Divergent and facile Lewis acid-mediated synthesis of N-alkyl 2-aminomethylene-1,3-indanediones and 2-alkylamino-1,4-naphthoquinones

Article abstract of DOI:10.1016/j.tetlet.2015.01.014

N-Alkyl 2-aminomethylene-1,3-indanediones and 2-alkylamino-1,4-naphthoquinones are known for their diverse and versatile bioactivities and applications. Traditionally, these two compounds were synthesized in separate routes using different materials. By e

Full text of DOI:10.1016/j.tetlet.2015.01.014

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
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Divergent and facile Lewis acid-mediated synthesis of N-alkyl
2-aminomethylene-1,3-indanediones and 2-alkylamino-1,
4-naphthoquinones
⇑
Qian Zhang, Cheng-Wei Tom Chang
Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT 84322-0300, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Alkyl 2-aminomethylene-1,3-indanediones and 2-alkylamino-1,4-naphthoquinones are known for
their diverse and versatile bioactivities and applications. Traditionally, these two compounds were syn-
thesized in separate routes using different materials. By employing Lewis acid, cycloaddition of alkyl
azides and 1,4-naphthoquinone can provide these two classes of compound in one-pot fashion. Among
the Lewis acids and conditions examined, TMSOTf under reflux offers the best overall yields. In addition,
the purification of both classes of compounds can be easily achieved using flash column chromatography
making this methodology feasible for scale-up synthesis of compounds with biological interests.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 8 December 2014
Revised 23 December 2014
Accepted 2 January 2015
Available online xxxx
Keywords:
2-Amino-1,4-naphthoquinone
Aminomethylene-1,3-indanedione
Antibacterial
Anticancer
Anti-inflammation
Molecules containing 1,4-naphthoquinone and 1,3-indanedione
scaffolds have long been attracting great interest due to their
diverse biological activities and applications.1 For example, com-
pounds bearing 2-alkyamino- or 2-arylamino-1,4-naphthoqui-
nones scaffolds have been studied for their activity as
antimycobacterial,2 neuro-protective,3 antiproliferative,4 and anti-
malarial5 agents (Fig. 1a). Aminomethylene-1,3-indanedione scaf-
folds can also been found in chemicals that exert various
bioactivities, including anti-inflammation,6 antibacteria,6 inhibi-
tion of b-amyloid7 and therapeutic for hypotension (Fig. 1b).8
In general, there are two main synthetic strategies for the syn-
thesis of 2-amino-1,4-naphthoquinones: one approach involves
the substitution of 2-halonaphthoquinones with amines (Scheme 1,
methods A and B).9 The second approach uses a conjugate addition
of amines to 1,4-naphthoquinone followed with an oxidation cata-
lyzed by molecular iodine under ultrasonic irradiation (Scheme 1,
method C).10 Method A requires the use of palladium whereas
method B needs the use of excess amines (7 equiv) and the yields
are modest (average yields around 40%). Method C appears to be
the best protocol to synthesize 2-amino-1,4-naphthoquinones.
For the synthesis of N-alkyl 2-aminomethylene-1,3-indanedi-
ones, several reported syntheses employ 1,3-indanedione, 6, and
a specific reagent N,N-dimethylformamide dimethyl acetal, 7 as
the starting compounds (Scheme 2, method A).11a–c In principal,
different alkyl groups can be introduced. Another method
involves the synthesis of 2-formyl-1,3-indanedione, 10 (Scheme 2,
method B).11d A subsequent imine formation allowed the synthesis
of N-alkyl 2-aminomethylene-1,3-indanediones. This method is
superior in offering more diverse N-alkyl groups.
Overall, these syntheses of N-alkyl 2-aminomethylene-1,3-
indanediones and 2-alkylamino-1,4-naphthoquinones require the
use of different starting materials, reagents and approaches, and
there is no concise method to produce both compounds concomi-
tantly in an one-step fashion. In 2003, Aube and co-worker reported
the synthesis of an enaminone, 12 from 2-cyclohexenone and ben-
zyl azide under the catalysis of Lewis acid (Scheme 3).12 Our group
has also discovered that cycloaddition of 1,4-naphthoquinone and
azides can lead to the formation of both 2-alkylamino-1,4-naphtho-
quinones 15 and N-alkyl 2-aminomethylene-1,3-indanediones 16
(Scheme 4).13,14 However, these two compounds were often not
observed in the employed conditions or isolated merely as the
minor products. Inspired by these results and the pressing
need for a simpler synthetic method, we decided to investigate in
Lewis acid-mediated cycloaddition of 1,4-naphthoquinone and
azides and tune the chemoselectivity to favor the synthesis of
N-alkyl 2-aminomethylene-1,3-indanediones and 2-alkylamino-
1,4-naphthoquinones.
We selected octyl azide (13a) as the model compound to react
with 1,4-naphthoquinone, and screened commonly used Lewis
acids and conditions to optimize the production of compounds
15a and 16a. Among the conditions we examined, we were
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2015.01.014
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zhang, Q.; Chang, C.-W. T. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.01.014

