Condensation of propargylic alcohols with N-methylcarbazole and carbazole in [bmim]PF6 ionic liquid; Synthesis of novel dipropargylic carbazoles using TfOH or Bi(NO3)3·5H2O as catalyst

Article abstract of DOI:10.1016/j.tetlet.2012.12.023

A series of doubly-propargylated N-methylcarbazole and carbazole derivatives were synthesized in good to excellent isolated yields in (bmim)PF₆ using triflic acid (10 mol %). The use of bismuth nitrate (20 mol %) instead of triflic acid allowed stepwise propargylation employing two different propargylic alcohols, to prepare mixed bis-propargylated carbazoles. Simple product isolation, mild reaction conditions, and repeated recycling and reuse of (bmim)PF₆ are added advantages of this IL-mediated synthetic method.

Full text of DOI:10.1016/j.tetlet.2012.12.023

Tetrahedron Letters 54 (2013) 965–969
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Condensation of propargylic alcohols with N-methylcarbazole and carbazole
in [bmim]PF6 ionic liquid; synthesis of novel dipropargylic carbazoles using
TfOH or Bi(NO3)3Á5H2O as catalyst
⇑
G. G. K. S. Narayana Kumar, 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:
A series of doubly-propargylated N-methylcarbazole and carbazole derivatives were synthesized in good
to excellent isolated yields in (bmim)PF6 using triflic acid (10 mol %). The use of bismuth nitrate
(20 mol %) instead of triflic acid allowed stepwise propargylation employing two different propargylic
alcohols, to prepare mixed bis-propargylated carbazoles. Simple product isolation, mild reaction condi-
tions, and repeated recycling and reuse of (bmim)PF6 are added advantages of this IL-mediated synthetic
method.
Received 16 November 2012
Revised 6 December 2012
Accepted 7 December 2012
Available online 17 December 2012
Keywords:
Di-propargylation
Carbazole
Ó 2012 Elsevier Ltd. All rights reserved.
Bismuth nitrate
Triflic acid
Ionic liquid
The carbazole moiety is a highly versatile heterocyclic platform
with application in natural products and medicinal chemistry, bio-
chemistry, and materials chemistry. Interest in carbazole deriva-
tives has stimulated the development of synthetic methods
directed toward the total synthesis of biologically active carbazole
alkaloids1 and antitubercular agents.2 Carbazole derivatives have
been employed in the design of sequence specific DNA binding
agents,3 used as antiproliferative agents,4 and applied in struc-
ture/activity relationship (SAR) studies.5 Carbazole diamides have
been utilized as receptors for anion binding.6 Conjugated polymers
incorporating carbazole units have blue-light emitting properties,7
and 3,6-bis(triethoxysilyl)carbazoles are precursors to mesoporous
materials.8 Carbazole-based acceptor molecules have been used in
organic solar cells,9 and as blue phosphorescent OLEDs.10
Since electrophilic substitution in N-methylcarbazole and car-
bazole is first directed to the C-3/C-6 positions, the corresponding
formyl-, acyl-, nitro-, and iodo-derivatives have typically served as
a starting point for the synthesis of other carbazoles. The feasibility
to build mixed di-substituted carbazoles by Pd-catalyzed C–H acti-
vation and cross coupling starting from appropriately disubstituted
diaryl acetamides was recently reported.11
yielding one-pot approach to synthesize a variety of 3,6-di-
propargylcarbazoles.
By using catalytic amounts of TfOH (10%) a variety of secondary
propargylic alcohols were reacted with N-methylcarbazole in
(bmim)PF6 as solvent to furnish the corresponding dipropargylated
derivatives 4–13 in isolated yields ranging from 65% to 93% (Fig. 1;
Table 1).15 Using the same procedure, in representative cases com-
pounds 14–16 were synthesized in respectable yields by dipropar-
gylation of parent carbazole ( Fig. 1; Table 2). The feasibility to
synthesize the 3,6-diallyl-substituted derivatives using the same
approach was shown by the synthesis of 17 in 92% isolated yield.
The NMR spectral data for the resulting products (Supplemen-
tary data) clearly indicate that the resulting compounds are sym-
metrically substituted that is either the two phenyls or the two
phenylethynyl groups are cofacial. Except for compounds 9–14
R2
R2
OH
10 mol% TfOH
(bmim)PF6
r.t.
R1
R1
+ R1
N
R
R2
In relation to recent studies from our laboratory focusing on
generation and chemistry of propargylic cations in room tempera-
ture ionic liquids (RT-ILs),12–14 we report here on a facile high
4-6 h
65-93%
N
R
R = H, Me
1 = Aryl
R2 = Ph, C4H9
R
⇑
Corresponding author. Tel.: +1 904 620 1503; fax: +1 904 620 3535.
E-mail address: kenneth.laali@UNF.edu (K.K. Laali).
Figure 1. Propargylation of N-methylcarbazole and carbazole in [bmim][PF6]/TfOH
system.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.023

