An efficient synthesis of pyrrole and fluorescent isoquinoline derivatives using NaN3/NH4Cl promoted intramolecular aza-annulation

Article abstract of DOI:10.1016/j.tetlet.2016.07.002

An efficient synthetic protocol of pyrroles and isoquinolines through NaN₃/NH₄Cl promoted intramolecular aza-annulation of formyl group with suitable alkenes or alkynes is described in high yield and regioselectivities. The metal fre

Full text of DOI:10.1016/j.tetlet.2016.07.002

Accepted Manuscript
An efficient synthesis of pyrrole and fluorescent isoquinoline derivatives using
NaN3/NH4Cl promoted intramolecular aza-annulation
Akash Jana, Susanta Kumar Manna, Suresh Kumar Mondal, Arabinda Mandal,
Saikat Kumar Manna, Avijit Jana, Bidyut Kumar Senapati, Manas Jana,
Shubhankar Samanta
PII:
S0040-4039(16)30823-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.002
TETL 47864
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 April 2016
30 June 2016
1 July 2016
Please cite this article as: Jana, A., Manna, S.K., Mondal, S.K., Mandal, A., Manna, S.K., Jana, A., Senapati, B.K.,
Jana, M., Samanta, S., An efficient synthesis of pyrrole and fluorescent isoquinoline derivatives using NaN3/
NH4Cl promoted intramolecular aza-annulation, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.07.002
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Tetrahedron Letters
An efficient synthesis of pyrrole and fluorescent isoquinoline derivatives using
NaN3/NH4Cl promoted intramolecular aza-annulation
Akash Jana,a Susanta Kumar Manna,b Suresh Kumar Mondal,a Arabinda Mandal,b Saikat Kumar Manna,a
Avijit Jana,c Bidyut Kumar Senapati,d Manas Janae and Shubhankar Samanta*b
aDepartment of Chemistry, Haldia Government College, Haldia 721657, India
bDepartment of Chemistry, Bidhannagar College, Kolkata 700064, India
cBiomaterials Group, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
dDepartment of Chemistry, Prabhat Kumar College, Contai 721401, India
eBose Institute, Division of Molecular Medicine, P-1/12, C.I.T. Scheme VII M, Kolkata 700054,India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient synthetic protocol of pyrroles and isoquinolines through NaN3/NH4Cl promoted
intramolecular aza-annulation of formyl group with suitable alkenes or alkynes is described in
high yield and regioselectivities. The metal free exo-trig and endo-dig aza-cyclisation has been
extended for the synthesis of bicyclic or tricyclic pyrroles along with environment sensitive
fluorescent isoquinoline derivatives. Reactions occur in excellent yields, broad scope and high
tolerance of functional groups. The synthetic utility of this methodology was demonstrated in
the short synthesis of the core structure of lamellarin Q.
Available online
Keywords:
Aza-cyclisation
Fused pyrrole
Fluorescent
2009 Elsevier Ltd. All rights reserved.
Isoquinoline
Sodium azide
reaction, transition metal catalysed cycloisomerisation and aza-
annulation reaction.7 Among them, azide base cyclisation is
Pyrrole and isoquinoline moiety are widely distributed in both
natural and artificial molecules.1 During the past decades, a wide
range of pyrroles have been isolated from natural sources which
shows different biological properties such as hypolipidemic,
antimicrobial, anti-inflammatory and anti-tumor activity.2 The
fused pyrrole alkaloid lamellarins were obtained from the
Prosobranch mollusc lamellarias, exhibits cytotoxic activity
against to the tumor cell lines.3 Similarly, a wide range of
isoquinoline alkaloids were isolated from different plant sources
and they have been proven to possess broad spectrum of bio-
activities.4 For example, 2-azaanthraquinones, isolated from
natural sources possess significant in vitro antibiotic activity
enormously used for the C–N bond formation due to their ease of
accessibility and evolution of environmentally benign N2 gas.8
The azide promoted thermal 1,3-dipolar cycloaddition between
azides and alkynes, transition metal catalysed intramolecular
cyclisation of alkyl azide to alkynyl- and alkenyl-systems10 were
well documented in literature but very few method involve via
metal free procedure to give corresponding pyrrole and
isoquinoline derivatives.11a For example the iodine-mediated
cyclisation of 2-alkynylbenzyl azides11b, triphenyl phosphine
mediated one-pot synthesis, cascade reaction of azides with
Morita–Baylis–Hillman acetates of acetylenic aldehydes were
used to give pyrrole and isoquinonile derivatives (Scheme-1).11
against
Mycobacterium
tuberculosis.5
Beside
their
However, we found that mild and regiospecific syntheses
starting from easily available starting materials to pyrrole and
isoquinoline derivatives are still been limited in literature.
Consequently, the synthesis of these N-heterocycles has been a
vigorously active area continues of study.
pharmaceutical importance, some derivatives of both pyrroles
and isoquinolines are also used as chiral ligands for the synthesis
of transition metal catalysts, organic light-emitting diodes and
sensitizers in dye-sensitized solar cells.6
Because of their potential broad spectrum applications, the
synthesis of substituted pyrroles and isoquinolines has attracted
considerable attention and many synthetic efforts have been
devoted so far to synthesize these classes of compounds.
Herein, we report a sodium azide promoted green synthesis of
pyrrole and isoquinoline derivatives via aza-exo-trig and aza-
endo-dig cyclisation respectively. A wide variety of aldehyes
including both of alicyclic and aromatic systems with an
available alkene or alkyne moiety (e.g., 1 & 3) has been
successfully underwent intramolecular aza-cyclisation to provide
The literature available methods for the construction of
pyrrole and isoquinoline derivatives are based on condensation

