Formal synthesis of (±)-brazilin and total synthesis of (±)-brazilane

Article abstract of DOI:10.1016/j.tet.2014.08.001

A convergent synthesis towards (±)-brazilin and (±)-brazilane has been reported from 3,4-dimethoxy benzaldehyde in <15 reaction steps. Palladium(II)-catalysed intramolecular Friedel-Crafts cyclisation and Lewis acid supported intermolecular Friedel-Crafts alkylation reactions have been demonstrated. A tetracyclic substituted indane common key intermediate is employed to furnish the desired two molecules in good to excellent yield. Pd(OH)₂has played a crucial role in the total synthesis of (±)-brazilane.

Full text of DOI:10.1016/j.tet.2014.08.001

Tetrahedron 70 (2014) 7560e7566
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formal synthesis of (ꢀ)-brazilin and total synthesis of (ꢀ)-brazilane
*
Jhillu Singh Yadav , Anand Kumar Mishra, Saibal Das
Natural Products Chemistry Division, CSIR Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, AP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 May 2014
Received in revised form 30 July 2014
Accepted 1 August 2014
Available online 6 August 2014
A convergent synthesis towards (ꢀ)-brazilin and (ꢀ)-brazilane has been reported from 3,4-dimethoxy
benzaldehyde in <15 reaction steps. Palladium(II)-catalysed intramolecular FriedeleCrafts cyclisation
and Lewis acid supported intermolecular FriedeleCrafts alkylation reactions have been demonstrated. A
tetracyclic substituted indane common key intermediate is employed to furnish the desired two mole-
cules in good to excellent yield. Pd(OH)2 has played a crucial role in the total synthesis of (ꢀ)-brazilane.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Brazilin
Brazilane
Haematoxylin
Brazilien
Pearlmann reagent
1. Introduction
unique natural products.12 In continuation of our interest, herein we
wish to report a formal synthesis of (ꢀ)-brazilin and a total synthesis
The compounds (þ)-brazilin (1),1 (þ)-haematoxylin (4),1
(þ)-brazilide A (3) and (ꢁ)-brazilein (6) are homoisoflavanoids,
collectively isolated from the alcoholic extraction of heartwood of
Caesalpinia sappan L. (Legminosae).2 Among these, brazilide A (3)
has been proposed as the newest constituent of this natural prod-
uct family.3 The ethanolic tinctures of above compounds are famous
in traditional Chinese medicine used for the treatment of emme-
niopathy, convulsion, straumatic disease and menstrual disorders.4
Recent report reveals that brazilin (1) possesses antitumour activity
and acts as telomerase inhibitor and produces DNA nicks.5 Hae-
matoxylin (4) is proven to be a potent inhibitor of protein tyrosine
kinase.6 In addition, haematoxylin and brazilin are easily oxidised
by air to brazilein (6) and haematein, respectively, and therefore
haematoxylin is used in histology as a dye7 finding application in
the production of dyes and ink. Brazilane (2) and haematoxylane
(5) are the reduced counterparts of brazilin and haematoxylin, re-
spectively, and have been known for some time8 (Fig. 1).
of (ꢀ)-brazilane using facile convergent approach.
2. Result and discussion
Retrosynthetically (Scheme 1), we envisioned that the tetracy-
clic skeleton of brazilin could arise from ether linkage between
primary alcohol with appropriate deprotected phenolic group of
intermediate (ꢀ)-8, while D ring could be installed by taking ad-
vantage of Lewis acid mediated feasible electrophilic substitution of
benzylic alcohol of diol (ꢀ)-10 with protected resorcinol 9.13 The
Unique structures and diverse biological activities of brazilin and
its related compounds have attracted many research groups towards
their synthesis.9 Most recently Zhang et al. have reported an elegant
enantioselective synthesis of (þ)-brazilin, (ꢁ)-brazilein and (þ)-bra-
zilide A10 followed by Hong-Bo Qin et al. reporting the synthesis of
(ꢀ)-brazilin and formal synthesis of (ꢀ)-brazilien and (ꢀ)-brazilide
A.11 Recentlywe have reported thetotalsynthesis of somestructurally
* Corresponding author. Tel.: þ91 40 2719 3737; fax: þ91 40 2716 0512;
e-mail addresses: yadavpub@iict.res.in, yadavpub@gmail.com (J.S. Yadav).
Fig. 1. Structure of selected homoisoflavonoids.
http://dx.doi.org/10.1016/j.tet.2014.08.001
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

J.S. Yadav et al. / Tetrahedron 70 (2014) 7560e7566
7561
diol (ꢀ)-10 could be accessed through intramolecular Friedele-
Crafts reaction of BayliseHillman adduct 11 following a simple
reaction sequence.14
After gaining access to the diol (ꢀ)-10, which contained A and B
rings of the target molecule, the next task was to introduce
remaining two rings, C and D. For introducing ring D we have
treated the diol (ꢀ)-10 with the di O-benzyl protected resorcinol17 9
in the presence of excess BF3$OEt2 to afford the addition product
(ꢀ)-8 with in situ deprotection of TBS group in 90% yield.12b,13
Substitution has occurred at the desired position was confirmed
by H NMR of the product where one singlet at
as a characteristic chemical sift for dibenzylic proton and three
singlets at 6.80, 6.76 and 6.49 and two doublets at 6.91,
d 4.82 ppm was found
d
d
J¼8.39 Hz and 6.60, J¼8.39 Hz, displaying J value corresponds to
orthoeortho coupling were observed in aromatic region. Having
compound (ꢀ)-8 in hand, we turned our attention towards the
incorporation of ring C, for that we have deprotected the benzy-
lether groups of compound (ꢀ)-8 using Pd/C and H2 to have the
tetraol (ꢀ)-17 in quantitative yield.18 Tetraol (ꢀ)-17 was then sub-
jected to Mitsunobu conditions to achieve anticipated cyclised
product (ꢀ)-7, unfortunately all our attempts have ended with loss
of starting material as it has formed a complex mixture, presumably
due to the presence and influence of more free hydroxyl groups.
