Diversity-Oriented Synthesis of Spiroannulated Benzofuran-3-one Scaffold of Leptosphaerin C and Congeners via Aryne Insertion

Article abstract of DOI:10.1021/acs.joc.7b00606

A concise synthesis of functionalized cyclohexenone-fused spirobenzofuran-3-ones under mild reaction conditions was developed. The reaction proceeds via insertion of aryne into the C-O bond followed by a regioselective intramolecular conjugate addition. The use of silyl-protected acid was crucial for the transformation. This protocol was successfully applied for the synthesis of leptosphaerin C core and its novel analogues.

Full text of DOI:10.1021/acs.joc.7b00606

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Article
Diversity-Oriented Synthesis of Spiroannulated Benzofuran-3-one
Scaffold of Leptosphaerin C and Congeners via Aryne Insertion
Ranjeet A. Dhokale, and Santosh B. Mhaske
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 11 Apr 2017
Downloaded from http://pubs.acs.org on April 11, 2017
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Diversity-Oriented Synthesis of Spiroannulated Benzofuran-3-one
Scaffold of Leptosphaerin C and Congeners via Aryne Insertion
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Ranjeet A. Dhokale and Santosh B. Mhaske*
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Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411 008, India
Abstract
A concise synthesis of functionalized cyclohexenone-fused spirobenzofuran-3-ones under mild
reaction condition has been developed. The reaction proceeds via insertion of aryne into C-O
bond followed by a regioselective intramolecular conjugate addition. The use of silyl-protected
acid was crucial for the transformation. This protocol has been successfully applied for the
synthesis of leptosphaerin C core and its novel analogues.
Introduction
The spiro-bicyclic scaffold, in particular the cycloalkane-fused benzofuran-3-ones are basic
structural framework found in various bioactive natural products and drugs (Figure 1).1
Designing efficient synthetic routes for spirobenzofuran-3-ones of biological significance have
found contemporary interest in the scientific community.1e,2 However, the construction of
spirocyclic skeleton has always been a challenging task, which requires synthetic design based
on specific strategies. The steric strain present on spiro carbon atom induces facile
rearrangements/ring opening that can lead to different compounds.3 Among the known natural
products containing spirocyclohexane benzofuran-3-one core, the polyketideleptosphaerin C
isolated from solid cultures of the ascomycete fungus Leptosphaeria sp.1b caught our attention
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because the compounds of this class exhibits antifungal properties and the synthesis of this
intriguing structural motif has not been reported.
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Figure 1: Natural products and drugs having cycloalkyl-fused spirobenzofuran-3-one core1
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Our group has been engaged in the development of novel and useful methodologies in aryne
chemistry,4 which prompted us to apply it in the construction of leptosphaerin C core and its
analogues. Such applications of arynes generated by various ways, in particular by Kobayashi’s
method,5 to synthesize key intermediates in the total synthesis of natural products is gaining
importance.6 Generally, the construction of spirocyclo-benzofuranones requires prefunctionalized
benzofuran ring, multiple steps, organo-/metal-catalyst and in some cases harsh reaction
conditions.1e,2 We planned to develop a milder and concise protocol using arynes, that would
install the spiro and the benzofuranone core in a single step.
We envisioned that insertion of aryne into C-O bond followed by intramolecular C-O bond
formation could be a promising method for the construction of 2-spirocyclohexane benzofuran-
3-one skeleton. In this context, the literature revealed that Larock et al reported the
o
intermolecular C-O addition of carboxylic acids to arynes at 120 C for the synthesis of o-
hydroxyaryl ketones, xanthones, 4-chromanones, and flavones,7 whereas Ma and coworkers
developed the methodology for chromone synthesis by using 2,3-allenoic acids.8 Very recently
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Guo and co-workers elegantly implemented the concept in the construction of o-hydroxy-
substituted arylphosphine oxides, -phosphinates, and -phosphonates using organophosphorous
acid substrates.9 However, to the best of our knowledge, synthesis of the above mentioned 2-
spirocyclohexane benzofuran-3-ones using aryne chemistry is not known in the literature. In this
report, we describe aryne insertion into C-O bond followed by Michael addition leading to
interesting spiro-bicyclic compounds at room temperature.
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Results and Discussion
Our study towards the development of the methodology began with the preparation of the desired
substrate 4 (Scheme 1). Several attempts to synthesize the compound 4 directly from acid 110 or
from dearomatized compound 311 met with failure.
Scheme 1: Synthesis of the key substrate 6
Hence, we planned for the substrate modification. The acid 1 was selectively protected12 using
triisopropylsilyl chloride (TIPSCl) to obtain ester 5, which on treatment with phenyliodine
diacetate (PIDA) furnished the silyl-protected dearomatized compound 6 in good yield.
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Table 1: Optimization studies to obtain spiro-bicyclic benzofuran-3-onea
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Solventb
8/9(yield %)c
entry
no
1
2
3
4
7 (equiv.) F- (equiv.)
additive
(equiv.)
temp
time (h)
THF
THF
ACN
2.0
4.0
4.0
4.0
CsF (3.0)
CsF (6.0)
CsF (6.0)
CsF (6.0)
-
-
-
-
rt
12
4-12
4
-
-
80-120 oC
rt
rt
-/60
-/45
THF-
4
ACN(1:1)
DCE/toluene
THF
5
6
4.0
2.0
CsF (6.0)
TBAF
-
-
rt-80oC
rt-80oC
4-12
4-12
-
-
(4.0)
7
8
9
10
11
12
THF
1,4-dioxane
toluene
toluene
toluene
2.0
2.0
2.0
2.0
2.5
3.0
KF (3.0)
KF (4.0)
KF (4.0)
KF (4.0)
KF (5.0)
KF (6.0)
18C6 (3.0)
18C6 (4.0)
18C6 (4.0)
18C6 (4.0)
18C6 (5.0)
18C6 (6.0)
rt
rt
rt
rt
rt
rt
4
12
4
12
4
20/10
20/5
32/7
24/5
42/8
52/6
toluene
4
a) all reactions were performed on 29 mg of 6, b) 0.5 mL of solvent, c) isolated yields
The optimization studies were performed on the aryne precursor 7 and the substrate 6 (Table 1,
selected entries). Initially, we performed reactions using CsF in different solvents at various
temperatures (Table 1, entries 1-5).The formation of expected spiro product 8 was not observed,
however the intermediate O-arylated product 9 could be isolated (Table 1, entries 3 and 4). It
indicates quenching of the aryl anion intermediate by acidic proton of acetonitrile. Hence, we
tried the reaction in THF using TBAF as a fluroride source, which also could not furnish the
expected product (Table 1, entry 6). However, use of KF and 18-crown-6 (18C6) in THF showed
the first indication of the formation of product 8 along with the ester 9 (Table 1, entry 7).
