A "click and activate" Approach in one-pot synthesis of a triazolyl-pyridazinone library

Article abstract of DOI:10.1021/ol200183b

A "click and activate" strategy was designed and executed in a four-component, stepwise condensation that led to a trisubstituted triazolyl-pyridazinone library. This one-pot process included regioselective azide substitution at 2-substituted-4,5-dichloro

Full text of DOI:10.1021/ol200183b

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1682–1685
A “Click and Activate” Approach in One-
Pot Synthesis of a Triazolyl-Pyridazinone
Library
Wenyuan Qian,* David Winternheimer, and Jennifer Allen
Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive,
Thousand Oaks, California 91320-1799, United States
wqian@amgen.com
Received January 20, 2011
ABSTRACT
A “click and activate” strategy was designed and executed in a four-component, stepwise condensation that led to a trisubstituted triazolyl-
pyridazinone library. This one-pot process included regioselective azide substitution at 2-substituted-4,5-dichloropyridazinones, followed by a Cu(I)
catalyzed triazole formation which triggered subsequent nucleophilic substitution at the neighboring position to achieve three points of diversity.
The efficient and precise assembly of molecular diversity
is one of the key aspects in library synthesis and medicinal
chemistry. Multiple component reactions (MCRs), in
which three or more reactants condense in a single reaction
vessel to form a new product containing portions of all
components, are well suited for this purpose.1,2 Although
all components are not necessarily condensed in a mechan-
istically concerted fashion, MCRs are a one-pot process
and are attractive in terms of atom- and step-economy,
operational simplicity, and environmental friendliness.
Recently, as the most significant example of click
chemistry,3 a Cu(I) catalyzed azide-alkyne cycloaddition
(CuAAC) to form 1,2,3-triazoles, first reported by the
Sharpless and Meldal groups, has attracted enormous
attention in both academia and industry.4-6 Compared
to traditional triazole syntheses, this new approach offers
not only high yields under mild conditions but also high
regioselectivity for the 1,4-disubstituted triazoles. As an
extension of this efficient reaction, some elegant examples
involving in situ formation of an organic azide followed by
click chemistry in one pot have also been disclosed.7
Efficient synthesis via CuAAC click chemistry and
unique physicochemicalproperties of triazolesmakesthem
attractivepartners for participation in multiplecomponent
condensations to form more complex structures with
potential biological activities. In the literature, triazole
formation has been combined with other reactions, such
as the Biginelli reaction,8 domino Wittig-Knoevenagel/
Diels-Alder reaction,9 and Ugi reaction,10 etc., either in
multiple steps or in one pot. However, in most existing
€
(1) (a) Domling, A. Chem. Rev. 2006, 106, 17. (b) Ramon, D. J.;
Miguel, Y. Angew. Chem., Int. Ed. 2005, 44, 1602. (c) Armstrong, R. W.;
Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem.
Res. 1996, 29, 123.
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(2) Multicomponent reactions; Zhu, J., Bienayme, H., Eds.; Wiley:
Weinheim, 2005.
(3) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004.
(4) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Tornøe, C. W.; Christensen,
C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
(5) For recent reviews, see: Thematic issue: Click chemistry: Function
follows form; Finn, M. G., Fokin, V. V., Eds.; Chem. Soc. Rev. 2010, 39,
1221.
(7) (a) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken,
E. Org. Lett. 2004, 6, 4223. (b) Feldman, A. K.; Colasson, B.; Fokin,
V. V. Org. Lett. 2004, 6, 3897. (c) Chittaboina, S.; Xie, F.; Wang, Q.
Tetrahedron Lett. 2005, 46, 2331. (d) Kumar, D.; Reddy, V. B.; Varma,
R. S. Tetrahedron Lett. 2009, 50, 2065. (e) Reddy, P. S.; Sreedhar, B.
Synthesis 2009, 24, 4203.
(8) Khanetskyy, B.; Dallinger, D.; Kappe, C. O. J. Comb. Chem.
2004, 6, 884.
(9) Ramachary, D. B.; Barbas, C. F., III. Chem.;Eur. J. 2004, 10,
5323.
(10) Akritopoulou-Zanze, I.; Gracias, V.; Djuric, S. W. Tetrahedron
Lett. 2004, 45, 8439.
(6) (a) Wu, P.; Fokin, V. V. Aldrichimica Acta 2007, 40, 7. (b)
Fournier, D.; Hoogenboom, R.; Schubert, U. S. Chem. Soc. Rev.
2007, 36, 1369. (c) Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev.
2007, 36, 1249.
r
10.1021/ol200183b
Published on Web 02/25/2011
2011 American Chemical Society