Subsequently, we have decided to selectively protect the tertiary
hydroxyl group of compound (ꢀ)-8. Initially protection of diol (ꢀ)-8
was achieved (Scheme 3) with the treatment of anisaldehyde di-
methyl acetal and catalytic CSA to give (ꢀ)-18 in 94% yield.19
Regioselective reductive ring-opening of the PMB acetal with
DIBAL-H in CH2Cl2 at ꢁ20 ꢂC has furnished the primary alcohol
(ꢀ)-19 in 95% yield.17
Scheme 1. Retrosynthetic analysis for (ꢀ)-brazilin.
The synthesis of brazilin has begun with construction of Bay-
liseHillman adduct 11 from commercially available aldehyde 1215
in reasonable yield. Then compound 11 was converted into its
substituted indene 14 using P2O5 in low yield.14 It is noteworthy to
mention that the yield of compound 14 was improved by
employing a protocol16 appeared during the same time by Xiang-
sheng Xu et al. where palladium-catalysed synthesis of indene
derivatives was achieved by intramolecular allylic arylation of
BayliseHillman acetate to build substituted indenes. Henceforth,
we have protected the free alcohol of BayliseHillman 11 with Ac2O
and pyridine in 90% yield followed by treatment with Pd(OAc)2,
K2CO3 and triphenylphosphine to achieve desired indene derivative
14 in 67% yield. Then, the ester moiety in 14 was reduced by using
DIBAL-H to obtain alcohol 15 in 92% yield.10 It was followed by TBS
protection of alcohol 15, which has provided the corresponding
TBS-ether 16 in excellent yield. And the dihydroxylation of 16 with
N-methylmorpholine (NMO) and OsO4 gave the desired diol (ꢀ)-10
(Scheme 2) in 90% yield.
Scheme 3.
Now after selective protection of tertiary alcohol, compound
(ꢀ)-19 was selectively di-O-debenzylated by using Raney-Ni and
hydrogen to produce triol (ꢀ)-20 in quantitative yield.20 By de-
signing triol (ꢀ)-20, we have reached a venue from where we were
ready to try Mitsunobu etherification to installed final C ring in
compound (ꢀ)-21 towards the target compound, brazilin. Un-
fortunately, this attempt also has met with no success, which might
be attributed to the earlier reason as well.
The strategy to construct C ring of the target molecule 1 was
changed and decided to prepare the primary alcohol of compound
(ꢀ)-19 as a leaving group. Therefore, mesylation of compound (ꢀ)-19
using MsCl and triethylamine in 97% yield was obtained. Then we
selectively has deprotected the di O-benzyl groups of mesylated
Scheme 2.

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J.S. Yadav et al. / Tetrahedron 70 (2014) 7560e7566
compound (ꢀ)-22 with Raney-Ni and hydrogen20 and subsequently
treated the unstable crude phenol with base (NaH) in THF at 0 ꢂC
temperature expecting the desired cyclised compound. To our de-
light the anticipated product (ꢀ)-21 was achieved in 90% yield over
two steps. The final steps for brazilin consisted of deprotection of
PMB ether and methoxy groups, we screened the conditions in-
cluding BBr3, DDQ, CAN, hydrogenationwith Pd/C andPd(OH)2/C, but
could not obtain the desired deprotected compound. Eventually the
deprotection of PMB ether group has accomplished using concd HCl
in dichloromethane at 0 ꢂC, to complete the formal synthesis of
(ꢀ)-brazilin 1 (Scheme 4). All spectra of compound (ꢀ)-7 were in
providentially formed compound (ꢀ)-24 with boron tribromide at
ꢁ78 ꢂC to room temperature gave the desired (ꢀ)-brazilane 2,
which is a synthetic derivative of brazilin 1. The spectroscopic data
of (ꢀ)-2 were found in full accordance with those reported in the
literature in all respects.8
3. Conclusion
In conclusion, a formal synthesis of (ꢀ)-brazilin 1 has been ac-
complished in 13 steps with 12% overall yield. During the synthesis
of (ꢀ)-brazilin 1, we could unveil Pd(OH)2 assisted reaction, which
has compiled in situ three steps (PMB deprotection, dehydration
and hydrogenation) in it and has led to the synthesis of (ꢀ)-bra-
zilane 2 in 14 steps with 19% overall yield. All the compounds ob-
tained in these protocols have looked promising and has been
submitted for their biological screening.
accordance with the reported value10
.
4. Experimental section
4.1. General
All the reagents and solvents were reagent grade and used
without purification unless specified otherwise. Technical grade
ethyl acetate and hexanes used for column chromatography were
distilled prior to use. When used as a reaction solvent, THF was
freshly distilled from sodium benzophenone ketyl. Column
chromatography was carried out using silica gel (60e120 mesh
and 100e200 mesh) packed in glass columns. All the reactions
were performed under an atmosphere of nitrogen in oven-dried
glassware with magnetic stirring. FTIR spectra were recorded as
KBr discs or neat. The 1H and 13C NMR spectra were recorded in
CDCl3, acetone-d6 and MeOH-d4 on 300, 500, 150 or 75 MHz
spectrometers at ambient temperature. HRMS were recorded at
5 ppm concentration in Agilent qtof instrument at ‘National
Center for Mass Spectroscopy, CSIR-Indian Institute of Chemical
Technology.’
Scheme 4.
Herein, we also report the total synthesis (ꢀ)-brazilane, which
was obtained en route while deprotection of PMB group of com-
pound (ꢀ)-21, as an instance of serendipity on the way for hy-
drogenation reaction in the synthetic strategy of (ꢀ)-brazilin
(Scheme 5). In order to deprotect PMB group, cyclised product
(ꢀ)-21 was treated with Pd/C, H2 in methanol solvent to complete
the formal synthesis of (ꢀ)-brazilin, but TLC has showed number
of products. The mass analysis of the crude mixture has showed
a base peak with value 299, attributed as the [MþH]þ of the di-
methyl brazilane (ꢀ)-24.
