A novel one-pot, three-component access to hexahydropyrrolo[2,1-a] isoquinolines by an alkylation-dehydrohalogenation-1,3-dipolar cycloaddition sequence

Article abstract of DOI:10.1055/s-2005-869908

A simple one-pot process for the alkylation of isoquinolines followed by a dehydrohalogenation of the quaternary salts formed and by an in situ trapping of azomethine ylides with appropriate dipolarophiles is described. This method has successfully been a

Full text of DOI:10.1055/s-2005-869908

PAPER
2039
A Novel One-Pot, Three-Component Access to Hexahydropyrrolo[2,1-a]iso-
quinolines by an Alkylation–Dehydrohalogenation–1,3-Dipolar Cycloaddition
Sequence
S
ynthesisof Pyrrolo[2
i
,1-
a
]iso
k
quinolines lós Nyerges,*a Barbara Somfai,a Judit Tóth,a László Tőke,a András Dancsó,b Gábor Blaskób
a
Fax +361(463)3648; E-mail: mnyerges@mail.bme.hu
EGIS Pharmaceuticals Ltd., 1475 Budapest P.O. Box 100, Hungary
b
Received 6 January 2005; revised 21 January 2005
Dedicated to Professor Anrás Lipták on his 70th birthday
salts are often hygroscopic and they can contain impuri-
ties formed during the preparation; e.g. when the resulting
iminium salts lose the a-hydrogen under the alkylation
conditions to give the corresponding azomethine ylides,
Abstract: A simple one-pot process for the alkylation of isoquino-
lines followed by a dehydrohalogenation of the quaternary salts
formed and by an in situ trapping of azomethine ylides with appro-
priate dipolarophiles is described. This method has successfully
been applied to the synthesis of benz[5,6]azepino[2,1-a]isoquino- they react with the starting imines as dipolarophile giving
‘dimeric’ products.13a
lines and 5,6-dihydroindazolo[3,2-a]isoquinoline 8-oxides via an
1,7-electrocyclization process of similar type azomethine ylides.
We now report the development of a new a one-pot, three
Key words: cycloadditions, electrocyclic reactions, heterocycles,
component reaction. Simply mixing together the hydro-
tandem reactions, ylides
chloride salt of 3,4-dimethoxy-dihydroisoquinolne 1, the
alkylating agent 2, and the required dipolarophile 3 in an-
hydrous ethanol followed by adding two equivalent of
The 1,3-dipolar cycloaddition of azomethine ylides is one
base resulted in the formation of the expected cycloadduct
of the most simple approaches for the construction of pyr-
4a–o (Scheme 1). The yields summarized in Table 1, are
superior to those reported in our earlier work. The spectral
data of 4a–o are given in Table 2.
rolidine derivatives.1 There are, however, many other syn-
thetically useful reactions of these dipoles, including the
1,5- and 1,7-electrocyclic2,3 ring closure of appropriately
The stereochemistry of the products derived from the re-
substituted dipolar systems. The deprotonation of imini-
action of methyl bromoacetate (Table 1, entries 1–10) is
um salts is a very attractive method for the generation of
described in our earlier papers.13 The relative stereochem-
azomethine ylides derived from nitrogen heterocycles.4
Dipoles derived from 4,5-dihydroimidazoles,5 pyrimi-
dine,6 phenanthridine,7 isoquinoline,8 pyrrolo[1,2-c]pyri-
midine,9 quinoxaline,10 and most often from pyridines in
solution-phase11 or on solid support12 have been prepared
by N-alkylation of the corresponding heterocycles with an
a-halo carbonyl compound and subsequent deprotonation
of the resulting aromatic quaternary salts.
istry of the cycloadducts 4k–o (entries 11–15) was estab-
1
lished on 4m mostly by H{1H} NOE studies. The most
important proof of their stereochemistry was the NOE en-
hancements indicated with arrows in Figure 1. Represen-
tative 1H and 13C NMR data for compound 4m supporting
its structure are collected in Table 3.
The 1,3-dipolar cycloadditions of azomethine ylides de-
rived from dihydroisoqinolinium salts by deprotonation
was previously studied in detail by us.13 The dipoles pro-
duced by dehydrohalogenation, reacted with a wide range
of dipolarophiles e.g. maleimides, maleates etc. We have
also investigated the use of isoquinolinium salts for the
tandem in situ generation of azomethine ylides and base
sensitive dipolarophiles.14 However, the isoquinolinium
Figure 1 NOE enhancements in 4m
Scheme 1 Reagents and conditions: i. Et3N, EtOH, r.t.
SYNTHESIS 2005, No. 12, pp 2039–2045
x
x.
x
x
.
2
0
0
5
Advanced online publication: 19.05.2005
DOI: 10.1055/s-2005-869908; Art ID: P00405SS
© Georg Thieme Verlag Stuttgart · New York

2040
M. Nyerges et al.
PAPER
Table 1 Compounds 4a–o Prepared
Entry
1
EWG
R1
R2
Producta
Yield (%)
87
CO2Me
NO2
4a
2
3
4
CO2Me
CO2Me
CO2Me
NO2
NO2
NO2
4b
4c
4d
87
92
98
5
6
CO2Me
CO2Me
NO2
NO2
4e
4f
97
95
7
CO2Me
NO2
4g
95
8
9
CO2Me
CO2Me
CO2Me
NO2
4h
4i
86
79
83
CO2Et
CO2Et
10
4j
11
12
PhCO
PhCO
NO2
NO2
4k
4l
93
92
13
14
15
PhCO
NO2
4m
4n
4o
98
86
82
PhCO
CO2Et
NO2
4-BrC6H4CO
a Satisfactory microanalyses obtained: C 0.3, H 0.3, N 0.2.
