Condensation of propargylic alcohols with indoles and carbazole in [bmim][PF6]/Bi(NO3)3·5H2O: A simple high yielding propargylation method with recycling and reuse of the ionic liquid

Article abstract of DOI:10.1016/j.tetlet.2012.04.026

Propargylation of a variety of substituted indoles as well as mono- and di-propargylation of carbazole are achieved in 80-94% isolated yields by employing catalytic amounts (10 mol %) of the readily available Bi(NO ₃)₃·5H₂

Full text of DOI:10.1016/j.tetlet.2012.04.026

Tetrahedron Letters 53 (2012) 3066–3069
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Condensation of propargylic alcohols with indoles and carbazole in
[bmim][PF6]/Bi(NO3)3Á5H2O: a simple high yielding propargylation method
with recycling and reuse of the ionic liquid
⇑
G.G.K.S. Narayana Kumar, Gopalakrishnan Aridoss, Kenneth K. Laali
Department of Chemistry, University of North Florida, 1 UNF Drive, Jacksonville, FL 32224, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Propargylation of a variety of substituted indoles as well as mono- and di-propargylation of carbazole are
achieved in 80–94% isolated yields by employing catalytic amounts (10 mol %) of the readily available
Bi(NO3)3Á5H2O in [bmim][PF6] ionic liquid (IL), with repeated recycling and reuse of the IL.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 8 March 2012
Revised 3 April 2012
Accepted 4 April 2012
Available online 13 April 2012
Keywords:
Propargylation
Indole
Carbazole
Bismuth nitrate
Ionic liquid
Owing to the importance of the indole moiety as a building
block of natural products, pharmaceuticals, and functional materi-
als, significant research efforts have been focused in recent years to
develop mild and selective synthetic routes to functionalized in-
doles.1,2 The carbazole moiety represents another significant het-
erocyclic building block in natural products that has also been
applied extensively in organic materials.3,4
Development of mild and selective methods for the direct
introduction of propagylic groups into indoles and carbazoles is a
desirable synthetic goal, thus allowing further elaboration of these
intermediates. To date a limited number of methods for direct in-
dole and carbazole propargylation have been reported, and no
examples for dipropargylated carbazole appear to exist.5–10
Focusing on earlier studies on indoles, in the context of their
work on ruthenium-catalyzed propargylation of aromatics, Uem-
ura and associates5 propargylated the parent indole with 1-phen-
ylpropyne-1-ol in DCE solvent in 52% yield. Since then several
other studies by other research groups have been reported that
employed CeCl3/MeNO2,6a Ce(OTf)3/MeNO2,6b FeCl3/MeNO2,7
Sc(OTf)3/DCE,8 InBr3/DCE,9 and TfOH or PTSA in MeCN or MeNO2.10
In relation to our recent studies focusing on the generation and
synthetic application of propargylic cations,11 and in continuation
of our work on electrophilic chemistry in ionic liquids as solvent
and catalysts,12 we report here on a facile, high yielding direct
propargylation method using propargyl alcohols 2a, 2b, and 2c
with a host of substituted indoles, and on mono- and dipropargy-
lation of carbazole with 2a, employing the readily available bis-
muth nitrate pentahydrate as promoter in [bmim][PF6] solvent
(Figs. 1–3).13
The results are summarized in Table 1, entries 1–7 show the
scope of the reaction for substituted indoles with propargylic alco-
hol 2a, with isolated yields in 80–94% range, employing very mild
conditions, and short reaction times. It is noteworthy that runs 2–7
employed recycled/reused IL,14 and exhibit a gradual decrease in
isolated yields from 94% to 81%.
Under the present reaction conditions 4-phenyl-3-butyn-2-ol
failed to undergo condensation with indoles. Whereas stabilization
of an
a-phenyl group seems necessary for the generation of an
incipient propargylic carbocation in this method, nature of the sub-
stituent at the alkynyl moiety is less critical. Thus propargylic alco-
hols 2b and 2c were successfully used in this study for the
propargylation of substituted indoles (Fig. 2) to give compounds
10–15 in respectable isolated yields. Once again, the IL was recy-
cled and reused in subsequent reactions without a notable de-
crease in the conversions.
The present method is also applicable to the propargylation of
carbazole (Fig. 3), to furnish the mono- and dipropargylated deriv-
atives by using 1.0 and 2.2 equiv of 2a, respectively, (compounds
17 and 18). Compound 18 was obtained as a single isomer (NMR).
In summarythe presentstudy has demonstrated the utilityof Bi(-
NO3)3Á5H2O as a mild and selective Lewis acid for the propargylation
⇑
Corresponding author. Tel.: +1 904 620 1503; fax: +1 904 620 3535.
E-mail address: kenneth.laali@UNF.edu (K.K. Laali).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.026

