One-pot synthesis of 3-triazolyl-2-iminochromenes via a catalytic three component cascade reaction

Article abstract of DOI:10.1021/ol401151z

A variety of 3-triazolyl-2-iminochromenes were synthesized in a one-pot, catalytic, three component condensation. In this event, a Cu(I)-catalyzed cycloaddition between 2-azidoacetonitrile and an acetylene formed a triazole and activated the neighboring methylene group, inducing an aldol-cyclization- dehydration sequence in the presence of a salicylaldehyde. Further elaboration led to more complex polyheterocycles.

Full text of DOI:10.1021/ol401151z

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
One-Pot Synthesis of 3‑Triazolyl-2-
iminochromenes via a Catalytic Three
Component Cascade Reaction
Wenyuan Qian,* Albert Amegadzie, David Winternheimer, and Jennifer Allen
Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks,
California 91320-1799, United States
wqian@amgen.com
Received April 24, 2013
ABSTRACT
A variety of 3-triazolyl-2-iminochromenes were synthesized in a one-pot, catalytic, three component condensation. In this event, a Cu(I)-catalyzed
cycloaddition between 2-azidoacetonitrile and an acetylene formed a triazole and activated the neighboring methylene group, inducing an
aldolÀcyclizationÀdehydration sequence in the presence of a salicylaldehyde. Further elaboration led to more complex polyheterocycles.
The efficient construction of diverse and elaborated
heterocycles from simple starting materials is highly desir-
able in medicinal chemistry and material sciences yet
remains a continuing challenge in organic synthesis. Multi-
ple component reactions (MCRs), due to their convergent
nature, are ideal tools to address this demand.1,2 Combin-
ing a series of “two-component” reactions in a reaction
vessel can be operationally efficient. However, many of
these one-pot, stepwise procedures require a specific order
of addition of components/reagents or different conditions
for each individual transformation. In contrast, “ideal”
MCRs are conducted under the same conditions by adding
all starting materials at the same time.2a,e Therefore, better
control of interactions among components/intermediates
and, thus, more organized reaction pathways are essential
in the design of new MCRs from existing reactions of
lower dimensions. In principle, there are two requirements in
“ideal” three-component reactions: (1) the direct product of
the first two component reaction should be able to react with
the next component automatically; (2) the third component
does not react irreversibly with the first two components to
complicate the outcome of the condensation.2e,f
In efforts to develop new MCRs, we were interested in
exploiting the high chemoselectivity of the Cu(I) catalyzed
azideÀalkyne cycloaddition (CuAAC) reaction. This “click
chemistry” has found many applications in drug discovery,
bioconjugation and material sciences in the past decade.3À5
CuAAC reaction is attractive for participation in multiple
component assembly processes due to its superior selectiv-
ity, reliability, and efficiency. In addition, alkyne and azide
groups have a unique window of reactivity that makes them
compatible with many other reactants. Utilizing these char-
acteristics, some groups have successfully combined triazole
formation with other reactions to construct more complex
structures.6 Nevertheless, the utility of the electronic out-
come of this powerful transformation has received little
attention. We reasoned that switching from the azide group
to the triazole group could have an impact on the reactivity
of its neighboring groups in subsequent transformations. In
accord with the design principles mentioned before, this
(3) (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.
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chemistry: Function follows form; Finn, M. G., Fokin, V. V., Eds. Chem.
Soc. Rev. 2010, 39, 1221À1408. (b) Agalave, S. G.; Maujan, S. R.; Pore,
V. S. Chem.;Asian J. 2011, 6, 2696.
ꢀ
(1) Multicomponent reactions; Zhu, J., Bienayme, H., Eds.; Wiley:
Weinheim, 2005.
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€
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(5) Click Chemistry for Biotechnology and Materials Science; Lahann,
J., Ed.; John Wiley & Sons: Hoboken, NJ, 2009.
r
10.1021/ol401151z
XXXX American Chemical Society

aspect of the CuAAC reaction provides opportunities to
construct new “ideal” MCRs.
applications in the fields of drug discovery,11 bioconjua-
tion, and sensors.12,13
Recently, we disclosed a general “click-and-activate”
protocol in Scheme 1: a click reaction on azide 1 provided
triazole 2 which led to activation of the leaving group
substituted conjugated double bond toward nuleophilic
attacktogive3inonepot.7 Thisconcept wasdemonstrated
in a facile synthesis of a triazolyl-pyridazinone library7a
and, later, in a one-pot assembly of triazole-fused pyrazi-
nopyridazindione tricycles.7b
Scheme 2. Wang’s Fluorogenic Click Reaction
Here we propose a conceptually different “click-and-
activate” protocol in Scheme 1: CuAAC of azide 4 should
make the methylene group in the resulting triazole 5 more
acidic and easily deprotonated by a base. Consequently,
the stabilized carbanion should be a good substrate to be
captured by a variety of electrophiles to afford 6 in one pot.
