Synthesis of bioactive 1-alkyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-diones and N-aryl-2-aminomethylene-1,3-indanediones using water as the solvent

Article abstract of DOI:10.1016/j.tetlet.2014.01.129

Through a [2+3] cycloaddition reaction, a new environmentally friendly method was developed to enable the synthesis of bioactive 1-alkyl-1H-naphtho[2, 3-d][1,2,3]triazole-4,9-diones and N-aryl-2-aminomethylene-1,3-indanediones using water as the solvent w

Full text of DOI:10.1016/j.tetlet.2014.01.129

Accepted Manuscript
Synthesis of bioactive 1-alkyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-diones and
N-aryl-2-aminomethylene-1,3-indanediones using water as the solvent
Qian Zhang, Jaya P. Shrestha, Cheng-Wei Tom Chang
PII:
S0040-4039(14)00185-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.129
TETL 44162
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 January 2014
21 January 2014
28 January 2014
Please cite this article as: Zhang, Q., Shrestha, J.P., Chang, C.T., Synthesis of bioactive 1-alkyl-1H-naphtho[2,3-
d][1,2,3]triazole-4,9-diones and N-aryl-2-aminomethylene-1,3-indanediones using water as the solvent,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.01.129
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Synthesis of Bioactive 1-Alkyl-1H-
naphtho[2,3-d][1,2,3]triazole-4,9-diones and
N-Aryl-2-aminomethylene-1,3-indanediones
Using Water as the Solvent
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Qian Zhang, Jaya P. Shrestha, and Cheng-Wei Tom Chang*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of bioactive 1-alkyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-diones and N-
aryl-2-aminomethylene-1,3-indanediones using water as the solvent
Qian Zhang, Jaya P. Shrestha, and Cheng-Wei Tom Chang∗
Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, Utah 84322-0300, U.S.A.
ARTICLE INFO
ABSTRACT
Article history:
Received
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Received in revised form
Accepted
Through a [2+3] cycloaddition reaction, a new environmentally friendly method was developed
to enable the synthesis of bioactive 1-alkyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-diones and N-
aryl-2-aminomethylene-1,3-indanediones using water as the solvent with good yields and
minimum requirement of purification. This new green synthetic protocol is simple and suitable
for scale-up synthesis.
Available online
Keywords:
naphthoquinone
indanedione
bioactive
water as solvent
green chemistry
Water has not been the common choice of solvent for organic
reactions due to the solubility and reactivity problems of organic
reactants in aqueous medium. Nevertheless, from the perspective
of green chemistry, water is considered as a superior solvent for
reactions because of its low cost, safety and lack of
environmental concerns. For example, the pioneering work of
Breslow in 1980 showed that Diels-Alder reactions could be
achieved in aqueous medium.1 Since then, more attention has
been devoted to the investigation of conducting various organic
reactions in aqueous medium.2 In 2005, Sharpless and coworkers
reported that several types of cycloaddition reactions could be
accelerated in aqueous suspension without catalyst, even for
water-insoluble substrates. Those reactions were conducted in a
form of heterogeneous suspension that required vigorous stirring
(so-called “on water reactions”).3 It was postulated that the
hydrophobic effects4 of the reactants in water could accelerate the
reaction rates, and enhance the selectivity of reactions. Recent
examples have also demonstrated the advantage of using water as
solvents for improving the efficiencies of organic reactions.
