Intramolecular Aryne-Furan Cycloadditions for the Synthesis of Anticancer Naphthalimides

Article abstract of DOI:10.1021/acs.joc.8b00531

An intramolecular aryne Diels-Alder reaction with a furan moiety was applied to the synthesis of dihydrobenzo[de]isochromenes as intermediates toward naphthalimides. After oxidation, this method offers an efficient approach for the synthesis of substitute

Full text of DOI:10.1021/acs.joc.8b00531

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Intramolecular Aryne-Furan Cycloadditions for
the Synthesis of Anticancer Naphthalimides
Sébastien Prévost, Ambre Dezaire, and Alexandre Escargueil
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00531 • Publication Date (Web): 29 Mar 2018
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Intramolecular Aryne-Furan
Cycloadditions for the Synthesis of
Anticancer Naphthalimides
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Sébastien Prévost,*†, ‡ Ambre Dezaire,§ Alexandre Escargueil§
†
Laboratoire de Synthèse Organique, CNRS, Ecole Polytechnique, ENSTA ParisTech, UMR
7652, Université ParisꢀSaclay, 828 Bd des Maréchaux, 91128 Palaiseau, France
‡ Museum National d’Histoire Naturelle, CNRS, UMR 7245 MCAM, Sorbonne Universités,
57 rue Cuvier (CP 54), 75005 Paris, France
§
Sorbonne Université, INSERM, Laboratory of Cancer Biology and Therapeutics, Centre de
Recherche SaintꢀAntoine, CRSA, Fꢀ75012 Paris, France
Abstract
An intramolecular aryne DielsꢀAlder reaction with a furan moiety was applied to the
synthesis of dihydrobenzo[de]isochromenes as intermediates towards naphthalimides. After
oxidation, this method offers an efficient approach for the synthesis of substituted
naphthalimides, which showed potent cytotoxic activity against HTꢀ29 human cancer cell
line.
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Naphthalimides and naphthalic anhydrides are important skeleton in chemistry.1
They are present in natural products and many bioactive compounds such as the antitumor
agent amonafide (Figure 1).2 These compounds exhibit a lot of biological properties including
antitumor activities as a result of their DNAꢀintercalating properties,3 activity against the
malaria parasite Plasmodium falciparum4 as well as antiviral properties.5 Naphthalimides are
also used as fluorescent probes for several applications such as cytochrome P450 1A,
glutathione or metal detection.6 Moreover their absorption and emission behavior is highly
dependent on their substitution pattern.7 Due to these fascinating properties, the synthesis of
new naphthalimide derivatives is of great interest in order to modify their biological and
physiochemical properties.
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Figure 1. Natural product and active compounds exhibiting naphthalic anhydride or
naphthalimide moieties
Despite all these applications, no general method has been developed to synthesize
the naphthalimide core allowing access to a wide range of substitutions. Most of the known
naphthalimides are only substituted in position 3 or 4 because their syntheses are realized
from commercially available anhydrides (Scheme 1a). Regarding this lack of diversity, we
were keen to develop a new versatile method to synthesize dihydrobenzo[de]isochromene
intermediates, in order to have a rapid access to substituted naphthalimides and to evaluate
their anticarcinogenic properties.
Our synthetic strategy was based on an intramolecular aryne DielsꢀAlder reaction
with a furan substituent to generate directly the tricyclic core of the molecule (Scheme 1b).
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Arynes are indeed wellꢀknown to react with furans through [4+2] cycloaddition and to
generate a naphthol, after acidꢀpromoted opening of the oxaꢀbridged product.8 However, the
regioselectivity of this reaction is substrate dependent.9 In our strategy, the intramolecular
character of the reaction would solve the regioselectivity issue and allow an easy access to the
dihydrobenzoisochromene tricylic core.10 Preliminary experiments on the DielsꢀAlder
reaction were attempted on aryne precursor 1 linked to the furan partner through an ester
bond, but desired DielsꢀAlder product 2 was not observed. Only sulfone 3, resulting of a thiaꢀ
Fries rearrangement, could be isolated in 41% yield (Scheme 1c).11 This led us to modify the
strategy, replacing the ester linker by a benzylic ether between the aryne and the furan partner.
The intramolecular DielsꢀAlder reaction was therefore expected to furnish
dihydrobenzoisochromenol B after oxabridge opening, while benzylic oxidation was foreseen
in order to install the anhydride moiety, as shown in scheme 1.
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Scheme 1. Synthetic Strategy towards Naphthalimides
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At the outset, we focused our attention on the DielsꢀAlder reaction of bromo
compound 4a (Table 1) which can be easily synthesized from 5ꢀmethylsalicylic acid. First, the
aryne was generated with nBuLi (1.8 eq.) in THF (0.1 M) at −78 °C. After completion of the
DielsꢀAlder reaction, the reaction was quenched and the residue was treated with pꢀ
toluenesulfonic acid to obtain naphthol 5a in 60% overall yield from 4a (Table 1, entry 1).
The optimization work proved the reaction concentration to be crucial, with a 77% yield
achieved when the DielsꢀAlder reaction was carried out at 0.01 M (Table 1, entry 3). Finally,
the use of sBuLi to form the benzyne moiety did not show any improvement of the reaction
(Table 1, entry 4).
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Table 1. Optimisation of the Intramolecular Diels-Alder Reactiona
Entry
BuLi
nBuLi
nBuLi
nBuLi
sBuLi
C (mol.Lꢀ1)b
0.1
Yield (%)c
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4
60
64
77
71
0.3
0.01
0.01
aReactions were carried out on 0.25 mmol scale. bConcentration of the DielsꢀAlder step. cIsolated yield.
With the optimized conditions in hand, we next investigated the substrate scope of
this intramolecular DielsꢀAlder reaction as shown in Scheme 2. Starting materials 4a-m were
easily prepared by triflation of phenols 13a-m, obtained in two steps from benzylic alcohols
12a-g. First, dihydrobenzoisochromenols substituted in position 6 with an alkyl, fluorine,
methoxy or aryl group (5a-e) were synthesized in good yields from oꢀbromoaryl triflates 4a-e.
The transformation was also compatible with more substituted products such as 5f and 5g,
although a higher concentration (0.05M) was required for this last substrate. Interestingly, the
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DielsꢀAlder reaction was also possible with substrates substituted on the furan moiety, giving
access to all possible substitutions on dihydrobenzoisochromenols. Indeed, products 5h-l,
substituted in position 2 with an aryl or an alkyl group, were obtained in moderate to good
yields. In certain cases (5i-j), the reaction was carried out at higher concentration in order to
achieve full conversion. Finally, dihydrobenzoisochromenol 5m, substituted in position 3, 4
and 6 was synthesized despite a moderate yield.
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Scheme 2. Scope of the Intramolecular Diels-Alder Reactiona
aReaction conditions: i) 4 (0.25 mmol), nBuLi (0.45 mmol), THF (25 mL), ꢀ78 °C to ꢀ40 °C; ii) pTSA (0.275
mmol), THF (1.65 mL), r.t. bstep i) was carried out at 0.05M.
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Then, we turned our attention to the double benzylic oxidation step in order to
generate naphthalic anhydrides. Dihydrobenzoisochromenols 5a-k were first methylated to
obtain dihydrobenzoisochromenes 6a-k with good yield (66ꢀ98%) and several oxidizing
reagent were screened.12 Pyridinium chlorochromate (PCC) in dichloromethane at 60 °C was
found to directly convert dihydrobenzoisochromenes 6a-k to corresponding anhydrides 7a-k
in good yields (32ꢀ86%; a lost was observed for 7c during the purification step due to a very
poor solubility). Interestingly, a lactone was exclusively formed when dichloroꢀ
dicyanobenzoquinone (DDQ) was used as oxidant.13 Finally, anhydrides 7a-k were converted
to naphthalimides 8a-k using N,Nꢀdimethylethylenediamine as primary amine (Scheme 3).
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Scheme 3. Synthesis of the Naphthalimide Productsa
aYields refer to the two steps.
Due to the known anticarcinogenic activity of naphthalimides, compounds 8a-k were
evaluated against the human colon carcinoma HTꢀ29 cell line (Table 2). All the synthesized
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products showed promising results, exhibiting a much higher activity, between 0.066 and
0.640 ꢀM, than the reference compound amonafide (4.67 ꢀM).3d In particular, naphthalimide
8f was the most active with an IC50 value of 66 nM, showing that the presence of an extended
aromatic character was beneficial to the cytotoxicity. On the other hand, the presence of a
phenyl ring in position 2 occasioned a drop in activity (compound 8h). In comparison,
naphthalimides were also tested on normal immortalized fibroblastic AB943 cells, displaying
lower activity against these normal cells, in the range of 0.463ꢀ2.4 ꢀM.