Compared to the first “click-and-activate electrophiles”
(CAE) protocol, this second “click-and-activate nucleo-
philes” (CAN) strategy should have even broader applica-
tion in terms of both the substrate scope and reaction types
involving stabilized carbanions.
Nevertheless, the existing preparations of 3-azidocou-
marins 7 require several synthetic steps involving strongly
acidic conditions to install the azide group.10 Apparently,
these procedures are tedious and particularly unsuitable for
the synthesis of acid labile 3-triazolyl-2-iminochromenes
which have not been reported in the literature. Here we
report a facile, one-pot synthesis of 3-triazolyl-2-imino-
chromene 9 directly from the condensation of 2-azidoa-
cetonitrile 10, acetylene 11, and salicylaldehyde 12 in a
tandem “CuAACÀaldolÀcyclizationÀdehydration” se-
quence (Scheme 3) as the first case study of our “click-and-
activate nucleophiles” (CAN) approach toward MCRs.
Scheme 1. “Click and Activate” in Two Different Ways
Scheme 3. One-Pot Synthesis of 3-Triazolyl-2-iminochromenes
Coumarins and chromenes are interesting biocompati-
ble heterocycles.8,9 Recently, 3-triazolylcoumarins 8 have
attracted particular attention after Wang’s group reported
an elegant fluorogenic CuAAC reaction between 3-azido-
coumarins 7 (as the profluorophore) and acetylenes
(Scheme 2).10 This fluorogenic chemistry has found many
In the literature, the CuI/NR3 combination has been a
convenient catalytic system for CuAAC reactions in or-
ganic solvents. Meanwhile, efficient deprotonation of the
activated methylene group is also desirable in an aldol
reaction. Therefore, it would be possible and beneficial to
use the same weak base to facilitate both steps in one pot.
Here we were also curious to see if the third component,
salicylaldehyde, had any effectontheCuAACstep(Table1).
When 0.1 equiv of 5-methylsalicylaldehyde 12a was added
to a 0.5 M ethanol solution of 2-azidoacetonitrile 10,14
1.0 equiv of phenylacetylene 11a, and 5 mol % of CuI,
(6) For examples of combining triazole formation with other reac-
tions to construct diverse structures, see: (a) Ramachary, D. B.; Barbas,
C. F., III. Chem.;Eur. J. 2004, 10, 5323. (b) Khanetskyy, B.; Dallinger,
D.; Kappe, C. O. J. Comb. Chem. 2004, 6, 884. (c) Akritopoulou-Zanze,
I.; Gracias, V.; Djuric, S. W. Tetrahedron Lett. 2004, 45, 8439. (d)
Gracias, V.; Darczak, D.; Gasiecki, A. F.; Djuric, S. W. Tetrahedron
Lett. 2005, 46, 9053. (e) Ackermann, L.; Potukuchi, H. K.; Landsberg,
D.; Vicente, R. Org. Lett. 2008, 10, 3081. (f) Donald, J. R.; Martin, S. F.
Org. Lett. 2011, 13, 852. (g) Donald, J. R.; Wood, R. R.; Martin, S. F.
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Kanter, F. J. J.; Lutz, M.; Spek, A. L.; Orru, R. V. A. Org. Biomol. Chem.
2008, 6, 3158.
(12) Droumaguet, C. L.; Wang, C.; Wang, Q. Chem. Soc. Rev. 2010,
39, 1233 and the references therein.
(7) (a) Qian, W.; Winternheimer, D.; Allen, J. Org. Lett. 2011, 13,
1682. (b) Qian, W.; Winternheimer, D.; Amegadzie, A.; Allen, J.
Tetrahedron Lett. 2012, 53, 271.
(8) O’Kennedy, R.; Thornes, R. D. Courmarins: Biology, Applica-
tions, and Mode of Action; Wiley &Sons: Chichester, 1997.
(9) For a recent review on chromane derivatives, see: Masesane, I. B.;
Desta, Z. Y. Beilstein J. Org. Chem. 2012, 8, 2166.
