Synthetic Method to Form 2,2′-Bis(naphthoquinone) Compounds

Article abstract of DOI:10.1021/acs.joc.7b02501

We have discovered a transition-metal-free approach to the synthesis of 2,2′-bis(naphthoquinones) using a Diels-Alder reaction of conjugated ketene silyl acetals with benzoquinone. Its monomer analogue can also be synthesized by simply increasing the equivalents of benzoquinone.

Full text of DOI:10.1021/acs.joc.7b02501

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A synthetic method to form 2,2‘-bis(naphthoquinone) compounds
Vishwajeet Jha, Navneet Goyal, Cheryl K. Stevens, Edwin Stevens, and Jayalakshmi Sridhar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02501 • Publication Date (Web): 07 Nov 2017
Downloaded from http://pubs.acs.org on November 10, 2017
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A synthetic method to form 2,2’-bis(naphthoquinone) compounds
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Vishwajeet Jha†, Navneet Goyal†, Cheryl K. Stevens‡, Edwin Stevens‡ and Jayalakshmi
Sridhar†,*
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†Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA
70125.
‡Department of Chemistry, Western Kentucky University, Bowling Green, KY
*Corresponding author: Ph: 504-520-7519, Email: jsridhar@xula.edu
O
OEt
reaction
Diels-Alder
R
OH
O
O
O
HWE-olefination
LDA,
TMSO
R
1,4-Benzoquinone
equivalents)
R
R
O
OH
(1-2
TMSCl
ABSTRACT: We have discovered a transition metal free approach to the synthesis of 2,2’-
bis(naphthoquinones) using Diels-Alder reaction of conjugated ketene silyl acetals with
benzoquinone. Its monomer analogue can also be synthesized by simply increasing the
equivalents of benzoquinone.
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The pharmacology of quinone molecules has generated significant interest over the past few
years as they serve as electron accepters in electron transport chain that are essential to nearly
every living organism.1 Many of these compounds have been reported in the elucidation of
biological mechanisms and help in development of the lead compounds for different therapeutic
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agents.
Quinone moieties have been found in several natural products2 including
sesquiterpenes3, the kinamycins4, and terphenylquinones5 etc. with several of them showing
biological or pharmacological activity. They are key structural components of numerous
therapeutic agents impacting many disease conditions, viz antimicrobial, antiparasitic, anti-
tumor, inhibition of PGE2 biosynthesis and anti-cardiovascular diseases6. Additionally, many
natural and artificial coloring substances (dyes and pigments) are quinone derivatives. Among
naturally occurring quinones7a, 2,2’-binaphthoquinones, including bilawsone (2),7b 3,3’-
bijuglone (3),7c-d biramentaceone (4),7e 3,3’-biplumbagin (5),7f-g mamegakinone (6),7h etc were
isolated from various plant species and found to exhibit different biological activities (Figure 1).
The synthesis of these bisquinone molecules has been a challenge.8a-k Tanoue et. al. have
reported the synthesis using oxidation of alkoxy-naphthols with AgO-40% HNO3,8h whereas
Takeya et. al. have reported the synthesis using oxidative dimerization of 1-naphthols with
SnCl4/O2.8i Recently, Tsubaki et. al. have shown its synthesis using Stille type reaction with
vinylstannanes8k (for schematic representation of literature precedence of bis(naphthoquinone)
syntheses, see scheme S1, supporting information). However, all these reports suffer from one or
more drawbacks such as use of expensive reagents, require specially modified starting materials
(substituted naphthalene derivatives, substituted naphthoquinones), use of toxic heavy metals
catalyst (like Pd, Pb, Sn catalyst) etc. In addition, they may not be always suitable for large-scale
synthesis. Biosynthetic pathway to these classes of compounds involves oxidative biaryl
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coupling of 1-naphthols to 2,2’-binaphthols followed by subsequent oxidation to 2,2’-
naphthoquinones.9
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Our interest in the design and development of new pharmacotherapeutics as kinase inhibitors
prompted an investigation into the synthesis of napthoquinones and anthraquinones, which
revealed a series of quinone analogs with excellent growth inhibition potency for refractive
breast tumors and showing high selectivity for inhibition of the PIM kinases.10
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Figure 1. Structure of quinone and bis(naphthoquinone) derivatives
O
O
HO
OH
O
O
OH
O
O
O
OH
O
OH
O
O
1
2
3
bilawsone
3,3'-bijuglone
O
OH
O
O
O
O
O
O
OH
O
OH
O
O
OH
OH
OH
O
O
4
6
5
biramentaceone
mamegakinone
3,3'-biplumbagin
We have previously reported the synthesis of a quinone derivative (compound 1, Figure 1) using
Diels-Alder reaction which showed very promising therapeutic potential for cancer in in-vitro
studies (scheme 1).11 Docking studies of compound 1 revealed that the methyl side chain was
placed in a hydrophobic environment and increase in the length and branching of the side chain
at C-7 could further enhance its activity.