Synthesis 2005, No. 12, 2039–2045 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolo[2,1-a]isoquinolines
2041
Table 2 Spectral Data of Compounds 4a–o Prepared
Prod-
uct
IR (KBr)
(cm–1)
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d
4a
4b
4c
4d
2952, 2855, 1741, 7.35 (5 H, m, Ph-H), 6.64 (1 H, s, H-7), 6.56 (1 H, s, H-10), 171.1 (quat.), 148.1 (quat.), 147.0 (quat.),
1611, 1576, 1550, 5.65 (1 H, dd, J = 3.5, 7.4, H-1), 5.39 (d, 1 H, 7.4, H-10b), 136.1 (quat.), 128.9 (2 × CH), 128.6 (CH),
1347, 1211, 1203, 4.65 (d, 1 H, 8.0, H-3), 4.34 (dd, 1 H, J = 8.0, 3.5, H-2), 3.87 128.4 (quat.), 127.8 (2 × CH), 122.8 (quat.),
1172, 1139, 1052
(3 H, s, ArOCH3), 3.82 (3 H, s, ArOCH3), 3.48 (m, 1 H, H- 113.4 (CH), 111.5 (CH), 95.4 (CH), 70.2
5), 3.34 (3 H, s, CO2CH3), 2.82 (1 H, m, H-5), 2.71 (1 H, m, (CH), 61.6 (CH), 55.8 ( OCH3), 55.7 (OCH3),
H-6), 2.63 (1 H, m, H-6)
52.1 (CH), 51.3 (OCH3), 46.7 (CH2), 27.1
(CH2)
2983, 2950, 2836, 7.16 (1 H, t, J = 8.0, Ar-5¢H), 6.80 (m, 3 H, Ar-H), 6.69 (1
169.0 (quat.), 159.3 (quat.), 148.2 (quat.),
1746, 1600, 1544, H, s, H-7), 6.63 (1 H, s, H-10), 5.13 (1 H, dd, J = 4.8, 8.1, H- 147.3 (quat.), 139.5 (quat.), 129.4 (quat.),
1524, 1490, 1466, 1), 4.14 (dd, 1 H, J = 8.5, 4.8, H-2), 4.12 (d, 1 H, 8.1, H-10b), 127.0 (CH), 126.1 (CH), 120.7 (quat.), 114.2
1388, 1264, 1204, 3.98 (1 H, d, J = 8.5, H-3), 3.87 (3 H, s, ArOCH3), 3.79 (3
1174, 1141, 1055 H, s, ArOCH3), 3.72 (3 H, s, ArOCH3), 3.55 (dd, 1 H, J =
(CH), 113.2 (CH), 111.5 (CH), 106.9 (CH),
94.6 (CH), 68.8 (CH), 67.6 (CH), 55.75 (
6.6, 10.2, H-5), 3.28 (3 H, s, CO2CH3), 2.79 (1 H, m, H-5), OCH3), 55.7 (OCH3), 55.0 (OCH3), 53.0
2.69 (1 H, m, H-6), 2.60 (1 H, m, H-6)
(CH), 51.2 (OCH3), 47.7 (CH2), 28.5 (CH2)
2980, 2952, 2833, 7.27 (2 H, d, J = 9.0, Ar-2¢ and 6¢H), 6.88 (2 H, d, J = 9.0,
1742, 1608, 1544, Ar-3¢ and 5¢H) 6.63 (1 H, s, H-7), 6.54 (1 H, s, H-10), 5.58
1523, 1488, 1391, (1 H, dd, J = 3.6, 7.2, H-1), 5.37 (d, 1 H, 7.2, H-10b), 4.62
171.2 (quat.), 159.3 (quat.), 148.0 (quat.),
147.1 (quat.), 129.1 (2 CH), 128.7 (quat.),
128.1 (quat.), 122.9 (quat.), 114.2 (2 CH),
1267, 1226, 1177, (1 H, d, J = 8.0, H-3), 4.28 (dd, 1 H, J = 8.0, 3.6, H-2), 3.83 113.4 (CH), 111.5 (CH), 96.0 (CH), 70.5
1056
(3 H, s, ArOCH3), 3.81 (3 H, s, ArOCH3), 3.79 (3 H, s,
ArOCH3), 3.50 (1 H, m, H-5), 3.36 (3 H, s, CO2CH3), 2.72
(1 H, m, H-5), 2.69 (1 H, m, H-6), 2.55 (1 H, m, H-6)
(CH), 64.0 (CH), 55.7 (OCH3), 55.6 (OCH3),
55.2 (OCH3), 51.4 (CH), 51.3 (OCH3), 46.0
(CH2), 26.7 (CH2)
2990, 2954, 2843, 6.91–6.78 (3 H, m Ar-H), 6.62 (1 H, s, H-7), 6.54 (1 H, s, H- 171.1 (quat.), 148.9 (quat.), 148.5 (quat.),
1738, 1610, 1543, 10), 5.58 (1 H, dd, J = 3.4, 6.9, H-1), 5.39 (1 H, d, J = 6.9,
1513, 1391, 1355, H-10b), 4.61 (1 H, d, J = 7.7, H-3), 4.30 (1 H, dd, J = 3.4,