966
G. G. K. S. N. Kumar, K. K. Laali / Tetrahedron Letters 54 (2013) 965–969
Table 1
a,b
Propargylation of N-methylcarbazole 1 with TfOH in (bmim)PF6
Entry
Alcohols
Products
Time (h)
Isolated yield (%)
OH
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1
4
89
3a
N
Me
4
OH
Me
Me
Ph
3b
Me
2
3
4
5
6
4.5
91
72
83
86
93
Ph
Ph
Ph
Ph
N
Me
5
6
7
8
OH
F
F
Ph
3c
F
6
N
Me
OH
Cl
Cl
Ph
3d
Cl
5.5
N
Me
OH
Br
Br
Ph
3e
Br
6
N
Me
MeO
OH
OMe
Ph
MeO
3f
4
Ph
Ph
Ph
Ph
N
Me
9
OH
S
S
S
Ph
3g
7
8
6
5
65
76
N
Me
10
Ph
OH
Ph
Ph
3h
N
Me
11

G. G. K. S. N. Kumar, K. K. Laali / Tetrahedron Letters 54 (2013) 965–969
967
Table 1 (continued)
Entry
Alcohols
Products
Time (h)
Isolated yield (%)
OH
F
F
3i
F
9
6
70
N
Me
12
OH
Me
Me
3j
Me
10
5
78
N
Me
13
a
Fresh (bmim)PF6 was used in runs 1 and 3, 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.
b
Table 2
a,b
Propargylation of carbazole 2 with TfOH in (bmim)PF6
Entry
Alcohols
Products
Time (h)
Isolated yield (%)
OH
Ph
Ph
Ph
Ph
Ph
1
Ph
5
80
3a
N
H
14
OH
Me
Me
Ph
3b
Me
2
5
83
Ph
Ph
N
H
15
OH
MeO
OMe
Ph
MeO
3f
3
4
4
5
84
92
Ph
Ph
Ph
N
16
Ph
H
OH
Ph
Ph
Ph
Ph
3k
N
17
H
a
Fresh (bmim)PF6 was used in runs 1 and 4, 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.
b
that were liquids others were solids and several attempts were
made to grow suitable crystals for X-ray analysis but these at-
tempts were unsuccessful.
cofacial) were also located, all within 1 kcal/mol of each other
(see Supplementary data).
Attempts to prepare the dipropargylated analogs with mixed
propargyl groups by stepwise monopropargylation using two dif-
ferent propargylic alcohols were not realized in acceptable yields
by using TfOH as catalyst due to disproportionation forming both
‘mixed’ and ‘pure’ products. This problem could be overcome by
using bismuth nitrate in place of TfOH to generate more selective
‘tamed’ propagylic cations in the IL solvent (Fig. 3). Utilizing this
method, the bis-propargylic derivatives 18 and 19 (along with 8
Structure optimization on compound 4 at the B3LYP/3-21G⁄
level indicated that 4a and 4c are both minima (see Fig. 2) with
4c (phenylethynyl groups cofacial) being more stable by only
1.4 kcal/mol relative to 4a (phenyl groups cofacial). It appears that
4c is stabilized by CH–pi interaction involving the two phenyl
groups in the phenylethynyl moieties. Several other minima
including
a
non-symmetrical isomer (phenylethynyl/phenyl

968
G. G. K. S. N. Kumar, K. K. Laali / Tetrahedron Letters 54 (2013) 965–969
Figure 2. Optimized structures for 4 by B3LYP-3-21G⁄.
R2
R4
OH
R1
R2
20 mol% Bi(NO3)3.5H2O
(bmim)PF6
R3
R1
+
N
R
OH
70 o
C
R = Me
N
R
16-20 h
49-66%
R1, R3= Aryl
R2 = Ph
R3
R4
R
4 = Ph, C4H9
Figure 3. Propargylation of N-methylcarbazole in [bmim][PF6]/Bi(NO3)3Á5H2O system.
Table 3
a,b
Propargylation of N-methylcarbazole 1 with Bi(NO3)3Á5H2O in (bmim)PF6
Entry
1
Alcohols
Products
Time (h)
Isolated yield (%)
3b
3f
Me
OMe
16
66b
Ph
Ph
N
Me
18
2
3e
3i
49
17
Me
Br
20
09
Ph
19
N
Me
Br
Br
Ph
Ph
N
Me
8
Me
Me
N
13
Me
a
Fresh (bmim)PF6 was used.
Symmetrically dipropargylated analogs were not detected.
b

