Formation of isoquinoline derivatives by the irradiation of N-acetyl-α-dehydrophenylalanine ethyl ester and its derivatives

Article abstract of DOI:10.3987/com-00-8999

The irradiation of a nitrogen-purged acetonitrile solution of the title compounds (1) with Pyrex filtered light was found to give isoquinoline derivatives (2) via the excited state (Z)-isomers, whereas in methanol 1-azetine derivative was also detected al

Full text of DOI:10.3987/com-00-8999

HETEROCYCLES, Vol. 53, No.10, 2000, pp. 2261 - 2274, Received, 4th July, 2000
FORMATION
OF ISOQUINOLINE
DERIVATIVES
BY
THE
IRRADIATION
OF N-ACETYL-α-DEHYDROPHENYLALANINE
ETHYL ESTER AND ITS DERIVATIVES
Hideki Hoshina, Hitoshi Tsuru, Kanji Kubo,† Tetsutaro Igarashi, and
Tadamitsu Sakurai*
Department of Applied Chemistry, Faculty of Engineering, Kanagawa University,
Kanagawa-ku, Yokohama 221-8686, Japan
†Institute of Advanced Material Study, 86, Kyushu University, Kasuga-koen,
Kasuga 816-8580, Japan
Abstract–The irradiation of a nitrogen-purged acetonitrile solution of the title
compounds (1) with Pyrex filtered light was found to give isoquinoline derivatives
(2) via the excited state (Z)-isomers, whereas in methanol 1-azetine derivative was
also detected along with 2 but side reactions occurred appreciably on prolonged
irradiation. An examination of substituent effects on the reactivities of the excited
state (Z)-isomers shows that the efficiency for formation of 2 undergoes great steric
and electronic effects of the substituent introduced into the benzene ring of 1,
though the bulkiness of the alkoxycarbonyl group in 1 affected this efficiency to
only a slight extent. On the other hand, in the presence of benzophenone as a
triplet sensitizer, the starting (Z)-isomer underwent an exclusive isomerization into the
corresponding (E)-isomer without yielding any isoquinoline derivative, being
consistent with the occurrence of the photocyclization reaction from the excited
singlet state (Z)-isomer.
It is well-known that numerous biomolecules and natural products contain various types of heterocyclic
compounds 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,1 as well as
in developing these photochemical reactions of synthetic utility. 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 biochemically and pharmaceutically useful products.2,3 As an extension
of the investigation into the photochemical processes of N-acetyl-α-dehydrophenylalanine derivatives [(Z)-
2-acetylamino-N-butyl-3-(4-substituted phenyl)-2-propenamides],2 we confined our attention to the
characterization of the excited state reactivities of N-acetyl-α-dehydrophenylalanine ethyl ester [ethyl (Z)-2-
acetylamino-3-(4-chlorophenyl)-2-propenoate, ((Z)-1a)] and its derivatives (1b–i). In this note we

present results that demonstrate that the photoreaction of 1 in MeCN gives isoquinoline derivatives without
forming any 1-azetines, and that the composition for the former product undergoes dramatic effects of
substituents on the benzene ring but the alkoxycarbonyl group exerts only a slight steric effect on this
composition.
COOR3
NHCOMe
COOEt
NHCOMe
R2
R1
1a (R1= Cl, R2= H);
Cl
1g (R3= Me); 1h (R3= i-Pr); 1i (R3= t-Bu)
1b (R1= R2= H);
1c (R1= Me, R2= H); 1d (R1= OMe, R2= H);
1e (R1= CF3, R2= H ); 1f (R1= R2= Cl)
The starting (Z)-isomers (1a–i) were prepared in good yields by the ring opening reactions of aryl
substituted oxazolones with alcohols in the presence of triethylamine.4 After a nitrogen purged MeCN
solution of 1a (4.0×10–3 mol dm–3) was irradiated with Pyrex filtered light (>280 nm) from a 400 W high
pressure Hg lamp for 24 h at room temperature, the product mixture obtained was subjected to preparative
thin layer chromatography over silica gel, which allowed us to isolate (Z)-1a (53%: isolated yield), (E)-1a
1
(11%), and 2a (12%). A careful H NMR analysis of the product mixture indicated the negligible
formation of the 1-azetine isomer (3a) (Scheme 1). Because 1-azetine derivatives are shown to be stable
under the irradiation conditions employed,2 it is very unlikely that 3a once formed decomposes during
irradiation.
COOEt
NHCOMe
NHCOMe
COOEt
COOEt
N
Me
N
hν
N2, MeCN
COOEt
Me
+
Cl
Cl
(Z)-1a
Cl
2a
Cl
(E)-1a
3a
Scheme 1. Product distribution derived from the photoreaction of (Z)-1a in MeCN
The finding that the photoproduct (2a) is stable enough such that it undergoes only negligible
1
decomposition under the irradiation conditions made it possible to monitor the reaction by means of H
NMR spectroscopy, as typically shown in Table 1. The result obtained for (Z)-1a demonstrates the rapid
production of (E)-1a and the subsequent increase in a composition for 2a with the decrease of (Z)-isomer