Changing the solvent to 1,4-dioxane, under the similar reaction condition did not show much
improvement (Table 1, entry 8). Finally, toluene was found to be the best choice (Table 1, entry
9-12). Although, we screened many other variations in mole ratio, solvent, time, temperature and
additives, the maximum possible yield of the spiro product 8 was 52% in our hands (Table 1,
entry 12).
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Scheme 2: Scope of the developed protocol on various aryne substratesa-c
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a) all reactions were performed on 25 mg of 6, b) 0.5 mL of toluene, c) isolated yields, d) ND = not determined
The scope of the optimized protocol was studied on varyingly substituted aryne precursors
(Scheme 2). In the case of unsymmetrical naphthalene based aryne precursor, the reaction
worked equally well as compared to the unsubstituted aryne precursor 7 to furnish the single
regioisomer spiro-product 10. The 2,5-dimethyl substituted aryne precursor gave the spiro-
product 11 in very good yield. Surprisingly, a complex product formation was observed for the
3,4-dimethyl aryne precursor and the spiro-product 12 could not be detected. Indane based aryne
precursor also provided less yield of the spiro-product 13.
For the difluro-substituted aryne precursor, the expected product 14 was formed in small amount,
but its purification could not meet the analytical requirements. These results points towards the
important role of electronic factors played by the methyl- and fluro- substituents in the formation
of spiro-products 11-13 and 14. In general, electron donating group substituted aryne precursors
furnished the corresponding spiro-products 15-19 in moderate to good yields. Interestingly,
excellent regioselectivities were observed for unsymmetrically substituted aryne precursors
furnishing 15 and 18 as the only regioisomers.
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Scheme 3: Synthesis of the substrate 24
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The scope of the optimized protocol with selected aryne precursors was also generalized on
unsymmetrically substituted dienone substrate 24, which was synthesized starting from aldehyde
2013a(Scheme 3). Good yield of spiro-product 25 was observed for 2,5-dimethyl substituted
aryne precursor (Scheme 4). Indane based aryne precursor provided moderate yield for the
corresponding spiro-product 26. The reactivity of alkyl substituted aryne precursors was found to
be similar to our previous study (Scheme 2). Electron donating group substituted aryne
precursors gave moderate to good yields of respective spiro-products 27-30. Same
regioselectivity was observed as in scheme 2 for unsymmetrically substituted electron-rich aryne
precursors to obtain spiro-compounds 27 and 28.
Scheme 4: The scope of the protocol on unsymmetrically substituted dienone 24a-c
a) all reactions were performed on 25 mg of 24, b) 0.5 mL of toluene, c) isolated yields
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A tentative mechanism for the formation of spiro-benzofuranones has been depicted in scheme 5.
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Scheme 5: Plausible Mechanism
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Encouraged by the generalization studies (Schemes 2 and 4), we planned to apply the optimized
protocol on dimethyl substituted dienone 35 for the synthesis of leptosphaerin C natural product,
which on bromination followed by carboxylation furnished the acid 33 in very good yields.
Silylation of the acid 33 using TIPS-chloride provided silyl ester 34, which on treatment with
PIDA in MeOH provided dimethyl substituted dieneone 35 in good yield (Scheme 6).
Scheme 6: Synthesis of dimethyl substituted dienone 35
The dienone 35 was then treated with methoxy substituted as well as unsubstituted aryne
precursors 36 and 7 respectively, under our developed reaction protocol. However, the desired
products 37/38 were not observed. We could isolate only the corresponding esters 39 and 40. We
feel that the stereoelectronic factors of the methyl group at the beta-position to silyl ester might
be affecting the C-O insertion, hence exclusive formation of O-arylated product was observed
(Scheme 7).
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Scheme 7: Attempts towards the synthesis of leptosphaerin C
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Since the dimethyl substituted spiro core 37 required for the synthesis of leptosphaerin C could
not be prepared directly, we decided to use spirobenzofuranone 27 (Scheme 4) as the substrate.
Having leptosphaerin C core compound 27 in hand our next target was its α-methylation.
Treatment of 27 with LDA and MeI furnished spiro ring opened product 41, whereas in the
presence of LiHMDS, spiro ring opening followed by rearrangement provided product 42
(Scheme 8). Efforts to decrease the reactivity of spiro-ring by protecting the carbonyl next to the
aromatic ring were also unsuccessful. Reaction of the substrate 27 with ethylene glycol in the
presence of p-TSA provided 44, but 43 was not observed. Assuming that the presence of the
double bond might be the reason behind the ring opening tenacity of the spiro-compound 27, it
was reduced but again we observed the ring opened product 47 when treated with NaH (Scheme
8). Though the actual natural product could not be synthesized, the products 41,42 and 47
obtained during our attempts to synthesize leptosphaerin C resembles the natural products
isolated along with leptosphaerin C.1b
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Scheme 8: Attempts towards the conversion of 27 to leptosphaerin C
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Conclusion
In summary, a diversity-oriented synthesis of spiroannulated benzofuran-3-ones for the concise
synthesis of leptosphaerin C core and its library has been demonstrated. The two new bonds C-C
and C-O have been formed by aryne insertion into C-O bond followed by intramolecular Micheal
addition at room temperature. Efforts were made for the first total synthesis of leptosphaerin C,
which also furnished novel compounds of biological interest. Screening of all the synthesized
spirobenzofuran-3-ones for antifungal properties and application of the developed protocol for
the synthesis of related natural products of this class is currently underway in our laboratory.
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Experimental Section
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General Information:
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All reagents and solvents were used as received from commercial sources unless and otherwise
noted. o-Silyl aryl triflates were synthesized by known procedures.15 Pre-coated plates (silica gel
60 PF254, 0.25 mm or 0.5 mm) were utilized for Thin Layer Chromatography (TLC). Column
chromatographic purifications were carried out on flash silica-gel (240-400 mesh) using
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petroleum ether and ethyl acetate as eluents. The H, C spectra were recorded on 200/400/500
MHz, 50/100/125 MHz NMR spectrometer respectively in CDCl3, DMSO-d6. TMS was used as
an internal standard. Chemical shifts were reported as δ values from standard peaks. Melting
points were recorded on Buchi instrument. High-resolution mass spectrometry (HRMS) was
performed on a TOF/Q-TOF mass spectrometer.
Experimental Procedures and data:
Triisopropylsilyl 5-hydroxy-2-methoxybenzoate (5):
To the solution of compound 110 (1.0 g, 5.95 mmol) in anhydrous DMF (5 mL) was added
morpholine (667 µl, 7.73 mmol) followed by TIPSCl 12 (1402 µl, 6.54 mmol). Reaction mixture
was stirred for 10 min. and diluted with deionised water. Further, it was extracted by 1,2
dichloromethane and dried over sodium sulphate. After evaporation of solvent, the crude product
was purified by using column chromatography on silica gel (1:4 EtOAc:Pet. Ether) to yield 5 as
a white solid (1.35 g, 70%).
