Furo[3,4-Z]benzodioxin cycloadditions - A One-Pot synthesis of functionalized Bis-Adducts

Article abstract of DOI:10.1002/ejoc.200800967

Furo[3,4-b]benzodioxin 1 was found to undergo a double Diels-Alder reaction with several dienophiles. The diene reacts directly with the suitable dienophile to give the mono- adduct intermediate that unexpectedly leads to a second cycloaddition at the int

Full text of DOI:10.1002/ejoc.200800967

FULL PAPER
DOI: 10.1002/ejoc.200800967
Furo[3,4-b]benzodioxin Cycloadditions – A One-Pot Synthesis of
Functionalized Bis-Adducts
Consol Bozzo,[a] Núria Mur,[a] Pere Constans,[a] and Maria Dolors Pujol*[a]
Keywords: Cycloaddition / Fused-ring systems / Polycycles / Dienophiles / Oxygen heterocycles
Furo[3,4-b]benzodioxin 1 was found to undergo a double
Diels–Alder reaction with several dienophiles. The diene re- two uninterrupted sequential cycloaddition reactions, inter-
acts directly with the suitable dienophile to give the mono- esting formation of stable bis-adducts was observed. The di-
adduct intermediate that unexpectedly leads to a second cy- enophile behavior of 1,4-benzodioxin is described for the first
to the extremely reactive arynes. With this methodology of
cloaddition at the internal, electron-rich, oxabicyclic C4a–
C10a double bond. The resulting bis-adducts were formed
under relatively mild conditions with dienophiles ranging
from maleic anhydride and dimethyl acetylenedicarboxylate
time in this work.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
been reported.[5] The chemistry of 1,4-benzodioxins and
their 2,3-dihydro derivatives has attracted special attention
due to the relevant biological activity of compounds pos-
sessing this nucleus.[6]
Introduction
For more than 70 years, the Diels–Alder (DA) cycload-
dition has been one of the most valuable and versatile reac-
tions found in organic synthesis, particularly in the prepara-
tion of interesting heterocyclic compounds.[1] The energy
differences of the HOMO/LUMO (the highest occupied
molecular orbital/the lowest unoccupied molecular orbital)
play important roles and allow three types of DA reactions
to be described: normal, inverse, and neutral. In the normal
reaction, a conjugated diene (HOMO) reacts with a dien-
ophile (LUMO), which can be an alkene or an alkyne bear-
ing electron-withdrawing groups. Through conjugation, the
energy of the LUMO antibonding π orbital is lowered to
an appropriate level for the reaction with the diene. Its
counterpart, the inverse electron demand reaction, is a
LUMO-diene/HOMO-dienophile controlled process. In the
neutral DA reaction, the two molecular orbital interactions
Results and Discussion
In this article, we report our studies on the cycloaddition
of furo[3,4-b]benzodioxins focusing on the synthesis of bis-
adducts.
In earlier work, we synthesized differently substituted di-
benzo[b,e][1,4]dioxins by using Diels–Alder reactions.[5b–5d]
The reaction of diene 1[5d] with dimethyl acetylenedicarbox-
ylate (DMAD) proceeds instantly in a low volume of tolu-
ene at 80 °C in a sealed tube (Scheme 1) to afford a mixture
of products that was fractionated by column chromatog-
raphy (hexane/ethyl acetate, 1:2).
Bis-adduct 3 was the major product isolated in moderate
yield. Even with a large excess of the dienophile, the bis-
adduct was the main compound obtained. The mono-ad-
duct was not found in significant amounts even when the
dienophile was used as the solvent. After the first cycload-
dition, the 1,4-benzodioxin framework acts as a new dieno-
phile for a second cycloaddition reaction. In fact, we ob-
served that the C4a–C10a double bond is the only reactive
site, and that the Diels–Alder reaction does not take place
at the C2–C3 position under these conditions.
(HOMO-diene/LUMO-dienophile
and
LUMO-diene/
HOMO-dienophile) are involved in the cycloaddition.[2,3]
Highly reactive cyclic dienes such as isobenzofuran deriva-
tives would be interesting and useful building blocks for the
preparation of bioactive compounds.
