Grob fragmentation of norbornyl α-diketones: A route to α-ketoenols and aromatic compounds

Article abstract of DOI:10.1021/jo200223a

An efficient acid-catalyzed Grob fragmentation of symmetrical and asymmetrically substituted norbornyl α-diketones to the corresponding six-membered α-ketoenols is reported. The regio- and stereochemical outcome of the Grob fragmentation of C2 mono- and disubstituted α-diketones was investigated. A single regioisomer resulting from a favorable half-chair intermediate was normally observed. A departure from the normal course was noticed for C2 disubstituted α-diketones possessing an exo-methyl and an endo-methoxycarbonyl derivative, giving the opposite regioisomers due to initial formation of the hemiketal. The bromo analogues of the C2 disubstituted α-diketones furnished an unusual byproduct, which appears to have been formed through highly reactive fused four-membered bicyclo[2.2.0]hexane intermediates. A plausible mechanistic proposal involving the gem-dihalo intermediate, which in one case was actually isolated as its BF₂-complex, is outlined. The fragmentation protocol was applied to various norbornyl substrates including bis-α-diketone derivatives. The methodology was successfully utilized for the synthesis of substituted aromatic compounds.

Full text of DOI:10.1021/jo200223a

ARTICLE
pubs.acs.org/joc
Grob Fragmentation of Norbornyl r-Diketones: A Route to
r-Ketoenols and Aromatic Compounds
Faiz Ahmed Khan*,†,‡ and Ch. Nageswara Rao†
†Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
‡Department of Chemistry, Indian Institute of Technology Hyderabad, Ordnance Factory Estate, Yeddumailaram 502205, India
S Supporting Information
b
ABSTRACT: An efficient acid-catalyzed Grob fragmentation of symmetrical and
asymmetrically substituted norbornyl R-diketones to the corresponding six-mem-
bered R-ketoenols is reported. The regio- and stereochemical outcome of the Grob
fragmentation of C2 mono- and disubstituted R-diketones was investigated. A single
regioisomer resulting from a favorable half-chair intermediate was normally observed.
A departure from the normal course was noticed for C2 disubstituted R-diketones
possessing an exo-methyl and an endo-methoxycarbonyl derivative, giving the opposite
regioisomers due to initial formation of the hemiketal. The bromo analogues of the C2
disubstituted R-diketones furnished an unusual byproduct, which appears to have
been formed through highly reactive fused four-membered bicyclo[2.2.0]hexane
intermediates. A plausible mechanistic proposal involving the gem-dihalo intermedi-
ate, which in one case was actually isolated as its BF2-complex, is outlined. The
fragmentation protocol was applied to various norbornyl substrates including bis-R-
diketone derivatives. The methodology was successfully utilized for the synthesis of
substituted aromatic compounds.
’ INTRODUCTION
fragmentation. Particularly, for monosubstituted diketones 3
(R2 = H), the regiochemical outcome resulting from the cleavage
of either bond a or b due to two competing carbonyl nucleofuge
groups would be an additional factor of curiosity.
Heterolytic fragmentation of a σ bond activated by electro-
fugal and nucleofugal groups situated in positions 1 and 3 on an
aliphatic chain, known as Grob fragmentation, is an important
tool in organic syntheses.1 This strategy is particularly rewarding
when fashioned in a stereoselectively constructed rigid bi- or
polycyclic system to eventually unravel the target skeleton. The
predictable stereochemical outcome of this fragmentation has
been elegantly utilized by Mulzer and others in a variety of
natural product syntheses.2,3
’ RESULTS AND DISCUSSIONS
Initially, norbornyl R-diketone 3a derived from DielsꢀAlder
adduct of cyclohexene with 5,5-dimethoxy-1,2,3,4-tetrachlorocy-
clo-pentadiene was subjected to a variety of acid-mediated
fragmentation conditions. The acids such as AcOH, 10% aq
HCl, TFA, and p-toluenesulfonic acid (PTSA) were explored in
combination with solvents such as AcOH, MeOH, 1,2-DCE,
toluene, and benzene. Optimization studies revealed that PTSA
in toluene gave the best results in terms of yield, reaction time,
and equivalents of acid used (Table 1).
The reaction conditions optimized for 3a were then extended
to other norbornyl R-diketones, and the results are summarized
in Table 1. The bromo analogue 3b also underwent smooth
transformation to give the corresponding R-ketoenol 4b in near
quantitative yield. Similarly, the chloro as well as bromo deriva-
tives of cyclopentane- and cyclooctane-fused norbornyl R-dike-
tones 3c,d,e,f furnished the corresponding bicyclic R-ketoenols
4c,d,e,f in high yield (Table 2, entries 3-6).
We have reported a highly efficient Grob fragmentation of
1,4,5,6-tetrahalo-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-one 1
(R = H), occurring spontaneously upon heating, to give trihalo-
phenol derivative 2.4 The alkyl- or aryl-substituted derivatives of
1 (R = alkyl or aryl) underwent transformation to 2 in presence of
an acid catalyst. It occurred to us that norbornyl R-diketones 3,
prepared efficiently from the corresponding tetrahalo norbornyl
derivatives,5 would be interesting substrates to study Grob
In order to probe the regiochemical outcome, monosubsti-
tuted norbornyl R-diketones (R2 = H) were considered. The
Received: January 30, 2011
Published: March 18, 2011
r
2011 American Chemical Society
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endo-phenyl substituted chloro and bromo derivatives 3g,h upon
treatment with PTSA exclusively furnished, in each case, a single
regioisomer 4g,h arising from the cleavage of bond a. The endo-
methoxycarbonyl derivatives 3i,j also showed a similar trend and
gave excellent yields of 4i,j (Table 2, entries 7ꢀ10).
A plausible mechanism to account for the exclusive formation
of a single regioisomer is depicted in Scheme 1. Protonation is
equally likely at either of the two competing carbonyl nucleofuge
groups 1 and 2. Protonation at carbonyl 1 of 3 triggers fragmen-
tation of bond a leading to half-chair X via the intermediate X1.
Since the substituent R1 would have a trans 1,3-relationship to
the newly formed axial CO2Me group, it occupies sterically
comfortable pseudoequatorial position. The enol moiety is well
poised for intramolecular hydrogen bonding. Alternatively, pro-
tonation at carbonyl 2 followed by cleavage of bond b is expected
to furnish the other possible regioisomer Y via the intermediate
Y1. This pathway is not preferred due to unfavorable 1,2-diaxial
disposition of R1 and newly formed CO2Me group.
Table 1. Solvent and Acid Screening for the Fragmentation
Reaction
Interestingly, the diester substituted R-diketones 5a and 5b
when subjected to acid-mediated reaction furnished substituted
aromatic compounds 6a and 6b (Scheme 2). The electron-
withdrawing ester substituent present at C-3 renders the
R-hydrogen acidic, thereby facilitating elimination of HX from
the initially formed enol intermediate and leading to the observed
aromatic products.
We turned our attention to C2 disubstituted R-diketones in
order to investigate the regio- and stereochemical outcome of the
Grob fragmentation. The R-diketones 7a,b possessing a methyl
as well as an ester groups at C2 were subjected to the fragmenta-
tion reaction (Scheme 3). Intriguingly, hemiketals 8a,b were
isolated in excellent yield when the reaction was stopped after
30 min. However, continuation of the reaction or exposing the
isolated hemiketals 8a,b to the same conditions for a prolonged
period furnished cleavage products (Scheme 3). Treatment of
the crude reaction mixture with diazomethane followed by
column purification gave a single diastereomer 9a as a colorless
viscous liquid in case of chloro analogue, whereas in case of
bromo derivative two diastereomers 10a and 10b were obtained.
Analysis of 1H and 13C NMR showed a close resemblance and
consistency between 9a and 10a, indicating that these two
belonged to the same series. The molecular connectivity in 9a
was unambiguously established through 2D NMR studies
no.
acid
solvent
t (h)
yield (%)
1
2
3
4
5
6
AcOH
AcOH
6
14
9
91
100
95
AcOHa
10% HClb
benzene
MeOH
1,2-DCE
benzene
Toluene
TFAc
4
100
100
98
p-TsOH (4 equiv)
p-TsOH (2 equiv)
3
2.5
a Excess (40 equiv). b 2 mL per 1 mmol. c 10 equiv.
Table 2. PTSA-Mediated Grob Fragmentation of 3
no.