2
Tetrahedron Letters
the corresponding pyrrole and isoquinoline derivatives
From the above experimentations, it has been found that
respectively (e.g., 2 & 4; Scheme-1).
NaN3/NH4Cl in aqueous methanol at 80 oC was the optimal
reaction condition for both aza-exo-trig cyclisation of 1a and
aza-endo-dig cyclisation of 3a to give pyrrole and isoquinoline
derivatives respectively.
Table-1. Standardisation of reaction condition for exo-trig-
aza and endo-dig-aza cyclisation.a
CO2Me
NH
Exo-trig-Cyclisation
R'
R'
2a
Additive-I/Additive-II
Ph
O
NH
Solvent
N
Scheme-1: Transition metal free azide-based cyclisation.
H
H
1a: R' = CO2Me
3a: R' = Ph
Endo-dig-cyclisation
4a
Initially, 1a was selected as a model substrate to optimize the
reaction conditions (Table 1). At the beginning, experiment using
NaN3 in aqueous-methanol under reflux condition, the desired
pyrrole derivative 2a was produced in 20% yield (Table 1, entry
1). Formation of pyrrole derivative 2a suggested that the aza-exo-
trig cyclisation proceeded through the imine intermediate which
is generated in the reaction medium by the reaction of formyl
group of 1a with sodium azide. To improve the yield, careful
optimisation of the reaction parameters and additives was
performed (Table 1, entries 2-5). During our investigation, it
observed that the addition of NH4Cl itself failed to give our
desired pyrrole derivative. Replacement of NH4Cl by NH4OAc
under similar reaction conditions produced the desired product 42
% yield (Table 1, entry 3). Addition of AcOH along with
NH4OAc further improved the yield of the desired product 2a
after 24 h (Table 1, entry 4). To our surprise, it has been found
that only NH3 gave 2a in 90% yield after 3 h (Table 1, entry 5).
Since, NaN3/NH4Cl is a good alternating source of HN3 for imine
formation,12 we carried out the same reaction in presence of
NaN3 & NH4Cl and found that the yield of 2a increased up to
99% within 2.5 h (Table 1, entry 6).The activation of unsaturated
double bond and liberation N2 gas is the main driving force for
best result of the above aza-exo-trig cyclisation. The non
ammoniated acidic salts did not improve the yield of the desired
product (Table 1, entries 7-9). Interestingly, when we changed
the solvent from MeOH-H2O to DMF, the yield of 2a was 95%
(Table 1, entry 10). But, THF or CH3CN under similar reaction
condition did not improve the yield of 2a (Table 1, entries 11 &
12). Furthermore, the reaction did not take place in non polar
solvents like benzene or toluene (Table 1, entries 13).This
observation indicated that the considerable amount of hydrazoic
acid is generated during aza-cyclization in aquous methanol or
DMF compared to less polar solvent.12,13
Entry
Solvent
Additive-
I
Additive-
II
Time
(h)
Yield
2a (%)
Yield
4a (%)
1
2
MeOH-H2O
MeOH-H2O
-----
NaN3
------
24
24
20
0
0
0
NH4Cl
3
4
MeOH-H2O
MeOH-H2O
NH4OAc
NH4OAc
-----
24
24
42
63
0
AcOH
50
5
MeOH-H2O
NH3
-----
3
90
64
6
MeOH-
H2O
MeOH-H2O
NH4Cl
NaN3
2.5
99a
82a
7
8
Al2(SO4)3
FeCl3
NaN3
NaN3
24
3
0b
0b
0
MeOH-H2O
MeOH-H2O
77
9
SnCl2
NaN3
3
73
52
10
11
12
13
DMF
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NaN3
NaN3
NaN3
NaN3
4
4
95
60
70
0c
80
30
63
0c
THF
CH3CN
Benzene
5
24
a Reagent and conditions: Substrate 1a/3a (1 mmol), additive-I/additive-II (3
mmol), solvent (5 ml), temperature 80 oC; MeOH-H2O (10:1). Similar
b
c
results were obtained when the reactions were run with ZnBr2. Similar
results were obtained when the reactions were run in toluene.
Under standard reaction condition, the scope and limitations of
this methodology were studied using a variety of aldehydes (1)
with an available alkene system (Table 2, 2a-i). Satisfactory
yields with high regioselectivities were obtained for aromatic
aldehydes. The aza-cyclisation of aliphatic or unsaturated
cycloalkenyl aldehydes which are typically more challenging
substrates in carbon-carbon bond forming reactions provided
fused bicyclic pyrrole derivatives in good yields (Table 2, 2j-2k).
Substituted aromatic aldehydes, in presence of electron-
donating and electron withdrawing groups provided excellent
yields (Table 2, 2a-2h). Thus, electronic effects could promote
the azide addition to formyl group or exo-trig-aza annulations
step. However, aldehyde with a t-butyl carboxylate in alkene part
furnished the desired pyrrole derivative 2h in 67% yield. We
suspect that the bulkier t-butyl carboxylate substituent of
cycloalkenyl aldehyde significantly reduces the degree of aza-
cyclisation reaction.
The above results encouraged us to initiate the aza-endo-dig
cyclisation of 3a. At first, it has been found that the imine
forming agents like NaN3, NH4Cl and NH4OAc were failed to
initiate the desired aza-cyclization (Table 1, entries 1-3).
Addition of AcOH with NH4OAc under similar conditions
initiated the aza-endo-dig cyclisation to give the desired
isoquinoline derivative 4a in 50% yield (Table 1, entry 4). Here,
the aza-endo-dig cyclisation is facilitated by the activation of the
triple bond with AcOH. Interestingly, when only aquous
ammonia was used as reagent the yield of 4a improved to 64%
within 3 h without any metal catalyst or any triple bond
activation (Table 1, entry 5). Like aza-exo-trig cyclization, the
use of NaN3/NH4Cl in MeOH-H2O again found to be effective
for the aza-endo-dig cyclization to give 4a in 82 % (Table 1,
entry 6). Further optimisation of reaction parameters like solvents
or addition of non ammoniated salt did not provide any fruitful
results (Table 1, entries 7-13).
Table-2. NaN3/NH4Cl promoted intramolecular aza-cyclisation
of 3-(2-formyl cycloalkenyl)-acrylic acid esters

