Novel oxidation of substituted pyrrolidines by N-bromosuccinimide - Rapid synthesis of pyrrolo[2,1-a]isoquinolines

Article abstract of DOI:10.1055/s-2007-977461

A new method for converting 1,2,3,5,6,10b-hexahydropyrrolo[2,1-a] isoquinolines into 5,6-dihydropyrrolo[2,1-a]isoquinolines using N-bromosuccinimide as an oxidant is presented. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-977461

LETTER
1259
Novel Oxidation of Substituted Pyrrolidines by N-Bromosuccinimide – Rapid
Synthesis of Pyrrolo[2,1-a]isoquinolines
O
xidation
u
of Pyrrolidin
d
es by
N
-Bro
i
mosuc
t
cinimide Tóth,a Linda Váradi,a András Dancsó,b Gábor Blaskó,b László Tőke,a Miklós Nyerges*a
a
Organic Chemical Technology Research Group of the Hungarian Academy of Sciences, Budapest University of Technology and
Economics, P.O.B. 91, 1521 Budapest, Hungary
b
EGIS Pharmaceuticals Ltd., P.O.B. 100, 1475 Budapest, Hungary
Fax +36(1)4633648; E-mail: mnyerges@mail.bme.hu
Received 11 January 2007
olinium salts 2 with triethylamine at ambient temperature
in the presence of the appropriate dipolarophiles gave the
corresponding cycloadducts in high yield (Scheme 1). Al-
ternatively, several of these cycloadducts could be pre-
pared directly from 1 using a one-step method described
by us.9g
Abstract: A new method for converting 1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinolines into 5,6-dihydropyrrolo[2,1-a]isoquin-
olines using N-bromosuccinimide as an oxidant is presented.
Key words: azomethine ylides, cycloadditions, oxidation, pyrroles
Considerable interest has been shown in substituted pyr-
rolo[2,1-a]isoquinolines due to their diverse biological
activities. Since the discovery of the potent cytotoxic and
topoisomerase I inhibitor activity of lamellarine alkaloids1
a number of new synthetic strategies have been developed
based on intramolecular oxidative biaryl couplings,2 ther-
mal reactions of 4-isoxazoline derivatives (obtained by
cycloadditions of 3,4-dihydroisoquinoline N-oxides with
alkynes),3 intramolecular Heck reactions4 and cycliza-
tions of 1- or 2-benzylisoquinolines.5,6
MeO
Br–
MeO
i
N
+
EWG
N
MeO
MeO
2
1
MeO
MeO
ii
N
EWG
Ar
+
NO2
H
3
O2N
Ar
4
There are many other methods for the synthesis of pyrrole
derivatives, including 1,3-dipolar cycloaddition of
azomethine ylides to alkynes followed by aromatization
of the intermediate pyrrolines.7 However, the preparation
of pyrroles by dehydrogenation of pyrrolidines has found
little application due to the lack of general methods and to
the forcing conditions required in most cases.8
Scheme 1 Reagents and conditions:(i) EWG–CH2Br, Et2O, r.t.; (ii)
Et3N, EtOH, r.t.
After several unsuccessful exploratory experiments using
various oxidizing agents (e.g. MnO2, DDQ, H2O2,
KMnO4) we decided to use NBS.10 NBS is most frequent-
ly used in the oxidations of sulfides to sulfoxides11 and al-
cohols to carbonyl compounds.12 This reagent is also
useful for the direct transformation of aldehydes into acid
bromides13 or nitriles.14 However, there are only a few re-
ports on the oxidation of heterocyclic compounds using
NBS, these include the oxidation of indoles to isatins,15
2,3-dihydrobenzofurans to benzofurans16 and isoxazoline
to isoxazole.17 There is also a two-step process (halogena-
tion with NBS and then dehydrohalogenation by a base)18
and in one case a 3,4-dihydroisoquinoline derivative has
been aromatized in refluxing carbon tetrachloride in the
presence of NBS.19
The development of a method that allows this reaction un-
der mild and neutral conditions should heighten the syn-
thetic potential of this conversion. In this communication
we report preliminary results of the direct conversion of
one certain type of pyrrolidines into the corresponding
pyrroles in excellent yields using N-bromosuccinimide
(NBS) under mild conditions.