4.2. Ethyl 2-((3,4-dimethoxyphenyl)(hydroxyl)methyl)acry-
late (11)
A mixture of the aromatic aldehyde 12 (1 g, 6.02 mmol) an
excess of ethyl acrylate (20 equiv, used as solvent and reagent),
and 1,4-diazabicyclo[2.2.2.]octane, DABCO (439 mg, 3.92 mmol)
was sonicated (1000 W, 25 kHz) for a certain period of time. The
ultrasound bath temperature was constantly monitored and kept
at 30e40 ꢂC during the reaction, through ice addition or by using
a refrigerated circulator. After a period for reaction completion
(10 h), the mixture was evaporated under reduced pressure to
remove the excess of acrylate. The residue was diluted with ethyl
acetate (30 mL). The organic solution was washed with 10%
aqueous HCl (2ꢃ10 mL), saturated NaHCO3 (20 mL), brine
(20 mL) and dried over anhydrous Na2SO4. After filtration and
solvent removal, the residue was filtered through a pad of gel of
silica to afford BH adduct 11 (1 g, 63% yield) as a colourless liquid;
Rf 0.3 (n-hexane/ethyl acetate, 4:1); IR (KBr) nmax 3300, 2851,
Scheme 5.
With the above assumption in mind, the reaction was repeated
with slight change in conditions, this time a non-protic solvent
(EtOAc) and Pearlmann reagent was used for hydrogenation. To our
success a solo product was formed, which was characterised as
compound (ꢀ)-24, established by 1H, 13C NMR and DEPT. This
transformation is believed to proceed through more than one
transformations, which have occurred in situ, initial deprotection of
PMB ether group to form (ꢀ)-7, followed by Pd(OH)2 promoted
dehydration (most probably unsaturation occurred at B/C ring
junction) to obtain 23, which was further followed by hydrogena-
tion furnishing (ꢀ)-24 in excellent yields. Deprotection of
1622, 1599, 1200, 1050; 1H NMR (500 MHz, CDCl3)
d 6.91 (1H, d,
J¼1.98 Hz, ArH), 6.87 (1H, dd, J¼8.24, 1.98 Hz, ArH), 6.81 (1H, d,
J¼8.24 Hz, ArH), 6.31 (1H, t, J¼0.91 Hz, CH2]C), 5.80 (1H, dist. t,
J¼1.22, 1.37 Hz, CH2]C), 5.50 (1H, s, OHCH), 4.16 (2H, dq, J¼7.17,
1.22 Hz, CO2CH2CH3), 3.86 (3H, s, OMe), 3.85 (3H, s, OMe), 1.24
(3H, t, J¼7.17 Hz, CO2CH2CH3); 13C NMR (125 MHz, CDCl3)
d 166.4,
148.9, 148.5, 142.3, 133.9, 125.5, 118.9, 110.8, 109.7, 72.9, 60.9, 55.8,
55.76, 14.01; MS (ESI): m/z¼249 [MþHꢁH2O]þ, 289 [MþNa]þ;
HRMS (ESI): calcd for C14H17O4 [MþHꢁH2O]þ: 249.1126; found:
249.1123.

J.S. Yadav et al. / Tetrahedron 70 (2014) 7560e7566
7563
4.3. Ethyl 2-(acetoxy(3,4-dimethoxyphenyl)methyl)acrylate
(13)
99e100 ꢂC; IR (KBr) nmax 3403, 2924, 2853, 1462, 1216, 1099, 1026;
1H NMR (300 MHz, CDCl3)
7.04 (1H, s, ArH), 6.91 (1H, s, ArH), 6.66
(1H, s, CH]C), 4.56 (2H, s, CH2OH), 3.90 (6H, s, OCH3), 3.38 (2H, s,
d
To the stirred solution of 11 (250 mg, 0.94 mmol) in DCM
were sequentially added pyridine (0.09 mL, 1.13 mmol), acetic
anhydride (0.1065 mL, 1.13 mmol) and catalytic amount of DMAP
at 0 ꢂC. Reaction mixture was allowed to stir for 10 h at room
temperature. Reaction mass quenched with water saturated so-
lution of copper sulfate, extracted with DCM, organic layer was
dried over anhydrous sodium sulfate and solvent was removed
under reduced pressure. The crude product was purified by col-
umn chromatography to afford acetate 13 (260.24 mg, 90%) as
a colourless oil; Rf 0.51 (n-hexane/ethyl acetate, 7:3); IR (KBr)
nmax 2926, 2851, 1744, 1722, 1516, 1463, 1370, 1230, 1141, 1027; 1H
ArCH2); 13C NMR (75 MHz, CDCl3)
d 148.3, 147.3, 147.1, 137.2, 135.8,
127.6, 108.2,104.7, 61.8, 56.3, 56.1, 38.9. MS (ESI): m/z¼229 [MþH]þ,
189 [MþHꢁH2O]þ; HRMS (ESI): calcd for C12H13O2 [MþHꢁH2O]þ:
189.09101; found: 189.09146.
4.7. tert-Butyl((5,6-dimethoxy-1H-inden-2-yl)methoxy)dime-
thylsilane (16)
To a solution of 15 (1.0 g, 4.8 mmol) in DCM (20 mL) at 0 ꢂC was
added imidazole (0.5 g, 7.2 mmol) followed by TBSCl (0.88 g,
5.8 mmol). Reaction mixture was stirred at same temperature until
complete consumption of starting material as indicated by TLC
(0.5 h). The reaction mixture was quenched with ice and extracted
with DCM (25 mL). The organic layer was washed with brine, dried
over anhydrous Na2SO4 and concentrated in vacuo. The crude
product was purified by flash chromatography (5% EtOAc/hexanes)
to give 16 (1.43 g, 92%) as a white solid; Rf 0.45 (n-hexane/ethyl
acetate, 9:1); mp 44e45 ꢂC; IR (KBr) nmax 2929, 2855, 1464, 1254,
NMR (300 MHz, CDCl3)
d
6.95 (1H, dd, J¼8.31, 1.88 Hz, ArH), 6.89
(1H, d, J¼1.88 Hz, ArH), 6.83 (1H, d, J¼8.31 Hz, ArH), 6.64 (1H, s,
CH2]C), 6.39 (1H, s, CH2]C), 5.84 (1H, s, CHOAc), 4.16 (2H, q,
J¼6.98 Hz, CO2CH2CH3), 3.88 (3H, s, OCH3), 3.87 (3H, s, OCH3),
2.11 (3H, s, COCH3), 1.23 (3H, t, J¼6.98 Hz, CO2CH2CH3); 13C NMR
(125 MHz, CDCl3)
d 169.5, 165.0, 149.1, 148.8, 139.9, 130.2, 125.0,
120.4, 111.0, 110.9, 73.1, 60.9, 55.85, 55.83, 21.1, 14.0; LCMS: m/
z¼331 [MþNa]þ.