examples, the triazole formation is always introduced
in the last step as the final decoration of the previous
intermediates.11
Efficient synthetic approaches that allow selective and
convenient derivatization of this pharmacological privileged
core structure would expand their assessment and value.
Because a variety of 2-substituted-4,5-dihalo-pyridazi-
nones (5) are commercially available or can be easily made,
there has been an ever growing amount of work in the
literature aimed at the selective functionalization of the 4-
and 5-positions.14,15 However, many existing approaches
are either nonregioselective or require stepwise reactions
(sometimes including protection and deprotection) and
separation of intermediates.
Scheme 1. Proposed “Click and Activate” General Approach
An alternative and largely unexplored approach for
incorporating click chemistry into multiple component
condensations would place the CuAAC step in the mid-
stage rather than the final step of the one-pot process.
One obvious advantage of introducing CuAAC click
chemistry earlier is that triazoles are usually chemically
more stable than alkynes or azides, thus resulting in
better compatibility with other reaction components.
More importantly, in our recent medicinal chemistry
program, we observed a subtle activation effect of the
triazole moiety on its neighboring groups in subsequent
transformations. Based on this observation, here we
propose a broader “click and activate” strategy illu-
strated in Scheme 1: After CuAAC click chemistry on
azide 1, the resulting triazole group in 2 allows activation
of the conjugated double bond with a leaving group
toward nucleophilic substitution to give 3 in one pot.
This double bond can be a part of an electron-deficient
aromatic or heteroaromatic ring.
Scheme 3
Here we report a one-pot synthesis of general structure 8
utilizing CuAAC as the key step that allows easy access to
three points of diversity on the pyridazinone scaffold
(Scheme 3). First, a regioselective azide substitution at
the 5-position of 5 is required. Withazide 6, a click reaction
with terminal acetylenes would be expected to give triazole
7 in a highly regioselective manner. As the final step in the
sequence, we reasoned that the formation of the triazole 7
should switch the reactivity of the 4-(chloro) position from
a “neutral” or “deactivated” (as in azide 6) to an “activated”
state toward nucleophilic attack due to the subtle electronic
effect of triazole. We set out to identify the optimal condi-
tions suitable for all elementary transformations to proceed
in a highly organized manner in one pot.
Scheme 2
The solvent effect of the nucleophilic substitution on the
4,5-dihalopyridazinones by amines, alkoxides, and al-
kylthiolates is well documented in terms of regioselec-
tivity.16,17 However, azide substitution on this core has
been studied to a lesser extent in the literature.17 In fact, all
reported examples required heating for extended periods
and favored substitution at the 5-position. To enable our
2-Substituted-4,5-dichloropyridazinone (5) provides an
ideal substrate to explore this approach (Scheme 2). 2,4,5-
Trisubstituted-3(2H)-pyridazinones (4) are well-known
compounds of agrochemical and pharmaceutical inte-
rest.12 Several commercial products containing this scaf-
fold, such as Chloridazon (herbicide),13 Pyridaben (miti-
cide/insecticide),13 and Emorfazone (anti-inflammatory
agent),12c are worth mentioning.
ꢁ
(14) (a) Maes, B. U. W.; R’kyek, O.; Kosmrlj, J.; Lemiere, G. L. F.;
Esmans, E.; Rozenski, J.; Dommisse, R. A.; Haemers, A. Tetrahedron
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2001, 57, 1323. (b) Riedl, Z.; Maes, B. U. W.; Monsieurs, K.; Lemiere,
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G. L. F.; Metyus, P.; Hajos, G. Tetrahedron 2002, 58, 5645. (c)
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Tapolcsanyi, P.; Maes, B. U. W.; Monsieurs, K.; Lemiere, G. L. F.;
Riedl, Z.; Hajos, G.; Van den Driessche, B.; Dommisse, R. A.; Matyus,
ꢂ
ꢀ
ꢀ
(11) For a one-pot, modular synthesis of trisubstituted 1,2,3-triazoles
involving direct arylation after click reaction, see: Ackermann, L.;
Potukuchi, H. K.; Landsberg, D.; Vicente, R. Org. Lett. 2008, 10, 3081.
P. Tetrahedron 2003, 59, 5919.
(15) Wu, B.; Wang, H.-L.; Pettus, L.; Wurz, R. P.; Doherty, E. M.;
Henkle, B.; McBride, H. G.; Saris, C. J. M.; Wong, L. M.; Plant, M. H.;
Sherman, L.; Lee, M. R.; Hsieh, F.; Tasker, A. S. J. Med. Chem. 2010,
53, 6398.
(16) (a) Pilgrim, K. H.; Pollard, G. E. J. Heterocycl. Chem. 1977, 14,
1039. (b) Lyga, J. W. J. Heterocycl. Chem. 1988, 25, 1757.
(17) (a) Kweon, D.-H.; Kang, Y.-J.; Chung, J.-A; Yoon, Y.-J.
J. Heterocycl. Chem. 1998, 35, 819. (b) Chung, H.-A.; Kweon, D.-H.;
Kang, Y.-J.; Park, J.-W.; Yoon, Y.-J. J. Heterocycl. Chem. 1999, 36, 905.
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(12) (a) Tisler, M.; Stanovnik, B. Adv. Heterocycl. Chem. 1990, 49,
385. (b) Coates, W. J. In Comprehensive Heterocyclic Chemistry; Ka-
tritzky, A. R, Rees, C. W., Eds.; Pergamon Press: Oxford, 1996; Vol. 6, p 1. (c)
Frank, H.; Heinisch, G. In Progress in Medicinal Chemistry; Ellis, G. P.,
Luscombe, D. K., Eds.; Elsevier Science: Amsterdam, 1990; Vol. 27, p 1. (d)
Frank, H.; Heinisch, G. In Progress in Medicinal Chemistry; Ellis, G. P.,
Luscombe, D. K., Eds.; Elsevier Science: Amsterdam, 1992; Vol. 29, p 141.
(13) BASF Web site.
Org. Lett., Vol. 13, No. 7, 2011
1683

