One-pot and catalyst-free synthesis of pyrroloquinolinediones and quinolinedicarboxylates

Article abstract of DOI:10.1039/c7gc01380a

A method for the catalyst-free synthesis of pyrroloquinolinediones and quinolinedicarboxylates is developed through a one-pot synthesis involving denitrogenation of azide, benzisoxazole formation, aza-Diels-Alder cycloaddition, and dehydrative aromatization. Only stoichiometric amounts of N₂ and H₂O are produced as by-products. A comprehensive green chemistry metrics analysis indicated that this method is much more efficient and greener than two reported methods for the synthesis of pyrroloquinolinediones.

Full text of DOI:10.1039/c7gc01380a

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One-pot and catalyst-free synthesis of pyrroloquinolinediones and
quinolinedicarboxylates†
Received 00th January 20xx,
Accepted 00th January 20xx
Xiaofeng Zhang,a Gagan Dhawan,a, b Alex Muthengi,a Shuai Liu,a Wei Wang,c Marc Legris c and Wei
Zhang*a
DOI: 10.1039/x0xx00000x
A method for catalyst-free synthesis of pyrroloquinolinediones and quinolinedicarboxylates is developed through a one-
pot synthesis involving denitrogenation of azide, benzisoxazole formation, aza-Diels-Alder cycloaddition, and dehydrative
aromatization. Only a stoichiometric amount of N2 and H2O is produced as byproducts. A comprehensive green chemistry
metrics analysis indicated that this method is much more efficient and greener than two reported methods for the
www.rsc.org/
synthesis
of
pyrroloquinolinediones.
Fig. 1 Bioactive pyrroloquinolines and pyrroloquinolinediones.
Introduction
Quinoline is a privileged scaffold which could be found in a wide
range of natural products, bioactive compounds, fluorescent and
phosphorescent probe molecules, and ligands for catalysis.1
Pyrroloquinolines and pyrroloquinolinediones are important
derivatives of quinolines. Compounds from these two subfamilies
of quinolines, such as luotonin A,2 camptothecin,3 mappicine,4 and
caspase-3 inhibitors,5 have significant biological activities (Figure 1).
Cyclization and cycloaddition reactions of 2-aminobenzaldehyde-
and maleimide-related compounds are two common methods for
the synthesis of pyrroloquinolinediones (Scheme 1).6 The reported
methods are multistep syntheses and usually require metal
catalysts. Introduced in this paper is a catalyst-free and one-pot
synthesis of pyrroloquinolinediones from readily available
azidobenzaldehydes and maleimides. The method is also applicable
for the synthesis of quinolinedicarboxylates.
Scheme 1 Processes A-F for the synthesis of pyrroloquinolinediones.
2-Azidobenzaldehydes are feasible synthon for diverse
a
nitrogen-heterocyclic compounds including benzisoxazoles and
quinolines.7 As part of our recent effort on the development of
multicomponent
reaction-based
synthesis
of
polycyclic
compounds,8 we have introduced a number of [3+2] cycloaddition-
initiated synthesis using substituted 2-azidobenzaldehydes as
starting materials (Scheme 2).9 After the [3+2] cycloaddition, the
azido group was used for another [3+2] cycloaddition or reduced to
amino group for further derivatization to form scaffolds I-III. In this
work, 2-azidobenzaldehydes are employed as a precursor for aza-
Diels-Alder cycloadditions to form pyrroloquinolinediones 1 and
quinolinedicarboxylates 2.
a.Department of Chemistry and Centre for Green Chemistry, University of
Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA.
E-mail: wei2.zhang@umb.edu
b.Department of Biomedical Science, Acharya Narendra Dev College, University of
Delhi, New Delhi-110019, India
c. School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an,
710062, China.
†Electronic Supplementary Information (ESI) available: Detailed experimental
procedures, compound characterization, NMR spectra, green chemistry metrics
analysis. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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o
4a in MeCN under microwave heating, at 115 C for 35 min, which
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DOI: 10.1039/C7GC01380A
Table
1.