R1, R2
X
p-TsOH (equiv) t (h) product (% yield)
1
2
-(CH2)4-
-(CH2)4-
-(CH2)3-
-(CH2)3-
-(CH2)6-
-(CH2)6-
Ph, H
Cl
Br
Cl
Br
Cl
Br
Cl
Br
2
1
2
1
3
2
2
1
2
1
2.5
2.5
1.5
0.5
4.0
4.0
1.5
1.0
2.0
0.75
4a (98)
4b (98)
4c (95)
4d (84)
4e (98)
4f (85)
4g (100)
4h (97)
4i (99)
4j (95)
Scheme 2. Grob Fragmentation of R-Diketone Followed by
in Situ Aromatization of R-Ketoenol
3
4
5
6
7
8
Ph, H
9
CO2Me, H Cl
CO2Me, H Br
10
Scheme 1. Plausible Mechanism for the Grob Fragmentation of Monosubstituted 3
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(HMBC). Contrary to C2 monosubstituted R-diketones, back-
side bond b ruptured in these cases to furnish 9a and 10a. The
isomer 10b, formed only in the case of the bromo analogue,
appeared to be unusual in the sense that the HMBC spectrum
showed similar molecular connectivity as 10a (see Supporting
Information). Therefore, in order to assign the structure unequi-
vocally, the bromo derivative 10b was subjected to single crystal
X-ray analysis.6a To our astonishment, the C1 center in 10b
(nonepimerizable!) got inverted.
Exclusive cleavage of back-side bond b (C4ꢀC7) could be due
to the initial formation of hemiketals 8a,b in which carbonyl 1 is
engaged thus facilitating the protonation at carbonyl 2. To
confirm this premise, 12a,b in which the ester is replaced with
a phenyl group were exposed to similar cleavage conditions.
Once again, chloro analogue 12a furnished a single isomer 13a,
whereas bromo analogue 12b resulted in a mixture of two
products 14a,b as depicted in Scheme 4. Structural assignments
for 13a and 14a were based on internal consistency and extensive
analysis of 2D NMR (HMBC, NOESY; see Supporting In-
formation). The difficulty encountered in the purification of the
minor isomer 14b was overcome by repeated crystallization of
enriched fractions obtained from preparative HPLC (hexane/
dichloromethane). The structure of isomer 14b was secured through
single crystal X-ray analysis.6b In accordance with our proposal, all
the products from 12a,b resulted via cleavage of front bond a.
Formation of 10b as well as 14b is highly unexpected on the
basis of the known mechanism. The inversion at the none-
pimerizable C1 or C4 centers (R-bromo ester substituted
carbon) in these compounds must be taking place via a novel
pathway. To rationalize the experimental results obtained so far
and particularly to account for the unusual products obtained in
case of bromo analogues, a comprehensive mechanistic pro-
posal is delineated in Scheme 5. Under acidic conditions the
proton could approach either carbonyl 1 or 2. If proton
approaches carbonyl 1, cleavage of bond a would lead to the
formation of intermediate a1, where as if proton approaches
carbonyl 2, cleavage of bond b would lead to the formation of
intermediate b1.
Scheme 3. Unusual Grob Fragmentation of C2 Disubstituted
R-Diketones 7a,b
Scheme 4. Grob Fragmentation of R-Diketones 12a,b
These intermediates would then lead to highly reactive fused
four-membered bicyclo[2.2.0]hexane intermediates a2 or b2 via
intramolecular nucleophilic displacement. The HX released
during this process would then trigger spontaneous opening of
a2 or b2, as depicted in Scheme 5, leading to gem-dihalo
substituted products a3 or b3. The gem-dihalo substituted
intermediate a3 or b3 could undergo one more iteration of the
Scheme 5. Plausible Mechanism for the Formation of Unusual Products
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above processes via intramolecular nucleophilic displacement to
a4 or b4 followed by HX-mediated regeneration of six-mem-
bered derivatives a5 or b5.
Formation of 14b, 10b corresponding to a5, b5 provided
experimental support for the proposed mechanism in Scheme 5.
Nevertheless, isolation of the gem-dibromo substituted product
a3 would provide additional support. In this endeavor 3j was
Synthesis of Highly Substituted Aromatic Compounds
(Benzene, Naphthalene, Anthracene, Indane, Biphenyl Deriv-
atives). The synthetic importance of catechol derivatives and
their presence in various forms in innumerable natural products
prompted us to develop a practical methodology through Grob
fragmentation of abundantly available norbornyl R-diketones.
Catechols, especially, protected as dioxolanes serve as flavors and
fragrances.9 Our aim was to get protected catechols directly in a
one-pot protocol from Grob fragmentation products.
subjected to BF3 Et2O in dichloromethane for 24 h. A crystalline
3
product was obtained upon storage of the reaction mixture in
deep refrigerator (ꢀ10 °C). A single crystal X-ray analysis of this
sparingly soluble material revealed its structure to be a BF2-
complex of gem-dibromo derivative 15 (Scheme 6).7,8a When
BF2-complex 15 was washed with 50% aqueous sodium bicarbo-
nate solution, decomplexed product 16 was obtained. It was also
noticed that depending on the delay in recording the 1H NMR
spectrum of 4j, tiny peaks corresponding to 16 popped up in the
otherwise clean spectrum. Interestingly, deliberate storage of a
1H NMR sample (CDCl3) of freshly crystallized batch of 4j,
initially showing no detectable peaks of 16 in PMR, showed
formation of a substantial amount of 16 (2:1 ratio) when
analyzed after 20 days of storage in a refrigerator. In order to
secure the structure of 4j unequivocally, a single crystal X-ray
analysis of a crystal picked from the above-mentioned authentic
batch was performed.8b Further, when another authentic portion
Grob fragmentation products 4a,b,e,f were treated with
DBU-CH2Cl2 to achieve aromatization as well as protection of
in situ generated catechol derivatives by CH2Cl2.10 The reaction
proceeded smoothly leading to protected aromatic compounds
21a,b,e,f in good yield (Table 3). Further, the tetrahydro-
naphthalene derivative 21a obtained from the fragmented pro-
duct 4a was transformed to naphthalene derivative 22 in
excellent yield via DDQ oxidation (Table 3).11
Mono-O-methylated catechol is an important structural ele-
ment in many common day-to-day use natural products such as
curcumin, vanillin, eugenol, gingerol, etc. Methylation of the enol
moiety in Grob fragmentation products followed by aromatiza-
tion would provide an easy access to mono-O-methylated
catechols. In order to demonstrate this, R-ketoenols 4c,d,g,h
were exposed to an ethereal solution of diazomethane followed
by DBU mediated aromatization. Excellent yields of mono-
O-methylated catechols derivatives 23c,d,g,h were obtained as
shown in Table 4.
of 4j was subjected to BF3 Et2O reaction, the same BF2-complex
3
15 was obtained (Scheme 6).
The fragmentation methodology was extended to bis-
R-diketones 17 and 19. Subjecting these derivatives to optimized
conditions furnished the two regiomeric products 18a,b and 20a,
b, respectively (Scheme 7). The products 18a and 20a are
formed as a result of front bondꢀfront bond fragmentation,
whereas 18b, 20b resulted from the cleavage of front bondꢀback
bond in the two norbornyl segments of 17 and 19.
An impressive extension of this convenient methodology to a
highly functionalized anthracene moiety is depicted in Scheme 8.
When the bis-diketone 24 was subjected to p-TsOH conditions,
an inseparable mixture of Grob-fragmented products 25a,b were
obtained. Methylation of enol using diazomethane followed by
DBU treatment of O-methylated products 26a,b gave a column
Table 3. Preparation of Methylene Protected Tetrahydro-
naphthalenes, Naphthalene, and Cyclooctane Appended
Aromatic Compounds
Scheme 6. Key Experimental Evidence for the Mechanistic
Proposal
no.
R1, R2
X
product (% yield)
1
2
3
4
-(CH2)4-
-(CH2)4-
-(CH2)6-
-(CH2)6-
Cl
Br
Cl
Br
21a (86)
21b (85)
21e (81)
21f (77)
a DBU, CH2Cl2, 0 °C to rt, 43 h. b) DDQ, C6H6, reflux, 36 h, 91%.
Scheme 7. Demonstration of Fragmentation Protocol to Bis-R-diketone Derivatives
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Table 4. Preparation of O-Methylated Indanols and
Biphenolic Compounds
24. The central ring aromatization of 27a,b was carried out in
presence of DDQ to obtain the highly substituted anthracene
derivatives 28a,b (Scheme 8).
’ CONCLUSIONS
In conclusion, a facile acid-catalyzed Grob fragmentation of
norbornyl R-diketone to six-membered R-ketoenols was achieved.