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Table 2. Biological Evaluation of Naphtalimides 8a-ka
Compounds
HTꢀ29 cell line
0.286 ± 0.026
0.148 ± 0.031
0.233 ± 0.080
0.466 ± 0.068
0.066 ± 0.011
0.448 ± 0.068
5.0 ± 1
AB943 cell line
1.5 ± 0.3
8a
0.810 ± 0.058
1.0 ± 0.5
8b
8c
0.760 ± 0.114
0.463 ± 0.055
2.4 ± 0.1
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8f
8g
8h
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0.640 ± 0.135
2.4 ± 0.5
8k
4.67
NT
amonafide
aIC50 (ꢀM, mean ± SEM)
In conclusion, we have developed
a
new method to synthesize
dihydrobenzoisochromenols based on an intramolecular aryne DielsꢀAlder reaction with
furans. This reaction proceeds efficiently with diverse substitutions and represents a powerful
way to have access to a wide variety of naphthalimides. These compounds were biologically
evaluated and showed significant cytotoxic activities, which may be related to their ability to
intercalate DNA. Further applications involving their fluorescence properties in chemical
biology will be explored.
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Experimental Section
Materials and methods
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All reactions were carried out in ovenꢀdried vessels under an atmosphere of argon and
in anhydrous solvents. Unless otherwise stated, all reagents were purchased from commercial
suppliers and used without further purification. All solvents used in the reactions were
distilled from appropriate drying agents prior to use. Reactions were monitored by TLC on
Merck silica gel 60ꢀF254 aluminium sheets (ref.1.05554.0001), using UV absorption then
vanillinꢀH2SO4 (1% vanillin in ethanol + 2% H2SO4) or basic permanganate (1% KMnO4 +
15% Na2CO3 in water) as staining system. The products were purified by silica gel column
chromatography (Geduran silica gel Si 60, 40ꢀ63 µm). Petroleum ether refers to 40/60
petroleum ether. NMR spectra were recorded on a Bruker 400 MHz Avance III spectrometer.
Proton chemical shifts are reported in ppm (δ) with the solvent resonance employed as the
internal standard (CDCl3 δ 7.26, DMSOꢀd6 δ 2.50). Data are reported as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, Q = quintuplet, h =
heptuplet, m = multiplet, br = broad), coupling constants (Hz) and integration. Carbon
chemical shifts are reported in ppm with the solvent resonance as the internal standard (CDCl3
δ 77.16, DMSOꢀd6 δ 39.52). High resolution mass spectra (HRꢀMS) were measured on an
ESIꢀQTOF mass spectrometer (Applied Biosystem QSTAR PulsarꢀI spectrometer) or by
positive electron impact on a doubleꢀfocusing highꢀresolution mass spectrometer (JEOL JMSꢀ
GCmate II mass spectrometer). Infrared spectra were recorded on a Perkin Elmer Spectrum
two FTIR spectrometer. Melting points were measured on a Büchi Bꢀ545 apparatus. Alcohols
12a-d and 12f-g were synthesized according to literature.14
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Preparation of benzyl alcohol 12e
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methyl 4'-(tert-butyl)-4-hydroxy-[1,1'-biphenyl]-3-carboxylate (10):
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To a solution of methyl 2ꢀhydroxyꢀ5ꢀiodobenzoate (2 g, 7.19 mmol, 1 eq.) and 4ꢀtertꢀ
butylphenylboronic acid (1.408 g, 7.91 mmol, 1.1 eq.) in dioxane (44 mL) was added
potassium carbonate (2.982 g, 21.58 mmol, 3 eq.) in H2O (14.4 mL). The mixture was purged
with argon during 20 min. Then, Pd2(dba)3 (198 mg, 0.22 mmol, 0.03 eq.) and
triphenylphosphine (226 mg, 0.86 mmol, 0.12 eq.) were added, the mixture was purged with
argon during 10 min and stirred under reflux overnight. The solvent was removed under
vacuum and EtOAc (40 mL) was added. The organic layer was washed with brine, dried over
Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography
(SiO2, Petroleum Ether/CH2Cl2 7:3) to obtain 10 (1.076 g, 3.78 mmol, 53% yield) as a white
solid.
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Rf = 0.40 (Petroleum Ether/CH2Cl2, 6:4). Mp = 95 °C. νmax (neat): 3256, 2949, 1675, 1484,
1
1178, 823 cmꢀ1. H NMR (400 MHz, CDCl3) δH = 10.75 (s, 1H), 8.06 (d, J = 2.4 Hz, 1H),
7.70 (dd, J = 8.6, 2.4 Hz, 1H), 7.52ꢀ7.43 (m, 4H), 7.05 (d, J = 8.6 Hz, 1H), 3.98 (s, 3H), 1.36
13
(s, 9H). C NMR (101 MHz, CDCl3) δC = 170.7, 160.9, 150.2, 137.1, 134.5, 132.5, 128.2,
126.4 (2C), 125.9 (2C), 118.1, 112.6, 52.5, 34.7, 31.5 (3C). HRMS (m/z) calcd for C18H20O3
[M+] 284.1412, found 284.1407.
methyl 5-bromo-4'-(tert-butyl)-4-hydroxy-[1,1'-biphenyl]-3-carboxylate (11):
To a solution of phenol 10 (1.052 g, 3.70 mmol, 1 eq.) in MeOH (27 mL) was added
dropwise a solution of bromine (220 ꢀL, 4.18 mmol, 1.13 eq.) in MeOH (8.6 mL). The
mixture was stirred at r.t. during 1 h 30 min. A saturated aqueous solution of NaHCO3 was
added and the aqueous phase was extracted with CH2Cl2 (3 x 30 mL). The combined organic
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layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The
residue was purified by flash chromatography (SiO2, Petroleum Ether/CH2Cl2 7:3) to obtain
11 (436 mg, 1.20 mmol, 32% yield) as a white solid.
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Rf = 0.46 (Petroleum Ether/CH2Cl2, 6:4). Mp = 104 °C. νmax (neat): 2957, 1679, 1441, 1244,
793 cmꢀ1. 1H NMR (400 MHz, CDCl3) δH = 11.42 (s, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.97 (d, J
= 2.2 Hz, 1H), 7.46 (s, 4H), 4.00 (s, 3H), 1.36 (s, 9H). 13C NMR (101 MHz, CDCl3) δC =
170.4, 157.3, 150.8, 137.5, 135.9, 133.5, 127.4, 126.4 (2C), 126.1 (2C), 113.6, 111.7, 53.0,
34.7, 31.5 (3C). HRMS (m/z) calcd for C18H19BrO3 [M+] 362.0518, found 362.0529.
3-bromo-4'-(tert-butyl)-5-(hydroxymethyl)-[1,1'-biphenyl]-4-ol (12e):
To a suspension of LiAlH4 (88 mg, 2.32 mmol, 2 eq.) in anhydrous THF (1.6 mL) was
added a solution of ester 11 (426 mg, 1.16 mmol, 1 eq.) in anhydrous THF (4 mL) at 0 °C.
The mixture was stirred at r.t. during 18 h. At 0 °C, a saturated aqueous solution of NH4Cl
was added and the aqueous phase was extracted with EtOAc. The combined organic layers
were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was
purified by flash chromatography (SiO2, Petroleum Ether/AcOEt 85:15) to obtain 12e (272
mg, 0.82 mmol, 70% yield) as a pale yellow solid.
Rf = 0.40 (Petroleum Ether/AcOEt, 75:25). Mp = 97 °C. νmax (neat): 3322, 2961, 1476, 831
cmꢀ1. 1H NMR (400 MHz, CDCl3) δH = 7.66 (d, J = 2.2 Hz, 1H), 7.44 (s, 4H), 7.36 (d, J = 2.2
13
Hz, 1H), 6.70 (br s, 6.70, 1H), 4.86 (s, 2H), 1.35 (s, 9H). C NMR (101 MHz, CDCl3) δC =
150.5, 150.5, 136.6, 134.9, 130.3, 127.4, 126.5 (2C), 126.5, 126.0 (2C), 111.1, 63.4, 34.7,
31.5 (3C). HRMS (m/z) calcd for C17H19BrO2 [M+] 334.0568, found 334.0570.
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General procedure for the synthesis of phenols 13
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To an iceꢀcooled solution of benzyl alcohol 12 (1 eq.) in anhydrous chloroform (0.44
M) was added dropwise phosphorus tribromide (0.5 eq.). The reaction mixture was stirred at
r.t. for 3 h. The reaction mixture was then cooled to 0 °C and H2O was added carefully. The
layers were separated and the aqueous layer was extracted twice with chloroform. The
combined organic layers were dried over Na2SO4 and concentrated under vacuum.
To a NaH (3.9 eq., 60% in mineral oil) suspension in anhydrous THF (0.48 M related
to bromo derivative) was added furfuryl alcohol (3 eq., dissolved in a small amount of
anhydrous THF if it is a solid). The reaction mixture was stirred at r.t. for 4 h. Then, the
previous bromo derivative (1 eq.) in anhydrous THF (0.48 M) was added dropwise. The
reaction mixture was stirred for 16 h under reflux. The reaction mixture was then cooled to 0
°C and 1% aqueous HCl was added carefully. The layers were separated and the aqueous
layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with
H2O, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash
chromatography (SiO2, Cyclohexane/Et2O).
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2-bromo-6-((furan-2-ylmethoxy)methyl)-4-methylphenol (13a):
Prepared from 7.65 mmol of 2ꢀbromoꢀ6ꢀ(hydroxymethyl)ꢀ4ꢀmethylphenol 12a to afford 1.653
g (5.56 mmol, 73% yield) of 13a as a colorless oil.