147.9 (quat.), 147.1 (quat.), 134.2 (quat.),
128.3 (quat.), 122.6 (quat.), 119.8 (CH),
111.2 (CH), 111.1 (CH), 111.0 (CH), 108.9
1265, 1172, 1115
7.7, H-2), 3.88 (3 H, s, ArOCH3), 3.86 (3H, s, ArOCH3),
3.83 (3 H, s, ArOCH3), 3.81 (3 H, s, ArOCH3), 3.43 (3 H, s, (CH), 95.6 (CH), 70.2 (CH), 63.8 (CH), 55.7
CO2CH3), 3.32 (1 H, m, H-5), 3.14 (1 H, m, H-5), 2.85 (1 H, (OCH3), 55.65 (OCH3), 55.6 (OCH3), 55.5
m, H-6), 2.73 (1 H, m, H-6)
(OCH3), 51.5 (CH), 51.4 (OCH3), 46.0 (CH2),
26.7 (CH2)
4e
4f
2920, 2951, 2866, 7.00–6.88 (3 H, m Ar-H), 6.64 (1 H, s, H-7), 6.55 (1 H, s, H- 171.1 (quat.), 148.2 (quat.), 147.8 (quat.),
1735, 1604, 1542, 10), 5.92 (2 H, s, OCH2O), 5.50 (1 H, dd, J = 3.4, 7.1, H-1), 147.4 (quat.), 147.2 (quat.), 134.8 (quat.),
1521, 1381, 1350, 5.33 (1 H, d, J = 7.1, H-10b), 4.57 (1 H, d, J = 7.7, H-3), 4.22 128.6 (quat.), 122.8 (quat.), 119.8 (CH),
1269, 1112, 1016
(1 H, dd, J = 3.4, 7.7, H-2), 3.81 (3 H, s, ArOCH3), 3.78 (3
111.5 (CH), 111.1 (CH), 111.0 (CH), 109.2
H, s, ArOCH3), 3.44 (3 H, s, CO2CH3), 3.27 (1 H, m, H-5), (CH), 100.9 (CH2), 95.7 (CH), 70.5 (CH),
3.11 (1 H, m, H-5), 2.84 (1 H, m, H-6), 2.64 (1 H, m, H-6)
63.9 (CH), 56.0 (OCH3), 55.8 (OCH3), 51.8
(CH), 51.6 (OCH3), 46.1 (CH2), 26.6 (CH2)
3041, 2994, 2837, 6.62 (1 H, s, H-7), 6.57 (2 H, s, Ar-2¢ and 6¢H), 6.54 (1 H, s, 171.3 (quat.), 153.4 (3 quat.), 148.1 (quat.),
1728, 1611, 1728, H-10), 5.60 (1 H, dd, J = 4.0, 7.1, H-1), 5.37 (1 H, d, J = 7.2, 147.3 (quat.), 137.5 (quat.), 128.3 (quat.),
1590, 1547, 1516, H-3), 4.60 (1 H, d, J = 7.1, H-10b), 4.30 (dd, 1 H, J = 4.0,
1467, 1368, 1234, 7.2, H-2), 3.86 (6 H, s, 2 OCH3), 3.85 (3 H, s, OCH3), 3.83 (2 CH) 95.7 (CH), 70.5 (CH), 63.9 (CH), 56.1
1132, 1012 (3 H, s, ArOCH3), 3.82 (3 H, s, OCH3), 3.47 (3 H, s, OCH3), (2 OCH3), 56.0 (OCH3), 55.9 (OCH3), 55.7
122.5 (quat.), 111.3 (CH), 109.0 (CH), 104.9
3.33 (1 H, m, H-5), 3.18 (1 H, m, H-5), 2.95–2.60 (2 H, m,
H-6)
(OCH3), 52.2 (CH), 51.6 (OCH3), 46.3 (CH2),
27.0 (CH2)
4g
3009, 2952, 2834, 8.19 (1 H, s, Ar-2¢H), 8.13 (1 H, d, J = 7.8, Ar-6¢H), 7.69 (1 170.4 (quat.), 148.3 (quat.), 148.2 (quat.),
1738, 1725, 1555, H, d, J = 7.8, Ar-4¢H), 7.53 (1 H, t, J = 7.8, Ar-5¢H), 6.60 (1 147.3 (quat.), 138.0 (quat.), 133.9 (CH),
1529, 1464, 1348, H, s, H-7), 6.53 (1 H, s, H-10), 5.67 (1 H, dd, J = 3.7, 6.8, H- 129.9 (quat.), 128.2 (CH), 122.9 (2 CH),
1259, 1229, 1215, 1), 5.38 (1 H, d, J = 7.1, H-3), 4.66 (1 H, d, J = 6.8, H-10b), 122.0 (quat.), 111.3 (CH), 109.0 (CH), 94.6
1195, 1176, 1138, 4.48 (dd, 1 H, J = 3.7, 7.1, H-2), 3.82 (3 H, s, OCH3), 3.79
1120, 1077, 1013 (3 H, s, OCH3), 3.40 (3 H, s, OCH3), 3.33 (1 H, m, H-5), 3.11 55.6 (OCH3), 51.7 (CH), 51.3 (OCH3), 45.9
(1 H, m, H-5), 2.84 (1 H, m, H-6), 2.68 (1 H, m, H-6) (CH2), 26.5 (CH2)
