A new approach towards the synthesis of pyrrolo[2,1-a]isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2009.12.026

Reaction of 5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline with activated alkynes affords stable tetrahydropyrrolo[2,1-a]isoquinolin-4-ium ylides. Further reactions of ylide 2 gives access to substituted dihydropyrrolo[2,1-a]isoquinolines in good yields.

Full text of DOI:10.1016/j.tetlet.2009.12.026

Tetrahedron Letters 51 (2010) 840–842
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Tetrahedron Letters
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A new approach towards the synthesis of pyrrolo[2,1-a]isoquinolines
*
Leonid G. Voskressensky , Anna V. Listratova, Alexander V. Bolshov, Oksana V. Bizhko, Tatiana N. Borisova,
Alexey V. Varlamov
Organic Chemistry Department of the Russian Peoples’ Friendship University, 6, Miklukho-Maklaia St., Moscow 117198, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of 5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline with activated alkynes affords
stable tetrahydropyrrolo[2,1-a]isoquinolin-4-ium ylides. Further reactions of ylide 2 gives access to
substituted dihydropyrrolo[2,1-a]isoquinolines in good yields.
Received 3 November 2009
Revised 26 November 2009
Accepted 4 December 2009
Available online 11 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Pyrrolo[2,1-a]isoquinolones have attracted considerable inter-
est because they possess antidepressant,1 muscarinic agonist, car-
diotonic2 and anticancer activity. Moreover, they can be used as
PET (positron emission tomography) radiotracers for imaging sero-
tonin uptake sites.3 The importance of these nitrogen heterocycles
is further enhanced by their utility as advanced intermediates for
the synthesis of alkaloids.4
Pyrrolo[2,1-a]isoquinoline is the core skeleton of a number of
antitumour alkaloids such as lamellarins5 and crysrine.6
The reported pathways towards this scaffold include (but are
not limited to) N-acyliminium Pictet-Spengler cyclizations,7,8
Bischler–Napieralski reaction9 or annelation of pyrrole to
isoquinolines.10,11
However, to prepare libraries of biologically active analogues of
such natural products for lead discovery and/or optimization in
medicinal chemistry, it is essential to have versatile synthetic
methods in hand. Thus we turned our attention towards develop-
ing a novel synthetic approach towards this heterocyclic system
based on the reaction of readily available tetrahydroisoquinolines
with electron-poor acetylenes.
The starting 5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroiso-
quinoline (1) required for the present study was obtained accord-
ing to the previously described method.13 The reaction of
isoquinoline 1 with methyl propiolate in methanol proceeded
smoothly at room temperature. The only product isolated from
the reaction in good yield (70%) was a stable pyrrolo[2,1-a]isoquin-
olinium ylide 214 (Scheme 2). The reaction of isoquinoline 1 with
DMAD required excess alkyne and a lower temperature (À5 °C),
however it failed to go to completion and ylide 315 was obtained
in a moderate yield of 30%.
We presume that the formation of the ylides 2 and 3 proceeds
via zwitterion A, the anionic part of which deprotonates a molecule
of methanol thus producing a highly basic methoxide anion. The
latter catalyzes the formation of B. Intramolecular nucleophilic at-
tack of the anionic centre in ylide B on the ester group leads to
elimination of methanol to form pyrroloisoquinolinium ylides 2
or 3 (Scheme 2). The intramolecular SN reaction in this case is prob-
ably facilitated by methanol.
