Synthesis of pyrrolo-[2,1-j]quinolone framework via intramolecular electrophilic ipso-cyclization

Article abstract of DOI:10.1016/j.tetlet.2012.12.014

The challenging pyrrolo-[2,1-j]quinolone core structure has been synthesized from N-(alkynoyl)-6-methoxytetrahydroquinoline in good yields using electrophilic cyclization as the key step. These reactions require simple starting materials and mild reaction

Full text of DOI:10.1016/j.tetlet.2012.12.014

Tetrahedron Letters 54 (2013) 1344–1347
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of pyrrolo-[2,1-j]quinolone framework via intramolecular
electrophilic ipso-cyclization
⇑
Lila Low-Beinart, Xiaohan Sun, Eli Sidman, Tanay Kesharwani
Chemistry Program, Bard College, PO Box 5000, Annandale-on-Hudson, NY 12504, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The challenging pyrrolo-[2,1-j]quinolone core structure has been synthesized from N-(alkynoyl)-6-meth-
oxytetrahydroquinoline in good yields using electrophilic cyclization as the key step. These reactions
require simple starting materials and mild reaction conditions. In addition, we have demonstrated that
the iodine moiety, which could be easily introduced in the final step, is very useful for further function-
alization by employing various palladium-catalyzed cross-coupling reactions.
Received 25 October 2012
Revised 2 December 2012
Accepted 5 December 2012
Available online 21 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Electrophilic cyclization
Iodocyclization
Intramolecular ipso-cyclization
1H-Pyrrolo-[2,1-j]quinolone
1H-Pyrrolo-[2,1-j]quinolone is a commonly found core struc-
ture in the family of tricyclic marine alkaloids such as Lepadifor-
mine1 and Cylindricine ( Fig. 1).2 The complex three-ring core
structure found in these molecules makes them intriguing syn-
thetic targets. These alkaloids exhibit interesting biological activi-
ties such as cytotoxicity against cancer cells, antiarrhythmic
properties, and other cardiovascular effects.3 Ever since Cylindri-
cines were isolated by Blackman et al.2 many attempts have been
made to synthesize them and the other marine alkaloids.4 In these
processes the synthesis of the core structure was lengthy, often
requiring several steps, and resulted in low to moderate yields.
Over the last decade halogen mediated electrophilic cyclization
reactions have emerged as a very useful method in organic synthe-
sis.5 Pioneering work in this area has been reported by Larock and
co-workers as they have reported synthesis of several heterocycles
and carbocycles including indole,6 benzofuran,7 benzo[b]thio-
phene,8 benzo[b]selenophene,9 furan,10 quinoline,11 isoquinoline,12
and benzopyran.13 Recently, synthesis of spiro[4.5]trienones was
reported via ipso-iodocyclization of 4-(p-Methoxyaryl)-1-
alkynes.14 Several variations of these ipso-cyclization reactions
have been reported since then.15
OH
R
Cl
A =
N
n-hexyl
C = OH
N
O
OMe
D =
E = OAc
H
H
SCN
F =
Cylindricine A-F
Lepadiformine
Figure 1. Core structures of naturally occurring Cylindricines and Lepadiformine.
R
I
O
O
2 equiv. I2
3 equiv. NaHCO3
R
N
N
CH3CN
MeO
O
Scheme 1. Synthesis of 1H-pyrrolo-[2,1-j]quinolone framework via ipso-
iodocyclization.
reaction conditions starting from commercially available 6-meth-
oxy-1,2,3,4-tetrahydroquinoline (1) in two or three steps.
Herein we describe a novel approach for the synthesis of the
1H-pyrrolo-[2,1-j]quinolone core structure using the electrophilic
ipso-cyclization of various N-(alkynoyl)-6-methoxytetrahydro-
quinolines (Scheme 1).16 This method can be used to synthesize
these highly functionalized heterocyclic compounds under mild
To synthesize N-(alkynoyl)-6-methoxytetrahydroquinolines 2
and 3, HATU coupling between tetrahydroquinoline 1, and phenyl-
propiolic acid or octynoic acid was performed. These couplings
were successful and produced propiolamides 2 and 3 in very high
yields of 81% and 93%, respectively (Scheme 2). N-(alkynoyl)-6-
methoxytetrahydro-quinolines 5–9 were synthesized by the
reaction of carbomoyl chloride 4 with alkynyl lithiums in yields
⇑
Corresponding author. Tel.: +1 845 752 2352.
E-mail address: tkesharw@bard.edu (T. Kesharwani).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.014