We have decided to study the dehydrogenation of
1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinolines
4
which were prepared by 1,3-dipolar cycloadditions of
azomethine ylides derived from dihydroisoqinolinium
salts previously studied in detail by us.9 The dipoles pro-
duced by dehydrohalogenation reacted with a wide-range
of dipolarophiles including maleimides, maleates and ni-
tro olefins. Accordingly, the reaction of 1 with methyl
bromoacetate or phenacyl bromides in anhydrous diethyl
ether gave the quaternary salts 2. Reacting these isoquin-
To our delight, we found that the colorless solutions of 4
in chloroform treated with NBS at room temperature
turned immediately yellow and after a simple work-up
procedure gave the desired 5,6-dihydropyrrolo[2,1-a]iso-
quinolines 5 (Scheme 2).
The reaction is exothermic and on a larger scale, external
ice-water cooling is necessary. To demonstrate the gener-
ality of this methodology, a broad range of different cy-
cloadducts were chosen. The results are summarized in
SYNLETT 2007, No. 8, pp 1259–1263
Advanced online publication: 08.05.2007
DOI: 10.1055/s-2007-977461; Art ID: D01207ST
© Georg Thieme Verlag Stuttgart · New York
1
6.
0
5.
2
0
0
7

1260
J. Tóth et al.
LETTER
MeO
MeO
MeO
MeO
Table 1. In general, modest to good overall yields were
obtained for all substrates. As a limitation of this method,
in the cases when the aromatic ring has two or more elec-
tron-donating substituents (Table 1, entries 4, 5 and 12)
the concomitant bromination of the 2-aryl substituent was
observed during the dehydrogenation process, this could
be avoided by using a lower reaction temperature.
i
N
N
EWG
EWG
H
O2N
O2N
Ar
Ar
4
5
Scheme 2 Reagents and conditions: (i) NBS, CHCl3, r.t.20
Table 1 Oxidation of Substituted Pyrrolidines with NBS
Entry EWG
Ar
Cycloadduct
Product
Reaction conditions
Yield
72%
MeO
N
CO2Me
MeO
1
CO2Me
4a9g
r.t.
O2N
5a
MeO
MeO
N
CO2Me
MeO
2
CO2Me
4b9g
r.t.
70%
O2N
OMe
5b
MeO
MeO
N
CO2Me
MeO
MeO
3
4
5
CO2Me
4c9g
0 °C
81%
O2N
OMe
OMe
5c
MeO
MeO
N
CO2Me
MeO
MeO
0 °C to r.t., NBS
(3 equiv)
CO2Me
4d9g
77%
O2N
Br
OMe
OMe
5d
MeO
MeO
N
CO2Me
OMe
0 °C, NBS
(3 equiv)
CO2Me
4e9g
60%
MeO
MeO
O2N
Br
OMe
OMe
MeO
5e
Synlett 2007, No. 8, 1259–1263 © Thieme Stuttgart · New York

LETTER
Oxidation of Pyrrolidines by N-Bromosuccinimide
1261
Table 1 Oxidation of Substituted Pyrrolidines with NBS (continued)
Entry EWG
Ar
Cycloadduct
Product
Reaction conditions
Yield
MeO
N
CO2Me
MeO
6
7
8
9
CO2Me
4f9g
r.t.
81%
85%
58%
77%
O2N
O2N
NO2
5f
MeO
MeO
N
COPh
PhCO
4g9g
r.t.
r.t.
r.t.
O2N
O2N
NO2
5g
MeO
N
COPh
Cl
MeO
4h
(69%)
PhCO
O2N
Cl
5h
MeO
MeO
O
N
4i
(70%)
(4-MeOC6H4)CO
OMe
O2N
5i
MeO
MeO
O
N
Cl
4j
(70%)
10
(4-MeOC6H4)CO
r.t.
68%
OMe
O2N
Cl
5j
MeO
O
N
MeO
4k
(73%)
5k
(59%)
11
(4-BrC6H4)CO
r.t.
Br
O2N
Cl
Cl
5k
MeO
MeO
O
N
O
O
4l
(84%)
0 °C to r.t., NBS
(3 equiv)
5l
(53%)
12
(4-BrC6H4)CO
Br
O2N
Br
O
O
5l
Synlett 2007, No. 8, 1259–1263 © Thieme Stuttgart · New York

1262
J. Tóth et al.
LETTER
MeO
MeO
MeO
MeO
path A
Ox.