These include [2+3] cycloaddition of nitrones and allenolates
without catalyst,5 1,3-dipolar cycloaddition reactions of
hydrophobic nitrones6 and 1,3-dipolar cycloaddition of azides
with terminal and 1-iodoalkynes using copper(I) catalyst.7
naphthoquinone derivatives as antibacterial,11 antifungal,12 and
antitumor agents.13 Furthermore, 1,4-naphthoquinone has also
been noted to uncouple mitochondria oxidative phosphorylation
leading to potential therapeutic applications.14 Compounds
bearing 2-methylene-1,3-indanedione or
2-methylene-4-
cyclopentene-1,3-diones scaffold have been studied for their
activity as antifungal agents,15 anticancer agents16 and therapeutic
for hypotension.17
O
O
OH
OH
O
OH
3
Naphthazarin
Antibacterial
Vitamin K1
O
O
O
O
Cl
Cl
O
Psychorubrin
Antitumor
Phygon
Antif ungal
OH
O
OMe
Bu
O
HN
R
Bu
O
O
hypertension
1,4-Naphthoquinone and 2-methylene-1,3-indanedione are
important structural units present in compounds that exert diverse
biological and pharmaceutical applications (Figure 1).8 For
instance, plants containing a naphthoquinone scaffold are widely
used in China and South American countries for treatment of
malignant and parasitic diseases.9 Several naphthoquinone
derivatives have been employed as inhibitors against vitamin K
TX-1926
anticancer
O
Fig. 1. Examples of molecules containing 1,4-naphthoquinone
and 2-methylene-1,3-indanedione scaffolds
Our group has previously reported the synthesis of 1-alkyl-
3,
1H-naphthotriazole-4,9-diones,
aminomethylene-1,3-indanediones,
and N-glycosyl-2-
5 that show prominent
dependent carboxylase.10 Other examples include the use of 1,4-
———
∗ Corresponding author. Tel.: 2-435-797-3545; fax: 2-435-797-3390; e-mail: tom.chang@usu.edu

2
Tetrahedron
anticancer and antibacterial activities (Scheme 1).18 The
110 °C. All the products were obtained in good purity without
column chromatography purification. However, the yields varied
depending largely on the chain length of the alky azides. Alkyl
azides are immiscible with water and have lower density than
water. Instead of forming a homogenous solution as the case in
DMF, alkyl azides float on top of water during the reaction which
will lead to the loss of azides through evaporation and, thus,
lower the yields. As the length of alkyl chain increases, the
boiling point of alkyl azide also increase and the yields improve,
likely due to lowering the loss through evaporation. For example,
for azides 2a-c, the yields were lower than corresponding
reactions in DMF. But when azides 2d-h were used, the yields
were very close to those conducted in organic solvent. As in the
case of hexadecyl azide 2h, the reaction could even be conducted
in refluxing water and still achieved good yield as compared with
the reaction carried out in DMF (entry 9, Table 1). In summary,
we have demonstrated that water can be used as a medium for the
cycloaddition/oxidation of 1,4-naphthoquinone and alkyl azides
with comparable efficiency as those conducted in DMF.
synthesis was carried out in organic solvents, such as DMF,
dioxane and toluene, using a [2+3] cycloaddition of alkyl azides
and 1,4-naphthoquinone followed with an oxidation in situ. We
have noted that cycloaddition of alkyl azides and 1,4-
naphthoquinone can lead to the formation of various heterocyclic
compounds upon the manipulation of reaction conditions, such as
temperature, solvent and the order of mixing reagents. In order to
optimize the yield for the desired product, 3, we have
investigated several synthetic protocols.18,19 For example, when
conducting the reaction in polar organic solvent, such as DMF,
the formation of by-products can be minimized (Scheme 1a). In
contrast, when conducting the reaction in a less polar organic
solvent like toluene, significant amounts of ring-expansion
products (N-alkyl-benzazepine-1,5-dione, 4) and ring contraction
products (N-alkyl-2-aminomethylene-1,3-indanedione, 5) were
also obtained in addition to compound 3 (Scheme 1b).
