion of 1 at
a given irradiation time. It is likely that the methoxy group as substituent R1 (1c) results in an
enhancement in the reactivity of the phenylacetyl carbonyl in the excited state (Scheme 3). Thus, the
observed substituent effects allow us to predict that the regioselective photocyclization of (Z)-1 would be

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HETEROCYCLES, Vol. 68, No. 5, 2006
applicable to the synthesis of various kinds of papaverine analogs.
The procedure for preparing the starting α-dehydroamino acids [(Z)-1] is very simple and easily applicable
to its related compounds. In addition, column chromatography on silica gel enables rapid separation of 2,
the Rf value of which is much larger than that of (Z)-1, (E)-1, and 3. The photocyclization of
(Z)-N-(substituted phenylacetyl)-α-dehydro(3,4-dimethoxy)phenylalaninamides described above, therefore,
provides a new synthetic route to papaverine analogs.
EXPERIMENTAL
General
13
1H and C NMR and IR spectra were taken with a JEOL JNM-A500 spectrometer and a Hitachi 270-30
infrared spectrophotometer, respectively. Chemical shifts were determined using tetramethylsilane as an
internal standard. Methanol and acetonitrile were purified according to the standard procedures9 and
freshly distilled prior to use. All other reagents used were obtained from commercial sources and were of
the highest grade available. MM2 and PM5 calculations were accomplished by using CAChe 5.0 for
Windows available from Fujitsu Ltd, 2002.
General Procedure for the Synthesis of (Z)-2-(Substituted benzyl)-4-(methoxy-substituted
benzylidene)-5(4H)-oxazolones. N-(Substituted phenylacetyl)glycine (0.10 mol), methoxy-substituted
benzaldehyde (0.11 mol) and sodium acetate (8.2 g, 0.10 mol) were added to acetic anhydride (100 mL)
and the resulting mixture was heated at 70–80 °C for 5–10 h with stirring. The mixture was cooled with
ice and then poured into ice-water (200 mL). The solid separated out was collected by filtration with
suction and washed with small amounts of cold ethanol. After the crude product had been air-dried at rt, it
was recrystallized from chloroform–hexane to give yellow crystals (20–27%).
(Z)-2-(3,4-Dimethoxybenzyl)-4-(3,4-dimethoxybenzylidene)-5(4H)-oxazolone: yield 24%; mp 157.0–
158.0 °C; IR (KBr): 1794, 1770, 1650 cm–1; 1H NMR (500 MHz, CDCl3): δ 3.85 (3H, s), 3.87 (3H,s), 3.89
(3H, s), 3.91 (2H, s), 3.93 (3H, s), 6.84 (1H, d, J= 8.3 Hz), 6.88 (1H, d, J= 2.0 Hz), 6.89 (1H, d, J= 8.3 Hz),
6.92 (1H, dd, J= 2.0, 8.3 Hz), 7.10 (1H, s), 7.46 (1H, dd, J= 2.0, 8.3 Hz), 7.97 (1H, d, J= 2.0 Hz), 8.01 (1H,
13
d, J= 2.0 Hz); C NMR (125.7 MHz, CDCl3): δ 35.7, 55.8, 56.0 (3C), 110.8, 111.3, 112.6, 113.9, 121.7,
125.4, 126.5, 127.5, 130.4, 132.3, 148.6, 149.1 (2C), 152.0, 166.2, 168.0.
(Z)-2-Benzyl-4-(3,4-dimethoxybenzylidene)-5(4H)-oxazolone: yield 23%; mp 152.0–153.0 °C; IR (KBr):
1839, 1797, 1650 cm–1; 1H NMR (500 MHz, CDCl3): δ 3.81 (3H, s), 3.93 (3H,s), 3.97 (2H, s), 6.88 (1H, d,
13
J= 8.6 Hz), 7.11 (1H, s), 7.27–7.39 (5H, m), 7.40 (1H, dd, J= 2.0, 8.6 Hz), 8.01 (1H, d, J= 2.0 Hz); C
NMR (125.7 MHz, CDCl3): δ 36.0, 55.8, 56.0, 110.7, 113.8, 126.5, 127.5, 127.6, 128.7 (2C), 129.5 (2C),
130.3, 132.3, 133.1, 149.1, 152.0, 166.0, 167.9.
(Z)-4-(3,4-Dimethoxybenzylidene)-2-(4-methoxybenzyl)-5(4H)-oxazolone: yield 22%; mp 128.0–

HETEROCYCLES, Vol. 68, No. 5, 2006
999
129.0 °C; IR (KBr): 1834, 1796, 1696, 1656 cm–1; 1H NMR (500 MHz, CDCl3): δ 3.80 (3H, s), 3.84 (3H,s),
3.91 (2H, s), 3.93 (3H, s), 6.85–6.90 (3H, m), 7.09 (1H, s), 7.29 (2H, d, J= 8.6 Hz), 7.42 (1H, dd, J= 2.0,
13
8.6 Hz), 8.01 (1H, d, J= 2.0 Hz); C NMR (125.7 MHz, CDCl3): δ 35.2, 55.3, 55.8, 56.0, 110.8, 113.8,
114.1 (2C), 125.0, 126.5, 127.6, 130.4, 130.5 (2C), 132.2, 149.1, 152.0, 159.1, 166.3, 168.0.