N
EWG
N
EWG
O2N
Ar
O2N
Ar
6
4
5
MeO
MeO
MeO
path B
– HNO2
N
EWG
N
EWG
MeO
O2N
Ar
Ar
7
8
Scheme 3
The structures of compounds 5 were determined using
Acknowledgment
13
1
NMR spectroscopy (1H, C, H–1H COSY, 1H–1H NOE
and 1H–13C HSQC). The route of the signal and structure
assignment of 5e is shown, as an example in Figure 1.
This work was financially supported by the National Fund for Sci-
ence and Research, Hungary (OTKA Project No. T 046196). A
grant from the EGIS Pharmaceuticals provided to J.T. is gratefully
appreciated.
The mechanism of oxidation of pyrrolidines 4 with NBS
has not been clearly established, although based on earlier
interpretations, it is generally accepted that a positively
charged halogen is the attacking species and gives a bro-
minated intermediate.10
References and Notes
(1) (a) Andersen, R. J.; Faulkner, D. J.; Cun-heng, H.; Van
Duyne, G. D.; Clardy, J. J. Am. Chem. Soc. 1985, 107, 5492.
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A., Eds.; Pergamon: Oxford, 2004, 1–26.
(2) (a) Yamaguchi, T.; Fukuda, T.; Ishibashi, F.; Iwao, M.
Tetrahedron Lett. 2006, 47, 3755. (b) Fujikawa, N.; Ohta,
T.; Yamaguchi, T.; Fukuda, T.; Ishibashib, F.; Iwao, M.
Tetrahedron 2006, 62, 594. (c) Iwao, M.; Takeuchi, T.;
Fujikawa, N.; Fukuda, T.; Ishibashi, F. Tetrahedron Lett.
2003, 44, 4443.
3.06
28.8
6.79
110.4
56.0
4.61
43.0
3.95CH3O
131.6
150.7
160.9
3.56
51.7
147.7
117.1 N
CO2CH3
3.89
CH3O
56.1
128.0
131.6
127.4
129.7
110.5
7.49
118.5
3.63
O2N
Br
109.8
3.83
OCH3
152.2
142.5
(3) (a) Díaz, M.; Guitián, E.; Castedo, L. Synlett 2001, 1164.
(b) Zhao, B.-X.; Yu, Y.; Eguchi, S. Tetrahedron 1996, 52,
12049.
111.0
150.4
56.1
CH3O
3.93
OCH3
3.96
(4) Olsen, C. A.; Parera, N.; Albericio, F.; Alvarez, M.
Tetrahedron Lett. 2005, 46, 2041.
61.04
61.2
Figure 1
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Chem. 2005, 70, 5119. (b) Ploypradith, P.; Mahidol, C.;
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Chang, F.-R.; Yeh, J.-L.; Chen, I.-J.; Wu, Y.-C. Bioorg.
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S.; Oda, T.; Iwao, M. J. Nat. Prod. 2002, 65, 500.
(e) Ruchirawat, S.; Mutarapat, T. Tetrahedron Lett. 2001,
42, 1205.
The spontaneous elimination of hydrogen bromide occurs
facilitated by the highly conjugated nature of the newly
formed double bond. We believe that the pyrrolidines 4
react with NBS to form pyrroline 6 exclusively according
to path A. The formation of isomeric pyrroline 7 is unlike-
ly because that would readily lose nitrous acid to form a
different pyrrole 8 as product.21 The last step is a sponta-
neous dehydrogenation leading to the formation of the
isolated pyrroles 5 (Scheme 3).22
(6) Fujita, R.; Watanabe, N.; Tomisawa, H. Chem. Pharm. Bull.
2002, 50, 225.
(7) (a) La Porta, P.; Capuzzi, L.; Bettarini, F. Synthesis 1994,
287. (b) DeShong, P.; Kell, D. A.; Sidler, D. R. J. Org.
Chem. 1985, 50, 2309. (c) Padwa, A.; Norman, B. H. J. Org.
Chem. 1990, 55, 4801. (d) Cironi, P.; Cuevas, C.;
Albericioa, F.; Alvarez, M. Tetrahedron 2004, 60, 8669.
(e) Cironi, P.; Manzanares, I.; Albericio, F.; Alvarez, M.
Org. Lett. 2003, 2959. (f) Ridley, C. P. M.; Reddy, V. R.;
Rocha, G.; Bushman, F. D.; Faulkner, D. J. Bioorg. Med.
