A mechanistic study on the Hooker oxidation: Synthesis of novel indane carboxylic acid derivatives from lapachol

Article abstract of DOI:10.1039/c2ob26737c

The Hooker oxidation is one of the most intriguing transformations wherein lapachol (1) is readily converted to norlapachol (2) in very good yield. This one-pot reaction involves a very intricate mechanism in which the alkyl side chain of lapachol is shortened by one carbon unit. Previous studies have unequivocally established the involvement of an indane carboxylic acid derivative 3, as a key intermediate (Hooker intermediate), and its simultaneous conversion to norlapachol (2) via the oxidative cleavage of vicinol diol and subsequent intramolecular aldol reaction of the resulting keto acid. However, the formation of the key Hooker intermediate 3 from lapachol (1) remains ambiguous. The present study has thrown some light on the formation of the key intermediate 3 from lapachol (1) via benzilic acid rearrangement of the corresponding labile o-diquinone intermediate 8 derived from lapachol. The involvement of o-diquinone intermediate 8 in the Hooker oxidation has been further established by trapping of this labile intermediate as the corresponding phenazine derivative 9. The involvement of benzilic acid rearrangement as a key step in the Hooker oxidation is further shown with a variety of o-quinones prepared from lapachol (1). The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2ob26737c

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A mechanistic study on the Hooker oxidation: synthesis
of novel indane carboxylic acid derivatives from
lapachol†
Cite this: Org. Biomol. Chem., 2013, 11,
459
Kenneth O. Eyong,a,b Manohar Puppala,a Ponminor Senthil Kumar,a Marc Lamshöft,c
Gabriel N. Folefoc,*b Michael Spiteller*c and Sundarababu Baskaran*a
The Hooker oxidation is one of the most intriguing transformations wherein lapachol (1) is readily con-
verted to norlapachol (2) in very good yield. This one-pot reaction involves a very intricate mechanism in
which the alkyl side chain of lapachol is shortened by one carbon unit. Previous studies have unequi-
vocally established the involvement of an indane carboxylic acid derivative 3, as a key intermediate
(Hooker intermediate), and its simultaneous conversion to norlapachol (2) via the oxidative cleavage of
vicinol diol and subsequent intramolecular aldol reaction of the resulting keto acid. However, the
formation of the key Hooker intermediate 3 from lapachol (1) remains ambiguous. The present study has
thrown some light on the formation of the key intermediate 3 from lapachol (1) via benzilic acid
rearrangement of the corresponding labile o-diquinone intermediate 8 derived from lapachol. The
involvement of o-diquinone intermediate 8 in the Hooker oxidation has been further established by
trapping of this labile intermediate as the corresponding phenazine derivative 9. The involvement
of benzilic acid rearrangement as a key step in the Hooker oxidation is further shown with a variety of
o-quinones prepared from lapachol (1).
Received 4th September 2012,
Accepted 7th November 2012
DOI: 10.1039/c2ob26737c
www.rsc.org/obc
with the function of enzymes that are critical for DNA replica-
Introduction
tion in cells.5 β-Lapachone has been the most extensively
Lapachol (1), a prenyl naphthoquinone and a principal con- studied among the cytotoxic naphthoquinones. Moreover, the
stituent of Newbouldia laevis, is widely used in African folk semisynthetic nor-β-lapachone and its amino derivatives are
medicine.1,2 It was first isolated by E. Paterno from Tabebuia also found to show potent antitumor activities against several
avellanedae (Bignoniaceae family) in 1882 and later found in cancer cell lines.6 A recent report on a pharmacophore model-
many other plant families such as Malvaceae, Verbenaceae, ing study of lapachol derivatives with cytotoxic activity in
Proteaceae, Leguminosae and Sapotaceae.3
human promyelocytic leukemia HL-60 cell line provides a valu-
Lapachol (1) and its derivatives exhibit a wide spectrum of able insight in designing new and more potent cytotoxic ana-
therapeutic activities such as, antiedemic, anti-inflammatory, logues.7 The biological activities and mode of action of
antimalarial, antitumor, antiviral, bactericidal, and fungi- lapachol and its analogues have become the subject of many
cidal.3 Moreover, atovaquone, a structural analogue of lapachol synthetic studies (Fig. 1).8
(1), in combination with proguanil is being used in the preven-
The Hooker oxidation is one of the most intriguing reac-
tions in organic chemistry.9 A historic example is the one pot
tion and treatment of malaria.4
Many natural and synthetic naphthoquinone derivatives conversion of lapachol (1) to norlapachol (2) which involves
have been extensively studied due to their ability to interfere the degradation of the prenyl side chain by one carbon unit
along with the reversal of regiochemistry of the 2-alkyl group
and the 3-hydroxy substituent (Scheme 1). Although this one-
pot reaction looks simple and takes place readily under mild
aDepartment of Chemistry, Indian Institute of Technology Madras, Chennai, 600036,
India. E-mail: sbhaskar@iitm.ac.in; Fax: (+91) 44-2257-0545
bDepartment of Organic Chemistry, University of Yaounde 1, BP 812 Yaounde,
reaction conditions (1% KMnO4–NaOH, 0 °C), a very intricate
mechanism is presumed to be involved.
This unusual reaction accompanied by its interesting
features has motivated synthetic organic chemists to explore
its mechanistic pathways since the seminal work reported by
Hooker. Later, Fieser modified the Hooker oxidation reaction
Cameroon
cInstitute of Environmental Research and Analytical Chemistry, Dortmund University
of Technology, 44227 Dortmund, Germany
†Electronic supplementary information (ESI) available. CCDC 897940. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2ob26737c
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Fig. 1 Biologically active naphthoquinone derivatives from lapachol (1).
