Synthesis of pyrrolo-/indolo[1,2-a ]quinolines and naphtho[2,1- b ]thiophenes from gem -dibromovinyls and sulphonamides

Article abstract of DOI:10.1021/ol5019085

A highly efficient and simple route for the synthesis of pyrrolo-/indolo[1,2-a]quinolines and naphtho[2,1-b]thiophenes from gem-dibromovinyls and sulphonamides is reported. The noteworthy feature of this report is that the methodology involves a two-step protocol to synthesize tri- and tetracyclic heterocycles in a one-pot fashion through the Cu(I)-catalyzed formation of ynamide followed by a Ag(I)-assisted intramolecular hydroarylation. The photophysical properties of representative examples of pyrrolo- and indolo[1,2-a]quinolines in solid and solution states have also been studied.

Full text of DOI:10.1021/ol5019085

Letter
pubs.acs.org/OrgLett
Synthesis of Pyrrolo-/Indolo[1,2‑a]quinolines and
Naphtho[2,1‑b]thiophenes from gem-Dibromovinyls and
Sulphonamides
Selvarangam E. Kiruthika, Avanashiappan Nandakumar, and Paramasivan Thirumalai Perumal*
Organic Chemistry Division, CSIR-Central Leather Research Institute, Adyar, Chennai-600020, Tamilnadu, India
S
* Supporting Information
ABSTRACT: A highly efficient and simple route for the synthesis of pyrrolo-/indolo[1,2-a]quinolines and naphtho[2,1-
b]thiophenes from gem-dibromovinyls and sulphonamides is reported. The noteworthy feature of this report is that the
methodology involves a two-step protocol to synthesize tri- and tetracyclic heterocycles in a one-pot fashion through the Cu(I)-
catalyzed formation of ynamide followed by a Ag(I)-assisted intramolecular hydroarylation. The photophysical properties of
representative examples of pyrrolo- and indolo[1,2-a]quinolines in solid and solution states have also been studied.
devise versatile methodologies for the construction of fused
quinolines.14
ver the past few decades, heteroatom substituted alkynes
Oare growing as an important class of substrates since they
have contributed significantly toward the construction of
various heterocycles. Remarkable advancements, both in
synthesis and in the study of synthetic utilities of alkynes
possessing N, O, P, or S atoms, are being constantly
reported.1−4 Among the several classes of nitrogen-containing
alkynes available, ynamides have attracted the special attention
of organic chemists which is undoubtedly evident from the
notable progress reported in recently.5 The emergence of
ynamides can be attributed to the exceptional stability and
versatile reactivity resulting in their profound use for the
insertion of nitrogen-based functionalities in organic mole-
cules.6 The distinct feature of ynamide reactivity is that it allows
regioselective addition of electrophiles or nucleophiles onto the
ynamide which may be due to the polarization of the nitrogen
triple bond or the possible chelation of the reagent with the
electron-withdrawing group (EWG).5a,e Hence the addition at
the α-position of the ynamides (position adjacent to the
nitrogen) is extensively being developed.7
Our preceding report pertained to the synthesis of 2-
amidoindoles from gem-vinyldihalides and sulphonamides
through an intramolecular hydroamidation reaction of 2-
amido substituted ynamides (Scheme 1a).15 In our continuing
effort to exploit the reactivity of ynamide at the α-position, we
herein wish to report the synthesis and photophysical study of
pyrrolo-/indolo[1,2-a]quinolines from 1-(2-(2,2-dibromo-
vinyl)phenyl)-1H-pyrrole/-indole and sulphonamides via intra-
molecular hydroarylation of ynamides possessing heterocyclic
nucleophiles within proximity (Scheme 1b).