M.p. 76-78 oC; 1H NMR (400 MHz, CDCl3, TMS) δ 7.35 (d, J = 3.2 Hz, 1H), 6.92 (dd, J = 3.2,
9.1 Hz, 1H), 6.77 (d, J = 9.1 Hz, 1H), 5.66 (bs, 1H), 3.74 (s, 3H), 1.37-1.26 (m, 3H), 1.05 (d, J =
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7.3 Hz, 18H); C NMR (100 MHz, CDCl3, TMS) δ 165.7, 154.2, 149.0, 121.3, 120.7, 118.8,
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113.7, 56.3, 17.8, 12.1; HRMS(ESI-TOF) m/z: [M+H]+ Calcd for C17H29O4Si 325.1830; Found
325.1830.
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Triisopropylsilyl 6,6-dimethoxy-3-oxocyclohexa-1,4-diene-1-carboxylate (6):
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To the precooled 0 oC solution of compound 5 (500 mg, 1.54 mmol) in anhydrous methanol (7.5
o
mL), PIDA (496 mg, 1.54 mmol) dissolved in methanol (6 mL) was added dropwise at 0 C.
After complete addition, reaction mixture was diluted by 1, 2-dichloromethane and further
quenched with aqueous NaHCO3.Further reaction mixture was extracted by 1, 2-
dichloromethane and dried over sodium sulfate. After evaporation of solvent, crude product was
purified by column chromatography on silica gel (1:9 EtOAc:Pet. Ether) to yield 6 as a yellow
liquid (380 mg, 69%).
1H NMR (500 MHz, CDCl3, TMS) δ 6.92 (d, J = 2.1 Hz, 1H), 6.80 (d, J = 10.1 Hz, 1H), 6.44
(dd, J = 2.1, 10.1 Hz, 1H), 3.33 (s, 6H), 1.44-1.33 (m, 3H), 1.12 (d, J = 7.3 Hz, 18H); 13C NMR
(125 MHz, CDCl3, TMS) δ 185.5,163.2, 145.9, 145.0, 134.9, 130.8, 95.1, 51.4, 17.7, 11.9;
HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for C18H30O5SiNa 377.1755; Found 377.1757.
2',2'-dimethoxy-3H-spiro[benzofuran-2,1'-cyclohexan]-3'-ene-3,5'-dione (8)
To a round bottom flask containing KF (28 mg, 0.49 mmol) and 18-crown-6-ether (129 mg, 0.49
mmol), was added 2-(trimethylsilyl)phenyl trifluoromethanesulfonate 7 (73 mg, 0.24 mmol) in
toluene (0.25 mL) and stirred for 1 h. To the above reaction mixture, compound 6 (29 mg, 0.082
mmol) in toluene (0.25 mL) was added and the reaction mixture was stirred for 4 h. Further,
reaction mixture was concentrated under reduce pressure and crude product was purified by
column chromatography on silica gel (1:4 EtOAc:Pet. Ether) to yield spiro compound 8 as a
white solid (11.7 mg, 52% yield) and compound 9 in 6%.
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M.p. 144-146 C; H NMR (400 MHz, CDCl3, TMS) δ 7.66-7.52 (m, 2H), 7.14-7.02 (m, 2H),
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6.76 (d, J = 10.3 Hz, 1H), 6.25 (d, J = 10.3 Hz, 1H), 3.25 (s, 3H), 3.23 (s, 3H), 2.85 (d, J = 17.1
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Hz, 1H), 2.76 (d, J = 17.1 Hz, 1H); C NMR (100 MHz, CDCl3, TMS) δ 197.1, 194.3, 170.5,
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144.9, 138.4, 131.6, 124.9, 122.6, 120.6, 113.5, 98.0, 90.4, 51.2, 50.5, 42.6; HRMS(ESI-TOF)
m/z: [M+Na]+ Calcd for C15H14O5Na 297.0733; Found 297.0731.
Phenyl 6,6-dimethoxy-3-oxocyclohexa-1,4-diene-1-carboxylate (9)
1
Reaction Time: 4 h, Rf: 0.35 (1:4 EtOAc:Pet. Ether); oil; 1.2 mg, 6%; H NMR (500 MHz,
CDCl3, TMS) δ 7.34 (t, J = 7.8 Hz, 2H), 7.20 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 7.8 Hz, 2H), 7.01
(d, J = 2.0 Hz, 1H), 6.81 ( d, J = 10.3 Hz, 1H), 6.43 (dd, J = 2.0, 10.3 Hz, 1H), 3.34 (s, 6H); 13C
NMR (125 MHz, CDCl3, TMS) δ 184.8, 162.1, 150.3, 144.7, 144.1, 135.4, 130.7, 129.5, 126.3,
121.3, 94.9, 51.6; HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for C15H14O5Na 297.0733; Found
297.0736.
Note: Same procedure was followed for preparation of Spiro compounds (10, 11, 13, 15-19) as
described for 8. Reactions were performed on 25 mg compound of 6.
2,2-Dimethoxy-1'H-spiro[cyclohexane-1,2'-naphtho[2,1-b]furan]-3-ene-1',5-dione (10):
1
Reaction Time: 2 h, Rf: 0.3 (1:4 EtOAc:Pet. Ether); oil; 11.44 mg, 50%; H NMR (500 MHz,
CDCl3, TMS) δ 8.66 (d, J = 7.9 Hz, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.61
(t, J = 7.0 Hz, 1H), 7.43 (t, J = 7.0 Hz, 1H), 7.23 (d, J = 9.2 Hz, 1H), 6.79 (d, J = 10.4 Hz, 1H),
6.28 (d, J = 10.4 Hz, 1H), 3.28 (s, 3H), 3.24 (s, 3H), 2.96 (d, J = 17.1 Hz, 1H), 2.83 (d, J = 17.1
13
Hz, 1H); C NMR (125 MHz, CDCl3, TMS) δ 196.7, 194.5, 173.3, 145.1, 140.4, 131.6, 130.2,
129.5, 129.3, 128.6, 125.8, 123.2, 113.7, 112.7, 98.1, 91.1, 51.3, 50.6, 42.8; HRMS(ESI-TOF)
m/z: [M+Na]+ Calcd for C19H16O5Na 347.0890; Found 347.0892.