Scheme 1 Hooker oxidation of lapachol (1) to norlapachol (2).
conditions using a two-step protocol,10,11 H2O2–Na2CO3 and
CuSO4–NaOH, and showed the involvement of the key inter-
mediate, indane carboxylic acid derivative 3 (Scheme 2).
Based on the isolated intermediate 3, Fieser proposed a
novel mechanism for the Hooker oxidation of lapachol (1) to
norlapachol (2) via vicinal diol cleavage of the intermediate 3
Scheme 2 Hooker oxidation under Fieser’s modified conditions.
carbon. The migration of the 13C-enriched carbon atom from
followed by intramolecular aldol reaction of the resulting the ethyl side chain to the naphthoquinone ring system of
triketo-acid 4 and subsequent decarboxylation of the aldol
adduct, α-hydroxy acid 5 (Scheme 3).
7 has provided valuable insight into the mechanism of for-
mation of norlapachol (2) from the key intermediate 3 during
The mechanism proposed by Fieser was further supported the Hooker oxidation (Scheme 4).
by the 13C-labeling studies carried out by Lee and co-workers
The mechanistic investigation on the Hooker oxidation of
lapachol (1) to norlapachol (2) has unequivocally established
ditions, hydroxynapthoquinone 6, enriched with 13C at the the involvement of the key intermediate 3, and subsequent
which are shown in Scheme 4.12 Under Hooker oxidation con-
C1-position of the ethyl substituent, underwent oxidation to
transformation to norlapachol (2). However, the mechanism/
mode of formation of the key intermediate 3 from lapachol (1)
furnish hydroxynaphthoquinone 7 wherein the isotopically
labeled carbon became part of the naphthoquinone sp2 during the Hooker oxidation still remains unclear.
460 | Org. Biomol. Chem., 2013, 11, 459–468
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Scheme 3 Proposed mechanism for the Hooker oxidation by Fieser.
Scheme 5 Trapping of labile intermediate 8 with o-phenylenediamine.
Scheme 4 13C Labeling studies on the Hooker oxidation.
Our continued interest in converting lapachol (1) to various
biologically active and pharmaceutically important molecules
recently resulted in the anti-tumor structure activity relation-
ship (SAR) studies of various naphthoquinones derived from
lapachol.13 In the present study, we report a systematic investi-
gation with a variety of examples to demonstrate the involve-
ment of benzilic acid rearrangement14 as a key step in the
Hooker oxidation, leading to the formation of the key inter-
mediate, indane carboxylic acid derivative, 3 from lapachol (1).
Fig. 2 ORTEP diagram of the phenazine derivative 9.
The phenazine derivative 9 was confirmed by 1H, 13C and
2D NMR spectral analyses. In addition, HRMS data for com-
pound 9 is found to be 331.1447, which is in agreement with
the calculated mass for a formula C21H19N2O2. Moreover, the
structure of the phenazine derivative 9 is unambiguously con-
firmed by single crystal X-ray analysis (Fig. 2).15
Results and discussion
Isolation of the labile o-diquinone intermediate 8 as the
corresponding phenazine derivative 9 under Hooker oxidation
reaction conditions has thrown some light on the mode of for-
mation of the key intermediate 3 from lapachol (1) (Scheme 6).
It is anticipated that, during Hooker oxidation, lapachol (1)
could undergo an epoxidation under basic conditions to form
a highly labile quinone epoxy-alcohol intermediate 1a, which
on further isomerisation would lead to base sensitive o-di-
quinone derivative 8. Exposure of o-diquinone derivative 8 to
o-phenylenediamine would then lead to phenazine derivative
9. Under basic conditions, in principle, the o-diquinone
Encouraged by the interesting transformation of lapachol (1)
to norlapachol (2), it is of interest to gain deeper insight on
the formation of the key intermediate, indane carboxylic acid
derivative, 3 from lapachol (1) during the Hooker oxidation.
Interestingly, lapachol (1) on exposure to Fieser reaction
conditions (H2O2–Na2CO3) at a lower temperature (0 °C)
resulted in the formation of a new labile intermediate 8, which
underwent further transformation, under the reaction con-
ditions, to give the Hooker intermediate 3 in good yield
(Scheme 5). However, the labile intermediate 8 was trapped
as the corresponding phenazine derivative 9 upon exposure to
o-phenylenediamine (Scheme 5).
derivative
8 could undergo benzilic acid rearrangement
leading to the formation of the key intermediate 3.
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Scheme 6 Plausible mechanism for the formation of o-diquinone 8 from lapa-
chol (1).
Scheme 7 Methylation of lapachol (1) under basic conditions.
To show the involvement of the base-labile o-diquinone
derivative 8 during the Hooker oxidation of lapachol (1) and
subsequent transformation to the key intermediate 3, it is
necessary to isolate the highly reactive quinone epoxy-alcohol
intermediate 1a or diquinone 8. However, all our efforts to
isolate the quinone epoxy-alcohol intermediate 1a under the
basic conditions were unsuccessful due to the presence of a
free hydroxyl group, which underwent facile epoxide ring
opening to give the corresponding equally reactive o-diquinone
intermediate 8 (Scheme 6).
Hence, it was expected that the protection of free hydroxy
group as the corresponding methyl ether derivative would
furnish the stable o-methylated lapachol derivative 10 by
restricting the in situ epoxide ring opening and subsequently
leading to the key intermediate 3 via o-diquinone derivative 8.
