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Synthesis of Chromones from 1,1-Diacylcyclopropanes: Towards the Synthesis of Bromophycoic Acid E Robert J Smith, Duong Nhu, Mitchell R Clark, Sinan Gai, Nigel T. Lucas, and Bill Corey Hawkins J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 25 Apr 2017 Downloaded from http://pubs.acs.org on April 26, 2017

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The Journal of Organic Chemistry

Synthesis of Chromones from 1,1-Diacylcyclopropanes: Towards the Synthesis of Bromophycoic Acid E

Robert J. Smith, Duong Nhu, Mitchell R. Clark, Sinan Gai, Nigel T. Lucas and Bill C. Hawkins* Department of Chemistry, University of Otago, Dunedin, New Zealand [email protected] Abstract A tandem deprotection-cyclization reaction of 1,1-diacylcyclopropanes is described which allows rapid access to structurally diverse 2,3-disubstituted chromones in good yields, and with straightforward purification. The utility of this reaction is showcased by the construction of the potent antibacterial marine natural product bromophycoic acid E scaffold. Graphical Abstract

Introduction

Benzopyrans and their subclass structures like chromones and flavones feature heavily in natural products and medicinally relevant compounds, exhibiting a vast array of biological activities including anti-cancer,1 anti-bacterial and antioxidant.2 The structural diversity within these classes of molecules is large and continues to expand (Figure 1). Conventional synthetic approaches to access the chromone scaffold typically require prolonged exposure to strong acids such as HCl or H2SO4,3 to facilitate the normally slow dehydration. The starting

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phenoxy-1,3-dicarbonyl compounds themselves are accessible via numerous methods including Claisen condensation3b and the Baker Venkataraman3a reaction. More recently various transition metal catalyzed reactions have been employed in the synthesis of chromones from salicaldehydes, including cobalt,4 rhodium,5 and ruthenium6 catalyzed annulation reactions with alkynes and rhodium catalysed annulation with diazo compounds.7 Carbonylative reactions have also been used to gain rapid entry to flavones.8 These methods provide access to chromones in moderate to high yields, however, they often require elevated temperatures, various additives and in the case of the carbonylative reactions, high pressures and carbon monoxide gas. This could limit both the widespread adoption and incorporation of sensitive functional groups. As part of our general research program focused around utilizing the latent energy found in strained ring systems,9 we sought to design a method whereby the release of ring strain could be used as a driving force to promote the slow dehydration step (Scheme 1). Ideally this would allow for the rapid synthesis of 2,3-disubstituted benzopyrans under mild reaction conditions.

Figure 1. Representative bioactive natural products containing a chromone, benzopyran or xanthone core.

Due to the significant number of biologically active compounds with embedded chromones, we chose to initially focus on these. Our strategy not only sought to capitalize on the 2 ACS Paragon Plus Environment

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generality of this approach but to also make improvements both in terms of gaining access to highly functionalized chromone based scaffolds and developing milder reaction conditions. Specifically, our design centered around the incorporation of various cyclopropanes in the 1,3-diketone species 7 (Scheme 1).

Scheme 1. Strain-promoted dehydration to gain improved access to 2,3-substituted chromones

The relief of ring and torsional strain in the intermediate 8 was expected to drive the dehydration and also provide a versatile handle for further functionalization at the 3-position of the resultant chromone providing access to more complex structures that would otherwise be difficult to achieve. For example, a recent report detailed the synthesis of 3-allylchromones from alkynones and allylic alcohols;10 this procedure worked well to produce various flavones (25-93%) but only two chromones were reported in 35% and 50% yield. Furthermore, elevated temperatures and long reactions times were required (100 oC, 8-12 h flavones, 24 h chromones). Even the syntheses of simple 2,3-dimethyl substituted chromones from 2-hydroxypropriophenone have relatively poor yields of 20-56%.11



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Recently a report from Ren and co-workers described the use of azido-cyclopropyl ketones (10) in the synthesis of dihydrofuroquinolines (11) and 4-quinolones (12), which are analogous to the chromone scaffold (Scheme 2).12

Scheme 2. Azido-cyclopropyl rearrangement

However, this study focused on the synthesis of dihydrofuroquinolines and as such, no extensive screening of substrate scope was carried out for the 4-quinolones with the investigations limited to 1,1-diacyl substituted cyclopropanes (Scheme 2). At the outset of our studies it was not clear if this could be applied to further substituted cyclopropanes or indeed phenolic compounds. Substituted cyclopropanes would allow for the incorporation of a functional group handle to facilitate structural modifications. Moreover, the establishment of a mild and functional group tolerant procedure would add to the generality of such an approach. Given the prevalence of the chromone scaffold embedded in bioactive compounds, both natural and synthetic, efficient access to 2,3-disubstituted chromones of the general structure 9 (Scheme 1) would be of significant interest to the organic chemistry community.