Scheme 2. Synthesis of 1-alkyl-1H-naphthotriazole-4,9-dione,
1-aryl-1H-naphthotriazole-4,9-dione
aminomethylene-1,3-indanedione using water as the solvent
and
N-aryl-2-
Scheme 1. Synthesis of 1-alkyl-1H-naphthotriazole-4,9-dione
and N-alkyl-2-aminomethylene-1,3-indanediones in organic
solvent
Table 1. Comparison of cycloaddition using alkyl azides in
DMF and waterd
Yield (%)b
DMFa
In an effort to enable the production of compound 3 in an
environmentally friendly process, we decided to investigate the
feasibility of conducting the optimized protocol in aqueous
medium (Scheme 2). To our delight, for most of the reactions
examined, we obtained comparable yields and the reactions
required minimum purification: no flash column chromatography
was needed for most cases. A distinct difference associated with
the type of azides employed was noted immediately. When alky
azides were used as the substrates, only compound 3 was
obtained in modest to good yields (Scheme 2a). However, when
aryl azides, 6 were used, compound 8 (ring contraction product)
were also obtained as the major by-products in several reactions
(Scheme 2b).
Entry
Alkyl Azide
Product
Waterat
70 °C
at 110 °C
1
2
3
4
5
6
C5H11N3, 2a
C6H13N3, 2b
C8H17N3, 2c
C9H19N3, 2d
C10H21N3, 2e
C11H23N3, 2f
3a
3b
3c
3d
3e
3f
40
49
62
38
54
47
21
26
32
34
37
52
The results from cycloaddition/oxidation of 1,4-
naphthoquinone and alkyl azides using water as the solvent are
summarized in Table 1 and the yields were compared with those
conducted in DMF. We have noted that the higher reaction
temperature may cause the formation of more by-products.
Therefore, all these reactions were conducted at 70 °C instead of

3
the reaction temperature increased to 90 °C, a mixture of ring
contraction product and cycloaddition products was obtained.
7
8
9
C12H25N3, 2g
C16H33N3, 2h
C16H33N3, 2h
3g
3h
3h
51
68
68
55
63
Since temperature can be a factor in controlling the product
formation, we have further examined the effect of temperature by
lowering the reaction temperature to 45 °C (Table 4). At this
temperature, the formation of products was very slow as
indicated by the low yields. Prolonged reaction time may help to
increase the yields. However, more ring contraction product, 8n
was also obtained. Therefore, we conclude that the cycloaddition
of aryl azides in aqueous medium is not selective for the
formation of compound 7. Nevertheless, selective formation of
compound 7 can be achieved using DMF as the solvent.
72c
aReference 19, 20. bIsolated yield. cReflux.. dGeneral condition:
0.2 g alkyl azide, 2 equiv. 1,4-naphthoquinone, 10 mL distilled
water. The suspension was stirred vigorously overnight.
With this promising preliminary result in hand, we decided to
study more alkyl azides with functional groups, such as hydroxy,
ester and aryl, attached to alkyl chain (Table 2). When using
water as the medium, all the tested azides offered comparable
yields of the desired products with the exception of compound
2m.
Table 3. Cycloadditions using aryl azidesb
Table 2. Cycloaddition using substituted alkyl azides in DMF
and waterc
Yield (%) of 3i-m
Cycloaddition Product
Entry
Azide
Yield of
7a (%)
Yield of 8
(%)
DMF at
110 °C
Water at
70 °Ca
Entry
1
Azide
Temp.
60 °C
7n21 (23)
8n22 (34)
8n (51)
51b
4721
2718b
56
54
32
phenyl azide,
6n (in H2O)
1
2
3
methyl azidoacetate, 2i
1,6-diazidohexane, 2j
6-azido-1-hexanol, 2k
90 °C 7n (trace)
60 °C
90 °C
60 °C
7n (27)
7n (35)
7o21 (35)
8n (trace)
phenyl azide,
6n (in DMF)
2
3
8n (20)
4-
8o23 (29)
4619
8121
33
48
azidotoluene,
6o (in H2O)
4
5
benzyl azide, 2l
anisyl azide, 2m
90 °C 7o (trace)
60 °C
7p21 (34)
8o (48)
8p24 (28)
8p (46)
8q25 (33)
8q (62)
8r26 (35)
8r (68)
4-
4
5
6
azidoanisole,
6p (in H2O)
aIsolated yield. bThis reaction was carried out at 80 °C. cGeneral
condition: 0.2 g alkyl azide, 2 equiv. 1,4-naphthoquinone, 10
mL distilled water. The suspension was stirred vigorously
overnight.
