This document describes various methods for synthesizing 1,2,3-triazoles from 4-amino-3-quinolinesulfonamides with a propargyl group. It discusses four reaction methods tried: (1) copper-catalyzed azide-alkyne cycloaddition, (2) phase transfer catalysis, (3) a two-step synthesis using an organic azide, and (4) a catalyst-free reaction in water. The copper-catalyzed and two-step methods produced the best yields of up to 99% and 82%, respectively. Thirteen new compounds were obtained and will be tested for potential anti-cancer activity, as the triazole, quin
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One-pot synthesis of triazole-linked sulfonamides for cancer studies
1. Various methods for one-pot synthesis
of 1,2,3-triazoles
from 4-amino-3-quinolinesulfonamides
with a propargyl group
Jerzy Bukowczan, Leszek Skrzypek, Stanisław Boryczka
Medical University of Silesia in Katowice
Department of Organic Chemistry
Jagiellońska 4, 41-200 Sosnowiec
commons.wikimedia.org
2. Introduction – cancer as a growing problem
„In a few years the nuber of deaths due to cancer in our country may equal
as deaths due to cardiovascular diseases, or even greater”
- prof. Witold Zatoński, Oncology Center, Warsaw.
2008 - 156 000 new cancer cases and 93 000 cancer-related deaths in Poland.
2025 - 176 000 Poles are estimated to be diagnosed with cancer each year.
In Canada more patients already die from cancer, than because of
cardiovascular diseases. From 2007 more men die due to cancer,
than from stroke and heart failure.
The total number of cancer patients will constantly grow
in Western society, due to its aging.
„The risk of this illness grows with age. Every 20 years of life
are a 10 times higher risk of a neoplastic disease”
- dr Joanna Didkowska, Oncology Center, Warsaw.
3. Sulfonamides - biological activity
Practical appliances in medicine:
– bacteriostatic,
– diuretic,
– antidiabetic,
– anti-inflammatory.
1992 – discovery of E 7010 sulfonamide,
which has anti-cancer activity (decreases tumor growth) [1].
Research from last decade suggests new potential uses for sulfonamides:
• antiviral,
• anti-cancer [2],
• antihistamine [3].
CH3O
SO2NH
NHN
OH
Sulfonamid E7010E 7010 sulfonamide
4. Why the triazole group?
1,2,3-triazole structure does not occur naturally,
but its many synthetic derivatives were obtained.
Some of them show interesting biological activities [4], for example:
– anti-cancer [5, 7, 8],
– antiviral against HIV,
– bactericidal and as beta-lactamase inhibitors,
– anti-allergic,
– antiepileptic,
– antitubercular,
– antifungal,
– anti-inflammatory,
– hypoglycemic [6].
N
N
N
H
N
N
N
H
1
2
34
5
1
2
34
5
1,2,3-triazol 1,2,4-triazol1,2,3-triazole 1,2,4-triazole
5. Triazoles and anti-cancer activity
Some triazole derivatives already found practical use in oncology,
like non-steroid aromatase inhibitors anastrozole and letrozole.
Other compounds containing this group are currently facing clinical trials [6].
In last years a former calcium-channel blocker carboxyamidotriazole,
which contains a 1,2,3-triazole group
was clinically tried as a potential
oncological drug [7, 8].
A group of 1,4-disubstituted 1,2,3-triazoles
was recently proved to have antimitotic
activity on breast cancer cells through
suppression of tubulin polymerization [6].
Cl
OCl
Cl
N
N
N
H2N
O
H2N
KarboksyamidotriazolCarboxyamidotriazole
Antimitotic 1,2,3-triazoles
6. Assumptions for the searched synthesis method
As demand for new anti-cancer drugs is growing and research shows
promising results for biological activity for sulfonamides, as well as
triazoles, an attempt was made to join those groups in one chemical
structure.
„Click chemistry” methods were chosen for synthesis purposes,
because of their rules:
joining simple, easily obtained units into more complicated structures,
minimum amount of reaction steps in uncomplicated conditions (i.e. „one pot”),
solvents easily separable from products (i.e. DMF and water mixture),
easy product separation and purification methods (i.e. filtration, crystallization).
7. Using an azide group –
the most common way of triazole synthesis
utilizes the copper(I)-catalyzed 1,3-dipolar cycloaddition mechanism,
has two variants – two-step or one-step, each of them can be a one-pot „click” reaction.
Two-step variant of triazole synthesis:
• step I: necessary organic azides are obtained,
• step II: triazole formation, catalyzed by copper(I) ions.