Results and Discussion

Initially our attention was focused on the unsubstituted cyclopropane 13, which was obtained using

standard

procedures.13

Treatment

of

the

allyl

ether

13

with

tetrakis(triphenylphosphine)palladium and potassium carbonate in methanol, and an acidic work up, afforded the phenol 14 in quantitative yield. Treatment with 0.5 M solution of


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sulfuric acid in methanol resulted in the fast formation of an intermediary lactol which then required longer exposure to the acidic conditions (24 h at room temperature) to effect the dehydration affording the methyl ether 15 in 55% yield (Scheme 3).

Scheme 3. Synthesis of chromones from unsubstituted cyclopropanes.

The reaction protocol could be simplified by filtering the crude reaction mixture after deallylation followed by the careful addition of sulfuric acid (~50 µL). Given the reluctance of the cyclopropane 14 to readily undergo dehydration, we conducted a time course competition experiment whereby an equimolar mixture of the unsubstituted diketone 1614 and 1,1diacylcyclopropane 14 were treated with 0.5 M solution of sulfuric acid in methanol at room temperature (Scheme 4).15

Scheme 4. Competition experiments reveal 1,3-diketone 16 faster than the cyclopropyl adduct 14.

Analysis of an aliquot of the reaction mixture after 90 min revealed complete conversion of the cyclopropane 14 to the lactol 18 along with unreacted diketone 16 and traces of flavone 17. After 7 hours, complete conversion of the diketone 16 to flavone 17 had occurred while the cyclopropyl lactol 18 remained unchanged; complete conversion of compound 18 to the 5 ACS Paragon Plus Environment


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chromone 15 took a further 17 hours.15 This suggests that the relief of ring strain in the unsubstituted cyclopropane is not a significant driving force for dehydration. In order to gain more synthetic utility and probe the role of the cyclopropane whilst also providing alternate functionalization at the 3-position of the resultant chromone, the phenyl cyclopropane 19a was synthesized following literature procedures from the 1,3-diketone 20 (Scheme 5).16

Scheme 5. Synthesis of chromones from phenyl cyclopropanes.

Treatment of compound 19a and 19b with tetrakis(triphenylphosphine)palladium and potassium carbonate smoothly provided the corresponding phenol which could then be converted to the methyl ether containing chromones, 22a and 22b, respectively, by treatment with a 0.5 M solution of sulfuric acid in methanol for 30 mins at room temperature. Alternatively the free alcohol (not shown) could be obtained by heating a solution of the intermediate phenol 24a in 2 M HCl.15 Unfortunately all efforts to synthesize the paranitrophenyl cyclopropane analog were unsuccessful, instead resulting in the corresponding dihydrofurans.15 To examine the stereo-electronic contributions of the cyclopropyl adduct to the dehydration step, a competition experiment between the unsubstituted diketone 2317 and 1,1-diacyl-26 ACS Paragon Plus Environment

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phenylcyclopropane 24a was conducted. After 20 mins cyclopropane 24a was completely converted to the chromone 22a with only traces of the chromone 25 arising from 1,3-diketone 23 (Scheme 6).

Scheme 6. Competition experiment shows the phenyl cyclopropyl adduct 24a/b dehydrates faster than the unsubstituted analog 23.

Clearly the rate of dehydration increases significantly upon the addition of the phenyl group onto the cyclopropane ring (20 min versus 24 hours),18 which could be due to either stereoelectronic effects and/or torsional strain. Efforts to delineate these contributions are the focus of current research. Notably, no discernible difference in dehydration rates was observed between 24a and 24b. Despite having a rapid method to gain access to 2,3-functionalized chromones we hoped to develop reaction conditions which did not require prolonged exposure to strong acid to promote dehydration. With this in mind we next examined vinyl cyclopropanes. Allylation of 2-hydroxyacetophenone (26a) followed by Claisen condensation with methyl benzoate provided the 1,3-diketone 28a in 67% yield (Scheme 7). Reaction with trans-1,4-dibromo-2butene provided the vinyl cyclopropane 29a as an inconsequential 1:1 mixture of diastereomers.