1215, 1103, 840; 1H NMR (300 MHz, CDCl3)
d 6.95 (1H, s, ArH), 6.82
(1H, s, ArH), 6.52 (1H, s, CH]C), 4.54 (2H, s, CH2OTBS), 3.87 (3H, s,
4.4. Ethyl 5,6-dimethoxy-1H-indene-2-carboxylate (14)
OCH3), 3.86 (3H, s, OCH3), 3.26 (2H, s, ArCH2), 0.93 (9H, s,
SiC(CH3)3), 0.08 (6H, s, Si(CH3)2); 13C NMR (125 MHz, CDCl3)
d 148.1,
To a stirred solution of 11 (2 g, 7.5 mmol) in CH2Cl2 was added
P2O5 (0.20 g) at room temperature. After 1 h, the mixture was di-
luted with H2O (10 mL) and extracted with Et2O (2ꢃ40 mL). The
combined organic layers were dried (anhydrous Na2SO4) and the
solvent was evaporated in reduced pressure. The crude product
obtained was purified by column chromatography (silica gel, 8%
EtOAc in hexanes) to afford indene 14 (0.58 g, 32%), as a colourless
crystalline solid.
147.9, 146.7, 137.6, 135.6, 126.4, 108.2, 104.5, 62.2, 56.2, 56.1, 38.8,
25.9, 18.4, ꢁ5.3; MS (ESI): m/z¼343 [MþNa]þ, 189 [MꢁOTBS]þ;
HRMS (ESI): calcd for C12H13O2 [MþOTBS]þ: 189.09101; found:
189.09160.
4.8. 2-((tert-Butyldimethylsilyloxy)methyl)-5,6-di,ethoxy-2,3-
dihydro-1H-indene-1,2-diol [( )-10]
The TBS-ether 16 (1.0 g, 3.1 mmol) was dissolved in acetone/
H2O (9:1, 10 mL) and cooled to 0 ꢂC. 4-Methylmorpholine-N-oxide
(0.73 g, 6.23 mmol) was added followed by osmium tetroxide (4%
in t-BuOH, 0.6 mL, 0.09 mmol) and the solution was warmed to
room temperature and was stirred for 10 h. Saturated aqueous
solution of Na2S2O3 (5 mL) was added and the mixture was stirred
for 1 h. Saturated aqueous solution of NaHCO3 (5 mL) was added
and the mixture was extracted with EtOAc (3ꢃ100 mL). The
combined organic phases were dried over anhydrous Na2SO4 and
concentrated. Crude product purified with flash column chro-
matography on silica gel to afford (ꢀ)-10 (0.65 g, 90%) as brown
solid; Rf 0.24 (n-hexane/ethyl acetate, 7:3); mp 70e71 ꢂC; IR (KBr)
nmax 3439, 2930, 2855, 1504, 1466, 1305, 1253, 1099, 1064, 988,
4.5. Compound 14 from BayliseHillman acetate 13
BayliseHillman acetate 13 (250 mg, 0.81 mmol), Pd(OAc)2
(9.0 mg, 0.04 mmol), K2CO3 (112 mg, 0.81 mmol), and Ph3P (8.5 mg,
0.16 mmol) were placed in an RB under nitrogen atmosphere. 1,4-
Dioxane (2.0 mL) was added via cannula. After the reaction mixture
was stirred at 110 ꢂC for 10 h, the solvent was removed under re-
duced pressure, and the residue was purified by silica gel chro-
matography (EtOAc/PE¼1:20) to give indenes 14 (135 mg, 67%) as
a crystalline solid; Rf 0.5 (n-hexane/ethyl acetate, 7:3); mp 101 ꢂC;
IR (KBr) nmax 2976, 2840, 1702, 1606, 1557, 1337, 1221, 1098; 1H NMR
(300 MHz, CDCl3)
d 7.64 (1H, s, ArH), 7.06 (1H, s, ArH), 7.02 (1H, s,
CH]C), 4.28 (2H, q, J¼7.17 Hz, CO2CH2CH3), 3.92 (3H, s, OCH3), 3.91
846; 1H NMR (500 MHz, CDCl3)
d 6.94 (1H, s, ArH), 6.72 (1H, s,
(3H, s, OCH3), 3.62 (2H, d, J¼1.32 Hz, ArCH2), 1.35 (3H, t, J¼7.17 Hz,
ArH), 4.90 (1H, d, J¼4.88 Hz, ArCH), 3.87 (3H, s, OCH3), 3.85 (3H, s,
OCH3), 3.76 (1H, d, J¼9.91 Hz, CH2OTBS), 3.71 (1H, d, J¼9.91 Hz,
CH2OTBS), 3.07 (1H, br s, OH), 2.93 (1H, d, J¼16.17 Hz, ArCH2),
2.86 (1H, d, J¼16.02 Hz, ArCH2), 2.79 (1H, br s d, J¼5.95 Hz, OH),
0.91 (9H, s, SiC(CH3)3), 0.10 (6H, s, Si(CH3)2); 13C NMR (125 MHz,
CO2CH2CH3); 13C NMR (75 MHz, CDCl3)
d 164.9, 149.7, 148.7, 141.1,
138.3, 135.8, 135.3, 107.6, 105.9, 60.2, 56.1, 38.3, 14.4; MS (ESI): m/
z¼249 [MþH]þ, 271 [MþNa]þ; HRMS (ESI): calcd for C14H17O4
[MþH]þ: 249.11214; found: 249.11212.
CDCl3)
d 149.6, 148.7, 133.9, 131.4, 107.9, 107.7, 81.7, 77.4, 67.9, 55.9,
4.6. (5,6-Dimethoxy-1H-inden-2-yl)methanol (15)
40.43, 25.8, 18.2, ꢁ5.43, ꢁ5.46; MS (ESI): m/z¼377 [MþNa]þ;
HRMS (ESI): calcd for C18H30NaO5Si [MþNa]þ: 377.1778; found:
377.1778.