(Z)-2-(3,4-Dichlorobenzyl)-4-(3,4-dimethoxybenzylidene)-5(4H)-oxazolone: yield 20%; mp 132.5–
133.5 °C; IR (KBr): 1786, 1651 cm–1; 1H NMR (500 MHz, CDCl3): δ 3.84 (3H, s), 3.94 (2H,s), 3.94 (3H, s),
6.90 (1H, d, J= 8.2 Hz), 7.14 (1H, s), 7.22 (1H, dd, J= 2.1, 8.2 Hz), 7.41 (1H, dd, J= 1.4, 8.2 Hz), 7.44 (1H,
d, J= 8.2 Hz), 7.50 (1H, d, J= 2,1 Hz), 7.96 (1H, d, J= 1.4 Hz); 13C NMR (125.7 MHz, CDCl3): δ 35.0, 55.7,
56.0, 110.8, 113.7, 126.3, 127.9, 128.9, 129.8, 130.6, 131.5, 131.9, 132.8, 133.07, 133.11, 149.2, 152.3,
164.8, 167.5.
(Z)-2-(4-Chlorobenzyl)-4-(3,4-dimethoxybenzylidene)-5(4H)-oxazolone: yield 20%; mp 144.5–
146.0 °C; IR (KBr): 1800, 1650 cm–1; 1H NMR (500 MHz, CDCl3): δ 3.82 (3H, s), 3.94 (2H,s), 3.94 (3H, s),
6.89 (1H, d, J= 8.6 Hz), 7.11 (1H, s), 7.31 (2H, d, J= 8.6 Hz), 7.33 (2H, d, J= 8.6 Hz), 7.41 (1H, d, J= 8.6
Hz), 7.97 (1H, s); 13C NMR (125.7 MHz, CDCl3): δ 35.4, 55.7, 56.0, 110.8, 113.8, 126.4, 127.7, 128.9 (2C),
130.1, 130.9 (2C), 131.6, 132.7, 133.6, 149.2, 152.2, 165.7, 167.7.
(Z)-4-(3,4-Dimethoxybenzylidene)-2-(4-fluorobenzyl)-5(4H)-oxazolone: yield 27%; mp 134.0–135.0 °C;
IR (KBr): 1744, 1653 cm–1; 1H NMR (500 MHz, CDCl3): δ 3.83 (3H, s), 3.94 (3H,s), 3.95 (2H, s), 6.89 (1H,
d, J= 8.3 Hz), 7.04 (2H, dd, J= 8.3, 8.9 Hz), 7.11 (1H, s), 7.34 (2H, dd, J= 5.5, 8.3 Hz), 7.42 (1H, dd, J=
2.1, 8.3 Hz), 7.98 (1H, d, J= 2.1 Hz); 13C NMR (125.7 MHz, CDCl3): δ 35.2, 55.7, 56.0, 110.7, 113.7, 115.6
(2C, d, J= 22 Hz), 126.4, 127.7, 128.7 (1C, d, J= 3 Hz), 130.1, 131.1 (2C, d, J= 9 Hz), 132.5, 149.1, 152.1,
162.4 (1C, d, J= 247 Hz), 165.7, 167.8.
General Procedure for the Synthesis of (Z)-N-Alkyl-3-(methoxy-substituted phenyl)-2-(substituted
phenylacetylamino)-2-propenamides [(Z)-1a–g].
(Z)-2-(Substituted benzyl)-4-(methoxy-substituted
benzylidene)-5(4H)-oxazolone (0.010 mol) was added to dry chloroform (20 mL) containing alkylamine
(0.011 mol) and a small amount of triethylamine and the resulting mixture was refluxed for 2–3 h. The
reaction mixture was concentrated to dryness and the residual solid was dissolved in ethanol (20 mL) and
then treated with activated charcoal powder. After removal of the solvent under reduced pressure, the
crude product obtained was recrystallized from ethanol-hexane affording colorless crystals (80–90%).
(Z)-N-Butyl-3-(3,4-dimethoxyphenyl)-2-(3,4-dimethoxyphenylacetylamino)-2-propenamide [(Z)-1a]:
yield 80%; mp 140.0–141.0 °C; IR (KBr): 3272, 1644, 1620 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 0.87
(3H, t, J= 7.3 Hz), 1.27 (2H, tq, J= 7.3, 7.3 Hz), 1.40 (2H, tt, J= 7.3, 7.3 Hz), 3.11 (2H, dt, J= 5.5, 7.3 Hz),
3.55 (2H, s), 3.64 (3H, s), 3.71 (3H, s), 3.74 (3H, s), 3.75 (3H, s), 6.76 (1H, d, J= 8.5 Hz), 6.84 (1H, dd, J=
1.8, 7.9 Hz), 6.90 (1H, d, J= 7.9 Hz), 6.94 (1H, br s), 6.95 (1H, dd, J= 1.8, 8.5 Hz), 6.97 (1H, s), 7.12 (1H,
13
d, J= 1.8 Hz), 7.71 (1H, t, J= 5.5 Hz), 9.43 (1H, s); C NMR (125.7 MHz, DMSO-d6): δ 13.7, 19.5, 31.2,

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HETEROCYCLES, Vol. 68, No. 5, 2006
38.7, 41.9, 55.2, 55.3 (2C), 55.5, 111.2, 111.8, 113.0, 113.1, 121.2, 122.7, 126.7, 127.7, 128.0, 128.2, 147.6,
148.2, 148.5, 149.1, 164.9, 169.9; Anal. Calcd for C25H32N2O6: C, 65.77; H, 7.06; N, 6.14. Found: C, 65.91;
H, 7.03; N, 6.35.