Although additions of isobenzofurans to a number of
dienophiles have already been reported,[4] to date and to the
best of our knowledge, no reaction using 1,4-benzodioxin
dienophiles has been described. Only a few examples of
dienes containing the 1,4-benzodioxin substructure have
The structure of adduct 3 was identified by MS (m/z =
1
546) and H NMR spectroscopy. The two singlets for the
[a] Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy,
University of Barcelona,
different methyl groups at δ = 1.53 and 1.74 ppm confirmed
the surprising structure of adduct 3. Analysis of the 13C
NMR spectrum of 3 showed three different quaternary car-
bon atoms bonded to oxygen {87.3 [C6(11)], 89.2 [C7(10)],
and 92.6 [C6a(10a)] ppm}, which proved that the second
Av. Diagonal 643, 08028-Barcelona, Spain
Fax: +34-934035941
E-mail: mdpujol@ub.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
2174
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Eur. J. Org. Chem. 2009, 2174–2178

Furo[3,4-b]benzodioxin Cycloadditions
Scheme 1. Cycloaddition with DMAD.
intermolecular cycloaddition occurred on the C4a–C10a mation of this adduct appears thus favored by the close
double bond of 2a. Albeit four bis-adducts with different
stereochemistries are theoretically possible, TLC and 1H
and 13C NMR spectroscopic analysis of the crude products
showed that only one single diastereomer was formed dur-
ing the cycloaddition.[7] The formed adduct was not the ex-
pected linear bis-adduct structure such as 4 (Figure 1), as it
was reported from the cycloaddition of other dienes with
acetylenic dienophiles[8a] and in related derivatives.[8b]
proximity of the two dioxygenated substructures separated
of the bulky groups.[9] Bis-adduct 3 was detected after only
2 min of reaction at 60 °C (41% yield). This result confirms
the high reactivity of mono-adduct 2a.
The fact that all these mono-adducts undergo subsequent
addition of the second mol of diene to give stable bis-ad-
ducts and that the double bond of 1,4-benzodioxin is the
dienophile instead of the classical double bond (conjugated
with electron-attracting substituent such as CO, CO2R, CN,
and NO2) constituted an unprecedented finding. With these
results, we have now turned our attention to the finding
that the double bond of the 1,4-benzodioxin framework is
an effective Diels–Alder dienophile for simple dienes, and
we decided to study the reaction of 1 with other dieno-
philes.
Figure 1. Bis-adduct 4.
Following the same conditions described previously, the
reaction of diene 1 with maleic anhydride gave bis-adduct
5 in 62% yield (Scheme 2). Intermediate mono-adduct 2b
possess only the double bond of the 1,4-benzodioxin sub-
structure. This adduct showed spectroscopic characteristics
similar to those of bis-adduct 3.
As our computational study indicates, a significant
charge rearrangement upon formation of adduct 3 occurs
outside of the near-neighboring reaction centers. The net
charge transfer from diene 1 to dienophile 2a, however, is
close to zero. This suggest that the observed regioselectivity
can be rationalized as not being HOMO–LUMO, but elec-
trostatically controlled, favoring the electron-deficient C4a
When the reaction time was decreased, mono-adduct 2b
and C10a carbon atoms over the electrophilic C2–C3 was detected and differentiated from bis-adduct 5 by the 1H
atoms. Furthermore, computational methods that are NMR spectroscopic data corresponding to the α-carbon-
known to fail in the modeling of weak contacts also fail to ylic–CH signal at 3.54 (mono-adduct) and 3.88 ppm (bis-
predict the stability of the product, which reinforces our adduct). Several conditions were assayed for the prepara-
hypothesis that intramolecular forces play a central role in tion of mono-adduct 2b, but this was difficult, as the mono-
both regioselectivity and stability.
adduct is more reactive than the starting dienophile. Purifi-
The interactions controlling the exo or endo selectivity in cation by column chromatography on silica gel results in
these cycloadditions are the result of electronic and steric hydrolysis of the anhydride. For this study, on the basis of
effects. The formation of the endo adduct suggests preferen- our previous results, toluene was chosen as the solvent. The
tial approach from the more accessible face on the primary diene/dienophile equivalents ratio was studied, and the re-
adduct, which implies a more favorable conformation by sults showed that 1:3 was the best stoichiometry. The influ-
placing the carbonyl groups at the opposite side. The for- ence of the temperature and reaction time was investigated.