To

our

delight,

treatment

of

29a

in

methanol

with

tetrakis(triphenylphosphine)palladium in the presence of potassium carbonate for 30 mins followed by an acidic workup (1 M HCl(aq)) provided the flavone 30a in an 87% yield, as confirmed by a crystal structure (Scheme 7). 7 ACS Paragon Plus Environment


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Scheme 7. Synthesis of flavone 30a and X-ray single crystal structure. O O

OH

allyl bromide, TBAI. K2CO3, DMF, RT

O O

O Ph

quant.

O

26

O

Ph

NaH, THF, reflux 67%

O 28a

27a

Br 4 steps 1 chromatographic separation

40%

Br K2CO3, DMSO 40% (dr 1:1) O OH O 30a

Ph

i) Pd(PPh3)4, K2CO3, MeOH, RT ii) H+ 87%

O

O Ph

O 29a

As a further improvement to this reaction sequence, it was found that column chromatographic purification was only necessary after the final step and that an acidic work up was not required; this not only improved the overall yield of 30a from 2hydroxyacetophenone (from 23% to 40%) but also made the procedure more appealing in a practical sense. Given the facile nature of the reaction, which cannot be readily explained using strain arguments, we speculate that the palladium facilitates cyclopropane opening via oxidative addition to produce the zwitterion 31 (Scheme 8). The tautomeric phenolate 32 could then attack the ketone to form the ring closed lactol 33, the oxygen anion of which could attack the allyl complex eventually leading to the flavone 30a (Path A, Scheme 8), which could account for the rate increase observed compared to the other cyclopropanes examined. However, we cannot rule out protonation/dehydration of the intermediate first (Path B).


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Scheme 8. Plausible mechanism for the formation of chromones from vinyl cyclopropanes.

Furthermore, treatment of a 1:1 mixture of dihydrofurans 35a and 35b, obtained using literature methods,19 with the standard reaction conditions (Pd(PPh3)4, K2CO3) smoothly provided the flavone 30a (Scheme 9). Thereby providing support for the first steps of the proposed mechanism as 36 is the enolate tautomer of 31. Further work on elucidating the mechanistic pathway is the focus of current research and will be reported in due course.

Scheme 9. Treatment of dihydrofurans 35a and b with Pd(PPh3)4 and K2CO3 provided the flavone 30a.

With an optimized reaction sequence in hand we examined the substrate scope of the reaction. To this end, a variety of vinylcyclopropyl-1,3-diketones were synthesized and subjected to the optimized procedure, the results of which are summarized in Table 1.



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Table 1. Substrate scope for chromone synthesisa,b.

a

Standard reaction conditions for the 4 step synthesis, Isolated yield over 4 steps from the corresponding 2hydroxyacetophenone.

b

Aromatic (30a,d), alkyl (30b)

and heteroaromatic (30c) substituents at R5 were well

tolerated with overall yields between 40 - 54% from 2-hydroxyacetophenone. In addition, variation of the 2-hydroxyacetophenone portion of the substrate was well tolerated (30e-30i) with generally higher yields (45 - 59%) and notably, aryl halides were shown to readily participate (30i) which could allow for further Pd-mediated couplings.


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As a further demonstration of this methodology, and in particular to utilize the unique 2,3functionalization of the chromone provided by this method, we sought to construct the tetracyclic core of the marine natural product bromophycoic acid E (2, Figure 1). Bromophycoic acid E was recently isolated from Fijian red alga Callophycus sp. and is a potent inhibitor of vancomycin resistant enterococcus faecium (1.6 µg/mL MIC).20 Specifically we surmised that the tetracyclic core of bromophycoic acid E could be constructed through an intramolecular Diels-Alder (IMDA) cycloaddition (Scheme 10). The chromone 30c itself was obtained from 2-hydroxyacetophenone in four steps and a 51% overall yield. Oxidation of 30c provided the corresponding enone 37 which was then engaged in a thermal IMDA cycloaddition, which after heating at reflux in toluene for 7 days provided the cycloadduct 38 in low yield (Scheme 10).

Scheme 10. Synthetic strategy towards bromophycoic acid E. O

O O

i) Pd(PPh3)4, MeOH, K2CO3 iii) 1M HCl

O OH O

O

O

30c

29c

Dess-Martin Periodinane 65%

1. Methyl acrylate, GrubbsII 2. TBSCl 3.LiAlH 4.AlCl3 25% over 3 steps

O O

OTBS

O

O

O

O

37

CO2Me

39 toluene,

toluene, 19%

75%

O O H O

OTBS H CO2Me

O

O

O

38

40

O

H

HO

H O Br

bromophycoic acid E (2)



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Alternatively, the chromone 30c readily underwent an olefin cross metathesis reaction with methyl acrylate to provide a trans-α,β-unsaturated ester (not shown). Protection of the secondary alcohol as the silyl ether, followed by reduction of the chromone,21 proceeded smoothly to provide the benzopyran 39 in 25% over three steps. Heating a solution of the benzopyran 39 in toluene for 16 h provided the cycloadduct 40, through an endo-antitransition state, as a single diastereomer in 75% yield.