(Z)-N-Benzyl-3-(3,4-dimethoxyphenyl)-2-(3,4-dimethoxyphenylacetylamino)-2-propenamide [(Z)-1b]:
1
yield 81%; mp 185.0–186.0 °C; IR (KBr): 3316, 3208, 1731, 1653, 1614 cm–1; H NMR (500 MHz,
DMSO-d6): δ 3.35 (2H, s), 3.64 (3H, s), 3.69 (3H, s), 3.74 (3H, s), 3.75 (3H, s), 4.38 (2H, d, J= 6.1 Hz),
6.74 (1H, d, J= 8.6 Hz), 6.84 (1H, dd, J= 1.8, 8.6 Hz), 6.89 (1H, d, J= 8.6 Hz), 6.94 (1H, d, J= 1.8 Hz),
6.96 (1H, dd, J= 1.8, 8.6 Hz), 7.08 (1H, s), 7.13 (1H, d, J= 1.8 Hz), 7.21–7.25 (1H, m), 7.27–7.32 (4H, m),
13
8.44 (1H, t, J= 6.1 Hz), 9.51 (1H, s); C NMR (125.7 MHz, DMSO-d6): δ 41.9, 42.5, 55.28, 55.34 (2C),
55.5, 111.2, 111.7, 113.1, 113.2, 121.3, 122.8, 126.5, 126.6, 127.0 (2C), 127.96, 127.99, 128.1 (2C), 128.5,
139.7, 147.6, 148.2, 148.5, 149.2, 165.2, 170.1; Anal. Calcd for C28H30N2O6: C, 68.56; H, 6.16; N, 5.71.
Found: C, 68.21; H, 6.09; N, 5.62.
(Z)-N-Butyl-3-(3,4-dimethoxyphenyl)-2-(4-methoxyphenylacetylamino)-2-propenamide [(Z)-1c]: yield
80%; mp 161.0–161.5 °C; IR (KBr): 3214, 1650, 1605 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 0.87 (3H, t,
J= 7.3 Hz), 1.27 (2H, tq, J= 7.3, 7.3 Hz), 1.40 (2H, tt, J= 7.3, 7.3 Hz), 3.11 (2H, dt, J= 6.1, 7.3 Hz), 3.56
(2H, s), 3.64 (3H, s), 3.74 (3H, s), 3.75 (3H, s), 6.79 (1H, d, J= 8.6 Hz), 6.89 (2H, d, J= 8.6 Hz), 6.965 (1H,
dd, J= 1.8, 8.6 Hz), 6.969 (1H, s), 7.12 (1H, d, J= 1.8 Hz), 7.24 (2H, d, J= 8.6 Hz), 7.71 (1H, t, J= 6.1 Hz),
13
9.45 (1H, s); C NMR (125.7 MHz, DMSO-d6): δ 13.7, 19.5, 31.2, 38.7, 41.4, 55.0, 55.3, 55.4, 111.3,
112.9, 113.6 (2C), 122.7, 126.7, 127.6, 127.7, 128.2, 130.2 (2C), 148.2, 149.1, 158.0, 164.9, 170.1; Anal.
Calcd for C24H30N2O5: C, 67.59; H, 7.09; N, 6.57. Found: C, 67.69; H, 7.00; N, 6.54.
(Z)-N-Butyl-3-(3,4-dimethoxyphenyl)-2-phenylacetylamino-2-propenamide [(Z)-1d]: yield 90%; mp
1
170.0–171.0 °C; IR (KBr): 3224, 1648, 1604 cm–1; H NMR (500 MHz, DMSO-d6): δ 0.88 (3H, t, J= 7.3
Hz), 1.28 (2H, tq, J= 7.3, 7.3 Hz), 1.41 (2H, tt, J= 6.7, 7.3 Hz), 3.12 (2H, dt, J= 5.5, 6.7 Hz), 3.63 (3H, s),
3.65 (2H, s), 3.76 (3H, s), 6.80 (1H, d, J= 8.5 Hz), 6.97 (1H, s), 6.98 (1H, dd, J= 1.8, 8.5 Hz), 7.13 (1H, d,
13
J= 1.8 Hz), 7.26 (1H, dd, J= 8.5, 8.5 Hz), 7.30–7.33 (4H, m), 7.77 (1H, t, J= 5.5 Hz), 9.53 (1H, s); C
NMR (125.7 MHz, DMSO-d6): δ 13.7, 19.4, 31.2, 38.7, 42.1, 55.2, 55.3, 111.3, 112.8, 122.7, 126.3, 126.6,
127.6, 128.1 (2C), 128.2, 129.2 (2C), 135.6, 148.2, 149.0, 164.8, 169.6; Anal. Calcd for C23H28N2O4: C,
69.68; H, 7.12; N, 7.07. Found: C, 69.95; H, 7.13; N, 6.97.
