One-pot synthesis of pyrrolo[2,1-a]isoquinoline-1-carboxamide derivatives via a four-component reaction

Article abstract of DOI:10.1055/s-2008-1032033

An effective route to functionalized 1,2,3,10b-tetrahydropyrrolo[2,1-a] isoquinoline-1-carboxamide derivatives is described. This involves reaction of N-alkyl-3-oxobutanamides, which result from the addition of amines to diketene, and dibenzoylacetylene in the presence of isoquinoline. The reactive 1:1 intermediate obtained from the addition of isoquinoline to dibenzoylacetylene is trapped by OH acids such as N-alkyl-3-oxobutanamides to produce the pyrrolo[2,1-a]isoquinoline-1-carboxamide derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032033

PAPER
429
One-Pot Synthesis of Pyrrolo[2,1-a]isoquinoline-1-carboxamide Derivatives
via a Four-Component Reaction
O
ne-Pot Synthesis
b
of Pyrrolo[2
d
,1-
a
]isoquino
o
line-1-carbo
l
xamide
a
D
erivative
l
s
i Alizadeh,* Nasrin Zohreh
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran 18716, Iran
Fax +98(21)88006544; E-mail: abdol_alizad@yahoo.com; E-mail: aalizadeh@modares.ac.ir
Received 9 July 2007; revised 20 November 2007
perature, to produce the 1-acetyl-N1-alkyl-2-hydroxy-3-
[(E)-2-oxo-2-phenylethylidene]-2-phenyl-1,2,3,10b-tet-
rahydropyrrolo[2,1-a]isoquinoline-1-carboxamide deriv-
atives 2 (Table 1).
Abstract: An effective route to functionalized 1,2,3,10b-tetrahy-
dropyrrolo[2,1-a]isoquinoline-1-carboxamide derivatives is de-
scribed. This involves reaction of N-alkyl-3-oxobutanamides,
which result from the addition of amines to diketene, and dibenzoyl-
acetylene in the presence of isoquinoline. The reactive 1:1 interme-
diate obtained from the addition of isoquinoline to dibenzoyl-
acetylene is trapped by OH acids such as N-alkyl-3-oxobutan-
amides to produce the pyrrolo[2,1-a]isoquinoline-1-carboxamide
derivatives.
The structure of compounds 2a–g was deduced from their
elemental analyses, IR spectra, and high-field 1H and 13
C
NMR spectra. The mass spectrum of 2a displayed the mo-
lecular ion peak at m/z 520, which is consistent with the
1:1:1:1 adduct of sec-butylamine, diketene, isoquinoline
and dibenzoylacetylene. The 1H NMR spectrum of 2a ex-
hibited nine signals readily recognized as arising from
three methyl groups (d = 0.79, d, 3JHH = 6.6 Hz; d = 1.02,
Key words: amine, diketene, dibenzoylacetylene, isoquinoline,
multicomponent reaction, pyrroloisoquinoline
3
t, JHH = 7.6 Hz; d = 2.10, s), one methylene group
Recently, multicomponent condensation reactions have
become one of the most powerful methods for the synthe-
sis of small molecule libraries, due to the fact that prod-
ucts are formed in a single step by simultaneous reaction
of several reagents and that the molecular diversity re-
quired for such combinatorial libraries can be achieved by
simply varying each component.1
(d = 1.56, m), two methine groups (d = 3.66, m; d = 6.44,
s), and vinylic CH (d = 6.16, s), NH (d = 6.26, t,
3JHH = 5.5 Hz) and OH (d = 9.56, s) protons, while the ar-
omatic moieties gave rise to characteristic signals in the
aromatic region of the spectrum. The proton-decoupled
13C NMR spectrum of 2a showed 29 distinct resonances,
in agreement with the pyrrolidinoisoquinoline structure.
Partial assignment of these resonances is given in the ex-
perimental section. The 1H and 13C NMR spectra of com-
pounds 2b–g are similar to those of 2a, except for the
amine moiety which exhibits characteristic signals with
appropriate chemical shifts (see experimental).