In a preliminary experiment we investigated the feasibility of
forming ynamide 4a by the Cu(I)-catalyzed reaction of gem-
dibromovinyl phenyl-1H-pyrrole 2a and N-benzyl-4-methyl-
benzenesulfonamide 3a.16 The reaction afforded a maximum
yield of 89% in the presence of 3 mol % CuI, 5 mol % 1, 10-
phenanthroline, and 3 equiv of Cs2CO3 in THF at rt (Scheme
2).
Upon the isolation of the ynamide 4a, we attempted the
intramolecular hydroarylation to achieve the target pyrrolo[1,2-
a]quinoline 5a (Table 1). Initially the screening was done with
Au/Ag catalysts. Among the Au/Ag salts screened, AgOTf
showed a promising catalytic tendency to afford pyrrolo[1,2-
Fused nitrogen heterocycles, in particular pyrrolo-/indolo-
[1,2-a]quinolines, occur in numerous natural products;9 display
a wide range of applications in pharmaceuticals,8 host−guest
chemistry,10 organic semiconductors,11 and liquid crystal
chemistry;12 and have also been found to exhibit electron
transport properties.13 Therefore, there is a growing demand to
Received: July 3, 2014
Published: August 11, 2014
© 2014 American Chemical Society
4424
dx.doi.org/10.1021/ol5019085 | Org. Lett. 2014, 16, 4424−4427

Organic Letters
Letter
a
Scheme 1. Synthesis of Heterocycles from gem-
Dibromovinyls and Sulfonamides
Scheme 4. Synthesis of Pyrrolo[1,2-a]quinolines 5a−j
Scheme 2. Synthesis of Ynamide 4a
a
Isolated yields after flash column chromatography.
Scheme 5. Synthesis of Indolo[1,2-a]quinolines 7a−d and
a
Table 1. Screening of Catalysts for the Intramolecular
Hydroarylation of Ynamide 4a
Naphtho[2,1-b]thiophenes 9a−e
a
b
entry
catalyst
AuCl3
solvent
time (h)
yield (%)
1
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DMF
CH3CN
24
0.5
24
5
−
90
2
AgOTf
AgCO2CH3
Zn(OTf)2
In(OTf)3
Yb(OTf)3
FeCl3
3
−
4
50
63
25
−
5
8
6
20
24
24
8
7
8
I2
−
a
Isolated yields after flash column chromatography.
9
Tf2NH
PNBSA
AgOTf
AgOTf
65
40
80
77
10
11
12
24
1
Scheme 6. Mechanism for the Synthesis of Pyrrolo[1,2-
a]quinolines 5a
0.75
a
All the reactions were performed using 5 mol % of the catalyst, at
b
room temperature. Isolated yields after column chromatography.
Scheme 3. Simultaneous/Sequential Synthesis of
Pyrrolo[1,2-a]quinoline 5
Zn(OTf)2 which provided the pyrrolo[1,2-a]quinoline 5a in
yields as low as 25% and 50% respectively. In(OTf)3 showed
reasonable catalytic activity, affording 5a in 63% yield. Other
catalysts such as FeCl3 and I2 (Table 1, entries 7 and 8) were
tried, but the reaction did not proceed to provide 5a. Bronsted
acids namely Tf2NH and p-nitrobenzenesulfonic acid (PNBSA)
were also used as catalysts (Table 1, entries 9 and 10).
However, AgOTf was found to be the optimum catalyst in
a]quinoline 5a (Table 1, entry 2) whereas AuCl3 (Table 1,
entry 1) and AgOCOCH3 (Table 1, entry 3) did not provide
the expected product. With the above results, the reaction was
attempted using other metal triflates (Table 1, entries 4−6).