90 °C 7p (trace)
p-azido-
fluorobenzene
, 6q (in H2O)
60 °C
90 °C
60 °C
90 °C
60 °C
7q21 (22)
7q (0)
p-azido-
chlorobenzene
, 6r (in H2O)
7r21 (21)
7r (0)
To our surprise, when aryl azides were used as substrates for
cycloaddition, we also isolated N-aryl-2-aminomethylene-1,3-
indanediones, 8n-s (ring contraction products) as the main by-
products as well as the desired products, 7n-s (cycloaddition
products) (Table 3). However, these by-products were not
observed when using alkyl azides as substrates (Tables 1 and 2).
We believe temperature and solvent play the key roles here, so
we ran the same reactions at 90 °C. At this temperature, reactions
of aryl azides and 1,4-naphthoquinone provided the ring
1-azido-2,4-
dimethoxy-
benzene, 6s
(in H2O)
7s (54)
8s24 (24)
7
90 °C 7s (trace)
8s (52)
aThe yields from reactions conducted at 60 °C were estimated
1
based on the integration ratio from H NMR. The yields from
contraction
products,
N-aryl-2-aminomethylene-1,3-
reaction conducted at 90 °C were isolated yields. bGeneral
condition: 0.2 g alkyl azide, 2 equiv. 1,4-naphthoquinone, 10
mL distilled water. The suspension was stirred vigorously
overnight.
indanediones, 8n-s as the dominant product with trace amount of
cycloaddition product, 1-alkyl-1H-naphthotriazole-4,9-diones,
7n-s in some cases. Interestingly, the ring contraction product
was not observed when alkyl azides were employed. For
example, cycloaddition using hexadecyl azide at reflux
conditions on water gave exclusively the cycloaddition product
(entry 9, Table 1). On the other hand, our group has also
established an optimal protocol for the selective synthesis of
cycloaddition product from aryl azides. When DMF was used as
the solvent, conducting the cycloaddition at 60 – 65 °C offered
only the cycloaddition products (Table 3, entry 2).21 However, as
Table 4. Cycloaddition using phenyl azid in waterb

4
Tetrahedron
Supporting Data 1H and 13C spectra of the synthesized
O
O
O
O
compound, and other experimental procedures can be found with
the online manuscript.
N
N
6n
N
1
+
H2O
NH
References and Notes
1 Rideout, D.C.; Breslow, R. J. Am. Chem. Soc. 1980,
102, 7816-7817.
1-aryl-1H-naphthotriazole
-4,9-dione, 7n
-aryl-2-aminomethylene
N
8n
-1,3-indanedione,
2
(a) Li, C. J. Chem Rev. 1993, 93, 2023-2035; (b) Li, C.
Yield of
7n21 (%)a
Yield of 8n
(%)
J.; Chan, T. H. Organic Reactions in Aqueous Media, John
Wiley, New York, 1997; (c) Organic Synthesis in Water,
Thomson Science, Glasgow, 1998; (d) Lindstrom, U. M. Chem.
Rev. 2002, 102, 2751-2772; (e) Li, C. J. Chem. Rev. 2005, 105,
3095-3166.
Entry
Temp.
Time
1
2
45 °C
45 °C
overnight
1 day
8
0
6
10
3 Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.;
Kolb, H. C.; Sharpless, K. B. Angew. Chem. Int. Ed. 2005, 44,
3275-3279.