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Scheme 1: Synthesis of compound 1 using Diels Alder Reaction
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8
9
OH
O
O
1,4-Benzoquinone
(a)
MeOOC
oC
-
LDA, THF, 78
CH2Cl2
TMSO
HCl, CH OH
(b)
3
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then TMSCl
7
O
8
1
7
53%
from
yield
Scheme 1 was employed for the preparation of the designed compounds. The synthetic strategy
started with commercially available 2-heptanone 9a which on Horner-Wadsworth-Emmons
(HWE) olefination gave the olefin 10a in 87% yield with a Z/E ratio of 1/4 (scheme 2).12 The
olefin 10a was treated with LDA and then trapped with TMSCl to give diene 11a, The diene 11a
was then subjected to the Diels-Alder reaction with benzoquinone13 as a dienophile afforded the
ketal 12a and subsequent cleavage of the ketal 12a with 1 N HCl should have yielded the
product 14a. The 1H-NMR of this product did not corresponding to the structure 14a where in
one proton belonging to the quinone ring was missing (Figure S1, see supporting information).
13C and DEPT NMR were not conclusive. The crystalized product was subjected to X-ray
crystallographic analysis, which clearly established the product to be a dimerized quinone
derivative 13a instead of its monomer analogue 14a (Figure S2, see supporting information).
The overall yield of the dimer product in this reaction was 67%. Changes to the reaction
conditions such as the use of different solvent, increasing/decreasing the reaction time,
concentration of HCl only lead to the formation of the dimerized product (Table 1).
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Scheme 2: Synthetic route for the formation of bis(napthoquinones)
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6
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8
OEt
1,4-Benzoquinone
LDA, THF
EtOOC
O
o
equivalents)
(1-2
Triethyl
phosphonoacetate
-
78 C
TMSO
R
R
R
CH2Cl2
o
rt
NaH, THF, 0 C to
then TMSCl
9
9
10a-e
87%
(Z/E:1/4)
11a-e
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9a:
9b:
9c:
9d:
9e:
R= butyl
R=methyl
R=isobutyl
R=isopropyl
R=pentyl
O
O
O
TMSO
OEt
OH
O
O
R
OH
O
O
HCl, CH3OH
67
R
R
R
OH
%
O
12a-e
14a-e
13a-e
DImer Formed
Not Formed
Only
Table 1: Modifications to reaction conditions for the Diels Alder reaction and subsequent
treatment with HCl.
No.
Solvent Reaction Concentration of Equivalents of Yield of 13a Yield of 14a
time
3h
Hydrochloric acid
Benzoquinone
(%)
47
21
56
67
65
64
59
62
34
16
(%)
0
1
2
CH3OH
CH2Cl2
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
1 N
1 N
1 N
1 N
1 N
1 N
1 N
2 N
Neat
1 N
1
1
3h
3h
3h
3h
1h
16h
3h
3h
3h
0
3
1.25
1.5
2
0
4
0
5
0
6
1.5
1.5
1.5
1.5
5
0
7
0
8
0
9
0
10
40
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The scope of this reaction was examined using various ketones bearing different side chains
(Table 2). It was observed that the reaction sequence displayed a wide substrate scope and was
compatible with varying side chains that were short, long or branched. Good yields (60 to 70%)
were obtained for all the substrates (Table 2). However, in case of 13b and 13d, we do observe
formation of monomer analogue as a minor product (6% yield for 14b and 8% yield for 14d).