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Rf = 0.32 (Cyclohexane/Et2O, 9:1).
ν
max (film): 3368, 2918, 1742, 1483, 1234, 741 cmꢀ1. H
NMR (400 MHz, CDCl3) δH = 7.46ꢀ7.41 (m, 1H), 7.28ꢀ7.23 (m, 1H), 6.96 (s, 1H), 6.92ꢀ6.88
(m, 1H), 6.39ꢀ6.33 (m, 2H), 4.64 (s, 2H), 4.55 (s, 2H), 2.24 (s, 3H). 13C NMR (101 MHz,
CDCl3) δC = 150.7, 149.6, 143.4, 132.6, 130.8, 128.8, 123.8, 110.5, 110.3, 110.2, 69.6, 64.3,
20.3. HRMS (m/z) calcd for C13H1379BrO3Na [MNa+] 318.9946, found 318.9944.
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2-bromo-4-fluoro-6-((furan-2-ylmethoxy)methyl)phenol (13b):
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Prepared from 1 mmol of 2ꢀbromoꢀ4ꢀfluoroꢀ6ꢀ(hydroxymethyl)phenol 12b to afford 208 mg
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(0.69 mmol, 69% yield) of 13b as a colorless oil.
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Rf = 0.35 (Cyclohexane /Et2O, 9:1).
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MHz, CDCl3) δH = 7.47ꢀ7.43 (m, 1H), 7.18 (dd, J = 7.7, 3.0 Hz, 1H), 6.91 (s, 1H), 6.89 (dd, J
= 8.3, 3.0 Hz, 1H), 6.40ꢀ6.35 (m, 2H), 4.64 (s, 2H), 4.56 (s, 2H). 19F NMR (376 MHz, CDCl3)
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δF = ꢀ122.4 (s, 1F). C NMR (101 MHz, CDCl3) δC = 156.0 (d, J = 242.3 Hz), 150.5, 148.2
(d, J = 2.7 Hz), 143.5, 125.1 (d, J = 7.4 Hz), 118.8 (d, J = 25.7 Hz), 114.6 (d, J = 23.4 Hz),
110.6, 110.4, 110.2 (d, J = 10.1 Hz), 69.0 (d, J = 1.5 Hz), 64.5. HRMS (m/z) calcd for
C12H1079BrFO3Na [MNa+] 322.9695, found 322.9698.
2-bromo-6-((furan-2-ylmethoxy)methyl)-4-methoxyphenol (13c):
Prepared from 2.57 mmol of 2ꢀbromoꢀ6ꢀ(hydroxymethyl)ꢀ4ꢀmethoxyphenol 12c to afford 439
mg (1.40 mmol, 55% yield) of 13c as a colorless oil.
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Rf = 0.27 (Cyclohexane /Et2O, 9:1).
ν
max (neat): 3359, 1480, 1044, 740 cmꢀ1. H NMR (400
MHz, CDCl3) δH = 7.46ꢀ7.42 (m, 1H), 7.00 (d, J = 3.0 Hz, 1H), 6.71 (d, J = 3.0 Hz, 1H), 6.69
(s, 1H), 6.39ꢀ6.34 (m, 2H), 4.64 (s, 2H), 4.55 (s, 2H), 3.74 (s, 3H). 13C NMR (101 MHz,
CDCl3) δC = 153.3, 150.7, 145.9, 143.4, 124.7, 117.2, 114.3, 110.5, 110.5, 110.3, 69.5, 64.3,
56.1. HRMS (m/z) calcd for C13H1379BrO4Na [MNa+] 334.9895, found 334.9903.
3-bromo-5-((furan-2-ylmethoxy)methyl)-[1,1'-biphenyl]-4-ol (13d):
Prepared from 1 mmol of 3ꢀbromoꢀ5ꢀ(hydroxymethyl)ꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀol 12d to afford 226
mg (0.63 mmol, 63% yield) of 13d as a pale yellow oil.
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Rf = 0.32 (Cyclohexane /Et2O, 9:1).
ν
max (neat): 3334, 1471, 1053, 761 cmꢀ1. H NMR (400
MHz, CDCl3) δH = 7.68 (d, J = 2.2 Hz, 1H), 7.54ꢀ7.48 (m, 2H), 7.47ꢀ38 (m, 3H), 7.36ꢀ7.29
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(m, 2H), 7.25 (s, 1H), 6.41ꢀ6.35 (m, 2H), 4.75 (s, 2H), 4.60 (s, 2H). C NMR (101 MHz,
CDCl3) δC = 151.4, 150.6, 143.5, 139.5, 134.7, 130.9, 129.0 (2C), 127.4, 126.8 (2C), 126.8,
124.4, 111.1, 110.6, 110.4, 69.8, 64.4. HRMS (m/z) calcd for C18H1679BrO3 [MH+] 359.0283,
found 359.0278.
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3-bromo-4'-(tert-butyl)-5-((furan-2-ylmethoxy)methyl)-[1,1'-biphenyl]-4-ol (13e):
Prepared from 0.80 mmol of 3ꢀbromoꢀ4'ꢀ(tertꢀbutyl)ꢀ5ꢀ(hydroxymethyl)ꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀol
12e to afford 133 mg (0.32 mmol, 40% yield) of 13e as a pale yellow oil.
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Rf = 0.51 (Petroleum Ether/Et2O, 75:25). νmax (neat): 3356, 2961, 1477, 831, 744 cmꢀ1. H
NMR (400 MHz, CDCl3) δH = 7.69 (d, J = 2.2 Hz, 1H), 7.48ꢀ7.42 (m, 5H), 7.32 (d, J = 2.2
Hz, 1H), 7.28 (br s, 1H), 6.40 (d, J = 3.1 Hz, 1H), 6.38 (dd, J = 3.1, 1.8 Hz, 1H), 4.75 (s, 2H),
4.60 (s, 2H), 1.36 (s, 9H). 13C NMR (101 MHz, CDCl3) δC = 151.2, 150.6, 150.4, 143.5,
136.6, 134.5, 130.8, 126.6, 126.5 (2C), 125.9 (2C), 124.2, 111.1, 110.6, 110.4, 69.8, 64.3,
34.6, 31.5 (3C). HRMS (m/z) calcd for C22H2379BrO3 [M+] 414.0831, found 414.0845.
1-bromo-3-((furan-2-ylmethoxy)methyl)naphthalen-2-ol (13f):
Prepared from 5.24 mmol of 1ꢀbromoꢀ3ꢀ(hydroxymethyl)naphthalenꢀ2ꢀol 12f to afford 198
mg (0.59 mmol, 11% yield) of 13f as a yellow oil.
Rf = 0.25 (Cyclohexane /Et2O, 9:1). ν
max (neat): 3497, 1452, 1403, 1148 cmꢀ1. 1H NMR (400
MHz, CDCl3) δH = 8.08 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.69 (s, 1H), 7.55 (ddd,
J = 8.2, 6.9, 1.1 Hz, 1H), 7.46 (dd, J = 1.8, 0.8 Hz, 1H), 7.38 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H),
7.15 (s, 1H), 6.42ꢀ6.35 (m, 2H), 4.84 (s, 2H), 4.62 (s, 2H). 13C NMR (101 MHz, CDCl3) δC =
150.9, 150.0, 143.4, 132.5, 129.2, 128.2, 127.8, 127.6, 125.6, 125.6, 124.4, 110.5, 110.3,
106.8, 69.4, 64.4. HRMS (m/z) calcd for C16H1479BrO3 [MH+] 333.0126, found 333.0131.
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1-bromo-3-((furan-2-ylmethoxy)methyl)-5,6,7,8-tetrahydronaphthalen-2-ol
(13g):
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Prepared from 2.78 mmol of 1ꢀbromoꢀ3ꢀ(hydroxymethyl)ꢀ5,6,7,8ꢀtetrahydronaphthalenꢀ2ꢀol
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12g to afford 356 mg (1.06 mmol, 38% yield) of 13g as a colorless oil.
Rf = 0.33 (Cyclohexane /Et2O, 9:1). ν
max (neat): 3319, 2925, 1469, 1045, 751 cmꢀ1. 1H NMR
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(400 MHz, CDCl3) δH = 7.43 (dd, J = 1.4, 1.2 Hz, 1H), 6.87 (s, 1H), 6.77 (s, 1H), 6.39ꢀ6.33
(m, 2H), 4.63 (s, 2H), 4.54 (s, 2H), 2.70 (dt, J = 11.6, 6.4 Hz, 4H), 1.85ꢀ1.76 (m, 2H), 1.76ꢀ
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1.67 (m, 2H). C NMR (101 MHz, CDCl3) δC = 151.1, 149.4, 143.2, 137.0, 130.6, 128.5,
121.2, 113.7, 110.5, 110.0, 69.1, 64.1, 30.5, 29.4, 23.3, 22.9. HRMS (m/z) calcd for
C16H1879BrO3 [MH+] 337.0439, found 337.0442.
2-bromo-4-methyl-6-(((3-phenylfuran-2-yl)methoxy)methyl)phenol (13h):
Prepared from 1 mmol of 2ꢀbromoꢀ6ꢀ(hydroxymethyl)ꢀ4ꢀmethylphenol 12a to afford 269 mg
(0.72 mmol, 72% yield) of 13h as a yellow oil.