L. Low-Beinart et al. / Tetrahedron Letters 54 (2013) 1344–1347
1345
R
The reaction of propiolamide 2 with I2 and NaHCO3 using
CH3CN as solvent resulted in the formation of the desired pyrrol-
o-[2,1-j]quinolone 10 in an excellent yield of 91% (Table 1, entry
1). To study the scope of this reaction, various electrophiles such
as Br2, NBS, and NIS were employed. Cyclization attempts using
Br2 and NBS were unsuccessful whereas NIS in acetic acid resulted
in the formation of 10 in a modest yield of 40% (entry 2). Since, NIS
resulted in a lower yield of product we continued our study of elec-
trophilic cyclization using I2 as the electrophile.
O
R
%
H
N
N
2
3
Ph
CO2H
phenyl 81
DIEA, HATU, THF
93
n-pentyl
MeO
MeO
1
Scheme 2. Synthesis of N-(alkynoyl)-6-methoxytetrahydroquinolines via HATU
coupling reaction.
To further study the scope of this reaction, substituted propiola-
mides were employed. Placing a tolyl functionality on the alkyne
furnished 11 in slightly lower yield than 10 (entry 3). Using the
stronger electron-rich group, p-methoxyphenyl, resulted in 83%
yield of 12 (entry 4). The heteroaryl and vinyl groups were success-
ranging from 49% to 73% (Scheme 3). Carbomoyl chloride 4 was
synthesized from the reaction of 6-methoxytetrahydro-quinoline
with phosgene using Et3N as a base. This reaction furnished 4 in
high yield of 80% (Scheme 3).
R
Cl
O
O
O
H
N
N
N
Cl
Cl
R
Li
Et3N,DCM
THF, -78 0 °C
MeO
MeO
MeO
1
4 80%
R
%
5
6
7
8
9
Me
58%
73%
MeO
S
66%
49%
52%
Scheme 3. Synthesis of N-(alkynoyl)-6-methoxytetrahydroquinolines from carbomoyl chloride 4 and alkynyl lithiums.
Table 1
Iodocyclization of N-(alkynoyl)-6-methoxytetrahydroquinolinesa
Entry
Alkyne
Reaction conditionsa
Product
Yieldb (%)
I
O
1
2
A
10
91
O
N
N
O
MeO
2
3
2
5
B
A
10
11
40c,d
89
Me
I
O
Me
N
O
O
N
N
O
MeO
MeO
OMe
I
O
MeO
4
6
A
12
83
N
O
(continued on next page)

1346
L. Low-Beinart et al. / Tetrahedron Letters 54 (2013) 1344–1347
Table 1 (continued)
Entry
Alkyne
Reaction conditionsa
Product
Yieldb (%)
S
I
O
S
5
7
A
13
76
O
N
N
O
MeO
I
O
6
8
A
14
66
O
O
N
N
N
O
MeO
MeO
I
O
7
8
3
9
A
A
15
16
45
N
O
I
O
0
O
N
N
O
MeO
a
b
c
All reactions were performed using 0.30 mmol of propiolamides, 2 equiv of I2, and 3 equiv of NaHCO3 in 6 mL of CH3CN at room temperature for 24 h.
Isolated yields.
Reaction was performed using 0.25 mmol of propiolamides and 2 equiv of NIS in 2 mL of CH3COOH at room temperature for 24 h.
Yield was determined by NMR using 2-bromobenzaldehyde as an internal standard.
d
I
R
Ph
Ph
I
O
O
N
O
O
RB(OH)2
cat. Pd(PPh3)4
Ph
Ph
R
N
N
N
I2
Na2CO3,
O
O
DMF, H2O
O
O
10
2
17
%
19
20
84%
I
I
O
O
Ph
Ph
S
89%
N
N
-MeI
Scheme 5. Functionalization of 10 using Suzuki cross-coupling reactions.
O
O
18
10
I
Scheme 4. Plausible mechanism for ipso-iodocyclization.
alkyne to form intermediate 17, followed by an ipso-attack from
the electron-rich aromatic ring to generate cationic intermediate
18 (Scheme 4). The presence of the methoxy group increases the
electron density on ipso-carbon, which in turn facilitates the neces-
sary attack on alkyne by the aromatic ring. The methyl group in
intermediate 18 is subsequently removed by the iodide nucleo-
phile via SN2 reaction.
In order to demonstrate the general utility of the ipso-iodocyc-
lization products, attempts were made to further functionalize 10
using Suzuki coupling reactions (Scheme 5). The Suzuki coupling
reaction using phenylboronic acid produced the desired product
with a high yield of 84%. The electron rich 3-thienylboronic acid re-
sulted in the formation of 20 in slightly higher yields of 89%.
fully employed, and the resulting products 13 and 14 were
obtained in good yields of 76% and 66% respectively (entries 5
and 6). The cyclization of the n-pentyl group to form 15 resulted
in the modest yield of 45% (entry 7) and the cyclization of the
tert-butyl functionality did not lead to any cyclized product 16
(entry 8). The difference in yields of the two alkyl functionalities
can be explained by their differing geometry. We believe that the
tert-butyl group is unable to approach the quinoline’s aromatic
ring because of its bulky size resulting in no cyclization.
The proposed mechanism of electrophilic ipso-iodocyclization
proceeds via initial co-ordination of electrophilic iodine with the

