NHC-Mediated Synthesis of Pyrrolo[2,1-a]isoquinolines and Their Photophysical Investigations

Article abstract of DOI:10.1002/asia.201601683

An NHC-mediated synthesis of pyrrolo[2,1-a]isoquinoline and indolizine derivatives with potential biological activity is reported (NHC=N-heterocyclic carbene). The preliminary photophysical studies of such compounds reveal that they have potential application in the sensing of volatile organic compounds (VOCs).

Full text of DOI:10.1002/asia.201601683

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Novel NHC-mediated synthesis of pyrrolo[2,1-a]isoquinolines and
their photophysical investigations.
Authors: Vijay Nair, Jagadeesh Krishnan, Balaraman
Vedhanarayanan, Sasidhar B.S., and Sunil Varughese
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To be cited as: Chem. Asian J. 10.1002/asia.201601683
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10.1002/asia.201601683
Chemistry - An Asian Journal
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Novel NHC-mediated synthesis of pyrrolo[2,1-a]isoquinolines and
their photophysical investigations.
Jagadeesh Krishnan, [a], [b] Balaraman Vedhanarayanan,[a], [b] B.S. Sasidhar, [a], [b] Sunil Varughese, [a]
and Vijay Nair[a]*
Dedicated to Professor R. H. Sahasrabudhey in commemoration of his birth centenary
Abstract: An NHC-mediated synthesis of pyrrolo[2,1-a]isoquinoline
and indolizine derivatives with potential biological activity is reported.
The preliminary photophysical studies of these compounds reveal
that they have potential application in the sensing of Volatile Organic
Compounds (VOCs).
white crystalline solid in 19% yield (Scheme 1).
Pyrrolo[2,1-a]isoquinoline
derivatives
constitute
an
important class of heterocyclic compounds, primarily due to the
remarkable biological properties of the lamellarine group of
alkaloids that are endowed with this framework.1 Inter alia, they
have been reported to inhibit topoisomerase,2 HIV and
integrase.3 Some other members of the group have been shown
to
possess
antiimflammatory,4
cardiovascular5
and
antidepressant6 properties. Some selected biologically relevant
pyrroloisoquinoline related compounds are shown in Figure 1. In
addition to biological activities, these π-conjugated molecules
possess excellent photophysical properties which can play
potential role in various applications such as optoelectronics,
sensing, etc.7 Not surprisingly, there has been enormous interest
in the synthesis of pyrrolo[2,1-a]isoquinoline derivatives.8
Although a number of protocols have been developed for their
synthesis, most of the endeavours relied on Huisgen [3+2]
dipolar cycloaddition reactions.9 A special mention may be made
of the visible light mediated strategies employed by Xia,10a
Glorius,10b Itoh10c and Yang.10d
Figure 1. Biologically active pyrroloisoquinoline related compounds.
In the context of the recent discovery of NHC-mediated
annulation of enals to a variety of electrophiles resulting in the
synthesis of a wide range of carbo and heterocyclic compounds
in several laboratories, including our own,11 it was of interest to
explore such a strategy for the construction of pyrrolo-[2,1-
a]isoquinolines. The successful culmination of our efforts in this
direction constitutes the subject matter of this communication.
In a prototype experiment, DBU (50 mol%) was added to a
suspension of 4-methoxycinnamaldehyde 1a (0.225 mmol), 2-(2-
ethoxy-2-oxoethyl)isoquinolin-2-ium bromide 2a (0.15 mmol),
and IMes.HCl 3a (15 mol%) in DCM and this mixture was stirred
for 24h at room temperature. The reaction mixture upon column
Scheme 1. NHC-mediated synthesis of pyrrolo[2,1-a]isoquinoline.
The structure 4a was established by single crystal X-ray
data (Figure 2) and all spectra features are consistent with it.
chromatography
afforded
the
product,
ethyl
2-(4-
methoxyphenyl)pyrrolo[2,1-a]isoquinoline-3-carboxylate 4a, as a
Figure 2. ORTEP diagram of 4a.
[a]
[b]
J. Krishnan, B. Vedhanarayanan, Dr. B. S. Sasidhar, Dr. S.
Varughese and Dr. V. Nair
Chemical Science and Technology Division, National Institute for
Interdisciplinary Science and Technology (CSIR-NIIST),
Trivandrum - 695 019, India.
In view of the pleasant result, detailed optimization studies
were undertaken. For this, commonly available NHC precursors
3a−f were used for screening (Table 1). Among the six catalysts
investigated, benzimidazolium catalyst 3c exhibited high
catalytic activity (Table 1, entry 3). After identifying NHC
precursor 3c as the optimal catalyst, the influence of solvent was
studied. Among the solvents tested, THF furnished the desired
product in good yield (Table 1, entry 7, 77%). Other solvents
such as CH3CN, chloroform, toluene and DME afforded the
product in moderate yields (Table 1, entries 8, 9, 10 and 11).