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Rf = 0.37 (Pentane/Et2O, 9:1).
ν
max (neat): 3350, 1481, 1053, 743, 699 cmꢀ1. H NMR (400
MHz, CDCl3) δH = 7.48 (d, J = 1.9 Hz, 1H), 7.46ꢀ7.37 (m, 4H), 7.36ꢀ7.29 (m, 1H), 7.28ꢀ7.24
(m, 1H), 6.88 (s, 1H), 6.84 (d, J = 1.3 Hz, 1H), 6.59 (d, J = 1.9 Hz, 1H), 4.66 (s, 2H), 4.63 (s,
2H), 2.22 (s, 3H). 13C NMR (101 MHz, CDCl3) δC = 149.6, 146.6, 142.8, 133.0, 132.7, 130.8,
129.1, 128.9 (2C), 128.1 (2C), 127.4, 126.5, 123.9, 111.6, 110.3, 69.6, 63.0, 20.3. HRMS
(m/z) calcd for C19H1779BrO3Na [MNa+] 395.0259, found 395.0261.
2-bromo-6-(((3-(4-methoxyphenyl)furan-2-yl)methoxy)methyl)-4-methylphenol
(13i):
Prepared from 1 mmol of 2ꢀbromoꢀ6ꢀ(hydroxymethyl)ꢀ4ꢀmethylphenol 12a to afford 215 mg
(0.53 mmol, 53% yield) of 13i as a colorless oil.
Rf = 0.30 (Pentane/Et2O, 9:1). ν
max (neat): 3361, 1516, 1247, 1033, 833 cmꢀ1. 1H NMR (400
MHz, CDCl3) δH = 7.45 (d, J = 1.8 Hz, 1H), 7.39ꢀ7.32 (m, 2H), 7.26 (s, 1H), 6.98ꢀ6.94 (m,
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1H), 6.94ꢀ6.91 (m, 2H), 6.83 (d, J = 1.1 Hz, 1H), 6.55 (d, J = 1.8 Hz, 1H), 4.66 (s, 2H), 4.61
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(s, 2H), 3.84 (s, 3H), 2.22 (s, 3H). C NMR (101 MHz, CDCl3) δC = 159.0, 149.6, 146.0,
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142.6, 132.6, 130.7, 129.2 (2C), 129.1, 126.2, 125.4, 123.9, 114.3 (2C), 111.6, 110.2, 69.5,
63.0, 55.4, 20.2. HRMS (m/z) calcd for C20H1979BrO4Na [MNa+] 425.0364, found 425.0357.
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2-bromo-4-methyl-6-(((3-(p-tolyl)furan-2-yl)methoxy)methyl)phenol (13j):
Prepared from 0.53 mmol of 2ꢀbromoꢀ6ꢀ(hydroxymethyl)ꢀ4ꢀmethylphenol 12a to afford 117
mg (0.30 mmol, 57% yield) of 13j as a yellow oil.
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Rf = 0.45 (Petroleum Ether/Et2O, 85:15).
ν
max (neat): 3362, 2920, 1483, 1051, 821 cmꢀ1. H
NMR (400 MHz, CDCl3) δH = 7.46 (d, J = 1.8 Hz, 1H), 7.35ꢀ7.29 (m, 2H), 7.25 (d, J = 1.6
Hz, 1H), 7.23ꢀ7.18 (m, 2H), 6.94 (br s, 1H), 6.83ꢀ6.79 (m, 1H), 6.56 (d, J = 1.8 Hz, 1H), 4.65
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(s, 2H), 4.62 (s, 2H), 2.38 (s, 3H), 2.22 (s, 3H). C NMR (101 MHz, CDCl3) δC = 149.8,
146.4, 142.8, 137.3, 132.8, 130.8, 130.1, 129.7 (2C), 129.2, 128.1 (2C), 126.6, 124.0, 111.7,
+
110.4, 69.7, 63.1, 21.4, 20.4. HRMS (m/z) calcd for C12H11O [MꢀC8H8BrO2 ] 171.0805, found
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171.0804; calcd for C8H7 BrO [MꢀC12H11O2 ] 197.9675, found 197.9669.
2-bromo-4-methyl-6-(((3-methylfuran-2-yl)methoxy)methyl)phenol (13k):
Prepared from 1.35 mmol of 2ꢀbromoꢀ6ꢀ(hydroxymethyl)ꢀ4ꢀmethylphenol 12a to afford 345
mg (1.11 mmol, 82% yield) of 13k as a pale yellow oil.
Rf = 0.19 (Petroleum Ether/Et2O, 95:5). νmax (neat): 3351, 2922, 1483, 1053, 743 cmꢀ1. H
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NMR (400 MHz, CDCl3) δH = 7.34 (d, J = 1.8 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.17 (s, 1H),
6.89ꢀ6.85 (m, 1H), 6.23 (d, J = 1.8 Hz, 1H), 4.62 (s, 2H), 4.51 (s, 2H), 2.24 (s, 3H), 2.03 (s,
3H). 13C NMR (101 MHz, CDCl3) δC = 149.8, 146.2, 142.4, 132.7, 130.7, 128.6, 123.8, 120.1,
+
113.1, 110.3, 70.0, 62.1, 20.3, 10.0. HRMS (m/z) calcd for C6H7O [MꢀC8H8BrO2 ] 95.0492,
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+
found 95.0493; calcd for C8H7 BrO [MꢀC12H11O2 ] 197.9675, found 197.9672.
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2-bromo-6-(((3-(4-fluorophenyl)furan-2-yl)methoxy)methyl)-4-methoxyphenol
(13l):
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Prepared from 0.70 mmol of 2ꢀbromoꢀ6ꢀ(hydroxymethyl)ꢀ4ꢀmethoxyphenol 12c to afford 146
mg (0.36 mmol, 51% yield) of 13l as a yellow solid.
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Rf = 0.43 (Petroleum Ether/Et2O, 7:3). MP = 78 °C. νmax (neat): 3385, 1515, 1481, 1224, 1046,
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838 cmꢀ1. 1H NMR (400 MHz, CDCl3) δH = 7.46 (d, J = 1.9 Hz, 1H), 7.43ꢀ7.35 (m, 2H), 7.13ꢀ
7.04 (m, 2H), 7.00 (d, J = 3.0 Hz, 1H), 6.69 (d, J = 3.0 Hz, 1H), 6.54 (d, J = 1.9 Hz, 1H),
6.53 (br s, 1H), 4.66 (s, 2H), 4.59 (s, 2H), 3.73 (s, 3H). 13C NMR (101 MHz, CDCl3) δC =
162.3 (d, J = 246.7 Hz), 153.3, 146.6, 145.8, 142.9, 129.7 (d, J = 8.0 Hz, 2C), 129.0 (d, J =
3.5 Hz), 125.6, 124.7, 116.4 (d, J = 139.0 Hz, 2C), 115.9, 114.7, 111.5, 110.5, 69.5, 63.0,
+
56.0. HRMS (m/z) calcd for C11H8FO [MꢀC8H8BrO3 ] 175.0554, found 175.0556; calcd for
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C8H8 BrO2 [MꢀC11H8FO2 ] 213.9624, found 213.9613.
2-bromo-4-methyl-6-(((4-phenylfuran-2-yl)methoxy)methyl)phenol (13m):
Prepared from 0.61 mmol of 2ꢀbromoꢀ6ꢀ(hydroxymethyl)ꢀ4ꢀmethylphenol 12a to afford 178
mg (0.48 mmol, 78% yield) of 13m as a pale yellow solid.
Rf = 0.23 (Petroleum Ether/Et2O, 9:1). MP = 69 °C. ν
max (neat): 3361, 1483, 1135, 757 cmꢀ1.
1H NMR (400 MHz, CDCl3) δH = 7.72 (d, J = 0.9 Hz, 1H), 7.50ꢀ7.43 (m, 2H), 7.41ꢀ7.34 (m,
2H), 7.31ꢀ7.24 (m, 1H), 7.17 (s, 1H), 6.95ꢀ6.91 (m, 1H), 6.90 (s, 1H), 6.68 (s, 1H), 4.68 (s,
2H), 4.58 (s, 2H), 2.25 (s, 3H). 13C NMR (101 MHz, CDCl3) δC = 151.9, 149.6, 139.1, 132.7,
132.2, 130.9, 129.0 (2C), 128.9, 127.4, 127.3, 125.9 (2C), 123.8, 110.3, 109.4, 69.6, 64.4,
20.3. HRMS (m/z) calcd for C19H1779BrO3 [M+] 372.0361, found 372.0361.
General procedure for the synthesis of bromo-triflates 4
To an iceꢀcooled solution of phenol 13 (1 eq.) and pyridine (1.8 eq.) in anhydrous
CH2Cl2 (0.17 M) was added triflic anhydride (1.2 eq.). The reaction mixture was stirred for 1
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h at r.t. The reaction mixture was then cooled to 0 °C and 1% aqueous HCl was added
carefully. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 x 25
mL). The combined organic layers were washed with brine, dried over Na2SO4 and
concentrated under vacuum. The residue was purified by flash chromatography (SiO2,
Cyclohexane/Et2O).