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2',2'-Dimethoxy-4,7-dimethyl-3H-spiro[benzofuran-2,1'-cyclohexan]-3'-ene-3,5'-dione (11):
5
6
o
Reaction Time: 16 h, Rf: 0.3 (1:4 EtOAc:Pet. Ether); Off White solid; m.p. 72-74 C; 15.4 mg,
7
8
1
72%; H NMR (400 MHz, CDCl3, TMS) δ 7.21 (d, J = 7.6 Hz, 1H), 6.75, (d, J = 10.5 Hz, 1H),
9
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6.68 (d, J = 7.6 Hz, 1H), 6.23 (d, J = 10.5 Hz, 1H), 3.27 (s, 3H), 3.23 (s, 3H), 2.84 (d, J = 16.9
Hz, 1H), 2.75 (d, J = 16.9 Hz, 1H), 2.45 (s, 3H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3,
TMS) δ 198.6, 194.9, 169.6, 144.4, 138.3, 137.3, 131.6, 123.6, 120.2, 118.0, 98.0, 90.0, 51.2,
50.3, 42.9, 17.4, 14.0; HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for C17H18O5Na 325.1046; Found
325.1047.
2',2'-dimethoxy-4,7-dimethyl-3H-spiro[benzofuran-2,1'-cyclohexan]-3'-ene-3,5'-dione (13):
Reaction Time: 12 h, Rf: 0.4 (1:4 EtOAc:Pet. Ether); Yellow solid; m.p. 102-104 oC; 5 mg, 22%;
1H NMR (400 MHz, CDCl3, TMS) δ 7.38 (s, 1H), 6.90 (s, 1H), 6.75 (d, J = 10.4 Hz, 1H), 6.23
(d, J = 10.4 Hz, 1H), 3.25 (s, 3H), 3.23 (s, 3H), 2.90-2.70 (m, 6H), 2.20-2.00 (m, 2H); 13C NMR
(100 MHz, CDCl3, TMS) δ 196.7, 194.7, 170.5, 157.8, 145.2, 139.4, 131.6, 119.4, 119.1, 109.1,
98.0, 90.9, 51.1, 50.5, 42.9, 33.8, 31.5, 25.9; HRMS(ESI-TOF) m/z: [M+H]+ Calcd for C18H19O5
315.1227; Found 315.1217.
2',2',4-Trimethoxy-3H-spiro[benzofuran-2,1'-cyclohexan]-3'-ene-3,5'-dione (15):
o
Reaction Time: 4 h, Rf: 0.4 (2:3 EtOAc:Pet. Ether); White solid; m.p. 128-130 C; 11.9 mg,
1
55%; H NMR (500 MHz, CDCl3, TMS) δ 7.49 (t, J = 8.2 Hz, 1H), 6.73 (d, J = 10.4 Hz, 1H),
6.63 (d, J = 8.6 Hz, 1H), 6.43 (d, J = 8.2 Hz, 1H), 6.22 (d, J = 10.4 Hz, 1H), 3.87 (s, 3H), 3.27 (s,
13
3H), 3.25 (s, 3H), 2.83 (d, J = 17.1 Hz, 1H), 2.77 (d, J = 17.1 Hz, 1H); C NMR (125 MHz,
CDCl3, TMS) δ 194.45, 194.44, 171.5, 158.7, 144.7, 139.9, 131.6, 109.8, 105.2, 103.9, 97.9,
90.4, 56.1, 51.2, 50.5, 42.8; HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for C16H16O6Na 327.0839;
Found 327.0842.
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2',2',4,7-tetramethoxy-3H-spiro[benzofuran-2,1'-cyclohexan]-3'-ene-3,5'-dione (16):
5
6
1
Reaction Time: 12 h, Rf: 0.2 (2:3 EtOAc:Pet. Ether); oil; 9.5 mg, 40%; H NMR (400 MHz,
7
8
9
CDCl3, TMS) δ 7.03 (d, J = 8.8 Hz, 1H), 6.74 (d, J = 10.4 Hz, 1H), 6.32 ( d, J = 8.8 Hz, 1H),
6.22 (d, J = 10.4 Hz, 1H), 3.81 (s, 6H), 3.28 (s, 3H), 3.25 (s, 3H), 2.86 (d, J = 16.8 Hz, 1H), 2.79
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13
(d, J = 16.8 Hz, 1H); C NMR (100 MHz, CDCl3, TMS) δ 194.8, 194.4, 160.9, 151.8, 144.5,
140.0, 131.6, 121.6, 111.1, 102.9, 97.9, 91.0, 56.9, 56.1, 51.2, 50.4, 42.7; HRMS(ESI-TOF) m/z:
[M+Na]+ Calcd for C17H18O7Na 357.0945; Found 357.0934.
2',2',5,6-Tetramethoxy-3H-spiro[benzofuran-2,1'-cyclohexan]-3'-ene-3,5'-dione (17):
o
Reaction Time: 24 h, Rf: 04 (2:3 EtOAc:Pet. Ether); off-white solid; m.p. 223-225 C; 9.9 mg,
42%; 1H NMR (500 MHz, CDCl3, TMS) δ 6.95 (s, 1H), 6.75 (d, J = 10.7 Hz, 1H), 6.56 (s, 1H),
6.23 (d, J = 10.7 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.28 (s, 3H), 3.21 (s, 3H), 2.91 (d, J = 16.8
13
Hz, 1H), 2.70 (d, J = 16.8 Hz, 1H); C NMR (125 MHz, CDCl3, TMS) δ 195.3, 194.6, 168.0,
159.0, 146.2, 145.5, 131.5, 111.7, 103.5, 98.0, 95.7, 91.0, 56.6, 56.3, 51.1, 50.6, 42.9;
HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for C17H18O7 Na 357.0945; Found 357.0943.
2',2',4,6-tetramethoxy-3H-spiro[benzofuran-2,1'-cyclohexan]-3'-ene-3,5'-dione (18):
o
Reaction Time: 12 h, Rf: 0.2 (2:3 EtOAc:Pet. Ether); White solid; m.p. 195-197 C; 9.0 mg,
38%; 1H NMR (400 MHz, CDCl3, TMS) δ 6.80 (d, J = 10.4 Hz, 1H), 6.28 (d, J = 10.4 Hz, 1H),
6.20 ( apparent s, 1H), 6.04 (apparent s, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.34 (s, 6H), 2.90 (d, J =
17.1 Hz, 1H), 2.79 (d, J = 17.1 Hz, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 194.6, 192.2,
173.5, 170.1, 159.5, 145.0, 131.5, 104.1, 97.9, 93.5, 91.2, 89.1, 56.1, 56.0, 51.1, 50.5, 43.0;
HRMS(ESI-TOF) m/z: [M+H]+ Calcd for C17H19O7 335.1125; Found 335.1124.