Scheme 2. Cycloaddition with maleic anhydride.
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C. Bozzo, N. Mur, P. Constans, M. D. Pujol
FULL PAPER
The best conditions for the formation of bis-adduct 5 were amount of bromopyridine and a shorter reaction time (5 h)
the maintenance of the reaction at 80 °C over 5 h. Indeed, afforded 6 (49%) and mono-adduct 2d (7%); diene 1 was
we could not observe cycloaddition at room temperature. also recovered (41%). Ultrasonic irradiation at room tem-
Then, we studied the cycloaddition without solvent, and the perature gave bis-adduct 6 (11%) and mono-adduct 2d
results showed that the formation of mono-adduct 2b was (13%); 1 was also recovered (61%). MS in combination
increased and the obtention of bis-adduct 5 decreased. The with 2D NMR heteronuclear (1H–13C HMQC) correlation
formation of carboxylic acid 2c, generated by hydrolysis of experiments allowed us to assign the signals of all protons
initial mono-adduct 2b, was also observed under these last and carbon atoms and to establish the possible structures
conditions. Diacid 2c can be reverted to the anhydride by of these compounds.
dehydration with P2O5.
The stereochemistry of bis-adduct 6 was determined by
As a part of our ongoing research program on Diels– proton NOESY experiments. Protons H-9 and H-10 exhibit
Alder cycloadditions, we previously reported that 3,4-dide- a NOESY correlation peak with H-4Ј and H-5Ј, whereas
hydropyridine (3,4-pyridyne) prepared from 3-bromopyr- H-8 and H-11 exhibit a correlation peak with H-3Ј and H-
idine, lithium bis(trimethylsilyl)amide, and diene 1 undergo 6Ј, respectively. Proton H-4 exhibits a correlation peak with
Diels–Alder cycloaddition to furnish novel adducts.[5d–5e] In methyl at C-5, whereas H-6Ј correlates with the methyl
the same way, treatment of diene 1 with 3,4-didehydropyr- group at C-13, suggesting that the conformation indicated
idine generated in situ from 3-bromopyridine gave bis-ad- for 6 is in accordance with the spectral observations (Fig-
duct 6 after 20 h (57% yield) (Scheme 3). The bis-adduct ure 2).
was easily purified by column chromatography and fully
characterized. Finally, with a shorter reaction time mono-
adduct 2d of the crude reaction mixture was isolated, but it
was unstable under the column chromatographic condi-
tions; after several attempts we were able to isolate and
characterize it properly. Adduct 2d is trapped rapidly and
in a diastereoselective manner undergoes a second cycload-
dition reaction to give bis-adduct 6c as a main compound.
Our thermochemical calculations for the formation of 6a–
Figure 2. Correlation observed in the NOESY spectrum of bis-ad-
duct 6.
d indicated that 6c is the most stable and plausibly formed
bis-adduct (see Supporting Information), suggesting that 6
has the same structure as that suggested by NOESY experi-
ments.
Spino et al. reported that dienophiles such as 2,3-dihy-
dro-1,4-benzodioxine and 2,3-dihydro-1,4-dioxane were un-
reactive with electron-poor dienes such as (E)-methyl-(6-
oxocyclohex-1-enyl)acrylate or dimethyl 2,3-dimethyl-
enesuccinate in Diels Alder cycloadditions.[10] In spite of
these results, the suggested reactivity of 1,4-benzodioxin as
a dienophile was confirmed with the reaction of commer-
cially available diene 7 and 1,4-benzodioxin 8[11] in toluene
at 115 °C. In this case, after complete consumption of the
starting material expected cycloadduct 9 was obtained in
only 7% yield together with main product 10 (85% yield).