Thus, methylation of lapachol (1) using methyl iodide in
presence of K2CO3 furnished the corresponding O-methylated
lapachol derivative 10 in 60% yield along with a diastereo-
isomeric mixture of the indanone ester 11 in 10% yield
(Scheme 7). Under these conditions, it is apparent that lapa-
chol (1) undergoes Hooker oxidation, leading to the formation
of indanone ester 11.
Scheme 8 Synthesis of epoxy-quinone ether 12.
Conversely, methylation of lapachol (1) using diazomethane
afforded the O-methylated lapachol 10 as the only product in
95% yield (Scheme 8). Interestingly, treatment of the O-methyl-
ated lapachol derivative 10 under Fieser reaction conditions
resulted in the isolation of the expected stable epoxy-quinone
ether 12 in 95% yield (Scheme 8).
The formation of the epoxy-quinone ether intermediate 12
establishes the involvement of highly reactive quinone epoxy-
alcohol intermediate 1a during Hooker oxidation and sub-
sequent isomerisation to o-diquinone derivative 8 (Scheme 6).
Further, the acid catalyzed hydrolysis of the epoxy-quinone
ether 12 with HClO4 in THF–water medium afforded the
highly unstable o-diquinone intermediate 8, which on further
exposure to aqueous NaOH, resulted in a smooth rearrange-
Scheme 9 Trapping of labile intermediate 8 as phenazine derivative 9.
Moreover, the labile compound 8 on treatment with o-phenyl-
ment to give the corresponding Hooker intermediate 3 as a enediamine, furnished the corresponding phenazine derivative
mixture of diastereomers in 90% yield (Scheme 9).
9 in very good yield (Scheme 9).
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Table 1 Esterification of the Hooker intermediate 3
Scheme 11 Plausible mechanism for the formation of indanone ester 11 via
C-alkylation followed by benzilic acid rearrangement.
Reaction conditions Yielda (%)13 Yielda (%) 14 Yielda (%) 15
Table 2 Benzilic acid rearrangement of various o-quinones derived from lapa-
chol (1)
1
2
MeOH, PTSA, reflux
NMU, KOH, Et2O
5
70
40
—
5
—
a Isolated yield.
Substrate
Time (h)
10
Product
Yielda (%)
80
1
2
3
6
90
70
Scheme 10 The role of benzilic acid rearrangement in Hooker oxidation.
10
The Hooker intermediate 3 was characterized by converting
it to the corresponding methyl ester 13. Exposure of the inter-
mediate 3 to PTSA in MeOH unexpectedly furnished the novel
tricyclic ether 14 in 40% yield along with trace amounts of
spiroether 15 and methyl ester 13. However, treatment of inter-
mediate 3 with diazomethane afforded the expected methyl
ester 13 in good yield (Table 1).
a Isolated yield.
Formation of the key intermediate 3 from o-diquinone 8
under basic conditions clearly indicates the involvement
of benzilic acid rearrangement as a key step in the Hooker
oxidation (Scheme 10).
Similarly, the formation of the indanone ester 11 in
Scheme 7 can be rationalized based on the benzilic acid
rearrangement (Scheme 11). It is likely that the lapachol (1) on
C-alkylation under basic conditions would lead to o-diquinone
derivative 8a which on subsequent benzilic acid rearrangement
followed by alkylation would lead to the indanone methyl
ester 11.
Moreover, the involvement of the intermediate 8 leading to
the formation of the Hooker intermediate 3 via benzilic acid
rearrangement is further tested with several o-quinones
derived from lapachol and the results are summarized in
Table 2. Following the literature procedure,7 lapachol upon
treatment with conc. H2SO4 afforded the β-lapachone (16),
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conditions, the key Hooker intermediate 3 is formed by the
benzilic acid rearrangement of the labile o-diquinone inter-
mediate 8. Thus, the lapachol (1) would undergo base
mediated epoxidation of enone to give quinone epoxy-alcohol
1a which on subsequent isomerisation would lead to o-di-
quinone intermediate 8. Under the reaction conditions, the
o-diquinone intermediate 8 would then undergo benzilic acid
rearrangement to afford the key Hooker intermediate 3. As pro-
posed by Fieser, the key Hooker intermediate 3 on oxidative
cleavage followed by intramolecular aldol reaction and sub-
sequent decarboxylation would ultimately lead to the norlapa-
chol (2) (Scheme 12).
Conclusion
In conclusion, the mechanism involved in the formation of
the Hooker intermediate 3 from lapachol (1) via benzilic acid
rearrangement as a key step has been investigated. Trapping of
the labile intermediate 8 as the corresponding phenazine
derivative 9 further supports our proposed mechanism. More-
over, the involvement of benzilic acid rearrangement was
further tested with a variety of o-quinones prepared from lapa-
chol (1), which resulted in the formation of novel indane carb-
oxylic acid derivatives. The molecules synthesized during the
course of our investigation will be tested for their biological
activities in the near future.
Experimental section
Synthesis of 2-hydroxy-3-(2-methylprop-1-enyl)naphthalene-
1,4-dione (2)
Scheme 12 Mechanism for the Hooker oxidation of lapachol (1) to norlapa-
chol (2).
To a stirred solution of lapachol (1) (102 mg, 0.42 mmol) in
dioxane–water (6 mL, 3 : 1) was added Na2CO3 (54 mg,
0.54 mmol). The resulting mixture was treated with 30% H2O2
which on exposure to aqueous NaOH underwent facile benzilic (0.2 mL) and stirred at 60 °C for 1.5 h, the reaction mass was
acid rearrangement to give the corresponding 2,3,4,5-tetra- cooled to 0 °C then treated with 36% HCl (0.5 mL), followed by
hydro-5-hydroxy-2,2-dimethylindeno[1,2-b]pyran-5-carboxylic
acid 17 in good yield.