The reaction was found to proceed with Yb(OTf)3 and
4425
dx.doi.org/10.1021/ol5019085 | Org. Lett. 2014, 16, 4424−4427

Organic Letters
Letter
Table 2. Optical Properties of Compounds 5a−b, 5g, 5j, and 7a−b
λmax,ab (nm)
λmax,em (nm)
Stokes shift (cm−1
)
a
b
a
c
b
a
b
compd
solution (ε M−1 cm−1
)
aggregation
solution (Φ)
aggregation
solid
solution
aggregation
5a
5b
5g
5j
362 (5631)
371 (4890)
371 (6408)
370 (5434)
405 (3966)
386 (5784)
370
378
377
378
413
427 (0.039)
444 (0.132)
447 (0.101)
447 (0.099)
481 (0.215)
480 (0.356)
474
450
455
483
508
496
438, 468
455
4205
4432
4583
4655
3901
5073
5930
4233
4547
5751
4528
4229
468
496
7a
7b
514, 557
410
515, 553
a
b
c
Recorded at 20 μM concentration in CH3CN. In CH3CN/H2O (1:99) mixture at 10 μM concentration. Quininine sulfate in 1 N H2SO4 was
used as a reference.
In studying the reaction scope, we next devoted our efforts to
synthesize fused tetracyclic nitrogen analogues by varying the
heterocyclic nucleophiles attached on the gem-dibromovinyl. A
reaction was carried out between gem-dibromovinyl phenyl-1H-
indole 6 with N-benzyl-4-methylbenzenesulfonamide 3a under
our standard conditions. To our delight the reaction afforded
the expected indolo[1,2-a]quinoline 7a in 83% yield. This
result was extended to synthesize other analogues of indolo-
[1,2-a]quinolines 7a−d by varying substituents on sulphona-
mides. Upon the successful synthesis of tricyclic and tetracyclic
quinolines, we wanted to probe the applicability when a
thiophene ring is introduced at the ortho position to the gem-
vinyldihalide. As we expected, the reaction proceeded under the
Cu(I)/Ag(I) conditions to yield the naphtho[2,1-b]thiophenes
9a−e in excellent yields (Scheme 5).
Figure 1. (a) Normalized absorption (dotted line) and PL (solid line)
spectra of compound 7b in solution state (blue) and aggregated
solution (CH3CN/H2O (1:99) mixture) state (red), solid (brown).
The inset in panel a: photo of 7b in CH3CN solution. (b) Ortep of 5g.
A mechanistic proposal for the formation of representative
fused nitrogen heterocycle 5a is described in Scheme 6. The
mechanism is based on the higher reactivity of the trans C−Br
bond of gem-dibromovinyl 2a toward oxidative addition with
Cu(I). Stereoselective coupling with 3a, followed by dehydro-
bromination, affords ynamide 4a. Then, activation of the C−N
triple bond by coordination to Ag+ allows intramolecular
hydroarylation, affording the resultant pyrrolo[1,2-a]quinoline
5a.
terms of both rate and yield (Table 1, entry 2). This might be
due to the possibility of chelation with the EWG of the
ynamide. We also found that the reaction proceeded only at rt.
The reaction was also attempted by increasing the temperature
to 80 °C; the pyrrolo[1,2-a]quinoline was not isolated, and the
reaction resulted in the formation of an undesirable mixture.
The accomplishment of the expected intramolecular hydro-
arylation prompted us to explore the one-pot synthesis of
pyrrolo[1,2-a]quinolines. The one-pot reaction was monitored
by the simultaneous addition of both Cu(I) and Ag(I) catalysts.
Unfortunately this reaction afforded the ynamide 4a in major
quantities and only a trace amount of the pyrrolo[1,2-
a]quinoline 5a was isolated (Scheme 3a). The reaction was
then tried with the initial addition of the copper catalyst and
addition of silver triflate upon the formation of ynamide 4a. In
contrast, the reaction readily afforded the pyrrolo[1,2-a]-
quinoline 5a in an 87% yield (Scheme 3b).