R''
R''
NaN3,NH4Cl
CO2R
NH
CO2R
MeOH-H2O(10:1),80 o
C
N
CHO
NaN3/NH4Cl
MeOH-H2O, 80 o
3
4
CHO
C
Z
Bicyclic or tricyclic
R'' = Phenyl, 4-nitro phenyl,4-fluro phenyl,
4-methyle phenyl, benzyloxy
Z
R = -Me,-Et, -t Bu
X
X
n
n
Z = -H, -OMe, -NO2
2
1
X = -CH2 or 'O'
n = 1 or 2
Me
Ph
Ph
Ph
CO2Me
Ph
CO2Me
NH
CO2Me
NH
CO2Me
NH
N
N
F
N
N
N
NH
MeO
MeO
MeO
MeO
OMe
4a: 82%
4d: 83%
4e: 68%
4b: 73%
MeO
4c: 76%
OMe
2b: 87%
NO2
2d: 95%
CO2tBu
2c: 99%
2a: 99 %
Ph
N
O
CO2Me
NH
CO2Et
NH
CO2Et
NH
N
N
NH
MeO
MeO
O2N
N
MeO
MeO
4g: 62%
4i: 53%
4f: 77%
4h: 87%
2e: 90%
2f: 98%
2g: 88%
CO2Me
NH
2h: 67%
CO2Me
NH
CO2Me
NH
Reagent and conditions: Substrate 3 (1 mmol), NaN3 (3 mmol), NH4Cl
(3 mmol), MeOH-H2O (5 ml, 10:1), 80 oC, time 2-3 h.
O
2j: 55%
2i: 90%
The strong electron withdrawing groups such as ‘F’ and ‘NO2’
at terminal acetylene carbon in aromatic ring of compound 3
provided the desired isoquinoline derivatives in good yields
(Table 3, 4f &4h). In contrast, the cycloalkenyl carbaldehydes 3i
underwent aza-endo-dig cyclisation in moderate yields to give
the corresponding isoquinolines 4i. The bezyloxy carbaldehyde
3g was also reacted successfully under similar conditions to
provide isoqunoline 4g in 62 % yield. Hence, this methodology
was applicable for both aliphatic and aromatic substituted
acetylene systems of 3. Interestingly, the blue fluorescent
property of all the isoquinoline derivatives further motivated our
research to study their photophysical property.
2k: 62%
Reagent and conditions: Substrate 1 (1 mmol), NaN3 (3 mmol), NH4Cl (3
mmol), MeOH-H2O (5 ml, 10:1), 80 oC, time 2-3 h.
A significant application of this methodology was further
demonstrated by the short synthesis of the core structure of
marine alkaloid lamellarin Q, which was isolated from Dendrilla
cacto in 1995.14 The lamellarins showed wide varieties of
biological activities like strong cytotoxic activity against tumor
cell lines, reversal of multidrug resistance, HIV-1 integrase
inhibition and antibiotic activity.3 Under optimized conditions for
the aza-cyclisation of (2E,4E)-methyl 5-formyl-4-phenylpenta-
In recent years there has been growing interest in designing
fluorescent probes with improved photophysical properties along
with specific abilities in sensing the environmental parameters
which is valuable to monitor the biological process in real
time.15,16 In this circumstance N- heterocyclic polyaromatic
compounds could be the ideal candidate to investigate as well as
to understand the environment of a biological specimen since
both the fluorescence intensity and the emission profile of N-
heterocycles are known to be highly sensitive to the polarity as
