Facile and highly efficient method for the C-alkylation of 2-hydroxy-1,4-naphthoquinone to nitroalkenes under catalyst-free 'on water' conditions

Article abstract of DOI:10.1016/j.tetlet.2009.06.107

C-Alkylation of 2-hydroxy-1,4-naphthoquinone to various nitroolefins was achieved under catalyst-free employing 'on water' conditions. The mechanism for the formation can be explained on the basis of dual activation of nitroalkene and 2-hydroxy-1,4-naphth

Full text of DOI:10.1016/j.tetlet.2009.06.107

Tetrahedron Letters 50 (2009) 5116–5119
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Tetrahedron Letters
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Facile and highly efficient method for the C-alkylation of
2-hydroxy-1,4-naphthoquinone to nitroalkenes under catalyst-free ‘on water’
conditions
Deepak Kumar Barange, Veerababurao Kavala, B. Rama Raju, Chun-Wei Kuo, Chi Tseng, Yu-Chen Tu,
*
Ching-Fa Yao
Department of Chemistry, National Taiwan Normal University, 88, Section 4, Tingchow Road, Taipei 116, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
C-Alkylation of 2-hydroxy-1,4-naphthoquinone to various nitroolefins was achieved under catalyst-free
employing ‘on water’ conditions. The mechanism for the formation can be explained on the basis of dual
activation of nitroalkene and 2-hydroxy-1,4-naphthoquinones via hydrogen bonding. Simple reaction
conditions, high yields of the products, and environmentally benign medium are attractive features of
this method.
Received 2 March 2009
Revised 17 June 2009
Accepted 23 June 2009
Available online 27 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Water is the most economical and environmentally benign
solvent in the world. It exhibits unique reactivity and selectivity
which are different from those of the conventional organic
solvents.1 Recently, reactions of water-insoluble organic com-
pounds that occur in aqueous suspensions (‘on water’) have
received a great deal of attention because of their high efficiency
and straightforward synthetic protocols.2 The advantages of
conducting organic reactions ‘on water’ can be attributed due to
the enhancement in rate and efficiency, ease of operation, and
improved safety profile owing to the excellent heat capacity of
water.2f From the green chemistry perspective, highly efficient and
environmentally benign synthetic methodology is often regarded
as a goal in modern organic chemistry. Thus, development of an effi-
cient and convenient synthetic methodology employing ‘on water’
conditions is the subject of interest in the recent days.
Quinone and naphthoquinone moieties are prevalent motifs in
various natural products which are associated with diverse
biological activities.3 Among the naphthoquinones, 2-hydroxy-
naphthoquinone derivatives are the molecules of interest as pig-
ments4 and biological entities.5 Besides, they serve as potential
synthetic precursors of carbocyclic and heterocyclic quinones,
including 5H-benzo[b]carbazole-6,11-diones,6 naphtho[2,3-b]fur-
an-4,9-diones7, and benzo[b]naphtha[2,3-d] furan-6,11-diones.8
In particular, the derivatives of C-alkylated 2-hydroxynapthoqui-
nones possess inhibitory effects on Epstein-Barr virus early antigen
(EBV–EA) activation,9 in vitro activity against the parasites such as
Toxoplasma gondii and Plasmodium falciparum.10 Lapachol and
Atovaquone are two important compounds of C-alkylated 2-
hydroxynapthoquinone derivatives, which exhibit numerous
biological activities such as antibacterial, antiplasmodial, antioxi-
dant, antimicrobial, antiprotozoal, antimalarial, trypanocidal, and
anti-HIV.11 In perspective of their important biological features in
medicinal chemistry, a large number of quinone derivatives and
related compounds have been synthesized in order to explore the
novel bioactive agents with enhanced pharmacological properties.
The C-alkylation of nitroolefins with various electron-rich donors
is the well-known C–C bond forming reaction. The Michael or Fri-
edel–Crafts adduct of nitroalkanes obtained can be further trans-
formed into diverse functionalities. In particular, the conjugate
adducts derived from naphthoquinone and nitroalkenes serve as
important building blocks for several bioactive molecules.12 To our
knowledge, very few methods have been reported for this transfor-
mation which includes the use of base12 and organocatalyst.13 In
continuation of our interest on the development of green synthetic
methodologies14, herein we wish to report an efficient and cata-
lyst-free protocol for the C-alkylation of 2-hydroxynaphthoquinone.
At the outset of our study, our attention was mainly focused to
develop a catalyst-free system for the C-alkylation of 2-hydroxy-
1,4-naphthoquinone with nitroolefins. With this in mind, we
choose to examine the C-alkylation of 2-hydroxy-1,4-naphthoqui-
none
1 with the Michael acceptor 1-methyl-4-(2-nitrovinyl)
benzene 2e as the model substrates to establish the reaction
conditions (Table 1). Initially, the reaction was conducted under
solvent-free conditions, which resulted in poor yields of the
Michael adduct (entry 1). Further, the fate of the reaction was
examined with various organic solvents including toluene, tetrahy-
drofuran, ethanol, acetonitrile, and N,N-dimethyl formamide.
Significantly, lower product yields were obtained for the perspec-
tive reaction in toluene, tetrahydrofuran, and ethanol (entries 2–
* Corresponding author. Tel.: +886 2 29309092; fax: +886 2 29324249.
E-mail addresses: cheyaocf@ntnu.edu.tw, cheyaocf@yahoo.com.tw (C.-F. Yao).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.107