The aromatization takes place in one step by opening of the
tetrahydrofuran ring and dehydration (Scheme 4). Here, the
in situ ring-opening of the oxabridge in intermediate 9 oc-
curs even in the absence of an acidic catalyst. Presumably,
the ring-opening reaction is assisted by the adjacent phenyl
Scheme 3. Cycloaddition with 3,4-pyridyne.
Reaction conditions such as time, amounts of substrate
and base, order of addition of the components, and tem-
perature were studied. The best results were obtained when
diene 1 was initially mixed with bis(trimethylsilyl)amide
(8 equiv.) and bromopyridine (8 equiv.) and heated at reflux
in dry tetrahydrofuran for 5.5 h. The mono-adduct was al-
ways accompanied by the bis-adduct, but it can be isolated
by column chromatography. When excess amounts of the
three components were initially mixed and heated at reflux
in dry tetrahydrofuran for 15 h, bis-adduct 6 (57%) was ob-
tained and 28% of unreacted diene 1 was recovered, but the
mono-adduct was not detected. The use of an excess Scheme 4. Preparation of adducts from 1,4-benzodioxin.
2176 Eur. J. Org. Chem. 2009, 2174–2178
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Furo[3,4-b]benzodioxin Cycloadditions
89.2 [C7(10)], 92.6 [C6a(10a)], 116.4 [CH, C3Ј(6Ј)], 117.1 [CH,
C1(4)], 121.9 [C, C4Ј(5Ј)], 124.9 [C2(3)], 137.5 [CH, C5a(11a)],
142.2 and 142.3 [C1Ј(2Ј) and C4a(12a)], 148.4 [C, C8(9)], 163.2 (C,
CO) ppm. MS (EI): m/z (%) = 546 (6) [M]+, 285 (23). C39H26O10
(654.63): calcd. C 65.93, H 4.80; found C 65.91, H 5.15.
groups driving the reaction in the desired direction. The
higher stability of analogues of 9 without phenyl groups
supports the latter suggestion.
Attempts to obtain suitable crystals of bis-adducts 3–6
to further validate the structure of the diastereoisomers by
X-ray analysis proved unsuccessful. Efforts to further define
the scope of this reaction by using other dienes are currently
underway in this laboratory.
4,11-Dimethyl-1,3,3a,4,11,11a-hexahydro-4,11-epoxyisobenzofuro-
[3,4-b][1,4]benzodioxin-1,3-dione (2b): Following the same condi-
tions for the preparation of 5 but reducing the time of reaction to
an 1 h, Yield: 12%. 1H NMR (200 MHz, CDCl3): δ = 1.71 (s, 6
H, -CH3), 3.54 [s, 2 H, C3a(11a)], 6.78 [m, 2 H, C6(9)H], 6.93 [m,
2 H, C7(8)H] ppm. 13C NMR (50.3 MHz, CDCl3): δ = 13.1 (CH3),
55.4 [C3a(11a)], 86.0 [C, C4(11)], 117.6 [CH, C6(9)], 125.3 [C7(8)],
139.0 [C, C4a(10a)], 142.1 [C5a(9a)], 167.7 (C, CO) ppm.
Conclusions
We found that 1,4-benzodioxins undergo Diels–Alder cy-
cloadditions with isobenzofuran dienes to generate a range
of new polycyclic systems. The intermolecular double cyclo-
1,4-Dimethyl-1,2,3,4-tetrahydro-1,4-epoxydibenzo[1,4]dioxin-2,3-di-
carboxylic Acid (2c): IR (KBr): ν = 3245 (OH, s), 1743 (CO, s),
˜
addition protocol presented herein was applied to the prep- 1256 (Ar–O, s), 1100 (C–O–C, s) cm–1
.
1H NMR (200 MHz,
CDCl3): δ = 1.66 (s, 6 H, -CH3), 3.37 [s, 2 H, C2(3)H], 6.68 [m, 2
H, C6(9)H], 6.77 [m, 2 H, C7(8)H], 9.23 (br. s, COOH) ppm.
aration of complex bis-adducts. The first cycloaddition con-
structs a new substrate serving as a dienophile for the sec-
ond Diels–Alder cycloaddition. Overall and unexpectedly,
from the two starting compounds bridged yet stable cy-
cloadducts were produced in remarkable yields. Finally, the
cycloadducts reported herein possess the common pharma-
cophore 1,4-benzodioxin moiety, which has great potential
in medicinal chemistry.