G. G. K. S. N. Kumar, K. K. Laali / Tetrahedron Letters 54 (2013) 965–969
969
5. Hammond, M.; Elliott, R. L.; Gillaspy, M. L.; Hager, D. C.; Hank, R. F.; LaFlamme,
J. A.; Oliver, R. M.; DaSilva-Jardine, P. A.; Stevenson, R. W.; Mack, C. M.; Cassella,
J. V. Bioorg. Med. Chem. Lett. 2003, 13, 1989–1992.
6. Gross, D. E.; Mikkilineni, V.; Lynch, V. M.; Sessler, J. L. Supramol. Chem. 2010, 22,
135–141.
7. Yang, C.; Song, H.-S.; Liu, D.-B. J. Mater. Sci. 2012, 47, 3315–3319.
8. Maegawa, Y.; Goto, Y.; Inagaki, S.; Shimada, T. Tetrahedron Lett. 2006, 47, 6957–
6960.
9. Banerjee, S.; Ali, F.; Nayak, P. K.; Agarwal, N. Solid Films 2012, 520, 2644–2650.
10. Zheng, C.-J.; Ye, J.; Lo, M.-F.; Fung, M.-K.; Ou, X.-M.; Zhang, X.-H.; Lee, C.-S.
Chem. Mater. 2012, 24, 643–650.
and 13 as minor competing products) were prepared in acceptable
yields (Table 3).16
The feasibility for recycling and reuse of (bmim)PF6 was tested
in several cases via repeated use of the IL in three consecutive runs
(see table footnotes).17
In summary we have shown that dipropargylation of N-meth-
ylcarbazole and parent carbazole can be effected conveniently in
the (bmim)PF6/TfOH system employing a variety of diaryl-propar-
gylic alcohols. Based on a feasibility experiment, the approach is
equally applicable to the synthesis of diallyl-derivatives using
sec-allyl alcohols. Stepwise propargylation using two different
propargylic alcohols was realized in representative cases with
(bmim)PF6/Bi(NO3)3.5H2O. Facile assembly of the resulting highly
functionalized derivatives, and the added advantage of recycling
and reuse of the IL, coupled with the possibility that the resulting
products could serve as building blocks in synthesis and catalysis,
make the reported method worthy of further elaboration.
11. Wang, S.; Mao, H.; Ni, Z.; Pan, Y. Tetrahedron Lett. 2012, 53, 505–508.
12. Aridoss, G.; Laali, K. K. Tetrahedron Lett. 2011, 52, 6859–6864.
13. Kumar, G. G. K. S. N.; Aridoss, G.; Laali, K. K. Tetrahedron Lett. 2012, 53, 3066–
3069.
14. Kumar, G. G. K. S. N.; Laali, K. K. Org. Biomol. Chem. 2012, 10, 7347–7355.
15. General procedure for dipropargylation of N-methylcarbazole and carbazole: An
oven-dried Schlenk tube was charged with (bmim)PF6 (4.0 mL) and N-
methylimidazole (1 mmol). The propargyl alcohol (2.2 mmol) was then
added followed by triflic acid (0.1 mmol) under N2 atmosphere at 0 °C and
the mixture was magnetically stirred at rt until completion (monitored by
TLC). Once the reaction was over, the contents were cooled to rt and extracted
with EtOAc/Hexane (2:3 vol/vol), 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 deionized water, dried with MgSO4 and
concentrated to give the crude product, which upon purification through
column chromatography furnished the desired products.
16. General procedure for the synthesis of unsymmetrical dipropargylated N-
methylcarbazole: The ionic liquid (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) dissolved in the IL. N-
Methylcarbazole (1 mmol) was then introduced into the Schlenk tube under
a nitrogen atmosphere followed by the desired propargylic alcohol (1.1 mmol).
The reaction mixture was magnetically stirred, initially at rt for about 10 min
followed by stirring in a pre-heated oil bath at 70 °C, until completion (as
monitored by TLC). Once the reaction was over, the contents were cooled to rt
and the new propargylic alcohol (1.1 mmol) was introduced followed by
Bi(NO3)3Á5H2O (10 mol %). The reaction mixture was magnetically stirred,
initially at rt for about 10 min followed by stirring in a pre-heated oil bath at
70 °C, until completion (as monitored by TLC). Once the reaction was over, the
contents were cooled to rt and extracted with EtOAc/Hexane (2:3 vol/vol), 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 deionized
water, dried with MgSO4 and concentrated to give the crude product, which
upon purification through column chromatography furnished the desired
products.
Acknowledgments
We thank the University of North Florida for support, Dr. Nelson
Zhao for NMR assistance, and Dr. Takao Okazaki for computational
help.
Supplementary data
Supplementary data (synthetic procedures, multinuclear NMR,
MS, and IR data for the new compounds, procedure for the synthe-
sis of various propargylic alcohol precursors along with their NMR
data, and structure optimizations) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.12.023.
References and notes
1. Knolker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303–4427.
2. Kantevari, S.; Yempala, T.; Surineni, G.; Sridhar, B.; Yogeeswari, P.; Sriram, D.
Eur. J. Med. Chem. 2011, 46, 4827–4833.
3. Stover, J. S.; Shi, J.; Jin, W.; Vogt, P. K.; Boger, D. L. J. Am. Chem. Soc. 2009, 131,
3342–3348.
17. Recycling and re-use 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. After
several successive runs, the used IL was cleaned up by dissolving in MeCN,
filtration, removal of solvent, and vacuum drying.
4. Hu, L.; Li, Z.-R.; Wang, Y.-M.; Wu, Y.; Jiang, J.-D.; Boykina, D. W. Bioorg. Med.
Chem. Lett. 2007, 17, 1193–1196.