To a solution of ethyl ester 14 (0.8 g, 3.22 mmol) in dry CH2Cl2
(15 mL) at ꢁ15 ꢂC was added DIBAL 2.5 M in hexane (5.72 mL,
8.0 mmol). Reaction mixture was stirred at same temperature for
1.0 h. Then reaction mixture was quenched with saturated aqueous
solution of sodium potassium tartarate, kept for vigorous stirring
until the two layers separated. Reaction mixture was extracted with
DCM (2ꢃ25 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The
crude product obtained was purified by column chromatography
(silica gel, 27% EtOAc in hexanes) to afford compound 15 (0.611 g,
92%), Rf 0.1 (n-hexane/ethyl acetate, 7:3); as a white solid; mp
4.9. 1-(2,4-Bis(benzyloxy)phenyl)-2-(hydroxymethyl)-5,6-
dimethoxy-2,3-dihydro-1H-inden-2-ol [( )-8]
To a solution of diol (ꢀ)-10 (0.50 g, 1.41 mmol) and di-
benzylether protected resorcinol 9 (0.60 g, 2.1 mmol) in dry
dichloromethane (12 mL) at ꢁ78 ꢂC was added BF3$Et2O (1.04 mL,
8.4 mmol) in two portions in the gap of 20 min. The reaction
mixture was stirred at ꢁ78 ꢂC for 30 min, then it was stirred at
0
ꢂC for another 30 min. A solution of saturated aqueous NaHCO3

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J.S. Yadav et al. / Tetrahedron 70 (2014) 7560e7566
(10 mL) was added. The layers were separated and the aqueous
layer was extracted with dichloromethane (3ꢃ30 mL). The com-
bined organic phases were washed subsequently with saturated
aqueous NaHCO3, brine and dried over anhydrous Na2SO4. After
removal of the solvents, the residue was chromatographed on
silica gel to afford (ꢀ)-8 (0.65 g, 90%) as a white solid; Rf 0.51 (n-
hexane/ethyl acetate, 1:1); mp 129e130 ꢂC; IR (KBr) nmax 3503,
3431, 2915, 1608, 1503, 1458, 1267, 1215, 1172, 1096, 1030; 1H NMR
4.12. (1-(2,4-Bis(benzyloxy)phenyl)-5,6-dimethoxy-2-(4-
methoxybenzyloxy)-2,3-dihydro-1H-inden-2-yl)methanol
[( )-19]
DIBAL-H (0.60 mL, 1.03 mmol, 25% of DIBAL-H in toluene) was
added slowly to a solution of compound (ꢀ)-18 (0.05 g, 0.79 mmol)
in CH2Cl2 at ꢁ20 ꢂC and the reaction mixture was stirred at the
same temperature while monitoring the progress of reaction by TLC
(1 h). After consumption of all the starting materials, the reaction
mixture was quenched with a saturated aqueous potassium sodium
tartrate solution and it was stirred vigorously at room temperature
for 1 h. The reaction mixture was extracted with CH2Cl2 (3ꢃ20 mL),
concentrated under reduced pressure and purified by silica gel
column chromatography to afford alcohol (ꢀ)-19 (600 mg, 95%) as
a yellow viscous liquid. Rf 0.25 (n-hexane/ethyl acetate, 7:3); IR
(KBr) nmax 3511, 2933, 1609, 1505, 1459, 1248, 1218, 1170, 1101, 1031;
(500 MHz, CDCl3)
d 7.48e7.33 (10H, m, ArHOBn), 6.92 (1H, d,
J¼8.39 Hz, ArH), 6.81 (1H, s, ArH), 6.77 (1H, s, ArH), 6.61 (1H, d,
J¼8.39 Hz, ArH), 6.50 (1H, s, ArH), 5.15e5.02 (4H, m, (eOCH2Ph)2),
4.83 (1H, s, ArCHAr), 3.88 (3H, s, OCH3), 3.76 (3H, s, OCH3),
3.65e3.47 (2H, m, CH2OH), 3.10 (1H, d, J¼16.17 Hz, ArCH), 2.92
(1H, d, J¼16.02 Hz, ArCH), 2.31 (1H, br s, OH); 13C NMR (75 MHz,
CDCl3)
d 159.2, 157.7, 148.5, 148.3, 136.7, 135.8, 135.1, 133.1, 131.3,
128.8, 128.6, 128.1, 127.9, 127.6, 118.9, 108.5, 107.9, 106.1, 100.7, 84.1,
70.89, 70.2, 68.4, 56.0, 55.9, 49.3, 41.8: MS (ESI): m/z¼513 [MþH]þ,
535 [MþNa]þ; HRMS (ESI): calcd for C32H36NO6 [MþNH4]þ:
530.25371; found: 530.25507.
1H NMR (500 MHz, CDCl3)
d 7.46e7.31 (10H, m, ArH), 6.84 (2H, d,
J¼8.5 Hz, ArH), 6.77e6.66 (5H, m, ArH), 6.57 (1H, s, ArH), 6.51 (1H,
dd, J¼8.54, 2.44 Hz, ArH), 5.07e5.03 (3H, m, OCH2Ph), 4.96 (1H, d,
J¼10.98 Hz, OCH2Ph), 4.90 (1H, s, ArCHAr), 4.31 (1H, d, J¼11.44 Hz,
OCH2PhOMe), 4.22 (1H, d, J¼11.29 Hz, OCH2PhOMe), 3.87 (3H, s,
OMe), 3.77 (3H, s, OMe), 3.76 (3H, s, OMe), 3.71e3.64 (2H, m,
CH2OH), 3.18 (1H, d, J¼16.02 Hz, ArCH2), 2.96 (1H, d, J¼15.86 Hz,
4.10. 4-(2-Hydroxy-2-(hydroxymethyl)-5,6-dimethoxy-2,3-
dihydro-1H-inden-1-yl)benzene-1,3-diol [( )-17]
ArCH2); 13C NMR (75 MHz, CDCl3)
d 158.6, 157.8, 148.4, 136.9, 136.4,
Mixture of (ꢀ)-8 (100 mg, 0.19 mmol) and Pd/C (10% Pd, 35 mg)
in EtOH was stirred for 12 h at room temperature under hydrogen
atmosphere. Reaction mixture was filtered over Celite, the filtrate
was concentrated under reduced pressure and purification by silica
gel column chromatography afforded (ꢀ)-17 (64 mg, quant.) as
a viscous liquid; Rf 0.54 (ethyl acetate); IR (KBr) nmax 3381, 2925,
2854, 1724, 1612, 1508, 1462, 1247, 1217, 1091, 1032, 757; 1H NMR
135.9, 132.2, 131.3, 130.95, 128.7, 128.6, 128.2, 127.9, 127.8, 127.5,
121.3, 113.4, 108.4, 107.6, 105.5, 100.1, 89.0, 70.6, 70.2, 65.1, 55.9,
55.2, 48.4, 37.9, 29.7; MS (ESI): m/z¼655 [MþNa]þ; HRMS (ESI):
calcd for C40H41O7 [MþH]þ: 633.28468; found: 633.28638.