2
Q. Zhang, C.-W. T. Chang / Tetrahedron Letters xxx (2015) xxx–xxx
R
Cl
(a)
N
N
N
O
O
O
O
O
O
R
Aryl
N
N
H
N
H
O
neuro-protective agent3
antiproliferative agent 4
antimycobacterial2
R'
(b)
O
O
O
Ar
HN NH
O
O
HN
R
HN
NH
R
O
O
antiinflammatory6
antibacterial6
β-amyloid aggregation inhibition7
antihypertension8
Figure 1. Examples of molecules containing 2-alkyamino 1,4-naphthoquinone and aminomethylene-1,3-indanedione scaffolds.
Method A
R1
R2
O
O
R1 OH
R2 OH
R1
R2
O
O
O
O
O
O
Method A
Br
Br
Br
H2
NMe2
OMe
MeO C NMe2
+
Pd/C
H
6
7
8
1
2
O
O
R1
O
O
NH(CH2)2OH
H2N CH2CH2OH
NHR3R4
1. R3R4NH
2. air
9
3
R2
Method B
O
O
O
O
O
(CH3O)3CH
O
OH
Ac2O
excess R3R4NH
AcOH, ether
Method B
Method C
1
3
6
O
10
O
O
O
O
NHR
NHR3R4
I2, EtOH
H2N
R
+
R3R4NH
ultrasonic
11
4
O
O
5
Scheme 2. Examples for the synthesis of 2-aminomethylene-1,3-indanediones.
Scheme 1. Previous synthetic strategies for the synthesis of 2-amino-1,4-
naphthoquinones.
N2
Bn
delighted to discover that both of the compounds 15a and 16a can
be obtained at room temperature as the dominant products
(Table 1). Compounds 15a and 16a have very different polarities
and, thus, can be readily separated via flash column chromatogra-
phy. Among the Lewis acids examined, TMSOTf provided the best
combined yields of compounds 15a and 16a while FeCl3 and ZnCl2
offered no products (Table 1, entries 2, 6, and 7). Without the pres-
ence of Lewis Acid, there were no products isolated as well (Table 1,
entry1). In all cases and various conditions we examined, it is not
possible to tune the selectivity in favoring specifically compounds
15a or 16a although compounds 16a were the major products in all
cases. Interestingly, no cycloaddition products, 14a were ever
observed in the presence of Lewis Acid. Finally, by increasing reac-
tion temperature to reflux (40 °C, the bp of CH2Cl2) and using two
equivalents of TMSOTf, we have improved the combined yields of
compounds 15a and 16a to 94% (Table 1, entry 9), which will be
used as the optimized condition for further studies.
N
Bn N3
N
Lewis acid
N
HN
Bn
O
O
O
12
enaminone
Scheme 3. Lewis acid-mediated ring contraction reactions.
nitrogen atom, N-3 is prone to react with the Lewis acid giving
17. The intermediate 17 undergoes ring contraction, rearrange-
ment, and fragmentation, and leads to the formation of 16
(Scheme 5, route A). In a different route, deprotonation and frag-
mentation of 17 can provide 15 (Scheme 5, route B). The intramo-
lecular ring-contraction of 17 can occur alone whereas the
deprotonation of 17 needs to involve a base, which may explain
higher yields for 16 over 15 in all the examined cases.
The role of Lewis acid is believed to facilitate the degradation of
triazoline intermediate following the cycloaddition in a mecha-
nism similar to the one proposed previously (Scheme 5).12,15 In
the presence of Lewis acid (TMSOTf), the most nucleophilic
Following the identification of optimal condition, we decided to
examine more alkyl azides (13b–k) of different alkyl chain length
and functional groups (Table 2). All the tested alkyl azides offered
expected 2-alkylamino-1,4-naphthoquinones (15b–k) and N-alkyl
Please cite this article in press as: Zhang, Q.; Chang, C.-W. T. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.01.014