Pyrrolidinoisoquinoline alkaloids are abundant in plant
products, and many exhibit interesting biological activi-
ty.2 Accordingly, much attention has focused on the de-
velopment of general approaches to these alkaloids.3
Syntheses of the pyrrolidinoisoquinoline ring subunit
have also been described in the literature.4 Boekelheide
and Godfrey synthesized racemic pyrrolidinoisoquinoline
using the Bischler–Napieralski reaction of 2-oxo-1-(2-
phenylethyl)pyrroline.4e Optically active (+)-pyrrolidi-
noisoquinoline was first obtained by the degradative re-
duction of the alkaloid norsecurinine during structural
elucidation.4b However, it is surprising that only a few ex-
amples of the asymmetric synthesis of the pyrrolidinoiso-
quinoline skeleton have been demonstrated.5
Although the mechanism of the reaction between isoquin-
oline and dibenzoylacetylene in the presence of N-alkyl-
3-oxobutanamides 3, which are derived from the addition
of primary amines to diketene, has not yet been estab-
lished in an experimental manner, a possible explanation
is proposed in Scheme 1. Based on the well-established
chemistry of isoquinoline as a nucleophile,6–10 it is reason-
able to assume that 2 results from initial addition of iso-
quinoline to dibenzoylacetylene and subsequent
protonation of the 1:1 adduct 4 by the N-alkyl-3-oxobu-
tanamide 3 as OH acid. Then, the positively charged ion 5
might be attacked by the conjugate base of the OH acid to
form intermediate 6, which in turn is converted into enol
7. Finally, cyclization of enol 7 leads to compound 2.
We wish to report a simple, one-pot, four-component re-
action between amine, diketene and dibenzoylacetylene in
the presence of isoquinoline leading to 1,2,3,10b-tetrahy-
dropyrrolo[2,1-a]isoquinoline-1-carboxamide derivatives
2.
Reaction of the N-alkyl-3-oxobutanamides 3, which are
derived from the addition of a primary amine 1 to
diketene, with dibenzoylacetylene in the presence of iso-
quinoline proceeds in dichloromethane at ambient tem-
In conclusion, the present method carries the advantages
that not only is the reaction performed under neutral con-
ditions, but also the substances can be mixed without any
activation or modification. The simplicity of the present
procedure makes it an interesting alternative to complex
multistep approaches.11,12
SYNTHESIS 2008, No. 3, pp 0429–0432
x
x
.
x
x
.2
0
0
8
Advanced online publication: 10.01.2008
DOI: 10.1055/s-2008-1032033; Art ID: Z16407SS
© Georg Thieme Verlag Stuttgart · New York

430
A. Alizadeh, N. Zohreh
PAPER
Table 1 Reaction of Amine 1, Diketene and Dibenzoylacetylene in the Presence of Isoquinoline
O
COPh
N
CH2Cl2
r.t., 8 h
Ph
+
+
+
RNH2
O
N
RHNOC
Ph
O
COPh
1
MeOC
O
H
2
1,2
a
R
Yield (%) of 2
s-Bu
i-Bu
t-Bu
allyl
Bn
78
80
85
85
80
84
85
b
c
d
e
f
2-ClC6H4CH2
CH3(CH2)3CH(CH2CH3)CH2
g
1-Acetyl-N1-(sec-butyl)-2-hydroxy-3-[(E)-2-oxo-2-phenyleth-
ylidene]-2-phenyl-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquino-
line-1-carboxamide (2a); Typical Procedure
O
H
O
O
O
O
+
O
RNH2
RHN
RHN
To a magnetically stirred soln of s-BuNH2 (0.073 g, 1 mmol) and
diketene (0.084 g, 1 mmol) in anhyd CH2Cl2 (5 mL) was added, af-
ter 5 h, isoquinoline (0.129 g, 1 mmol), and finally a soln of diben-
zoylacetylene (0.234 g, 1 mmol) in anhyd CH2Cl2 (3 mL) was added
dropwise at r.t. over 10 min. The reaction mixture was then allowed
to stir for 2 h. The solvent was removed under reduced pressure and
the residue was subjected to silica gel column chromatography
(hexane–EtOAc, 7:1). The separated pyrroloisoquinoline was re-
crystallized (EtOH).
3
COPh
COPh
+
–
N
N
+
COPh
COPh
O
4
O
3
H
Yield: 0.41 g (78%); yellow crystals; mp 180–182 °C (dec).
–
N
RHN
+
IR (KBr): 3390 (OH), 3040 (NH), 1740 (COMe), 1656 (COPh),
1610 (CONH), 1594 (C=C), 1565 and 1502 cm–1 (Ar).