(CH), 70.1 (CH), 64.0 (CH), 55.8 (OCH3),
4h
3009, 2973, 2942, 8.57 (1 H, d, J = 1.8, Py-2¢H), 8.55 (dd, 1 H, J = 1.8, 5.0, Py- 170.3 (quat.), 149.4 (quat.), 149.3 (CH),
2837, 1732, 1611, 4¢H), 7.71 (1 H, m, Py-5¢H), 7.29 (dd, 1 H, J = 5.0, 7.8, Py- 148.0 (quat.), 147.2 (quat.), 135.0 (CH),
1576, 1554, 1520, 6¢H), 6.63 (1 H, s, H-7), 6.54 (1 H, s, H-10), 5.63 (1 H, dd, 131.7 (CH), 128.3 (quat.), 123.5 (CH), 122.1
1481, 1430, 1411, J = 3.8, 7.0, H-1), 5.38 (1 H, d, J = 7.3, H-3), 4.68 (1 H, d,
(quat.), 111.3 (CH), 109.0 (CH), 94.5 (CH),
1384, 1368, 1260, J = 7.0, H-10b), 4.38 (dd, 1 H, J = 3.8, 7.3, H-2), 3.84 (3 H, 69.7 (CH), 63.9 (CH), 55.8 (OCH3), 55.6
1208, 1169, 1048, s, OCH3), 3.81 (3 H, s, OCH3), 3.41 (3 H, s, OCH3), 3.31 (1 (OCH3), 51.6 (OCH3), 49.2 (CH), 45.8 (CH2),
1026, 1009
H, m, H-5), 3.14 (1 H, m, H-5), 2.85 (1 H, m, H-6), 2.69 (1 26.3 (CH2)
H, m, H-6)
Synthesis 2005, No. 12, 2039–2045 © Thieme Stuttgart · New York

2042
M. Nyerges et al.
PAPER
Table 2 Spectral Data of Compounds 4a–o Prepared (continued)
Prod-
uct
IR (KBr)
(cm–1)
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d
4i
2991, 2890, 2835, 7.30 (5 H, m, Ph-H), 6.61 (1 H, s, H-7), 6.58 (1 H, s, H-10), 173.6 (quat.), 172.1 (quat.), 147.3 (quat.),
2739, 2677, 1724, 5.28 (1 H, d, J = 8.3, H-10b), 4.46 (1 H, d, J = 7.8, H-3), 4.24 146.9 (quat.), 138.8 (quat., Ph-1¢C), 128.4 (2
1609, 1522, 1465, (2 H, q, J = 7.2, OCH2), 4.02 (1 H, dd, J = 5.3, 7.8, H-2), 3.85 CH, Ph-2¢ and 6¢C), 128.3 (CH, Ph-4¢C),
1453, 1355, 1319, (3 H, s, OCH3), 3.82 (3 H, s, OCH3), 3.74 (1 H, dd, J = 5.3, 127.8 (2 CH, Ph-3¢ and 5¢C), 127.1 (quat., C-
1280, 1256, 1199, 8.3, H-1), 3.33 (3 H, s, OCH3), 3.23 (1 H, m, H-5), 3.11 (1
6a), 126.0 (quat., C-10a), 111.1 (CH, C-7),
1133, 1112, 1029 H, m, H-5), 2.85 (1 H, m, H-6), 2.60 (1 H, m, H-6), 1.39 (3 109.8 (CH, C-10), 62.9 (CH, C-10b), 60.9
H, t, J = 7.2, CH3)
(OCH2), 55.8 (OCH3), 55.7 (OCH3), 55.4
(CH, C-1), 51.4 (OCH3), 49.9 (CH, C-2), 46.2
(CH2, C-5), 26.0 (CH2, C-6), 14.3 (CH3)
4j
2970, 2890, 2740, 8.27 (2 H, d, J = 8.4, Ar-2¢ and 6¢H), 7.88 (2 H, d, J = 8.4,
172.6 (quat.), 171.3 (quat.), 149.3 (quat.),
1727, 1611, 1523, Ar-2¢ and 6¢H), 6.61 (1 H, s, H-7), 6.56 (1 H, s, H-10), 5.23 147.2 (quat.), 146.7 (quat.), 144.8 (quat.),
1467, 1456, 1430, (1 H, d, J = 8.2, H-10b), 4.56 (1 H, d, J = 7.9, H-3), 4.26 (2 128.5 (2 CH), 123.6 (2 CH), 128.5 (quat.),
1411, 1382, 1352, H, q, J = 7.4, OCH2), 4.11 (1 H, dd, J = 5.0,d 7.9, H-2), 3.87 125.5 (quat.), 111.4 (CH), 110.2 (CH), 62.7
1322, 1270, 1191, (3 H, s, OCH3), 3.84 (3 H, s, OCH3), 3.70 (1 H, dd, J = 5.0
1111, 1067, 1029 8.2, H-1), 3.35 (3 H, s, OCH3), 3.29 (1 H, m, H-5), 3.15 (1
(CH), 60.7 (OCH2), 55.8 (OCH3), 55.6