G. G. K. S. Narayana Kumar et al. / Tetrahedron Letters 53 (2012) 3066–3069
3067
H
N
OH
R1
R
.
10 mol% Bi(NO3)3 5H2O
R
R1
+
Ph
N
H
(bmim)PF6
Ph
Ph
Ph
2a
3-9
1a-1g
Figure 1. Propargylation of indoles with 2a in [bmim][PF6]/Bi(NO3)3Á5H2O system.
H
N
OH
.
R2
10-15
10 mol% Bi(NO3)3 5H2O
(bmim)PF6
R2
+
R
N
H
1b-1f
R1
R1
R
2b-2c
OH
OH
Ph
Ph
Si
2b
2c
Figure 2. Propargylation of indoles with 2b and 2c in [bmim][PF6]/Bi(NO3)3Á5H2O system.
OH
OH
H
N
Ph
Ph
NH
Ph
Ph
2.2 equv
2a
1.0 equiv
2a
Ph
Ph
.
.
10 mol% Bi(NO3)3 5H2O
10 mol% Bi(NO3)3 5H2O
N
H
16
(bmim)PF6
(bmim)PF6
Ph
Ph
Ph
Ph
18
17
Figure 3. Propargylation of carbazole with 2a in [bmim][PF6]/Bi(NO3)3Á5H2O system.
Table 1
Propargylation of indoles and carbazole with Bi(NO3)3 5H2O in [bmim][PF6]a,b
Entry
Indoles and Carbazole
Alcohols
Products
Temp (°C)
Time (h)
Isolated yield (%)
OH
NH
N
H
Ph
1
Ph
Ph
Ph
35
3
92
94
1a
Ph
2a
Ph
3
F
OH
Ph
NH
F
N
H
2
3
40
40
4
4
1b
Ph
2a
Ph
4
Br
OH
Ph
NH
Br
N
H
91
88
1c
Ph
Ph
2a
Ph
5
NC
OH
Ph
NH
NC
N
4
5
35
40
3
5
H
Ph
Ph
1d
2a
6
Ph
O2N
OH
Ph
NH
O2N
N
87
H
1e
2a
Ph
7
Ph
(continued on next page)

3068
G. G. K. S. Narayana Kumar et al. / Tetrahedron Letters 53 (2012) 3066–3069
Table 1 (continued)
Entry
6
Indoles and Carbazole
MeO
Alcohols
Products
Temp (°C)
Time (h)
Isolated yield (%)
OH
NH
MeO
Ph
N
H
Ph
Ph
50
4
80
1f
Ph
2a
Ph
8
OH
Ph
NH
N
H
7
45
4
81
1g
Ph
2a
Ph
NH
9
Br
OH
Ph
Br
N
H
8
9
60
55
60
8
6
8
86
89
90
1c
2b
Ph
Ph
10
11
NC
OH
Ph
NH
NC
N
H
1d
2b
O2N
OH
Ph
NH
O2N
N
10
H
1e
Ph
2b
12
NH
F
OH
F
Ph
N
H
Si
11
12
13
35
35
45
2
91
89
86
1b
Ph
2c
Si
13
Br
OH
Ph
NH
Br
N
H
Si
Si
2.5
3.5
1c
Ph
2c
OH
Si
14
O2N
NH
O2N
Ph
Ph
N
H
1e
Ph
2c
OH
Si
15
NH
N
Ph
Ph
H
14
50
4
84
16
2a
Ph
17
Ph
Ph
OH
H
N
Ph
N
H
Ph
Ph
15c
60
6
90
16
2a
Ph
18
a
b
c
Fresh [bmim][PF6] was used in runs 1, 8, 11 and 14, whereas recycled IL was used in others.
The [bmim][PF6] could be reused without purification for up to three runs, after which it was purified and reused (see SI file).
2.2 equiv of propargylic alcohol.