composition. In a previous study2 it was strongly suggested that the isoquinoline is formed via cyclization
process from the excited state (Z)-isomer while the cyclization reaction from the (E)-isomer is responsible
for the appearance of 1-azetine derivative. In addition to Chem 3D modeling of (Z)-1a and (E)-1a which
shows that the (Z)-isomer adopts a most suitable conformation for the cyclization affording 2a, these
considerations led us to propose Scheme 2 that explains the observed product distribution. We previously
showed that the 24 h irradiation of N-acetyl-α-dehydrophenylalaninamide derivative [(Z)-2-acetylamino-N-
butyl-3-(4-chlorophenyl)-2-propenamide] in MeCN affords isoquinoline (32%) and 1-azetine (trans + cis,
19%) derivatives along with (Z)- (33%) and (E)-isomers (16%).2 A comparison of this result with the
product composition obtained by the 24 h irradiation of (Z)-1a confirms that the replacement of
butylaminocarbonyl group in the α-dehydrophenylalaninamide derivative by ethoxycarbonyl lowers the
reactivity of the excited state (Z)-isomer.
Table 1. Relation between irradiation time and composition (%) of each
compound in MeCN
Time/h
Compound
0
2
4
8
12
18
24
(Z)-1a
(E)-1a
2a
100
83.9
14.3
1.8
80.3
15.8
3.9
77.8
15.0
7.2
73.5
14.6
11.9
70.8
13.9
15.3
69.0
12.7
18.3
COOEt
COOEt
NH
H
NH
O
OH
Me
hν
Cyclization
H shift
-H O
2
Z-1a
Z-1a*
Me
H
2a
Cl
Cl
I
H
N
H
N
O
HO
Me
H
Me
COOEt
COOEt
H
H
hν
H abstraction
-H O
2
3a
E-1a
E-1a*
Cl
Cl
II
Scheme 2. Proposed mechanism for the formation of 2a

If we adopt this mechanism for the formation of the isoquinoline derivative (2a), we forced to explain the
reason for the complete suppression of cyclization from the excited state (E)-isomer. Chem 3D modeling
of I and II (Scheme 2), precursors of the isoquinoline (2a) and the 1-azetine (3a), respectively, shows that
the distance between lone pairs of electrons on the ring nitrogen and the ethoxy oxygen is shorter in the
latter precursor than in the former. It is, thus, very likely that there is much stronger electronic repusion
between the lone pairs of electrons in II, compared with I. This repulsion may greatly slow down the rate
for the cyclization reaction of (E)-1a in the excited state to result in an exclusive deactivation of the (E)-
isomer. Then, we expect that the hydrogen bonding solvation of the azetidine ring nitrogen by MeOH
molecules weaken the electronic repulsion enabling the cyclization reaction from the excited state (E)-isomer
to proceed. On irradiation of a MeOH solution of (Z)-1a for 12 h under the same conditions, there
appeared substantial amounts of the trans-azetine isomer (3a) (about 5%, 1H NMR analysis), whose ring
proton signals with the J3,4 value of 7.3 Hz were detected at 4.71 and 5.64 ppm (DMSO-d6), along with 2a
(about 8%). This observation is consistent with our expectation, thus providing a piece of evidence in
support of the interpretation described above. In MeOH having a great hydrogen bonding solvation ability,
however, the undesirable side reactions occurred to a large extent on prolonged irradiation. The presence
of byproducts and the relatively low stability of the 1-azetine isomer made it very difficult to isolate
analytical grade 3a.
In Table 2 are shown substituent effects on the product distribution and composition obtained for (Z)-1a in
MeCN. Interestingly, the introduction of strong electron donating (OMe) and electron withdrawing (CF3)
groups at the para position on the benzene ring greatly reduces the composition for the isoquinoline
derivative (2a), whereas this composition as well as the efficiency of the isomerization into (E)-1a
undergoes only a minor stereoelectronic effect of the alkyl substituents. In addition, a comparison of the
excited state reactivity of (Z)-1a with that of (Z)-1f reveals that the replacement of the ortho hydrogen on
the benzene ring in 1a by relatively bulky chlorine enhances the isomerization efficiency but completely
suppresses the formation of the corresponding isoquinoline derivative. (Z)-1a–f in MeCN exhibit the first
UV absorption bands at 281 (1b; molar absorption coefficient, εmax= 1.7×104), 286 (1a; εmax= 2.1×104),
288 (1c; εmax= 2.2×104), 303 (1d; εmax= 2.4×104), 284 (1e; εmax= 1.4×104), and 283 nm (1f; εmax= 1.6×
104 dm3 mol–1 cm–1). A comparison of these UV spectral data confirms that the electron donating MeO
substituent (1d) shifts the absorption band to longer wavelength (22 nm) with increasing its intensity,
compared with the H (1b), whereas the absorption of 1b is slightly red shifted (2 nm) with decreasing its
intensity on introducing the electron withdrawing CF3 group (1e) into 1b. These findings strongly
suggest a contribution of the resonance structures (III) and (IV) to the overall structures in the excited state.
The relative rate for the deactivation of the excited state (Z)-isomer is considered to increase with an increase
in the contribution of these resonance structures. On the other hand, MM2 calculations for the ground
state conformation of 1a and 1f suggest that the introduction of an additional chlorine atom at the ortho
position exerts a fairly large steric effect on the bond forming step between the acetyl carbonyl carbon and
the phenyl ortho carbon of (Z)-1f in the excited state (Figure 1). This must be reflected in a lowering of
the relative rate for the cyclization process. In addition, the increased relative rate for the isomerization into
(E)-1f also further slows down the cyclization reaction to give a negligible amount of the isoquinoline