(OCH3), 55.3 (CH), 51.3 (OCH3), 49.6 (CH),
H, m, H-5), 2.80 (1 H, m, H-6), 2.42 (1 H, m, H-6), 1.40 (3 46.2 (CH2), 25.7 (CH2), 14.2 (CH3)
H, t, J = 7.4, CH3)
4k
3004, 2914, 2828, 7.49 (5 H, s, Ph-H), 7.07 (1 H, t, J = 7.5, Ph-4¢H), 7.04 (2 H, 193.8 (quat.), 148.4 (quat.), 147.4 (quat.),
1696, 1611, 1560, d, J = 7.5, Ph-2¢ and 6¢H), 6.91 (2 H, d, J = 7.5, Ph-3¢ and
1543, 1452, 1318, 5¢H), 6.72 (1 H, s, H-7), 6.67 (1 H, s, H-10), 5.13 (1 H, dd,
137.4 (quat.), 135.5 (quat.), 131.8 (2 CH),
129.0 (2 CH),128.8 (2 CH), 128.3 (2 CH),
1263, 1239, 1176, J = 4.4, 7.9, H-1), 4.78 (1 H, d, J = 8.3, H-3), 4.24 (dd, 1 H, 127.9 (CH), 127.3 (CH), 126.2 (quat.), 111.7
984
J = 4.4, 8.3, H-2), 4.23 (1 H, d, J = 7.9, H-10b), 3.89 (3 H, s, (quat.), 107.1 (CH), 95.8 (CH), 71.7 (CH),
ArOCH3), 3.81 (3 H, s, ArOCH3), 3.58 (1 H, m, H-5), 3.39 68.3 (CH), 55.9 (OCH3), 55.8 (OCH3), 54.2
(1 H, m, H-5), 2.79 (1H, m, H-6), 2.58 (1 H, m, H-6)
(CH), 48.3 (CH2), 28.7 (CH2)
4l
3014, 2922, 2834, 8.05 (1 H, d, J = 7.8, Ar2-4¢H), 8.04 (1 H, s, Ar2-2¢H), 7.80
2822, 1698, 1612, (2 H, d, J = 7.5, Bz-2¢ and 6¢H), 7.61 (1 H, d, J = 7.8, Ar2-
195.5 (quat.), 148.4 (quat.), 148.3 (quat.),
147.5 (quat.), 138.2 (quat.), 136.1 (quat.),
1561, 1544, 1503, 6¢H), 7.54 (1 H, t, J = 7.4, Bz-4¢H), 7.42 (3 H, m, Bz-3¢ and 133.9 (CH), 133.8 (CH), 129.9 (CH), 128.9
1451, 1314, 1257, 5¢H and Ar2-5¢H), 6.62 (1 H, s, H-7), 6.57 (1 H, s, H-10),
(2 CH), 128.2 (2 CH), 127.8 (quat.), 123.0
1240, 1211, 1156, 5.99 (1 H, dd, J = 5.4, 7.8, H-1), 5.58 (1 H, d, J = 6.9, H-3), (CH), 122.5 (quat.), 121.9 (CH), 111.3 (CH),
1098
5.20 (1 H, d, J = 7.8, H-10b), 4.69 (d, 1 H, J = 6.0, H-2), 3.85 109.4 (CH), 95.6 (CH), 72.1 (CH), 64.05
(3 H, s, ArOCH3), 3.84 (3 H, s, ArOCH3), 3.53 (1 H, m, H- (CH), 56.0 (OCH3), 55.8 (OCH3), 51.5 (CH),
5), 3.32 (1 H, m, H-5), 2.86 (2 H, m)
46.8 (CH2), 27.6 (CH2)
4m
4n
4o
2999, 2938, 2836, 7.75 (2 H, d, J = 7.4, Bz-2¢ and 6¢H), 7.50 (1 H, t, J = 7.4,
197.0 (quat.), 148.7 (quat.), 148.3 (quat.),
1736, 1542, 1520, Bz-4¢H), 7.37 (2 H, d, J = 7.4, Bz-3¢ and 5¢H), 6.74 (1 H, dd, 148.1 (quat.), 147.3 (quat.), 137.0 (quat.),
1463, 1450, 1367, J = 1.8, 8.3, Ar2-6¢H), 6.69 (1 H, d, J = 8.3, Ar2-5¢H), 6.62 (1 133.0 (CH), 128.5 (2 CH), 128.45 (quat.),
1262, 1239, 1149, H, s, H-7), 6.59 (1 H, d, J = 1.8, Ar2-2¢H), 6.56 (1 H, s, H-
128.2 (quat.), 127.8 (2 CH), 122.7 (quat.),
120.3 (CH), 111.5 (CH), 111.3 (CH), 111.25
(CH), 109.3 (CH), 96.5 (CH), 71.9 (CH),
63.95 (CH), 55.9 (OCH3), 55.75 (OCH3), 55.7
1027
10), 5.70 (1 H, dd, J = 3.9, 7.2, H-1), 5.55 (1 H, d, J = 7.2,
H-3), 5.34 (1 H, d, J = 7.2, H-10b), 4.41 (dd, 1 H, J = 3.9,
7.2, H-2), 3.85 (3 H, s, ArOCH3), 3.83 (3 H, s, ArOCH3),
3.79 (3 H, s, ArOCH3), 3.69 (3 H, s, ArOCH3), 3.42 (1 H, m, (2 OCH3), 52.1 (CH), 46.5 (CH2), 26.8 (CH2)