Previously, we reported on tandem transformations of tetrahy-
droisoquinolines with electron-donating groups on the benzene
fragment under the action of activated alkynes.12 This reaction al-
lowed us to obtain substituted benzoazocines in one step. How-
ever, the reactivity of tetrahydroisoquinolines possessing
electron-withdrawing groups with activated alkynes has not been
studied. Since it is known that the reaction proceeds via interme-
diate zwitterion A, the result of Michael addition of the tertiary
N-atom of the tetrahydropyridine ring to the activated alkyne,
we wondered if the presence of electron-withdrawing groups
would affect the nature of intermediate A thus leading to new
products, or, whether the reaction does not depend on the effects
of the substituents on the benzene ring (Scheme 1).
new products
Y
X
R
R
R'
N
N
X
Y
R'
A
R = electron-withdrawing group
R'
N
R
X
Y
* Corresponding author. Tel./fax: +7 495 955 07 79.
E-mail address: lvoskressensky@sci.pfu.edu.ru (L.G. Voskressensky).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.026

L. G. Voskressensky et al. / Tetrahedron Letters 51 (2010) 840–842
841
CO2Me
E
Br
Br
Br
Br
Me
X
Me
N
MeCN
N
N
N
X
MeOH
Me
Me
1
1
A
NO2
NO2
Br
NO2
NO2
A
E
MeO2C
Br
Br
- OMe
MeOH
Br
Me
MeO
N
N
E
Me
Me
Me
- MeOH
X
N
N
X
NO2
NO2
B
NO2
NO2 O
E
MeO2C
B
4
OMe
E = CO2Me
-MeOH
Br
Scheme 3.
2
X = H
Me
3 X = CO2Me
N
Br
X
Br
NO2
RCl
O
2 3
,
N
N
DMF, Et3N
Scheme 2.
O2N
O2N
O
R
2
5-7
O
The structure of ylide 2 was unambiguously assigned by X-ray
analysis. A suitable crystal was obtained by slow evaporation of a
methanolic solution of compound 2. The refined X-ray structure16
of ylide 2 is shown in Figure 1.
O
S
O
;
5 R =
6 R =
O
We found that the solvent used in the reaction of isoquinoline 1
with methyl propiolate defines the reaction pathway. Thus, in the
case of acetonitrile, the only product isolated from the reaction was
1-vinyl substituted isoquinoline 4.17 We presume that in the case
of an aprotic solvent, zwitterion A rearranges to ylide B and the lat-
ter undergoes a Stevens rearrangement leading to compound 4
(Scheme 3).
F
O
S
O
7
R =
Scheme 4.
Recently we demonstrated that stable benzo[b]pyrrolo[2,1-
f][1,6]naphthyridin-4-ium ylides underwent O-acylation under
the action of acetic anhydride.18 We carried out analogous reac-
tions of ylide 2 with 2-phenylethanoyl chloride, 4-fluoro-1-ben-
zene- and 2-naphthalenesulfonyl chloride. The reactions did not
require any special conditions and proceeded smoothly at room
temperature in 1-2 hours. In all cases the O-acylation was accom-
panied by elimination of a methyl group and subsequent aromati-
zation of the pyrrole fragment giving pyrroloisoquinolines 5–719–21
in good preparative yields (Scheme 4).
In conclusion, we have demonstrated the synthesis of the pyr-
rolo[2,1-a]isoquinoline core via a new tandem Michael addition–
intramolecular nucleophilic substitution reaction of easily avail-
able tetrahydroisoquinolines with electron-poor alkynes. The reac-
tion results in the formation of unusually stable ammonium ylides
2 and 3, which can be further modified, thus providing access to
polysubstituted pyrrolo[2,1-a]isoquinoline frameworks. Work
aimed at exploring other tetrahydroisoquinolines bearing elec-
tron-withdrawing groups as well as other alkynes in this transfor-
mation is underway and will be reported in due course.
Acknowledgement
The financial support of the Russian Foundation for Basic Re-
search (Grant 08-03-00226-a) is gratefully acknowledged.
Reference and notes
1. Sorgi, K. L.; Maryanoff, C. A.; McComsey, D. F.; Graden, D. W.; Maryanoff, B. E. J.
Am. Chem. Soc. 1990, 112, 3567–3579.