Monosubstituted norbornyl R-diketones (R2 = H) furnished a
single regioisomer via cleavage of bond a. However, C2 disub-
stituted R-diketone possessing an exo-methyl and an endo-
methoxycarbonyl derivative gave the opposite regioisomers
due to initial formation of hemiketals. The selectivity reverted
back when the endo-methoxycarbonyl group was changed to a
phenyl group in the aforementioned derivatives. The bromo
analogues of the aforesaid C2 disubstituted R-diketones furn-
ished an unusual byproduct, which is probably formed via a
highly reactive fused four-membered bicyclo[2.2.0]hexane inter-
mediates. The gem-dihalo derivative described in the proposed
mechanism was isolated as its BF2-complex. The fragmentation
protocol was also demonstrated to various substrates including
bis-R-diketone derivatives. The methodology was successfully
utilized for the synthesis of a variety of substituted aromatic
compounds.
no.
R1, R2
X
product (% yield)
1
2
3
4
-(CH2)3-
-(CH2)3-
Ph, H
Cl
Br
Cl
Br
23c (91)
23d (80)
23g (93)
23h (82)
Ph, H
a CH2N2, Et2O/MeOH, 0 °C, 20 min. b) DBU, CH2Cl2, 0 °C, 1 h.
Scheme 8. Synthesis of Highly Substituted Anthracene
Derivativesa
’ EXPERIMENTAL SECTION
General Methods. All reactions were performed in oven-dried
apparatus. Commercial grade solvents were distilled before use. Melting
points were obtained in open capillary tubes and are uncorrected.
Infrared spectra were recorded as KBr pellets (solids), or as thin films
1
on NaCl flats (liquids). H NMR was recorded at 400 MHz unless
otherwise mentioned 500 MHz. Proton decoupled 13C NMR was
recorded at 100 MHz unless otherwise mentioned 125 MHz. 2D
NMR experiments were conducted for the structure confirmation of
some of the compounds (see Supporting Information for HMBC of 9a,
10b and NOESY and HMBC for 13a). Single crystal X-ray analysis was
carried out for the structure elucidation of compounds 4d, 10b, 14b and
15 (see Supporting Information for CIF data files). HRMS were
recorded using electron spray ionization (ESI) or electron ionization
(EI) mode.
Methyl 1,4-Dichloro-3-hydroxy-2-oxo-1,2,4a,5,6,7,8,8a-
octahydronaphthalene-1-carboxylate (4a). To a stirred solu-
tion of R-diketone 3a (200 mg, 0.652 mmol) in toluene (4 mL) was
added p-toluenesulfonic acid (p-TsOH, 225 mg, 1.305 mmol), and the
reaction mixture was refluxed for 2.5 h. The solvent was removed under
reduced pressure. The residue was dissolved in ethyl acetate (20 mL),
washed with saturated NaHCO3 (5 mL) and brine (5 mL), and dried
over anhydrous Na2SO4. After evaporation of solvent under reduced
pressure, the crude reaction mixture was purified by silica gel column
chromatography to afford the colorless crystalline compound with near
quantitative yield. Rf (10% ethyl acetate in hexane) 0.5, colorless
1
crystalline solid, mp 120 °C, yield 98% (187 mg, 0.639 mmol); H
NMR (400 MHz, CDCl3) δ 6.20 (s, 1H), 3.83 (s, 3H), 3.11 (d, 1H, J =
3.6 Hz), 2.88 (td,1H, J = 3.8, 12.2 Hz), 2.45 (d, 1H, J = 12.2 Hz), 2.05
(dd, 1H, J = 3.4, 13.1 Hz), 1.84 (dd, 1H, J = 3.8, 7.8 Hz), 1.61ꢀ1.50 (m,
2H), 1.38ꢀ1.18 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 183.3, 166.5,
144.0, 130.3, 74.6, 54.2, 46.3, 38.3, 28.9, 24.7, 21.8, 21.1; IR (KBr) 3423,
2949, 2858, 1735, 1693, 1632, 1448, 1351, 1248, 1168, 855, 714 cmꢀ1
HRMS (EI) calcd for C12H14O4Cl2, 292.0269; found, 292.0269.
Methyl 1,4-Dibromo-3-hydroxy-2-oxo-1,2,4a,5,6,7,8,8a-oc-
tahydronaphthalene-1-carboxylate (4b). Experimental pro-
cedure is similar to that for compound 4a. Rf (10% ethyl acetate in
hexane) 0.5, colorless crystalline solid, mp 121 °C, yield 98% (193 mg,
;
a Reagents and conditions: a) p-TsOH, toluene, reflux, 3 h, 94%; b)
CH2N2, Et2O-MeOH, 0 °C, 30 min.; c) DBU, MeI, CH2Cl2, 0 °C to rt,
24; d) DDQ, C6H6, reflux, 100 °C, 20 h.
chromatographically separable mixture of tetramethylated com-
pounds 27a,b with an impressive 45% and 35% overall yield from
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0.504 mmol); 1H NMR (400 MHz, CDCl3) δ 6.29 (s, 1H), 3.80 (s, 3H),
3.24 (s, 2H), 2.93 (td, 1H, J = 3.5, 12.7 Hz), 2.43 (d, 1H, J = 13.4 Hz),
2.06 (d, 1H, J = 13.2 Hz), 1.81 (d, 1H, J = 13.2 Hz), 1.54 (s, 2H),
1.37ꢀ1.13 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 182.2, 166.7,
144.8, 123.9, 69.1, 54.3, 46.9, 39.3, 31.2, 25.0, 23.2, 20.8. IR (KBr) 3420,
(s, 1H), 4.19 (dd, 1H, J = 4.7, 10.4 Hz), 3.92 (s, 3H), 3.39 (dd, 1H, J =
4.7, 13.9 Hz), 2.70 (dd, 1H, J = 10.4, 13.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 183.0, 165.8, 144.2, 139.8, 131.6, 129.03, 128.2, 128.0, 67.3,
54.5, 45.9, 44.3; IR (KBr) 3320, 3040, 2955, 1745, 1695, 1640, 1490,
1440, 1320, 1195, 1020, 910, 855, 810, 750, 700 cmꢀ1; HRMS (EI) calcd
for C14H12O4Cl2, 401.9102; found, 401.9101.
2965, 2910, 1745, 1695, 1635, 1450, 1430, 1350, 1170, 1015, 855 cmꢀ1
HRMS (ESI) calcd for C12H14O4Br, 2379.9259; found, 379.9258.
;
Dimethyl 1,4-Dichloro-5-hydroxy-6-oxocyclohex-4-ene-
1,3-dicarboxylate (4i). Experimental procedure is similar to that
for compound 4a. Rf (20% ethyl acetate in hexane) 0.5, colorless
crystalline solid, mp 155ꢀ156 °C, yield 99% (100 mg, 0.34 mmol);
1H NMR (400 MHz, CDCl3) δ 6.36 (s, 1H), 3.84 (s, 3H), 3.82 (dd, 1H,
J = 6.5, 7.9 Hz), 3.79 (s, 3H), 3.17 (dd, 1H, J = 5.6, 13.9 Hz), 2.83
(dd, 1H, J = 7.3, 14.1 Hz); 13C NMR (100 MHz, CDCl3) δ 182.2, 169.7,
165.7, 143.7, 125.3, 66.4, 54.5, 53.2, 45.9, 37.7; IR (KBr) 3385, 2985,
Methyl 4,7-Dichloro-6-hydroxy-5-oxo-2,3,3a,4,5,7a-hexa-
hydro-1H-indene-4-carboxylate (4c). Experimental procedure is
similar to that for compound 4a. Rf (10% ethyl acetate in hexane) 0.6,
colorless solid, mp 104 °C, yield 95% (200 mg, 0.72 mmol); 1H NMR
(400 MHz, CDCl3) δ 3.78 (s, 3H), 3.29ꢀ3.19 (m, 2H), 2.29ꢀ2.26
(m, 1H), 2.07ꢀ1.92 (m, 2H), 1.73ꢀ1.63 (m, 2H), 1.52ꢀ1.47 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 183.1, 166.4, 142.8, 130.7.0, 71.9, 54.3,
47.3, 44.6, 32.6, 26.1, 22.4; IR (KBr) 3450, 2995, 1750, 1690, 1640, 1430,
1240, 1110, 1000, 810 cmꢀ1; HRMS (EI) calcd for C11H12O4Cl2,
278.0113; found, 278.0110.
1745, 1700, 1650, 1440, 1355, 1170, 1030, 975, 900, 835, 740, 705 cmꢀ1
HRMS (EI) calcd for C10H10O6Cl2, 295.9854; found, 295.9857.