H-5), 3.28 (1 H, m, H-5), 2.88 (1 H, m, H-6), 2.73 (1 H, m,
H-6)
2992, 2870, 2834, 8.24 (2H, d, J = 8.4 Hz, Ar-2¢ and 6¢ H), 8.02 (2H, d, J = 8.4 197.1 (quat.), 173.4 (quat.), 149.3 (quat.),
2677, 1724, 1698, Hz, Ar-3¢ and 5¢ H), 7.78 (2H, d, J = 7.5 Hz, Bz-2¢ and 6¢H), 147.8 (quat.), 147.2 (quat.), 144.9 (quat.),
1611, 1524, 1465, 7.68 (1H, t, J = 7.5 Hz, Bz-4¢H), 7.39 (2H, d, J = 7.5 Hz, Bz- 137.1 (quat.), 133.2 (CH), 128.7 (2 x CH),
1455, 1355, 1333, 3¢ and 5¢H), 6.64 (1H, s, H-7), 6.60 (1H, s, H-10), 5.72 (1H, 128.5 (2 x CH), 128.4 (quat.), 127.8 (2 x CH),
1295, 1259, 1197, dd, J = 3.9 and 7.4 Hz, H-1), 5.54 (1H, d, J = 7.2 Hz, H-3), 123.7 (2 x CH), 122.9 (quat.), 111.4 (CH),
1130, 1112, 1011
5.30 (1H, d, J = 7.4 Hz, H-10b), 4.40 (dd, 1H, J = 3.9 and 7.2 109.4 (CH), 96.4 (CH), 71.8 (CH), 63.9 (CH),
Hz, H-2), 3.85 (3H, s, Ar-OMe), 3.84 (3H, s, Ar-OMe), 4.24 55.9 (OCH3), 55.8 (OCH3), 52.0 (CH), 46.6
(2H, q, J = 7.4 Hz, OCH2), 3.44 (1H, m, H-5), 3.22 (1H, m, (CH2), 26.8 (CH2)
H-5), 2.84 (1H, m, H-6), 2.71 (1H, m, H-6); 1.39 (3H, t, J =
7.2 Hz, CH3)
2990, 2948, 2841, 7.50 (2 H, d, J = 8.8, Ar3-3¢ and 5¢H), 7.47 (2 H, d, J = 8.8, 193.7 (quat.), 159.1 (quat.), 148.2 (quat.),
1704, 1539, 1519, Ar3-2¢ and 6¢H), 6.94 (1 H, t, J 7.9, Ar2-5¢H), 6.71 (1 H, s, 147.3 (quat.), 138.7 (quat.), 135.5 (quat.),
1455, 1384, 1263, H-7), 6.66 (1 H, s, H-10), 6.60 (1 H, d, J = 7.9, Ar2-4¢H), 131.6 (2 CH), 129.3 (CH), 129.0 (2 CH),
1239, 1145, 1022, 6.51 (1 H, t, J = 7.9, Ar2-6¢H), 6.45 (1 H, s, Ar2-2¢H), 5.13 128.0 (quat.), 127.2 (quat.), 126.0 (quat.),
988
(1 H, dd, J 4.5, 7.9, H-1), 4.76 (1 H, d, J = 8.3, H-3), 4.22 120.9 (CH), 114.2 (CH), 113.5 (CH), 111.6
(m, 2 H, H-2 and H-10b), 3.88 (3 H, s, ArOCH3), 3.80 (3 (CH), 106.9 (CH), 95.5 (CH), 71.5 (CH),
H, s, ArOCH3), 3.56 (3 H, s, ArOCH3), 3.55 (1 H, m, H-5), 67.9 (CH), 55.8 (OCH3), 55.7 (OCH3), 54.8
3.36 (1 H, m, H-5), 2.78 (1 H, m, H-6), 2.58 (1 H, m, H-6) (OCH3), 54.0 (CH), 48.1 (CH), 28.7 (CH2)
Synthesis 2005, No. 12, 2039–2045 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolo[2,1-a]isoquinolines
2043
Table 3 Selected 1H and 13C NMR Chemical Shifts, H,H Couplings and Measured NOE and HMQC Connectivities for Compound 4m
Assignment
H-1
dH
1H{1H} NOE Connections
dC
HMQC Correlations
H-2, H-3
5.70 (dd)a
4.41 (dd)b
5.53 (d)
3.28 (m)
3.42 (m)
2.73 (m)
2.88
H-10b, H-9, Ar4-6¢H
95.5
52.1
71.9
48.5
–
H-2
H-3, H-6a, Ph-2¢ and 6¢H, Ar4-2¢ and 6¢H
Ar2-2¢H, Ar2-6¢H, H-3
H-1, H-2, H-5a
H-3, H-10b
–
H-3
H-2, Ph-2¢ and 6¢H
H-5a
–
H-5b
–
H-6a
–
26.8
–
H-5a, H-7
–
H-6b
–
H-7
6.62 s
8-OCH3, H-6a, H-6b
9-OCH3, H-10b, H-1
H-1, Ar4-2¢ and 6¢H, H-9
111.3
109.3
63.9
H-6
H-10
H-10b
6.56 s
H-10b
5.38 d
H-1, H-3, H-10
a J1,10b = 7.3 Hz, J1,2 = 3.9 Hz.
b J2,3 = 7.2 Hz.