4a,12a-(o-Phenylenedioxy)-4,5,12,13-tetramethyl-1,3,3a,4,4a,5,-
12,12a,13,13a-decahydro-5,12:4,13-diepoxyisobenzofuro[5,6-b]diben-
zo[1,4]dioxin-1,3-dione (5): An oven-dried flask equipped with a
magnetic stirring bar was charged with diene 1 (40 mg, 0.59 mmol)
and maleic anhydride (58 mg, 0.59 mmol) in dry toluene (drops).
The reaction mixture was heated at 80 °C for 5 h after which the
mixture was cooled to room temperature, adsorbed onto silica gel,
and then purified by column chromatography (hexane/ethyl acetate,
85:15) to afford dimer 5 as a yellow solid (31 mg, 0.0062 mmol,
Experimental Section
62%). M.p. 247–248 °C. IR (KBr): ν 1741 and 1720 (CO, s), 1269,
˜
1230 (Ar–O, s), 1084 (C–O–C, s) cm–1 1H NMR (500 MHz,
.
General Data: 1H NMR spectra were recorded with a Varian Gem-
ini 300 or 500 spectrometer by using tetramethylsilane as internal
standard and CDCl3 as solvent; chemical shifts are given in ppm
and coupling constants are expressed in Hz. 13C NMR spectra were
recorded with a Varian Gemini 50.3 or 75.5 MHz spectrometer.
Melting points were determined with a Gallenkamp apparatus and
are uncorrected. IR spectra were recorded with a FTIR Perkin–
Elmer 1600 spectrophotometer. Mass spectra were recorded with
a Hewlett–Packard spectrometer 5988-A (70 eV). Chromatography
was carried out on SiO2 (silica gel 60, SDS, 60–200 µm). Micro-
analyses were determined with a Carlo Erba 1106 Analyser at
Serveis Cientifico-Tècnics, University of Barcelona, and all new
compounds have given C, H, N analyses within Ϯ0.4% of the theo-
retical values. All reagents were of commercial quality or purified
before use, and the organic solvents were of analytical grade or
purified by standard procedures.
CDCl3): δ = 1.52 [s, 6 H, C5(12)-CH3], 1.71 [s, 6 H, C4(13)-CH3],
3.88 [s, 2 H, C3a(13a)], 6.70 [m, 2 H, C7(10)H], 6.90 [m, 6 H,
C8Ј(9Ј)H, C3Ј(6Ј)H and C4Ј(5Ј)H] ppm. 13C NMR (50.3 MHz,
CDCl3): δ = 12.4 (CH3), 13.1 (CH3), 50.6 [C3a(13a)], 87.9 [C,
C5(12)], 88.9 [C4(13)], 89.9 [C4a(12a)], 116.4 [CH, C3Ј(6Ј)], 117.2
[CH, C7(10)], 122.9 [C, C4Ј(5Ј)], 125.2 [C8(9)], 137.7 [C, C5a(11a)],
142.1 and 142.7 [C1Ј(2Ј) and C6a(10a)], 169.6 (C, CO) ppm. MS
(EI): m/z (%) = 502 (18) [M]+, 202 (100). C28H22O9 (502.48): calcd.
C 66.93, H 4.41; found C 66.57, H 4.59.