derivative (2f), as observed (Table 2).
Table 2. Substituent effects on the composition of each compound obtained by 2 and 24 h
irradiations of the starting (Z)-1a–i (4.0×10–3 mol dm–3) in MeCN
Composition (%)
Irradiation
time/h
Compound
(Z)-1
(E)-1
2
1a (R1= Cl, R2= H, R3= Et)
2
83.9
65.8
14.3
15.9
1.8
24
18.3
1b (R1= R2= H, R3= Et)
2
80.0
63.6
18.6
18.7
1.4
24
17.7
1c (R1= Me, R2= H, R3= Et)
1d (R1= OMe, R2= H, R3= Et)
1e (R1= CF3, R2= H, R3= Et)
1f (R1= R2= Cl, R3= Et)
2
81.0
65.0
17.5
17.7
1.5
24
17.3
2
86.1
81.6
13.6
14.7
0.3
3.7
24
2
79.0
76.1
21.0
21.0
0
24
2.9
2
75.0
61.4
25.0
38.6
0
0
24
1g (R1= Cl, R2= H, R3= Me)
1h (R1= Cl, R2= H, R3= i-Pr)
1i (R1= Cl, R2= H, R3= t-Bu)
2
83.0
73.0
17.0
16.2
0
24
11.8
2
81.8
69.6
16.8
16.0
1.4
24
14.4
2
74.9
67.6
25.1
20.0
0
24
12.4
OEt
O
H
H
O
OEt
NH
NH
CF
MeO
O
3
Me
O
Me
III
IV

O
O
O
O
N
O
O
N
Cl
Cl
Cl
1a
1f
Figure 1. Energy-minimized conformations of 1a and 1f
It is an important issue to elucidate the spin multiplicity of the excited state from which the cyclization of 1
takes place forming isoquinoline derivatives. For this purpose we chose (Z)-1a as the starting material
and benzophenone (BP) as a triplet sensitizer,5,6 and a nitrogen purged MeCN solution of (Z)-1a (4.0×10–3
mol dm–3) containing BP (4.0 ×10–2 mol dm–3) was irradiated at room temperature with light of
wavelengths longer than 340 nm, which permitted selective excitation of the sensitizer. The fact that the
room temperature phosphorescence of BP is quenched by (Z)-1a (2.0–8.0×10–4 mol dm–3) according to
the Stern-Volmer equation, I0/I= 1 + 690[(Z)-1a], where I and I0 refer to the phosphorescence intensities
with and without 1a, respectively, demonstrates that BP acts as a good triplet sensitizer. An inspection of
Table 3 reveals that triplet BP accelerates only the isomerization without forming any isoquinoline derivative
1
(2a). Because a H NMR analysis of the reaction mixtures showed no sign of the appearance of BP
derived product(s), this finding allows us to conclude that the photocyclization reaction of 1 proceeds
preferentially through its excited singlet state and, hence, substantiates the involvement of the resonance
structures (III) and (IV) in the excited singlet state (Z)-1.
Table 3. The composition of each compound obtained by the BP(4.0×10–2 mol dm–3)-
sensitized reaction ofꢀ(Z)-1a (4.0×10–3 mol dm–3) in nitrogen saturated MeCN
Composition (%)
Irradiation
time /h
(Z)-1a
100
(E)-1a
2a
0
2
4
6
9
0
52.7
53.8
53.4
53.7
0
0
0
0
0
47.3
46.2
46.6
46.3
Although there are extensive synthetic routes to isoquinoline derivatives,7 convenient photochemical routes

to these derivatives are scarcely known.8 The procedure for preparing the starting 1 is very simple and is
easily applicable to its related compounds. The photoreaction of substituted N-acetyl-α-
dehydrophenylalanines described above, therefore, provides a synthetic method that enables us to obtain
various kinds of isoquinoline derivatives without accompanying the appearance of 1-azetines.
EXPERIMENTAL
General
13
1H and C NMR and IR spectra were taken with a JEOL JNM-A500 spectrometer and a Hitachi 270-30
infrared spectrometer, respectively. Chemical shifts were determined using tetramethylsilane as an internal
standard. UV absorption spectra were recorded on a Shimadzu UV-2200 spectrophotometer. A cell with
a 10 mm pathlength was used. The phosphorescence spectra of BP at rt were measured in the presence
and absence of (Z)-1a under nitrogen with a Shimadzu RF-5000 spectrofluorimeter. The 366 nm light
was used for the selective excitation of BP. MeOH and MeCN 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 calculations were accomplished by using the Mac
SPARTAN Plus available from Wavefunction, Inc.
General Procedure for the Synthesis of (Z)-2-Methyl-4-(substituted benzylidene)-5(4H)-
oxazolones. N-Acetylglycine (15.0 g, 0.13 mol), substituted benzaldehyde (0.15 mol) and sodium
acetate (8.0 g, 0.10 mol) were added to acetic anhydride (150 mL) and the resulting mixture was heated at
70–85 °C for 1–2 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 EtOH. After the crude product had been air-dried at rt, it was recrystallized from CHCl3–hexane to
give yellow crystals (60–73%).
(Z)-2-Methyl-4-(4-methoxybenzylidene)-5(4H)-oxazolone. mp 109.5–110.0 °C. IR (KBr): 1800,
1800, 1776, 1662, 1263 cm–1. 1H NMR (500 MHz, CDCl3): δ 2.39 (3H, s), 3.87 (3H, s), 6.96 (2H, d,
J= 8.5 Hz), 7.11 (1H, s), 8.06 (2H, d, J= 8.5 Hz).
(Z)-2-Methyl-4-(4-methylbenzylidene)-5(4H)-oxazolone.
mp 135.0–136.0 °C.
IR (KBr):
1809, 1776, 1656, 1266 cm–1. 1H NMR (500 MHz, CDCl3): δ 2.38 (3H, s), 2.39 (3H, s), 7.11 (1H, s),
7.23 (2H, d, J= 8.3 Hz), 7.96 (2H, d, J= 8.3 Hz).
(Z)-2-Methyl-4-benzylidene-5(4H)-oxazolone.
mp 152.0–152.5 °C.
IR (KBr): 1779, 1659,
1266 cm–1. 1H NMR (500 MHz, CDCl3): δ 2.38 (3H, s), 7.13 (1H, s), 7.39–7.44 (3H, m), 8.04–8.09
(2H, m).
(Z)-2-Methyl-4-(4-chlorobenzylidene)-5(4H)-oxazolone.
mp 143.0–144.0 °C.
IR (KBr):