(Z)-N-Butyl-2-(3,4-dichlorophenylacetylamino)-3-(3,4-dimethoxyphenyl)-2-propenamide
[(Z)-1e]:
yield 82%; mp 202.0–203.0 °C; IR (KBr): 3302, 1653, 1647 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 0.87
(3H, t, J= 7.6 Hz), 1.27 (2H, tq, J= 7.6, 7.6 Hz), 1.41 (2H, tt, J= 6.9, 7.6 Hz), 3.13 (2H, dt, J= 6.2, 6.9 Hz),
3.67 (2H, s), 3.68 (3H, s), 3.76 (3H, s), 6.79 (1H, d, J= 8.3 Hz), 6.97 (1H, dd, J= 2.1, 8.3 Hz), 7.00 (1H, s),
7.12 (1H, d, J= 2.1 Hz), 7.31 (1H, dd, J= 2.1, 8.3 Hz), 7.59 (1H, d, J= 2.1 Hz), 7.60 (1H, d, J= 8.3 Hz),
7.89 (1H, t, J= 6.2 Hz), 9.58 (1H, s); 13C NMR (125.7 MHz, DMSO-d6): δ 13.7, 19.5, 31.3, 38.8, 41.0, 55.3,
55.4, 111.2, 113.0, 122.6, 126.6, 127.99, 128.03, 129.2, 129.8, 130.3, 130.7, 131.3, 136.9, 148.3, 149.2,

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164.8, 168.9; Anal. Calcd for C23H26N2O4Cl2: C, 59.36; H, 5.63; N, 6.02. Found: C, 59.33; H, 5.45; N, 5.88.
(Z)-N-Butyl-2-(4-chlorophenylacetylamino)-3-(3,4-dimethoxyphenyl)-2-propenamide [(Z)-1f]: yield
90%; mp 187.0–188.0 °C; IR (KBr): 3310, 3136, 1671, 1647 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 0.88
(3H, t, J= 7.3 Hz), 1.27 (2H, tq, J= 6.7, 7.3 Hz), 1.41 (2H, tt, J= 6.7, 7.3 Hz), 3.13 (2H, dt, J= 5.5, 7.3 Hz),
3.65 (2H, s), 3.66 (3H, s), 3.76 (3H, s), 6.80 (1H, d, J= 8.6 Hz), 6.96 (1H, dd, J= 1.8, 8.6 Hz), 6.99 (1H, s),
7.12 (1H, d, J= 1.8 Hz), 7.34 (2H, d, J= 8.6 Hz), 7.39 (2H, d, J= 8.6 Hz), 7.83 (1H, t, J= 5.5 Hz), 9.55 (1H,
s); 13C NMR (125.7 MHz, DMSO-d6): δ 13.7, 19.5, 31.2, 38.7, 41.4, 55.3, 55.4, 111.3, 113.0, 122.7, 126.6,
127.9, 128.1 (3C), 131.15, 131.23 (2C), 134.7, 148.3, 149.1, 164.9, 169.4; Anal. Calcd for C23H27N2O4Cl: C,
64.11; H, 6.32; N, 6.50. Found: C, 63.77; H, 6.29; N, 6.40.
(Z)-N-Butyl-3-(3,4-dimethoxyphenyl)-2-(4-fluorophenylacetylamino)-2-propenamide [(Z)-1g]: yield
85%; mp 175.0–175.5 °C; IR (KBr): 3296, 3136, 1668, 1648 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 0.87
(3H, t, J= 7.4 Hz), 1.27 (2H, tq, J= 6.9, 7.4 Hz), 1.41 (2H, tt, J= 6.9, 7.4 Hz), 3.12 (2H, dt, J= 5.7, 6.9 Hz),
3.64 (2H, s), 3.66 (3H, s), 3.76 (3H, s), 6.82 (1H, d, J= 8.6 Hz), 6.98 (1H, s), 7.00 (1H, dd, J= 1.7, 8.6 Hz),
7.12 (1H, d, J= 1.7 Hz), 7.15 (2H, dd, J= 8.6, 9.1 Hz), 7.35 (2H, dd, J= 5.7, 8.6 Hz), 7.79 (1H, t, J= 5.7 Hz),
13
9.52 (1H, s); C NMR (125.7 MHz, DMSO-d6): δ 13.6, 19.4, 31.2, 38.6, 41.1, 55.2, 55.3, 111.3, 112.8,
114.8 (2C, d, J= 20 Hz), 122.7, 126.6, 127.8, 128.1, 131.0 (2C, d, J= 9 Hz), 131.8, 148.2, 149.1, 161.2 (1C,
d, J= 243 Hz), 164.8, 169.6; Anal. Calcd for C23H27N2O4F: C, 66.65; H, 6.57; N, 6.76. Found: C, 66.40; H,
6.28; N, 6.83.
General Procedure for the Irradiation of (Z)-1a–g. A methanol solution of (Z)-1 (1.0×10–3 mol dm–3,
500 mL), placed in a Pyrex vessel, was irradiated for a given period of time under nitrogen with
Pyrex-filtered light from a 400 W high pressure Hg lamp at rt. At a given irradiation time, an appropriate
amount of the solution (5 mL) was pipetted off and concentrated to dryness in vacuo giving the residue
1
which was subjected to H NMR spectral analysis in dimethyl-d6 sulfoxide. The composition was
1
estimated from the area ratio of a given H NMR signal for each compound. The remaining solution
irradiated for 360 min was concentrated to dryness under reduced pressure and the resulting residue was
subjected to preparative thin-layer chromatography over silica gel (developing solvent: ethyl
acetate-hexane or ethyl acetate-chloroform). In order to isolate (E)-1, a methanol solution of (Z)-1 (1.0×
10–3 mol dm–3, 500 mL) was independently irradiated for 60 min under the same conditions. For the
purpose of isolating and purifying the photoproducts, column chromatography over silica gel (230 mesh,
Merck) was also used. Physical and spectroscopic properties of the (E)-isomers and isoquinoline
derivatives (papaverine analogs, 2) isolated are as follows.