Chem. 2002, 10, 3285. (g) Banwell, M.; Flynn, B.;
Hockless, D. Chem. Commun. 1997, 2259. (h) Poissonnet,
G.; Theret-Bettiol, M.-H.; Dodd, R. H. J. Org. Chem. 1996,
61, 2273.
In summary we have explored a convenient two-step
reaction path which provides a useful route to 5,6-dihy-
dropyrrolo[2,1-a]isoquinolines 5 via a 1,3-dipolar cyclo-
addition and an NBS-promoted oxidation sequence.
Further studies into oxidizing other heterocyclic com-
pounds using NBS is in progress as well as possible
conversions of the formed pyrrole derivatives.
Synlett 2007, No. 8, 1259–1263 © Thieme Stuttgart · New York

LETTER
Oxidation of Pyrrolidines by N-Bromosuccinimide
1263
(8) (a) Southwick, P. L.; Sapper, D. I.; Pursglove, L. A. J. Am.
Chem. Soc. 1950, 72, 4940. (b) Cossy, J.; Pete, J.-P.
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(London) 1959, 1129. (d) Oussaid, B.; Garrigues, B.;
Soufiaoui, M. Can. J. Chem. 1994, 72, 2483. (e) Bonnaud,
B.; Bigg, D. C. H. Synthesis 1994, 465. (f) Gupta, P.;
Bhaduri, A. P. Synth. Commun. 1998, 28, 3151.
(9) (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) Tischer, T.; Tőke, L.; Tóth, G. Acta Chim. Hung. 1990,
127, 171. (e) Fejes, I.; Nyerges, M.; Tőke, L.; Pak, C. S.
Tetrahedron 2000, 56, 639. (f) Fejes, I.; Nyerges, M.;
Szöllőssy, Á.; Blaskó, G.; Tőke, L. Tetrahedron 2001, 57,
1129. (g) Nyerges, M.; Somfai, B.; Tóth, J.; Dancsó, A.;
Blaskó, G.; Tőke, L. Synthesis 2005, 2039.
powder. All new compounds afforded correct elemental
analyses and spectroscopic data.
Selected examples: Methyl 8,9-dimethoxy-1-nitro-2-
phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-
carboxylate (5a): IR (KBr): 2956, 2833, 1700, 1609, 1591,
1561, 1547, 1506, 1452, 1439, 1355, 1284, 1262, 1236,
1217, 1195, 1181, 1136, 1100, 1072, 1016 cm–1; 1H NMR
(500 MHz, CDCl3): d = 7.39 (m, 4 H, Ph-H and H-10), 7.29
(m, 2 H, Ph-H), 6.79 (s, 1 H, H-7), 4.58 (t, J = 6.7 Hz, 2 H,
H-5), 3.94 (s, 3 H, OMe), 3.86 (s, 3 H, OMe), 3.53 (s, 3 H,
OMe), 3.06 (t, J = 6.7 Hz, 2 H, H-6); 13C NMR (125 MHz,
CDCl3): d = 161.3 (q), 150.2 (q), 147.9 (q), 136.4 (q), 132.3
(q), 130.9 (q), 129.6 (q), 129.5 (2 × CH), 128.1 (q), 127.8
(CH), 127.6 (2 × CH), 117.2 (q), 114.7 (q), 110.5 (CH),
109.9 (CH), 56.5 (CH3), 56.0 (CH3), 51.4 (CH3), 43.0 (CH2),
28.8 (CH2).
Methyl 8,9-dimethoxy-2-(2-bromo-3,4,5-trimethoxy-
phenyl)-1-nitro-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-
carboxylate (5e): IR (KBr): 2993, 2940, 2840, 1709, 1669,
1563, 1505, 1475, 1443, 1427, 1410, 1387, 1361, 1343,
1301, 1287, 1260, 1214, 1195, 1138, 1107, 1049, 1013 cm–1;
1H NMR (500 MHz, CDCl3): d = 7.49 (s, 1 H, H-10), 6.79
(s, 1 H, H-7), 6.63 (s, 1 H, Ar2-6¢H), 4.61 (m, 2 H, H-5), 3.96
(s, 3 H, OMe), 3.95 (s, 3 H, OMe), 3.93 (s, 3 H, OMe), 3.89
(s, 3 H, OMe), 3.83 (s, 3 H, OMe), 3.06 (m, 2 H, H-6);
13C NMR (125 MHz, CDCl3): d = 160.9 (q), 152.2 (q), 150.7
(q), 150.4 (q), 147.7 (q), 142.5 (q), 131.6 (q), 131.5 (q),
129.7 (q), 128.0 (q), 127.4 (q), 118.6 (q), 117.1 (q), 111.0
(q), 110.5 (CH), 110.4 (CH), 109.8 (CH), 61.2 (CH3), 61.0
(CH3), 56.13 (CH3), 56.12 (CH3), 56.0 (CH3), 51.7 (CH3),
43.0 (CH2), 28.8 (CH2).