1800, 1773, 1659, 1260 cm–1. 1H NMR (500 MHz, CDCl3): δ 2.40 (3H, s), 7.05 (1H, s), 7.39 (2H, d,
J= 8.3 Hz), 8.01 (2H, d, J= 8.3 Hz).
(Z)-2-Methyl-4-[4-(trifluoromethyl)benzylidene]-5(4H)-oxazolone.
mp
110.0–112.0
°C.
IR (KBr): 1806, 1779, 1665, 1257 cm–1. 1H NMR (500 MHz, CDCl3): δ 2.43 (3H, s), 7.12 (1H, s),
7.68 (2H, d, J= 8.3 Hz), 8.18 (2H, d, J= 8.3 Hz).
(Z)-2-Methyl-4-(2,4-dichlorobenzylidene)-5(4H)-oxazolone.
1
mp 173.0–174.0 °C.
IR
(KBr): 1809, 1785, 1656, 1266 cm–1. H NMR (500 MHz, CDCl3): δ 2.42 (3H, s), 7.33 (1H, dd, J= 2.0,
8.3 Hz), 7.47 (1H, d, J= 2.0 Hz), 7.54 (1H, s), 8.67 (1H, d, J= 8.3 Hz).
General Procedure for the Synthesis of Alkyl ( Z)-2-Acetylamino-3-(substituted phenyl)-
2-propenoates [( Z)-1a–i]. (Z)-2-Methyl-4-(substituted benzylidene)-5(4H)-oxazolone (0.020 mol)
was added to alcohol (200 mL) containing small amounts of triethylamine and the resulting solution was
refluxed for 2–4 h. After removal of the solvent under reduced pressure, the solid residue obtained was
recrystallized from CHCl3-hexane affording colorless crystals (60–70%).
Ethyl (Z)-2-Acetylamino-3-(4-chlorophenyl)-2-propenoate [(Z)-1a].
mp 152.0–153.0 °C.
IR (KBr): 3268, 1725, 1659, 1257 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 1.24 (3H, t, J= 7.0 Hz),
2.00 (3H, s), 4.17 (2H, q, J= 7.0 Hz), 7.14 (1H, s), 7.47 (2H, d, J= 8.6 Hz), 7.64 (2H, d, J= 8.6 Hz),
9.62 (1H, s). 13C NMR (125.7 MHz, DMSO-d6): δ 14.0, 22.4, 60.8, 127.5, 128.6, 129.1, 131.3,
132.4, 133.6, 164.8, 169.3. Anal. Calcd for C13H14NO3Cl: C, 58.33; H, 5.27; N, 5.23. Found: C,
58.28; H, 4.97; N, 4.96.
Ethyl (Z)-2-Acetylamino-3-phenyl-2-propenoate [(Z)-1b].
mp 99.5–100.0 °C.
IR (KBr):
3256, 1725, 1659, 1245 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 1.23 (3H, t, J= 7.0 Hz), 1.99 (3H, s),
4.16 (2H, q, J= 7.0 Hz), 7.15 (1H, s), 7.36–7.43 (3H, m), 7.62 (2H, d, J= 7.3 Hz), 9.61 (1H, s). 13C
NMR (125.7 MHz, DMSO-d6): δ 14.1, 22.4, 60.7, 126.9, 128.6, 129.2, 129.7, 130.7, 133.4, 164.9,
169.4. Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.82; H, 6.19; N, 5.89.
Ethyl (Z)-2-Acetylamino-3-(4-tolyl)-2-propenoate [(Z)-1c].
mp 142.0–144.0 °C. IR (KBr):
3268, 1722, 1659, 1251 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 1.23 (3H, t, J= 7.0 Hz), 1.99 (3H, s),
2.32 (3H, s), 4.15 (2H, q, J= 7.0 Hz), 7.14 (1H, s), 7.23 (2H, d, J= 8.2 Hz), 7.52 (2H, d, J= 8.2 Hz),
9.54 (1H, s). 13C NMR (125.7 MHz, DMSO-d6): δ 14.1, 20.9, 22.4, 60.7, 126.1, 129.2, 129.8, 130.6,
131.1, 139.1, 165.1, 169.3. Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C,
67.86; H, 6.63; N, 5.58.
Ethyl (Z)-2-Acetylamino-3-(4-methoxyphenyl)-2-propenoate [(Z)-1d]. mp 115.0–116.5 °C.
IR (KBr): 3274, 1722, 1662, 1251 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 1.23 (3H, t, J= 7.0 Hz),

