TABLE 1. One-Pot Synthesis of 1-Alkyl 1H-Naphtho[2,3-d][1,2,3]-
triazole-4,9-dione
SCHEME 2. Proposed Routes for the Formation of 3 and 7
entry
alkyl bromides
isolated yield (%) ratio of 3/7a
1
2
3
4
5
6
7
benzyl bromide (6a)
butyl bromide (6b)
pentyl bromide (6c)
octyl bromide (6d)
dodecayl bromide (6e)
hexadecayl bromide (6f)
3a,7 96%
100/0
3.0/1
4.7/1
3b, 50% 7b, 25%
3c, 41% 7c, 12%
3d, 52% 7d, 10%
3e, 64% 7e, 4%
3f, 68% 7f, 4%
8.2/1
10.0/1
14.8/1
8.1/1
intermediate, sodium naphtho[2,3-d][1,2,3]triazole-4,9-dione, 8
(path a, Scheme 2). An SN2 nucleophilic substitution via either
N-1/N-3 or N-2 of 8 toward the corresponding alkyl bromides
yields products 3 or 7, respectively. In a different route, alkyl
azide can be formed first via an SN2 nucleophilic substitution
of azide (N3-) and then offer only product 3 according to our
previously reported cycloaddition/oxidation process7 (path b,
Scheme 2). Finally, a Michael addition of azide with naphtho-
quinone under prolonged reaction and higher temperature can
lead to the formation of 2-amino-1,4-naphthoquinone, 10 (path
c, Scheme 2).11a,c
6-hydroxyhexyl bromide (6g) 3g, 58% 7g, 5%
a The ratio of 3/7 was determined based on the integral ratio of 1H
NMR from the mixture of 3 and 7.
nent method has also been shown to selectively offer 1- and
2-substituted 1,2,3-triazoles.13 Both reports, however, do not
have the structural scaffold of naphthoquinone fused with 1,2,3-
triazole that resembles 3 or 7. Molecules with the integration
of quinone or naphthoquinone scaffolds are of particular interest
due to their capability of disrupting the redox process of
ubiquinone leading to their potential uses as antimicrobial and
anticancer agents.8 Multistep syntheses for the structural scaffold
that is close to compound 3 have been reported.10 To our
knowledge, we only noticed a compound similar to 7, 2-amino
2H-naphtho[2,3-d][1,2,3]triazole-4,9-dione, in the literature,
which was also prepared via a multistep fashion.14 Therefore,
our method offers an unique and simple syntheses of not only
compound 3 but also the unusual compound 7.
Although our one-pot protocol provided a convenient access
to both compounds 3 and 7, a potential problem emerged. In
all cases, we encountered difficulty in the separation of 3 and
7, which displayed almost identical Rf values on TLC and were
mostly inseparable with use of silica gel-based column chro-
matography when eluted with commonly used organic solvents.
An interesting study on the tautomerism of 1,2,3-triazoles has
reported that 1-methylbenzotriazole is more basic than 2-me-
thylbenzotriazole.15 Thus, we speculated that compounds 3 and
7 should exert different basicity, which could be used as means
to achieve their separation. To our delight, a mixture of 3 and
7 can be easily separated and purified by using column
chromatography eluted with a slightly acidic solution of hexane/
CH2Cl2/HOAc.
Potential electrophiles that can be used in our one-pot protocol
were also examined. These electrophiles include epoxides
(11-13), 4-mesylated N-tert-butoxycarbonylpiperidine (14),7
1-chloroadamantane (15), methyl bromoacetate (17), ethyl
bromoacetate (18), diethyl 2-bromoethylphosphonate (19), and
2,3,4,6-tetra-O-acetyl-D-glucopyranosyl bromide, 20 (Table 2).