The dimerization of compound 1 was attempted by changing the reaction condition without any
success. Under all attempted variations in reaction conditions only the monomer derivative was
obtained.
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Table 2: Substrate scope of dimerization reaction
R
Compound No.
Product
Yield (%)
O
OH
O
67
Butyl
13a
O
OH
O
O
OH
O
60
61
Methyl
13b
O
OH
O
O
OH
O
Isobutyl
13c
13d
O
OH
OH
OH
O
O
OH
O
Isopropyl
70
69
O
O
O
OH
O
Pentyl
13e
O
O
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We believe the Diels Alder reaction between compound 11 and 1,4-benzoquinone takes place in
the traditional manner to yield the cyclohexene product 12. The addition of 1N HCl facilitates
the cleavage of the ketal and subsequent enol intermediate I (Scheme 3). Aromatization of the
cyclohexadiene ring in intermediate I requires the use of oxidizing reagents. It has been shown
that residual excess benzoquinone present in the reaction medium acts as the oxidizing agent
leading to the formation of the intermediate II (Scheme 3, step 1). Intermediate II (NQ) can also
act as an autooxidizing agent due to the presence of a quinone ring in the structure and this
intermediate can participate in the autooxidation of intermediate I to intermediate II (Scheme 3,
step 2) resulting in the formation of a hydroquinone intermediate III (HNQ). Any protonation of
the carbonyls of the quinone will preferably happen on the carbonyl that is on the opposite side
to the hydroxyl group of the adjacent ring to give the intermediate IV. This is due to the carbonyl
group ortho to the phenolic group having an H-bond with the hydroxyl group. Michael addition
on the protonated intermediate IV by the intermediate III will lead to the formation of the
intermediate VI. A further oxidation of this intermediate with benzoquinone yields the dimerized
binaphthoquinone product. The plausible mechanism for the synthesis of dimer is shown in
scheme 3.
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The proposed mechanism is greatly dependent on the oxidizing property of benzoquinone at
multiple points and that the unreacted benzoquinone present in the reaction medium plays the
key role in product formation. Not only does it act as a dienophile for the Diels-Alder reaction,
but also influences the oxidation-reduction process which could be confirmed by the fact that on
increasing the number of equivalents of benzoquinone the yields of dimer also increases and
finally plateauing at 1.5 equivalents of benzoquinone (table 1). A shortage of benzoquinone
might lead to the formed intermediate II to also act as an autooxidizing agent. To test this
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thought, the same reaction was performed with a large excess (5 equivalents) of benzoquinone
(Table 1, Entry 10). When we use large excess of benzoquinone (5 equi.), most of the
intermediate I is converted to intermediate II in step 1 and very little intermediate I is present to
undergo oxidation with intermediate II in step 2 and hence we get monomer as a major product
which supports the proposed mechanism (Scheme 4).
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Scheme 3: Proposed mechanism for the formation of the dimer bis(naphthoquinone)
OH
O
1
Step
OH
O
O
O
O
TMSO
OEt
OH
O
OH
HBQ
O
BQ
1 N
HCl
R
R
R
Aromatization
II
12
I
O
2
Step
OH OH
OH
O
HNQ
NQ
R
R
OH
II
O
O
III
H
H
autooxidation
O
O
OH
O
O
O
H+
R
R
R
OH
IV
I
O
II
Step 3
OH
O
H
OH OH
O
O
R
OH OH
+
R
R
R
OH
OH
OH
O
III
OH
IV
V
OH
O
O
O
R
OH
R
OH
O
O
H
+
BQ
HBQ
-
H
H
R
OH
R
OH
Oxidation
OH
VI
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Scheme 4: Reaction using a large excess (5 equivalents) of benzoquinone
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6
7
8
9
O
5
eq.
Benzoquinone
HCl, CH OH
1)
2)
OH
O
OEt
R
OH
O
O
3
+
TMSO
10
11
12
13
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R
R
R
O
OH
O
13a
14a
11a
=
=
16%
40%
yield
yield
In conclusion, a synthetic method has been discovered for the synthesis of 2,2’-
bis(naphthoquinones) using Diels-Alder reaction of conjugated ketene silyl acetals derived from
commercially available ketones and benzoquinone dienophile which underwent
dimerizationupon deprotection of the phenolic -OH to give the 2,2‘-bis(naphthoquinones)
analogues. The bioactivity of these compounds is being investigated.