E-mail: vijaynair_2001@yahoo.com
J. Krishnan, B. Vedhanarayanan and Dr. B. S. Sasidhar
Academy of Scientific and Innovative Research, New Delhi-110001,
India.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Subsequently, we examined the effect of bases on the reaction.
Among the five bases tested, DBU furnished the desired product
in good yield. Finally it was found that raising the temperature of
the reaction resulted in a lower yield of product (table 1, entry
16). Based on the above results, it was clear that the formation
of pyrroloisoquinoline carboxylate in higher yield was facilitated
by the combination of benzimidazolium precatalyst 3c and DBU
in THF as the solvent at room temperature (entry 7).
the reaction of enal with NHC undergoes aerial oxidation to form
the acyl azolium intermediate II.12 The latter on Michael type
reaction
with
isoquinolinium
ylide
delivers
the
tetrahydropyrroloisoquinoline
derivative
III.
Subsequent
nucleophilic addition to the carbonyl group of III followed by the
ejection of NHC leads to the carbonyl derivative of
tetrahydropyrroloisoquinoline
IV.
Conceivably
of the latter afforded the
on
two
13
consecutive aerial oxidations8j,
desired pyrolloisoquinoline derivative VII.
Table 1. Condition Optimization[a]
Table 2. NHC-mediated synthesis of pyrrolo[2,1-a]isoquinolines.[a], [b]
Entry
Catalyst
base, solvent,temp., time (h)
Yield (%)[b]
1
3a
3b
3c
3d
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
DBU, DCM, rt, 24
DBU, DCM, rt, 24
DBU, DCM, rt, 24
DBU, DCM, rt, 24
DBU, DCM, rt, 24
DBU, DCM, rt, 24
DBU, THF, rt, 12
DBU, CH3CN, rt, 24
DBU, CHCl3, rt, 24
DBU, Toluene, rt, 24
DBU, DME, rt, 24
KOtBu, THF, rt, 24
K2CO3, THF, rt, 24
DMAP, THF, rt, 24
NEt3, THF, rt, 12
DBU, THF, 65 oC, 12
19
26
55
11
21
30
77
52
38
45
31
13
23
24
71
35
2
3
4
5
6
[a]
Reactions were carried out with 1 (0.225 mmol), 2 (0.15 mmol), 3c (15
mol%), DBU (50 mol%) in 2 mL of THF (stirred for 12h at rt). [b] isolated yield.
7
8
Table 3. NHC mediated synthesis of indolizines. [a], [b]
9
10
11
12
13
14
15
16
[a] Reactions were carried out with 1 (0.225 mmol), 5 (0.15 mmol), 3c (15
mol%), DBU (50 mol%) in 2 mL of THF (stirred for 12h at rt). [b] isolated yield.
[a] Reaction conditions: 1a (0.225 mmol), 2a (0.15 mmol), carbene precursor
(15mol %), base (50mol%) in 2 mL of solvent. [b] isolated yield.
As already stated, pyrrolo[2,1-a]isoquinoline based
compounds are well known for their biological properties such as
cytotoxicity, cell differentiation inhibition, etc. However, only
limited attempts have been made to understand the
photophysical properties of these compounds. In view of this, we
have carried out preliminary photophysical investigation, of the
series of pyrrolo[2,1-a]isoquinoline derivatives accessed by
synthesis.
The absorption spectrum of 4l showed three peaks at 279
(λmax), 350 and 369 nm in CHCl3 solution at concentration of 1 ×
10-4 M. The emission spectrum of 4l exhibited two emission
peaks at 379 and 395 nm with a shoulder band around 416 nm.
The life time measurement of 4l solution in CHCl3 provided a
Subsequent studies were focused on the scope of the
reaction. As shown in Table 2, the reaction works well for a
range of enals having electron-withdrawing or electron donating
substituents on the 4th position of β-aryl ring. The reaction
proceeds
smoothly
for
5-bromo-2-(2-ethoxy-2-
oxoethyl)isoquinolin-2-ium bromide (4i-4k). In all the cases
products were obtained in moderate to good yields.
The scope of the reaction was further explored by
employing pyridine moiety instead of isoquinoline (Table 3). It
was found that the method was successful in the synthesis of
various substituted phenylindolizine carboxylates in good yields
(6a-6e).
A plausible mechanism for the reaction may be advanced
as follows (Scheme 2). Initially the homoenolate I generated by
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value of 2.16 ns. The fluorescence quantum yield of 4l
measured as 68%.
Interestingly, it was observed that the colorless CHCl3
solution of 4l changed to bright green while adding 1 equivalent
(eq.) of trifluoroacetic acid (TFA) (Figure 3a). This change was
reversible with the addition of 1 eq. of triethylamine (TEA). After
addition of TFA, all the three absorption peaks (279, 350 and
369 nm) of 4l decreased and became broad in nature. At the
same time, a new absorption band appeared around 430 nm.