G. G. K. S. Narayana Kumar et al. / Tetrahedron Letters 53 (2012) 3066–3069
3069
6. (a) Silveira, C. C.; Mendes, S. R.; Wolf, L.; Martins, G. M. Tetrahedron Lett. 2010,
51, 4560–4562; (b) Silveira, C. C.; Mendes, S. R.; Martins, G. M. Tetrahedron Lett.
2012, 53, 1567–1570.
7. Jana, U.; Maiti, S.; Biswas, S. Tetrahedron Lett. 2007, 48, 7160–7163.
8. Yadav, J. S.; Reddy, B. V. S.; Rao, K. V. R.; Kumar, G. G. K. S. N. Tetrahedron Lett.
2007, 48, 5573–5576.
of indoles and carbazole. When used in catalytic amounts, it can be
dissolved in [bmim][PF6] upon sonication to form an embedded cat-
alyst for propargylation of indole and carbazole with propargyl alco-
hols. With mild reaction conditions and respectable isolated yields,
coupled to recycling and reuse of the IL, the reported method has
the potential to be used widely.
9. Yadav, J. S.; Reddy, B. V. S.; Rao, K. V. R.; Kumar, G. G. K. S. N. Synthesis 2007,
3205–3210.
10. Sanz, R.; Miguel, D.; Martínez, A.; Gohain, M.; García-García, P.; Fernández-
Rodríguez, M. A.; Álvarez, E.; Rodríguez, F. E. J. Org. Chem. 2010, 7027–7039.
11. (a) Aridoss, G.; Sarca, V. D.; Ponder, J. F., Jr; Crowe, J.; Laali, K. K. Org. Biomol.
Chem. 2011, 9, 2518–2529; (b) Aridoss, G.; Laali, K. K. Tetrahedron Lett. 2011, 52,
6859–6864.
Acknowledgements
We thank the University of North Florida for support and Dr.
Nelson Zhao of this department for NMR assistance.
12. (a) Laali, K. K.; Gettwert, V. J. J. Org. Chem. 2001, 66, 35–40; (b) Laali, K. K.;
Gettwert, V. J. J. Fluorine Chem. 2001, 107, 31–34; (c) Laali, K. K.; Borodkin, G. I. J.
Chem. Soc. Perkin Trans. 2002, 2, 953–957; (d) Sarca, V. D.; Laali, K. K. Green
Chem. 2004, 6, 245–248; (e) Laali, K. K.; Sarca, V. D.; Okazaki, T.; Brock, A.; Der,
P. Org. Biomol. Chem. 2005, 3, 1034–1042; (f) Sarca, V. D.; Laali, K. K. Green
Chem. 2006, 8, 615–620; (g) Laali, K. K.; Okazaki, T.; Bunge, S. J. Org. Chem.
2007, 72, 6758–6762; (h) Hubbard, A.; Okazaki, T.; Laali, K. K. Aust. J. Chem.
2007, 60, 923–927; (i) Hubbard, A.; Okazaki, T.; Laali, K. K. J. Org. Chem. 2008,
73, 316–319; (j) Pavlinac, J.; Laali, K. K.; Zupan, M.; Stavber, S. Aust. J. Chem.
2008, 61, 946–955; (k) Pavlinac, J.; Zupan, M.; Laali, K. K.; Stavber, S.
Tetrahedron 2009, 65, 5625–5662; (l) Kalkhambkar, R. G.; Waters, S. N.; Laali,
K. K. Tetrahedron Lett. 2011, 52, 867–871; (m) Kalkhambkar, R. G.; Laali, K. K.
Tetrahedron Lett. 2011, 52, 1733–1737; (n) Kalkhambkar, R. G.; Laali, K. K.
Tetrahedron Lett. 2011, 52, 5525–5529; (o) Aridoss, G.; Laali, K. K. Eur. J. Org.
Chem. 2011, 2827–2835; (p) Aridoss, G.; Laali, K. K. Eur. J. Org. Chem. 2011,
6343–6355; (q) Aridoss, G.; Laali, K. K. J. Org. Chem. 2011, 76, 8088–8094.
13. General procedure for propargylation of indoles and carbazole: The ionic liquid
(3.5–4.0 mL) was charged into an oven-dried Schlenk tube under a nitrogen
atmosphere and Bi(NO3)3Á5H2O (10 mol %) was added and upon sonication (for