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2,2-Dimethoxy-7'H-spiro[cyclohexane-1,6'-[1,3]dioxolo[4,5-f]benzofuran]-3-ene-5,7'-dione
(19):
7
8
9
Reaction Time:16 h, Rf: 0.4 (2:3 EtOAc:Pet. Ether); off -white solid; m.p. 150-152 oC; 13.5 mg,
60%; 1H NMR (400 MHz, CDCl3, TMS) δ 6.89 (s, 1H), 6.73 (d, J = 10.5 Hz, 1H), 6.51 (s, 1H),
6.22 (d, J = 10.5 Hz, 1H), 6.01 (apparent d, 2H), 3.27 (s, 3H), 3.23(s, 3H), 2.85 (d, J = 16.9 Hz,
1H), 2.73 (d, J = 16.9 Hz, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 195.0, 194.4, 169.4, 157.3,
145.1, 144.7, 131.5, 113.4, 102.8, 101.3, 97.9, 94.5, 91.7, 51.1, 50.5, 42.8; HRMS(ESI-TOF)
m/z: [M+Na]+ Calcd for C16H14O7 +Na 341.0632; Found 341.0634.
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2,5-dimethoxy-4-methylbenzoic acid (21):
The compound 21 as a white solid was prepared from compound 2013a according to the literature
procedure.13b
Aqueous hydrogen peroxide (30%, 6.5 mL, 57.7 mmol) was added dropwise to a stirred solution
of 50% aq. KOH (3.2 mL, 28.8 mmol) and 20 (1.3 g, 7.2 mmol) in methanol (20 mL) at 65oC for
20 min. The mixture was then stirred at the same temperature for 24 h, cooled, acidified with
concentrated hydrochloride to afford 21 (1.0 g, 70%) as a white solid.
1
M.p. 124-126 oC; H NMR (500 MHz, DMSO-d6, TMS) δ 12.43 (bs, 1H), 7.19 (s, 1H), 6.98 (s,
1H), 3.76 (s, 3H), 3.75 (s, 3H), 2.19 (s, 3H); 13C NMR (125 MHz, DMSO-d6, TMS) δ 167.1,
152.7, 150.9, 131.9, 118.4, 116.0, 112.4, 56.6, 55.8, 16.5; HRMS(ESI-TOF) m/z: [M+H]+ Calcd
for C10H13O4 197.0809; Found 197.0809.
2,5-dimethoxy-4-methylbenzoic
acid
compound
with
5-hydroxy-2-methoxy-4-
methylbenzoic acid (22):
The compound 22 (1.0 g, 65%) as a grey solid was prepared from compound 21 according to the
literature procedure10 as used in synthesis of compound 1.
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A solution of 21 (1.65 g, 8.4 mmol) in 6 mL concentrated sulfuric acid was heated to 55 C for
48 h. The reaction was then poured to. A precipitate formed and the reaction mixture was
allowed to stand overnight. The resulting crystals were dried in vacuo to afford 22 as grey solid
(1.0 g, 65%).
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M.p. 156-158 oC; 1H NMR (500 MHz, DMSO-d6, TMS) δ 12.31 (bs, 1H), 9.12 (bs, 1H), 7.13 (s,
1H), 6.86 (s, 1H), 3.72 (s, 3H), 2.15 (s, 3H); 13C NMR (125 MHz, DMSO-d6, TMS) δ 167.0,
151.7, 148.8, 130.2, 118.4, 116.6, 115.9, 56.7, 16.6; HRMS(ESI-TOF) m/z: [M+H]+ Calcd for
C9H11O4 183.0652; Found 183.0651.
Triisopropylsilyl 5-hydroxy-2-methoxy-4-methylbenzoate (23):
The compound 23 (740 mg, 40%) as a white solid was prepared from compound 22 (1 g, 5.4
mmol) following the same procedure12 as used in synthesis of compound 5.
o
1
Reaction Time: 10 min, Rf: 0.4 (1:9 EtOAc:Pet. Ether); White solid; 75-77 C; H NMR (400
MHz, CDCl3, TMS) δ 7.36 (s, 1H), 6.76 (s, 1H), 4.94 (bs, 1H), 3.84 (s, 3H), 2.29 (s, 3H), 1.50-
1.10 (m, 3H), 1.13 (d, J = 7.6 Hz, 18H); 13C NMR (100 MHz, CDCl3, TMS) δ 165.2, 154.4,
146.9, 130.9, 118.5, 118.4, 115.3, 56.4, 17.9, 16.5, 12.1; HRMS(ESI-TOF) m/z: [M+Na]+ Calcd
for C18H30O4Si + Na 361.1806; Found 361.1806.
Triisopropylsilyl 6,6-dimethoxy-4-methyl-3-oxocyclohexa-1,4-diene-1-carboxylate (24):
The compound 24 (1.04 g, 94%) as a yellow oil was prepared from compound 23 (1.02 g, 3.0
mmol) following the same procedure as used in synthesis of compound 6.
1
Reaction Time: 5 min, Rf: 0.5 (1:9 EtOAc:Pet. Ether); oil; H NMR (400 MHz, CDCl3, TMS) δ
6.90 (s, 1H), 6.56 (unresolved q, 1H), 3.30 (s, 6H), 1.97 (unresolved d, 3H), 1.45-1.30 (m, 3H),
1.12 (d, J = 7.3 Hz, 18H); 13C NMR (100 MHz, CDCl3, TMS) δ 186.3, 163.2, 145.8, 140.4,
138.2, 135.0, 95.5, 51.3, 17.7, 15.2, 11.9; HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for
C19H32O5SiNa 391.1911; Found 391.1912.
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Note: Same procedure was followed for preparation of Spiro compounds (25-30) as described
for 8. Reactions were performed on 25 mg of compound 24.
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2',2'-dimethoxy-4,4',7-trimethyl-3H-spiro[benzofuran-2,1'-cyclohexan]-3'-ene-3,5'-dione
(25):
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1
Reaction Time: 16 h, Rf: 0.4 (1:4 EtOAc:Pet. Ether); oil; 13.4 mg, 62%; H NMR (400 MHz,
CDCl3, TMS) δ 7.22 (d, J = 7.3 Hz, 1H), 6.67 (d, J = 7.3 Hz, 1H), 6.51 (q, J = 1.2 Hz, 1H), 3.30
(s, 1H), 3.20 (s, 1H), 2.92 (d, J = 16.5 Hz, 1H), 2.69 (d, J = 16.5 Hz, 1H), 2.44 (s, 3H), 2.20 (s,
13
3H), 1.90 (d, J = 1.2 Hz, 3H); C NMR (100 MHz, CDCl3, TMS) δ 199.0, 195.0, 170.0, 138.9,
138.8, 138.2, 137.3, 123.5, 120.2, 118.1, 98.3, 90.4, 51.1, 50.1, 42.8, 17.4, 15.5, 14.0;
HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for C18H20O5Na) 339.1203; Found 339.1205.