D. K. Barange et al. / Tetrahedron Letters 50 (2009) 5116–5119
5117
Table 1
Table 2
Solvent screening for the C-alkylation of 2-hydroxy-1,4-naphthoquinone with 1-
The C-alkylation of 2-hydroxy-1,4-naphthoquinone with nitroolefins
methyl-4-(2-nitrovinyl)benzene (2e)
O
O
R
CH3
NO2
Water
80 ºC
NO2
R
OH
OH
O
O
O
2a-m
3a-m
Water
80 ºC
O
NO2
1
O
NO2
Entry
1
R
Product16,17
Time (h)
10
Yielda,b (%)
90
OH
H3C
OH
1
2e
3e
O
3a
Entry
Solvent
Temp (°C)
Time (h)
Yieldsa,b (%)
2
3
3b
3c
12
16
85
88
1
2
3
4
5
6
7
8
Neat
Toluene
THF
EtOH
MeCN
DMF
H2O
80
80
65
80
80
80
25
80
24
24
24
24
24
16
24
12
20
30
45
55
70
92
40
97
O
4
5
3d
3e
12
12
90
90
H2O
CH3
a
All the reactions were conducted in 1 mmol scale.
H3C
Yields were determined from crude 1H NMR spectra using toluene as internal
b
standard.
6
3f
10
82
CF3
4). In contrast, improved yields were obtained in acetonitrile and
N,N-dimethyl formamide which may be due the presence of trace
amounts of water in the solvent. However, lower yields of the
products were accomplished with anhydrous acetonitrile and
N,N-dimethyl formamide. On the other hand, we tested the alkyl-
ation reaction employing ‘on water’ conditions and found that this
was the best in terms of yields and conversion in shorter reaction
times (Table 1, entry 8). Hence, 1.0 equiv of 2-hydroxy-1,4-naph-
tho quinone 1 was reacted with 1.2 equiv of 1-methyl-4-(2-nitro-
vinyl)benzene 2e under catalyst-free conditions on water at 80 °C
affording 2-hydroxy-3-(2-nitro-1-p-tolylethyl) naphthalene-1,4-
dione 3e in moderate to good yields. Having established the opti-
mal reaction conditions, a wide range of nitroalkenes were treated
with 2-hydroxy-1,4-naphthoquinone under the optimized reaction
conditions to obtain the corresponding 2-hydroxy-3-(2-nitro-1-
arylethyl) naphthalene-1,4-dione derivatives.16 The results are
summarized in Table 2.
7
8
3g
3h
10
10
85
86
Cl
Br
9
10
11
3i
8
20
18
86
84
88
NO2
3j
S
3k
O
12
3l
12
12
85
80
N
As can be seen from the Table 2, the Michael addition of 2-hydro-
xy-1,4-naphthaquinone proceeded well with various nitroolefins
(2a–m). The aliphatic nitroalkene reacted smoothly with 2-hydro-
xy-1,4-naphthoquinone under the present reaction conditions to
give the product in high yield (entry 1). The C-alkylation of 2-hydro-
xy-1,4-naphthoquinone was controlled by the electronic factors of
the b-nitrostyrenes. The reaction time varied according to the nature
of the substituent on the b-nitrostyrene. For example, the conjugate
addition of 2-hydroxy-1,4-naphthoquinone with b-nitrostyrene
containing electron-donating groups (OMe and Me) required longer
reaction times for the completion of the reaction (entries 3–5). How-
ever, nitroolefins bearing electron-withdrawing groups (Cl, Br, CF3,
and NO2) required relatively shorter reaction times to furnish the
Michael adducts in good yields (entries 6–9). Acid-sensitive furan
and thiophene moieties survived under the present reaction condi-
tions. Interestingly, the reaction conditions are equally efficient for
the sterically hindered substrates such as 1-(2-nitrovinyl) naphtha-
lene and 3-(2-nitrovinyl)-1-phenyl-1H-indole to afford their corre-
sponding alkylated product in good yields (entries 12 and 13). All
the products obtained were characterized by 1H NMR, 13C NMR,
LC–MS, and HRMS.
13
3m
Ph
a
All the reactions were conducted in 3 mmol scale.
Isolated yields.
b
the present reaction conditions, we obtained the trans diastereo-
mer as the sole product (precursor compound) in good yield
(Scheme 1). The trans isomer was confirmed by NOE studies. No
NOE enhancement was observed by saturation of either of the
protons H3 or H2, which showed that H3 and H2 are aligned in
trans orientation. The relative configuration of the product can be
*
*
assigned as 2S 3R .
We assume that the water may act as amphiphilic dual catalyst
in this reaction.2g (Scheme 2). Hence, we speculate that water may
activate the nitro group of b-nitrostyrene and the hydroxyl group
of 2-hydroxynaphthoquinone through hydrogen bonding. This
facilitates the addition of 2-hydroxynaphthoquinone to the b-
nitrostyrene to form the intermediate (A) which upon losing the
proton gives the adduct (B). The adduct (B) abstracts the proton
either from water or from 2-hydroxynaphthoquinone to afford
aci-nitro compound (C). This aci-nitro compound tautomerizes to
furnish the nitro alkylated product.
Further, the structure of the representative compound 3i was
confirmed by single crystal X-RD analysis shown in Figure 1.
It was reported earlier that the product (3n) furnished by the
reaction of 2-hydroxynaphthoquinone (1) with 1-nitrocyclohexene
(2n) served as the precursor compound of 5H-benzo[b]carbazole-
6,11-dione, which exhibited antineoplastic activity.12 Hence, under
Further to examine our speculation, we conducted the reaction
of 1-methyl-4-(2-nitrovinyl)benzene (2e) with 2-hydroxynaptho-
quinone in D2O (Scheme 3). We were able to obtain only the deu-
terated product which can be detected from the crude 1H NMR and