about 15 min) was dissolved in the IL. The respective indoles (1 mmol) or
Supplementary data
Supplementary data (multinuclear NMR (1H, 13C, 15N, 19F) and
other characterization data are furnished for the new compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.04.026.
References and notes
1. (a) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608–9644; (b)
Bandini, M.; Eichholzer, A.; Umani-Ronchi, A. Mini-Rev. Org. Chem. 2007, 4,
115–124; (c) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett
2005, 1199–1222.
2. (a) Bronner, S. M.; Im, G.-J.; Garg, N. K. In Heterocycles in Natural Product
Synthesis; Majumdar, K. C.; Chattopadhyay, S. K., Eds.; Wiley-VCH, 2011; pp
221–265.; (b) Vicente, R. Org. Biomol. Chem. 2011, 9, 6469–6480; (c) Pelkey, E.
T. Topics in Heterocyclic Chemistry In Heterocyclic Scaffolds I: Indole; Gribble, G.
W., Ed.; Springer-Verlag: Berlin, 2010; Vol. 26, pp 141–191; (d) Saracoglu, N.
Top. Heterocycl. Chem. 2007, 11, 1–61; (e) Pelkey, E. T. Five-Membered Ring
Systems: Pyrroles and Benzo Derivatives In Progress in Heterocyclic Chemistry;
Gribble, G. W., Joule, J. A., Eds.; Elsevier Science: New York, 2006; Vol. 18, pp
150–186; (f) Agarwal, S.; Caemmerer, S.; Filali, S.; Froehner, W.; Knoell, J.;
Krahl, M. P.; Reddy, K. R.; Knoelker, H.-J. Curr. Org. Chem. 2005, 9, 1601–1614.
3. (a) Grimsdale, A. C.; Chan, K. L.; Martin, R. E.; Jokisz, P. G.; Holmes, A. B. Chem.
Rev. 2009, 109, 897–1091; (b) Cheng, Y.-J.; Yang, S.-H.; Hsu, Ch.-S. Chem. Rev.
2009, 109, 5868–5923; (c) Lo, S.-Ch.; Burn, P. L. Chem. Rev. 2007, 107, 1097–
1116; (d) Knolker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303–4427.
4. (a) Yang, C.; Song, H.-S.; Liu, D.-B. J. Mater. Sci. 2012, 47, 3315–3319; (b) Wang,
S.; Mao, H.; Ni, Z.; Pan, Y. Tetrahedron Lett. 2012, 53, 505–508.
carbazole (1 mmol) was then introduced into the Schlenk tube under
a
nitrogen atmosphere followed by the desired propargylic alcohol (1 mmol).
The reaction mixture was magnetically stirred, initially at rt for about 10 min
followed by stirring in a pre-heated oil bath at 35–60 °C (as specified; refer to
Tables 1), until completion (as monitored by TLC). Once the reaction was over,
the contents were cooled to rt and extracted with dry diethyl ether or with
EtOAc/Hexane (2:3 vol/vol in the case of 5-nitro and 5-cyano indole
derivatives), until the final extraction did not show a spot corresponding to
the starting material or to the product. The combined organic extracts were
washed with DI water, dried with MgSO4, and concentrated to give the crude
product, which upon purification through column chromatography furnished
the desired products.
14. Re-use and recycling of IL: After extraction, the ionic liquid was dried under
high-vacuum at 60–70 °C for about 6 h and re-used in successive runs.
5. Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Hidai, M.; Uemura, S. J. Am. Chem.
Soc. 2002, 124, 11846–11847.