Development of reaction conditionsa
Entry
Catalyst
(equiv)
Temp
(oC)
Solvent
Time
1a
(%)b
1
2
3
4
5
6
CuI (0.1)
AlCl3 (0.3)
DIPEA (1.0)
-
DIPEA (1.0)
-
85
85
85
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
12 h
3 h
12 h
12 h
35 min
35 min
39
ND
88
71
90
85
115 (w)
115 (w)
92 (89)
7
8
9
-
-
-
CH3CN
EtOH
toluene
35 min
35 min
35 min
92
15
71
150 (w)
115 (w)
115 (w)
Scheme 2 2-Azidobenzaldehyde-based synthesis of heterocycles.
a1:1.1 of 3a:4a. bDetected by LC, isolated yield in parenthesis.
afforded pyrroloquinolinedione 1a in 89% isolated yield (entry 6).
Results and Discussion
Literature search revealed that benzisoxazoles 6 generated from
With the optimized reaction conditions in hand, we carried out
denitrogenation of 2-azidobenzaldehydes 3 could be used as reactions with a series of 2-azidobenzaldehydes 3 and maleimides 4
precursors for aza-Diels-Alder cycloaddition10 or metal-catalyzed
[4+2] annulation reactions.11 Based on this information, we
proposed a one-pot synthesis of pyrroloquinolinediones 1 involving
thermal denitrogenation of 2-azidobenzaldehydes 3, cyclization of
nitrenes 5, aza-Diels-Alder reaction of benzisoxazoles 6 with
maleimides 4, and dehydrative aromatization of 7 (Scheme 3).
Table 2.
One-pot synthesis of pyrroloquinolinediones 1 and
quinolinedicarboxylates 2.a
Scheme 3. Proposed one-pot synthesis of pyrroloquinolinediones 1.
A clean conversion of 2-azidobenzaldehyde 3a to benzisoxazole
o
6a under microwave heating at 115 C for 20 min was observed by
1H-NMR analysis (see SupInf). We then carried out a model reaction
of 2-azidobenzaldehyde 3a and N-methyl maleimide 4a to establish
the reaction conditions for the one-pot synthesis. After screening a
series of metal catalysts including CuI and AlCl3, we found that none
of these catalysts gave greater than 40% yield of product 1a (Table
1, entries 1&2). A reaction without metal catalyst but using N,N-
diisopropylethylamine (DIPEA) as a base gave 1a in 88% yield (entry
3). A reaction without using a base gave 1a in 71% yield (entry 4). It
was found that microwave heating significantly reduced the
reaction time (entries 5-9). The optimized condition was to conduct
the catalyst-free reaction without a base, and using 1:1.1 of 3a and
a Conditions: 1:1.1 of 3:4 (or 8) in MeCN, w heating at 115 oC for 35
min, isolated yields
2 | J. Name., 2012, 00, 1-3
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for the synthesis of pyrroloquinolinediones 1 bearing different R1
Scheme
pyrroloquinolinediones.
4.
Processes
A-C
for
the
sVyinewthAertsicisle Onlionef
and R2 groups (Table 2). The isolated yields of products 1a-l are in
DOI: 10.1039/C7GC01380A
the
The AE for Process C is less than 100% due to the formation of
H2O and N2 as by-products (Table 3). However, it has inherited high
atom
range of 75-93%. By replacing maleimides 4 with dimethyl fumarate
8 (E-isomer), reactions produced quinolinedicarboxylates 2a-e in
75-90% yields.12 A similar result was obtained using dimethyl
maleate (Z-isomer) for the synthesis of 2a. A reaction with 1,4-
naphthoquinone didn’t give product 9.
Table 3. Green Metrics (AE, AEf, CE, RME, OE and MP) for Processes A-C
Process Isolation Yield
AE
(%)
AEf
(%)
CE
(%)
RME
(%)
OE
(%)
MP
(%)
steps
(%)
Evaluation of green chemistry credentials of the one-pot
synthesis (Process C) for pyrroloquinolinediones and comparison it
with two literature methods highlighted in Scheme 4 (Processes A
and B) was done by performing a series of green metrics
calculations13,14 (see SupInf for the definition of different metrics
and related calculations). Since 2-aminobenzaldehyde and
maleimide used in the Processes A and B are closely related to the
starting materials used in the Process C (Scheme 4), which make the
comparison more meaningful. Process A is a four-step synthesis
starting from 2-aminobenzaldehyde.6f Process B starting from N-
butyl maleimide has an intermediate 16 which was not isolated, it
was treated as a three-step synthesis for calculation.6b First of all,
atom economy (AE) and atom efficiency (AEf) were calculated to
estimate the amount of the reactants that will remain in the
product. But these metrics ignores the inorganic reagents as well as
solvents that are not incorporated into the final product. Moreover,
significant stoichiometric excess is also not considered in AE and
AEf. Therefore, carbon efficiency (CE), reaction mass efficiency
(RME), overall efficiency (OE), process mass intensity (PMI), solvent
intensity (SI), water intensity (WI), E-factor (E) and mass
productivity (MP) were also calculated (Tables 3 and 4).
