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

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.

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

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

NN

H

N

NN

H1

2

34

5

1

2

34

5

1,2,3-triazol 1,2,4-triazol1,2,3-triazole 1,2,4-triazole

Triazoles and anti-cancer activitySome 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-triazoleswas recently proved to have antimitoticactivity on breast cancer cells through

suppression of tubulin polymerization [6].

Cl

OCl

ClN

NN

H2N

O

H2N

KarboksyamidotriazolCarboxyamidotriazole

Antimitotic 1,2,3-triazoles

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).

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 soduHC CH

N N

N

ArH2O

CHCR1R2 N3Cu+

R1 C CH

N N

N

R2

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 BrNaN3

R1 N3

R2 C C H(R2)

askorbinian soduCuSO4

C C

N N

N

(R2)H R2

R1

R1 C CH

N N

N

R2Cu+

CHCR1 NaN3 R2 X

sodium ascorbate,CuSO4

R X NaN3 R1 C CHH2O

brak katalizatoraHC C

N N

N

R1

R

C CH

N N

NR

R1

catalyst-free

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 BrNaN3

R1 N3

R2 C C H(R2)

askorbinian soduCuSO4

C C

N N

N

(R2)H R2

R1

R1 C CH

N N

N

R2Cu+

CHCR1 NaN3 R2 X

R X NaN3 R1 C CHH2O

brak katalizatoraHC C

N N

N

R1

R

C CH

N N

NR

R1

R1 C CH

N N

N

R2Cu+

CHCR1 NaN3 R2 X

TBA-Br

Cu+

catalyst-free

Chemical groups chosen for research

+ +

N

NR2R1

SO2NHCH2 C CH

N

NHCH2 C CH

SO2NH R1

CH2

CH2 CH CH2

CH2 CH CCH3

CH3

R=

NN

N

benzyl

allyl

3-methyl-2-butenylTriazole ringformed fromNaN3 or R-N3

and propargyl bond

Main substrates:

4-propargylamino-3-quinolinesulfonamides

4-amino-3-quinoline(N-propargyl)sulfonamides

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 1H NMR and MS.

Reactions carried out - IA: Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC),

solvents: DMF/water 4:1 or tert-butanol/water 1:1.

N

NR2R1

SO2NHCH2 C CH

NaN3

O

OO

O CHOH

CH2OH

Na2CO3 CuSO4R Br

N

N

R2R1

SO2NHCH2 C CH

NN

N R

N

NHCH2 C CH

SO2NH R1

CuSO4Na2CO3

O

OO

O CHOH

CH2OH

NaN3R Br

R

N

NHCH2 C CH

SO2NH

NN

N

R1

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.

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.

Reactions carried out - IIIC: Two-step cycloaddition of organic azide to alkyne

N

N

R2R1

SO2NHCH2 C CH

NN

N R

N

NR2R1

SO2NHCH2 C CH

RN3 CuI

R

N

NHCH2 C CH

SO2NH

NN

N

R1

N

NHCH2 C CH

SO2NH R1

CuIRN3

Step I: organic azide synthesis in DMF,no product separation

Step II: actualcycloadditionin chloroform,organic azideadded as DMF solution

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 stableand can be used for several reactions.

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 CHH2O

brak katalizatoraHC C

N N

N

R1

R

C CH

N N

NR

R1

catalyst-free

DMF/

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%)

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 CCH3

CH3

R=13 new compounds were obtainedand will be tested on cancer cells.

Reaction yields depended onchemical group by the N1 atomin triazole ring:

80-99%

40-55%

70-80%

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

Thank you for your attention!

Literature:• [1] Nozomu Koyanagi, Takeshi Nagasu, Fumiko Fujita, et al. In Vivo Tumor Growth Inhibition Produced by a

Novel Sulfonamide, E7010, against Rodent and Human Tumors. Cancer Res 1994;54:1702-1706.• [2] Scozzafava A, Owa T, Mastrolorenzo A, Supuran CT. Anticancer and antiviral sulfonamides. Curr Med Chem.

2003 Jun;10(11):925-53.• [3] Smits RA, Adami M, Istyastono EP, Zuiderveld OP, van Dam CM, de Kanter FJ, Jongejan A, Coruzzi G, Leurs

R, de Esch IJ. Synthesis and QSAR of quinazoline sulfonamides as highly potent human histamine H4 receptor inverse agonists. J Med Chem. 2010 Mar 25;53(6):2390-400.

• [4] Pinhua Lia, Lei Wang. One-Pot Synthesis of 1,2,3-Triazoles from Benzyl and Alkyl Halides, Sodium Azide and Alkynes in Water Under Transition-Metal-Catalyst Free ReactionConditions. Letters in Organic Chemistry, 2007, 4, 23-26.