L. Low-Beinart et al. / Tetrahedron Letters 54 (2013) 1344–1347
1347
6420; (f) Lapointe, G.; Schenk, K.; Renaud, P. Org. Lett. 2011, 13, 4774–4777; (g)
Perry, M. A.; Morin, M. D.; Slafer, B. W.; Rychnovsky, S. D. J. Org. Chem. 2012, 77,
3390–3400.
In summary, the pyrrolo-[2,1-j]quinolonecore structure was
successfully synthesized in high yields using electrophilic cycliza-
tion reaction. I2 was successfully employed as electrophile in these
cyclization reactions. Cyclization with NIS resulted in low yield of
the product. Our efforts to synthesize bromine analogues of
pyrrolo-[2,1-j]quinolone were unsuccessful as the cyclization reac-
tion with Br2 and NBS failed for reasons that we do not presently
understand. Alkynes bearing aryl, heteroaryl, vinyl, and alkyl
groups were successfully cyclized. The core structure was further
functionalized using Suzuki cross-coupling reactions.
5. For a recent review on electrophilic cyclization of alkynes, see: Godoi, B.;
Schumacher, R. F.; Zeni, G. Chem. Rev. 2011, 111, 2937–2980.
6. (a) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2006, 71, 62–69; (b) Worlikar, S.
A.; Neuenswander, B.; Lushington, G. H.; Larock, R. C. J. Comb. Chem. 2009, 11,
875–879; (c) Chen, Y.; Cho, C.-H.; Shi, F.; Larock, R. C. J. Org. Chem. 2009, 74,
6802–6811.
7. Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292–10296.
8. (a) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905–1909; (b) Cho, C.-H.; Jung,
D.-I.; Neuenswander, B.; Larock, R. C. ACS Comb. Sci. 2011, 13, 501–510; (c) Cho,
C.-H.; Neuenswander, B.; Larock, R. C. J. Comb. Chem. 2010, 12, 278–285.
9. Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2006, 71, 2307–2312.
10. (a) Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70, 7679; (b) Cho, C.-H.;
Larock, R. C. ACS Comb. Sci. 2011, 13, 272–279.
Acknowledgments
11. Zhang, X. X.; Campo, M. A.; Yao, T.; Larock, R. C. Org. Lett. 2005, 7, 763–766.
12. (a) Huang, Q.; Hunter, J. A.; Larock, R. C. Org. Lett. 2001, 3, 2973; (b) Huang, Q.;
Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67, 3437; (c) Markina, N.;
Mancuso, R.; Neuenswander, B.; Lushington, G.; Larock, R. C. ACS Comb. Sci.
2011, 13, 265–271.
The authors wish to thank the Bard Summer Research Institute
and the National Science Foundation Major Research Instrumenta-
tion Award 1039659 for the support of this research. The authors
would also like to thank Dr. Teresa A. Garrett, Dr. Craig Anderson
and Dr. Emily McLaughlin for their help.
13. Worlikar, S. A.; Kesharwani, T.; Yao, T.; Larock, R. C. J. Org. Chem. 2007, 72,
1347–1353.
14. Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 12230–12231.
15. (a) Tang, B.-X.; Zhang, Y.; Song, R.; Tang, D.; Deng, G.; Wang, Z.; Xie, Y.; Xia, Y.;
Li, J. J. Org. Chem. 2012, 77, 2837–2849; (b) Likhar, P. R.; Racharlawar, S. S.;
Karkhelikar, M. V.; Subhas, M. S.; Sridhar, B. Synthesis 2011, 2407–2414; (c)