A
B
C
4
19.14 57.98 11.1
4.54
1.98
3.42 0.26
3
1
25.35 69.58 17.64 61.53
90 83.92 75.53 85.68
15.8 22.71 0.13
72.0 85.80 5.48
The value closer to 100%, the greener the process
1
0
8
6
4
2
0
0
0
0
0
0
A
B
C
A
E
Y
i
e
l
d
A
E
f
C
E
R
M
E
O
E
M
P
G
r
e
e
n
M
e t r i c s
Table 4. Green Metrics (PMI, E factor, SI and WI) for Processes A-C
PMI
(g/g)
E
(g/g)
SI
WI
(g/g)
Process
(g/g)
A
B
C
389.67
794.31
18.26
388.67
793.31
17.26
250.44
877.81
14.56
14.15
2982.46
2.31
Lower is the value, better is the process
4
3
2
1
0
0
0
0
0
0
0
0
0
0
0
0
0
A
B
C
P
M
I
E
e
S
c
I
W
I
G
r
e
n
M
e
t
r
i
s
economy (83.92%) and atom efficiency (75.53%) which is
significantly better than those for Process A (57.98% and 11.1%)
and Process B (69.58% and 17.64%). The calculated CE (85.68%) for
Process C justifies for excess stoichiometry in reaction conditions
and
90% yield of the product even though number of carbons remains
the same. As RME includes all reactant mass, yield, and atom
economy, it is the most useful metric to determine the greenness of
the process. Calculations of RME gave even more noteworthy
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results for Process C (72.0%) compared to Process A (1.98%) and
Process B (15.8%). RME is calculated based on the purified product,
the solvent used for purification takes account. Process A has four
purification steps, its RME (1.98%) is worse than Process B (15.8%),
and much worse than Process C (72.0%). Similarly, PMI evaluation
also showed Process C (18.26) is far more superior to Process A
(389.67) and Process B (794.31). Moreover, the OE of Process A
(3.42%) and B (22.71%) are very less compared to Process C
(85.80%). Mass productivity is useful for industry as it focusses on
resource consumption. The MP for the Processes A (0.26%) and B
(0.13%) are also less than that of Process C (5.48%). This means that
mass being wasted in making the product is more in Processes A
and B in comparison to Process C. The RME and MP of Process C
also rationalize less than 100% yield and the need for a 10% molar
excess of N-propylmaleimide.
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Solvents including water used in a chemical process is also
recognized as a threat to environment and therefore, reduction in
their usage is the need of the hour. Thus, solvent intensity (SI) and
water intensity (WI) values were determined. Large excess of
solvent including water were used in processes A and B compared
to process C leading to enormous difference in their values.
Conclusions
A
highly efficient and metal catalyst-free synthesis of
pyrroloquinolinediones and quinolinedicarboxylates is developed
through a one-pot and quadruple reaction sequence involving
denitrogenation/benzisoxazole
formation/aza-Diels-Alder
cycloaddition/dehydrative aromatization. Other than reaction
solvent MeCN, no catalyst and additives were used, and only N2 gas
and H2O were generated as byproducts from the reaction process.
Compared to two reported methods for pyrroloquinolinediones, the
new method is much more efficient and better in all aspects of
green chemistry metrics analysis.
8
Acknowledgements
This work was supported by the Centre for Green Chemistry of
UMass Boston. GD wishes to gratefully acknowledge University
Grants Commission of India for the award of UGC-Raman
Fellowship.
Notes and references
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Graphical Abstract
Abstract: A method for catalyst-free synthesis of pyrroloquinolinediones and
quinolinedicarboxylates is developed through a one-pot synthesis involving
denitrogenation of azide, benzisoxazole formation, aza-Diels-Alder cycloaddition,
and aromatization for pyridine. Only a stoichiometric amount of N2 and H2O is
produced as byproducts. Green metrics analysis indicated that this method is
much more efficient than two reported methods for the synthesis of
pyrroloquinolinediones.