Similarly, the emission bands (379, 395, and 416 nm ) were
vanished and a new emission band was appeared around 520
nm (Figure 3b). We also observed the visual emission color
change from a mixture of violet and blue to green. To study the
periodic changes of the absorption and emission spectra in the
presence of TFA and TEA, a titration experiment was carried out
with various equivalents of TFA and TEA (Figure 4). Each
addition of TFA (0.1 eq. of TFA) resulted in the periodic
decrease in the absorption peaks at 279, 350 and 369 nm and
periodic increase in the absorption peak at 430 nm. Even 0.3-0.5
equivalents of TFA were good enough to give considerable
changes in the absorption and fluorescence spectra (Figure 4).
The recovery of the absorption peak at 279, 350 and 369 nm
was observed while adding CHCl3 solution of TEA. The changes
of emission spectra while adding TFA and TEA were indicated in
the Figure 4b. It clearly show that the periodic decrease in the
emission peaks at 379, 395, and 416 nm and increase of the
same at 520 nm upon addition of TFA and vice versa upon
addition of TEA.
Scheme 2. Mechanism of the reaction.
To shed some light on the mechanism of the reaction, we
carried out an experiment with 2-bromoenal 7 and 2-(2-ethoxy-2-
oxoethyl)isoquinolin-2-ium bromide 2a in presence of
benzimidazolium catalyst 3c and DBU in THF (Scheme 3.). This
reaction afforded the product as ethyl 2-phenylpyrrolo[2,1-
a]isoquinoline-3-carboxylate in 21% yield. This experiment
provides support for the intermediacy of α, β-unsaturated acyl
azolium invoked in Scheme 2.14
All other derivatives showed similar changes in the
absorption and emission spectra with the addition of TFA and
TEA (see supporting information). These changes in the
photophysical properties could be attributed to the nitrogen atom
in the poly heterocyclic ring being protonated and deprotonated
upon addition of TFA and TEA respectively. In order to study the
ability of these compounds to act as acid sensors in film state,
we drop casted the CHCl3 solution of 4l in a quartz substrate
and the resultant film was exposed to saturated vapours of
[a] Reaction was carried out with 7 (0.225 mmol), 2a (0.15 mmol), 3c (15
mol%), DBU (50 mol%) in 2 mL of THF (stirred for 24h at rt). [b] isolated yield.
Scheme 3. Reaction of isoquinolium salt with 2-bromo enal. [a], [b]
various
volatile
acids
(trifluoroacetic
acid, formic acid,
acetic
propionic
acid,
acid
and butric acid.
The changes in
the
emission
intensities at 395
and 520 nm after
exposure
sec)
measured
(30
were
and
compared (Figure 5). Among these acids, TFA showed better
sensing ability because of its higher vapour pressure and higher
acidity compared to other acids. This film could be reused
several times after exposing to air for 3 to 5 minutes. For
practical application, the same film can be prepared on filter
paper strip by drop casting the chloroform solution and used to
detect volatile acids (Figure 5b). Thus, the preliminary
photophysical studies reveal that these compounds have
potential application in the sensing of VOCs (Volatile Organic
Compounds) such as acetic acid, substituted propionic acid, etc,
which are biomarkers present in the exhaled breath of cancer
patients.15, 16 A detailed investigation regarding sensing ability of
these fluorescent compounds are in progress.
Figure 3. Absorption (a) and emission (b) spectra of 4l with the addition
of 1 eq. of trifluoroacetic acid (TFA) and 1 eq. of triethyl amine (TEA) in
CHCl3. Insets of Figure 3a and b show color changes after addition of
TFA and TEA under ambient and UV light respectively.
The absorption spectrum of 4l showed three peaks at 279
(λmax), 350 and 369 nm in CHCl3 solution at concentration of 1 ×
10-4 M. The emission spectrum of 4l exhibited two emission
peaks at 379 and 395 nm with a shoulder band around 416 nm.
The life time measurement of 4l solution in CHCl3 provided a
value of 2.16 ns. The fluorescence quantum yield of 4l
measured as 68%.
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In conclusion, we have developed a facile synthesis of
pyrrolo[2,1-a]isoquinolines and indolizines with potential
biological activities. The simple and mild reaction conditions and
the good yields of products are likely to make the reaction
attractive for its application in the synthesis of a variety of natural
and unnatural pyrrolo[2,1-a]isoquinolines and indolizines. The
preliminary photophysical studies reveal that these compounds
have potential application in the sensing of VOCs which are
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Acknowledgements
We thank the Science & Engineering Research Board
(SERB), New Delhi, for the project SB/S1/OC-22/2014. We also
thank the Council of Scientific and Industrial Research (CSIR)
and the University Grants Commission (UGC) New Delhi, for
financial assistance. We thank Dr. Rajeev S. Menon for valuable
suggestions.
Keywords: N-heterocyclic carbenes • indolizines •pyrrolo[2,1-
a]isoquinolines • Organocatalysis • acyl azolium
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