3
4
45 °C
45 °C
2 days
4 days
13
25
9
13
4
(a) Breslow, R. Acc. Chem. Res. 1991, 24, 159-164; (b)
Blokzijl, W.; Engberts, J. B. F. N. Angew. Chem. Int. Ed. Engl.
1993, 32, 1545-1579; (c) Otto, S.; Engberts, J. B. F. N. Org.
Biomol. Chem. 2003, 1, 2809-2820; (d) Pirrung, M. C.; Sarma,
K. D.; Wang, J. J. Org. Chem. 2008, 73, 8723-8730.
aThe yields were estimated based on the integration ratio
b
from 1H NMR. General condition: 0.2 g alkyl azide, 2 equiv.
1,4-naphthoquinone, 10 mL distilled water. The suspension
was stirred vigorously overnight.
5 Cruz, D. G.; Tejidor, D.; Armas, P.; Morales, E. Q.;
Tellado, F. G. Chem. Commun. 2006, 2798-2800.
In conclusion, we have demonstrated that [2+3] cycloaddition
6 Argyropoulou, E. C.; Sarridis, P.; Gkizis, P. Green
Chem. 2009, 11, 1906-1914.
between 1,4-naphthoquinone and alkyl/aryl azides can be carried
out in heterogeneous aqueous medium with good yield and
minimum requirement of purification. There is an interesting
difference between alkyl azides and aryl azides in terms of the
major products isolated at different temperatures. When alkyl
azides were used, 1-alkyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-
diones were the dominant products. When aryl azides were used,
N-aryl-2-aminomethylene-1,3-indanediones could be the major
products if the reactions were conducted at high temperature (90
°C). These two classes of compounds have been studied for their
biological activities. Investigation of the antibacterial and
antifungal activities of the synthesized compounds is being
pursued. We are currently also exploring the conditions for the
selective synthesis of 1-aryl-1H-naphtho[2,3-d][1,2,3]triazole-
4,9-diones and N-alkyl-2-aminomethylene-1,3-indanediones in
heterogeneous aqueous medium. Since the reactions conducted in
aqueous medium can readily offer a large quantity, the developed
protocols may expedite the discovery of practical products
following the screen for biological activities.
7
2010, 12, 2127-2130.
A´ lvarez, J. G.; D´ıez, J.; Gimeno, J. Green Chem.
8
(a) Lednicer, D. Strategies for Organic Drug Synthesis
and Design, John Wiley & Sons: New York, 1998; (b) Gringauz,
A. Introduction to Medicinal Chemistry, How does Drugs Act
and Why? Wile-VCH: Weinheim, Germany, 1997.
9
Babula, P.; Adam, V.; Havel, L.; Kizek, R.
Naphthoquinones and their Pharmacological Properties (in
Czech). Ceská a Slovenská Farmacie, 2007, 56, 114-120.
10 Dhaon, M. K.; Lehrman, S. R.; Rich, D. H.; Engelke, J.
A.; Suttie, J. W. J. Med. Chem. 1984, 27, 1196-1201.
11 (a) Zhang, C.; Ondeyka, J. G.; Zink, D. L.; Basilio, A.;
Vicente, F.; Collado, J.; Platas, G.; Bills, G.; Huber, J.; Dorso,
K.; Motyl, M.; Byrne, K.; Singh, S. B. J. Nat. Prod. 2008, 71,
1304-1307; (b) Shen, C.-C.; Syu, W.-J.; Li, S.-Y.; Lin, C.-H.;
Lee, G.-H.; Sun, C.-M. J. Nat. Prod. 2002, 65, 1857-1862.
General procedure for cycloaddition between 1,4-
naphthoquinone and alkyl/aryl azides using water as the solvent.
The alkyl/aryl azides (ca. 0.2 g) and naphthoquinone (2 equiv.)
were added into a 50 mL round bottom flask containing distilled
water (10 mL), and the reaction mixture was heated and stirred
vigorously for overnight. After being cooled to room
temperature, the solid was collected using Buchner funnel. The
collected solid was stirred in 30 mL of ethyl ether for 2 hours to
dissolve excess 1,4-naphthoquinone. The product was collected
using Buchner funnel and washed with another 30 mL
12
Chem. 2003, 51, 3824-3828.