(E)-1a: yield 33%; mp 139.0–140.0 °C (EtOAc-hexane); IR (KBr): 3310, 1641 cm–1; 1H NMR (500 MHz,
DMSO-d6): δ 0.79 (3H, t, J= 7.3 Hz), 1.13 (2H, tq, J= 7.3, 7.3 Hz), 1.30 (2H, tt, J= 6.7, 7.3 Hz), 3.02 (2H,
dt, J= 6.1, 6.7 Hz), 3.47 (2H, s), 3.69 (3H, s), 3.72 (3H, s), 3.73 (3H, s), 3.75 (3H, s), 6.76 (1H, dd, J= 1.8,
8.5 Hz), 6.80 (1H, s), 6.81 (1H, dd, J= 1.8, 8.5 Hz), 6.84 (1H, d, J= 8.5 Hz), 6.86 (1H, d, J= 1.8 Hz), 6.88

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(1H, d, J= 8.5 Hz), 6.92 (1H, d, J= 1.8 Hz), 7.99 (1H, t, J= 6.1 Hz), 9.63 (1H, s); C NMR (125.7 MHz,
DMSO-d6): δ 13.6, 19.5, 30.4, 38.6, 42.2, 55.2, 55.4 (2C), 55.5, 111.5, 111.6, 111.8, 113.1, 115.5, 120.8,
121.1, 128.0, 128.3, 132.2, 147.6, 147.8, 148.2, 148.5, 164.8, 169.1; Anal. Calcd for C25H32N2O6: C, 65.77;
H, 7.06; N, 6.14. Found: C, 65.46; H, 6.84; N, 5.99.
1
(E)-1b: yield 30%; mp 125.0–126.0 °C (EtOAc-hexane); IR (KBr): 3262, 1653, 1605 cm–1; H NMR (500
MHz, DMSO-d6): δ 3.49 (2H, s), 3.57 (3H, s), 3.72 (3H, s), 3.73 (3H, s), 3.75 (3H, s), 4.27 (2H, d, J= 6.1
Hz), 6.71–6.75 (2H, m), 6.76 (1H, s), 6.82 (1H, dd, J= 1.8, 8.5 Hz), 6.84 (1H, s), 6.89 (1H, d, J= 8.5 Hz),
13
6.93 (1H, d, J= 1.8 Hz), 7.16–7.23 (5H, m), 8.54 (1H, t, J= 6.1 Hz), 9.73 (1H, s); C NMR (125.7 MHz,
DMSO-d6): δ 42.1, 42.4, 55.2, 55.4 (2C), 55.6, 111.5, 111.7, 111.8, 113.1, 116.4, 120.8, 121.1, 126.6, 127.5
(2C), 127.7, 127.9 (2C), 128.3, 131.8, 138.6, 147.6, 147.9, 148.2, 148.5, 165.0, 169.2; Anal. Calcd for
C28H30N2O6: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.88; H, 5.98; N, 5.91.
1
(E)-1c: yield 36%; mp 153.0–154.0 °C (EtOAc-hexane); IR (KBr): 3238, 1641 cm–1; H NMR (500 MHz,
DMSO-d6): δ 0.79 (3H, t, J= 7.3 Hz), 1.12 (2H, tq, J= 7.3, 7.3 Hz), 1.29 (2H, tt, J= 7.3, 7.3 Hz), 3.02 (2H,
dt, J= 5.5, 7.3 Hz), 3.47 (2H, s), 3.69 (3H, s), 3.72 (3H, s), 3.73 (3H, s), 6.76 (1H, dd, J= 1.8, 8.5 Hz), 6.79
(1H, br s), 6.84 (1H, d, J= 8.5 Hz), 6.85 (1H, s), 6.88 (2H, d, J= 8.5 Hz), 7.21 (2H, d, J= 8.5 Hz), 7.99 (1H,
13
t, J= 5.5 Hz), 9.65 (1H, s); C NMR (125.7 MHz, DMSO-d6): δ 13.6, 19.5, 30.4, 38.6, 41.7, 55.0, 55.2,
55.4, 111.5, 111.6, 113.6 (2C), 115.4, 120.7, 127.8, 128.0, 130.0 (2C), 132.2, 147.8, 148.2, 158.0, 164.8,
169.2; Anal. Calcd for C24H30N2O5: C, 67.59; H, 7.09; N, 6.57. Found: C, 67.70; H, 6.82; N, 6.48.