COPh
5
COPh
1H NMR (500 MHz, CDCl3): d = 0.79 (d, J = 6.6 Hz, 3 H, CHCH3),
1.02 (t, J = 7.6 Hz, 3 H, CH2CH3), 1.56 (m, 2 H, CH2CH3), 2.10 (s,
3 H, CH3), 3.66 (m, 1 H, CHNH), 6.16 (s, 1 H, NC=CH), 6.26 (t,
J = 5.5 Hz, 1 H, NH), 6.36 (d, J = 7.6 Hz, 1 H, C6H), 6.44 (s, 1 H,
C10bH), 6.90 (d, J = 7.5 Hz, 1 H, C5H), 7.04 (t, J = 7.2 Hz, 1 H, CH
of isoquinoline), 7.15 (t, J = 7.3 Hz, 2 H, 2 × CH of isoquinoline),
7.23 (t, J = 7.4 Hz, 1 H, CH of isoquinoline), 7.26 (t, J = 7.4 Hz, 1
H, CH of Ph), 7.31 (t, J = 7.4 Hz, 2 H, 2 × CH of Ph), 7.37 (t, J = 7.6
Hz, 2 H, 2 × CH of Ph), 7.46 (t, J = 7.1 Hz, 1 H, CH of Ph), 7.53 (d,
J = 7.2 Hz, 2 H, 2 × CH of Ph), 7.82 (d, J = 7.9 Hz, 2 H, 2 × CH of
Ph), 9.56 (s, 1 H, OH).
H
H
COPh
COPh
COPh
N
N
2
COPh
OH
RHNOC
RHNOC
O
7
6
Scheme 1
Amines and diketene were obtained from Merck (Germany) and
Fluka (Switzerland) and were used without further purification.
Dibenzoylacetylene was prepared according to a literature proce-
dure.13,14 Melting points were measured on an Electrothermal 9100
apparatus. Elemental analyses for C, H and N were performed using
a Heraeus CHN-O-Rapid analyzer. Mass spectra were recorded on
a Finnigan-Matt 8430 mass spectrometer operating at an ionization
potential of 20 eV. 1H and 13C NMR spectra were measured (CDCl3
solution) with a Bruker DRX-500 Avance spectrometer at 500.1
and 125.7 MHz, respectively. IR spectra were recorded on a Shi-
madzu IR-460 spectrometer. Chromatography columns were pre-
pared from Merck silica gel, 230–240 mesh.
13C NMR (125.7 MHz, CDCl3): d = 10.35 (CH2CH3), 19.55
(CHCH3), 31.00 (CH3), 31.04 (CH2CH3), 47.60 (CHNH), 64.51
(C10b), 77.26 (C1), 85.58 (COH), 89.21 (NC=CH), 116.74 (C6H),
121.25 (C5H), 125.74 (CH of Ph), 125.82 (CH of isoquinoline),
126.10 (2 × CH of Ph), 127.84 (2 × CH of Ph), 128.11 (2 × CH of
Ph), 128.25 (CH of isoquinoline), 128.30 (2 × CH of Ph), 128.55
(CH of isoquinoline), 129.13 (CH of isoquinoline), 129.87 (C10a),
130.50 (C6a), 131.93 (CH of Ph), 138.29 (CipsoCOH), 139.79 (Cipso
-
CO), 165.30 (NC=CH), 166.99 (CONH), 188.86 (COPh), 202.20
(COMe).
MS: m/z (%) = 520 (2) [M+], 421 (8), 368 (85), 364 (22), 360 (80),
316 (22), 298 (12), 185 (15), 154 (12), 130 (50), 105 (100), 77 (90),
58 (9), 43 (47).
Synthesis 2008, No. 3, 429–432 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Pyrrolo[2,1-a]isoquinoline-1-carboxamide Derivatives
431
Anal. Calcd for C33H32N2O4 (520.62): C, 76.13; H, 6.20; N, 5.38.
Found: C, 76.31; H, 6.40; N, 5.49.
Anal. Calcd for C33H32N2O4 (520.62): C, 76.13; H, 6.20; N, 5.38.
Found: C, 76.32; H, 6.31; N, 5.30.
1-Acetyl-2-hydroxy-N1-isobutyl-3-[(E)-2-oxo-2-phenyleth-
ylidene]-2-phenyl-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquino-
line-1-carboxamide (2b)
1-Acetyl-N1-allyl-2-hydroxy-3-[(E)-2-oxo-2-phenylethylidene]-
2-phenyl-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-1-
carboxamide (2d)
Yield: 0.42 g (80%); yellow crystals; mp 163–165 °C (dec).
Yield: 0.43 g (85%); yellow crystals; mp 185–187 °C (dec).
IR (KBr): 3395 (OH), 3040 (NH), 1699 (COMe), 1659 (COPh),
1620 (CONH), 1593 (C=C), 1564 and 1501 cm–1 (Ar).
IR (KBr): 3395 (OH), 3040 (NH), 1699 (COMe), 1663 (COPh),
1605 (CONH), 1592 (C=C), 1563 and 1498 cm–1 (Ar).