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2-bromo-6-((furan-2-ylmethoxy)methyl)-4-methylphenyl
(4a):
trifluoromethanesulfonate
Prepared from 5.46 mmol of 2ꢀbromoꢀ6ꢀ((furanꢀ2ꢀylmethoxy)methyl)ꢀ4ꢀmethylphenol 13a to
afford 1.924 g (4.48 mmol, 82% yield) of 4a as a colorless oil.
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Rf = 0.46 (Cyclohexane /Et2O, 95:5).
ν
max (film): 2922, 1416, 1215, 866 cmꢀ1. H NMR (400
MHz, CDCl3) δH = 7.45ꢀ7.42 (m, 1H), 7.42ꢀ7.39 (m, 1H), 7.38ꢀ7.33 (m, 1H), 6.39ꢀ6.33 (m,
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2H), 4.63 (s, 2H), 4.54 (s, 2H), 2.35 (s, 3H). C NMR (101 MHz, CDCl3) δC = 151.1, 143.2,
141.7, 140.1, 134.2, 133.7, 129.9, 118.7 (q, J = 320.8 Hz), 115.9, 110.5, 110.1, 66.4, 64.8,
20.8. HRMS (m/z) calcd for C14H1279BrF3O5SNa [MNa+] 450.9439, found 450.9433.
2-bromo-4-fluoro-6-((furan-2-ylmethoxy)methyl)phenyl trifluoromethanesulfonate (4b):
Prepared from 0.65 mmol of 2ꢀbromoꢀ4ꢀfluoroꢀ6ꢀ((furanꢀ2ꢀylmethoxy)methyl)phenol 13b to
afford 248 mg (0.57 mmol, 88% yield) of 4b as a colorless oil.
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Rf = 0.65 (Cyclohexane /Et2O, 9:1).
ν
max (neat): 2915, 1412, 1211, 1134, 863 cmꢀ1. H NMR
(400 MHz, CDCl3) δH = 7.43 (dd, J = 1.8, 0.9 Hz, 1H), 7.37ꢀ7.30 (m, 2H), 6.39ꢀ6.33 (m, 2H),
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4.65 (s, 2H), 4.56 (s, 2H). F NMR (376 MHz, CDCl3) δF = ꢀ72.1 (s, 3F), ꢀ109.9 (s, 1F). C
NMR (101 MHz, CDCl3) δC = 161.3 (d, J = 253.6 Hz), 150.7, 143.4, 139.6 (d, J = 3.5 Hz),
136.7 (d, J = 8.6 Hz), 120.7 (d, J = 26.6 Hz), 118.7 (q, J = 320.8 Hz), 117.1, 115.9 (d, J =
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24.7 Hz), 110.6, 110.4, 66.0, 64.9. HRMS (m/z) calcd for C13H9 BrF4O5SNa [MNa+]
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454.9188, found 454.9192.
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2-bromo-6-((furan-2-ylmethoxy)methyl)-4-methoxyphenyl
(4c):
trifluoromethanesulfonate
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Prepared from 1.28 mmol of 2ꢀbromoꢀ6ꢀ((furanꢀ2ꢀylmethoxy)methyl)ꢀ4ꢀmethoxyphenol 13c
to afford 478 mg (1.07 mmol, 84% yield) of 4c as a colorless oil.
Rf = 0.28 (Cyclohexane /Et2O, 95:5). ν
max (neat): 2943, 1407, 1206, 859 cmꢀ1. 1H NMR (400
MHz, CDCl3) δH = 7.42 (d, J = 0.7 Hz, 1H), 7.12ꢀ7.06 (m, 2H), 6.38ꢀ6.33 (m, 2H), 4.64 (s,
2H), 4.53 (s, 2H), 3.82 (s, 3H). 13C NMR (101 MHz, CDCl3) δC = 159.3, 151.0, 143.3, 137.2,
135.2, 119.0, 118.7 (q, J = 320.6 Hz), 116.8, 113.9, 110.5, 110.2, 66.4, 64.7, 56.1. HRMS
(m/z) calcd for C14H1279BrF3O6SNa [MNa+] 466.9388, found 466.9396.
3-bromo-5-((furan-2-ylmethoxy)methyl)-[1,1'-biphenyl]-4-yl trifluoromethanesulfonate
(4d):
Prepared from 0.52 mmol of 3ꢀbromoꢀ5ꢀ((furanꢀ2ꢀylmethoxy)methyl)ꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀol
13d to afford 202 mg (0.41 mmol, 79% yield) of 4d as a colorless oil.
1
Rf = 0.64 (Cyclohexane /Et2O, 9:1).
ν
max (neat): 1409, 1207, 1132, 859 cmꢀ1. H NMR (400
MHz, CDCl3) δH = 7.82ꢀ7.79 (m, 1H), 7.79ꢀ7.75 (m, 1H), 7.59ꢀ7.53 (m, 2H), 7.50ꢀ7.37 (m,
4H), 6.40ꢀ6.33 (m, 2H), 4.73 (s, 2H), 4.58 (s, 2H). 13C NMR (101 MHz, CDCl3) δC = 151.0,
143.3, 142.9, 142.9, 138.2, 134.5, 132.2, 129.2 (2C), 128.7, 127.8, 127.3 (2C), 118.7 (q, J =
320.9 Hz), 116.6, 110.5, 110.2, 66.5, 64.8. HRMS (m/z) calcd for C19H1579BrF3O5S [MH+]
490.9776, found 490.9772.
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3-bromo-4'-(tert-butyl)-5-((furan-2-ylmethoxy)methyl)-[1,1'-biphenyl]-4-yl
trifluoromethanesulfonate (4e):
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7
8
9
Prepared from 0.31 mmol of 3ꢀbromoꢀ4'ꢀ(tertꢀbutyl)ꢀ5ꢀ((furanꢀ2ꢀylmethoxy)methyl)ꢀ[1,1'ꢀ
biphenyl]ꢀ4ꢀol 13e to afford 153 mg (0.28 mmol, 90% yield) of 4e as a pale yellow oil.
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Rf = 0.45 (Petroleum Ether/Et2O, 95:5). νmax (neat): 2963, 1412, 1209, 1133, 861 cmꢀ1. H
NMR (400 MHz, CDCl3) δH = 7.80 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.55ꢀ7.46
(m, 4H), 7.43 (dd, J = 1.8, 0.8 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H), 6.37 (dd, J = 3.2, 1.8 Hz,
1H), 4.73 (s, 2H), 4.58 (s, 2H), 1.37 (s, 9H). 13C NMR (101 MHz, CDCl3) δC = 151.9, 151.0,
143.3, 142.8, 142.7, 135.3, 134.4, 132.0, 127.6, 127.0 (2C), 126.1 (2C), 118.7 (q, J = 320.7
Hz), 116.6, 110.5, 110.2, 66.5, 64.8, 34.8, 31.4 (3C). HRMS (m/z) calcd for C23H2279BrF3O5S
[M+] 546.0323, found 546.0299.
1-bromo-3-((furan-2-ylmethoxy)methyl)naphthalen-2-yl trifluoromethanesulfonate (4f):
Prepared from 0.59 mmol of 1ꢀbromoꢀ3ꢀ((furanꢀ2ꢀylmethoxy)methyl)naphthalenꢀ2ꢀol 13f to
afford 192 mg (0.41 mmol, 70% yield) of 4f as a white solid.
Rf = 0.44 (Cyclohexane /Et2O, 9:1). Mp = 52 °C. ν
max (film): 2906, 1408, 1223, 895, 750 cmꢀ1.
1H NMR (400 MHz, CDCl3) δH = 8.29 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 7.87 (d, J = 8.1 Hz,
1H), 7.66 (ddd, J = 7.8, 6.9, 0.8 Hz, 1H), 7.63ꢀ7.56 (m, 1H), 7.44 (d, J = 0.8 Hz, 1H), 6.44ꢀ
6.35 (m, 2H), 4.84 (s, 2H), 4.63 (s, 2H). 13C NMR (101 MHz, CDCl3) δC = 151.2, 143.3,
142.7, 133.0, 132.3, 130.7, 129.1, 128.6, 128.5, 128.1, 127.9, 118.8 (q, J = 321.2 Hz), 117.0,
110.5, 110.2, 67.1, 64.8. HRMS (m/z) calcd for C17H1379BrF3O5S [MH+] 464.9619, found
464.9615.
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1-bromo-3-((furan-2-ylmethoxy)methyl)-5,6,7,8-tetrahydronaphthalen-2-yl
trifluoromethanesulfonate (4g):
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7
8
Prepared from 0.96 mmol
of 1ꢀbromoꢀ3ꢀ((furanꢀ2ꢀylmethoxy)methyl)ꢀ5,6,7,8ꢀ
9
tetrahydronaphthalenꢀ2ꢀol 13g to afford 386 mg (0.82 mmol, 85% yield) of 4g as a colorless
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oil.