5,12-Dimethyl-5,12-dihydro-5,12-epoxy[1,4]benzodioxino[2,3-g]iso-
quinoline (2d) and 5a,13a-(o-Phenylenedioxy)-5,6,13,14-tetramethyl-
5,5a,6,13,13a,14-hexahydro-5,14:6,13-diepoxydibenzo[1,4]dioxino-
[2,3-g]isoquinoline (6): To a 50-mL flask equipped with a magnetic
stirring bar and condenser, previously flamed and purged with ar-
gon, was added bromopyridine (0.27 mL, 2.80 mmol) in dry THF
Dimethyl 1,4-Dimethyl-1,4-dihydro-1,4-epoxydibenzeno[1,4]dioxin- (1 mL). The solution was cooled externally with a bath of ice and
2,3-dicarboxylate (2a) and Dimethyl 6a,10a-(o-Phenylenedioxy)- NaOAc, and a solution Li(Me3Si)2N was slowly added (1  in
6,7,10,11-tetramethyl-6,6a,7,10,10a,11-hexahydro-6,11:7,10-di- THF, 7.40 mL, 7.40 mmol). Then, the mixture was immersed in a
epoxynaphtho[2,3-b][1,4]benzodioxin-8,9-dicarboxylate (3): An
oven-dried flask equipped with a magnetic stirring bar was charged
with diene 1 (42 mg, 0.32 mmol) and dimethyl acetylenedicarboxyl-
ate (45 mg, 0.32 mmol) in dry toluene (drops). The reaction mix-
ture was heated at 120 °C for 20 min after which the mixture was
cooled to room temperature, adsorbed onto silica gel, and then
purified by column chromatography (hexane/ethyl acetate, 85:15)
to afforded dimer 3 as a white solid (30 mg, 0.055 mmol, 41%).
Under these conditions, mono-adduct 2a was not observed. Data
45 °C oil bath; typically, the internal temperature of the reaction
was 38 °C. At this temperature, diene 1 (250 mg, 1.24 mmol) was
added by a funnel over 30 min, and the resulting mixture was
heated at reflux until bromopyridine was completely consumed as
judged by TLC (5 h). The mixture was cooled to room temperature,
adsorbed onto silica gel, and then purified by column chromatog-
raphy (hexane/ethyl acetate, 70:30). Monomer 2d was obtained as
an oil (27 mg, 7% yield) and dimer 6 was isolated as a white solid
(168 mg, 49%). Also starting diene 1 was recovered (70 mg, 28%).
for 3: M.p. 236–238 °C. IR (KBr): ν = 1721 (CO, s) 1269, 1229 Data for mono-adduct 2d: IR (KBr): ν = 1753 (C=C, s) 1600 (C=N,
˜
˜
(Ar–O, s) 1085 (C–O–C, s) cm–1. 1H NMR (500 MHz, CDCl3): δ
s) 1220 and 1278 (Ar–O, s) 1081 (C–O–C, s) cm–1
.
1H NMR
= 1.53 [s, 6 H, C6(11)-CH3], 1.74 [s, 6 H, C7(10)-CH3], 3.64 (s, 6 (300 MHz, CDCl3): δ = 1.82 (s, 3 H, C5-CH3), 1.87 (s, 3 H, C12-
H, -OCH3), 6.73 [m, 2 H, C1(4)H], 6.79 [m, 4 H, C3Ј(6Ј)H and CH3), 6.70 (m, 2 H, C7H, C10H), 6.83 (m, 2 H, C8H, C9H), 7.19
C4Ј(5Ј)H], 6.87 [m, 2 H, C2(3)H] ppm. 13C NMR (50.3 MHz, (dd, J = 4.5 Hz, J = 1 Hz, 2 H, 1 H, C4H), 8.40 (d, J = 4.5 Hz, 1
CDCl3): δ = 12.6 (CH3), 13.0 (CH3), 52.1 (CH3-O), 87.3 [C6(11)], H, C3H), 8.40 (d, J = 4.5 Hz, 1 H, C3H), 8.42 (d, J = 1 Hz, 1 H,
Eur. J. Org. Chem. 2009, 2174–2178
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C. Bozzo, N. Mur, P. Constans, M. D. Pujol
FULL PAPER
C1H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 12.4 (CH3,C5-
CH3), 12.7 (CH3, C12-CH3), 84.8 (C12), 85.0 (C5), 114.0 (CH, C4),
117.3 (CH, C7), 117.4 (CH, C10), 124.8 (CH, C8 and C9), 137.9
(CH, C1), 142.3 (C, C6a and C10a) 144.4 (C, C5a), 145.6 (C,
C11a), 145.7 (C, C12a), 148.4 (CH, C3), 160.6 (C, C4a) ppm. MS
(EI): m/z (%) = 279 (30) [M]+, 264 (5) [M– CH3]+, 251(11), 202 (4),
148 (100), 77 (11). C17H13NO3 (279.29): calcd. C 73.11, H 4.69, N
5.01; found C 73.45, H 4.98, N 4.97. Data for bis-adduct 6: M.p.