• [5] Sandip G. Agalave, Dr. Suleman R. Maujan, Dr. Vandana S. Pore. Click Chemistry: 1,2,3-Triazoles as Pharmacophores. Volume 6, Issue 10, pages 2696–2718, October 4, 2011.

• [6] Bankowska E., Wróblewski A. E. Derivatives of 1,2,3-triazole. Potential drugs? Wiadomości Chemiczne, 2012, [Z] 66, 11-12, s. 993-1022

• [7] Hussain MM, Kotz H, Minasian L, Premkumar A, Sarosy G, Reed E, Zhai S, Steinberg SM, Raggio M, Oliver VK, Figg WD, Kohn EC. Phase II trial of carboxyamidotriazole in patients with relapsed epithelial ovarian cancer. J Clin Oncol. 2003 Dec 1;21(23):4356-63.

• [8] Rashida A. Karmali, Yulia Maxuitenko, Greg Gorman , John G. Page. Carboxyamidotriazole Orotate and Cytotoxic Chemotherapy have a Synergistic Effect on Tumor Inhibition in Glioblastoma and Colon Xenograft Mouse Models. Cancer Therapy Vol 8, 71-80, 2011.

• [9] Yury A. Rozina, Johann Lebanb, Wim Dehaenc, Valentine G. Nenajdenkod, Vasiliy M. Muzalevskiyd, Oleg S. Eltsova, Vasiliy A. Bakuleva. Regioselective synthesis of 5-trifluoromethyl-1,2,3-triazoles via CF3-directed cyclization of 1-trifluoromethyl-1,3-dicarbonyl compounds with azides. Tetrahedron, Volume 68, Issue 2, 14 January 2012, Pages 614–618

• [10] Jyothi Vantikommua, Sadanandam Palleb, Punganuru Surendra Reddyb, Vinodkumar Ramanathamb, Mukkanti Khaggab, Venkateswara Rao Pallapothula. Synthesis and cytotoxicity evaluation of novel 1,4-disubstituted 1,2,3-triazoles via CuI catalysed 1,3-dipolar cycloaddition. European Journal of Medicinal Chemistry, Volume 45, Issue 11, November 2010, Pages 5044–5050

• [11] Yubo Jiang, Chunxiang Kuang, Qing Yang. The Use of Calcium Carbide in the Synthesis of 1-Monosubstituted Aryl 1,2,3-Triazole via Click Chemistry. Synlett, 2009, 3163-3166.

• [12] J. Barluenga, C. Valdés, G. Beltrán, M. Escribano, F. Aznar. Developments in Pd Catalysis: Synthesis of 1 H-1,2,3-Triazoles from Sodium Azide and Alkenyl Bromides. Angew. Chem. Int. Ed., 2006, 45, 6893-6896.

• [13] L.-Y. Wu, Y.-X. Xie, Z.-S. Chen, Y.-N. Niu, Y.-M. Liang. A Convenient Synthesis of 1-Substituted 1,2,3-Triazoles via CuI/Et3N Catalyzed ‘Click Chemistry' from Azides and Acetylene Gas. Synlett, 2009, 1453-1456.

• [14] A. Kolarovič, M. Schnürch, M. D. Mihovilovic. Tandem Catalysis: From Alkynoic Acids and Aryl Iodides to 1,2,3-Triazoles in One Pot J. Org. Chem., 2011, 76, 2613-2618.

• [15] Y. Jiang, C. Kuang, Q. Yang. Copper(I) Iodide-Catalyzed Synthesis of 4-Aryl-1H-1,2,3-triazoles from anti-3-Aryl-2,3-dibromopropanoic Acids and Sodium Azide. Synthesis, 2010, 4256-4260.

• [16] J. Boyer, Monocyclic Triazoles and Benzotriazoles, in: R. Elderfield (editor), Heterocyclic Compounds, Vol. 7, Izd. Mir, Moscow (1965), p. 296.

• [17] Huisgen, R. Centenary Lecture - 1,3-Dipolar Cycloadditions. Proceedings of the Chemical Society of London (1961) p. 357

• [18] K. Kacprzak. Efficient One-Pot Synthesis Of 1,2,3-Triazoles From Benzyl And Alkyl Halides. Synlett 2005(6): 0943-0946

• [19] Morten Meldal, Christian Wenzel Tornøe. Cu-Catalyzed Azide-Alkyne Cycloaddition. Chem. Rev. 2008, 108, 2952–3015

• [20] Chittaboina, Xie, Wang. One-pot synthesis of triazole-linked glycoconjugates. Tetrahedron Letters. 2005; 46:2331–2336.