2. Maryanoff, B. E.; Maryanoff, C. A.; McComsey, D. F.; Sorgi, K. L.; US Patent,
4,837,328, 1989; Chem. Abstr. 1990, 112, 20913.
3. Goodman; Shi, M. M.; Bing, Z. US Patent, 6,162,417, 2000; Chem. Abstr. 2000,
134, 56570.
4. Mikhailovskii, A. G.; Shklyuaev, V. S. Heterocycl. Compd. 1997, 33, 243–265.
5. Andersen, R. J.; Faulkner, J.; Cun Heng, H.; Van Duyne, G.; Clardy, J. J. Am. Chem.
Soc. 1985, 107, 5492–5495.
6. Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002, 58, 6795–6798.
7. Nielsen, T. E.; Meldal, M. J. Comb. Chem. 2005, 7, 599–610.
8. Allin, S. M.; Gaskell, S. N.; Towler, J. M. R.; Bulman Page, P. C.; Saha, B.;
McKenzie, M. J.; Martin, W. P. J. Org. Chem. 2007, 72, 8972–8975.
9. Boekelheide, V.; Godfrey, J. J. Am. Chem. Soc. 1953, 75, 3679–3685.
Figure 1. ORTEP structure of 2.

842
L. G. Voskressensky et al. / Tetrahedron Letters 51 (2010) 840–842
10. Nakayama, N.; Imanura, N.; Kanazawa, T.; Yoneda, S.; Sugimoto, T.; Yoshida, Z.
Heterocycles 1983, 20, 168.
11. Landoni, N.; Lesma, G.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2007, 72, 9765–
9768.
12. Voskressensky, L. G.; Listratova, A. V.; Borisova, T. N.; Alexandrov, G. G.;
Varlamov, A. V. Eur. J. Org. Chem. 2007, 6106–6117.
isoquinoline 4 (179 mg, 50%) as a greenish oil. 1H NMR (400 MHz, CDCl3): d
2.51 (s, 3H, N-CH3), 2.77–2.88 (m, 2H, 4-CH2), 2.93–3.08 (m, 2H, 3-CH2), 3.71 (s,
3H, OCH3), 5.12 (d, J = 6.5 Hz, 1H, @CH–COCH3), 5.62 (d, J = 16.0 Hz, 1H, 1-H),
6.96 (dd, J = 6.6, J = 16.0 Hz, 1H, @CH), 7.26–7.27 (m, 2H, CH-Ar) ppm. 13C NMR
(100 MHz, CDCl3): d 28.1, 41.5, 44.4, 51.6, 58.7, 123.8, 123.9, 130.6, 130.7,
132.0, 136.9, 144.5, 148.2, 165.3 ppm. IR (KBr):
m
1725, 1654 cmÀ1. EI MS: m/z
13. Ray, M.; Vergnani, T.; Dreiding, A. S. Helv. Chim. Acta 1985, 68, 1828–1834.
14. 7-Bromo-4-methyl-10-nitro-1-oxo-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-
4-ium ylide (2): To a solution of 2-methyl-5-bromo-8-nitro-1,2,3,4-tetrahyd-
roisoquinoline (1) (275 mg, 1 mmol) in MeOH (15 mL) was added methyl
propiolate (0.11 mL, 1.2 mmol). The reaction mixture was stirred at room
temperature (TLC monitoring). After completion of the reaction, the wine-red
precipitate formed was collected by filtration and dried in air. The yield of ylide
2 was 250 mg (77%); mp 280–282 °C (dec) (MeOH). 1H NMR (400 MHz, DMSO-
d6): d 2.88 (dt, J = 6.7, J = 11.9 Hz, 1H, 6-CH2), 3.18 (s, 3 H, N-CH3), 3.23–3.30 (m,
2H, 6-CH2 and 5-CH2), 4.23 (dd, J = 6.0, J = 11.2 Hz, 1H, 5-CH2), 6.57 (d,
J = 3.4 Hz, 1H, 2-H), 7.19 (d, J = 8.7 Hz, 1H, 8-H), 7.54 (d, J = 8.7 Hz, 1H, 9-H),
7.62 (d, J = 3.4 Hz, 1H, 3-H) ppm. 13C NMR (100 MHz, DMSO-d6): d 26.6, 48.7,
57.2, 107.6, 122.8, 124.6, 124.8, 125.1, 127.1, 131.2, 140.7, 145.4, 166.0 ppm. IR
(%) 356 (5), 354 (5) [M+], 339 (19), 337 (18), 280 (95), 278 (100), 270 (45), 262
(53), 248 (35), 225 (43), 223 (47), 168 (11), 144 (23), 115 (11), 42 (13). Calcd
for C14H15BrN2O3 (355.18): C, 47.34; H, 4.26; N, 7.86. Found: C, 47.53; H, 4.43;
N, 7.65.