(E)-1d: yield 39%; mp 148.0–149.0 °C (EtOAc-hexane); IR (KBr): 3238, 3028, 1660, 1644 cm–1; 1H NMR
(500 MHz, DMSO-d6): δ 0.79 (3H, t, J= 7.3 Hz), 1.12 (2H, tq, J= 7.3, 7.3 Hz), 1.30 (2H, tt, J= 7.3, 7.3 Hz),
3.02 (2H, dt, J= 5.5, 7.3 Hz), 3.56 (2H, s), 3.69 (3H, s), 3.72 (3H, s), 6.77 (1H, dd, J= 1.8, 8.5 Hz), 6.80
(1H, s), 6.84 (1H, d, J= 8.5 Hz), 6.86 (1H, d, J= 1.8 Hz), 7.22–7.25 (1H, m), 7.29–7.33 (4H, m), 8.00 (1H, t,
J= 5.5 Hz), 9.72 (1H, s); 13C NMR (125.7 MHz, DMSO-d6): δ 13.6, 19.5, 30.4, 38.6, 42.6, 55.2, 55.4, 111.5,
111.6, 115.5, 120.7, 126.4, 127.9, 128.2 (2C), 129.1 (2C), 132.2, 135.9, 147.8, 148.2, 164.8, 168.8; Anal.
Calcd for C23H28N2O4: C, 69.68; H, 7.12; N, 7.07. Found: C, 69.30; H, 7.18; N, 6.90.
(E)-1e: yield 38%; mp 177.0–178.0 °C (EtOAc-hexane); IR (KBr): 3421, 1655, 1637 cm–1; 1H NMR (500
MHz, DMSO-d6): δ 0.84 (3H, t, J= 6.9 Hz), 1.18 (2H, tq, J= 6.9, 7.4 Hz), 1.33 (2H, tt, J= 6.9, 7.4 Hz), 3.08
(2H, dt, J= 5.7, 6.9 Hz), 3.65 (2H, s), 3.74 (3H, s), 3.78 (3H, s), 6.82 (1H, d, J= 1.7 Hz), 6.84 (1H, s), 6.90
(1H, d, J= 8.6 Hz), 6.91 (1H, dd, J= 1.7, 8.6 Hz), 7.34 (1H, dd, J= 1.7, 8.0 Hz), 7.62 (1H, d, J= 1.7 Hz),
13
7.64 (1H, d, J= 8.0 Hz), 8.11 (1H, t, J= 5.7 Hz), 9.85 (1H, s); C NMR (125.7 MHz, DMSO-d6): δ 13.7,
19.6, 30.4, 38.6, 41.4, 55.3, 55.5, 111.5, 111.6, 116.0, 120.8, 127.8, 129.2, 129.6, 130.3, 130.7, 131.1,
132.0, 137.0, 147.9, 148.2, 164.7, 168.0; Anal. Calcd for C23H26N2O4Cl2: C, 59.36; H, 5.63; N, 6.02. Found:
C, 59.28; H, 5.37; N, 5.76.
1
(E)-1f: yield 42%; mp 155.0–156.0 °C (EtOAc-hexane); IR (KBr): 3397, 1676, 1657 cm–1; H NMR (500

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1003
MHz, DMSO-d6): δ 0.79 (3H, t, J= 7.4 Hz), 1.12 (2H, tq, J= 6.9, 7.4 Hz), 1.29 (2H, tt, J= 6.9, 6.9 Hz), 3.02
(2H, dt, J= 5.7, 6.9 Hz), 3.56 (2H, s), 3.68 (3H, s), 3.72 (3H, s), 6.77 (1H, dd, J= 1.7, 8.6 Hz), 6.79 (1H, s),
6.85 (1H, d, J= 8.6 Hz), 6.86 (1H, d, J= 1.7 Hz), 7.32 (2H, d, J= 8.6 Hz), 7.38 (2H, d, J= 8.6 Hz), 8.03 (1H,
13
t, J= 5.7 Hz), 9.75 (1H, s); C NMR (125.7 MHz, DMSO-d6): δ 13.6, 19.6, 30.4, 38.6, 41.7, 55.3, 55.4,
111.5, 111.6, 115.7, 120.8, 127.8, 128.1 (2C), 131.0 (2C), 131.2, 132.1, 134.9, 147.9, 148.2, 164.7, 168.5;
Anal. Calcd for C23H27N2O4Cl: C, 64.11; H, 6.32; N, 6.50. Found: C, 64.07; H, 6.15; N, 6.28.
(E)-1g: yield 35%; mp 148.5–149.0 °C (EtOAc-hexane); IR (KBr): 3435, 1655, 1638 cm–1; 1H NMR (500
MHz, DMSO-d6): δ 0.79 (3H, t, J= 7.6 Hz), 1.13 (2H, tq, J= 7.6, 7.6 Hz), 1.30 (2H, tt, J= 6.9, 7.6 Hz), 3.02
(2H, dt, J= 6.2, 6.9 Hz), 3.55 (2H, s), 3.69 (3H, s), 3.72 (3H, s), 6.77 (1H, dd, J= 2.1, 8.3 Hz), 6.80 (1H, s),
6.85 (1H, d, J= 8.3 Hz), 7.15 (2H, dd, J= 8.9, 8.9 Hz), 7.16 (1H, d, J= 2.1 Hz Hz), 7.33 (2H, dd, J= 5.5, 8.9
Hz), 8.03 (1H, t, J= 6.2 Hz), 9.74 (1H, s); 13C NMR (125.7 MHz, DMSO-d6): δ 13.7, 19.6, 30.4, 38.6, 41.6,
55.3, 55.5, 111.5, 111.6, 114.8 (2C, d, J= 22 Hz), 115.6, 120.8, 127.9, 130.9 (2C, d, J= 7 Hz), 132.10,
132.14, 147.9, 148.2, 161.0 (1C, d, J= 246 Hz), 164.8, 168.8; Anal. Calcd for C23H27N2O4F: C, 66.65; H,
6.57; N, 6.76. Found: C, 66.47; H, 6.42; N, 6.75.