Q. Zhang, C.-W. T. Chang / Tetrahedron Letters xxx (2015) xxx–xxx
3
O
O
O
O
O
O
O
O
R
R
RN3
13
1
N
N
N
N
TMSOTf
R
N3
N
N
N
TfO-
N
N
3
17
TMS
triazoline
O
O
O
R
14
routeA
TMSOTf
O
major product
R
R
O
H
O
N
N
N
N
HN
R
N
N
TfO-
+
+
TMS
TfO-
NH
R
19
20
O
O
17
TMS
O
O
O
16
15
route B
minor products
Scheme 4. Cycloaddition of 1,4-naphthoquinone and azides.
O
R
R
N
N
N
TfOH
N
N
N
TMS
TfOH
N2
TMS
N2
18
O
O
Table 1
Optimisation studiesa
O
13a
O
C8H17N3,
Lewis acid
O
O
R
N
R
H
N
H
O
+
TMSOTf
16
O
15
TMSOTf
O
O
O
HN C8H17
N
N
Scheme 5. Proposed mechanism of Lewis acid-mediated cycloaddition.
N
C8H17
N
H
O
O
15a
C8H17
O
14a
16a
Table 2
Preparation of N-alkylated 2-aminomethylene-1,3-indanediones
O
Entry Lewis acid (equiv) Temp
Yield of 15a14 (%)a Yield of 16aa (%)
O
O
TMSOTf
(2 equiv )
HN
R
1
2
3
4
5
6
7
8
9
None
rt
rt
rt
rt
rt
rt
rt
0
24
12
14
9
0
45
31
33
29
0
+
+
RN3
TMSOTf (1)
BF3ÁEt2O (1)
AlCl3 (1)
SnCl4 (1)
FeCl3 (1)
ZnCl2 (1)
TMSOTf (1)
TMSOTf (2)
R
DCM
N
H
R = alkyl
13b-k
Reflux
O
O
O
16b-k
15b-k
0
0
0
Entry
Alkyl azide
Yield of 15 (%)
Yield of 16 (%)
Reflux 28
Reflux 35
49
59
1
2
3
4
5
6
7
8
9
C
C
C
C
16H33N3, 13b
15b16 (27)
15c14 (26)
15d (29)
16b (57)
16c (46)
16d (51)
16e (53)
16f (51)
16g (52)
16h17 (55)
16i (48)
16j (64)
16k13 (58)
12H25N3, 13c
11H23N3, 13d
10H21N3, 13e
C9H19N3, 13f
C6H13N3, 13g
a
The two products with different polarities could be easily separated by flash
chromatography. For entry 2, the yield is the isolated yield. For the rest, the yield is
15e14 (24)
15f14 (32)
15g14 (34)
15h14 (32)
15i17 (25)
15j (34)
estimated based on the integration of 1H NMR.
C5H11N3, 13h
CH3OC(O)CH2N3, 13i
CH3(OCH2CH2)4N3, 13j
Benzyl azide, 13k
2-aminomethylene-1,3-indanediones (16b–k) with combined
yields ranging from 70% to 98%. The separation of these two prod-
ucts can all be readily achieved due to the drastic polarity differ-
ences of these two products. In addition, all 2-alkyamino-1,
4-naphthoquinones, 15b–k, show a very distinct reddish color vis-
ible on TLC plates that further facilitate the purification process.
In conclusion, we have reported a divergent and facile synthesis
of two heterocyclic adducts from cycloaddition of 1,4-naphthoqui-
none and alkyl azides, N-substituted 2-amino-1,4-naphthoqui-
nones, and N-substituted 2-aminomethylene-1,3-indanediones.
Both classes of compounds have been known to exert therapeutic
bioactivities. In the presence of TMSOTf, both classes of compounds
with the variation of the N-alkyl groups can be obtained in a one-
step fashion with excellent combined yields. The developed
method employs cost-effective alkyl azides and 1,4-naphthoqui-
none as the starting materials. In addition, the purification of both
classes of compounds can be easily achieved using flash column
chromatography making this methodology feasible for scale-up
synthesis of lead compounds with biological interests.
10
15k3b (28)
General procedure for Lewis acid-mediated cycloaddition of
1,4-naphthoquinone and azides
0.5 g 1,4-naphthoquinone, 1.5 equiv of alkyl azide, and 2 equiv
of TMSOTf were dissolved into 20 mL methylene dichloride in a
50 mL round bottom flask. The reaction mixture was refluxed for
overnight. The reaction can be monitored by TLC (eluted with
Hexane/EtOAc = 3/1). 2-Alkylamino-1,4-naphthoquinones have Rf
values around 0.5 whereas N-alkylated 2-aminomethylene-1,3-
indanediones naphthoquinones have Rf values around 0.2. After
completion of the reaction, the reaction mixture was quenched
by adding aqueous NaHCO3 and extracted with DCM. The com-
bined organic layers were washed with water, brine, and dried
over anhydrous Na2SO4. The residue obtained after the evaporation
of solvent was subjected to flash chromatography. Gradient
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4
Q. Zhang, C.-W. T. Chang / Tetrahedron Letters xxx (2015) xxx–xxx
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