1H NMR (500 MHz, CDCl3): d = 0.92 (d, J = 6.7 Hz, 3 H, CH3 of i-
Bu), 0.97 (d, J = 6.7 Hz, 3 H, CH3 of i-Bu), 1.77 (sept, J = 6.7 Hz,
1 H, CH of i-Bu), 2.11 (s, 3 H, CH3), 2.61 (m, 1 H, CH2NH), 3.09
(m, 1 H, CH2NH), 6.20 (s, 1 H, NC=CH), 6.35 (d, J = 7.6 Hz, 1 H,
C6H), 6.44 (s, 1 H, C10bH), 6.49 (t, J = 6.0 Hz, 1 H, NH), 6.92 (d,
J = 7.6 Hz, 1 H, C5H), 7.00 (d, J = 7.5 Hz, 1 H, CH of isoquinoline),
7.15 (t, J = 8.0 Hz, 2 H, 2 × CH of isoquinoline), 7.22 (t, J = 7.5 Hz,
1 H, CH of Ph), 7.26 (d, J = 7.4 Hz, 1 H, CH of isoquinoline), 7.32
(t, J = 7.8 Hz, 2 H, 2 × CH of Ph), 7.38 (t, J = 7.5 Hz, 2 H, 2 × CH
of Ph), 7.46 (t, J = 7.4 Hz, 1 H, CH of Ph), 7.50 (d, J = 7.3 Hz, 2 H,
2 × CH of Ph), 7.82 (d, J = 7.8 Hz, 2 H, 2 × CH of Ph), 9.48 (s, 1 H,
OH).
1H NMR (500 MHz, CDCl3): d = 2.11 (s, 3 H, CH3), 3.50 (m, 1 H,
CH2NH), 3.81 (m, 1 H, CH2NH), 5.15 (d, J = 10.2 Hz, 1 H,
CH2=CH), 5.31 (d, J = 17.1 Hz, 1 H, CH2=CH), 5.72 (m, 1 H,
CH2=CH), 6.20 (s, 1 H, NC=CH), 6.35 (d, J = 7.6 Hz, 1 H, C6H),
6.43 (s, 1 H, C10bH), 6.50 (t, J = 6.0 Hz, 1 H, NH), 6.92 (d, J = 7.6
Hz, 1 H, C5H), 7.00 (d, J = 7.4 Hz, 1 H, CH of isoquinoline), 7.16
(t, J = 7.9 Hz, 2 H, 2 × CH of isoquinoline), 7.23 (t, J = 7.1 Hz, 1 H,
CH of Ph), 7.26 (d, J = 7.1 Hz, 1 H, CH of isoquinoline), 7.32 (t,
J = 7.1 Hz, 2 H, 2 × CH of Ph), 7.38 (t, J = 7.5 Hz, 2 H, 2 × CH of
Ph), 7.46 (t, J = 7.0 Hz, 1 H, CH of Ph), 7.49 (d, J = 7.6 Hz, 2 H, 2
× CH of Ph), 7.82 (d, J = 7.0 Hz, 2 H, 2 × CH of Ph), 9.48 (s, 1 H,
OH).
13C NMR (125.7 MHz, CDCl3): d = 20.35 (CH3 of i-Bu), 20.37
(CH3 of i-Bu), 28.22 (CH of i-Bu), 31.00 (CH3), 47.44 (CH2NH),
64.21 (C10b), 77.28 (C1), 85.79 (COH), 89.22 (NC=CH), 116.61
(C6H), 121.20 (C5H), 125.64 (2 × CH of Ph), 125.96 (CH of Ph),
126.13 (CH of isoquinoline), 127.84 (2 × CH of Ph), 128.02 (2 × CH
of Ph), 128.31 (2 × CH of Ph), 128.32 (CH of isoquinoline), 128.59
(CH of isoquinoline), 129.13 (CH of isoquinoline), 129.82 (C10a),
13C NMR (125.7 MHz, CDCl3): d = 30.96 (CH3), 42.46 (CH2NH),
64.16 (C10b), 77.40 (C1), 85.78 (COH), 89.26 (NC=CH), 116.59
(CH2=CH), 116.72 (C6H), 121.18 (C5H), 125.73 (2 × CH of Ph),
125.98 (CH of Ph), 126.15 (CH of isoquinoline), 127.84 (2 × CH of
Ph), 128.06 (2 × CH of Ph), 128.31 (CH of isoquinoline), 128.59 (2
× CH of Ph), 128.60 (CH of isoquinoline), 129.14 (CH of isoquin-
oline), 129.81 (C10a), 130.21 (C6a), 131.97 (CH of Ph), 133.72
(CH2=CH), 138.07 (CipsoCOH), 139.76 (CipsoCO), 165.72
(NC=CH), 166.51 (CONH), 188.94 (COPh), 202.11 (COMe).