well as the hydrogen-bonding ability of the solvent.17,18 With this
intension the photophysical properties of one of the isoquinoline
derivative 4c was investigated in details. The UV–vis absorption
spectra of the synthesized compound 4c was investigated in
different solvent (Table 4) at room temperature as shown in
supporting information. The absorption spectra of 4c in different
solvent except methanol exhibited an intense absorption band at
257 nm and a weak absorption band at ~ 308 nm. In methanol
solvent, compound 4c display three absorption peaks at 262, 269
and 305 nm respectively. The fluorescence property of the
compound 4c is strongly influenced by the nature of the solvent
(Fig 1a). When nonpolar solvents (e.g., n-hexane) were used the
compound was showing only a weak fluorescence with emission
maxima of 351 nm, whereas in a polar solvent (e.g. Acetonitrile)
the emission intensity was greatly enhanced and also a slight red
shifting of the emission spectra was observed. But, in case of H-
bonding donor solvent (e.g. MeOH) a large red shifting of the
emission spectrum was noted. The above mentioned solvent
dependent fluorescence properties of the compound 4c can be
2,4-dienoate
(1l)
and
(2E,4E)-methyl
5-formyl-4,5-
diphenylpenta-2,4-dienoate (1m) in MeOH-H2O produced the
multi-substituted pyrrole derivatives 2l and 2m respectively in
good yields. Interestingly, the structure of compound 2m is
analogous to the lamellarin Q (Scheme 2). Hence, this
methodology highlights synthesis of various kinds of pyrrole
derivatives using single reagent system.
HO
MeO2C
CO2Me
NH
R1
R2
CO2Me
R1
NaN3/NH4Cl
MeOH-H2O, 80 o
C
CHO
NH
R2
1l: R1 = Ph, R2= H
1m: R1 = Ph, R2 = Ph
HO
2l: R1 = Ph, R2 = H, 59%
2m: R1 = Ph, R2 = Ph, 62%
lamellarin Q
Scheme-2: Synthesis of the core structure of lamellarin Q.
To further evaluate the broad feasibility of the present reagent
system, we have investigated various aza-endo-dig cyclisations
on 3-(1-arenyl)-2-cycloalkene-1-al (3). To our expectation, the
attempted aza-endo-dig cyclisation of 3a-3i proceeded smoothly
and furnished fluorescent isoquinoline derivatives 4a-4i with 53-
87 % yield (Table 3).
Table-3. NaN3/NH4Cl mediated aza-endo-dig cyclisation of
3-(1-arenyl)-2-cycloalkene-1-al.
1
1
attributed to its closely lying π–π* and n–π* excited states.
Therefore, in nonpolar solvent the non-fluorescent n–π*
transition became the lowest energy transition and thus the low
intensity emission spectrum was observed. But, when polar
solvent was being employed the lone pair of the nitrogen atom
got stabilized by interacting with the solvent and thus the