18. Voskressensky, L. G.; Vorobiev, I. V.; Borisova, T. N.; Varlamov, A. V. J. Org.
Chem. 2008, 73, 4596–4601.
19. 7-Bromo-10-nitro-5,6-dihydropyrrolo[2,1-a]isoquinolin-1-yl 2-phenylacetate (5):
Yield (65%) yellow crystals mp 210–212 °C (hexane/EtOAc). 1H NMR (400 MHz,
CDCl3): d 3.17 (t, J = 6.3 Hz, 2H, 5-CH2), 3.80 (s, 2H, COCH2Ph), 4.12 (t, J = 6.3 Hz,
2H, 6-CH2), 6.28 (d, J = 3.0 Hz, 1H, 3-H), 6.67 (d, J = 3.0 Hz, 1H, 2-H), 7.24–7.26
(m, 1H, CH-Ph), 7.30–7.33 (m, 2H, 2CH-Ph), 7.35–7.36 (m, 2H, 2CH-Ph), 7.46 (d,
J = 8.7 Hz, 1H, 8-CH), 7.55 (d, J = 8.7 Hz, 1H, 9-CH) ppm. 13C NMR (100 MHz,
DMSO-d6): d 30.7, 39.6, 42.7, 102.1, 110.9, 121.1, 122.8, 124.6, 126.9, 127.6,
(KBr):
m
1618, 1558 cmÀ1. EI MS: m/z (%) 324 (98), 322 (94) [M+], 314 (14), 308
128.3 (2C), 129.4 (2C), 129.6, 133.6, 135.3, 136.0, 144.7, 168.3 ppm. IR (KBr): m
(53), 306 (52), 305 (31), 294 (11), 293 (21), 292 (12), 291 (15), 281 (11), 280
(27), 278 (23), 277 (21), 265 (23), 256 (27), 254 (25), 252 (31), 251 (17), 225
(16), 223 (19), 213 (43), 211 (41), 210 (14), 196 (11), 185 (17), 169 (13), 143
(11), 141 (12), 129 (11), 115 (12), 104 (16), 102 (14), 96 (33), 94 (30), 81 (52),
79 (25), 77 (18), 65 (11), 63 (13), 57 (13), 52 (12), 51 (11), 43 (45). Calcd for
C13H11BrN2O3 (323.14): C, 48.32; H, 3.43; N, 8.67. Found: C, 48.59, H 3.61, N
8.43.
1751, 1527 cmÀ1. EI MS: m/z (%) 428 (11), 426 (13) [M+], 312 (7), 311 (23), 310
(95), 308 (100), 293 (32), 291 (34), 277 (27), 263 (11), 253 (23), 223 (13), 212
(21), 198 (13), 185 (53), 173 (15), 162 (12), 156 (19), 155 (32), 145 (27), 133
(29), 119 (23), 105 (35), 92 (10), 91 (82), 85 (67), 81 (85), 65 (43), 59 (31), 55
(83), 45 (16), 43 (76). Calcd for C20H15BrN2O4 (427.25): C, 56.22; H, 3.54; N,
6.56. Found: C, 56.51; H, 3.32; N, 7.69.
20. 7-Bromo-1-(4-fluorophenylsulfonyloxy)-10-nitro-5,6-dihydropyrrolo[2,1-
a]isoquinoline (6): Yield (72%) yellow crystals mp 212–213 °C (hexane/EtOAc).