(10) Filler, R. Chem. Rev. 1963, 63, 21.
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3976. (c) More, K. M.; Wemple, J. Synthesis 1977, 791.
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(b) Lee, J. C.; Lee, J. Y.; Lee, J. M. Synth. Commun. 2005,
35, 1911. (c) Sharma, V. B.; Jain, S. L.; Sain, B. J. Mol.
Catal. A: Chem. 2005, 227, 47. (d) Khurana, J. M.;
Kandpal, B. M. Tetrahedron Lett. 2003, 44, 4909.
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1347.
(15) Tatsugi, J.; Zhiwei, T.; Izawa, Y. ARKIVOC 2001, (i), 67.
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Matsuda, K.; Iibuchi, N.; Ogawa, M. Heterocycles 1997, 45,
1657.
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2006, 42, 243.
(18) (a) Pelletier, J. C.; Cava, M. P. J. Org. Chem. 1987, 52, 616.
(b) Pelletier, J. C.; Cava, M. P. Synthesis 1987, 474.
(19) Stanforth, S. P. J. Heterocycl. Chem. 1987, 531.
(20) General procedure for the preparation of compounds
5a–l: The corresponding cycloadduct (4, 1.0 mmol) was
dissolved in CHCl3 (10 mL) and NBS (0.17 g, 1.1 mmol)
was added in one portion. The solution immediately turned
yellow. After 30 min stirring H2O (10 mL) was added and
the organic layer was washed with further portions of H2O
(2 × 10 mL) and brine (10 mL), then dried (MgSO4) and
evaporated in vacuo. The residue was triturated with cold
EtOH and filtered to yield the title product as a yellow
3-(4-Bromobenzoyl)-2-(2-chlorophenyl)-8,9-dimethoxy-1-
nitro-5,6-dihydropyrrolo[2,1-a]isoquinoline (5k): IR (KBr):
3010, 2943, 1633, 1586, 1502, 1471, 1442, 1405, 1355,
1261, 1218, 1148, 1095, 1068, 1056, 1014 cm–1; 1H NMR
(500 MHz, CDCl3): d = 7.54 (s, 1 H, H-10), 7.41 (d, J = 8.4
Hz, 2 H, Ar3-2¢ and 6¢H), 7.25 (d, J = 8.4 Hz, 2 H, Ar3-3¢ and
5¢H), 7.19 (d, J = 7.9 Hz, 1 H, Ar2-6¢H), 7.07 (t, J = 7.9 Hz,
1 H, Ar2-5¢H), 6.97 (d, J = 7.9 Hz, 1 H, Ar2-3¢H), 6.95 (d,
J = 7.9 Hz, 1 H, Ar2-4¢H), 6.81 (s, 1 H, H-7), 4.45 (m, 1 H,
H-5), 4.34 (m, 1 H, H-5), 3.96 (s, 3 H, OMe), 3.90 (s, 3 H,
OMe), 3.10 (m, 2 H, H-6); 13C NMR (125 MHz, CDCl3):
d = 186.6 (q), 150.6 (q), 147.8 (q), 136.7 (q), 134.3 (q), 133.1
(q), 132.3 (CH), 132.2 (q), 131.0 (q), 130.9 (2 × CH), 130.5
(2 × CH), 129.3 (CH), 129.1 (CH), 128.3 (q), 127.5 (q),
126.7 (q), 126.3 (CH), 125.3 (q), 117.0 (q), 110.6 (CH),
110.5 (CH), 56.2 (CH3), 56.0 (CH3), 43.3 (CH2), 29.0 (CH2).
(21) Fejes, I.; Nyerges, M.; Blaskó, G.; Tőke, L.; Pak, C. S.
Tetrahedron 2000, 43, 8545.
(22) Nyerges, M.; Tőke, L. Tetrahedron Lett. 2005, 46, 7531.
Synlett 2007, No. 8, 1259–1263 © Thieme Stuttgart · New York

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