130.34 (C6a), 131.95 (CH of Ph), 138.15 (CipsoCOH), 139.78 (Cipso
-
CO), 165.78 (NC=CH), 166.64 (CONH), 188.90 (COPh), 202.27
(COMe).
MS: m/z (%) = 520 (4) [M+], 403 (5), 360 (8), 342 (15), 298 (7), 185
(18), 170 (14), 142 (9), 129 (24), 105 (100), 77 (72), 58 (12), 43
(55).
MS: m/z (%) = 504 (3) [M+], 444 (4), 406 (3), 364 (6), 360 (10), 342
(12), 254 (6), 236 (10), 185 (12), 170 (14), 143 (11), 129 (49), 105
(100), 88 (77), 43 (73).
Anal. Calcd for C32H28N2O4 (504.58): C, 76.17; H, 5.59; N, 5.55.
Found: C, 76.19; H, 5.63; N, 5.43.
Anal. Calcd for C33H32N2O4 (520.62): C, 76.13; H, 6.20; N, 5.38.
Found: C, 76.10; H, 6.30; N, 5.40.
1-Acetyl-N1-benzyl-2-hydroxy-3-[(E)-2-oxo-2-phenyleth-
ylidene]-2-phenyl-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquino-
line-1-carboxamide (2e)
1-Acetyl-N1-(tert-butyl)-2-hydroxy-3-[(E)-2-oxo-2-phenyleth-
ylidene]-2-phenyl-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquino-
line-1-carboxamide (2c)
Yield: 0.44 g (80%); yellow crystals; mp 165–168 °C (dec).
Yield: 0.44 g (85%); yellow crystals; mp 175–177 °C (dec).
IR (KBr): 3395 (OH), 3040 (NH), 1696 (COMe), 1665 (COPh),
1600 (CONH), 1595 (C=C), 1565 and 1501 cm–1 (Ar).
IR (KBr): 3405 (OH), 3025 (NH), 1701 (COMe), 1665 (COPh),
1620 (CONH), 1591 (C=C), 1560 and 1495 cm–1 (Ar).
1H NMR (500 MHz, CDCl3): d = 2.14 (s, 3 H, CH3), 3.99 (dd,
J = 15.0, 4.4 Hz, 1 H, CH2Ph), 4.49 (dd, J = 14.9, 4.1 Hz, 1 H,
CH2Ph), 6.21 (s, 1 H, NC=CH), 6.36 (d, J = 7.5 Hz, 1 H, C6H), 6.47
(s, 1 H, C10bH), 6.73 (br, 1 H, NH), 6.93 (d, J = 7.6 Hz, 1 H, C5H),
7.07 (d, J = 7.5 Hz, 1 H, CH of isoquinoline), 7.16 (t, J = 7.3 Hz, 1
H, CH of isoquinoline), 7.18 (t, J = 7.2 Hz, 1 H, CH of isoquino-
line), 7.24 (t, J = 7.3 Hz, 1 H, CH of Ph), 7.28–7.39 (m, 10 H, 10 ×
CH of Ar), 7.44–7.48 (m, 3 H, 3 × CH of Ph), 7.82 (d, J = 7.6 Hz, 2
H, 2 × CH of Ph), 9.50 (s, 1 H, OH).
13C NMR (125.7 MHz, CDCl3): d = 31.04 (CH3), 44.15 (CH2NH),
64.19 (C10b), 77.39 (C1), 85.77 (COH), 89.28 (NC=CH), 116.67
(C6H), 121.22 (C5H), 125.66 (2 × CH of Ph), 126.02 (CH of Ph),
126.22 (CH of isoquinoline), 127.35 (CH of Ph), 127.87 (2 × CH of
Ph), 127.94 (2 × CH of Ph), 127.95 (CH of isoquinoline), 128.15 (2
× CH of Ph), 128.35 (2 × CH of Ph), 128.42 (CH of isoquinoline),
128.67 (2 × CH of Ph), 129.18 (CH of isoquinoline), 129.85 (C10a),
130.13 (C6a), 132.04 (CH of Ph), 137.66 (CipsoCH2NH), 137.98
(CipsoCOH), 139.69 (CipsoCO), 166.03 (NC=CH), 166.52 (CONH),
188.94 (COPh), 202.20 (COMe).