4.13. 4-(2-(Hydroxymethyl)-5,6-dimethoxy-2-(4-
methoxybenzyloxy)-2,3-dihydro-1H-inden-1-yl)benzene-1,3-
diol [( )-20]
(300 MHz, CD3OD)
d
6.84 (1H, s, ArH), 6.71 (1H, d, J¼8.31 Hz, ArH),
6.45 (1H, s, ArH), 6.32 (1H, d, J¼2.27 Hz, ArH), 6.25 (1H, dd, J¼8.31,
2.45 Hz, ArH), 4.53 (1H, s, ArCHAr), 3.78 (3H, s, OMe), 3.64 (3H, s,
OMe), 3.57 (2H, s, CH2OH), 3.12 (1H, d, J¼16.05 Hz, ArCH2), 2.83 (1H,
A suspension of compound (ꢀ)-19 (100 mg, 0.158 mmol) and
Raney-Ni (50 mg) in ethanol (7 mL) was stirred under hydrogen
(balloon) at room temperature for 18 h. The reaction mixture was
filtered through Celite pad, washed with methanol thoroughly
(5ꢃ20 mL) and concentrated to give the crude triol, which is pu-
rified by the column chromatography to afford (ꢀ)-20 (71 mg,
quant. yield) as a colourless viscous liquid. Rf 0.83 (ethyl acetate); IR
(KBr) nmax 3280, 2921, 2852, 1729, 1601, 1527, 1461, 1212, 1169, 1097,
d, J¼16.05 Hz, PhCH2); 13C NMR (75 MHz, CD3OD)
d 158.6, 158.1,
149.9, 149.8, 137.7, 134.5, 133.3, 117.3, 110.2, 110.0, 107.9, 104.0, 86.6,
68.2, 56.8, 56.7, 43.2, 30.8; MS (ESI): m/z¼355 [MþNa]þ; HRMS
(ESI): calcd for C18H19O6 [MꢁH]þ: 331.11890; found: 331.11906.
4.11. 10-(2,4-Bis(benzyloxy)phenyl)-50,60-dimethoxy-2-(4-
methoxybenzyl)-10,30-dihydrospiro[[1,3]dioxolane-4,20-in-
dene] [( )-18]
763; 1H NMR (300 MHz, CD3OD)
d 6.83 (1H, s, ArH), 6.77 (2H, d,
J¼8.68 Hz, ArH), 6.66 (2H, d, J¼8.68 Hz, ArH), 6.62e6.53 (2H, m,
ArH), 6.31 (1H, d, J¼2.45 Hz, ArH), 6.20 (1H, dd, J¼8.30, 2.45 Hz,
ArH), 4.62 (1H, s, ArCHAr), 4.36 (2H, s, eOCH2PhOMe), 3.89 (1H, d,
J¼11.89 Hz, CH2OH), 3.80 (3H, s, OMe), 3.69 (3H, s, OMe), 3.68 (3H,
s, OMe), 3.71e3.65 (1H, m, CH2OH), 3.13 (2H, d, J¼3.58 Hz, ArCH2);
MS (ESI): m/z¼475 [MþNa]þ.
Anisaldehyde dimethyl acetal (0.2 mL, 1.17 mmol) and a cata-
lytic amount of azeotropically dried CSA were added to a stirred
solution of diol (ꢀ)-8 (0.50 g, 0.97 mmol) in CH2Cl2 (12 mL) at 0 ꢂC.
The reaction mixture was stirred at room temperature for 1 h. It
was then quenched with aqueous NaHCO3, extracted with CH2Cl2
(3ꢃ20 mL), dried with anhydrous Na2SO4, evaporated and purified
on silica gel using 15% EtOAc/hexane as eluent to furnish the
protected diol (ꢀ)-18 (0.60 g, 94%) as a viscous liquid. Rf 0.51 (n-
hexane/ethyl acetate, 7:3); IR (KBr) nmax 1610, 1503, 1455, 1249,
4.14. (1-(2,4-Bis(benzyloxy)phenyl)-5,6-dimethoxy-2-(4-
methoxybenzyloxy)-2,3-dihydro-1H-inden-2-yl)methyl-
methanesulfonate [( )-22]
1169, 1030; 1H NMR (300 MHz, CDCl3)
d
7.52e7.31 (17H, m, ArH),
To
a
cooled solution (0 ꢂC) of alcohol (ꢀ)-19 (400 mg,
7.21e7.16 (1H, m, ArH), 6.99 (1H, d, J¼8.49 Hz, ArH), 6.84e6.50
(12H, m, ArH), 5.73 (1H, s, OCHO), 5.14e5.03 (8H, m, OCH2Ph), 4.94
(1H, d, J¼6.23 Hz, ArCHAr), 4.43 (1H, d, J¼8.30 Hz, CH2PhOCH3),
4.26e4.14 (1H, m, CH2PhOCH3), 3.97 (1H, d, J¼8.12 Hz,
CH2PhOCH3), 3.87 (5H, s, OCH3), 3.77 (3H, s, OCH3), 3.75 (5H, s,
OCH3), 3.72 (3H, s, OCH3), 3.35e3.05 (4H, m, ArCH2, eOCH2); 13C
0.632 mmol) and triethylamine (0.34 mL, 2.52 mmol) in dichloro-
methane (10 mL) was added dropwise mesylchloride (0.103 mL,
1.26 mmol). After stirring at the same temperature for 30 min, water
(10 mL) was added, aqueous solution was extracted with DCM
(3ꢃ30 mL), dried (anhydrous MgSO4) and concentrated to give the
crude mesylate, which is purified by the column chromatography to
afford (ꢀ)-22 (448 mg, 97%) as a colourless viscous liquid. Rf 0.24 (n-
hexane/ethyl acetate, 7:3); IR (KBr) nmax 3449, 2923, 2854, 1608,
1504, 1353, 1288, 1248, 1172, 1098; 1H NMR (300 MHz, CDCl3)
NMR (75 MHz, CDCl3)
d 159.2, 157.7, 148.5, 148.3, 136.6, 135.8,
135.1, 133.1, 132.7, 132.5, 131.9, 131.3, 130.6, 129.9, 128.8, 128.6,
128.3, 128.1, 127.9, 127.6, 118.8, 114.2, 108.4, 107.9, 106.1, 100.7, 84.1,
70.9, 70.2, 68.4, 56.1, 56.0, 55.5, 49.3, 41.7; MS (ESI): m/z¼631
[MþH]þ, 653 [MþNa]þ; HRMS (ESI): calcd for C40H39O7 [MþH]þ:
631.26903; found: 631.27020.