H2O and saturated with SO2, nitrogen gas was purged through
the reaction mass for 30 min. Then by 25% NaOH solution
Similarly, norlapachol (2) on exposure to conc. H2SO4 (1 mL) and CuSO4 (0.4 g, 2.5 mmol, in 3.5 mL H2O) were
afforded nor β-lapachone 18, which readily underwent benzilic
acid rearrangement under basic conditions to give the corre- room temperature, filtered through a celite bed, the filtrate
added and stirred at 50 °C for 1 h, the reaction mass cooled to
sponding indane carboxylic acid derivative 19 in 90% yield.
The structure of the compounds 17 and 19 were confirmed
was treated with conc. HCl (0.5 mL) to adjust the pH to 2 and
extracted with CH2Cl2 (3 × 5 mL), dried over anhydrous Na2SO4
by the HRMS and 2D NMR spectral analyses. Furthermore, and the solvent was removed under reduced pressure to give
acetylation of lapachol (1) followed by bromination of the crude compound. Column chromatographic purification of the
resulting 2-acetyllapachol afforded 3-bromo-β-lapachone 20,7
crude compound over silica gel using 20–30% EtOAc in hexane
which on exposure to aqueous NaOH underwent smooth as solvent gradient afforded pure compound 2 (97 mg, 90%
benzilic acid rearrangement to give the corresponding yield) as a yellow solid; IR (neat) 3364, 2928, 1661, 1645, 1593,
1
1377, 1343, 1325, 1300, 1277 cm−1; H NMR (400 MHz, CDCl3)
hydroxy-acid 21 in 70% yield (Table 2).
Based on our experimental observations, a plausible mech- δ 7.87–7.80 (m, 2 H), 7.50–7.40 (m, 2 H), 7.25 (bs, 1 H), 5.72
anism for the Hooker oxidation of lapachol (1) to norlapachol (s, 1 H), 1.72 (d, J = 4.4 Hz, 3 H), 1.40 (d, J = 4.8 Hz, 3 H);
13C NMR (100 MHz, CDCl3) δ 184.8, 181.6, 151.2, 143.7, 134.9,
(2) is delineated in Scheme 12. It is evident from our studies
that during the Hooker oxidation under Fieser reaction 133.0, 132.9, 129.5, 126.9, 126.1, 120.9, 113.6, 26.6, 21.8;
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HRMS (ESI) m/z calcd for C14H13O3 (M+ + H) 229.0859, found Methylation of lapachol (1)
228.0858.
Lapachol (1), (50 mg, 0.20 mmol) in acetonitrile (3 mL) was
heated on a steam bath under reflux until it dissolved.
The resulting solution was cooled to room temperature and
anhydrous potassium carbonate (31 mg, 0.22 mmol) followed
by methyl iodide (20 μL, 0.32 mmol) was added at room temp-
erature. The reaction mixture was allowed to reflux for 6 h, the
resulting solution was cooled to room temperature and the
solvent was removed under reduced pressure. The residue
was diluted with water (5 mL) and CH2Cl2 (5 mL), the layers
were separated; the aqueous layer was extracted with CH2Cl2
(2 × 5 mL). The combined organic layer was dried over an-
hydrous Na2SO4 and the solvent was removed under reduced
pressure to give crude compound. Column chromatographic
purification of the crude compound over silica gel using
5–15% EtOAc in hexane as solvent gradient afforded pure
compound 10 (32 mg, 60% yield) along with a diastereomeric
mixture of methyl 1-hydroxy-2-methyl-2-(3-methylbut-2-en-
1-yl)-3-oxo-2,3-dihydro-1H-indene-1-carboxylate 11 (6 mg, 10%
yield) as a light yellow solid.
Synthesis of 1,2-dihydroxy-2-(3-methylbut-2-en-1-yl)-3-oxo-2,3-
dihydro-1H-indene-1-carboxylic acid (3)
To a stirred solution of compound 12 (30 mg, 0.11 mmol) in
THF–H2O (3 mL 1 : 1) at 0 °C was added 70% HClO4 (2 μL,
0.2 eq.). The reaction mixture was stirred for 24 h at the same
temperature. The crude residue at 0 °C was treated with 3 N
NaOH (2 mL) and then stirred for 2 h at room temperature.
The resultant mixture was acidified to pH 5 using 5% HCl
(2 mL); the solvent was removed under reduced pressure. The
residue was diluted with water (5 mL) and CH2Cl2 (5 mL), the
layers were separated, the reaction mixture was extracted with
CH2Cl2 (2 × 5 mL), the combined organic layer was dried
over anhydrous Na2SO4 and the solvent was removed under
reduced pressure to give the crude product. Column chromato-
graphic purification of the crude compound over silica gel
using 5–10% EtOAc in hexane as solvent gradient afforded
pure compound 3 (27 mg, 90% yield) as an amorphous
material; IR (neat) 3337, 2945, 2834, 1718, 1651, 1386,
Spectral data for 2-methoxy-3-(3-methylbut-2-enyl)-
naphthalene-1,4-dione (10)
1260 cm−1; H NMR (400 MHz, CD3OD) δ 7.71–7.63 (m, 3 H),
1
7.50–7.46 (m, 1 H), 5.08 (m, 1 H), 2.62 (dd, J = 14.4, 6.8 Hz,
1 H), 2.16 (dd, J = 14.4, 6.8 Hz, 1 H), 1.53 (s, 3 H), 1.37 (s, 3 H);
13C NMR (100 MHz, CD3OD) δ 207.3, 154.2, 137.7, 137.5,
137.4, 133.0, 131.5, 126.0, 125.2, 120.5, 90.2, 87.5, 36.5 28.0;
HRMS (ESI) m/z calcd for C15H16O5Na (M+ + Na) 299.0890,
found 299.0890.