1.99 (3H, s), 3.79 (3H, s), 4.14 (2H, q, J= 7.0 Hz), 6.98 (2H, d, J= 8.8 Hz), 7.18 (1H, s), 7.61 (2H, d,
J= 8.8 Hz), 9.48 (1H, s). 13C NMR (125.7 MHz, DMSO-d6): δ 14.1, 22.4, 55.3, 60.6, 114.3, 124.6,
125.9, 131.5, 131.7, 160.1, 165.2, 169.3. Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32.
Found: C, 63.57; H, 6.21; N, 5.26.
Ethyl
(Z)-2-Acetylamino-3-[4-(trifluoromethyl)phenyl]-2-propenoate
[(Z)-1e].
mp121.0–
122.0 °C. IR (KBr): 3322, 1740, 1677, 1260 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 1.25 (3H, t, J=
7.2 Hz), 2.00 (3H, s), 4.19 (2H, q, J= 7.2 Hz), 7.17 (1H, s), 7.76 (2H, d, J= 8.2 Hz), 7.80 (2H, d, J=
8.2 Hz), 9.74 (1H, s). 13C NMR (125.7 MHz, DMSO-d6): δ 13.9, 22.4, 60.9, 124.0 (q, J= 272 Hz),
125.3 (q, J= 3 Hz), 128.0, 128.7 (q, J= 31 Hz), 129.1, 130.1, 137.7, 164.7, 169.4. Anal. Calcd for
C14H14NO3F3: C, 55.82; H, 4.68; N, 4.65. Found: C, 55.91; H, 4.41; N, 4.58.
Ethyl (Z)-2-Acetylamino-3-(2,4-dichlorophenyl)-2-propenoate [(Z)-1f]. mp126.0–127.0
°C. IR (KBr): 3238, 1722, 1662, 1278 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 1.24 (3H, t, J= 7.0
Hz), 1.93 (3H, s), 4.19 (2H, q, J= 7.0 Hz), 7.08 (1H, s), 7.47 (1H, dd, J= 2.1, 8.5 Hz), 7.61 (1H, d, J=
8.5 Hz), 7.72 (1H, d, J= 2.1 Hz), 9.64 (1H, s). 13C NMR (125.7 MHz, DMSO-d6): δ 13.9, 22.3, 61.0,
123.7, 127.4, 128.9, 129.6, 130.9, 131.1, 133.8, 134.0, 164.3, 169.1. Anal. Calcd for C13H13NO3Cl2:
C, 51.68; H, 4.34; N, 4.64. Found: C, 51.68; H, 3.96; N, 4.62.
Methyl (Z)-2-Acetylamino-3-(4-chlorophenyl)-2-propenoate [(Z)-1g].
mp 155.0–156.0 °C.
IR (KBr): 3214, 1734, 1668, 1248 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 2.00 (3H, s), 3.71 (3H, s),
7.16 (1H, s), 7.48 (2H, d, J= 8.5 Hz), 7.64 (2H, d, J= 8.5 Hz), 9.65 (1H, s). 13C NMR (125.7 MHz,
DMSO-d6): δ 22.4, 52.2, 127.2, 128.6, 129.6, 131.4, 132.3, 133.7, 165.4, 169.4. Anal. Calcd for
C12H12NO3Cl: C, 56.82; H, 4.77; N, 5.52. Found: C, 56.82; H, 4.65; N, 5.38.
Isopropyl (Z)-2-Acetylamino-3-(4-chlorophenyl)-2-propenoate [(Z)-1h]. mp 143.0–144.0 °C.
°C. IR (KBr): 3238, 1713, 1668, 1263 cm–1. 1H NMR (500 MHz, DMSO-d 6): δ 1.23 (6H, d, J= 6.1
Hz), 1.99 (3H, s), 4.96 (1H, q, J= 6.1 Hz), 7.09 (1H, s), 7.47 (2H, d, J= 8.5 Hz), 7.64 (2H, d, J= 8.5
Hz), 9.60 (1H, s). 13C NMR (125.7 MHz, DMSO-d6): δ 21.5, 22.4, 68.3, 128.0, 128.6, 128.7, 131.3,
132.4, 133.5, 164.4, 169.3. Anal. Calcd for C14H16NO3Cl: C, 59.68; H, 5.72; N, 4.97. Found: C, 59.85;
H, 5.82; N, 5.12.
tert-Butyl (Z)-2-Acetylamino-3-(4-chlorophenyl)-2-propenoate [(Z)-1i].
mp 118.0–119.0 °C.
°C. IR (KBr): 3226, 1725, 1659, 1260 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 1.45 (9H, s), 1.98
(3H, s), 7.04 (1H, s), 7.46 (2H, d, J= 8.5 Hz), 7.61 (2H, d, J= 8.5 Hz), 9.53 (1H, s). 13C NMR
(125.7 MHz, DMSO-d6): δ 22.3, 27.5, 80.5, 128.2, 128.5, 128.7, 131.2, 132.6, 133.3, 163.9, 169.2.
Anal. Calcd for C15H18NO3Cl: C, 60.91; H, 6.13; N, 4.74. Found: C, 60.97; H, 5.86; N, 4.35.
General Procedure for the Irradiation of (Z)-1a–i. A solution of (Z)-1 (4.0×10–3 mol dm–3) in