Among the three epoxides tested, only propylene oxide 11
provided the expected products (entries 1-3, Table 2). When
compound 147 was employed, both 1- and 2-alkyl 2H-naph-
tho[2,3-d][1,2,3]triazole-4,9-diones, 3k and 7k, were obtained
(entry 4). However, the yield was much lower than other
examples we examined in Table 1. The reason could be
attributed to the slower rate of nucleophilic substitution of the
secondary mesylated group as compared to that of the primary
alkyl bromides, which led to the decomposition of the ionic
intermediate 8 and, hence, the lower yields. For the same reason,
when 1-chloroadamantane, 15, was employed, no reaction was
noticed (entry 5). Nevertheless, 1-azidoadamantane, 16, can still
react with naphthoquinone and form 1-adamantyl 1H-naph-
tho[2,3-d][1,2,3]triazole-4,9-dione, 3l, with 52% yield by using
our previously reported method.7 These results imply that
cycloaddition of azide (N3-) and naphthoquinone (path a,
Scheme 2) should occur much faster than the SN1 nucleophilic
substitution of azide (N3-) or 8 toward 1-chloroadamantane.
Surprisingly, when compounds 17 and 18 were used, we
did not obtain the expected products from alkyl R-azidoac-
etate generated in situ (entries 6 and 7). Rather, the products
isolated were determined to be 1-methyl 1H-naphtho[2,3-
d][1,2,3]triazole-4,9-dione, 3m, and 2-methyl 2H-naphtho-
[2,3-d][1,2,3]triazole-4,9-dione, 7m, generated from 17, and
1-ethyl 1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione, 3n, and
2-ethyl 2H-naphtho[2,3-d][1,2,3]triazole-4,9-dione, 7n, pro-
duced from 18. The ionic intermediate 8 can be viewed as a
“soft” nucleophile.20,21 The ester function group of 17 and
Naphthoquinone can react with azido compounds via a [2+3]
cycloaddition,11b,c or with various nucleophiles through a
Michael addition and/or oxidation process.11c,16 Judging from
the structure of azide,17 and the isolated products, we favor the
cycloaddition mechanism. The formation of compounds 3 and
7 occurred likely through an initial cycloaddition of azide (NaN3)
with naphthoquinone followed with an oxidation by excess
naphthoquinone leading to the formation of an ionic pair
(13) Kamijo, S.; Huo, Z.; Jin, T.; Kanazawa, C.; Yamamoto, Y. J. Org. Chem.
2005, 70, 6389–6397.
(14) Sun, D.; Watson, W. H. J. Org. Chem. 1997, 62, 4082–4084.
(15) Tomas, F.; Abboud, J.-L. M.; Laynez, J.; Notario, R.; Santos, J.; Nilsson,
S. O.; Catalan, J.; Claramunt, R. M.; Elguero, J. J. Am. Chem. Soc. 1989, 111,
7348–7353.
(16) (a) Liu, B.; Ji, S.-J. Synth. Commun. 2008, 38, 1201–1211. (b) del Corral,
J. M. M.; Castro, M. A.; Gordaliza, M.; Martin, M. L.; Gualberto, S. A.; Gamito,
A. M.; Cuevasc, C.; Feliciano, A. S. Bioorg. Med. Chem. 2005, 13, 631–644.
(c) Parker, K. A.; Sworin, M. E. J. Org. Chem. 1981, 46, 3218–3223.
(17) Pauling, L.; Brockway, L. O. J. Am. Chem. Soc. 1937, 59, 13–20.
(18) Although no expected products were obtained, we did isolate 1,4-bis((2-
hydroxy-3-phenoxy)propoxy)naphthylene, 21, as the major component. Please
refer to the SI for spectroscopic data of this compound.
(19) Similar to entry 2, we isolated 1,4-bis((2-hydroxy-2-phenyl)ethoxy)naph-
thylene, 22, as the major component. Please refer tothe SI for spectroscopic
data of this compound.
J. Org. Chem. Vol. 74, No. 11, 2009 4415