IR (neat) 2922, 2855, 1661, 1602, 1450, 1333, 1254 cm−1
;
1H NMR (500 MHz, CDCl3) δ 8.08–8.04 (m, 2 H), 7.72–7.67 (m,
2 H), 5.15–5.12 (m, 1 H), 4.13 (s, 3 H), 3.31 (d, J = 7.0 Hz, 2 H),
1.79 (s, 3 H) 1.69 (s, 3 H); 13C NMR (125 MHz, CDCl3) 185.3,
181.8, 157.4, 134.7, 133.7, 133.6, 133.2, 132.0, 131.5, 126.2,
126.0, 120.0, 61.2, 25.8, 23.0, 17.9; HRMS (ESI) m/z calcd for
C16H17O3 (M+ + H) 257.1172, found 257.1173.
Synthesis of 6-hydroxy-6-(3-methylbut-2-enyl)benzo[a]-
phenazin-5(6H)-one (9)
Spectral data for methyl 1-hydroxy-2-methyl-2-(3-methylbut-
2-enyl)-3-oxo-2,3-dihydro-1H-indene-1-carboxylate (11)
To a stirred solution of compound 12 (100 mg, 0.36 mmol) in
THF–H2O (8 mL, 1 : 1) at 5 °C, was added 70% HClO4 (7 μL,
0.073 mmol). The reaction mixture was stirred for 3 h at the
same temperature, then o-phenylenediamine (50 mg,
0.5 mmol) dissolved in CH3CN (1 mL) was added at 5 °C. The
reaction mixture was stirred for 3 h, at room temperature, the
reaction mixture was diluted with CH2Cl2 (5 mL), and extracted
with CH2Cl2 (2 × 5 mL). The combined organic layer was dried
over anhydrous Na2SO4 and the solvent was removed under
reduced pressure to give crude compound. Column chromato-
graphic purification of the crude compound over silica gel
using 15–25% EtOAc in hexane as solvent gradient afforded
pure compound 9 (97 mg, 80% yield) as a crystalline white
solid, M. p. 156–158 °C; IR (neat) 3733, 2352, 1684, 1595, 1540,
White solid, M. p. 77–79 °C; IR (neat) 3493, 3320, 2925, 1723,
1601, 1456, 1378, 1265, 1188, 743 cm−1 1H NMR (500 MHz,
;
CDCl3) δ 7.84 (dd, J = 7.5, 1.5 Hz, 1 H), 7.73 (td, J = 7.5, 1.5 Hz,
1 H), 7.61 (dd, J = 7.5, 1.2 Hz, 1 H), 7.52 (td, J = 7.5, 1.2 Hz,
1 H), 5.01 (td, J = 7.5, 1.2 Hz, 1 H), 4.22 (s 1 H), 3.61 (s, 3 H),
2.45 (dd, J = 7.5, 1.2 Hz, 1 H), 2.05 (dd, J = 7.5, 1.2 Hz, 1 H),
1.61 (s, 3 H), 1.45 (s, 3 H), 1.12 (s, 3 H); 13C NMR (125 MHz,
CDCl3) 206.6, 174.3, 150.0, 136.9, 134.5, 134.1, 129.4, 123.5,
122.9, 118.6, 83.2, 59.7, 53.2, 34.9, 25.6, 17.4, 14.6; HRMS (ESI)
m/z calcd for C17H21O4 (M+ + H) 289.1434, found 289.1434.
Synthesis of 1a-methoxy-7a-(3-methylbut-2-en-1-yl)-1a,7a-
dihydronaphtho[2,3-b]oxirene-2,7-dione (12)
;
1455, 1373 cm−1 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J = To a stirred solution of compound 10, (60 mg, 0.23 mmol) in
8.0 Hz, 1 H), 8.20–8.17 (m, 1 H), 8.15–8.12 (m, 1 H), 8.06 (d, J = dioxane (2 mL) and water (2 mL) at room temperature was
7.6 Hz, 1 H), 7.83–7.74 (m, 3 H), 7.61 (t, J = 7.6 Hz, 1 H), 4.92 added Na2CO3 (28 mg, 0.26 mmol). The resulting mixture was
(t, J = 7.6 Hz, 1 H), 4.42 (s, 1 H), 2.66 (d, J = 7.6 Hz, 2 H), 1.50 treated with 30% H2O2 (60 μL) and stirred at room temperature
(s, 3 H), 1.14 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ199.0, for 1.5 h. The reaction mixture was diluted with saturated
153.3, 143.9, 142.2, 141.4, 137.8, 136.1, 135.2, 131.5, 130.8, brine solution (5 mL) and extracted with CH2Cl2 (2 × 5 mL),
130.7, 130.5, 129.5, 129.2, 127.3, 125.7, 116.0, 81.9, 43.2, 25.8, the combined organic layer was dried over anhydrous Na2SO4
17.7; HRMS (ESI) m/z calcd for C21H19N2O2 (M+ + H) 331.1441, and the solvent was removed under reduced pressure to give
found 331.1447.
crude compound. Column chromatographic purification of the
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crude compound over silica gel using 5–10% EtOAc in hexane (s, 3 H), 2.45–2.41 (m, 1 H), 1.97–1.88 (m, 3 H), 1.43 (s, 3 H),
as solvent gradient to afford pure compound 12 (60 mg, 95% 1.30 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 201.8, 173.5,
yield) as a amorphous material; IR (neat) 2921, 2854, 1702, 148.2, 135.6, 135.3, 129.9, 124.2, 123.5, 95.8, 85.0, 82.4, 53.9,
1596, 1454, 1253, 1017 cm−1 1H NMR (400 MHz, CDCl3) 38.3, 33.0, 28.4, 28.1; HRMS (ESI) m/z calcd for C16H18O5Na
;
δ 8.06–7.99 (m, 2 H), 7.76–7.72 (m, 2 H), 5.24–5.20 (m, 1 H), (M+ + Na) 313.1046, found 313.1053.