d
7.50e7.29 (11H, m, ArH), 6.88e6.47 (8H, m, ArH), 5.12e4.96 (4H, m,
OCH2Ph), 4.83 (1H, s, ArCHAr), 4.48e4.26 (4H, m, OCH2PhOMe and
CH2OMs), 3.88 (3H, s, OMe), 3.76 (3H, s, OMe), 3.74 (3H, s, OMe), 3.32

J.S. Yadav et al. / Tetrahedron 70 (2014) 7560e7566
7565
(1H, d, J¼15.86 Hz, ArCH2), 3.11 (1H, d, J¼15.10 Hz, ArCH2), 2.68 (3H,
s, CH3SO2); 13C NMR (125 MHz, CDCl3)
158.9, 158.6, 157.7, 148.6,
stirred under hydrogen (balloon) for 2 h. The reaction mixture was
filtered through Celite pad, washed with EtOAc thoroughly
(5ꢃ20 mL) and concentrated, crude product purified with column
chromatography to afford dimethyl brazilane (ꢀ)-24 in quantitative
yield as a solid; Rf 0.34 (n-hexane/ethyl acetate, 7:3); mp 169 ꢂC
(decomposition); IR (KBr) nmax 3380, 2925, 2853, 1741, 1621, 1595,
d
136.9,136.7,135.6,131.5,130.8,128.7,128.6,128.3,128.2,128.1,128.0,
127.7, 127.5, 120.2, 118.1, 113.3, 108.2, 107.5, 105.7, 100.2, 87.2, 73.0,
70.53, 70.16, 66.2, 56.0, 55.2, 48.9, 38.2, 37.1, 31.5, 29.7; MS (ESI): m/
z¼728 [MþH]þ, 733 [MþNa]þ; HRMS (ESI): calcd for C41H46NO9S
[MþNH4]þ: 728.2888; found: 728.2901.
1501,1465,1304,1277,1153; 1H NMR (500 MHz, CDCl3)
d 7.28 (1H, s,
ArH), 6.86 (1H, s, ArH), 6.77 (1H, s, ArH), 6.52 (1H, dd, J¼8.39,
2.59 Hz, ArH), 6.37 (1H, d, J¼2.44 Hz, ArH), 4.21 (1H, d, J¼6.56, Hz,
ArCHAr), 4.11 (1H, dd, J¼10.98, 4.42 Hz, CH2Oe), 3.84 (6H, s, OMe),
3.61 (1H, dist. t, J¼10.52, 10.68 Hz, CH2Oe), 3.17 (1H, dd, J¼15.71,
7.17 Hz, ArCH2), 2.95e2.87 (1H, m, CH2CHCH2), 2.59 (1H, dd, J¼15.71,
4.15. 9,10-Dimethoxy-6a-(4-methoxybenzyloxy)-6,6a,7,11b-
tetrahydroindeno[2,1-c]chromen-3-ol [( )-21]
A suspension of mesylate (ꢀ)-22 (400 mg, 0.60 mmol) and
Raney-Ni (100 mg) in ethanol (7 mL) was stirred under hydrogen
(balloon) at room temperature for 18 h. The reaction mixture was
filtered through Celite pad, washed with methanol thoroughly
(5ꢃ20 mL) and concentrated. Due to unstable nature of hydroge-
nated product it was used in next step without any further purifi-
cation. To cooled (0 ꢂC) solution of hydrogenated diol (283 mg,
0.534 mmol) was added NaH (25 mg, 1.07 mmol). After stirring at
the same temperature for 30 min, reaction was quenched with ice,
solution was extracted with EtOAc (3ꢃ30 mL), dried (anhydrous
MgSO4) and concentrated to give the crude product, which is pu-
rified by the column chromatography to afford (ꢀ)-21 (220 mg,
90.25% for two steps) as a yellow solid; mp 148 ꢂC (decomposition);
Rf 0.6 (n-hexane/ethyl acetate, 1:1); IR (KBr) nmax 3393, 1614, 1506,
1462, 1337, 1298, 1250, 1216, 1164, 1126, 1078, 1027; 1H NMR
1.98 Hz, ArCH2); 13C NMR (125 MHz, CDCl3)
d 155.5, 155.1, 148.4,
148.2, 137.2, 132.6, 130.9, 116.0, 108.6, 108.4, 107.9, 103.7, 66.8, 56.1,
56.0, 43.2, 36.8, 33.9; MS (ESI): m/z¼299 [MþH]þ, 321 [MþNa]þ
4.18. 6,6a,7,11b-Tetrahydroindeno[2,1-c]chromene-3,9,10-triol
(2) [( )-brazilane]
To a solution of compound (ꢀ)-24 (20 mg, 0.067 mmol) in dry
dichloromethane (3 mL) at ꢁ78 ꢂC was added dropwise a solution
of boron tribromide (0.019 mL, 0.20 mmol). The reaction mixture
was then stirred at ꢁ78 ꢂC for 1 h and further was stirred at room
temperature for 1 h. The reaction was quenched by the addition of
methanol (0.6 mL), then diluted with water (5 mL). The aqueous
phase was extracted with EtOAc (3ꢃ10 mL). The combined organic
phases were washed with brine (5 mL), dried over anhydrous
Na2SO4 and concentrated. Flash column chromatography on silica