Recently we described the first examples of the 1,7-elec- the presence of an alkylating agent and triethylamine, tet-
trocyclization of ester-stabilized a,b:g,d-unsaturated rahydrobenz[5,6]azepino[2,1-a]isoquinolines 6a–c were
azomethine ylides, which were generated by the deproto- obtained in a single step (Scheme 2). The yields (entries
nation method from the corresponding isoquinolinium 1–3) and spectral data are summarized in Tables 4 and 5,
salts.15 Starting from 1-(2,2-diphenylethenyl)-3,4- respectively.
dimethoxy-6,7-dihydroisoquinoline hydrochloride (5a) in
Table 4 Compounds 6 and 7 Prepared
Entry
1
R
R1
R2
–
Starting Material
R3
Product
Yield (%)
88
Me
5a
CO2Me
6a
2
3
4
Me
Me
Me
–
5a
5a
5b
Ph
6b
6c
7a
82
75
89
–
CH2=CH
CH2=CH
H
5
6
7
Me
Et
Cl
H
5c
5d
5e
CH2=CH
CH2=CH
CH2=CH
7b
7c
7d
96
94
94
Et
Cl
Synthesis 2005, No. 12, 2039–2045 © Thieme Stuttgart · New York

2044
M. Nyerges et al.
PAPER
Table 5 Spectral Data of Compounds 6 Prepared
Product
IR (KBr)
(cm–1)
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d
6a
3429, 2985, 2957,
2834, 1723, 1513,
1491, 1464, 1450,
1423, 1355, 1342,
1275, 1234, 1212,
1178, 1149, 1025
7.63 (m, 2 H, Ar-H), 7.40 (m, 2 H, Ar-H), 170.7 (quat. C), 149.3 (quat. C), 147.4 (quat. C), 146.2
7.26 (m, 6 H, Ar-H), 7.11 (s, 1 H, H-1), (quat. C), 144.5 (quat. C), 143.8 (quat. C), 128.6 (quat. C),
6.64 (s, 1 H, H-14), 5.52 (s, 1 H, H-14a), 128.5 (CH), 128.2 (2 CH), 127.9 (CH), 127.8 (CH), 127.5
4.82 (s, 1 H, H-8), 3.89 (s, 6 H, 2 OCH3), (2 CH), 127.1 (quat. C), 126.5 (CH), 126.0 (CH), 119.5
3.34 (s, 3 H, CO2CH3), 3.31 (m, 2 H, CH2- (quat. C), 110.4 (CH), 107.2 (CH), 102.1 (CH), 76.5 (CH),
6), 2.18 (m, 2 H, CH2-5)
62.1 (CH), 55.8 (OCH3), 55.7 (OCH3), 51.3 (CO2CH3),
46.5 (CH2), 29.0 (CH2)
6b
6c
3482, 2945, 2925,
2830, 1609, 1500,
1463, 1337, 1270,
1231, 1212, 1175,
1148, 1020
7.53 (m, 2 H, Ar-H), 7.33 (m, 2 H, Ar-H), 147.6 (quat. C), 147.4 (quat. C), 145.5 (quat. C), 143.6
7.20 (m, 2 H, Ar-H), 7.02 (m, 7 H, Ar-H), (quat. C), 138.4 (quat. C), 129.9 (2 CH), 129.2 (quat. C),
6.87 (m, 3 H, Ar-H), 6.63 (s, 1 H, H-14), 129.1 (CH), 128.1 (2 CH), 127.9 (3 CH), 127.7 (quat. C),
5.50 (s, 1 H, H-14a), 5.17 (s, 1 H, H-8),
127.4 (quat. C), 127.0 (CH), 126.9 (3 CH), 125.7 (2 CH),
3.89 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 120.1 (quat. C), 110.7 (CH), 107.2 (CH), 103.2 (CH), 77.8
3.08 (m, 1 H, CH2-6), 3.02 (m, 1 H, CH2- (CH), 63.2 (CH), 55.9 (2 CH3), 45.6 (CH2), 29.4 (CH2)
6), 2.70 (m, 2 H, CH2-5)
3471, 2951, 2935,
2922, 2840, 1611,
1504, 1462, 1272,
1226, 1218, 1179,
1022
7.44 (m, 2 H, Ar-H), 7.33 (m, 2 H, Ar-H), 149.3 (quat. C), 149.2 (quat. C), 145.9 (quat. C), 144.6
7.25–7.11 (m, 7 H, Ar-H), 6.64 (s, 1 H, H- (quat. C), 136.5 (quat. C), 129.7 (quat. C), 129.2 (2 CH),
14), 5.67 (s, 1 H, H-14a), 5.46–5.33 (m, 3 128.3 (2 CH), 128.0 (quat. C), 127.6 (2 CH), 127.5 (2 CH),
H, vinyl-H and H-8), 5.23 (dd, 1 H, J =
2.8, 8.6, vinyl-H), 3.88 (s, 3 H, OCH3),
3.87 (s, 3 H, OCH3), 3.20–3.05 (m, 2 H,
CH2-6), 2.76–2.55 (m, 2 H, CH2-5)
126.2 (2 CH), 126.1 (CH2), 126.1 (CH), 119.9 (quat. C),
112.5 (CH), 109.8 (CH), 103.7 (CH), 78.5 (CH), 60.9 (CH),
55.9 (2 OCH3), 45.2 (CH2), 29.4 (CH2)
Finally, we have studied the 1,7-electrocyclization reac-
tion of isoquinolinium azomethine ylides onto a nitro
group to give benz-1,2,6-oxadiazepine intermediates,
which undergo ring contraction to form indazole N-ox-
ides.16 In this way, the reaction of 3,4-dihydro-1-(2-nitro-
phenyl)isoquinolium hydrochlorides 5b–e with allyl
bromide and triethylamine gave the expected isoquinoline
Column chromatography was performed using Merck Kieselgel 60
70–230 mesh, TLC on aluminum sheets coated with Kieselgel 60
F254. Plates were stained with anisaldehyde solution [glacial AcOH
(100 mL), conc. H2SO4 (2 mL) and anisaldehyde (1 mL)] and heat-
ed at ca. 150 °C. IR spectra were measured on a Bruker VECTOR
22 FT-IR instrument. NMR spectra were obtained on a Varian
INOVA 500 and a Bruker 250 instrument. Chemical shifts are given
relative to TMS. All solvents were purified according to standard
procedures and the isoquinolines 5a–e were prepared by the method
of Cortes et al.20 The spectral and physical properties of compounds
7a–d have been reported earlier.16b
fused indazole N-oxides 7a–d in
a single step
(Scheme 2).16b The yields (entries 4–7) are summarized in
Table 4.