;
Dimethyl 1,4-Dibromo-5-hydroxy-6-oxocyclohex-4-ene-
1,3-dicarboxylate (4j). Experimental procedure is similar to that
for compound 4a. Rf (20% ethyl acetate in hexane) 0.5, colorless
crystalline solid, mp 126ꢀ127 °C, yield 95% (100 mg, 0.26 mmol);
1H NMR (400 MHz, CDCl3) δ 6.48 (s, 1H), 3.93 (dd, 1H, J = 5.3, 8.1
Hz),3.83 (s, 3H), 3.79 (s, 3H), 3.27 (dd, 1H, J = 5.3, 14.0 Hz), 2.92
(dd, 1H, J = 8.1, 14.0 Hz); 13C NMR (100 MHz, CDCl3) δ 181.2, 169.9,
165.8, 145.1, 116.1, 57.7, 56.4, 54.6, 53.1, 47.8, 39.1; IR (KBr) 3400, 2990,
1735, 1695, 1650, 1435, 1350, 1170, 1075, 870, 780, 735, 695 cmꢀ1;HRMS
(ESI) calcd for C10H10O6Br2 (M þ H), 384.8922; found, 384.8926.
Trimethyl 4-Chloro-5,6-dihydroxybenzene-1,2,3-tricar-
boxylate (6a). Experimental procedure is similar to that for compound
4a. Rf (20% ethyl acetate in hexane) 0.4, colorless crystalline solid, mp
140 °C, yield 97% (60 mg, 0.18 mmol); 1H NMR (400 MHz, CDCl3)
δ 11.30 (s, 1H), 6.30 (s, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 168.8, 166.9, 165.2, 150.1, 143.3, 126.2,
124.2, 122.3, 108.7, 53.6, 53.0, 52.9; IR (KBr) 3300, 3028, 1738, 1722,
1690, 1598, 1436, 1220, 998, 932, 878, 830, 812, 774, 727 cmꢀ1; HRMS
(EI) calcd for C12H11O8Cl, 318.0142; found, 318.0143.
Trimethyl 4-Bromo-5,6-dihydroxybenzene-1,2,3-tricar-
boxylate (6b). Experimental procedure is similar to that for com-
pound 4a. Rf (20% ethyl acetate in hexane) 0.4, colorless crystalline solid,
mp 148ꢀ149 °C, yield 95% (60 mg, 0.16 mmol); 1H NMR (400 MHz,
CDCl3) δ 11.31 (s, 1H), 6.37 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.83
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 166.8, 165.9, 149.5,
144.6, 126.4, 126.1, 111.5, 109.3, 53.6, 53.57, 53.0; IR (KBr) 3300, 3025,
1740, 1720, 1680, 1590, 1430, 990, 920, 770, 730 cmꢀ1; HRMS (ESI)
calcd for C12H11O8Br, 361.9637; found, 361.9630.
Methyl 4,7-Dibromo-6-hydroxy-5-oxo-2,3,3a,4,5,7a-hex-
ahydro-1H-indene-4-carboxylate (4d). Experimental procedure
is similar to that for compound 4a. Rf (10% ethyl acetate in hexane) 0.6,
colorless solid, mp 100 °C, yield 84% (200 mg, 0.54 mmol); 1H NMR
(400 MHz, CDCl3) δ 3.81 (s, 3H), 3.40ꢀ3.34 (m, 2H), 2.39ꢀ2.34
(m, 1H), 2.12ꢀ2.00 (m, 2H), 1.75ꢀ1.69 (m, 1H), 1.67ꢀ1.61 (m, 1H),
1.56ꢀ1.51 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 182.0, 166.6,
143.8, 124.0, 64.8, 54.3, 48.0, 45.8, 34.6, 27.4, 22.0; IR (KBr) 3450, 2965,
1735, 1675, 1630, 1430, 1230, 1105, 1000, 805 cmꢀ1. Anal. Calcd for
C11H12O4Br2: C, 35.90; H, 3.29. Found: C, 35.72; H, 3.11.
Methyl 1,4-Dichloro-3-hydroxy-2-oxo-1,2,4a,5,6,7,8,9,-
10,10a-decahydrobenzo[8]annulene-1-carboxylate (4e). Ex-
perimental procedure is similar to that for compound 4a. Basic alumina
column purification is essential to obtain pure product. Rf (10% ethyl
acetate in hexane) 0.6, colorless solid, mp 108ꢀ109 °C, yield 98% (100
1
mg, 0.31 mmol); H NMR (400 MHz, CDCl3) δ 6.03 (s, 1H), 3,78
(s, 3H), 2.96 (s, 2H), 1.88ꢀ1.18 (m, 8H); 13C NMR (100 MHz,
CDCl3) δ 183.6, 199.9, 140.4, 129.8, 73.4, 54.2, 44.4, 41.8, 27.9, 26.1; IR
(KBr) 3450, 2995, 1775, 1690, 1640, 1480, 1450, 1370, 1190, 1015, 835,
750 cmꢀ1; HRMS (ESI) calcd for C14H18O4Cl2 (M þ H), 321.0660;
found, 321.0660.
Methyl 1,4-Dibromo-3-hydroxy-2-oxo-1,2,4a,5,6,7,8,9,-
10,10a-decahydrobenzo[8]annulene-1-carboxylate (4f). Ex-
perimental procedure is similar to that for compound 4a. Basic alumina
column purification is essential to obtain pure product. Rf (10% ethyl
acetate in hexane) 0.5, colorless viscous liquid, yield 85% (150 mg, 0.37
mmol); 1H NMR (400 MHz, CDCl3) δ 6.17 (s, 1H), 3.77 (s, 3H), 3.09
(s, 2H), 1.76ꢀ1.18 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 182.7,
166.6, 54.4, 52.7, 45.1, 43.1, 29.7, 27.8, 26.2; IR (KBr) 3400, 2945, 1740,
1675, 1635, 1450, 1005, 795 cm1; HRMS (ESI) calcd for C14H18O4Br2
(M þ H), 408.9650; found, 408.9651.
Hemiketal 8a. Experimental procedure is similar to that for
compound 4a except for the time and stoichiometry of the reaction
(Scheme 3). Rf (40% ethyl acetate in hexane) 0.4, colorless crystalline
1
solid, mp 152ꢀ154 °C, yield 94% (130 mg, 0.42 mmol); H NMR
(400 MHz, CDCl3 þ DMSO-d6, 20:1) δ 4.50 (bs, 1H), 3.69 (s, 3H),
3.63 (s, 3H), 2.54 (d, 1H, J = 13.4 Hz), 2.48 (d, 1H, J = 13.4 Hz), 1.54
(s, 3H, Me); 13C NMR (100 MHz, CDCl3 þ DMSO-d6, 20:1) δ 192.7,
173.2, 102.5, 78.4, 73.9, 52.5, 51.7, 51.6, 41.3, 17.8; IR (KBr) 3150, 2900,
1760 (br), 1430, 1370 cmꢀ1; HRMS (EI) calcd for C11H12Cl2O6,
310.0011; found, 310.0011.
Methyl 1,4-Dichloro-3-hydroxy-2-oxo-5-phenylcyclohex-
3-enecarboxylate (4g). Experimental procedure is similar to that for
compound 4a. Rf (20% ethyl acetate in hexane) 0.5, colorless crystalline
solid, mp 127ꢀ128 °C, yield 100% (150 mg, 0.48 mmol); 1H NMR (400
MHz, CDCl3) δ 7.43ꢀ7.36 (m, 3H), 7.23 (d, 2H, J = 6.8 Hz), 6.42
(s, 1H), 4.10 (dd, 1H, J = 4.9, 10.2 Hz), 3.91 (s, 3H), 3.22 (dd, 1H, J =
4.9, 13.9 Hz), 2.55 (dd, 1H, J = 10.5, 13.9 Hz); 13C NMR (100 MHz,
CDCl3) δ 183.0, 168.8, 144.2, 139.9, 131.6, 129.03, 128.97, 128.1, 67.3,
54.5, 45.9, 44.3; IR (KBr) 3350, 3040, 2955, 1745, 1695, 1640, 1490,
1440, 1320, 1195, 1020, 910, 855, 810, 750, 700 cmꢀ1; HRMS (ESI)
calcd for C14H12O4Cl2 (M þ H), 315.0191; found, 315.0190.
Methyl 1,4-Dibromo-3-hydroxy-2-oxo-5-phenylcyclohex-
3-enecarboxylate (4h). Experimental procedure is similar to that for
compound 4a. Rf (20% ethyl acetate in hexane) 0.5, colorless crystalline
solid, mp 145ꢀ146 °C, yield 97% (160 mg, 0.40 mmol); 1H NMR (400
MHz, CDCl3) δ 7.46ꢀ7.38 (m, 3H), 7.23 (d, 2H, J = 6.8 Hz), 6.55
Hemiketal 8b. Experimental procedure is similar to that for
compound 4a except for the time and stoichiometry of the reaction
(Scheme 3). Rf (40% ethyl acetate in hexane) 0.4, colorless crystalline
1
solid, mp 188ꢀ189 °C, yield 90% (150 mg, 0.38 mmol); H NMR
(400 MHz, CDCl3 þ DMSO-d6, 20:1) δ 3.71 (s, 3H), 3.67 (s, 3H), 2.58
(d, 1H, J = 13.3 Hz), 2.47 (d, 1H, J = 13.3 Hz), 1.54 (s, 3H); 13C NMR
(100 MHz CDCl3 þ DMSO-d6, 20:1) δ 193.4, 173.8, 102.5, 101.1, 72.7,
66.6, 52.6, 52.5, 51.5, 44.2, 21.1; IR (KBr) 3150, 2900, 1760 (br),
1430 cmꢀ1; HRMS (ESI) calcd for C11H12Br2O6 (M þ H), 398.9079;
found, 398.9072.