5118
D. K. Barange et al. / Tetrahedron Letters 50 (2009) 5116–5119
Table 3
*
Comparison of 1H NMR and 13C NMR spectra of compounds 3e and 3e
*
Compound 3e
Compound 3e
1H Spectrum
13C Spectrum
C2
5.43 (dd, J = 13.2, 9.0 Hz, 1H)
5.29 (dd, J = 9.0, 6.4 Hz, 1H)
5.09 (dd, J = 13.2, 6.4 Hz, 1H)
77.3
5.25 (d, J = 6.8 Hz, 1H)
C3
C2
C3
5.09 (d, J = 6.8 Hz, 1H)
76.7 (t, J = 23.0 Hz)
38.2
38.7
the Table 3. D2O experiment supports that this reaction follows
path II mechanism as shown in Scheme 2.
This method is also amenable for the large-scale reactions. In
this context, we performed the reaction of 2-hydroxynapthoqui-
none (50 mmol) with 1-methyl-4-(2-nitrovinyl) benzene (2e)
(60 mmol) in 50 mL of water under the present conditions and
we obtained the product (3e) in high yield (85%).
In summary, we have developed an efficient and catalyst-free C-
alkylation of 2-hydroxy-1,4-naphthoquinones to nitroalkenes
employing ‘on water’ conditions to afford 2-hydroxy-3-functional-
ized naphthoquinones in good yields. Simple reaction conditions,
catalyst-free and easy isolation of the compounds are the attractive
features of this methodology. Moreover, this protocol was also
proved to be efficient on a multigram scale, which will be applica-
ble for industrial processes.
Figure 1. X-ray crystal structure of 3i (ORTEP view).15
O
O
NO2
Water
80 ºC / 16h
NO2
OH
OH
O
O
1
2n
3n (80%)
Acknowledgment
Scheme 1. Reaction of 2-hydroxy-1,4-naphthoquinone with 1-nitrocyclohexene.
Financial support for this work by the National Science Council
of the Republic of China is gratefully acknowledged.
Supplementary data
O
O
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.107.
N
O
O
H
N
-H
O
H
O
N
H
O
O
H
O
O
H
H
O
O
H
H
O
O
O
H
H
H
References and notes
O
O
H
O
O
H
H
H
A
B
O
H
Path II
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O
O
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NO2
N
OH
O
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H
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OH
O
C
Scheme 2. Plausible mechanism for the formation of nitroalkylated 2-
hydroxynaphthoquinone.
13C NMR spectrum (Table 3). Spectral comparison of deuterated
product (3e ) and undeuterated product (3e) can be seen from
*
CH3
O
O
NO2
D2O
NO2
D
80 ºC, 10 h
OH H3C
OH
O
O
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1
2e
3e* (85%)
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nyl)benzene (2e) in D2O.