MeCN (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 regular time intervals, an appropriate
amount of the solution (5 mL) being irradiated was pipetted off and concentrated to dryness in vacuo giving
1
the residue which was subjected to H NMR analysis in DMSO-d6. The composition was estimated from
1
the area ratio of a given H NMR signal for each compound. After 24 h irradiation, the remaining solution
was concentrated to dryness under reduced pressure and the resulting residue was subjected to column
chromatography over silica gel (230 mesh, Merck) eluting with EtOAc-hexane. For the purpose of
isolating and purifying the photoproducts, preparative TLC plate (silica gel) was also used. Physical and
spectroscopic properties of the isolated isomers ((E)-1a–i) and isoquinolines (2a–e) and (2g–i) are as
follows.
(E)-1a. Oily liquid. IR (neat): 3310, 1719, 1635, 1245 cm–1. 1H NMR (500 MHz, DMSO-d6):δ 1.08
(3H, t, J= 7.3 Hz), 1.95 (3H, s), 4.08 (2H, q, J= 7.3 Hz), 6.51 (1H, s), 7.29 (2H, d, J= 8.6 Hz),
7.38 (2H, d, J= 8.6 Hz), 10.05 (1H, s). 13C NMR (125.7 MHz, DMSO-d6): δ 13.4, 22.3, 60.6, 117.4,
128.2, 129.5, 130.1, 131.8, 133.2, 164.4, 168.0. Anal. Calcd for C13H14NO3Cl: C, 58.33; H, 5.27; N,
5.23. Found: C, 58.33; H, 5.30; N, 5.00.
( E)-1b. Oily liquid. IR (neat): 3280, 1725, 1635, 1245 cm–1. 1H NMR (500 MHz, DMSO-d6): δ
1.06 (3H, t, J= 7.3 Hz), 1.95 (3H, s), 4.07 (2H, q, J= 7.3 Hz), 6.52 (1H, s), 7.19 (2H, d, J= 7.3 Hz),
7.25 (1H, d, J= 7.3 Hz), 7.32 (2H, dd, J= 7.3, 7.3 Hz), 10.01 (1H, s). 13C NMR (125.7 MHz, DMSO-
d6): δ 13.4, 22.4, 60.5, 118.8, 127.3, 127.8, 128.2, 129.5, 134.2, 164.6, 168.0. Anal. Calcd for
C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.88; H, 6.64; N, 6.00.
( E)-1c. Oily liquid. IR (neat): 3280, 1725, 1662, 1245 cm . 1H NMR (500 MHz, DMSO-d6): δ
–1
1.08 (3H, t, J= 7.3 Hz), 1.94 (3H, s), 2.28 (3H, s), 4.07 (2H, q, J= 7.0 Hz), 6.46 (1H, s), 7.09 (2H, d,
J= 8.2 Hz), 7.12 (2H, d, J= 8.2 Hz), 9.97 (1H, s). 13C NMR (125.7 MHz, DMSO-d6): δ 13.5, 20.7,
22.4, 60.5, 119.1, 127.9, 128.7, 128.8, 131.3, 136.8, 164.8, 168.0. Anal. Calcd for C14H17NO3: C,
68.00; H, 6.93; N, 5.66. Found: C, 68.05; H, 7.12; N, 5.58.
( E)-1d. Oily liquid. IR (neat): 3284, 1732, 1666, 1258 cm . 1H NMR (500 MHz, DMSO-d 6): δ
–1
1.10 (3H, t, J= 7.3 Hz), 1.93 (3H, s), 3.75 (3H, s), 4.08 (2H, q, J= 7.3 Hz), 6.45 (1H, s), 6.88 (2H, d,
J= 8.5 Hz), 7.15 (2H, d, J= 8.5 Hz), 9.91 (1H, s). 13C NMR (125.7 MHz, DMSO-d6): δ 13.6, 22.3,
55.1, 60.4, 113.7, 119.7, 126.5, 127.7, 129.4, 158.7, 164.9, 168.0. Anal. Calcd for C14H17NO4: C,
63.87; H, 6.51; N, 5.32. Found: C, 63.59; H, 6.64; N, 5.64.
(E)-1e. mp 98.5–99.0 °C. IR (KBr): 3322, 1740, 1677, 1260 cm–1. 1H NMR (500 MHz, DMSO-
d6): δ 1.06 (3H, t, J= 7.3 Hz), 1.98 (3H, s), 4.09 (2H, q, J= 7.3 Hz), 6.62 (1H, s), 7.40 (2H, d, J= 7.9
Hz), 7.65 (2H, d, J= 7.9 Hz), 10.15 (1H, s). 13C NMR (125.7 MHz, DMSO-d 6): δ 13.3, 22.4, 60.8,
116.5, 124.2 (q, J= 271 Hz), 125.0 (q, J= 4 Hz), 127.4 (q, J= 31 Hz), 128.4, 131.4, 138.7, 164.2,