Experimental section:
All reactions were performed in flame-dried glassware. Liquids and solutions were transferred
using syringes. Air- and moisture- sensitive materials were stored, protected and handled under
an atmosphere of argon, with appropriate glassware. Technical grade solvents for extraction and
chromatography (cyclohexane, dichloromethane and ethyl acetate) were used without
purification. All reagents were purchased from standard suppliers (Sigma-Aldrich, Alfa Aesar
and Fisher Scientific). Starting materials, if commercial, were purchased and used as such,
provided that adequate checks (NMR) had confirmed the claimed purity.
All NMR spectra were recorded on an Agilent 400 MHz using TMS as an internal solvent
reference. High resolution MS was performed at the University of Texas at Austin on the Agilent
6530 Accurate-Mass Q-TOF LC/MS and Waters Micromass AutoSpec Ultima GC/MS giving
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high resolution ESI and CI. Aluminum backed 60 F254 silica plates were used for thin layer
chromatography. Flash chromatography was performed using the Teledyne Isco CombiFlash
automated column machine. Melting points were obtained using a Mel-Temp melting point
apparatus. The X-ray intensity data were measured with MoKα radiation using a Bruker APEX
II single crystal x-ray diffractometer at the Western Kentucky University, Bowling Green, KY.
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General procedure for Horner-Wadsworth-Emmons olefination:
To the solution of triethylphosphonoacetate (2.2 mL, 11.01 mmol) and NaH (0.264 g, 11.01
mmol) in tetrahydrofuran (THF), ketone (7 mmol) dissolved in THF was added and the whole
o
mixture was stirred at 0 C for 12h. It was then quenched with aqueous ammonium chloride
solution (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure
to give crude product. It was then purified by silica gel column chromatography using n-
hexane/ethyl acetate (94:06) as eluent to afford the olefination products (10a-e) in Z/E ratio 2:8
(determined by 1H NMR).
Ethyl (E)-3-methyloct-2-enoate (10a): Compound 10a was prepared from compound 9a using
the general procedure. The reaction was performed on 7 mmol scale and we got Ethyl (E)-3-
methyloct-2-enoate 10a as a colorless liquid (1.121 g, 87%). Rf: 0.30 (5% EtOAc:95% hexane).
1H NMR (CDCl3) (Z/E:2/8) δ= 5.65 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.60 (t, J = 7.8 Hz, 0.4H),
2.14-2.09 (m, 4H), 1.87 (s, 0.6H), 1.50-1.43 (m, 2H), 1.32-1.25 (m, 7H), 0.88 (t, J = 6.6 Hz, 3H)
13
ppm. C{1H}NMR (CDCl3) (Z/E:2/8) δ= 166.9, 166.4, 160.8, 160.3, 115.9, 115.3, 59.4, 40.9,
33.3, 31.8, 31.3, 27.9, 27.0, 25.1, 22.5, 22.4, 18.7, 14.3, 13.9 ppm. HRMS (ESI-TOF) m/z [M +
H]+ calcd. for C11H21O2 185.1536; Found 185.1534.
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Ethyl (E)-3-methylpent-2-enoate14 (10b): Compound 10b was prepared from compound 9b
using the general procedure. The reaction was performed on 4 mmol scale and we got Ethyl (E)-
3-methylpent-2-enoate 10b as a colorless liquid (0.460 g, 81%). Rf: 0.30 (5% EtOAc:95%
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1
hexane). H NMR (CDCl3) (Z/E:2/8) δ= 5.65 (s, 0.8H), 5.62 (s, 0.2H), 4.17-4.12 (m, 2H), 2.62
(q, J = 7.5 Hz, 0.4H), 2.18-2.13 (m, 4H), 1.87 (s, 0.6H), 1.29-1.25 (m, 3H), 1.08-1.04 (m, 3H)
13
ppm. C{1H}NMR (CDCl3) (Z/E:2/8) δ= 166.9, 166.3, 162.0, 161.5, 115.4, 114.4, 59.4, 33.7,
26.5, 24.6, 18.7, 14.3, 12.5, 11.9 ppm.