Table 1. Solvent Screening for Regioselective Azide Substitu-
tion at Room Temperaturea
Scheme 5
% conversion
at 30 min
% conversion
at 90 min
solvent
toluene
DCM
0
0
0
0
THF
0
0
dioxane
MeOH
MeCN
DMSO
DMF
0
0
0
0
6 h at room temperature. In parallel, azide 10 failedtoafford
any HPLC detectable amount of morpholine substitution
product 13 under the same conditions, pointing to the
importance of activation by the triazole.
Having established suitable conditions and secured the
selectivity in each step separately, we conducted the entire
synthesis in one pot: A 2.5 M solution of 4,5-dichloro-2-
phenylpyridazin-3(2H)-one 9 was treated with 1.1 equiv of
sodium azide, and the reaction was stirred at room tem-
perature for 2 h until 9 was consumed as indicated by TLC.
The reaction mixture was diluted with MeCN and was
treated with 2 equiv of N-diisopropylethylamine (DIPEA),
1.2 equiv of phenylacetylene, and a catalytic amount of
1
4
85
96
95
98
a The solvent screening was conducted at a concentration of 1 M. The
conversion was calculated based on HPLC peak area integrations of
9 and 10 at 254 nm. In DMF, the reaction gave similar conversion at
2.5 M. The isolated yield was 78%.
proposed one-pot reaction sequence, we sought to identify
a solvent that provided high selectivity and acceptable
reaction rates at room temperature. Among the various
solventswe screened, polar aproticsolventssuchasDMSO
and DMF gave the best results (Table 1). This step with 9 is
fast and highly regioselective to give 10. In addition, this
reaction only requires a minimal amount of DMF. When
using 1 equiv of NaN3, no bis-azido product was observed.
Scheme 6. One-Pot Condensation with Amines
Scheme 4
Although DMF was the best solvent for the azide sub-
stitution, it gave rise to a significant amount of side products
in the CuAAC click reaction under standard conditions.
Instead, acetonitrile as the solvent provided a much cleaner
result for this step (Scheme 4). Because there was no pre-
cedence for using DMF as the solvent for the azide substitu-
tion on 4,5-dichloropyridazinone 5inthefirststep,westudied
the regioselectivity after triazole formation by 2-D HNMR.
A clear NOE between the proton on the 6-position of the
pyridazinone core in 11 and the proton on the triazole moiety
was detected by NOESY experiments, supporting the desired
regiochemistry of both transformations (Scheme 4).
The concept of the “click and activate” approach was
clearly demonstrated in the following control experiments
(Scheme 5). Treatment of triazole 11 with 2 equiv of
morpholine in DMF led to 100% conversion to 12a in
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Org. Lett., Vol. 13, No. 7, 2011