1H NMR (500 MHz, CDCl3): d = 1.13 [s, 9 H, C(CH3)3], 2.09 (s, 3
H, CH3), 6.11 (s, 1 H, NH), 6.15 (s, 1 H, NC=CH), 6.36 (d, J = 7.6
Hz, 1 H, C6H), 6.39 (s, 1 H, C10bH), 6.89 (d, J = 7.6 Hz, 1 H, C5H),
7.09 (d, J = 7.6 Hz, 1 H, CH of isoquinoline), 7.14 (d, J = 7.3 Hz, 1
H, CH of isoquinoline), 7.18 (t, J = 7.5 Hz, 1 H, CH of isoquino-
line), 7.23 (t, J = 7.1 Hz, 1 H, CH of isoquinoline), 7.27 (t, J = 7.4
Hz, 1 H, CH of Ph), 7.34 (t, J = 8.0 Hz, 2 H, 2 × CH of Ph), 7.37 (t,
J = 7.8 Hz, 2 H, 2 × CH of Ph), 7.46 (t, J = 7.3 Hz, 1 H, CH of Ph),
7.55 (d, J = 7.6 Hz, 2 H, 2 × CH of Ph), 7.82 (d, J = 7.4 Hz, 2 H, 2
× CH of Ph), 9.63 (1 H, s, 1 H, OH).
13C NMR (125.7 MHz, CDCl3): d = 28.10 [C(CH3)3], 31.05 (CH3),
51.41 [C(CH3)3], 64.63 (C10b), 77.51 (C1), 85.34 (COH), 89.20
(NC=CH), 116.90 (C6H), 121.28 (C5H), 125.75 (2 × CH of Ph),
126.07 (CH of Ph), 126.22 (CH of isoquinoline), 127.85 (2 × CH of
Ph), 128.16 (2 × CH of Ph), 128.20 (CH of isoquinoline), 128.31 (2
× CH of Ph), 128.39 (CH of isoquinoline), 129.18 (CH of isoquin-
oline), 129.83 (C10a), 130.55 (C6a), 131.94 (CH of Ph), 138.74
(CipsoCOH), 139.77 (CipsoCO), 164.91 (NC=CH), 167.07 (CONH),
188.83 (COPh), 202.03 (COMe).
MS: m/z (%) = 554 (2) [M+], 493 (3), 360 (7), 342 (15), 236 (14),
185 (17), 170 (25), 129 (39), 105 (100), 91 (38), 77 (90), 58 (26), 43
(37).
MS: m/z (%) = 520 (2) [M+], 342 (31), 130 (19), 105 (100), 77 (76),
57 (54), 51 (26), 43 (73).
Synthesis 2008, No. 3, 429–432 © Thieme Stuttgart · New York

432
A. Alizadeh, N. Zohreh
PAPER
Anal. Calcd for C36H30N2O4 (554.64): C, 77.96; H, 5.45; N, 5.05.
Found: C, 77.90; H, 5.50; N, 5.10.
(CipsoCO), 165.75 (NC=CH), 166.42 (CONH), 188.89 (COPh),
202.20 (COMe).
MS: m/z (%) = 576 (3) [M+], 365 (8), 360 (14), 343 (8), 236 (10),
212 (8), 185 (14), 170 (18), 154 (6), 142 (8), 129 (24), 115 (16), 105
(100), 85 (6), 77 (94), 57 (20), 43 (67).
1-Acetyl-N1-(2-chlorobenzyl)-2-hydroxy-3-[(E)-2-oxo-2-phen-
ylethylidene]-2-phenyl-1,2,3,10b-tetrahydropyrrolo[2,1-a]iso-
quinoline-1-carboxamide (2f)
Anal. Calcd for C37H40N2O4 (576.73): C, 77.06; H, 6.99; N, 4.86.
Found: C, 77.10; H, 6.95; N, 4.71.
Yield: 0.49 g (84%); yellow crystals; mp 180–182 °C (dec).
IR (KBr): 3300 (OH), 3040 (NH), 1697 (COMe), 1664 (COPh),
1617 (CONH), 1594 (C=C), 1564 and 1500 cm–1 (Ar).
1H NMR (500 MHz, CDCl3): d = 2.15 (s, 3 H, CH3), 4.26 (dd,
J = 15.5, 5.2 Hz, 1 H, CH2Ph), 4.50 (dd, J = 15.2, 6.2 Hz, 1 H,
CH2Ph), 6.22 (s, 1 H, NC=CH), 6.35 (d, J = 7.5 Hz, 1 H, C6H), 6.44
(s, 1 H, C10bH), 6.89 (br, 1 H, NH), 6.92 (d, J = 7.6 Hz, 1 H, C5H),
7.05 (d, J = 7.3 Hz, 1 H, CH of isoquinoline), 7.16 (t, J = 7.4 Hz, 2
H, 2 × CH of isoquinoline), 7.20 (t, J = 7.3 Hz, 1 H, CH of isoquin-
oline), 7.20–7.27 (m, 5 H, 5 × CH of Ph), 7.36–7.39 (m, 4 H, 4 × CH
of Ph), 7.44–7.47 (m, 3 H, 3 × CH of Ph), 7.82 (d, J = 7.5 Hz, 2 H,
2 × CH of Ph), 9.50 (s, 1 H, OH).