Rf = 0.37 (Cyclohexane /CH2Cl2, 8:2). νmax (neat): 2936, 1406, 1204, 1132, 857 cmꢀ1. H
1
NMR (400 MHz, CDCl3) δH = 7.44ꢀ7.40 (m, 1H), 7.27 (s, 1H), 6.38ꢀ6.33 (m, 2H), 4.62 (s,
13
2H), 4.52 (s, 2H), 2.82ꢀ2.71 (m, 4H), 1.88ꢀ1.79 (m, 2H), 1.79ꢀ1.70 (m, 2H). C NMR (101
MHz, CDCl3) δC = 151.2, 143.2, 141.8, 139.8, 139.1, 130.2, 129.5, 119.1, 118.7 (q, J = 320.7
Hz), 110.5, 110.0, 66.5, 64.6, 30.9, 30.0, 23.0, 22.3. HRMS (m/z) calcd for C17H1779BrF3O5S
[MH+] 468.9932, found 468.9922.
2-bromo-4-methyl-6-(((3-phenylfuran-2-yl)methoxy)methyl)phenyl
trifluoromethanesulfonate (4h):
Prepared
from
0.55
mmol
of
2ꢀbromoꢀ4ꢀmethylꢀ6ꢀ(((3ꢀphenylfuranꢀ2ꢀ
yl)methoxy)methyl)phenol 13h to afford 215 mg (0.43 mmol, 77% yield) of 4h as a yellow
oil.
Rf = 0.46 (Cyclohexane /CH2Cl2, 8:2). ν
max (neat): 1408, 1206, 1132, 860 cmꢀ1. 1H NMR (400
MHz, CDCl3) δH = 7.49ꢀ7.44 (m, 3H), 7.44ꢀ7.37 (m, 3H), 7.36ꢀ7.29 (m, 2H), 6.59 (d, J = 1.9
13
Hz, 1H), 4.68 (s, 2H), 4.63 (s, 2H), 2.33 (s, 3H). C NMR (101 MHz, CDCl3) δC = 146.9,
142.7, 141.7, 140.1, 134.2, 133.7, 133.0, 130.0, 128.9 (2C), 128.1 (2C), 127.4, 126.4, 118.7
(q, J = 320.3 Hz), 115.9, 111.5, 66.6, 63.6, 20.9. HRMS (m/z) calcd for C20H1679BrF3O5SNa
[MNa+] 526.9752, found 526.9750.
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2-bromo-6-(((3-(4-methoxyphenyl)furan-2-yl)methoxy)methyl)-4-methylphenyl
trifluoromethanesulfonate (4i):
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9
Prepared from 0.48 mmol of 2ꢀbromoꢀ6ꢀ(((3ꢀ(4ꢀmethoxyphenyl)furanꢀ2ꢀyl)methoxy)methyl)ꢀ
4ꢀmethylphenol 13i to afford 188 mg (0.35 mmol, 73% yield) of 4i as a colorless oil.
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Rf = 0.30 (Cyclohexane /CH2Cl2, 8:2). ν
max (neat): 1517, 1409, 1208, 862 cmꢀ1. 1H NMR (400
MHz, CDCl3) δH = 7.43 (d, J = 1.8 Hz, 1H), 7.42ꢀ7.35 (m, 3H), 7.35ꢀ7.31 (m, 1H), 6.97ꢀ6.91
13
(m, 2H), 6.54 (d, J = 1.8 Hz, 1H), 4.67 (s, 2H), 4.60 (s, 2H), 3.84 (s, 3H), 2.33 (s, 3H). C
NMR (101 MHz, CDCl3) δC = 159.1, 146.3, 142.5, 141.7, 140.1, 134.2, 133.8, 130.0, 129.2
(2C), 126.0, 125.5, 118.7 (q, J = 322.0 Hz), 115.9, 114.3 (2C), 111.5, 66.6, 63.6, 55.4, 20.8.
HRMS (m/z) calcd for C21H1879BrF3O6SNa [MNa+] 556.9857, found 556.9857.
2-bromo-4-methyl-6-(((3-(p-tolyl)furan-2-yl)methoxy)methyl)phenyl
trifluoromethanesulfonate (4j):
Prepared
from
0.29
mmol
of
2ꢀbromoꢀ4ꢀmethylꢀ6ꢀ(((3ꢀ(pꢀtolyl)furanꢀ2ꢀ
yl)methoxy)methyl)phenol 13j to afford 136 mg (0.26 mmol, 90% yield) of 4j as a yellow oil.
1
Rf = 0.47 (Petroleum Ether/Et2O, 9:1). νmax (neat): 2924, 1412, 1211, 1135, 866 cmꢀ1. H
NMR (400 MHz, CDCl3) δH = 7.44 (d, J = 1.8 Hz, 1H), 7.42ꢀ7.38 (m, 1H), 7.37ꢀ7.29 (m, 3H),
7.24ꢀ7.18 (m, 2H), 6.56 (d, J = 1.8 Hz, 1H), 4.67 (s, 2H), 4.61 (s, 2H), 2.39 (s, 3H), 2.32 (s,
3H). 13C NMR (101 MHz, CDCl3) δC = 146.6, 142.6, 141.7, 140.1, 137.2, 134.2, 133.7, 130.1,
130.0, 129.6 (2C), 127.9 (2C), 126.3, 118.7 (q, J = 320.8 Hz), 115.9, 111.6, 66.5, 63.6, 21.3,
20.9. HRMS (m/z) calcd for C21H1879BrF3O5S [M+] 518.0010, found 518.0004.
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2-bromo-4-methyl-6-(((3-methylfuran-2-yl)methoxy)methyl)phenyl
trifluoromethanesulfonate (4k):
6
7
8
Prepared
from
1.03
mmol
of
2ꢀbromoꢀ4ꢀmethylꢀ6ꢀ(((3ꢀmethylfuranꢀ2ꢀ
9
yl)methoxy)methyl)phenol 13k to afford 335 mg (0.76 mmol, 73% yield) of 4k as a pale
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yellow oil.
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Rf = 0.26 (Petroleum Ether/CH2Cl2, 9:1).
ν
max (neat): 1411, 1208, 1134, 864 cmꢀ1. H NMR
(400 MHz, CDCl3) δH = 7.42ꢀ7.38 (m, 1H), 7.37ꢀ7.34 (m, 1H), 7.33 (d, J = 1.8 Hz, 1H), 6.22
(d, J = 1.8 Hz, 1H), 4.60 (s, 2H), 4.51 (s, 2H), 2.35 (s, 3H), 2.05 (s, 3H). 13C NMR (101 MHz,
CDCl3) δC = 146.6, 142.3, 141.6, 140.1, 134.1, 133.9, 129.8, 119.9, 118.7 (q, J = 320.8 Hz),
115.8, 113.1, 66.2, 62.7, 20.9, 9.9. HRMS (m/z) calcd for C15H1479BrF3O5S+ [M+] 441.9697,
found 441.9686.
2-bromo-6-(((3-(4-fluorophenyl)furan-2-yl)methoxy)methyl)-4-methoxyphenyl
trifluoromethanesulfonate (4l):
Prepared from 0.35 mmol of 2ꢀbromoꢀ6ꢀ(((3ꢀ(4ꢀfluorophenyl)furanꢀ2ꢀyl)methoxy)methyl)ꢀ4ꢀ
methoxyphenol 13l to afford 164 mg (0.30 mmol, 87% yield) of 4l as a yellow oil.
Rf = 0.53 (Petroluem Ether/Et2O, 7:3). ν
max (neat): 2923, 1410, 1212, 864 cmꢀ1. 1H NMR (400
MHz, CDCl3) δH = 7.44 (d, J = 1.8 Hz, 1H), 7.44ꢀ7.37 (m, 2H), 7.14ꢀ7.04 (m, 4H), 6.54 (d, J
13
= 1.8 Hz, 1H), 4.67 (s, 2H), 4.58 (s, 2H), 3.79 (s, 3H). C NMR (101 MHz, CDCl3) δC =
162.3 (d, J = 246.6 Hz), 159.3, 146.8, 142.7, 137.2, 135.0, 129.7 (d, J = 8.0 Hz, 2C), 129.0 (d,
J = 3.5 Hz), 125.5, 119.0, 118.7 (q, J = 320.6 Hz), 116.9, 115.7, 115.0 (d, J = 183.6 Hz, 2C),
111.5, 66.6, 63.4, 56.1. HRMS (m/z) calcd for C20H1579BrF4O6S [M+] 537.9709, found
537.9704.
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2-bromo-4-methyl-6-(((4-phenylfuran-2-yl)methoxy)methyl)phenyl
trifluoromethanesulfonate (4m):
6
7
8
Prepared
from
0.44
mmol
of
2ꢀbromoꢀ4ꢀmethylꢀ6ꢀ(((4ꢀphenylfuranꢀ2ꢀ
9
yl)methoxy)methyl)phenol 13m to afford 221 mg (0.44 mmol, 99% yield) of 4m as a pale
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yellow oil.
Rf = 0.41 (Petroleum Ether/Et2O, 9:1). ν
max (neat): 1409, 1207, 1131, 861 cmꢀ1. 1H NMR (400
MHz, CDCl3) δH = 7.71 (d, J = 0.9 Hz, 1H), 7.51ꢀ7.44 (m, 2H), 7.43ꢀ7.41 (m, 1H), 7.41ꢀ7.34
13
(m, 3H), 7.31ꢀ7.24 (m, 1H), 6.68 (s, 1H), 4.69 (s, 2H), 4.57 (s, 2H), 2.35 (s, 3H). C NMR
(101 MHz, CDCl3) δC = 152.2, 141.7, 140.2, 139.0, 134.3, 133.7, 132.3, 130.0, 129.0 (2C),
127.4, 127.3, 126.0 (2C), 118.7 (q, J = 320.9 Hz), 115.9, 109.3, 66.7, 65.0, 20.9. HRMS (m/z)
calcd for C20H1679BrF3O5S [M+] 503.9854, found 503.9850.