1H NMR (400 MHz, CDCl3): d 2.94-2.96 (m, 2H, 5-CH2), 4.02 (t, J = 6.3 Hz, 2H, 6-
CH2), 6.21 (d, J = 3.0 Hz, 1H, 3-H), 6.67 (d, J = 3.0 Hz, 1H, 2-H), 6.86–6.89 (m, 2H,
CH-Ar), 7.41 (m, 2H, 8-H and 9-H), 7.61–7.64 (m, 2H, 2CH-Ar) ppm. 13C NMR
15. 7-Bromo-3-(methoxycarbonyl)-4-methyl-10-nitro-1-oxo-1,5,6,10b-
tetrahydropyrrolo[2,1-a]isoquinolin-4-ium ylide (3): To an ice-cold solution of 2-
methyl-5-bromo-8-nitro-1,2,3,4-tetrahydroisoquinoline
(1)
(100 mg,
0.34 mmol) in MeOH (5 mL) was added DMAD (0.3 mL, 2.38 mmol). The
reaction mixture was kept at À5 °C (TLC monitoring). The wine-red precipitate
formed was collected by filtration and dried in air. The yield of ylide 3 was
42 mg (30%); mp 288–290 °C (dec) (MeOH). 1H NMR (400 MHz, DMSO-d6): d
3.11 (ddd, J = 6.0, J = 12.4, J = 18.2 Hz, 1H, 6-CH2), 3.29–3.31 (m, 2H, 6-CH2 and
5-CH2), 3.35 (s, 3H, N-CH3), 3.86 (s, 3H, CO2CH3), 4.51–4.54 (m, 1H, 5-CH2), 7.35
(d, J = 5.5 Hz, 1H, 8-H), 7.47 (s, 1H, 2-H), 7.57 (d, J = 5.5 Hz, 1H, 9-H) ppm. 13C
NMR (100 MHz, DMSO-d6): d 32.8, 41.6, 51.7, 53.8, 98.7, 114.3, 117.5, 118.2,
2
(100 MHz, DMSO-d6): d 30.4, 42.7, 103.4, 113.7, 115.7 (d, 2C, JC,F = 23 Hz),
121.3, 121.5, 124.4, 127.0, 127.9, 128.0, 131.0 (d, 2C, 3JC,F = 10 Hz), 133.3, 135.5,
144.7, 165.6 (d, 1JC,F = 255 Hz) ppm. IR (KBr):
m
1592, 1527 cmÀ1. EI MS: m/z (%)
468 (11), 466 (12) [M+], 307 (37), 291 (11), 280 (25), 279 (100), 277 (94), 261
(13), 251 (11), 250 (33), 233 (7), 228 (23), 198 (29), 184 (10), 182 (24), 170
(13), 169 (16), 155 (22), 154 (28), 144 (12), 143 (23), 129 (23), 127 (26), 126
(27), 116 (26), 115 (50), 102 (24), 95 (31), 89 (17), 82 (12), 81 (60), 75 (27), 69
(26), 55 (18), 53 (26), 51 (42), 44 (14), 43 (26). Calcd for C18H12BrFN2O5S
(467.27): C, 46.27; H, 2.59; N, 6.00. Found: C, 46.61; H, 2.37; N, 5.91.