3.85 (s, 3 H), 3.0 (dd, J = 14.5, 7.5 Hz, 1 H), 2.64 (dd, J = 14.5,
Spectral data for (1′S,2S)-methyl 1′-hydroxy-5,5-dimethyl-3′-oxo-
1′,3′,4,5-tetrahydro-3H-spiro[furan-2,2′-indene]-1′-carboxylate
(15)
6.5 Hz, 1 H), 1.75 (s, 3 H), 1.71 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 190.1, 189.7, 136.0, 134.5, 134.2, 132.4, 131.6, 127.5,
127.2, 116.8, 85.9, 70.0, 56.9, 25.9, 24.5, 18.1; HRMS (ESI) m/z
calcd for C16H17O4 (M+ + H) 273.1121, found 273.1124.
White crystalline solid, M. p. 160–162 °C; IR (neat) 3562, 3056,
2983, 1731, 1429, 1266 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.82
(td, J = 6.8, 1.2 Hz, 1 H), 7.74 (td, J = 6.4, 0.8 Hz, 1 H), 7.67 (dt,
Methylation of Hooker intermediate (3)
PROCEDURE A. To a stirred solution of 50% KOH (30 mL) in J = 6.0, 4.0 Hz, 1 H), 7.53 (dt, J = 6.0, 0.8 Hz, 1 H), 3.66 (s, 3 H),
diethyl ether (10 mL) at 0 °C, N-nitroso-N-methylurea (130 mg, 3.44 (bs, 1 H), 1.93–1.90 (m, 2 H), 1.78–1.72 (m, 2 H), 1.46 (s, 3
1.2 mmol) was added gently. The resulting yellow coloured H), 1.0 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 202.4, 171.5,
organic layer was separated, dried over KOH pellets and added 135.1, 133.6, 130.1, 125.3, 124.1, 79.4, 74.9, 53.2, 31.1, 29.7,
to compound 3 (50 mg, 0.18 mmol) in ether (5 mL), the reac- 28.5, 27.5; HRMS (ESI) m/z calcd for C16H18O5Na (M+ + Na)
tion mixture was stirred for 2 h and the solvent was removed 313.1046, found 313.1053.
under reduced pressure. Column chromatographic purification
of the crude compound over silica gel using 10–25% EtOAc in
hexane as solvent gradient afforded pure compound 13 (70%
Synthesis of 2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-
5,6-dione (16)7
yield).
To a stirred solution of lapachol (1), (242 mg, 1.0 mmol), was
PROCEDURE B. To a stirred solution of compound 3 (25 mg, added water (7 mL), followed by conc. H2SO4 (0.8 mL,
0.09 mmol) in toluene (5 mL) were added dry methanol (1 mL) 1.5 mmol), the resulting reaction mixture was stirred for 3 h,
and para-toluenesulphonic acid (4 mg, 0.018 mmol), the at room temperature. The thus obtained orange solid, was fil-
resulting mixture was refluxed with a Dean Stark apparatus for tered and washed with ice cold water (3 × 5 mL), the crude
5 h. After completion of the reaction, the solvent was removed product was dried under vacuum and column chromato-
under reduced pressure; the resultant mixture was diluted graphic purification of the crude compound over silica gel
with EtOAc (7 mL), washed with saturated NaHCO3 solution (2 using 20–30% EtOAc in hexane as solvent gradient afforded
× 5 mL), water (2 × 5 mL) and brine solution (5 mL) and dried pure compound β-lapachone 16 (97 mg, 40%), as an orange
over anhydrous Na2SO4. The solvent was removed under solid; IR (neat) 3526, 3479, 2625, 1726, 1670, 1460, 1361,
reduced pressure, and then column chromatographic purifi- 1270 cm−1 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz,
;
cation of the crude compound over silica gel using 10–25% 1 H), 7.80 (d, J = 7.6 Hz, 1 H), 7.63 (t, J = 7.6 Hz, 1 H), 7.49 (t,
EtOAc in hexane as solvent gradient afforded pure compounds J = 7.6 Hz, 1 H), 2.55 (t, J = 6.8 Hz, 2 H), 1.84 (t, J = 6.4 Hz,
13 (5%), 14 (40%) and 15 (5%) yields respectively.
2 H), 1.45 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 180.0, 178.7,
162.2, 134.9, 132.7, 130.8, 130.2, 128.7, 124.2, 112.8, 79.4, 31.7,
26.8, 16.2; HRMS (ESI) m/z calcd for C15H15O3 (M+ + H)
243.1016, found 243.2763.