Tang, B.-X.; Yin, Q.; Tang, R.-Y.; Li, J.-H. J. Org. Chem. 2008, 73, 9008–9011; (d)
Wang, Z.-Q.; Tang, B.-X.; Zhang, H.-P.; Wang, F.; Li, J.-H. Synthesis 2009, 6, 891–
902; (e) Yu, Q.-F.; Zhang, Y.-H.; Yin, Q.; Tang, B.-X.; Tang, R.-Y.; Zhong, P.; Li, J.-
H. J. Org. Chem. 2008, 73, 3658–3661; (f) Tang, B. X.; Tang, D. J.; Tang, S.; Yu, Q.
F.; Zhang, Y. H.; Liang, Y.; Zhong, P.; Li, J. H. Org. Lett. 2008, 10, 1063–1066.
16. Method: To a 6 dram vial containing alkyne (0.30 mmol), 4 mL of CH3CN and
NaHCO3 (0.90 mmol, 76 mg) were added. To this solution I2 (0.60 mmol,
152 mg) dissolved in 2 mL CH3CN was added and the solution was allowed to
stir for 24 h. Reaction was quenched with H2O (10 mL) and Na2S2O7 was added
to remove excess I2. This mixture was extracted with DCM (3 Â 20 mL) and the
resulting organic layer was dried over Na2SO4. After concentration under
vacuum, the crude product was purified by column chromatography using
hexanes/ethyl acetate (5:1) as the eluent. 2-iodo-1-phenyl-6,7-dihydro-3H-
pyrrolo[2,1-j]quinoline-3,9(5H)-dione (10) was isolated as a light yellow solid
(110 mg, 91%): mp 229–230 oC; 1H NMR (400 MHz, CDCl3) d 7.45–7.32 (m, 3H),
7.07 (dd, J = 8.1, 1.6 Hz, 2H), 6.54 (d, J = 9.8 Hz, 1H), 6.36 (t, J = 1.7 Hz, 1H), 6.20
(dd, J = 9.8, 1.7 Hz, 1H), 4.24 (dd, J = 14.2, 8.0 Hz, 1H), 2.93–2.79 (m, 1H), 2.63–
2.41 (m, 2H), 2.15–2.02 (m, 1H), 1.97–1.80 (m, 1H); 13C NMR (101 MHz, CDCl3)
d 184.5, 171.5, 159.9, 157.4, 145.6, 132.1, 131.6, 130.1, 129.5, 128.64, 128.62,
128.1, 128.0, 98.3, 74.2, 37.69, 27.1, 26.2; HRMS (ESI+, m/z) calcd for
(C18H15INO2)+ (M+H)+ 404.0142, found 404.0126.
Supplementary data
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2012.12.014.
References and notes
1. (a) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercauteren, J.; Weber, J. F.;
Boukef, K. Tetrahedron Lett. 1994, 35, 2691–2694; (b) Abe, H.; Aoyagi, S.;
Kibayashi, C. J. Am. Chem. Soc. 2000, 122, 4583–4592; (c) Abe, H.; Aoyagi, S.;
Kibayashi, C. Angew. Chem., Int. Ed. 2002, 41, 3017–3020.
2. (a) Blackman, A. J.; Li, C.; Hockless, D. C. R.; Skelton, B. W.; White, A. H.
Tetrahedron 1993, 49, 8645–8656; (b) Li, C.; Blackman, A. J. Aust. J. Chem. 1994,
47, 1355–1361; (c) Li, C.; Blackman, A. J. Aust. J. Chem. 1995, 48, 955–965.
3. (a) Jugé, M.; Grimaud, N.; Biard, J. F.; Sauviat, M. P.; Nabil, M.; Verbist, J. F.; Petit,
J.-Y. Toxicon 2001, 39, 1231–1237; (b) Raub, M. F.; Cardelina, J. H.; Choudhary,
M. I.; Ni, C.-Z.; Clardy, J.; Alley, M. C. J. Am. Chem. Soc. 1991, 113, 3178.
4. (a) Molander, G. A.; Rönn, M. J. Org. Chem. 1999, 64, 5183–5187; (b) Abe, H.;
Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 2000, 41, 1205–1208; (c) Abe, H.;
Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2005, 127, 1473–1480; (d) Lee, M.;
Lee, T.; Kim, E.; Ko, H.; Kim, D.; Kim, S. Org. Lett. 2006, 8, 745–748; (e) Donohoe,
T. J.; Brian, P. M.; Hargaden, G. C.; O’Riordan, T. J. C. Tetrahedron 2010, 66, 6411–