The azide reacts with a triple carbon bond:
– Aryl azide addition to acetylene in gas form [13] or created in situ from calcium carbide[11]:
– Organic azide addition to acetylene group:
Ar N3 CaC2
1 : 1,3
Cu
+
askorbinian sodu
HC CH
N N
N
ArH2O
CHCR1R2 N3
Cu
+
R1 C CH
N N
N
R2
8. One-step and one-pot variants of triazole synthesis:
- Tandem one-pot reaction [18]:
- Copper-catalyzed inorganic azide and organic halide
addition to an acetylene group (CuAAC variant) [10]:
- Catalyst-free reaction in aqueous conditions [4]:
R1 Br
NaN3
R1 N3
R2 C C H(R2)
askorbinian sodu
CuSO4
C C
N N
N
(R2)H R2
R1
R1 C CH
N N
N
R2
Cu
+
CHCR1 NaN3 R2 X
sodium ascorbate,
CuSO4
R X NaN3 R1 C CH
H2O
brak katalizatora
HC C
N N
N
R1
R
C CH
N N
N
R
R1
catalyst-free
9. Synthesis methods chosen for research
One-pot copper-catalyzed azide-alkyne cycloaddition (CuAAC) [10]:
One-pot phase transfer catalysis (PTC) [20]:
Two-step (tandem) cycloaddition of organic azide to alkyne [18]:
Catalyst-free cycloaddition in aqueous solution [4]:
R1 Br
NaN3
R1 N3
R2 C C H(R2)
askorbinian sodu
CuSO4
C C
N N
N
(R2)H R2
R1
R1 C CH
N N
N
R2
Cu
+
CHCR1 NaN3 R2 X
R X NaN3 R1 C CH
H2O
brak katalizatora
HC C
N N
N
R1
R
C CH
N N
N
R
R1
R1 C CH
N N
N
R2
Cu
+
CHCR1 NaN3 R2 X
TBA-Br
Cu+
catalyst-free
10. Chemical groups chosen for research
+ +
N
N
R2R1
SO2NHCH2 C CH
N
NHCH2 C CH
SO2NH R1
CH2
CH2 CH CH2
CH2 CH C
CH3
CH3
R=
N
N
N
benzyl
allyl
3-methyl-2-butenylTriazole ring
formed from
NaN3 or R-N3
and propargyl bond
Main substrates:
4-propargylamino-3-quinolinesulfonamides
4-amino-3-quinoline(N-propargyl)sulfonamides
11. Analytical methods used
reaction ends were determined by means of TLC
on aluminium oxide or silicone oxide,
eluents:
chloroform/ethanol 20:1 or chloroform/tetrahydrofuran 10:2,
results were observed under UV 254 nm.
compound structures were determined by 1
H NMR and MS.
12. Reactions carried out - I
A: Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC),
solvents: DMF/water 4:1 or tert-butanol/water 1:1.
N
N
R2R1
SO2NHCH2 C CH
NaN3
O
OO
O CHOH
CH2OH
Na2CO3 CuSO4R Br
N
N
R2R1
SO2NHCH2 C CH
N
N
N R
N
NHCH2 C CH
SO2NH R1
CuSO4Na2CO3
O
OO
O CHOH
CH2OH
NaN3R Br
R
N
NHCH2 C CH
SO2NH
N
N
N
R1
13. Reactions A (CuAAC) - results
good yields
(up to 92%),
easy product separation:
precipitation from water and filtration or extraction (chloroform),
both organic bromides and chlorides can be substrates
with similar yields,
slightly better yields for DMF/water for allyl-substituted triazoles.
14. Reactions carried out - II
B: Phase transfer catalysis (PTC)
phase transfer catalyst: tetrabutylammonium bromide (TBA-Br).
substrates and catalysts like in CuAAC reaction,
solvents: chloroform, ethanol and water 10:1:1.
Results:
good yields (up to 90%),
difficulties in purifying product from remains of TBA-Br.
15. Reactions carried out - III
C: Two-step cycloaddition of organic azide to alkyne
N
N
R2R1
SO2NHCH2 C CH
N
N
N R
N
N
R2R1
SO2NHCH2 C CH
RN3 CuI
R
N
NHCH2 C CH
SO2NH
N
N
N
R1
N
NHCH2 C CH
SO2NH R1
CuIRN3
Step I: organic azide synthesis in DMF,
no product separation
Step II: actual
cycloaddition
in chloroform,
organic azide
added as
DMF solution
16. Reactions C (two-step) - results
good yields (up to 82%),
oganic azide synthesis has to be carried out
24h prior to the actual cycloaddition,
the azide solution in DMF is chemically stable
and can be used for several reactions.
17. Reactions carried out - IV
D: Catalyst-free cycloaddition
solvent: water or water/DMF
has to be carried out in 100 °C,
produces mixture of regioisomers 1,4 and 1,5.
R X NaN3 R1 C CH
H2O
brak katalizatora
HC C
N N
N
R1
R
C CH
N N
N
R
R1
catalyst-free
DMF/
18. Reactions D (catalyst-free) - results
reaction in aqueous solution can be applied only for
liquid substrates, forming emulsion in water
for solid reagents an additive solvent such as DMF is
required
the formed mixture of regioisomers
is difficult to separate
mediocre yields (around 40-50%)
19. Conclusions
CuAAC and two-step cycloaddition seem to be
the most effective methods with many
potential appliances.
One-pot CuAAC reaction may be best for the
pharmaceutical industry due to its simplicity and
short reaction time (24-48h).
CH2
CH2 CH CH2
CH2 CH C
CH3
CH3
R=
13 new compounds were obtained
and will be tested on cancer cells.
Reaction yields depended on
chemical group by the N1 atom
in triazole ring:
80-99%
40-55%
70-80%
20. Other possible activities?
Published research suggests other biological actions
possible for compounds containing quinoline,
sulfonamide and triazole gropups:
antitubercular
bactericidal
metallo-beta-lactamase inhibiting
anti-inflammatory
21. Thank you
for your attention!
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