References
(1) (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (b) Ugi, I. J. Prakt. Chem./Chem.-Ztg. 1997, 339,
499. (c) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.;
Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123.
(d) Ugi, I. Proc. Est. Acad. Sci., Chem. 1998, 47, 107.
(e) Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.
Eur. J. 2000, 6, 3321. (f) Lee, D.; Sello, J. K.; Schreiber, S.
L. Org. Lett. 2000, 2, 709.
13C NMR (125.7 MHz, CDCl3): d = 31.28 (CH3), 41.67 (CH2NH),
64.22 (C10b), 77.38 (C1), 85.70 (COH), 89.30 (NC=CH), 116.63
(C6H), 121.23 (C5H), 125.52 (2 × CH of Ph), 126.01 (CH of Ph),
126.21 (CH of isoquinoline), 127.09 (CH of 2-ClC6H4), 127.87 (2 ×
CH of Ph), 128.08 (2 × CH of Ph), 128.33 (2 × CH of Ph), 128.39
(CH of isoquinoline), 128.53 (CH of isoquinoline), 128.62 (CH of
isoquinoline), 129.13 (CH of 2-ClC6H4), 129.33 (CH of 2-ClC6H4),
129.88 (C10a), 130.08 (CH of 2-ClC6H4), 130.12 (C6a), 132.02 (CH
of Ph), 133.60 (CipsoCl), 133.63 (CipsoCH2NH), 137.50 (CipsoCOH),
139.70 (CipsoCO), 166.21 (NC=CH), 166.54 (CONH), 188.93
(COPh), 202.15 (COMe).
(2) (a) Boekelheide, V. Alkaloids 1960, 7, 201. (b) Hill, R. K.
Alkaloids 1967, 9, 483.
(3) (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41,
4367. (b) Lete, E.; Egiarte, A.; Sotomayor, N.; Vicente, T.;
Villa, M.-J. Synlett 1993, 41. (c) Tsuda, Y.; Sakai, Y.;
Kaneko, M.; Ishiguro, Y. Heterocycles 1981, 15, 431.
(4) (a) Morlacchi, F.; Losacco, V. J. Heterocycl. Chem. 1976,
13, 165. (b) Saito, S.; Tanaka, T.; Kotera, K.; Nakai, H.;
Sugimoto, N.; Horii, Z.-I.; Ikeda, M.; Tamura, Y. Chem.
Pharm. Bull. 1965, 13, 786. (c) Veenstra, S. J.; Speckamp,
W. N. J. Am. Chem. Soc. 1981, 103, 4645. (d) Iketubosin,
G. O.; Mathieson, D. W. J. Pharm. Pharmacol. 1963, 15,
810. (e) Boekelheide, V.; Godfrey, J. C. J. Am. Chem. Soc.
1953, 75, 3679.
(5) (a) Sorgi, K. L.; Maryanoff, C. A.; McComsey, D. F.;
Graden, D. W.; Maryanoff, B. E. J. Am. Chem. Soc. 1990,
112, 3567. (b) Maryanoff, B. E.; McComsey, D. F.; Mutter,
M. S.; Sorgi, K. L.; Maryanoff, C. A. Tetrahedron Lett.
1988, 29, 5073. (c) Maryanoff, B. E.; McComsey, D. F. J.
Heterocycl. Chem. 1985, 22, 911. (d) Maryanoff, B. E.;
McComsey, D. F.; Almond, H. R. Jr.; Mutter, M. S.; Bemis,
G. W.; Whittle, R. R.; Olofson, R. A. J. Org. Chem. 1986,
51, 1341.
MS: m/z (%) = 589 (2) [M+], 417 (4), 402 (5), 375 (4), 298 (13), 273
(10), 190 (25), 129 (40), 105 (100), 89 (13), 77 (70), 43 (34).
Anal. Calcd for C36H29ClN2O4 (589.08): C, 73.40; H, 4.96; N, 4.76.
Found: C, 73.50; H, 5.00; N, 4.59.
1-Acetyl-N1-(2-ethylhexyl)-2-hydroxy-3-[(E)-oxo-2-phenyleth-
ylidene]-2-phenyl-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquino-
line-1-carboxamide (2g)
Yield: 0.49 g (85%); yellow crystals; mp 175–78 °C (dec).
IR (KBr): 3405 (OH), 3045 (NH), 1699 (COMe), 1662 (COPh),
1610 (CONH), 1595 (C=C), 1565 and 1501 cm–1 (Ar).