Spectral data for methyl 1,2-dihydroxy-2-(3-methylbut-2-enyl)-
3-oxo-2,3-dihydro-1H-indene-1-carboxylate (13)
Obtained as white crystalline solid M. p. 148–150 °C; IR (neat)
1
Synthesis of 2,3,4,5-tetrahydro-5-hydroxy-2,2-dimethylindeno-
[1,2-b]pyran-5-carboxylic acid (17)
3606, 3597, 1729, 1368, 1262, 1102 cm−1; H NMR (400 MHz
CDCl3) δ 7.78 (d, J = 7.6 Hz, 1 H), 7.69 (dt, J = 7.6, 0.8 Hz, 1 H),
7.62 (d, J = 7.6 Hz, 1 H), 7.53 (dt, J = 7.6, 0.8 Hz, 1 H), 5.06 (qt, A solution of β-lapachone 16 (50 mg, 0.2 mmol) in acetonitrile
J = 6.8, 2.4, 1.2 Hz, 1 H), 4.43 (s, 1 H), 3.62 (s, 3 H), 3.16 (bs, (2 mL), at room temperature was treated with 3 N NaOH solu-
1 H), 2.74 (dd, J = 14.8, 8.4 Hz, 1 H), 2.10 (dd, J = 14.8, 6.8 Hz, tion (1 mL). The resultant mixture was stirred for 10 h at room
1 H), 1.64 (s, 3 H), 1.49 (s, 3 H); 13C NMR (100 MHz, CDCl3) temperature and the mixture was acidified to pH 5 using 5%
δ 202.2, 173.0, 148.6, 137.6, 135.5, 135.0, 130.2, 124.3, 123.6, HCl (2 mL) and the solvent was removed under reduced
116.5, 87.5, 83.3, 53.8, 34.0, 26.0, 18.0; HRMS (ESI) m/z calcd pressure. The residue was diluted with water (5 mL) and
for C16H22NO5 (M+ + NH4) 308.1493, found 308.3498.
CH2Cl2 (5 mL). The layers were separated, the reaction mixture
was extracted with CH2Cl2 (2 × 5 mL), the combined organic
layer was dried over anhydrous Na2SO4 and the solvent was
removed under reduced pressure to give crude compound.
Column chromatographic purification of the crude compound
Spectral data for (4aS,9bR)-methyl 4a-hydroxy-2,2-dimethyl-
5-oxo-2,3,4,4a,5,9b-hexahydroindeno[1,2-b]pyran-9b-
carboxylate (14)
White crystalline solid; M. p. 90–92 °C; IR (neat) 3562, 3386, over silica gel using 10–20% EtOAc in hexane as solvent gradi-
1733, 1459, 1375, 1279 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.81 ent afforded pure compound 17 (43 mg, 80% yield) as a
(d, J = 7.6 Hz, 1 H), 7.63 (dt, J = 7.6, 1.2 Hz, 1 H), 7.57 (d, J = reddish amorphous material; IR (neat) 3636, 3470, 1723, 1656,
1
7.6 Hz, 1 H), 7.52 (dt, J = 7.6, 0.8 Hz, 1 H), 4.41 (bs, 1 H), 3.64 1460, 1370, 1270 cm−1; H NMR (400 MHz, CDCl3) δ 8.12–8.05
466 | Org. Biomol. Chem., 2013, 11, 459–468
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(m, 2 H), 7.76–7.53 (m, 2 H), 2.71–2.67 (m, 2 H), 1.71–1.67 (m, reduced pressure to give crude compound. Column chromato-
2 H), 1.27 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 185.0, 153.2, graphic purification of the crude compound over silica gel
135.0, 133.1, 129.6, 127.1, 126.9, 126.4, 126.3, 124.9, 71.2, using 10–20% EtOAc in hexane as solvent gradient afforded
41.7, 36.9, 29.2, 18.5; HRMS (ESI) m/z calcd for C15H16O4Na pure corresponding acetate derivative of lapachol (43 mg, 80%
(M+ + Na) 283.0941, found 283.0946.
yield) as a light yellow oil. A solution of acetate derivative of
lapachol in CH2Cl2 (8 mL) at room temperature, was treated
with Br2 (40 μL, 1.44 mmol) for 10 min. The solvent was
removed under reduced pressure to give crude compound.
Synthesis of 2,2-dimethyl-2,3-dihydronaphtho[1,2-b]furan-4,5-
dione (18)
To a stirred solution of norlapachol 2 (50 mg, 0.21 mmol) at Column chromatographic purification of the crude compound
0 °C, was added water (2 mL) followed by conc. H2SO4 (0.2 mL, over silica gel using 10–20% EtOAc in hexane as solvent gradi-
0.31 mmol) and the resultant mixture was stirred for 3 h at ent afforded pure compound 20 (440 mg, 95% yield) as a
room temperature. The reaction mass was diluted with ice yellow colour solid; IR (neat) 3526, 3479, 2625, 1726, 1670,
cold water (5 mL) and the compound was extracted using 1460, 1361, 1270 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.04 (t, J =
CH2Cl2 (2 × 5 mL). The combined organic layer was dried over 8.0 Hz, 1 H), 7.81 (t, J = 8.0 Hz, 1 H), 7.67 (q, J = 7.6 Hz, 1 H),
anhydrous Na2SO4 and the solvent was removed under 7.53 (q, J = 7.6 Hz, 1 H), 4.29–4.23 (m, 1 H), 3.24–3.16 (m, 1 H),
reduced pressure to give the crude product. Column chromato- 3.02–2.93 (m, 1 H), 1.63 (d, J = 9.6 Hz, 3 H), 1.60 (d, J = 9.6 Hz,
graphic purification of the crude compound over silica gel 3 H); 13C NMR (100 MHz, CDCl3) δ 179.1, 177.9, 161.1, 135.0,
using 10–15% EtOAc in hexane as solvent gradient afforded 131.6, 131.2, 130.0, 128.8, 124.3, 111.0, 81.1, 49.9, 27.9, 26.1,
pure compound 18 (40 mg, 80% yield) as a red solid; IR (neat) 23.7.