In conclusion, we have developed an efficient one-pot
process for the synthesis of the pyrrolo[2,1-a]isoquinoline
derivatives. This method provides an easy access to this
heterocyclic framework, which is frequently found in
compounds displaying valuable pharmacological
activity17 or in alkaloids such as jamtines18 or lamerra-
lines.19 Such one-pot procedures could provide also a con-
venient entry to other functionalized nitrogen
heterocycles, such as benz[5,6]azepino[2,1-a]isoquino-
lines or fused indazole N-oxides, that are of interest in or-
ganic synthesis.
One-Pot Synthesis of Methyl, 2-Aryl-8,9-dimethoxy-1-nitro-
1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline-3-carboxy-
lates 4; General Procedure
6,7-Dimethoxy-3,4-dihydroisoquinolinium hydrochloride (1; 0.23
g, 1 mmol) was suspended in EtOH (10 mL) and the appropriate
alkylating agent 2 (1 mmol), dipolarophile 3 (1 mmol) and Et3N (0.3
mL, 0.23 g, 2.2 mmol) were added. The reaction mixture was stirred
for 12 h at r.t. After the reaction was complete, the product was col-
lected by filtration and recrystallized from EtOH (Tables 1 and 2).
Scheme 2 Reagents and conditions: i. R3CH2Br, Et3N, EtOH, r.t.
Synthesis 2005, No. 12, 2039–2045 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolo[2,1-a]isoquinolines
2045
One-Pot Synthesis of Benz[5,6]azepino[2,1-a]isoquinoline-8-
carboxylates 6 and Indazolo[3,2-a]-5,6-dihydroisoquinoline 8-
Oxides 7; General Procedure
The corresponding 3,4-dihydroisoquinolinium hydrochloride (1
mmol) was suspended in EtOH (10 mL) and the appropriate alkyl-
ating agent (1 mmol) and Et3N (0.3 mL, 0.23 g, 2.2 mmol) were
added. The reaction mixture was stirred for 48 h at r.t. After the re-
action was complete, the product was collected by filtration and re-
crystallized from EtOH (Tables 4 and 5).
(10) Zhou, J.; Zhang, L.; Hu, Y.; Hu, H. J. Chem. Res., Synop.
1999, 552.
(11) (a) Zhang, L.; Liang, F.; Sun, L.; Hu, Y.; Hu, H. Synthesis
2000, 1733. (b) Miki, Y.; Nakamura, N.; Yamakawa, Y.;
Hachike, H.; Matsushita, K. Heterocycles 2000, 53, 2143.
(c) Sliwa, W. Heterocycles 1996, 43, 2005.
(12) (a) Goff, D. A. Tetrahedron Lett. 1999, 40, 8741.
(b) Brooking, P.; Crawshaw, M.; Hird, N. W.; Jones, C.;
MacLachlan, W. S.; Readshaw, S. A.; Wilding, S. Synthesis
1999, 1986.
(13) (a) Bende, Z.; Simon, K.; Tóth, G.; Tőke, L.; Weber, L.
Liebigs Ann. Chem. 1982, 924. (b) Bende, Z.; Bitter, I.;
Tőke, L.; Weber, L.; Tóth, G.; Janke, F. Liebigs Ann. Chem.
1982, 2146. (c) Bende, Z.; Tőke, L.; Weber, L.; Tóth, G.;
Janke, F.; Csonka, G. Tetrahedron 1983, 40, 369. (d) Tóth,
G.; Tischner, T.; Bende, Z.; Szejtli, G.; Tőke, L. Monatsh.
Chem. 1990, 121, 529. (e) Tischer, T.; Tőke, L.; Tóth, G.
Acta Chim. Hung. 1990, 127, 171. (f) Janke, F.;
Himmelreich, U.; Tóth, G.; Tischer, T.; Bende, Z.; Tőke, L.
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Acknowledgment
This work was financially supported by the National Fund for Sci-
ence and Research, Hungary (OTKA Project No. T 046196). N. M.
thanks the Hungarian Academy of Sciences for a Bolyai J. fel-
lowship.
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Synthesis 2005, No. 12, 2039–2045 © Thieme Stuttgart · New York