General procedure for the intramolecular Diels-Alder reaction
To a solution of 4 (0.25 mmol, 1 eq.) in anhydrous THF (25 or 5 mL) was added
dropwise nBuLi (180 ꢀL, 0.45 mmol, 2.5 M in hexanes, 1.8 eq.) at ꢀ78 °C. The reaction
mixture was warmed to ꢀ40 °C in 1 h and, then, a saturated aqueous solution of NH4Cl was
added dropwise. The layers were separated and the aqueous layer was extracted with EtOAc
(3 x 30 mL). The combined organic layers were washed with H2O and brine, dried over
Na2SO4 and concentrated under vacuum.
The crude was dissolved in THF (1.65 mL) and pTSA (47 mg, 0.275 mmol, 1.1 eq.)
was added. The reaction mixture was stirred at r.t. for 30 min and a saturated aqueous solution
of NaHCO3 was added. The layers were separated and the aqueous layer was extracted with
EtOAc (3 x 10 mL). The combined organic layers were washed with H2O, and brine, dried
over Na2SO4 and concentrated under vacuum. The residue was purified by flash
chromatography (SiO2, Cyclohexane/Et2O).
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8-methyl-1,3-dihydrobenzo[de]isochromen-6-ol (5a):
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5
6
7
8
9
Prepared from 0.25 mmol of 2ꢀbromoꢀ6ꢀ((furanꢀ2ꢀylmethoxy)methyl)ꢀ4ꢀmethylphenyl
trifluoromethanesulfonate 4a (C = 0.01 M) to afford 39 mg (0.19 mmol, 77% yield) of 5a as a
white solid.
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Rf = 0.37 (Cyclohexane /Et2O, 6:4). MP = 176 °C. ν
max (film): 3264, 1591, 1071, 818 cmꢀ1. 1H
NMR (400 MHz, CDCl3) δH = 7.80 (s, 1H), 7.04 (s, 1H), 6.93 (d, J = 7.4 Hz, 1H), 6.73 (d, J =
7.4 Hz, 1H), 5.32 (s, 1H), 5.02 (s, 2H), 5.00 (s, 2H), 2.51 (s, 3H). 13C NMR (101 MHz,
CDCl3) δC = 150.0, 135.0, 132.5, 126.3, 125.1, 124.1, 123.0, 119.4, 119.2, 108.5, 69.5, 69.4,
22.2. HRMS (m/z) calcd for C13H13O2 [MH+] 201.0916, found 201.0904.
8-fluoro-1,3-dihydrobenzo[de]isochromen-6-ol (5b):
Prepared from 0.25 mmol of 2ꢀbromoꢀ4ꢀfluoroꢀ6ꢀ((furanꢀ2ꢀylmethoxy)methyl)phenyl
trifluoromethanesulfonate 4b (C = 0.01 M) to afford 38 mg (0.19 mmol, 75% yield) of 5b as a
white solid.
Rf = 0.27 (Cyclohexane /Et2O, 7:3). MP = 168 °C. νmax (film): 3304, 1605, 1522, 1254, 864
1
cmꢀ1. H NMR (400 MHz, CDCl3) δH = 7.66 (dd, J = 10.6, 2.5 Hz, 1H), 6.99 (ddd, J = 8.5,
2.5, 1.2 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 5.31 (s, 1H), 5.02 (s, 2H),
19
13
4.99 (s, 2H). F NMR (376 MHz, CDCl3) δF = ꢀ113.9 (s, 1F). C NMR (101 MHz, CDCl3)
δC = 160.3 (d, J = 245.8 Hz), 150.1 (d, J = 5.2 Hz), 135.8 (d, J = 8.3 Hz), 125.3, 125.3 (d, J =
1.8 Hz), 125.1 (d, J = 2.9 Hz), 119.4 (d, J = 2.2 Hz), 111.3 (d, J = 25.7 Hz), 109.4, 104.5 (d, J
= 22.7 Hz), 69.3, 69.0 (d, J = 2.2 Hz). HRMS (m/z) calcd for C12H10FO2 [MH+] 205.0665,
found 205.0655.
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8-methoxy-1,3-dihydrobenzo[de]isochromen-6-ol (5c):
4
5
6
7
8
9
Prepared from 0.25 mmol of 2ꢀbromoꢀ6ꢀ((furanꢀ2ꢀylmethoxy)methyl)ꢀ4ꢀmethoxyphenyl
trifluoromethanesulfonate 4c (C = 0.01 M) to afford 41 mg (0.19 mmol, 76% yield) of 5c as a
white solid.
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Rf = 0.17 (Cyclohexane /Et2O, 7:3). MP = 132 °C. νmax (neat): 3247, 1590, 1251, 1211, 816
1
cmꢀ1. H NMR (400 MHz, CDCl3) δH = 7.33 (d, J = 2.1 Hz, 1H), 6.86 (d, J = 1.2 Hz, 1H),
6.84 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 5.70 (br s, 1H), 5.01 (s, 2H), 4.99 (s, 2H),
3.92 (s, 3H). 13C NMR (101 MHz, CDCl3) δC = 157.3, 149.7, 134.3, 125.3, 125.0, 123.6,
117.8, 113.6, 109.1, 98.9, 69.4, 69.2, 55.5. HRMS (m/z) calcd for C13H13O3 [MH+] 217.0865,
found 217.0855.
8-phenyl-1,3-dihydrobenzo[de]isochromen-6-ol (5d):
Prepared from 0.25 mmol of 3ꢀbromoꢀ5ꢀ((furanꢀ2ꢀylmethoxy)methyl)ꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀyl
trifluoromethanesulfonate 4d (C = 0.01 M) to afford 53 mg (0.20 mmol, 81% yield) of 5d as a
white solid.
Rf = 0.20 (Cyclohexane /Et2O, 75:25). MP = 182 °C. νmax (neat): 3208, 1587, 1393, 1064, 815,
695 cmꢀ1. 1H NMR (400 MHz, CDCl3) δH = 8.26 (d, J = 1.5 Hz, 1H), 7.76ꢀ7.69 (m, 2H), 7.51ꢀ
7.44 (m, 3H), 7.41ꢀ7.34 (m, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 7.5 Hz, 1H), 5.41 (s,
1H), 5.11 (s, 2H), 5.04 (s, 2H). 13C NMR (101 MHz, CDCl3) δC = 150.8, 141.3, 138.0, 133.2,
129.0 (2C), 127.6 (2C), 127.6, 127.2, 125.1, 124.3, 120.5, 120.2, 118.6, 108.9, 69.5, 69.5.
HRMS (m/z) calcd for C18H15O2 [MH+] 263.1072, found 263.1062.
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8-(4-(tert-butyl)phenyl)-1,3-dihydrobenzo[de]isochromen-6-ol (5e):
Prepared from 0.25 mmol of 3ꢀbromoꢀ4'ꢀ(tertꢀbutyl)ꢀ5ꢀ((furanꢀ2ꢀylmethoxy)methyl)ꢀ[1,1'ꢀ
biphenyl]ꢀ4ꢀyl trifluoromethanesulfonate 4e (C = 0.01 M) to afford 59 mg (0.185 mmol, 74%
yield) of 5e as a white solid.
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Rf = 0.24 (Petroleum Ether/Et2O, 75:25). MP = 193 °C. νmax (neat): 3323, 2959, 1588, 1211,
833 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6) δH = 10.11 (s, 1H), 8.21 (d, J = 1.5 Hz, 1H), 7.74ꢀ
7.65 (m, 2H), 7.55 (d, J = 1.5 Hz, 1H), 7.54ꢀ7.46 (m, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.84 (d, J
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= 7.6 Hz, 1H), 5.02 (s, 2H), 4.92 (s, 2H), 1.32 (s, 9H). C NMR (101 MHz, DMSOꢀd6) δC =
152.2, 149.9, 137.5, 135.9, 133.4, 126.7, 126.5 (2C), 125.8 (2C), 124.2, 122.9, 120.6, 119.4,
117.6, 108.2, 68.4, 68.3, 34.3, 31.1 (3C). HRMS (m/z) calcd for C22H22O2 [M+] 318.1620,
found 318.1608.
4,6-dihydrodibenzo[de,g]isochromen-1-ol (5f):
Prepared from 0.25 mmol of 1ꢀbromoꢀ3ꢀ((furanꢀ2ꢀylmethoxy)methyl)naphthalenꢀ2ꢀyl
trifluoromethanesulfonate 4f (C = 0.01 M) to afford 41 mg (0.17 mmol, 69% yield) of 5f as a
white solid.