3-Butylaminocarbonyl-6,7-dimethoxy-1-(3,4-dimethoxybenzyl)isoquinoline (2a): yield 46%; mp
140.0–140.5 °C (EtOAc); IR (KBr): 3388, 1743, 1665 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 0.92 (3H, t,
J= 7.3 Hz), 1.33 (2H, tq, J= 7.3, 7.3 Hz), 1.54 (2H, tt, J= 6.7, 7.3 Hz), 3.36 (2H, dt, J= 6.1, 6.7 Hz), 3.67
(3H, s), 3.69 (3H, s), 3.92 (3H, s), 3.92 (3H, s), 4.56 (2H, s), 6.82 (1H, d, J= 7.9 Hz), 6.83–6.85 (1H, m),
13
7.12 (1H, br s), 7.56 (1H, s), 7.60 (1H, s), 8.25 (1H, s), 8.68 (1H, t, J= 6.1 Hz); C NMR (125.7 MHz,
DMSO-d6): δ 13.7, 19.6, 31.5, 38.3, 40.4, 55.3, 55.4, 55.77, 55.82, 104.5, 107.1, 111.8, 112.9, 117.2, 120.7,
123.3, 131.6, 133.0, 141.4, 147.2, 148.6, 150.7, 152.5, 157.0, 164.3; Anal. Calcd for C25H30N2O5: C, 68.47;
H, 6.90; N, 6.39. Found: C, 68.14; H, 6.82; N, 6.19.
3-Benzylaminocarbonyl-6,7-dimethoxy-1-(3,4-dimethoxybenzyl)isoquinoline (2b): yield 45%; mp
174.0–175.0 °C (EtOAc); IR (KBr): 3370, 3064, 1677, 1600 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 3.64
(3H, s), 3.65 (3H, s), 3.92 (3H, s), 3.92 (3H, s), 4.57 (2H, s), 4.58 (2H, d, J= 6.1 Hz), 6.80 (1H, d, J= 8.5
Hz), 6.86 (1H, dd, J= 1.8, 8.5 Hz), 7.13 (1H, d, J= 1.8 Hz), 7.25 (1H, dd, J= 7.3, 7.3 Hz), 7.33 (2H, dd, J=
13
7.3, 7.3 Hz), 7.36 (2H, d, J= 7.3 Hz), 7.57 (1H, s), 7.61 (1H, s), 8.29 (1H, s), 9.29 (1H, t, J= 6.1 Hz); C
NMR (125.7 MHz, DMSO-d6): δ 40.4, 42.3, 55.3, 55.4, 55.79, 55.84, 104.5, 107.1, 111.8, 112.8, 117.6,
120.6, 123.4, 126.7, 127.3 (2C), 128.3 (2C), 131.6, 133.0, 139.7, 141.3, 147.2, 148.6, 150.8, 152.6, 157.1,
164.5; Anal. Calcd for C28H28N2O5: C, 71.17; H, 5.97; N, 5.93. Found: C, 71.33; H, 5.90; N, 5.96.
3-Butylaminocarbonyl-6,7-dimethoxy-1-(4-methoxybenzyl)isoquinoline (2c): yield 43%; mp
152.0–153.0 °C (EtOAc); IR (KBr): 3340, 1656, 1617 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 0.93 (3H, t,
J= 7.3 Hz), 1.34 (2H, tq, J= 7.3, 7.3 Hz), 1.54 (2H, tt, J= 7.3, 7.3 Hz), 3.34 (2H, dt, J= 6.1, 7.3 Hz), 3.68
(3H, s), 3.90 (3H, s), 3.92 (3H, s), 4.56 (2H, s), 6.83 (2H, d, J= 8.5 Hz), 7.30 (2H, d, J= 8.5 Hz), 7.56 (1H,
s), 7.56 (1H, s), 8.24 (1H, s), 8.62 (1H, t, J= 6.1 Hz); 13C NMR (125.7 MHz, DMSO-d6): δ 13.7, 19.6, 31.4,

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38.4, 39.8, 54.9, 55.75, 55.82, 104.5, 107.1, 113.7 (2C), 117.2, 123.2, 129.8 (2C), 131.1, 133.0, 141.4,
150.7, 152.5, 157.0, 157.6, 164.2; Anal. Calcd for C24H28N2O4: C, 70.57; H, 6.91; N, 6.86. Found: C, 70.17;
H, 6.89; N, 6.79.
1-Benzyl-3-butylaminocarbonyl-6,7-dimethoxyisoquinoline (2d): yield 48%; mp 137.0–138.0 °C
(EtOAc); IR (KBr): 3394, 3322, 1653 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 0.87 (3H, t, J= 7.3 Hz), 1.33
(2H, tq, J= 7.3, 7.3 Hz), 1.54 (2H, tt, J= 7.3, 7.3 Hz), 3.35 (2H, dt, J= 5.5, 7.3 Hz), 3.89 (3H, s), 3.92 (3H,
s), 4.64 (2H, s), 7.18 (1H, dd, J= 7.3, 7.3 Hz), 7.27 (2H, dd, J= 7.3, 7.3 Hz), 7.38 (2H, d, J= 7.3 Hz), 7.557
(1H, s), 7.563 (1H, s), 8.26 (1H, s), 8.61 (1H, t, J= 5.5 Hz); 13C NMR (125.7 MHz, DMSO-d6): δ 13.7, 19.6,
31.4, 38.4, 40.9, 55.7, 55.8, 104.4, 107.1, 117.3, 123.3, 126.1, 128.3 (2C), 128.8 (2C), 133.0, 139.2, 141.4,
150.8, 152.6, 156.7, 164.2; Anal. Calcd for C23H26N2O3: C, 72.99; H, 6.92; N, 7.40. Found: C, 72.63; H,
6.81; N, 7.75.