168.1. Anal. Calcd for C14H14NO3F3: C, 55.82; H, 4.68; N, 4.65. Found: C, 56.01; H, 4.56; N, 4.25.
(E)-1f. mp 100.0–101.0 °C. IR (KBr): 3322, 1695, 1626, 1254 cm–1. 1H NMR (500 MHz, DMSO-
d6): δ 1.01 (3H, t, J= 7.0 Hz), 1.99 (3H, s), 4.02 (2H, q, J= 7.0 Hz), 6.68 (1H, s), 7.20 (1H, d, J= 8.2
Hz), 7.39 (1H, dd, J= 1.8, 8.2 Hz), 7.65 (1H, d, J= 1.8 Hz), 10.13 (1H, s). 13C NMR (125.7 MHz,
DMSO-d6): δ 13.4, 22.5, 60.7, 114.4, 127.1, 128.6, 130.6, 131.8, 132.2, 132.6, 133.1, 163.7, 168.3.
Anal. Calcd for C13H13NO3Cl2: C, 51.68; H, 4.34; N, 4.64. Found: C, 51.45; H, 4.20 N, 4.49.
(E)-1g. mp 99.0–100.0 °C. IR (KBr): 3250, 1731, 1662, 1245 cm–1. 1H NMR (500 MHz, DMSO-
d6): δ 1.96 (3H, s), 3.61 (3H, s), 6.50 (1H, s), 7.20 (2H, d, J= 8.6 Hz), 7.38 (2H, d, J= 8.6 Hz), 10.10
(1H, s). 13C NMR (125.7 MHz, DMSO-d6): δ 22.3, 51.8, 117.4, 128.3, 129.4, 129.7, 131.9, 133.1,
165.0, 168.1. Anal. Calcd for C12H12NO3Cl: C, 56.82; H, 4.77; N, 5.52. Found: C, 56.76; H, 4.99;
N, 5.21.
(E)-1h. mp 73.0–74.0 °C. IR (KBr): 3340, 1722, 1638, 1254 cm–1. 1H NMR (500 MHz, DMSO-
d6): δ 1.08 (6H, d, J= 6.1 Hz), 1.95 (3H, s), 4.92 (1H, q, J= 6.1 Hz), 6.47 (1H, s), 7.21 (2H, d, J= 8.6
Hz), 7.38 (2H, d, J= 8.6 Hz), 10.02 (1H, s). 13C NMR (125.7 MHz, DMSO-d6): δ 21.0, 22.3, 68.2,
116.8, 128.2, 129.6, 130.6, 131.7, 133.3, 163.9, 168.0. Anal. Calcd for C14H16NO3Cl: C, 59.68; H,
5.72; N, 4.97. Found: C, 59.73; H, 5.39; N, 4.57.
(E)-1i. mp 119.0–120.0 °C. IR (KBr): 3256, 1731, 1668, 1281 cm–1. 1H NMR (500 MHz, DMSO-
d6): d 1.32 (9H, s), 1.95 (3H, s), 6.49 (1H, s), 7.31 (2H, d, J= 8.6 Hz), 7.38 (2H, d, J= 8.6 Hz), 9.90
(1H, s). 13C NMR (125.7 MHz, DMSO-d6): d 22.4, 27.3, 81.2, 117.1, 128.0, 129.8, 131.5, 131.7,
133.7, 163.1, 168.0. Anal. Calcd for C15H18NO3Cl: C, 60.91; H, 6.13; N, 4.74. Found: C, 60.65; H,
5.87; N, 4.55.
Ethyl 7-Chloro-1-methylisoquinoline-3-carboxylate (2a).
mp 98.5–100.5 °C.
IR (KBr):
1731, 1278, 1233 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 1.37 (3H, t, J= 7.2 Hz), 2.93 (3H, s), 4.39
(2H, q, J= 7.2 Hz), 7.90 (1H, dd, J= 2.1, 8.9 Hz), 8.24 (1H, d, J= 8.9 Hz), 8.37 (1H, br s), 8.51 (1H, s).
13C NMR (125.7 MHz, DMSO-d6): δ 14.2, 22.1, 60.9, 121.8, 124.9, 128.8, 130.9, 131.5, 133.6,
134.1, 140.5, 158.4, 164.9. Anal. Calcd for C13H12NO2Cl: C, 62.53; H, 4.84; N, 5.61. Found: C,
62.55; H, 4.84; N, 5.38.
Ethyl 1-Methylisoquinoline-3-carboxylate (2b). mp 100.5–102.0 °C. IR (KBr): 1731, 1287,
1242 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 1.37 (3H, t, J= 7.0 Hz), 2.94 (3H, s), 4.39 (2H, q, J=
7.0 Hz), 7.83 (1H, dd, J= 7.0, 7.9 Hz), 7.88 (1H, dd, J= 7.0, 7.9 Hz), 8.19 (1H, d, J= 7.9 Hz), 8.31
(1H, d, J= 7.9 Hz), 8.49 (1H, s). 13C NMR (125.7 MHz, DMSO-d6): δ 14.2, 22.1, 60.9, 122.2, 125.8,
128.1, 128.7, 129.7, 130.9, 135.0, 140.1, 158.8, 169.4. Anal. Calcd for C13H13NO2: C, 72.54; H,
6.09; N, 6.51. Found: C, 72.57; H, 6.03; N, 6.56.