Ethyl (E)-3,6-dimethylhept-2-enoate (10c): Compound 10c was prepared from compound 9c
using the general procedure. The reaction was performed on 4 mmol scale and we got Ethyl (E)-
3,6-dimethylhept-2-enoate 10c as a colorless liquid (0.565 g, 83%). Rf: 0.30 (5% EtOAc:95%
hexane). 1H NMR (CDCl3) (Z/E:2/8) δ= 5.64 (s, 0.8H), 5.61 (s, 0.2H), 4.11 (q, J = 7.2 Hz, 2H),
2.61-2.57 (m, 0.4H), 2.13-2.08 (m, 4H), 1.85 (s, 0.6H), 1.57-1.48 (m, 1H), 1.35-1.29 (m, 2H),
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1.26-1.23 (m, 3H), 0.91-0.86 (m, 6H) ppm. C{1H}NMR (CDCl3) (Z/E:2/8) δ= 166.8, 166.3,
160.9, 160.5, 115.7, 115.2, 59.3, 38.8, 37.2, 36.5, 31.4, 28.4, 27.6, 25.0, 22.4, 18.7, 14.3, 14.1
ppm. HRMS (ESI-TOF) m/z [M + H]+ calcd. for C11H21O2 185.1542; Found 185.1537.
Ethyl (E)-3,5-dimethylhex-2-enoate (10d): Compound 10d was prepared from compound 9d
using the general procedure. The reaction was performed on 4 mmol scale and we got Ethyl (E)-
3,5-dimethylhex-2-enoate 10d as a colorless liquid (0.603 g, 82%). Rf: 0.30 (5% EtOAc:95%
1
hexane). H NMR (CDCl3) (Z/E:2/8) δ= 5.68 (s, 0.2H), 5.61 (s, 0.8H), 4.14-4.09 (m, 2H), 2.54
(d, J = 7.4 Hz, 0.4H), 2.11 (s, 2.4H), 1.97 (d, J = 7.0 Hz, 1.6H), 1.85-1.82 (m, 1.6H), 1.27-1.23
(m, 3H), 0.89-0.85 (m, 6H) ppm. 13C{1H}NMR (CDCl3) (Z/E:2/8) δ= 166.7, 166.4, 159.4,
159.1, 117.0, 116.6, 59.3, 50.5, 41.6, 27.3, 26.1, 25.4, 22.3, 18.5, 14.2, 12.5 ppm. HRMS (ESI-
TOF) m/z [M + H]+ calcd. for C10H19O2 171.1380; Found 171.1380.
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Ethyl (E)-3-methylnon-2-enoate (10e): Compound 10e was prepared from compound 9e using
the general procedure. The reaction was performed on 3 mmol scale and we got Ethyl (E)-3-
methylpent-2-enoate 10b as a colorless liquid (0.504 g, 85%). Rf: 0.30 (5% EtOAc:95% hexane).
1H NMR (CDCl3) (Z/E:2/8) δ= 5.65 (s, 1H), 4.16-4.11 (m, 2H), 2.60 (t, J = 7.7 Hz, 0.4H), 2.14-
2.10 (m, 4H), 1.87 (s, 0.6H), 1.47-1.44 (m, 2H), 1.28-1.25 (m, 9H), 0.89-0.86 (m, 3H) ppm.
13C{1H}NMR (CDCl3) (Z/E:2/8) δ= 166.9, 166.4, 160.8, 160.4, 115.9, 115.3, 59.4, 40.9, 33.4,
31.7, 31.6, 29.4, 28.8, 28.2, 27.3, 25.1, 22.6, 22.5, 18.7, 14.3, 14.0 ppm. HRMS (ESI-TOF) m/z
[M + H]+ calcd. for C12H23O2 199.1693; Found 199.1690.