3325
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ARTICLE
Dimethyl 2,5-Dichloro-4-methoxy-1-methyl-3-oxocyclo-
hex-4-ene-1,2-dicarboxylate (9a). Experimental procedure is si-
milar to that for compound 4a except for the time and stoichiometry of
the reaction (Scheme 3). Rf (15% ethyl acetate in hexane) 0.6, colorless
BF2 Complex 15. To a stirred solution of diketone 3j (100 mg, 0.25
mmol) in dry dichloromethane (2 mL) was added excess BF3 Et2O
3
(0.5 mL) at room temperature over a period of 4 min under argon. The
reaction mixture was stirred for 24 h at 35 °C. After the reaction mixture
cooled in a refrigerator at 0 to ꢀ10 °C over a period of 10ꢀ12 h, a
colorless crystalline material (70 mg/100 mg) of 15 was separated from
the reaction mixture. The mother liquor was further purified by silica gel
column chromatography to obtain the pure compound. Rf (30% ethyl
acetate in hexane) 0.4, colorless crystalline compound, mp 178 °C, yield
95%; 1H NMR (400 MHz, CDCl3 þ DMSO-d6, 20:1) δ 3.80 (s, 3H),
3.70(t, 1H, J = 4.8 Hz), 3.67 (s, 3H), 3.02 (dd, 1H, J = 5.6, 18.5 Hz),
2.76 (dd, 1H, J = 4.0, 18.5 Hz); 13C NMR (100 MHz, CDCl3 þ DMSO-
d6, 20:1) δ 178.5, 170.6, 168.9, 151.9, 147.6, 107.0, 61.2, 55.8, 52.7, 52.6,
1
viscous liquid, yield 76% (40 mg, 0.12 mmol); H NMR (400 MHz,
CDCl3) δ 3.83 (s, 3H), 3.74 (s, 3H), 3.71 (s, 3H), 3.32 (d, 1H, J =
18.6 Hz), 2.94 (d, 1H, J = 18.6 Hz), 1.65 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 181.4, 171.5, 165.2, 146.5, 138.3, 75.5, 59.9, 54.0, 53.1, 52.6,
42.1, 21.1; IR (neat) 2975, 1745, 1720, 1700, 1630, 1445, 1050, 990, 810,
830, 750 cmꢀ1; HRMS (EI) calcd for C12H14O6Cl2, 324.0167; found,
324.0167.
Dimethyl 2,5-Dibromo-4-methoxy-1-methyl-3-oxocyclo-
hex-4-ene-1,2-dicarboxylate (10a). Experimental procedure is
similar to that for compound 4a except for the time and stoichiometry
of the reaction (Scheme 3) and the methylation of enol followed the
diazomethane treatment protocol. Rf (15% ethyl acetate in hexane) 0.6,
colorless viscous liquid, yield 36% (150 mg, 0.34 mmol); 1H NMR (400
MHz, CDCl3) δ 3.83 (s, 3H), 3.74 (s, 3H), 3.72 (s, 3H), 3.49 (d, 1H, J =
18.9 Hz), 3.08 (d, 1H, J = 18.9 Hz), 1.72 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 180.5, 171.6, 165.2, 147.7, 129.6, 69.9, 59.6, 54.1, 53.4, 53.1,
44.8, 21.4; IR (KBr) 2925, 1750, 1720, 1690, 1620, 1430, 1375, 1010,
890, 800, 730 cmꢀ1; HRMS (ESI) calcd for C12H14O6Br2Na, 434.9055,
found, 434.9324.
Dimethyl 2,5-Dibromo-4-methoxy-1-methyl-3-oxocyclo-
hex-4-ene-1,2-dicarboxylate (10b). Experimental procedure is
similar to that for compound 4a except for the time and stoichiometry
of the reaction (Scheme 3). Rf (15% ethyl acetate in hexane) 0.6,
colorless crystalline solid, mp 87ꢀ88 °C, yield 39% (150 mg, 0.34
mmol); 1H NMR (400 MHz, CDCl3) δ 3.86 (s, 3H), 3.76 (s, 3H), 3.68
(s, 3H), 3.06 (d,1H, J = 19.2 Hz), 2.88 (d, 1H, J = 19.2 Hz), 1.49 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 180.3, 171.3, 165.6, 147.9, 126.1, 68.5,
59.4, 54.2, 53.1, 51.2, 44.6, 21.2; IR (KBr) 2928, 1752, 1721, 1694, 1629,
1428, 1372, 1030, 802, 731 cmꢀ1; HRMS (ESI) calcd for C12H14O6Br2-
Na, 434.9055; found, 434.9324.
26.1; IR (KBr) 3150, 1720, 1630, 1400, 1310, 1060, 900, 770 cmꢀ1
.
Dimethyl 6,6-Dibromo-4-hydroxy-5-oxocyclohex-3-ene-
1,3-dicarboxylate (16). To the homogeneous solution of BF2
complex 15 (32 mg, 0.07 mmol) in ethyl acetate (10ꢀ15 mL), was
added 50% NaHCO3 solution. The mixture was vigorously shaken in a
separating funnel, and the separated organic layer was washed with brine
and dried over anhydrous Na2SO4. The solvent was evaporated under
reduced pressure to obtain a viscous liquid without any further purifica-
tion. Rf (30% ethyl acetate in hexane) 0.4, brown viscous liquid, yield
95%; 1H NMR (400 MHz, CDCl3) δ11.43 (s, 1H, OH), 3.83 (s, 3H),
3.70 (s, 4H), 3.04 (dd, 1H, J = 5.1, 18.4 Hz), 2.79 (dd, 1H, J = 3.3,
18.4 Hz); 13C NMR (100 MHz, CDCl3) δ 178.7, 171.1, 169.1, 152.6,
107.2, 61.4, 56.4, 53.1, 53.0, 26.5; IR (KBr) 2990, 1730, 1670, 1615,
1440, 870, 740 cmꢀ1; HRMS (ESI) calcd for C10H10O6Br2 (M þ H),
384.8922; found, 384.8926.
Dimethyl 1,4,5,8-Tetrachloro-2,7-dihydroxy-3,6-dioxo-
4,4a,4b,5,6,8a,9,9a-octahydro-3H-fluorene-4,5-dicarboxy-
late (18a). Experimental procedure is similar to that for compound 4a.
Rf (30% ethyl acetate in hexane) 0.5, colorless solid, mp 222ꢀ223 °C,
1
yield 59% (75 mg, 0.15 mmol); H NMR (400 MHz, CDCl3) δ 3.90
(d, 2H, J = 5.3 Hz), 3.81 (s, 3H), 3.28 (td, 2H, J = 5.3, 9.8 Hz), 1.94
(t, 2H, J = 9.8 Hz); 13C NMR (100 MHz, CDCl3 þ DMSO-d6 (20:1))
δ 181.7, 165.5, 145.6, 125.5, 71.4, 54.2, 49.7, 43.0, 27.1; IR (KBr) 3590,
3528, 2964, 1750, 1702, 1636, 1460, 1243, 991, 703, 542 cmꢀ1; HRMS
(ESI) calcd for C17H14O8Cl4 (M þ H), 486.9521; found, 486.9525.
Dimethyl 1,4,5,8-Tetrachloro-3,7-dihydroxy-2,6-dioxo-
2,4a,4b,5,6,8a,9,9a-octahydro-1H-fluorene-1,5-dicarboxy-
late (18b). Experimental procedure is similar to that for compound 4a.
Rf (30% ethyl acetate in hexane) 0.5, colorless solid, mp 219ꢀ220 °C,
Methyl 1,4-Dichloro-3-hydroxy-5-methyl-2-oxo-5-phe-
nylcyclohex-3-enecarboxylate (13a). Experimental procedure is
similar to that for compound 4a. Rf (15% ethyl acetate in hexane) 0.6,
1
colorless viscous liquid, yield 83% (100 mg, 0.30 mmol); H NMR
(500 MHz, CDCl3) δ 7.37ꢀ7.34 (2H, m), 7.30ꢀ2.25 (3H, m), 3.86 (s,
3H), 3.10 (d, 1H, J = 11.8 Hz), 2.78 (d, 1H, J = 11.8 Hz), 1.70 (s); 13C
NMR (125 MHz, CDCl3) δ 183.0, 167.6, 144.4, 143.8, 136.3, 128.7,
127.4, 126.5, 66.3, 54.2, 50.5, 45.8, 25.5; IR (KBr) 3450, 1735, 1710,
1640, 1450, 1350, 1235, 1010, 880, 775 cmꢀ1; HRMS (ESI) calcd for
C15H14O4Cl2 (M þ H), 329.0347; found, 329.0347.