2,2-dimethoxy-4-methyl-6',7'-dihydrospiro[cyclohexane-1,2'-indeno[5,6-b]furan]-3-ene-
3',5(5'H)-dione (26):
o
1
Reaction Time: 36 h, Rf: 0.4 (1:4 EtOAc:Pet. Ether); Yellow solid; 91-93 C; 7.9 mg, 35%; H
NMR (500 MHz, CDCl3, TMS) δ 7.36 (s, 1H), 6.90 (s, 1H), 6.50 (q, J = 1.5 Hz, 1H), 3.23 (s,
6H), 2.90-2.75 (m, 6H), 2.10-2.00 (m, 2H), 1.89 (q, J = 1.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3, TMS) δ 196.8, 194.8, 170.5, 157.7, 139.9, 139.3, 138.7, 119.3, 119.2, 109.0, 98.4, 91.2,
51.0, 50.4, 42.9, 33.8, 31.5, 25.9, 15.5; HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for C19H20O5Na
351.1203; Found 351.1204.
2', 2’, 4-trimethoxy-4'-methyl-3H-spiro [benzofuran-2, 1’-cyclohexan]-3'-ene-3, 5’-dione
(27):
Reaction Time: 4 h, Rf: 0.5 (2:3 EtOAc:Pet. Ether); Off-white solid; 139-141 oC; 10.9 mg, 50%;
1H NMR (500 MHz, CDCl3, TMS) δ 7.48 (t, J = 8.2 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.48 (q, J
= 1.22 Hz, 1H), 6.42 (d, J = 8.5 Hz, 1H), 3.87 (s, 3H), 3.27 (s, 3H), 3.23 (s, 3H), 2.84 (d, J =
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16.8 Hz, 1H), 2.77 (d, J = 16.8 Hz, 1H), 1.88 (d, J = 1.22 Hz, 3H); 13C NMR (125 MHz, CDCl3,
TMS) δ 194.7, 194.6, 171.5, 158.7, 139.8, 139.2, 138.9, 109.9, 105.2, 103.8, 98.3, 90.7, 56.1,
51.1, 50.4, 42.7, 15.4; HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for C17H18O6Na 341.0996; Found
341.0995.
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2',2',4,6-tetramethoxy-4'-methyl-3H-spiro[benzofuran-2,1'-cyclohexan]-3'-ene-3,5'-dione
(28):
1
Reaction Time: 12 h, Rf: 0.2 (2:3 EtOAc:Pet. Ether); oil; 10.7 mg, 45%; H NMR (400 MHz,
CDCl3, TMS) δ 6.47 (s, 1H), 6.13 (d, J = 1.2 Hz, 1H), 5.96 (d, J = 1.2 Hz, 1H), 3.81 (s, 3H), 3.79
(s, 3H), 3.26 (s, 3H), 3.24 (s, 3H), 2.81 (s, 2H), 1.86 (s, 3H); 13C NMR (100 MHz, CDCl3, TMS)
δ 194.7, 192.4, 173.5, 170.1, 159.4, 139.5, 138.8, 104.1, 98.3, 93.4, 91.5, 89.0, 56.02, 56.0, 51.0,
50.4, 43.0, 15.4; HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for C18H20O7Na 371.1101; Found
371.1096.
2', 2', 5, 6-tetramethoxy-4'-methyl-3H-spiro[benzofuran-2,1'-cyclohexan]-3'-ene-3,5'-dione
(29):
1
Reaction Time: 24 h, Rf: 0.4 (1:3 EtOAc:Pet. Ether); oil; 7.1 mg, 30%; H NMR (500 MHz,
CDCl3, TMS) δ 6.94 (s, 1H), 6.55 (s, 1H), 6.51 (q, J = 1.5 Hz, 1H), 3.89 (s, 3H), 3.80 (s, 3H),
3.25 (s, 3H), 3.20 (s, 3H), 2.90 (d, J = 17.0 Hz, 1H), 2.73 (d, J = 17.0 Hz, 1H), 1.89 (d, J = 1.5
13
Hz, 3H); C NMR (125 MHz, CDCl3, TMS) δ 195.4, 194.8, 168.0, 158.9, 146.2, 140.2, 138.7,
111.8, 103.5, 98.5, 95.7, 91.4, 56.6, 56.3, 51.0, 50.4, 42.9, 15.5; HRMS(ESI-TOF) m/z: [M+Na]+
Calcd for C18H20O7Na 371.1101; Found 371.1103.
2,2-dimethoxy-4-methyl-7'H-spiro[cyclohexane-1,6'-[1,3]dioxolo[4,5-f]benzofuran]-3-ene-
5,7'-dione (30):
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9
Reaction Time: 24 h, Rf: 0.4 (2:3 EtOAc:Pet. Ether); off-white solid; 186-188 oC; 9.1 mg, 40%;
1H NMR (500 MHz, CDCl3, TMS) δ 6.87 (s, 1H), 6.51 (s, 1H), 6.49 (q, J = 1.5 Hz, 1H), 6.00 (m,
2H), 3.24 (s, 3H), 3.22 (s, 3H), 2.83 (d, J = 16.8 Hz, 1H), 2.76 (d, J = 16.8 Hz, 1H), 1.88 (d, J =
1.5 Hz, 3H); 13C NMR (125 MHz, CDCl3, TMS) δ 195.1, 194.6, 169.4, 157.2, 144.6, 139.8,
138.8, 113.5, 102.8, 101.3, 98.3, 94.5, 92.1, 51.0, 50.4, 42.9, 15.5; HRMS(ESI-TOF) m/z:
[M+Na]+ Calcd C17H16O7 Na 355.0788; Found 355.0791.
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3-Bromo-4-methoxy-2,6-dimethylphenol (32):
o
To the precooled 0 C solution of 4-methoxy-2,6-dimethylphenol14 31 (1.00 g, 6.4 mmol) in
carbon tetrachloride (30 mL) was added N- bromosuccinimde (1.28 g, 7.2 mmol) portionwise
over 15-30 mins. The reaction mixture was stirred for 60 min. Then reaction mixture was diluted
with carbon tetrachloride and quenched by saturated sodium thiosulphate solution. The organic
layer was separated and dried over sodium sulphate. After evaporation of solvent, the crude
product was purified by using column chromatography on silica gel (1:9 EtOAc:PE) to yield 32
as a light brown solid (1.08 g, 72%).
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M.p. 102-104 C; H NMR (400 MHz, CDCl3, TMS) δ 6.60 (s, 1H), 4.42 (s, 1H), 3.84 (s, 3H),
2.38 (s, 3H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3, TMS) δ 149.9, 146.3, 125.3, 122.4,
112.3, 111.8, 56.8, 16.4, 16.2.