To examine the scope of the present methodology we
extended the reaction conditions to synthesize various
derivatives of pyrrolo[1,2-a]quinolines 5 (Scheme 4). The
reaction was explored by varying the substituents on both
substrates 2 and 3. The reaction proceeded well for almost all
substrates bearing electron-rich, halogen, or heterocyclic
substituents. The reaction also performed well when the
electron-withdrawing counterpart on 2 was altered from -Ts to
-Ms. The structure of the compounds 5 was confirmed by X-ray
single crystal analysis (Figure 1b).17 We also found that the
reaction outcome was dependent on the nature of the EWG on
the amide 3. The sulphonamides were found to be the best
coupling partners for the intramolecular hydroarylation
reaction.15 The reaction could not proceed to give the desired
pyrrolo[1,2-a]quinoline by varying the nature of the EWG on
the amide (−Boc, −COCF3, −COCH3), even when the
temperature and catalyst loading were increased.
After accomplishing the synthesis of various fused quinolines
and naphthothiophenes, we found that the synthesized
compounds exhibited interesting photo luminescence proper-
ties in solid and solution states. Among the compounds
synthesized, unfortunately the naphtho[2,1-b]thiophenes did
not show any distinct photophysical properties. Hence we
attempted to study the photophysical properties of representa-
tive examples. Compounds 5a−b, 5g, 5j, and 7a−b were used
to study the photophysical properties in solid and solution
states (Table 2). The absorption maxima of the compounds in
CH3CN solution showed absorption maxima in the range of
362−405 and 370−413 nm for the solution and aggregation
states, respectively. The results also indicated that the
compounds displayed shifts in PL spectra in the solution,
solid, and aggregation states. The emission results showed a red
shift for indolo[1,2-a]quinolines (Table 2, Figure 1) compared
to pyrrolo[1,2-a]quinolines which was a common observation
in the solid, solution, and aggregation states. The quantum
efficiencies (Φ) ranged from 0.039 to 0.356 in the solution
state, and moreover the indolo[1,2-a]quinolines displayed
higher quantum efficiencies than the pyrrolo[1,2-a]quinolines.
The Stokes shifts for the representatives in the solution and
aggregation states have also been calculated (Table 2).
In conclusion this letter brings forth a simple and convenient
route for the synthesis of fused heterocycles from gem-
vinyldihalides and sulfonamides involving Cu(I) and Ag(I) as
4426
dx.doi.org/10.1021/ol5019085 | Org. Lett. 2014, 16, 4424−4427

Organic Letters
Letter
2790. (e) Dooleweerdt, K.; Ruhland, T.; Skrydstrup, T. Org. Lett.
2009, 11, 221. (f) Kramer, S.; Dooleweerdt, K.; Lindhardt, A. T.;
Rottlander, M.; Skrydstrup, T. Org. Lett. 2009, 11, 4208.
catalysts. Thus, this method is economical, practical, and
reliable and more advantageous as it involves milder reaction
conditions, a shorter reaction time, and high yields. The
compounds were found to exhibit photophysical properties,
and some of the representative examples of the pyrrolo- and
indolo[1,2-a]quinolines under study have exhibited distinct
fluorescence in the solid, solution, and aggregation states.
(7) For selected examples of addition at the α-position of ynamides,
see: (a) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.; Coverdale, H.;
Frederick, M. O.; Shen, L.; Zificsak, C. A. Org. Lett. 2003, 5, 1547.
(b) Zhang, Y. Tetrahedron Lett. 2005, 46, 6483. (c) Zhang, Y.
Tetrahedron 2006, 62, 3917. (d) Zhang, Y.; Hsung, R. P.; Zhang, X.;
Huang, J.; Slafer, B. W.; Davis, A. Org. Lett. 2005, 7, 1047. (e) Yang,
Y.; Wang, L.; Zhang, J.; Jin, Y.; Zhu, G. Chem. Commun. 2014, 50,
2347.