3-Butylaminocarbonyl-1-(3,4-dichlorobenzyl)-6,7-dimethoxyisoquinoline (2e): yield 50%; mp 174.0–
1
175.0 °C (EtOAc); IR (KBr): 3375, 1654 cm–1; H NMR (500 MHz, DMSO-d6): δ 0.92 (3H, t, J= 7.6 Hz),
1.31 (2H, tq, J= 7.6, 7.6 Hz), 1.51 (2H, tt, J= 6.9, 7.6 Hz), 3.33 (2H, dt, J= 6.2, 6.9 Hz), 3.93 (3H, s), 3.95
(3H, s), 4.66 (2H, s), 7.38 (1H, dd, J= 2.1, 8.3 Hz), 7.55 (1H, d, J= 8.3 Hz), 7.59 (1H, s), 7.60 (1H, s), 7.75
13
(1H, d, J= 2.1 Hz), 8.27 (1H, s), 8.53 (1H, t, J= 6.2 Hz); C NMR (125.7 MHz, DMSO-d6): δ 13.7, 19.6,
31.4, 38.3, 39.5, 55.8, 55.9, 104.1, 107.2, 117.4, 123.3, 128.8, 129.5, 130.4, 130.7, 131.1, 133.0, 140.4,
141.3, 151.0, 152.7, 155.7, 164.1; Anal. Calcd for C23H24N2O3Cl2: C, 61.75; H, 5.41; N, 6.26. Found: C,
61.41; H, 5.20; N, 5.95.
3-Butylaminocarbonyl-1-(4-chlorobenzyl)-6,7-dimethoxyisoquinoline (2f): yield 42%; mp 206.0–
1
206.5 °C (EtOAc); IR (KBr): 3362, 1663 cm–1; H NMR (500 MHz, DMSO-d6): δ 0.93 (3H, t, J= 7.4 Hz),
1.32 (2H, tq, J= 7.4, 7.4 Hz), 1.52 (2H, tt, J= 6.9, 7.4 Hz), 3.34 (2H, dt, J= 5.7, 6.9 Hz), 3.92 (3H, s), 3.93
(3H, s), 4.64 (2H, s), 7.32 (2H, d, J= 8.6 Hz), 7.42 (2H, d, J= 8.6 Hz), 7.55 (1H, s), 7.58 (1H, s), 8.27 (1H,
13
s), 8.57 (1H, t, J= 5.7 Hz); C NMR (125.7 MHz, DMSO-d6): δ 13.7, 19.6, 31.4, 38.4, 40.0, 55.8, 55.9,
104.2, 107.1, 117.4, 123.3, 128.2 (2C), 130.77 (2C), 130.81, 133.0, 138.2, 141.4, 150.9, 152.7, 156.2,
164.2; Anal. Calcd for C23H25N2O3Cl: C, 66.90; H, 6.10; N, 6.78. Found: C, 66.52; H, 6.32; N, 6.72.
3-Butylaminocarbonyl-6,7-dimethoxy-1-(4-fluorobenzyl)isoquinoline (2g): yield 46%; mp 166.0–
1
167.0 °C (EtOAc); IR (KBr): 3347, 1659 cm–1; H NMR (500 MHz, DMSO-d6): δ 0.92 (3H, t, J= 7.6 Hz),
1.32 (2H, tq, J= 7.6, 7.6 Hz), 1.53 (2H, tt, J= 6.9, 7.6 Hz), 3.35 (2H, dt, J= 6.2, 6.9 Hz), 3.92 (3H, s), 3.92
(3H, s), 4.63 (2H, s), 7.11 (2H, dd, J= 9.0, 9.0 Hz), 7.43 (2H, dd, J= 5.5, 9.0 Hz), 7.56 (1H, s), 7.57 (1H, s),
8.26 (1H, s), 8.59 (1H, t, J= 6.2 Hz); 13C NMR (125.7 MHz, DMSO-d6): δ 13.7, 19.6, 31.4, 38.4, 40.0, 55.8,
55.9, 104.3, 107.1, 115.0 (2C, d, J= 20 Hz), 117.4, 123.3, 130.7 (2C, d, J= 9 Hz), 133.0, 135.3, 141.4,
150.9, 152.6, 156.5, 160.8 (1C, d, J= 243 Hz), 164.2; Anal. Calcd for C23H25N2O3F: C, 69.68; H, 6.36; N,
7.07. Found: C, 69.60; H, 6.11; N, 6.93.

HETEROCYCLES, Vol. 68, No. 5, 2006
1005
ACKNOWLEDGMENT
This research was partially supported by a “High-Tech Research Project” from the Ministry of Education,
Sports, Culture, Science and Technology, Japan.
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