gel afforded the (ꢀ)-brazilane 2 (17 mg, 92%) as a white solid; Rf
0.48 (n-hexane/ethyl acetate, 1:1); mp 155e156 ꢂC; IR (KBr) nmax
3421, 2925, 2854, 1728, 1658, 1505, 1461, 1280, 1157, 1118, 1074; 1H
(500 MHz, CDCl3)
d 7.54e7.51 (1H, m, ArH), 7.29 (1H, s, ArH), 6.87
(1H, s, ArH), 6.72e6.63 (4H, m, ArH), 6.48e6.45 (2H, m, ArH), 4.61
(1H, dd, J¼10.68, 1.52 Hz, CH2Oe), 4.42 (1H, d, J¼10.83 Hz, CH2Oe),
4.33 (1H, s, ArCHAr), 4.12 (2H, q, J¼11.29 Hz, OCH2PhOMe), 3.97
(3H, s, OMe), 3.89 (3H, s, OMe), 3.70 (3H, s, OMe), 3.23 (1H, d,
J¼15.71 Hz, ArCH2), 2.88 (1H, d, J¼15.71 Hz, ArCH2); 13C NMR
NMR (500 MHz, acetone-d6) d 8.22 (1H, s, ArOH), 7.67 (1H, s, ArOH),
(125 MHz, CDCl3)
d 158.7, 155.6, 155.1, 148.2, 148.1, 133.2, 130.1,
7.59 (1H, s, ArOH), 7.21 (1H, d, J¼8.24 Hz, ArH), 6.81 (1H, s, ArH),
6.68 (1H, s, ArH), 6.47 (1H, dd, J¼8.24, 2.44 Hz, ArH), 6.26 (1H, d,
J¼2.44 Hz, ArH), 4.09 (1H, d, J¼6.56, Hz, ArCHAr), 4.04 (1H, dd,
J¼10.98, 4.57 Hz, CH2Oe), 3.49 (1H, t, J¼10.37 Hz, CH2Oe), 3.04 (1H,
dd, J¼15.56, 7.17 Hz, ArCH2), 2.83e2.76 (1H, m, CH2CHCH2), 2.50
(1H, dd, J¼15.6, 2.28 Hz, ArCH2); 13C NMR (125 MHz, acetone-d6)
128.3, 125.0, 116.7, 113.4, 108.9, 108.3, 106.9, 103.5, 83.1, 73.2, 65.5,
56.4, 56.2, 55.2, 49.9, 37.3; MS (ESI): m/z¼435 [MþH]þ; HRMS (ESI):
calcd for C26H26NaO6 [MþNa]þ: 457.1622; found: 457.1650.
4.16. 9,10-Dimethoxy-6,6a,7,11b-tetrahydroindeno[2,1-c]chro-
mene-3,6a-diol [( )-7]
d
157.5, 156.4, 144.9, 144.6, 137.8, 132.7, 131.8, 116.1, 112.6, 112.3,
109.3, 104.0, 67.2, 43.5, 37.8, 34.2; MS (ESI): m/z¼271 [MþH]þ, 293
[MþNa]þ; HRMS (ESI): calcd for C16H13O4 [MꢁH]þ: 269.08138;
found: 269.08224.
To the stirred solution of compound (ꢀ)-21 (25 mg, 0.057 mmol)
in dichloromethane was added concd HCl (0.1 mL). Reaction mix-
ture was allowed to stir for 1 h. After consumption of all the starting
material (monitored by TCL), the reaction mixture was quenched
with solid sodium bicarbonate. The reaction mixture was extracted
with CH2Cl2 (3ꢃ20 mL), washed with sodium bicarbonate solution,
dried over anhydrous Na2SO4, concentrated under reduced pres-
sure, and purified by silica gel column chromatography to afford the
dimethylbrazilin (ꢀ)-7 (10 mg, 60%) as a yellow solid; Rf 0.48 (n-
hexane/ethyl acetate, 1:1); mp 184e185 ꢂC; IR (KBr) nmax 3422,
2924, 2853, 1715, 1619, 1501, 1463, 1259, 1220, 1084; 1H NMR
Acknowledgements
A.K.M. thanks Council of Scientific and Industrial Research
(CSIR), New Delhi for fellowships. The authors also thank the
Council of Scientific and Industrial Research (CSIR)-New Delhi for
financial support under ORIGIN programme (CSC-0108) (12th five-
year plan), J.C. Bose and CSIR Bhatnagar Fellowship.
(300 MHz, methanol-d4)
d
7.28 (1H, d, J¼8.31 Hz, ArH), 6.89 (1H, s,
Supplementary data
ArH), 6.83 (1H, s, ArH), 6.50 (1H, dd, J¼8.31, 2.27 Hz, ArH), 6.31 (1H,
d, J¼2.27 Hz, ArH), 4.06 (1H, s, ArCHAr), 3.96 (1H, d, J¼10.76 Hz,
CH2Oe), 3.80 (3H, s, OMe), 3.79 (3H, s, OMe), 3.73 (1H, d,
J¼11.33 Hz, CH2Oe), 3.10 (1H, d, J¼15.86 Hz, ArCH2), 2.91 (1H, d,
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.08.001.
J¼15.86 Hz, ArCH2); 13C NMR (125 MHz, methanol-d4)
d 156.6,
References and notes
154.4, 148.8, 148.4, 137.1, 131.4, 130.7, 113.9, 108.78, 108.76, 102.9,
76.8, 69.4, 55.3, 55.2, 50.1, 41.7; MS (ESI): m/z¼315 [MþH]þ; HRMS
(ESI): calcd for C18H18NaO5 [MþNa]þ: 337.1046; found: 337.1065.
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