ASSOCIATED CONTENT
■
S
* Supporting Information
(8) (a) Hazra, A.; Mondal, S.; Maity, A.; Naskar, S.; Saha, P.; Paira,
R.; Sahu, K. B.; Paira, P.; Ghosh, S.; Sinha, C.; Samanta, A.; Banerjee,
S.; Mondal, N. B. Eur. J. Med. Chem. 2011, 46, 2132. (b) Santarem, M.;
1
Experimental section; H and 13C NMR spectra; mass, UV−
visible, and PL spectra of representative compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
́
Vanucci-Bacque, C.; Lhommet, G. J. Org. Chem. 2008, 73, 6466.
(c) Kemnitzer, W.; Kuemmerle, J.; Jiang, S. C.; Sirisoma, N.;
Kasibhatla, S.; Crogan-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S. X.
Bioorg. Med. Chem. Lett. 2009, 19, 3481. (d) Pearson, W. H.; Fang, W.
K. J. Org. Chem. 2000, 65, 7158.
AUTHOR INFORMATION
Corresponding Author
■
(9) (a) Gribble, G. W. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. S. V., Eds.; Pergamon Press:
New York, 1996; Vol. 2, pp 207−257. (b) Le Quesne, P. W.; Dong, Y.;
Blythe, T. A. Alkaloids: Chem. Biol. Perspect. 1999, 13, 237−287.
(c) Janosik, T.; Bergman, J. In Progress in Heterocyclic Chemistry;
Gribble, G. W., Joule, J. A., Eds.; Pergamon: Amsterdam, 2003; Vol.
15, pp 140−166.
(10) (a) Cram, D. J. Nature 1992, 356, 29. (b) Schwartz, E. B.;
Knobler, C. B.; Cram, D. J. J. Am. Chem. Soc. 1992, 114, 10775.
(c) Dijkstra, P. J.; Skowronska-Ptasinska, M.; Reinhoudt, D. N.; Den
Hertog, H. J.; Van Eerden, J.; Harkema, S.; De Zeeuw, D. J. Org. Chem.
1987, 52, 4913.
(11) (a) Ahmed, E.; Briseno, A. L.; Xia, Y.; Jenekhe, S. A. J. Am.
Chem. Soc. 2008, 130, 1118. (b) Zhu, L.; Kim, E.-G.; Yi, Y.; Ahmed, E.;
Jenekhe, S. A.; Coropceanu, V.; Bredas, J.-L. J. Phys. Chem. C 2010,
114, 20401.
(12) (a) Chandrasekhar, S. Advances in Liquid Crystals; Academic
Press: New York, 1982; Vol. 5, p 47. (b) Chandrase\khar, S.;
Ranganath, G. S. Rep. Prog. Phys. 1990, 53, 57. (c) Praefcke, K.; Kohne,
B.; Singer, D. Angew. Chem., Int. Ed. 1990, 29, 177.
*E-mail: ptperumal@gmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors S.E.K. and A.N. thank the Council of Scientific and
Industrial Research (CSIR), New Delhi, India for the research
fellowship. The authors thank Dr. Luxmi Varma, NIIST for
HRMS analysis and Dr. D. Gayathri, Department of Biophysics,
University of Madras for single crystal X-ray analysis.
REFERENCES
■
(1) For selected examples on nitrogen-containing alkynes, see:
(a) Istrate, F. M.; Buzas, A. K.; Jurberg, I. D.; Odabachian, Y.; Gagosz,
F. Org. Lett. 2008, 10, 925. (b) Nadipuram, A. K.; David, W. M.;
Kumar, D.; Kerwin, S. M. Org. Lett. 2002, 4, 4543. (c) Compain, G.;
Jouvin, K.; Mingot, A. M.; Evano, G.; Marrot, J.; Thibaudeau, S. Chem.
Commun. 2012, 48, 5196.
(13) Leontie, L.; Druta, I.; Danac, R.; Rusa, G. I. Synth. Met. 2005,
155, 138.
(2) For selected examples on oxygen-containing alkynes, see:
(a) Jouvin, K.; Bayle, A.; Legrand, F.; Evano, G. Org. Lett. 2012, 14,
1652. (b) Tran, V.; Minehan, T. G. Org. Lett. 2012, 14, 6100.