Rf = 0.21 (Cyclohexane/Et2O, 7:3). MP = 221 °C. νmax (film): 3428, 1686, 1578, 1397, 1088,
1
754 cmꢀ1. H NMR (400 MHz, DMSOꢀd6) δH = 10.59 (s, 1H), 9.74ꢀ9.68 (m, 1H), 7.91ꢀ7.84
(m, 1H), 7.63ꢀ7.54 (m, 2H), 7.53 (s, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H),
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4.99 (s, 2H), 4.98 (s, 2H). C NMR (101 MHz, DMSOꢀd6) δC = 155.2, 131.3, 130.3, 129.8,
128.2, 127.8, 127.5, 126.0, 125.9, 123.6, 122.6, 121.2, 118.1, 112.7, 68.8 (2C). HRMS (m/z)
calcd for C16H13O2 [MH+] 237.0916, found 237.0910.
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4,6,8,9,10,11-hexahydrodibenzo[de,g]isochromen-1-ol (5g):
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5
Prepared
from
0.25
mmol
of
1ꢀbromoꢀ3ꢀ((furanꢀ2ꢀylmethoxy)methyl)ꢀ5,6,7,8ꢀ
6
7
8
9
tetrahydronaphthalenꢀ2ꢀyl trifluoromethanesulfonate 4g (C = 0.05 M) to afford 25 mg (0.10
mmol, 41% yield) of 5g as a white solid.
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Rf = 0.30 (Cyclohexane /Et2O, 8:2). MP = 125 °C. νmax (neat): 3180, 2926, 1577, 1417, 1023,
818 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6) δH = 9.65 (s, 1H), 6.92 (d, J = 7.7 Hz, 1H), 6.84 (s,
1H), 6.75 (s, J = 7.7 Hz, 1H), 4.84 (s, 4H), 3.49ꢀ3.40 (m, 2H), 2.85ꢀ2.76 (m, 2H), 1.79ꢀ1.66
(m, 4H). 13C NMR (101 MHz, DMSOꢀd6) δC = 154.4, 132.4, 131.8, 129.0, 127.6, 123.3,
122.9, 122.9, 120.0, 109.7, 68.8, 68.5, 30.6, 29.3, 23.5, 22.0. HRMS (m/z) calcd for C16H17O2
[MH+] 241.1229, found 241.1220.
8-methyl-4-phenyl-1,3-dihydrobenzo[de]isochromen-6-ol (5h):
Prepared
from
0.25
mmol
of
2ꢀbromoꢀ4ꢀmethylꢀ6ꢀ(((3ꢀphenylfuranꢀ2ꢀ
yl)methoxy)methyl)phenyl trifluoromethanesulfonate 4h (C = 0.01 M) to afford 35 mg (0.13
mmol, 51% yield) of 5h as a white solid.
Rf = 0.28 (Cyclohexane /Et2O, 85:15). MP = 178 °C. νmax (neat): 3201, 1597, 1402, 913, 700
1
cmꢀ1. H NMR (400 MHz, CDCl3) δH = 7.83 (s, 1H), 7.46ꢀ7.32 (m, 3H), 7.31ꢀ7.25 (m, 2H),
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7.07 (s, 1H), 6.72 (s, 1H), 5.55 (br s, 1H), 5.02 (s, 2H), 4.98 (s, 2H), 2.52 (s, 3H). C NMR
(101 MHz, CDCl3) δC = 149.7, 140.2, 134.8, 134.1, 132.8, 129.2 (2C), 128.4 (2C), 127.4,
126.5, 123.5, 123.5, 121.8, 119.5, 110.9, 69.6, 68.4, 22.1. HRMS (m/z) calcd for C19H17O2
[MH+] 277.1229, found 277.1226.
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4-(4-methoxyphenyl)-8-methyl-1,3-dihydrobenzo[de]isochromen-6-ol (5i):
Prepared from 0.25 mmol of 2ꢀbromoꢀ6ꢀ(((3ꢀ(4ꢀmethoxyphenyl)furanꢀ2ꢀyl)methoxy)methyl)ꢀ
4ꢀmethylphenyl trifluoromethanesulfonate 4i (C = 0.05 M) to afford 11 mg (0.04 mmol, 14%
yield) of 5i as a white solid.
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Rf = 0.13 (Cyclohexane /Et2O, 85:15). MP = 172 °C. ν
max (neat): 3191, 1606, 1509, 834 cmꢀ1.
1H NMR (400 MHz, CDCl3) δH = 7.82 (s, 1H), 7.26ꢀ7.21 (m, 2H), 7.06 (s, 1H), 6.99ꢀ6.94 (m,
2H), 6.74 (s, 1H), 5.36 (s, 1H), 5.01 (s, 2H), 4.98 (s, 2H), 3.87 (s, 3H), 2.52 (s, 3H). 13C NMR
(101 MHz, CDCl3) δC = 159.0, 149.6, 134.7, 133.7, 132.9, 132.6, 130.3 (2C), 126.6, 123.4,
123.4, 121.9, 119.4, 113.9 (2C), 111.1, 69.6, 68.5, 55.5, 22.1. HRMS (m/z) calcd for C20H19O3
[MH+] 307.1334, found 307.1328.
8-methyl-4-(p-tolyl)-1,3-dihydrobenzo[de]isochromen-6-ol (5j):
Prepared
from
0.25
mmol
of
2ꢀbromoꢀ4ꢀmethylꢀ6ꢀ(((3ꢀ(pꢀtolyl)furanꢀ2ꢀ
yl)methoxy)methyl)phenyl trifluoromethanesulfonate 4j (C = 0.05 M) to afford 30 mg (0.11
mmol, 42% yield) of 5j as a white solid.
Rf = 0.24 (Petroleum Ether/Et2O, 7:3). MP = 180 °C. νmax (neat): 3304, 2919, 1602, 1405,
1
1215, 822 cmꢀ1. H NMR (400 MHz, CDCl3) δH = 7.83 (s, 1H), 7.27ꢀ7.17 (m, 4H), 7.06 (s,
1H), 6.74 (s, 1H), 5.39 (br s, 1H), 5.01 (s, 2H), 4.99 (s, 2H), 2.52 (s, 3H), 2.42 (s, 3H). 13C
NMR (101 MHz, CDCl3) δC = 149.6, 137.2, 137.1, 134.7, 134.0, 132.8, 129.2 (2C), 129.1
(2C), 126.6, 123.4, 123.4, 121.8, 119.4, 111.0, 69.6, 68.5, 22.1, 21.4. HRMS (m/z) calcd for
C20H18O2 [M+] 290.1307, found 290.1315.
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4,8-dimethyl-1,3-dihydrobenzo[de]isochromen-6-ol (5k):
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5
Prepared
from
0.25
mmol
of
2ꢀbromoꢀ4ꢀmethylꢀ6ꢀ(((3ꢀmethylfuranꢀ2ꢀ
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7
8
9
yl)methoxy)methyl)phenyl trifluoromethanesulfonate 4k (C = 0.01 M) to afford 44 mg (0.21
mmol, 82% yield) of 5k as a white solid.
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Rf = 0.21 (Petroleum Ether/Et2O, 8:2). MP = 233°C. νmax (neat): 3264, 2917, 2849, 1591,
1406, 1213, 1061, 843 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6) δH = 9.80 (s, 1H), 7.69 (s, 1H),
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7.01 (s, 1H), 6.63 (s, 1H), 4.88 (s, 2H), 4.86 (s, 2H), 2.41 (s, 3H), 2.20 (s, 3H). C NMR (101
MHz, DMSOꢀd6) δC = 150.9, 132.2, 131.7, 128.1, 126.0, 122.6, 122.3, 119.7, 119.5, 111.0,
67.9, 66.3, 21.5, 17.8. HRMS (m/z) calcd for C14H14O2 [M+] 214.0994, found 214.0984.
4-(4-fluorophenyl)-8-methoxy-1,3-dihydrobenzo[de]isochromen-6-ol (5l):
Prepared from 0.25 mmol of 2ꢀbromoꢀ6ꢀ(((3ꢀ(4ꢀfluorophenyl)furanꢀ2ꢀyl)methoxy)methyl)ꢀ4ꢀ
methoxyphenyl trifluoromethanesulfonate 4l (C = 0.01 M) to afford 18 mg (0.06 mmol, 23%
yield) of 5l as a white solid.
Rf = 0.29 (Petroleum Ether/Et2O, 6:4). MP = 153 °C. νmax (neat): 3419, 2924, 1604, 1510,
1
1221, 1158, 841 cmꢀ1. H NMR (400 MHz, CDCl3) δH = 7.35 (d, J = 2.5 Hz, 1H), 7.30ꢀ7.22
(m, 2H), 7.16ꢀ7.08 (m, 2H), 6.93ꢀ6.88 (m, 1H), 6.72 (s, 1H), 5.28 (br s, 1H), 4.99 (s, 2H),
13
4.92 (s, 2H), 3.95 (s, 3H). C NMR (101 MHz, CDCl3) δC = 162.3 (d, J = 246.4 Hz), 157.3,
149.3, 136.1 (d, J = 3.1 Hz), 134.9, 131.5, 130.8 (d, J = 8.0 Hz, 2C), 125.2 (d, J = 116.3 Hz),
123.8, 122.2, 115.3, 114.8 (d, J = 146.8 Hz, 2C), 111.3, 98.9, 69.4, 68.2, 55.6. HRMS (m/z)
calcd for C19H15FO3 [M+] 310.1005, found 310.0991.
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