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General procedure for Diels-Alder reaction:
8,8'-Dihydroxy-6,6'-dipentyl-[2,2'-binaphthalene]-1,1',4,4'-tetraone (13a): A mixture of
ethyl 3-methyloct-2-enoate 10a (0.185 g, 1 mmol) in THF (3 mL) was slowly added dropwise to
o
a 2.0 M solution of lithium diisopropylamide (0.75 mL, 1.5 mmol) in THF cooled to -78 C
under argon atmosphere. The temperature was allowed to gradually rise to -35 oC in 2h. After 2h,
chlorotrimethylsilane (0.2 mL, 1.5 mmol) was slowly added and allowed to stir for 15 min. The
cooling bath was removed and the reaction was allowed to stir an additional 45 min at room
temperature, after which the THF was removed under reduced pressure. The resulting yellow oil
was dissolved in hexane and the lithium salt was removed by filtration. The filtrate was
concentrated to afford a bright yellow oil of (E)-((1-ethoxy-3-methyleneoct-1-en-1-
yl)oxy)trimethylsilane as a crude product which was used as such for the next step without
further purification.
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To a solution of above product in dichloromethane (6 mL) at 0 C was added 1,4-benzoquinone
(0.162 g, 1.5 mmol). The reaction mixture was allowed to stir under nitrogen atmosphere for
16h. The dichloromethane was evaporated under reduced pressure and the crude solid was
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dissolved in methanol (6 mL). The solution was cooled to 0 C and a 1N HCl (4 mL) solution
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was added. The reaction mixture was allowed to stir for an additional 3h. After 3h the crude
mixture was concentrated, extracted with dichloromethane, washed with water, dried over
sodium sulfate and concentrated to afford a solid. Purification of the solid via flash column
chromatography n-hexane/ethyl acetate (95:05) afforded 8,8'-dihydroxy-6,6'-dipentyl-[2,2'-
binaphthalene]-1,1',4,4'-tetraone (13a) as a bright orange solid. (0.163 g, 67%). Rf: 0.25 (5%
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EtOAc:95% hexane). H NMR (CDCl3) δ= 11.73 (s, 2H, ArOH), 7.51 (s, 2H, benzene H), 7.12
(s, 2H, benzene H), 6.98 (s, 2H, quinone H), 2.69 (t, J = 7.3 Hz, 4H, CH2), 1.67-1.64 (m, 4H),
1.33 (m, 8H), 0.90 (t, J = 6.3 Hz, 6H, CH3) ppm. 13C{1H}NMR (CDCl3) δ= 187.1, 183.6, 162.2,
154.0, 143.2, 138.5, 131.6, 123.9, 120.1, 112.9, 36.4, 31.3, 30.1, 22.4, 13.9 ppm. HRMS (ESI-
TOF) m/z [M + H]+ calcd. for C30H31O6 487.2113; Found 487.2115. mp 172-174 oC.
6,6'-Diethyl-8,8'-dihydroxy-[2,2'-binaphthalene]-1,1',4,4'-tetraone (13b): Compound 13b
was prepared from compound 10b using same procedure as reported for 13a. The reaction was
performed on 1 mmol scale and we got 6,6'-Diethyl-8,8'-dihydroxy-[2,2'-binaphthalene]-
1
1,1',4,4'-tetraone 13b as an orange solid. (0.120 g, 60%). Rf: 0.25 (5% EtOAc:95% hexane). H
NMR (CDCl3) δ= 11.74 (s, 2H, ArOH), 7.54 (s, 2H, benzene H), 7.15 (s, 2H, benzene H), 6.99
(s, 2H, quinone H), 2.75 (q, J = 7.3 Hz, 4H, CH2), 1.30 (t, J = 7.6 Hz, 6H, CH3) ppm.
13C{1H}NMR (CDCl3) δ= 187.1, 183.5, 162.3, 155.2, 143.2, 138.5, 131.7, 123.4, 119.7, 112.9,
29.4, 14.5 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C24H18O6Na 425.1003; Found
425.0096. mp 208-210 oC.