3-Hydroxy-6-methoxy-2,4-dimethylbenzoic acid (33):
To the solution of 32 (850 mg, 3.67 mmol) in anhydrous THF (20 mL) was added n-BuLi ( 11
o
mmol, 1M THF solution) at -78 C under argon atmosphere. Then carbon dioxide gas was
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purged into the above reaction mixture for 30 min at -78 C. The reaction mixture was stirred at
room temperature for 2 h. Excess of n-BuLi was quenched by saturated ammonium chloride and
extracted with ethyl acetate. The organic layer was dried over sodium sulphate. After
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M.p. 166-168 oC; H NMR (400 MHz, DMSO-d6, TMS) δ 12.75 (bs, 1H), 7.96 (s, 1H), 6.65 (s,
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1H), 3.66 (s, 3H), 2.17 (s, 3H), 2.06 (s, 3H); C NMR (100 MHz, DMSO- d6, TMS) δ 169.2,
148.4, 146.8, 126.3, 124.1, 122.4, 111.6, 56.2, 17.3, 13.7; HRMS(ESI-TOF) m/z: [M+H]+ Calcd
for C10H13O4 197.0809; Found 197.0808.
Triisopropylsilyl 3-hydroxy-6-methoxy-2,4-dimethylbenzoate (34):
The compound 34 was prepared from compound 33 (800 mg, 4.0 mmol) following the same
procedure12 as used in synthesis of compound 5 to afford the title compound 34 as a white solid
(1.00 g, 70%).
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Reaction Time: 10.0 min, Rf: 0.3 (1:4 EtOAc:Pet. Ether); White solid; 87-89 C; H NMR (400
MHz, CDCl3, TMS) δ 6.47 (s, 1H), 3.66 (s, 3H), 2.16 (s, 3H), 2.15 (s, 3H), 1.40-1.26 (m, 3H),
1.07 (d, J = 7.3 Hz, 18H); 13C NMR (100 MHz, CDCl3, TMS) δ 168.0, 149.8, 145.8, 124.9,
124.7, 121.8, 111.5, 56.1, 17.8, 16.6, 13.1, 12.1; HRMS(ESI-TOF) m/z: [M+H]+ Calcd for
C19H33O4Si 353.2143; Found 353.2146.
Triisopropylsilyl 6,6-dimethoxy-2,4-dimethyl-3-oxocyclohexa-1,4-diene-1-carboxylate (35):
The compound 35 (292 mg, 67%) was prepared from compound 34 (400 mg, 1.1 mmol)
following the same procedure as used in synthesis of compound 6.
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Reaction Time: 5 min, Rf: 0.3 (1:9 EtOAc:Pet. Ether); solid; H NMR (400 MHz, CDCl3, TMS)
δ 6.37 (d, J = 1.5 Hz, 1H), 3.23 (s, 6 H), 1.92 (s, 3H), 1.90 (d, J = 1.5 Hz, 3H), 1.36-1.26 (m,
13
3H), 1.07 (d, J = 1.07, 18H); C NMR (100 MHz, CDCl3, TMS) δ 186.2, 165.0, 144.2, 138.6,
138.4, 135.6, 95.3, 51.3, 17.7, 15.8, 13.0, 12.1; HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for
C20H34O5SiNa 405.2068; Found 405.2063.
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3-methoxyphenyl 6,6-dimethoxy-2,4-dimethyl-3-oxocyclohexa-1,4-diene-1-carboxylate (39):
To a round bottom flask containing KF (22 mg, 0.39 mmol), 18-crown-6-ether (103 mg, 0.39
mmol), was added aryne precursor 36 (64 mg, 0.19 mmol) in toluene (0.25 mL) and stirred for 1
h. To the above reaction mixture, compound 35 (25 mg, 0.065 mmol) in toluene (0.25 mL) was
added and the reaction mixture was stirred for 4 h. Further reaction mixture was concentrated
under reduce pressure and crude product was purified by column chromatography on silica gel
(1:4 EtOAc:Pet. Ether) to yield compound 39 as an oil (7.0 mg, 32% yield).
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1H NMR (500 MHz, CDCl3, TMS) δ 7.24 (t, J = 8.2 Hz, 2H), 6.70-6.78 (m, 2H), 6.67
(unresolved q, 1H), 6.47 (s, 1H), 3.75 (s, 3H), 3.32 (s, 6H), 2.02 (s, 3H), 1.94 (unresolved d, 3H);
13C NMR (125 MHz, CDCl3, TMS) δ 185.6, 163.6, 160.6, 151.1, 142.1, 138.6, 138.5, 137.2,
129.9, 113.7, 112.1, 107.6, 95.2, 55.5, 51.5, 15.9, 13.1; HRMS(ESI-TOF) m/z: [M+H]+ Calcd for
C18H21O6 333.1333; Found 333.1337.
phenyl 6,6-dimethoxy-2,4-dimethyl-3-oxocyclohexa-1,4-diene-1-carboxylate (40):
Same procedure was repeated as for compound 39 to obtain 40 (4.0 mg) from 35 (25.0 mg, 0.065
mmol) and 7 (58 mg, 0.19 mmol).
1
Reaction Time: 4 h, Rf: 0.4 (1:4 EtOAc:Pet. Ether); oil; 4.0 mg, 20.0 %; H NMR (400 MHz,
CDCl3, TMS) δ 7.35 (t, J = 7.8 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 8.3 Hz, 2H), 6.48
(unresolved q, 1H), 3.32 (s, 6H), 2.03 (s, 3H), 1.94 (unresolved d, 3H); 13C NMR (125 MHz,
CDCl3, TMS) δ 185.6, 163.7, 150.2, 142.1, 138.6, 138.5, 137.2, 129.6, 126.3, 121.5, 95.2, 51.5,
15.8, 13.2; HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for C17H18O5Na 325.1046; Found 325.1044.
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(5-hydroxy-2-methoxy-4-methylphenyl)(2-hydroxy-6-methoxyphenyl)methanone (41):
To the compound 27 (20 mg, 0.062 mmol) in anhydrous THF (0.5 mL) was added 1M LDA in
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THF (125 μl, 0.125 mmol) at -78 C and stirred for 10 min. To the above reaction mixture
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methyl iodide (9.8 μl, 0.069 mmol) was added at -78 C. The reaction mixture was allowed to
attain room temperature and stirred for 8 h. After completion of starting material, reaction was
quenched by aqueous ammonium choride and extracted by ethyl acetate. Further, organic layer
was concentrated under reduce pressure and crude product was purified by column
chromatography on silica gel (3:2 EtOAc:Pet. Ether) to yield compound 41 as a yellow solid (8.8
mg, 49%).
o
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M.p. 167-169 C; H NMR (400 MHz, CDCl3, TMS) δ 12.04 (s, 1H), 7.27 (t, J = 8.2 Hz, 1H),
6.68 (s, 1H), 6.59 (s, 1H), 6.54 (d, J = 8.6 Hz, 1H), 6.23 (d, J = 8.6 Hz, 1H), 4.62 (bs, 1H), 3.57
(s, 3H), 3.41 (s, 3H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3, TMS) δ 198.8, 163.3, 161.4,
150.7, 147.3, 136.2, 130.9, 127.5, 114.6, 113.8, 112.7, 110.3, 101.5, 56.3, 55.5, 16.4;
HRMS(ESI-TOF) m/z: [M+H]+ Calcd for C16H17O5 289.1071; Found 289.1070.