(13) For some recent examples in bioconjugation and sensors, see:
(a) Hong, V.; Presolski, S. I.; Ma, C.; Finn, M. G. Angew. Chem., Int. Ed.
2009, 48, 9879. (b) Du, L.; Ni, N.; Li, M.; Wang, B. Tetrahedron Lett.
2010, 51, 1152. (c) Kamaruddin, M. A.; Ung, P.; Hossain, M. I.;
Jarasrassamee, B.; O’Malley, W.; Thompson, P.; Scanlon, D.; Cheng,
H.-C.; Graham, B. Bioorg. Med. Chem. Lett. 2011, 21, 329. (d) Zhou, Y.;
Liu, K.; Li, J.-Y.; Fang, Y.; Zhao, T.-C.; Yao, C. Org. Lett. 2011, 13,
1290. (e) Morris, J. C.; McMurtrie, J. C.; Bottle, S. E.; Fairfull-Smith,
K. E. J. Org. Chem. 2011, 76, 4964.
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Wang, Q. Org. Lett. 2004, 6, 4603.
(11) (a) Peterson, L. B.; Blagg, B. S. J. Bioorg. Med. Chem. Lett. 2010,
20, 3957. (b) Soto-Ortega, D. D.; Murphy, B. P.; Gonzalez-Velasquez,
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(14) In all related experiments in this paper, the volatile and poten-
tially hazardous 2-azidoacetonitrile 10 was prepared by treatment of a 10
M chloroacetonitrile solution in DMF with 1 equiv of sodium azide for 2
h and was then diluted with ethanol and used directly without isolation.
B
Org. Lett., Vol. XX, No. XX, XXXX

virtually no effect was observed on the rate of triazole
formation (7% and 8% conversion at 2 h, entries 1 and 3,
respectively). Interestingly, a combination of 0.1 equiv of
12a and 0.1 equiv of triethylamine greatly accelerated the
CuAAC reaction (entry 4, Table 1). The reaction rate under
this condition is 2-fold faster than that in the presence of
only triethylamine, and over 20-fold faster than that in the
absence of the base, as indicated by the approximate t1/2 of
the three parallel reactions (∼1 h, ∼2 h, and >24 h for
entries 4, 2, and 1, respectively). It is known that deproto-
nated salicylaldehyes act as versatile bidentate ligands to
form a wide variety of Cu complexes with different coordi-
nation numbers and geometries.15 In the literature, some
ligands significantly accelerate the CuAAC reaction via
activation or stabilization of the catalytic Cu(I) species.16
So it is feasible that deprotonated 12a can play a similar
chelating role to promote the reaction, albeit to a lesser
extent. Another possible reason for this intriguing rate
acceleration could be the ability of 12a to buffer the basicity
of the triethylamine and facilitate the protonation of the
5-cuprated 1,2,3-triazole key intermediate in the final stage
of the CuAAC catalytic cycle.16f
The “click-and-activate” concept was demonstrated in
the following control experiments (Scheme 4). Treatment
of triazole 13a in ethanol with 1 equiv of 12a and 1 equiv
of triethylamine led to 85% conversion to 3-triazolyl-2-
iminochromene 9a in 24 h. In comparison, azide 10 failed
to afford any amount of 3-azido-2-iminochromene 14 under
the same conditions. Benzylnitrile was also tested, and only
a trace of conversion to 3-phenyl-2-iminochromene 15 was
detected after 24 h.
Scheme 4. Control Experiments on 2-Iminochromene Formation
Since the same base and solvent can be used in both
steps, it was convenient to run the entire three component
condensation in one pot (9a in Scheme 5) as follows: To a
1 M ethanol solution of 10 were added 11a (1.1 equiv), 12a
(1 equiv), and triethylamine (2 equiv). As expected from
control experiments, no desired transformation was ob-
served. Upon adding a catalytic amount of CuI (5 mol %),
the mutually promoted CuAACÀaldolÀcyclizationÀ
dehydration cascade was triggered. Both the intermediate
13a and the final product 9a were detected by HPLC in
5 min. After stirring for 24 h, the solvents were removed
under reduced pressure and the residue was suspended in
water and then filtered. The collected solid was sequen-
tially washed with 2% of NH4OH, water, and methanol
and was air-dried on the filtering funnel for 1 h to give
analytically pure product 9a (68% yield). It should be
mentioned that the easy purification by filtration and
washing was critical not only for operational simplicity
but also because attempts to purify the product by silica gel
column led to partial hydrolysis of the 2-iminochromene to
the corresponding coumarin.