D. K. Barange et al. / Tetrahedron Letters 50 (2009) 5116–5119
5119
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16. General procedure for the C-alkylation of 2-hydroxy-1,4-naphthoquinones:
A
mixture of 2-hydroxy-1,4-naphthoquinone (1) (3 mmol) and b-nitrostyrene
(2) (3.6 mmol) was suspended in 5 mL of water, and the reaction mixture was
heated at 80 °C. The progress of the reaction was monitored by TLC. After
completion of the reaction, solid product obtained was filtered and washed with
water (2 Â 10 mL) and n-hexane (3 Â 10 mL). Then the solid was dried under
vacuum to obtain the product (3) in almost pure form. In case of liquid
compounds, the crude reaction mixture was diluted with EtOAc (50 mL) and
washed with water (3 Â 10 mL). The organic layer was dried over anhydrous
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17. Spectral data: 2-hydroxy-3-(4-methyl-1-nitropentan-2-yl)naphthalene-1,4-dione
(3a). Light brown solid; mp: 80–82 °C. 1H NMR (400 MHz, DMSO-d6) d 11.48
(br s, 1H), 7.99 (d, J = 7.4 Hz, 2H), 7.87–7.78 (m, 2H), 4.92 (dd, J = 12.3, 9.2 Hz,
1H), 4.75 (dd, J = 12.3, 6.0 Hz, 1H), 4.04–3.96 (m, 1H), 1.46–1.38 (m, 2H), 1.36–
1.29 (m, 1H), 0.86 (d, J = 6.4 Hz, 3H), 0.82 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6) d 183.9, 180.7, 156.8, 134.7, 133.3, 131.9, 129.8, 126.0, 125.7, 120.7,
77.7, 38.7, 32.1, 25.5, 23.2, 21.7. MS (ESI) (m/z) (relative intensity) 303 (M+, 24),
256 (35), 241 (50), 231 (100), 200 (97), 187 (38). HRMS (ESI) calcd for
C16H17NO5Na (M+Na)+ 326.1015, found: 326.1004. 2-Hydroxy-3-(2-nitro-1-
phenylethyl)naphthalene-1,4-dione (3b). Yellow solid; m.p.: 154–156 °C. 1H
NMR (400 MHz, DMSO-d6) d 11.50 (br s, 1H), 7.94–7.92 (m, 2H), 7.77–7.71 (m,
2H), 7.40 (d, J = 6.9 Hz, 2H), 7.30 (t, J = 6.8 Hz, 2H), 7.21 (d, J = 6.7 Hz, 1H), 5.47
(dd, J = 13.2, 8.7 Hz, 1H), 5.31 (dd, J = 8.7, 6.9 Hz, 1H), 5.16 (dd, J = 13.2, 6.9 Hz,
1H). 13C NMR (100 MHz, DMSO-d6) d 183.8, 180.9, 156.4, 138.5, 134.8, 133.3,
131.7, 129.8, 128.6, 127.9, 127.1, 126.0, 125.8, 120.8, 76.7, 38.6. MS (ESI) (m/z)
(relative intensity) 323 (M+, 13), 322 (100), 275 (77). HRMS (ESI) calcd for
C18H13NO5Na (M+Na)+ 346.0713, found: 346.0691.
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