(6) (a) Huisgen, R. Proc. Chem. Soc., London 1961, 357.
(b) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 633.
(c) Garner, P.; Ho, W. B.; Grandhee, S. K.; Youngs, W. J.;
Kennedy, V. O. J. Org. Chem. 1991, 56, 5893. (d) Garner,
P.; Ho, W. B.; Shin, C. J. Am. Chem. Soc. 1993, 115, 10742.
(e) Monn, J. A.; Valli, M. J. Org. Chem. 1994, 59, 2773.
(f) Fiswick, C. W. G.; Foster, R. J.; Carr, R. E. Tetrahedron
Lett. 1996, 37, 3915.
1H NMR (500 MHz, CDCl3): d = 0.85–0.94 (m, 6 H, 2 × CH3 of 2-
ethylhexyl), 1.26–1.40 (m, 8 H, 4 × CH2 of 2-ethylhexyl), 1.45 (m,
1 H, CH of 2-ethylhexyl), 2.11 (s, 3 H, CH3), 2.71 (m, 1 H, CH2NH),
3.22 (m, 1 H, CH2NH), 6.19 (s, 1 H, NC=CH), 6.35 (d, J = 7.6 Hz,
1 H, C6H), 6.42 (br, 1 H, NH), 6.45 (s, 1 H, C10bH), 6.92 (d, J = 7.6
Hz, 1 H, C5H), 6.98 (d, J = 7.9 Hz, 1 H, CH of isoquinoline), 7.15
(t, J = 7.5 Hz, 2 H, 2 × CH of isoquinoline), 7.22 (t, J = 7.6 Hz, 1 H,
CH of Ph), 7.26 (d, J = 7.5 Hz, 1 H, CH of isoquinoline), 7.32 (t,
J = 7.7 Hz, 2 H, 2 × CH of Ph), 7.39 (t, J = 7.7 Hz, 2 H, 2 × CH of
Ph), 7.46 (t, J = 7.5 Hz, 1 H, CH of Ph), 7.49 (d, J = 7.6 Hz, 2 H, 2
× CH of Ph), 7.82 (d, J = 7.9 Hz, 2 H, 2 × CH of Ph), 9.48 (s, 1 H,
OH).
(7) (a) Huisgen, R. Topics in Heterocyclic Chemistry; Castle,
R., Ed.; Wiley & Sons: New York, 1969, Chap. 8, 223.
(b) Huisgen, R. Z. Chem. 1968, 8, 290.
(8) Huisgen, R.; Morikawa, M.; Herbig, K.; Brunn, E. Chem.
Ber. 1967, 100, 1094.
13C NMR (125.7 MHz, CDCl3): d = 10.94 (CH3 of 2-ethylhexyl),
14.10 (CH3 of 2-ethylhexyl), 23.08 (CH2 of 2-ethylhexyl), 24.43
(CH2 of 2-ethylhexyl), 28.84 (CH2 of 2-ethylhexyl), 29.69 (CH2 of
2-ethylhexyl), 31.15 (CH3), 39.08 (CH of 2-ethylhexyl), 42.74
(CH2NH), 64.23 (C10b), 77.40 (C1), 85.78 (COH), 89.21 (NC=CH),
116.61 (C6H), 121.19 (C5H), 125.59 (2 × CH of Ph), 125.95 (CH of
Ph), 126.11 (CH of isoquinoline), 127.83 (2 × CH of Ph), 128.04 (2
× CH of Ph), 128.27 (CH of isoquinoline), 128.30 (2 × CH of Ph),
128.55 (CH of isoquinoline), 129.12 (CH of isoquinoline), 129.80
(C10a), 130.38 (C6a), 131.94 (CH of Ph), 138.21 (CipsoCOH), 139.79
(9) Nair, V.; Sreekanth, A. R.; Abhilash, N.; Bhadbhade, M. M.;
Gonnade, R. C. Org. Lett. 2002, 4, 3575.
(10) Nair, V.; Sreekanth, A. R.; Biju, A. T.; Nigam, P. R.
Tetrahedron Lett. 2003, 44, 729.
(11) King, F. D. Tetrahedron 2007, 63, 2053.
(12) Allin, S. M.; James, S. L.; Martin, W. P.; Smith, T. A. D.
Tetrahedron Lett. 2001, 42, 3943.
(13) Skattebol, L.; Jones, E. R. H.; Whiting, M. C. Org. Synth.,
Coll. Vol. IV 1963, 792.
(14) Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C.
J. Chem. Soc. 1946, 39.
Synthesis 2008, No. 3, 429–432 © Thieme Stuttgart · New York