Table 1. Additive Effects on CuAAC Reaction
In this three component condensation, two rings and
four bonds of three different types (one CÀC, one CÀO,
and two CÀN bonds) are formed in one pot. It is striking
that all four new bonds are formed with2-azidoacetonitrile
(10) which comprises only six heavy atoms. This small
molecule of remarkable bond-forming potential remains
latent in the presence of the other two components until a
catalyst is introducedto stitchthem together via our designed
pathway.
The easy execution of this three component reaction pro-
vides rapid access to substituent diversity on the 3-triazolyl-
2-iminochromene scaffold by condensing a variety of
salicylaldehydes 12 and alkynes 11 with 10 as shown
in Scheme 5. Both electron-donating groups such as
alkoxy- and electron-withdrawing groups such as bromo-,
dichloro-, and fluoro- are tolerated at various positions
on the salicylaldehyde component. On the other side, a
range of alkynes bearing electron-rich (9hÀj, 9n) and
electron-poor (9kÀm, 9o) aryl or heteroaryl groups can
be easily incorporated. Several less reactive alkyl sub-
stituted acetylenes were also installed in decent yields
(9f, 9pÀr).
a The conversion was calculated based on relative HPLC peak area
integrations of 13a and 11a at 215 nm.
(15) (a) Perez, E.; Moreno-Manas, M.; Sebastian, R. M.; Vallribera, A.;
Jutand, A. Eur. J. Inorg. Chem. 2010, 7, 1013. (b) Guo, H.; Zhao, G. Asian J.
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C. A.; Thies, W. R.; Shiemke, A. D. J. Am. Chem. Soc. 1981, 103, 4073.
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K. B.; Fokin, V. V. Org. Lett. 2004, 6, 2853. (b) Rodionov, V. O.; Presolski,
S. I.; Gardinier, S.; Lim, Y.-H.; Finn, M. G. J. Am. Chem. Soc. 2007, 129,
12696. (c) Rodionov, V. O.; Presolski, S. I.; Daz, D.; Fokin, V. V.; Finn,
M. G. J. Am. Chem. Soc. 2007, 129, 12705. (d) He, Y.; Bian, Z.; Kang, C.;
Cheng, Y.; Gao, L. Chem. Commun. 2010, 46, 3532. (e) Shao, C.; Wang, X.;
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Org. Lett., Vol. XX, No. XX, XXXX
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Scheme 5. Reaction Scope
Scheme 6. One-Pot Condensation Leading to Coumarin Trimer 16
Scheme 7. Further Elaboration
In conclusion, the “click-and-activate nucleophiles”
(CAN) protocol is a simple and powerful strategy in the
rational design of novel multiple component reactions. As
exemplified in this early case study, this approach utilizes
the subtle change in the electronic character following
triazole formation, along with the narrow distribution of
reactivity of azides and alkynes, to manage the reaction
sequence in an orderly fashion in one pot. Future efforts
willfocus on the designofothercatalytic MCRsemploying
this concept and postcondensation manipulations2b to
construct other complex scaffolds.
The bond-forming efficiency of this novel MCR was further
showcased in a one-pot synthesis of a star-shaped coumarine
trimer 16 by condensing tripropargylamine with an excess of
10 and 5-tert-butylsalicylaldehyde, followed by a facile hy-
drolysis in the same pot (Scheme 6). A total of 12 bonds were
formed in this pseudo-seven component assembly process.
In addition, this three-component condensation gener-
ated new functionalizable sites on 9. Further elaboration
was quickly explored to afford a more complex scaffold
(Scheme 7):Treatment of9rwith2-bromo-4-methylaniline
provided 17. Then, an intramolecular CÀH functionaliza-
tion on the triazole moiety led to a diazepine ring.17 Over-
all, a novel 6À6À7À5À6 pentacycle 18 was constructed in
a very short reaction sequence.
Acknowledgment. The authorsthank Dr. Randy Jensen
(Amgen) for help in 2D NMR studies and Dr. Iain
Campuzano (Amgen) for supplying HRMS data. D.W.
thanks Amgen Therapeutic Discovery for financial aid in a
summer internship.
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.
(17) (a) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V.
Org. Lett. 2007, 9, 2333. (b) Fiandanese, V.; Marchese, G.; Punzi, A.;
Iannone, F.; Rafaschieri, G. G. Tetrahedron 2010, 66, 8846.
The authors declare no competing financial interest.
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