copper(I) iodide. After 30 min, 2 equiv of morpholine were
added and the reaction was stirred overnight to afford
product 12a in 60% isolated yield. In a simpler procedure,
2 equiv of morpholine were added to the in situ formed
azide inMeCN, togetherwithphenylacetylene and copper-
(I) iodide, affording 12a directly in a comparable yield
(54%). The entire procedure was performed at room
temperature without extra caution for air and moisture.
The simple operation and the mild conditions of this one-
pot procedure provide an easy access to a wide diversity of
the triazolyl-pyridazinone scaffold 12 by condensing a
variety of 2-substituted-4,5-dichloro-pyridazinones 5, so-
dium azide, terminal acetylenes, and amines as shown in
Scheme 6. Substituted phenyl, alkyl, and substituted benzyl
groups are all tolerated at the 2-position of the pyridazinone
core. Similarly, a range of alkynes, such as phenylacetylenes
bearing electron-donating (12c, 12k) or -withdrawing
groups (12e, 12f, 12h, 12j, 12n) and smaller acetylenes with
other functional groups, can be easily incorporated with
high regioselectivity. Likewise, a wide spectrum of different
primary and cyclic or acyclic (12c) secondary amines were
readily installed due to the activation effect after click
reaction. These included bicyclic amines (12b) and amines
with one (12g, 12j) or even two (12h) chiral centers. The
overall yields are moderate to very good as a result of the
combined efficiency of three individual transformations.
In order to extend the scope of this strategy, several
carbon nucleophiles were briefly explored (Scheme 7).
After in situ azide substitution followed by CuAAC click
reaction, the reaction mixture was treated with 1.2 equiv of
DBU and 1.2 equiv of diethyl malonate to give 14a-c in
good yields. Surprisingly, a cyclic ketoacetate led to 14d
Scheme 7. One-Pot Condensation with Carbon Nucleophiles
bearing a quaternary center in very good yield under the
sameconditions. One-pot condensation withothertypesof
nucleophiles will be the subject of future studies.
In summary, the CuAAC “click and activate” strategy
presented herein is a powerful approach in diversity-
oriented, multiple component condensation sequences.
As demonstrated in the first case study in this paper,18
the regioselective triazole formation not only stitches
together an alkyne and an azide but also switches the
reactivity of the neighboring group, triggering the facile
in situ nucleophile trapping to introduce additional
diversity. The one-pot execution of this strategy is very
simple and suitable for rapid assembly of molecular
complexity, with four new bonds being formed in this
case. Application of this general concept to the construc-
tion of other triazole-containing scaffolds with potential
biological activity is underway.
Acknowledgment. The authors wish to thank Chris
Wilde (Amgen) for help in 2D NMR studies and Dr. Paul
Schnier (Amgen) for supplying HRMS data. The authors
wish to thank Dr. Michael Bartberger (Amgen) for in-
sightful discussions. D.W. would like to thank Amgen
CR&D for financial aid in a summer internship.
(18) To the best of our knowledge, this is the first example of one-
pot, multiple component condensation sequence by a CuAAC “click
and activate” approach. Early examples of 4-alkylamino-5-triazolyl-
pyridazinone were synthesized in three separate steps. However,
extended heating and the potential regiochemical control issue in
the “nonclick” triazole formation step limits the scope of this old
procedure and makes it unsuitable for one-pot operation. See: (a)
Karklins, A.; Gudriniece, E. Latvijas PSR Zinatnu Akademijas Vestis,
Kimijas Serija 1969, 5, 579. (b) Gudriniece, E.; Urbans, V. Latvijas
PSR Zinatnu Akademijas Vestis, Kimijas Serija 1971, 1, 82. (c)
Urbans, V.; Gudriniece, E.; Urbans, V. Latvijas PSR Zinatnu Aka-
demijas Vestis, Kimijas Serija 1972, 1, 107.
Supporting Information Available. Experimental pro-
cedures, compound characterization data, and NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 7, 2011
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