1
3526, 3478, 2625, 1726, 1670, 1460, 1356, 1270 cm−1; H NMR
(400 MHz, CDCl3,) δ 8.06 (d, J = 7.6 Hz, 1 H), 7.62 (bs, 2 H),
7.58–7.56 (m, 1 H), 2.93 (s, 2 H), 1.60 (s, 6 H); 13C NMR
(100 MHz, CDCl3) δ 181.4, 175.7, 168.8, 134.5, 131.9, 130.9,
Synthesis of 2,3,4,5-tetrahydro-3,5-dihydroxy-2,2-
dimethylindeno-[1,2-b]pyran-5-carboxylic acid (21)
129.4, 127.9, 124.6, 115.0, 93.8, 39.3, 28.4; HRMS (ESI) m/z
A solution of compound 20 (75 mg, 0.23 mmol) in acetonitrile
(2 mL) at room temperature was treated with 3 N NaOH solu-
calcd for C14H13O3 (M+ + H) 229.0859, found 229.0863.
Synthesis of 3,4-dihydro-4-hydroxy-2,2-dimethyl-2H-indeno-
[1,2-b]furan-4-carboxylic acid (19)
tion (1 mL) and was stirred for 10 h at room temperature.
The reaction mixture was acidified to pH 5 using 5% HCl
(2 mL) and the solvent was removed under reduced pressure.
The reaction mass was diluted with water (5 mL) and CH2Cl2
(5 mL). The layers were separated, the reaction mixture was
extracted with CH2Cl2 (2 × 5 mL), the combined organic layer
was dried over anhydrous Na2SO4 and the solvent was removed
under reduced pressure to give crude product. Column
chromatographic purification of the crude compound over
silica gel using 10–20% EtOAc in hexane as solvent gradient
afforded pure compound 21 (45 mg, 70% yield) as a yellow
crystalline solid; M. p. 118–120 °C; IR (neat) 3324, 3240, 3058,
A solution of nor β-lapachone 18 (50 mg, 0.21 mmol) in aceto-
nitrile (2 mL) at room temperature, was treated with 3 N NaOH
solution (1 mL) and the resultant mixture was stirred for 6 h at
room temperature. The reaction mixture was acidified to pH 5
using 5% HCl (2 mL) and the solvent was removed under
reduced pressure. Diluted the residue with water (5 mL) and
CH2Cl2 (5 mL). Layers were separated, the reaction mixture was
extracted with CH2Cl2 (2 × 5 mL), combined organic layer was
dried over anhydrous Na2SO4 and the solvent was removed
under reduced pressure to give crude compound. Column
chromatographic purification of the crude compound over
silica gel using 10–20% EtOAc in hexane as solvent gradient
afforded pure compound 19 (49 mg, 90% yield) as a yellow
crystalline solid; M. p. 94–96 °C; IR (neat) 3526, 3479, 2625,
1668, 1633, 1345, 1268 cm−1 1H NMR (400 MHz, CD3OD)
;
δ 7.95 (d, J = 7.6 Hz, 2 H), 7.69–7.64 (m, 2 H), 3.56 (dd, J = 9.6,
3.3 Hz, 1 H,), 2.77–2.66 (m, 2 H), 1.16 (s, 6 H); 13C NMR
(100 MHz, CD3OD) δ 187.0, 156.2, 134.0, 132.6, 130.3, 125.8,
125.4, 122.2, 77.0, 72.6, 25.5, 24.2, 24.0; HRMS (ESI) m/z calcd
for C15H16O5Na (M+ + Na) 299.0889, found 299.0900.
1
1726, 1670, 1460, 1361, 1270 cm−1; H NMR (400 MHz, CDCl3)
δ 8.11–8.06 (m, 2 H), 7.76–7.66 (m, 2 H), 2.87 (s, 2 H), 1.30 (s, 6
H); 13C NMR (100 MHz, CDCl3) δ 186.2, 181.2, 155.3, 134.8,
133.5, 132.5, 129.8, 127.0, 126.3, 121.0, 72.8, 36.8, 29.7; HRMS
(ESI) m/z calcd for C14H15O4 (M+ + H) 247.0965, found
247.0980.
Acknowledgements
Synthesis of 3-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[h]-
Dr Eyong thanks the TWAS-UNESCO Associate Scheme, IIT-
Madras and DAAD for financial Support, M. P. (SRF)
chromene-5,6-dione (20)7
To a stirred solution of lapachol (1), (350 mg, 1.44 mmol) in thanks CSIR (New Delhi) for a research fellowship. The
CH2Cl2 (8 mL), at 0 °C, 2,6-lutidine (0.33 mL, 2.9 mmol) and authors thank the DST and CSIR, New Delhi, for financial
acetyl chloride (0.2 mL, 2.9 mmol) were added successively. support, and DST-FIST program for infrastructure facilities.
The resulting reaction mixture was stirred for 3 h, at room The authors also thank Mr V. Ramkumar for single crystal
temperature. The reaction mixture was concentrated under X-ray analysis.
This journal is © The Royal Society of Chemistry 2013
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Organic & Biomolecular Chemistry
R. C. Montenegro, M. O. De Moraes, M. F. R. Pinto,
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468 | Org. Biomol. Chem., 2013, 11, 459–468
This journal is © The Royal Society of Chemistry 2013