4-hydroxy-1,8-dimethoxy-3-methyl-9H-xanthen-9-one (42):
To the compound 27 (20 mg, 0.062 mmol) in anhydrous THF (0.5 mL) was added 1M LiHMDS
o
in THF (125 μl, 0.125 mmol) at -78 C and stirred for 10 min. To the above reaction mixture
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methyl iodide (9.8 μl, 0.069 mmol) was added at -78 C. The reaction mixture was allowed to
attain room temperature and stirred for 8 h. After completion of starting material, reaction was
quenched by aqueous ammonium choride and extracted by ethyl acetate. Further organic layer
was concentrated under vacuuo and crude product was purified by column chromatography on
silica gel (3:2 EtOAc:Pet. Ether) to yield compound 42 as a major compound (yellow solid, 5.5
mg, 30%).
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M.p. 209-211 oC; 1H NMR (500 MHz, CDCl3, TMS) δ 7.45 (t, J = 7.9 Hz, 1H), 6.91 (d, J = 8.6
Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 6.49 (s, 1H), 5.42 (s, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 2.31 (s,
3H); 13C NMR (125 MHz, CDCl3, TMS) δ 175.9, 160.7, 156.4, 152.5, 144.0, 135.5, 133.9,
129.9, 113.6, 112.1, 108.9, 108.2, 106.2, 56.7, 56.4, 16.4; HRMS(ESI-TOF) m/z: [M+H]+ Calcd
for C16H15O5 287.0914; Found 287.0915.
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4-methoxy-4'-methyl-3H-dispiro[benzofuran-2,1'-cyclohexane-2',2''-[1,3]dioxolan]-3'-ene-
3,5'-dione (44):
To the compound 27 (20 mg, 0.062 mmol) in methanol (0.5 mL) was added ethylene glycol (3.5
μl, 0.062 mmol), and catalytic p-TSA (1 mg, 0.0062 mmol) at rt. The reaction mixture was
stirred for 12 h. After complete consumption of starting material, reaction was quenched by
aqueous sodium bicarbonate and extracted with ethyl acetate. Further, organic layer was
concentrated under vacuuo and crude product was purified by column chromatography on silica
gel (1:4 EtOAc:Pet. Ether) to yield compound 44 as a Yellow solid (13.5 mg, 70 %).
M.p. 185-187 oC; 1H NMR (400 MHz, CDCl3, TMS) δ 7.47 (t, J = 8.5 Hz, 1H), 6.60 (d, J = 7.9
Hz, 1H), 6.42 (d, J = 7.9 Hz, 1H), 6.25 (apparent q, 1H), 4.05-4.00 (m, 2H), 4.00- 3.90 (m, 2H),
13
3.86 (s, 3H), 2.90 (d, J = 16.5 Hz, 1H), 2.85 (d, J = 16.5 Hz, 1H), 1.84 (apparent d, 3H) ; C
NMR (100 MHz, CDCl3, TMS) δ 194.9, 194.4, 172.3, 158.5, 139.7, 139.1, 138.8, 110.1, 105.6,
104.7, 103.8, 89.8, 66.8, 66.5, 56.1, 42.2, 15.4; HRMS(ESI-TOF) m/z: [M+H]+ Calcd for
C17H17O6 317.1020; Found 317.1021.
2',2',4-trimethoxy-4'-methyl-3H-spiro[benzofuran-2,1'-cyclohexane]-3,5'-dione (45):
To the compound 27 (100 mg, 0.31 mmol) in ethanol (1 mL) was added Pd 10% (10 mg).
Reaction mixture as kept for stirring under H2 gas for 8 h. After complete consumption of
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starting material, reaction was filtered through celite. The reaction mixture was concentrated
under vacuum. The crude product was further purified by silica gel column chromatography (2:3
EtOAc: Pet. Ether) to yield 45 (54.5 mg, 54%) as off-white solid.
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M.p. 155-157 oC; 1H NMR (400 MHz, CDCl3, TMS) δ 7.47 (t, J = 8.3 Hz, 1H), 6.59 (d, J = 8.3
Hz, 1H), 6.40 (d, J = 7.8 Hz, 1H), 3.86 (s, 3H), 3.49 (s, 3H), 3.11 (s, 3H), 3.01 (d, J = 14.2 Hz,
1H), 2.49-2.58 (m, 1H), 2.30-2.18 (m, 2H), 2.14-2.10 (m, 1H), 1.09 (d, J = 6.9 Hz, 3H); 13C
NMR (100 MHz, CDCl3, TMS) δ 205.9, 197.4, 172.2, 158.5, 139.7, 109.4, 104.9, 103.5, 99.7,
91.9, 56.0, 50.7, 49.7, 44.9, 40.7, 34.2, 13.7; HRMS(ESI-TOF) m/z: [M+Na]+ Calcd for
C17H20O6Na 343.1152; Found 343.1155.
(2,5-dimethoxy-4-methylphenyl)(2,6-dimethoxyphenyl)methanone (47):
o
To the precooled 0 C solution of compound 45 (10 mg, 0.031 mmol) in THF (0.25 mL) was
added NaH (2.25 mg, 0.093 mmol). The reaction mixture was allowed to attain room
temperature and further stirred for 12 h. After consumption of starting material reaction mixture
was diluted with water and ethyl acetate. Further, aqueous layer was extracted with ethyl acetate
3 times and dried over sodium sulphate. After evaporation of solvent, the crude product was
purified by using column chromatography on silica gel (1:4 EtOAc:PE) to yield compound 47 as
a yellow solid (4.4 mg, 44%).
o
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M.p. 124-126 C; H NMR (400 MHz, CDCl3, TMS) δ 7.29 (s, 1H), 7.19 (t, J = 8.5 Hz, 1H),
6.66 (s, 1H), 6.51 (d, J = 8.5 Hz), 3.73 (s, 3H), 3.64 (s, 6H), 3.47 (s, 3H), 2.18 (s, 3H); 13C NMR
(100 MHz, CDCl3, TMS) δ 193.1, 157.1, 154.6, 151.8, 134.4, 129.7, 125.8, 122.3, 116.4, 112.0,
104.1, 57.0, 56.0, 55.8, 16.8; HRMS(ESI-TOF) m/z: [M+H]+ Calcd for C18H21O5 317.1384;
Found 317.1373.
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ASSOCIATED CONTENT
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Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI:
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1H, 13C, DEPT NMR spectra of all the compounds (PDF).
AUTHOR INFORMATION:
Corresponding Author
*E-mail: sb.mhaske@ncl.res.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
R.A.D thanks UGC-New Delhi for fellowship. S.B.M. gratefully acknowledges generous
financial support from DST and CSIR-ORIGIN, New Delhi.
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