1
yield 37% (75 mg, 0.15 mmol); H NMR (400 MHz, CDCl3) δ 6.30
(s, 1H), 6.18 (s, 1H), 3.98 (d, 1H, J = 7.3 Hz), 3.88 (s, 3H), 3.84 (d, 1H,
J = 7.3 Hz), 3.80 (s, 3H), 3.43ꢀ3.34 (m, 2H), 2.54ꢀ2.47 (m, 1H),
2.18ꢀ2.09 (m, 1H); 13C NMR (100 MHz, CDCl3 þ DMSO-d6, 15:1) δ
181.6, 181.4, 165.7, 145.2,143.3, 128.1, 125.5, 71.7, 54.2, 50.5, 46.8, 45.0,
41.9, 32.1; IR (KBr) 3381, 2959, 1759, 1708, 1676, 1634, 1365, 1246,
1044, 764 cmꢀ1; HRMS (ESI) calcd for C17H14O8Cl4 (M þ H),
486.9521; found, 486.9525.
Methyl 1,4-Dibromo-3-hydroxy-5-methyl-2-oxo-5-phe-
nylcyclohex-3-enecarboxylate (14a). Experimental procedure is
similar to that for compound 4a. Rf (15% ethyl acetate in hexane) 0.6,
1
colorless viscous liquid, yield 55% (400 mg, 0.96 mmol); H NMR
(400 MHz, CDCl3) δ 7.37ꢀ7.25 (m, 5H), 6.61 (bs, 1H), 3.85 (s, 3H)
3.25 (d, 1H, J = 14.5 Hz), 2.92 (d, 1H, J = 14.5 Hz), 1.67 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 182.0, 168.0, 145.3, 144.7, 130.7, 128.6,
127.4, 126.6, 58.0, 54.4, 51.5, 47.5, 25.1; IR (KBr) 3450, 1730, 1700,
1640, 1450, 1350, 1235, 1010, 885, 770 cmꢀ1; HRMS (EI) calcd for
C15H14O4Br2, 415.9259; found, 415.9259.
Methyl 1,4-Dibromo-3-hydroxy-5-methyl-2-oxo-5-phe-
nylcyclohex-3-enecarboxylate (14b). Experimental procedure is
similar to that for compound 4a. Rf (10% ethyl acetate in hexane) 0.5,
colorless crystalline solid, mp 158 °C, yield 18% (400 mg, 0.96 mmol);
1H NMR (400 MHz, CDCl3) δ 7.34ꢀ7.22 (m, 5H), 6.68 (bs, 1H), 3.45
(d, 1H, J = 13.8 Hz), 3.04 (s, 3H), 2.91 (d, 1H, J = 13.8 Hz), 1.76 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 182.4, 166.4, 145.4, 141.3, 128.9, 128.4,
127.4, 127.1, 58.1, 53.4, 51.6, 47.2, 32.3; IR (KBr) 3450, 1735, 1695,
1635, 1450, 1355, 1240, 1010, 880, 775 cmꢀ1; HRMS (EI) calcd for
C15H14O4Br2, 415.9259; found, 415.9259.
Dimethyl 1,4,6,9-Tetrachloro-3,7-dihydroxy-2,8-dioxo-
1,2,4a,5a,8,9,9a,9b-octahydrodibenzo[b,d]furan-1,9-dicar-
boxylate (20a). Experimental procedure is similar to that for com-
pound 4a. Rf (30% ethyl acetate in hexane) 0.4, colorless solid, mp
1
178ꢀ179 °C, yield 38% (50 mg, 0.10 mmol); H NMR (400 MHz,
CDCl3) δ 6.50 (bs, 2H), 4.73 (d, 2H, J = 4.2 Hz), 4.11 (d, 2H, J = 4.2
Hz), 3.80 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 180.7, 164.1, 144.4,
123.1, 78.9, 69.6, 55.0, 50.1; IR (KBr) 3400, 2995, 1715, 1650, 1440,
1345, 1245, 1015, 945, 870 cmꢀ1; HRMS (ESI) calcd for C16H12O9Cl4
(M þ H), 488.9313; found, 488.9316.
Dimethyl 1,4,6,9-Tetrachloro-3,8-dihydroxy-2,7-dioxo-
1,2,4a,5a,6,7,9a,9b-octahydrodibenzo[b,d]furan-1,6-dicar-
boxylate (20b). Experimental procedure is similar to that for com-
pound 4a. Rf (30% ethyl acetate in hexane) 0.4, colorless solid, mp
3326
dx.doi.org/10.1021/jo200223a |J. Org. Chem. 2011, 76, 3320–3328

The Journal of Organic Chemistry
ARTICLE
1
175ꢀ176 °C, yield 49% (50 mg, 0.10 mmol); H NMR (400 MHz,
CDCl3) δ 6.41 (bs, 1H), 6.26 (bs, 1H), 5.07 (d, 1H, J = 7.3 Hz), 4.79
(d, 1H, J = 5.1 Hz), 4.10 (dd, 1H, J = 2.5, 7.3 Hz), 3.87 (s, 3H), 3.80
(s, 3H), 3.65 (dd, 1H, J = 2.5, 5.1 Hz); 13C NMR (100 MHz, CDCl3 þ
DMSO-d6, 15:1) δ 180.8, 179.9, 165.5, 164.5, 146.2, 144.2, 124.0, 121.9,
78.0, 77.0, 70.2, 69.9, 54.6, 54.4, 51.6, 47.1; IR (KBr) 3400, 1750, 1695,
1640, 1430, 1345, 1245 cmꢀ1; HRMS (ESI) calcd for C16H12O9Cl4
(M þ H), 488.9313; found, 488.9316.
1225, 1160, 955, 770 cmꢀ1; HRMS (EI) calcd for C13H9O4Cl,
264.0189; found, 264.0186.
Methyl 6-Chloro-4-hydroxy-5-methoxybiphenyl-3-car-
boxylate (23g). To a stirred solution of substrate (50 mg, 0.16 mmol)
in methanol (2 mL) was added the ethereal solution of diazomethane at
ice bath temperature, which was prepared freshly from its precursor
(N-methyl, N-nitroso-urea, 50 mg) in 50% KOH solution in ether layer
(10 mL). The excess diazomethane was quenched with a drop of AcOH.
The solvent was removed under reduced pressure, and the crude
reaction mixture was purified by silica gel column chromatography. A
portion of methylated compound (0.08 mmol) was dissolved in
dichloromethane (1 mL), and DBU (121 mg, 0.79 mmol) was added
at ice bath temperature. The reaction mixture was allowed to rt (30 °C).
After 6 h the reaction mixture was acidified with 10% aqueous HCl, and
the reaction mixture was extracted with ethyl acetate (3 ꢁ 5 mL). The
combined organic layers were washed with brine and dried over Na2SO4.
The solvent was removed under reduced pressure. The crude reaction
mixture was purified by silica gel column chromatography to obtain the
aromatized compound 23g. Rf (10% ethyl acetate in hexane) 0.6,
colorless solid, mp118ꢀ119 °C, yield 93%; 1H NMR (400 MHz,
CDCl3) δ 10.98 (s, 1H), 7.59 (s, 1H), 7.41ꢀ7.36 (m, 5H), 3.96
(s, 3H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 155.0,
145.1, 138.5, 133.6, 132.4, 129.6, 128.1, 127.6, 126.0, 111.8, 60.5, 52.6;
IR (KBr) 2900, 1670, 1600, 1445, 1335, 1030, 800, cmꢀ1; HRMS (ESI)
calcd for C15H13O4Cl, 293.0580; found, 293.0586.
Methyl
9-Chloro-5,6,7,8-tetrahydronaphtho[2,3-d][1,-
3]dioxole-4-carboxylate (21a). To a stirred solution of substrate
(150 mg, 0.512 mmol) in dichloromethane (2 mL), was added DBU
(311 mg, 2.05 mmol) at ice bath temperature. The reaction mixture was
allowed to rt (30 °C). After 3 days the reaction mixture was acidified with
10% aqueous HCl, and the reaction mixture was extracted with ethyl
acetate (3 ꢁ 5 mL). The combined organic layers were washed with
brine and dried over Na2SO4. The solvent was removed under reduced
pressure. The crude reaction mixture was purified by silica gel column
chromatography to obtain the aromatized compound 21a. Rf (10% ethyl
acetate in hexane) 0.6, colorless solid, mp 59ꢀ60 °C, yield 86% (40 mg,
0.14 mmol); 1H NMR (400 MHz, CDCl3) δ 5.98 (s, 2H), 3.83 (s, 3H),
2.76 (t, 2H, J = 6.4 Hz), 2.62 (t, 2H, J = 6.4 Hz), 1.74ꢀ1.63 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 165.7, 145.5, 142.7, 131.1, 128.9, 117.3,
112.4, 101.9, 52.1, 27.8, 27.0, 22.5, 22.2; IR (KBr) 2950, 1715, 1620,
1505, 1440, 940, 770 cmꢀ1; HRMS (EI) calcd for C13H13O4Cl,
268.0502; found, 268.0503.