Acknowledgments
Financial support from the Spanish Ministerio de Educación y Ci-
encia (CTQ2007-60614/BQU), University of Barcelone, Spain
(ACES, 2006-07), and the Departament de la Generalitat de Cata-
lunya, Spain (2005-SGR-00180) is gratefully acknowledged.
244–246 °C. IR (KBr): ν = 1748 (CO, s) 1606 (C=N, s) 1233 and
˜
1271 (Ar–O, s) 1088 (C–O–C, s) cm–1 1H NMR (500 MHz,
.
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Tetrahedron 1988, 44, 2093–2099.
a) T. V. Lee, A. J. Leigh, C. B. Chapleo, Synlett 1989, 30–32; b)
N. Ruiz, C. Buon, M. D. Pujol, G. Guillaumet, G. Coudert,
Synth. Commun. 1996, 26, 2057–2066; c) N. Ruiz, M. D. Pujol,
G. Guillaumet, G. Coudert, Tetrahedron Lett. 1992, 33, 2965–
2968; d) C. Bozzo, M. D. Pujol, Heterocycl. Commun. 1996, 2,
163–167; e) C. Bozzo, M. D. Pujol, Synlett 2000, 550–552.
a) G. Guillaumet, “1,4-Dioxans, Oxathians, Dithians and
Benzo Derivatives” in Comprehensive Heterocyclic Chemistry II
(Eds.: A. J. Boulton, A. R. Katrizky, C. W. Rees, E. F. V.
Seriven), Pergamon, New York, 1996, vol. 6; b) Y. Satoh, C.
Powers, L. M. Toledo, T. J. Kowalsi, P. A. Peters, E. F. Kimble,
J. Med. Chem. 1995, 38, 68–76; c) M. Romero, P. Renard, D.-
H. Caignard, G. Atassi, X. Solans, P. Constans, C. Bailly,
M. D. Pujol, J. Med. Chem. 2007, 50, 294–307; d) D. T. An-
derson, W. M. Horspool, J. Chem. Soc. Perkin Trans. 1 1997,
532–536.
CDCl3): δ = 1.56 (s, 3 H, C6-CH3), 1.58 (s, 3 H, C13-CH3), 1.85
(s, 3 H, C5-CH3), 1.90 (s, 3 H, C14-CH3), 6.59 (m, 4 H, C3ЈH,
C4ЈH, C5ЈH, C6ЈH), 6.77 (m, 2 H, C8H, C11H), 6.87 (m, 2 H,
C9H, C10H), 7.05 (dd, J = 4.5 Hz, J = 0.5 Hz, 1 H, C4H), 8.31
(d, J = 4.5 Hz, 1 H, C3H), 8.40 (d, J = 0.5 Hz, 1 H, C1H) ppm.
13C NMR (50.3 MHz, CDCl3): δ = 12.6 (CH3,C5-CH3, C6-CH3,
C13-CH3), 12.9 (CH3, C14-CH3), 87.0 (C14), 87.2 (C5), 87.4 (C6
and C13), 116.0, 116.2, 116.3 (CH, C4, C3Ј, C6Ј), 117.0 (CH, C8),
117.1 (CH, C11), 121.6 and 121.8 (C, C4Ј and C5Ј), 124.9 (C9 and
C10), 137.5 and 137.7 (C, C6a and C12a), 141.7 and 141.9 (C1Ј
and C2Ј), 142.1 (C1), 142.4 (C7a and C11a), 142.7 (C, C14a), 148.5
(CH, C3), 156.2 (C, C4a) ppm. MS (EI): m/z (%) = 481 (3) [M]+,
279 (100), 264 (14) [279 – CH3]+, 251 (41), 202 (27), 147 (9).
C29H23NO6 (481.50): calcd. C 72.34, H 4.81, N 2.91; found C
72.16, H 4.90, N 2.97.