(c) Tudjarian, A. A.; Minehan, T. G. J. Org. Chem. 2011, 76, 3576.
(d) Bai, Y.; Yin, J.; Kong, W.; Mao, M.; Zhu, G. Chem. Commun. 2013,
49, 7650.
(3) For selected examples on phosphorus-containing alkynes, see:
(a) Lahrache, H.; Robin, S.; Rousseau, G. Tetrahedron Lett. 2005, 46,
1635. (b) Mo, J.; Kang, D.; Eom, D.; Kim, S. H.; Lee, P. H. Org. Lett.
2013, 15, 26. (c) Lera, M.; Hayes, C. J. Org. Lett. 2000, 2, 3873. (d) Li,
X.; Yang, F.; Wu, Y.; Wu, Y. Org. Lett. 2014, 16, 992.
(4) For selected examples on sulphur-containing alkynes, see: (a) Su,
Q.; Zhao, Z. J.; Xu, F.; Lou, P. C.; Zhang, K.; Xie, D. X.; Shi, L.; Cai,
Q. Y.; Peng, Z. H.; An, D. L. Eur. J. Org. Chem. 2013, 1551.
(b) Riddell, N.; Tam, W. J. Org. Chem. 2006, 71, 1934. (c) Shao, X.;
Wang, X.; Yang, T.; Lu, L.; Shen, Q. Angew. Chem., Int. Ed. 2013, 52,
3457.
(14) For selected examples on the synthesis of pyrrolo-/indolo[1,2-
a]quinolines, see: (a) Sarkar, S.; Bera, K.; Jalal, S.; Jana, U. Eur. J. Org.
Chem. 2013, 6055. (b) Liu, X. Y.; Che, C. M. Angew. Chem., Int. Ed..
2008, 47, 3805. (c) Chai, D. I.; Lautens, M. J. Org. Chem. 2009, 74,
3054. (d) Shukla, S. P.; Tiwari, R. K.; Verma, A. K. J. Org. Chem. 2012,
77, 10382. (e) Aggarwal, T.; Kumar, S.; Dhaked, D. K.; Tiwari, R. K.;
Bharatam, P. V.; Verma, A. K. J. Org. Chem. 2012, 77, 8562.
(15) Kiruthika, S. E.; Perumal, P. T. Org. Lett. 2014, 16, 484.
(16) See Supporting Information for detailed optimization for the
synthesis of ynamide 4a.
(17) Crystallographic data for compound 5g in this paper have been
deposited with the Cambridge crystallographic data centre as
supplemental publication no. CCDC 1010852.
(5) For reviews on ynamides, see: (a) Evano, G.; Coste, A.; Jouvin, K.
Angew. Chem., Int. Ed. 2010, 49, 2840. (b) Zificsak, C. A.; Mulder, J. A.;
Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57,
7575. (c) Zhang, Y.; Hsung, R. P. ChemTracts 2004, 17, 442.
(d) Katritzky, A. R.; Jiang, R.; Singh, S. K. Heterocycles 2004, 63, 1455.
(e) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang,
Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064.
(6) For selected examples on synthetic utility of ynamides, see:
(a) Kramer, S.; Odabachian, Y.; Overgaard, J.; Rottlander, M.; Gagosz,
F.; Skrydstrup, T. Angew. Chem., Int. Ed. 2011, 50, 5090. (b) Couty, S.;
Meyer, C.; Cossy, J. Angew. Chem., Int. Ed. 2006, 45, 6726. (c) Davies,
P. W.; Cremonesi, A.; Dumitrescu, L. Angew. Chem., Int. Ed. 2011, 50,
8931. (d) Huang, P.; Chen, Z.; Yang, Q.; Peng, Y. Org. Lett. 2012, 14,
4427
dx.doi.org/10.1021/ol5019085 | Org. Lett. 2014, 16, 4424−4427