8,8'-Dihydroxy-6,6'-diisopentyl-[2,2'-binaphthalene]-1,1',4,4'-tetraone (13c): Compound 13c
was prepared from compound 10c using same procedure as reported for 13a. The reaction was
performed on 1 mmol scale and we got 8,8'-Dihydroxy-6,6'-diisopentyl-[2,2'-binaphthalene]-
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1,1',4,4'-tetraone 13c as an orange solid. (0.148 g, 61%). Rf: 0.25 (5% EtOAc:95% hexane). 1H
NMR (CDCl3) δ= 11.74 (s, 2H, ArOH), 7.53 (s, 2H, benzene H), 7.14 (s, 2H, benzene H), 6.99
(s, 2H, quinone H), 2.71 (t, J = 7.3 Hz, 4H, CH2), 1.65-1.60 (m, 2H), 1.56-1.52 (m, 4H), 0.96 (d,
J = 6.8 Hz, 12H, CH3) ppm. 13C{1H}NMR (CDCl3) δ= 187.0, 183.5, 162.2, 154.2, 143.2, 138.5,
131.6, 123.9, 120.1, 112.8, 39.6, 34.3, 27.7, 22.4 ppm. HRMS (CI-magnetic sector) m/z [M]+
calcd. for C30H30O6 486.2042; Found 486.2036. mp 204-206 oC.
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8,8'-Dihydroxy-6,6'-diisobutyl-[2,2'-binaphthalene]-1,1',4,4'-tetraone (13d): Compound 13d
was prepared from compound 10d using same procedure as reported for 13a. The reaction was
performed on 1 mmol scale and we got 8,8'-Dihydroxy-6,6'-diisobutyl-[2,2'-binaphthalene]-
1,1',4,4'-tetraone 13d as an orange solid. (0.161 g, 70%). Rf: 0.25 (5% EtOAc:95% hexane). 1H
NMR (CDCl3) δ= 11.74 (s, 2H, ArOH), 7.49 (s, 2H, benzene H), 7.11 (s, 2H, benzene H), 6.99
(s, 2H, quinone H), 2.58 (d, J = 7.5 Hz, 4H, CH2), 2.01-1.94 (m, 2H), 0.95 (d, J = 6.7 Hz, 12H,
CH3) ppm. 13C{1H}NMR (CDCl3) δ= 187.1, 183.6, 162.0, 152.9, 143.2, 138.5, 131.5, 124.7,
120.7, 112.9, 45.7, 29.8, 22.3 ppm. HRMS (CI-magnetic sector) m/z [M]+ calcd. for C28H26O6
458.1729; Found 458.1725. mp 212-214 oC.
6,6'-Dihexyl-8,8'-dihydroxy-[2,2'-binaphthalene]-1,1',4,4'-tetraone (13e): Compound 13e
was prepared from compound 10e using same procedure as reported for 13a. The reaction was
performed on 1 mmol scale and we got 6,6'-Dihexyl-8,8'-dihydroxy-[2,2'-binaphthalene]-
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1,1',4,4'-tetraone 13e as an orange solid. (0.178 g, 69%). Rf: 0.25 (5% EtOAc:95% hexane). H
NMR (CDCl3) δ= 11.74 (s, 2H, ArOH), 7.52 (s, 2H, benzene H), 7.13 (s, 2H, benzene H), 6.99
(s, 2H, quinone H), 2.70 (t, J = 7.6 Hz, 4H, CH2), 1.69-1.65 (m, 4H), 1.32 (m, 12H), 0.89 (t, J =
6.5 Hz, 6H, CH3) ppm. 13C{1H}NMR (CDCl3) δ= 187.1, 183.6, 162.2, 154.0, 143.2, 138.5,
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131.6, 123.9, 120.1, 112.8, 36.4, 31.6, 30.4, 28.8, 22.5, 14.0 ppm. HRMS (CI-magnetic sector)
m/z [M]+ calcd. for C32H34O6 514.2355; Found 514.2370. mp 168-170 oC.