118.7, 124.9, 132.5, 139.4, 150.1, 165.7, 169.9 IR (KBr):
m 1714, 1629,
1521 cmÀ1. EI MS: m/z (%) 382 (33), 380 (37) [M+], 337 (11), 276 (10), 264
(13), 263 (17), 255 (32), 254 (63), 242 (23), 209 (10), 197 (11), 182 (16), 171
(17), 170 (24), 169 (27), 168 (33), 166 (41), 165 (37), 164 (29), 140 (14), 139
(26), 129 (18), 128 (35), 127 (37), 126 (26), 118 (12), 117 (35), 116 (46), 115
(63), 113 (100), 114 (57), 112 (45), 103 (16), 101 (26), 89 (14), 81 (29), 76 (22),
77 (17), 69 (15), 63 (23), 59 (44), 45 (33), 43 (58). Calcd for C15H13BrN2O3
(381.18): C, 47.26; H, 3.44; N, 7.35. Found: C, 47.42; H, 3.51; N, 7.47.
16. CCDC 737829 (for 2) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre, 12 Union Road, Canbridge CB1 1 EZ, UK; Fax
+44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk.
21. 7-Bromo-1-(2-naphthylsulfonyloxy)-10-nitro-5,6-dihydropyrrolo[2,1-
a]isoquinoline (7): Yield (68%) yellow crystals mp 208–209 °C (hexane/EtOAc).
1H NMR (400 MHz, CDCl3): d 3.28–3.33 (m, 2H, 5-CH2), 3.95 (t, J = 6.6 Hz, 2H, 6-
CH2), 6.22 (d, J = 3.0 Hz, 1H, 3-H), 6.97 (d, J = 8.7 Hz, 1H, 8-H), 7.04 (d, J = 3.0 Hz,
1H, 2-H), 7.24 (d, J = 8.7 Hz, 1H, 9-H), 7.27 (dd, J = 2.1, J = 8.7 Hz, 1H, CH-Ar),
7.59–7.63 (m, 1H, CH-Ar), 7.69–7.71 (m, 1H, CH-Ar), 7.72–7.74 (m, 1H, CH-Ar),
7.85 (d, J = 9.1 Hz, 1H, CH-Ar), 7.96 (dd, J = 0.8, J = 8.5 Hz, 1H, CH-Ar), 8.04 (d,
J = 2.6 Hz, 1H, CH-Ar) ppm. 13C NMR (100 MHz, DMSO-d6): d 30.2, 42.7, 103.6,
113.8, 121.2 (2C), 122.1, 123.8, 126.6, 127.6, 127.7, 128.3, 128.8, 129.3, 129.6,
129.9 (2C), 130.7, 133.5, 134.8, 135.0, 144.4 ppm. IR (KBr):
m
1524 cmÀ1. EI MS:
17. Methyl
(2E)-3-(5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinolin-1-yl)-
m/z (%) 500 (45), 499 (10), 498 (46) [M+], 310 (34), 309 (100), 307 (94), 293
(12), 291 (19), 280 (63), 279 (81), 277 (79), 262 (12), 251 (13), 250 (34), 212
(17), 208 (22), 198 (16), 191 (17), 175 (26), 170 (29), 160 (18), 129 (23), 128
(62), 127 (89), 115 (78), 102 (13), 101 (17), 89 (16), 81 (82), 64 (24), 55 (27), 44
(12), 43 (66). Calcd for C22H15BrN2O5S (499.33): C, 52.92; H, 3.03; N, 5.61.
Found: C, 53.12; H, 2.87; N, 5.75.
acrylate (4): To a solution of 5-bromo-2-methyl-1,2,3,4-tetrahydro-8-nitro-
isoquinoline (1) (275 mg, 1 mmol) in MeCN (15 mL) was added methyl
propiolate (0.11 mL, 1.2 mmol). The reaction mixture was stirred at room
temperature (TLC monitoring). After completion of the reaction, the solvent
was evaporated under reduced pressure and the resulting residue was purified
by column chromatography with hexane/EtOAc (1:15) as eluent to give