4
Tetrahedron Letters
emissive 1π–π* transition becomes the most probable transition
derivative 4c can be considered as a potential environment
state over the n–π* transition which results in concomitant
enhancement of the emission intensity. Now, in case of methanol
which is a polar as well as strong H-bonding donor solvent
therefore strongly interact with the lone pair electron of the
nitrogen atom, and therefore greatly stabilized the lone pair
sensitive fluorophore (Supporting Information).
In summary, a highly efficient and regioselective intramolecular
aza-cyclisation for pyrrole and fluorescent isoquinoline
derivatives has been developed on alkenyl or alkynyl
carbaldehydes using NaN3/NH4Cl. The reagent system was found
to be mild, air stable, metal free and thus provided a greener
alternative to heterocyclic ring synthesis. Moreover, the aza-
cyclisation was successfully applied to a short access of the core
structure of naturally occurring lamellarin Q. Further application
of this methodology for the synthesis of other heterocycles and
more complex alkaloid scaffolds are underway.
1
electron on N atom and thereby n–π* excited state energy
increases in higher extent and consequently inversion in energy
level of the excited states has been taken place and the emissive
1π–π* becomes the LUMO along with H-bonding may also lower
the solvent relaxation processes which finally results in strong
red shifting of the emission spectra. Further, to better understand
the effect of hydrogen bonding interaction on the fluorescence
properties of the compound 4c, the emission spectra of 4c were
recorded in acetonitrile–water binary mixtures (Fig 1b).
Acknowledgement
Financial support from DST (SB/FT/CS-189/2012) and
chemistry department of Bidhannagar College is gratefully
acknowledged.
(b)
(a)
References and notes
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Fig.1 (a) Fluorescence spectra of 4c (4× 10-5 M) in different solvent
[λext=257nm]. (b) Fluorescence emission changes of 4c (4× 10-5 M) in CH3CN
and in increasing percentage of water in CH3CN [λext=257nm].
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It observed that on the addition of increasing amounts of water
the fluorescence intensity of the compound 4c at 371 nm was
gradually decreases with a simultaneous appearance of a new
peak at 504 nm as well as concomitant increase in emission
intensity and reaches a maximum in a 80% water which can be
attributed to the protonation of the “N” atom to results in the
formation of isoquinolium cation. The calculated fluorescence
quantum yield of compound 4c in different solvent system
clearly showed that the solvent polarity plays an important role in
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Table 4. Fluorescence quantum yields of compound 4c (Φ) in
different solvents
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a
Solvent
λmax (nm)
λem
(nm)
Stokes shift
(b-a)c
(φF)d
b
Acetonitrile
257
257
368
112
0.24
0.20
Dichloromethane
363
357
365
360
351
487
106
100
108
103
94
Ethyl acetate
Chloroform
Tetrahydrofuran
Hexane
257
257
257
257
262
0.17
0.16
0.14
0.05
0.10
5.
6.
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Methanol
225
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aMolar absorption coefficient at the maximum absorption wavelength.
c
bMaximum emission wavelength. Difference between maximum absorption
wavelength and maximum emission wavelength. dFluorescence quantum
yield (257 nm for all solvent except MeOH, for MeOH λext= 262 nm, error
limit within ± 5%).
The above photophysical study revealed that the compound 4c
exhibits strong fluorescence with moderate quantum yield.
Interestingly the fluorescence properties were found to be highly
sensitive to the solvent in terms of their polarity, hydrogen
bonding ability and pH of the medium. Thus, the isoquinoline
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.

6
Tetrahedron
Graphical Abstract
An efficient synthesis of pyrrole and
fluorescent isoquinoline derivatives using
NaN3/NH4Cl promoted intramolecular aza-
annulation
Leave this area blank for abstract info.
Akash Jana,a Susanta Kumar Manna,b Suresh Kumar Mondal,a Arabinda Mandal,b Saikat Kumar Manna,a Avijit
Jana,c Bidyut Kumar Senapati,d Manas Jana,e Shubhankar Samanta,*b
O
Easy access to bicyclic or tricyclic
pyrrole and isoquinoline derivatives
CO2R
NH
CO2R
OMe
NH
CHO
NaN3,NH4Cl
1
3
2
MeOH:H2O(10:1), 80 0
C
or
R''
or
Short synthetic route
lamillraine Q analog
i) Metal free exo-trig-aza,
endo-dig aza-cyclisation
ii) Moisture tollarent
iii) High yield
CHO
R''
N
iv) environmentally benign
4

Highlights
 Synthesis of pyrrole and isoquinoline
derivatives
 NaN3/NH4Cl promoted aza-annulation
 synthesize the core structure of Lamellarins
Q
 The blue fluorescent
property of
isoquinoline derivatives
 The transition metal free procedure