[3]
[4]
[5]
[6]
6,11-Diphenyl-5a,6,11,11a-tetrahydro-6,11-epoxinaphtho[2,3-b][1,4]-
benzodioxin (9): IR (KBr): ν = 1267 (Ar–O, s) cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 5.09 [s, 2 H, H5a(11a)], 6.74 [m, 2 H, C1(4)
H], 6.83 [m, 2 H, C2(3)H], 7.04 [br. s, 4 H, C7(10) and C8(9)H],
7.24 (m, 2 H, CHpara), 7.52 (m, 4 H, CHmeta), 7.87 (m, 4 H, CHortho
)
ppm. 13C NMR (75.5 MHz, CDCl3): δ = 77.7 [CH, C5a(11a)],
117.1 [CH, C1(4)], 121.7 [CH, C2(3)], 122.2 [C, C8(9)], 126.2 (CH,
Cpara), 127.6 (CH, Cortho), 128.5 [CH, C7(10)], 128.6 (CH, Cmeta
)
ppm. The quaternary C was not distinguished. MS (EI): m/z (%)
= 404 (1) [M]+, 270 (100). C28H20O3 (404.46): calcd. C 83.15, H
4.98; found C 83.43, H 4.62.
6,11-Diphenylnaphtho[2,3-b][1,4]benzodioxin (10): An oven-dried
flask equipped with a magnetic stirring bar was charged with 1,4-
benzodioxin (110 mg, 0.82 mmol) and isobenzofuran (180 mg,
0.67 mmol) in dry toluene (1 mL). The reaction mixture was heated
at 115 °C for 21 h after which the mixture was cooled to room
temperature, adsorbed onto silica gel, and then purified by column
chromatography (hexane/ethyl acetate, 90:10). Title compound 10
was isolated as a white solid (219 mg, 85%) together with the ad-
duct 9 (7%). M.p. 246–247 °C. IR (KBr): ν = 1278 (Ar–O, s) cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 6.74 [m, 2 H, C1(4)H], 6.83 [m,
[7] a) M. J. Fieser, J. Haddadin, J. Am. Chem. Soc. 1964, 86, 2081–
2082; b) J. Sauer, R. Sustman, Angew. Chem. 1980, 92, 773–
801; c) J. Sauer, Angew. Chem. 1967, 79, 76-94.
[8] a) J. A. Berson, J. Am. Chem. Soc. 1953, 75, 1241–1241; b)
G. S. Smith, P. W. Dibble, R. E. Sandborn, J. Org. Chem. 1986,
51, 3762–3768.
2 H, C2(3)H], 7.24 [m, 2 H, C8(9)H], 7.45–7.58 [m, 12 H, CHpara
,
CHmeta
,
CHortho and C7(10)H] ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 116.3 [CH, C1(4)], 123.4 [CH, C2(3)], 124.2 [C,
C6(11)], 125.0 (CH) and 125.5 [(CH) C8(9) and C7(10)], 127.5 (CH,
Cpara), 128.2 (CH, Cortho), 130.1 [CH, C6a(10a)], 130.9 (CH, Cmeta),
134.4 [C, C1(1ЈЈ)], 138.4 [C, C5a(11a)], 141.5 [C, C4a(12a)] ppm.
MS (EI): m/z (%) = 386 (100) [M]+, 276 (15) [M – 15]+.
C28H18O2·½H2O (395.47): calcd. C 85.04, H 4.84; found C 84.82,
H 4.67.
[9] M. Brandil, M. Meyer, J. Sühnel, J. Biomol. Struct. Dyn. 2001,
18, 545–555.
[10] C. Spino, H. Rezael, Y. L. Dory, J. Org. Chem. 2004, 69, 757–
764.
[11] J. A. Berson, J. Am. Chem. Soc. 1953, 75, 1241–1241.
Supporting Information (see footnote on the first page of this arti-
Received: October 2, 2008
cle): Computational studies and NMR spectra of the compounds.
Published Online: March 12, 2009
2178
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Eur. J. Org. Chem. 2009, 2174–2178