Ethyl 7-Methyl-1-methylisoquinoline-3-carboxylate (2c). mp 93.5–94.0 °C. IR (KBr): 1731,
1287, 1242 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 1.37 (3H, t, J= 6.1 Hz), 2.58 (3H, s), 2.91 (3H, s),
4.38 (2H, q, J= 6.1 Hz), 7.71 (1H, d, J= 7.6 Hz), 8.07 (1H, d, J= 7.6 Hz), 8.07 (1H, br s), 8.42 (1H, s).
13C NMR (125.7 MHz, DMSO-d6): δ 14.3, 21.7, 22.1, 60.8, 122.1, 124.7, 128.3, 128.5, 132.9, 133.1,
139.4, 139.8, 158.0, 165.3. Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C,
73.05; H, 6.63; N, 6.00.
Ethyl 7-Methoxy-1-methylisoquinoline-3-carboxylate (2d). mp 115.0–116.0 °C. IR (KBr):
1728, 1699, 1290, 1254 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 1.36 (3H, t, J= 7.3 Hz), 2.91 (3H, s),
3.99 (3H, s), 4.37 (2H, q, J= 7.3 Hz), 7.51 (1H, d, J= 8.6 Hz), 7.52 (1H, br s), 8.11 (1H, d, J= 8.6 Hz),
8.42 (1H, s). 13C NMR (125.7 MHz, DMSO-d6): δ 14.3, 22.2, 55.7, 60.6, 104.4, 122.0, 123.0, 129.7,
130.1, 130.4, 138.2, 157.0, 159.9, 165.3. Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71.
Found: C, 68.48; H, 6.34; N, 5.89.
Ethyl 7-Trifluoromethyl-1-methylisoquinoline-3-carboxylate (2e).
mp 91.0–92.5 °C.
IR
(KBr): 1743, 1716, 1284, 1242 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 1.38 (3H, t, J= 6.7 Hz), 3.03
(3H, s), 4.41 (2H, q, J= 6.7 Hz), 8.14 (1H, dd, J= 1.2, 8.5 Hz), 8.43 (1H, d, J= 8.5 Hz), 8.60 (1H, s),
8.64 (1H, br s). 13C NMR (125.7 MHz, DMSO-d6): δ 14.2, 22.2, 61.2, 121.7, 123.8, 126.0 (q, J= 272
Hz), 126.2 (q, J= 3 Hz), 127.2, 129.2 (q, J= 32 Hz), 130.6, 136.9, 142.1, 160.3, 164.9. Anal. Calcd
for C14H12NO2F3: C, 59.37; H, 4.27; N, 4.95. Found: C, 59.54; H, 4.13; N, 4.67.
Methyl 7-Chloro-1-methylisoquinoline-3-carboxylate (2g). mp 125.0–126.0 °C. IR (KBr):
1716, 1284, 1236 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 2.93 (3H, s), 3.92 (3H, s), 7.91 (1H, dd, J=
2.4, 8.6 Hz), 8.24 (1H, d, J= 8.6 Hz), 8.37 (1H, br s), 8.53 (1H, s). 13C NMR (125.7 MHz, DMSO-
d6): δ 22.1, 52.2, 121.9, 124.9, 128.8, 130.9, 131.5, 133.5, 134.1, 140.2, 158.3, 165.4. Anal. Calcd
for C12H10NO2Cl: C, 61.16; H, 4.28; N, 5.94. Found: C, 60.79; H, 4.51; N, 5.62.
Isopropyl 7-Chloro-1-methylisoquinoline-3-carboxylate (2h).
mp 100.0–101.0 °C.
IR
(KBr): 1706, 1284, 1244 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 1.38 (6H, d, J= 6.4 Hz), 2.93 (3H,
s), 5.22 (1H, q, J= 6.4 Hz), 7.89 (1H, dd, J= 2.1, 8.5 Hz), 8.23 (1H, d, J= 8.5 Hz), 8.35 (1H, d, J= 2.1
Hz), 8.47 (1H, s). 13C NMR (125.7 MHz, DMSO-d6): δ 21.7, 22.1, 68.5, 121.7, 124.9, 128.7, 130.9,
131.4, 133.5, 134.0, 140.8, 158.3, 164.4. Anal. Calcd for C14H14NO2Cl: C, 63.76; H, 5.35; N, 5.31.
Found: C, 63.62; H, 5.18; N, 5.27.
tert-Butyl 7-Chloro-1-methylisoquinoline-3-carboxylate (2i). mp 91.0–92.0 °C. IR (KBr):
1704, 1287, 1248 cm–1. 1H NMR (500 MHz, DMSO-d6): δ 1.60 (9H, s), 2.92 (3H, s), 7.88 (1H, dd, J=
2.4, 9.2 Hz), 8.21 (1H, d, J= 9.2 Hz), 8.35 (1H, br s), 8.41 (1H, s). 13C NMR (125.7 MHz, DMSO-
d6): δ 22.2, 27.8, 81.1, 121.4, 125.0, 128.7, 130.9, 131.4, 133.6, 133.9, 141.7, 158.2, 164.1. Anal.

Calcd for C15H16NO2Cl: C, 64.87; H, 5.81; N, 5.04. Found: C, 64.63; H, 5.87; N, 4.92.
trans-2-Methyl-3-(4-chlorophenyl)-4-ethoxycarbonyl-1-azetine (trans-3a).
We succeeded
13
in isolating trans-3a (oily liquid) whose IR, 1H, and C NMR spectra were consistent with the proposed
structure, although the trans-isomer was contaminated with small amounts of by-product(s) and/or the
azetine derived decomposition product(s). IR (neat): 3323, 1744, 1666, 1260, 1224 cm–1. 1H NMR
(500 MHz; DMSO-d6): d 1.21 (3H, t, J= 7.3 Hz), 2.06 (3H, d, J= 1.2 Hz), 4.17 (2H, q, J= 7.3 Hz), 4.71
(1H, dd, J= 1.2, 7.3 Hz), 5.64 (1H, d, J= 7.3 Hz), 7.36 (2H, d, J= 8.5 Hz), 7.48 (2H, d, J= 8.5 Hz).
13C NMR (125.7 MHz, DMSO-d6): d 13.4, 13.9, 61.1, 75.8, 81.5, 127.6, 128.8, 133.0, 138.6, 165.7,
170.3.
Sensitization Effects on the Photoreactivity of (Z)-1a.
For the purpose of examining
sensitization effects on the product distribution and composition, an MeCN solution (40 mL) of (Z)-1a (4.0
×10–3 mol dm–3) containing BP (4.0×10–2 mol dm–3), placed in a Pyrex vessel, was irradiated under
nitrogen at rt with light of wavelengths longer than 340 nm (Corning 0-52 glass filter) from a 450 W high
pressure Hg lamp. At suitable time intervals, an aliquot (5 mL) of the solution was pipetted off and
1
concentrated to dryness in vacuo. The resulting residue was dissolved in DMSO-d6 and subjected to H
NMR analysis.
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