Methyl 9-Bromo-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]
dioxole-4-carboxylate (21b). Experimental procedure is similar
to that for compound 21a. Rf (10% ethyl acetate in hexane) 0.6, colorless
Methyl 6-Bromo-4-hydroxy-5-methoxybiphenyl-3-car-
boxylate (23h). Experimental procedure is similar to that for com-
pound 23g. Rf (10% ethyl acetate in hexane) 0.6, colorless solid, mp
1
1
solid, mp 68ꢀ69 °C, yield 85% (30 mg, 0.10 mmol); H NMR (400
110ꢀ112 °C, yield 74% (50 mg, 0.15 mmol); H NMR (400 MHz,
MHz, CDCl3) δ 5.98 (s, 2H), 3.83 (s, 3H), 2.76 (t, 2H, J = 6.4 Hz), 2.61
(t, 2H J = 6.4 Hz), 1.73ꢀ1.60 (m, 4H); 13C NMR (100 MHz, CDCl3)
δ 165.8, 144.8, 144.3, 131.1, 129.9, 113.0, 107.1, 101.5, 52.1, 29.8, 27.9,
CDCl3) δ 10.98 (s, 1H), 7.57 (s, 1H), 7.42ꢀ7.33 (m, 5H), 3.95 (s, 3H),
3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.3, 154.6, 146.2, 140.3,
134.3, 129.6, 128.0, 127.6, 125.9, 125.5, 112.3, 60.4, 52.6; IR (KBr) 2900,
1720, 1680, 1600, 1445, 1340, 1035, 910, 800 cmꢀ1; HRMS (ESI) calcd
for C15H13O4Br (M þ H), 337.0075; found, 337.0074.
22.6; IR (KBr) 1720, 1610, 1510, 1450, 1050, 930, 785, 770 cmꢀ1
HRMS (EI) calcd for C13H13O4Br, 311.9997; found, 311.9994.
;
Compound 21e. Experimental procedure is similar to that for
compound 21a. Rf (10% ethyl acetate in hexane) 0.6, colorless solid, mp
80ꢀ82 °C, yield 81% (80 mg, 0.27 mmol); 1H NMR (400 MHz,
CDCl3) δ 5.99 (s, 2H), 3.83 (s, 3H), 2.86ꢀ2.79 (m, 4H), 1.64ꢀ1.61 (m,
4H), 1.30 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 166.2, 145.2, 142.9,
134.3, 132.8, 116.5, 113.1, 101.9, 52.3, 2.19, 31.5, 29.3, 27.9, 26.19,
Methyl 7-Chloro-5-hydroxy-6-methoxy-2,3-dihydro-1H-
indene-4-carboxylate (23c). Experimental procedure is similar to
that for compound 23g. Rf (10% ethyl acetate in hexane) 0.6, colorless
solid, mp 90 °C, yield 91% (75 mg, 0.29 mmol); 1H NMR (400 MHz,
CDCl3) δ 11.30 (s, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.19 (t, 2H, J =
7.4 Hz), 2.87 (t, 2H, J = 7.6 Hz), 2.03 (t, 2H, J = 7.6 Hz); 13C NMR (100
MHz, CDCl3) δ 171.5, 155.3, 143.1, 141.3, 133.8, 130.9, 109.1, 60.4,
52.1, 36.2, 31.9, 23.8; IR (KBr) 2900, 1665, 1600, 1570, 1420, 1095, 995,
895, 805, 770 cmꢀ1; HRMS (EI) calcd for C12H13O4Cl, 256.0502;
found, 256.0507.
26.16; IR (KBr) 2950, 1725, 1630, 1490, 1440, 1220, 940, 785 cmꢀ1
HRMS (EI) calcd for C15H17O4Cl, 296.0815; found, 296.0818.
;
Compound 21f. Experimental procedure is similar to that for
compound 21a. Rf (10% ethyl acetate in hexane) 0.6, colorless solid, mp
1
Methyl 7-Bromo-5-hydroxy-6-methoxy-2,3-dihydro-1H-
indene-4-carboxylate (23d). Experimental procedure is similar to
that for compound 23g. Rf (10% ethyl acetate in hexane) 0.6, colorless
72 °C, yield 77% (80 mg, 0.23 mmol); H NMR (500 MHz, CDCl3)
δ 6.04 (s, 2H), 3.89 (s, 3H), 2.93 (t, 2H, J = 5.0 Hz), 2.88 (t, 2H, J = 4.8
Hz), 1.68 (dd, 4H J = 4.2, 10.8 Hz), 1.35 (t, 4H, J = 2.2 Hz); 13C NMR
(100 MHz, CDCl3) δ 166.4, 144.6, 134.2, 134.0, 113.7, 106.2, 101.6,
52.4, 31.7, 30.5, 29.8, 29.4, 26.3, 26.1; IR (neat) 2950, 1720, 1490, 1440,
1060, 940, 740 cmꢀ1; HRMS (EI) calcd for C15H17O4Br, 340.0310;
found, 340.0315.
1
solid, mp 78ꢀ80 °C, yield 82% (50 mg, 0.15 mmol); H NMR (400
MHz, CDCl3) δ 11.30 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.22 (t, 2H, J =
7.7 Hz), 2.87 (t, 2H, J = 7.7 Hz), 2.03 (t, 2H, J = 7.6 Hz); 13C NMR (100
MHz, CDCl3) δ 171.6, 154.9, 144.2, 141.1, 135.7, 121.9, 109.7, 60.3,
52.3, 36.5, 34.3, 23.6; IR (KBr) 2900, 1675, 1600, 1575, 1425, 1330,
1095, 895, 805,770 cmꢀ1; HRMS (ESI) calcd for C12H13O4BrNa,
322.9895; found, 322.9851.
Methyl 9-Chloronaphtho[2,3-d][1,3]dioxole-4-carboxy-
late (22). To a stirred solution of compound 21a (20 mg, 0.074 mmol)
in benzene (2 mL) was added 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ, 33.6 mg, 0.148 mmol). The reaction mixture was refluxed for 36
h and then passed through a Celite pad and washed with ethyl acetate.
The solvent was removed under reduced pressure. The crude reaction
mixture was purified by silica gel column chromatography to afford light
brown color solid compound 22. Rf (5% ethyl acetate in hexane) 0.5,
Compounds 25a,b (Mixture). Experimental procedure is similar
to that for compound 4a. Rf (30% ethyl acetate in hexane) 0.4, colorless
liquid, yield 94% (282 mg, 0.56 mmol); 1H NMR (400 MHz, CDCl3)
δ 6.14 (bs, 4H), 3.86 (s, 6H), 3.82 (s, 6H), 3.28ꢀ3.10 (m, 8H), 2.73ꢀ2.69
(m, 2H), 2.42ꢀ2.32 (m, 4H), 2.21ꢀ2.17 (m, 2H); 13C NMR (100 MHz,
CDCl3þDMSOꢀD6, 15:1) δ 181.5, 181.4, 165.5, 165.4, 143.2, 142.9,
128.7, 128.2, 73.5, 72.9, 53.9, 38.2, 37.4, 36.7, 29.6, 24.8, 19.2; IR (KBr)
1
colorless solid, mp 124 °C, yield 91%; H NMR (500 MHz, CDCl3)
δ 8.52 (dd, 1H, J = 2.7, 5.0 Hz), 8.10 (dd, 1H, J = 2.7, 5.2 Hz), 7.49 (dd,
2H, J = 2.7, 5.2 Hz), 6.20 (s, 2H), 4.00 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 165.2, 148.8, 143.9, 128.2, 127.8, 126.6, 125.8, 125.4, 123.3,
112.2, 106.1, 102.5, 52.3; IR (KBr) 2950, 1700, 1650, 1605, 1500, 1450,
2950, 1760, 1730, 1700, 1620, 1440, 1240, 1010, 920, 840 cmꢀ1
.