Meazza, G.; Wedge, F. E.; Dayan, D. E. J. Agric. Food
13
(a) Lin, A. J.; Sartorelli, A. C. J. Med. Chem. 1976, 19,
1336-1338; (b) Paull, K. D.; Zee-Cheng, R. K. Y.; Cheng, C. C.
J. Med. Chem. 1976, 19, 337-339; (c) ) Fan, E.; Shi, W.; Lowary,
T. L. J. Org. Chem. 2007, 72, 2917-2928.
14
(a) Wrighton, M. S. Science. 1986, 231, 32-37.; (b)
Wallace, K. B.; Starkov, A. A. Annu. Rev. Pharmacol. Toxicol.
2000, 40, 353-388; (c) He, X.; Zhou, Y.; Zhou, Y.; Wang, L.; Li,
T.; Bi, Z.; Zhang, M.; Shen, T. J. Mater. Chem. 2000, 10, 873-
877.
Acknowledgment. We acknowledge the support from
Department of Chemistry and Biochemistry, Utah State
University.
15 Babu, K. S.; Li, X.-C.; Jacob, M. R.; Zhang, Q.; Khan,
S. I.; Ferreira, D.; Clark, A. M. J. Med. Chem. 2006, 49, 7877-
7886.

5
16
(a) Hori, H.; Nagasawa, H.; Ishibashi, M.; Uto, Y.;
22
1992, 7, 208.
Barnish, I. T.; Gibson, M. S. J. Chem. Res. Synop.
Hirata, A.; Saijo, K.; Ohkura, K.; Kirk, K. L.; Uehara, Y. Bioorg.
Med. Chem. 2002, 10, 3257–3265. (b) Inayama, S.; Mamoto, K.;
Shibata, T.; Hirose, T. J. Med. Chem. 1976, 19, 433-436.
23 Hassanein. A. Z. A. E. B. Synth. Commun. 2000, 30,
3883-3895.
24. Goldfarb. D. S. U.S. Pat. US20090163545 A1.
25 Gasjuna, L.; Karklina, A.; Gudriniece, E.; Paulins, J.
17 Baut, L.; Guillaume, S.; Creuzet, L.; Feniou, M. H.;
Pontagnier, C.; Prat, H. U.S. Pat. 4,758,561.
18 (a) Zhang, J.; Chang, C.-W. T. J. Org. Chem. 2009, 74,
685-695; (b) Zhang, J.; Chang, C.-W. T. J. Org. Chem. 2009, 74,
4414-4417.
Latvijas PSR Zinatnu Akademijas Vestis, Kimijas Serija. 1980, 1,
98-101.
26 Wolfgang, H.; Detlef, K. Archiv der Pharmazie.
Weinheim, Germany, 1982, 315, 68-78.
19 Fosso, M. Y.; Chan, K. Y.; Gregory, R. G.; Chang, C.-
W. T. ACS. Comb. Sci. 2012, 14, 231-235.
20 Chan, K. Y.; Zhang, J.; Chang, C.-W. T. Bioorg. Med.
Chem. Lett. 2011, 21, 6353-6356.
Click here to remove instruction text...
21 Shrestha, J. P.; Fosso, M. Y.; Bearss, J. and Chang, C.-
W. T. unpublished results.

6
Tetrahedron
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template box below.
Synthesis of Bioactive 1-Alkyl-1H-
naphtho[2,3-d][1,2,3]triazole-4,9-diones and
N-Aryl-2-aminomethylene-1,3-indanediones
Using Water as the Solvent
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Qian Zhang, Jaya P. Shrestha, and Cheng-Wei Tom Chang*
Fonts or abstract dimensions should not be