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5-Hydroxy-7-pentylnaphthalene-1,4-dione (14a): Compound 14a was prepared using same
procedure as reported for 13a using 5 equivalent of 1,4-benzoquinone. The reaction was
performed on 1 mmol scale and we got 5-Hydroxy-7-pentylnaphthalene-1,4-dione 14a as an
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orange solid. (0.098 g, 40%). Rf: 0.30 (5% EtOAc:95% hexane). H NMR (CDCl3) δ= 11.89 (s,
1H), 7.47 (s, 1H), 7.10 (s, 1H), 6.93 (s, 2H), 2.68 (t, J = 7.6 Hz, 2H), 1.65 (m, 2 H), 1.34 - 1.26
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(m, 4H), 0.90 (t, J = 7.1 Hz, 3 H) ppm. C{1H}NMR (CDCl3) δ= 189.7, 184.7, 161.7, 153.5,
139.4, 138.8, 131.5, 123.6, 119.9, 113.1, 36.4, 31.3, 30.2, 22.4, 13.9 ppm. HRMS (ESI-TOF) m/z
[M + H]+ calcd. for C15H17O3 245.1168; Found 245.1172. mp 84-86 oC.
7-Ethyl-5-hydroxynaphthalene-1,4-dione (14b): Compound 14b was prepared using same
procedure as reported for 13a. The reaction was performed on 1 mmol scale and we got 7-ethyl-
5-hydroxynaphthalene-1,4-dione 14b as an orange solid. (0.012 g, 6%). Rf: 0.30 (5%
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EtOAc:95% hexane). H NMR (CDCl3) δ= 11.89 (s, 1H, ArOH), 7.49 (s, 1H, benzene H), 7.12
(s, 1H, benzene H), 6.93 (s, 2H, quinone H), 2.73 (q, J = 7.7 Hz, 2H, CH2), 1.28 (t, J = 7.5 Hz,
3H, CH3) ppm. 13C{1H}NMR (CDCl3) δ= 189.7, 184.6, 161.8, 154.6, 139.4, 138.8, 131.6, 122.9,
119.5, 113.0, 29.4, 14.5 ppm. HRMS (ESI-TOF) m/z [M + H]+ calcd. for C12H11O3 203.0703;
Found 203.0701. mp 108-110 oC.
5-Hydroxy-7-isobutylnaphthalene-1,4-dione (14d): Compound 14d was prepared using same
procedure as reported for 13a. The reaction was performed on 1 mmol scale and we got 5-
hydroxy-7-isobutylnaphthalene-1,4-dione 14d as an orange solid. (0.019 g, 8%). Rf: 0.30 (5%
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EtOAc:95% hexane). H NMR (CDCl3) δ= 11.87 (s, 1H, ArOH), 7.42 (s, 1H, benzene H), 7.05
(s, 1H, benzene H), 6.91 (s, 2H, quinone H), 2.54 (d, J = 7.3 Hz, 2H, CH2), 1.98-1.91 (m, 1H),
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0.92 (d, J = 6.6 Hz, 6H, CH3) ppm. 13C{1H}NMR (CDCl3) δ= 189.7, 184.7, 161.5, 152.3, 139.4,
138.8, 131.4, 124.3, 120.4, 113.1, 45.7, 29.8, 22.3 ppm. HRMS (ESI-TOF) m/z [M+H]+ calcd.
for C14H15O3 231.1021; Found 231.1012. mp 114-116 oC.
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Acknowledgement:
We would like to thank Dr. Kathleen Morgan, from the chemistry department, Xavier University
of Louisiana, for helpful discussions on the proposed mechanism of the dimerization reaction.
We acknowledge the financial support for this work by the Louisiana Biomedical Research
Network NIH Grant [8P20GM103424]. We acknowledge the additional support of the NIH
BUILD Grant [TL4M118968], the Louisiana Cancer Research Consortium, the Cell and
Molecular Biology Core NIH-RCMI [2G12MD007595-06] and the Center for Undergraduate
Research at Xavier University of Louisiana. We thank the University of Texas, Austin, Mass
Spectrometry Facility for the HRMS analysis of our samples.
Notes
The authors declare no competing financial interest.
Supporting Information:
The Supporting Information is available free of charge on the ACS Publications website.
13
1H, C NMR spectra of compounds described in the experimental section, ORTEP diagram of
13a, crystallography data for compound 13a, 1H NMR comparison of monomer 1 and dimer 13a,
schematic representation of literature precedence of bis(naphthoquinone) syntheses.
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12. Z & E ratio was determined using 1H NMR data.
13. For the usage of benzoquinones in Diels-Alder reactions see: Nawrat, C. C.; Moody, C. J.
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3625.
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