Compounds 26a,b (Mixture). Rf (30% ethyl acetate in hexane)
0.5, colorless solid, mp 200ꢀ202 °C, quantitative yield; 1H NMR
3327
dx.doi.org/10.1021/jo200223a |J. Org. Chem. 2011, 76, 3320–3328

The Journal of Organic Chemistry
ARTICLE
(400 MHz, CDCl3) δ 3.86 (s, 6H), 3.82 (s, 6H), 3.73 (s, 6H), 3.71 (s,
6H), 3.26ꢀ3.07 (m, 8H), 2.58ꢀ2.39 (m, 4H), 1.59ꢀ1.31 (m, 4H);
HRMS (ESI) calcd for C20H20Cl4O8 (M þ H), 528.9990; found,
528.9998.
(3) (a) Ley, S. V.; Antonello, A.; Balskus, E. P.; Booth, D. T.;
Christensen, S. B.; Cleator, Ed.; Gold, H.; H€ogenauer, K.; H€unger, U.;
Myers, R. M.; Oliver, S. F.; Simic, O.; Smith, M. D.; Søhoel, H.;
Woolford, A. J. A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12073. (b)
Mehta, G.; Mohal, N. Tetrahedron Lett. 2001, 42, 4227. (c) Mehta, G.;
Mohal, N. Tetrahedron Lett. 1999, 40, 5791. (d) Boivin, J.; Pothier, J.;
Ramos, L.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 9239. (e) G€ossinger,
E.; M€uller, R.; Pitterna, T. Tetrahedron 1990, 46, 407. (f) Bree, J. V.;
Anteunis, M. J. O. Tetrahedron 1977, 33, 3321.
(4) (a) Khan, F. A.; Choudhury, S. Eur. J. Org. Chem. 2006,
2006, 672. (b) Khan, F. A.; Choudhury, S. Synth. Commun. 2006,
36, 3749.
(5) (a) Khan, F. A.; Prabhudas, B.; Dash, J.; Sahu, N. J. Am. Chem.
Soc. 2000, 122, 9558. (b) Khan, F. A.; Dash, J.; Sudheer, Ch.; Sahu, N.;
Parasuraman, K. J. Org. Chem. 2005, 70, 7565. (c) Khan, F. A.; Sahu, N.
J. Catal. 2005, 231, 438.
Dimethyl 4,8-Dichloro-2,3,6,7-tetramethoxy-9,10-dihy-
droanthracene-1,5-dicarboxylate (27a). Experimental proce-
dure is similar to that for compound 23g except that MeI was added
during the DBU reaction. Rf (30% ethyl acetate in hexane) 0.5, colorless
solid, mp 158ꢀ160 °C, yield 45% (130.5 mg, 0.269 mmol, from 24); 1H
NMR (400 MHz, CDCl3) δ 3.99 (s, 6H), 3.94 (s, 4H), 3.89 (s, 6H), 3.87
(s, 6H); 13C NMR (125 MHz, CDCl3) δ 167.3, 149.6, 148.1, 129.3,
129.2, 128.2, 126.8, 62.0, 60.9, 52.7, 30.1; IR (KBr) 2900, 1730, 1570,
1460, 1420, 1280, 1100, 980, 810, 770 cmꢀ1; HRMS (EI) calcd for
C22H22O8Cl2, 484.0692; found, 484.0697.
Dimethyl 4,5-Dichloro-2,3,6,7-tetramethoxy-9,10-dihy-
droanthracene-1,8-dicarboxylate (27b). Experimental proce-
dure is similar to that for compound 23g except that MeI was added
during the DBU reaction. Rf (30% ethyl acetate in hexane) 0.5, yellow
color solid, mp 114ꢀ115 °C, yield 35% (101.5 mg, 0.209 mmol, from
(6) (a) CCDC 798279 (10b). (b) CCDC 798280 (14b) contains
the supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
1
(7) Selected references for BF2-complex: (a) Ono, K.; Hashizume,
J.; Yamaguchi, H.; Tomura, M.; Nishida, J.-i.; Yamashita, Y. Org. Lett.
2009, 11, 4326. (b) Zyabrev, K.; Doroshenko, A.; Mikitenko, E.;
Slominskii, Y.; Tolmachev, A. Eur. J. Org. Chem. 2008, 1550. (c) Maeda,
H.; Terasaki, M.; Haketa, Y.; Mihashia, Y.; Kusunosea, Y. Org. Biomol.
Chem. 2008, 6, 433. (d) Maeda, H.; Ito, Y. Inorg. Chem. 2006, 45, 8205.
24); H NMR (400 MHz, CDCl3) δ 4.08 (t, 2H, J = 1.8 Hz), 3.94
(s, 6H), 3.90 (s, 6H), 3.88 (s, 6H), 3.80 (t, 2H, J = 1.8 Hz); 13C NMR
(125 MHz, CDCl3) δ 167.2, 149.6, 148.1, 129.6, 129.4, 128.3, 126.5,
61.9, 60.9, 52.5, 30.5, 30.0; IR (KBr) 2900, 1730, 1600, 1460, 1420, 1280,
1100, 980, 810, 770 cmꢀ1; HRMS (EI) calcd for C22H22O8Cl2,
484.0692; found, 484.0697.
^
(e) Stefane, B. Org. Lett. 2010, 12, 2900.
Dimethyl 4,8-Dichloro-2,3,6,7-tetramethoxyanthracene-
1,5-dicarboxylate (28a). Experimental procedure is similar to that
for compound 22. Rf (15% ethyl acetate in hexane) 0.5, yellow color
solid, mp 148 °C, yield 87% (30 mg, 0.06 mmol); 1H NMR (500 MHz,
CDCl3) δ 8.62 (s, 2H), 4.07 (s, 6H), 3.98 (s, 6H), 3.95 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 167.0, 151.0, 149.0, 127.3, 125.9, 125.8,
122.6, 120.8, 62.2, 61.2, 52.8; IR (KBr) 2950, 1735, 1535, 1450, 1410,
1360, 1230, 1030, 895, 820, 770 cmꢀ1; HRMS (EI) calcd for
C22H20O8Cl2, 482.0535; found, 482.0536.
Dimethyl 4,5-Dichloro-2,3,6,7-tetramethoxyanthracene-
1,8-dicarboxylate (28b). Experimental procedure is similar to that
for compound 22. Rf (15% ethyl acetate in hexane) 0.5, yellow color
solid, mp 135 °C yield 90% (25 mg, 0.05 mmol); 1H NMR (500 MHz,
CDCl3) δ 9.09 (s, 1H) 8.27 (s, 1H), 4.09 (s, 6H), 4.03 (s, 6H), 4.02
(s, 6H); IR (KBr) 2950, 1735, 1535, 1450, 1410, 1360, 1230, 1030, 895, 820,
770 cmꢀ1; HRMS (EI) calcd for C22H20O8Cl2, 482.0535; found, 482.0536.
(8) (a) CCDC 798281 (15). (b) CCDC 798282 (4j) contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(9) Catechol references: (a) Surburg, H.; Panten, J. Common
Fragrance and Flavor Materials, 5th ed.; Wiley-VCH: Weinheim, 2006.
(b) Bashall, A. P.; Collins, J. F. Tetrahedron Lett. 1975, 22, 3489. (c)
Cabiddu, M. G.; Cadoni, E.; Montis, S. D.; Fattuoni, C.; Melis, S.; Usai,
M. Tetrahedron 2003, 59, 4383. (d) Gensler, W. J.; Samour, C. M.;
Wang, S. Y.; Johnson, F. J. Am. Chem. Soc. 1960, 82, 1714.
(10) DBU references: (a) Sabatꢀe, M.; Llebaria, A.; Molins, E.;
Miravitlles, C.; Delgado, A. J. Org. Chem. 2000, 65, 4826. (b) Ghosh,
N. Synlett 2004, 3, 574.
(11) (a) Fu, P. P.; Harvey, R. G. Tetrahedron Lett. 1977, 24, 2059. (b)
Abad, A.; Agullꢀo, C.; Arnꢀo, M.; Domingo, L. R.; Zaragozꢀa, R. J. J. Org.
Chem. 1988, 53, 3761.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra,
S
b
HRMS, and crystallographic data files in CIF format. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: faiz@iith.ac.in.
’ ACKNOWLEDGMENT
F.A.K. gratefully acknowledges DST and CSIR for financial
support. C.N.R. thanks CSIR for a senior research fellowship.
’ REFERENCES
(1) (a) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. 1967, 6, 1.
(b) Grob, C. A. Angew. Chem., Int. Ed. 1969, 8, 535.
(2) (a) Prantz, K.; Mulzer, J. Angew. Chem. 2009, 121, 5130; Angew.
Chem., Int. Ed. 2009, 48, 5030. (b) Prantz, K.; Mulzer, J. Chem. Rev. 2010,
110, 3741. (c) Prantz, K.; Mulzer, J. Chem.—Eur. J. 2010, 16, 485.
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