Conclusions

In conclusion we have reported the expedient synthesis of a series of diverse 2,3-disubstituted chromones in good to excellent yield, requiring only one chromatographic separation and mild acid-free reaction conditions. This methodology is a valuable complementary approach to existing strategies for the synthesis of chromones and related structures. The generality of the approach was exemplified by rapid construction of the scaffold of the known potent antibacterial marine natural product bromophycoic acid E.

Experimental Section General Thin layer chromatography (tlc) was performed on ALUGRAM® aluminium-backed UV254 silica gel 60 (0.20 mm) plates. Compounds were visualized with either p-anisaldehyde or 20% w/w phosphomolybdic acid in ethanol. Column chromatography was performed using silica gel 60. Infrared spectra were recorded on a Bruker Optics Alpha ATR FT-IR spectrometer. High resolution mass-spectra (HRMS) were recorded on a Bruker microTOFQ mass spectrometer using an electrospray ionisation (ESI) source in either the positive or negative modes. 1H NMR spectra were recorded at either 400 MHz on a Varian 400-MR


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NMR system or at 500 MHz on a Varian 500 MHz AR premium shielded spectrometer. All spectra were recorded from samples in CDCl3 at 25 °C in 5 mm NMR tubes. Chemical shifts are reported relative to the residual chloroform singlet at δ 7.26 ppm. Resonances were assigned as follows: chemical shift (multiplicity, coupling constant(s), number of protons, assigned proton(s)). Multiplicity abbreviations are reported by the conventions: s (singlet), d (doublet), dd (doublet of doublets), ddd (doublet of doublet of doublets), t (triplet), td (triplet of doublets), q (quartet), qd `(quartet of doublets), m (multiplet). Proton decoupled 13C NMR spectra were recorded at either 100 MHz on a Varian 400-MR NMR system or at 125 MHz on a Varian 500 MHz AR premium shielded spectrometer under the same conditions as the 1H NMR spectra. Chemical shifts have been reported relative to the CDCl3 triplet at δ 77.16 ppm. Dichloromethane (CH2Cl2) was dried using a PURE SOLV MD-6 solvent purification system. All other solvents and reagents were used as received. X-ray Crystallography The crystal was attached with Paratone N oil to a CryoLoop supported in a copper mounting pin, then quenched in a cold nitrogen stream. Data were collected at 100 K using Cu-Kα radiation (micro-source, mirror monochromated) using an Agilent SuperNova diffractometer with Atlas detector. The data processing was undertaken within the CrysAlisPro software;22 combined analytical numeric absorption and multiscan scaling corrections were applied to the data.22-23 The structure was solved by direct methods with SHELXS-97, and extended and refined with SHELXL-9724 using the X-Seed interface.25 The non-hydrogen atoms were modelled with anisotropic displacement parameters. Hydrogen atoms were placed in calculated positions and refined using a riding model with fixed C–H distances (sp2-CH 0.95 Å, sp3-CH3 0.98 Å, sp3-CH2 0.99 Å) and isotropic displacement parameters estimated as Uiso(H) = 1.2Ueq(C), except for CH3 where Uiso(H) = 1.5Ueq(C). Crystallograpic data have



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been deposited with the Cambridge Crystallographic Data Centre (CCDC 1531847) and can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif. General Procedures 1,3-Diketone To a solution of the required 2-hydroxyacetophenone (1 eq) in DMF was added K2CO3 (3 eq), TBAI (0.1 eq) and the solution was stirred for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic extracts were washed with water (x3) and brine (x1), dried over Na2SO4 and reduced in vacuo to provide the allyl ether in sufficient purity to be used in the next step. To a solution of the 2-(2-propen-1-yloxy)acetophenone derivative (1 eq) in THF cooled to 0 °C was added NaH (2.5 eq) with stirring for 15 minutes. After this time the reaction was warmed to room temperature and a solution of the desired ester (1-2 eq) in anhydrous THF was added and the solution refluxed for 20 hours. The reaction was quenched with 2 M HCl and extracted with EtOAc (x 2). The combined organic extracts were washed with water (x1) and brine (x1), dried and reduced in vacuo. The residue was of sufficient purity to be used in the next step, but an analytically pure sample could be obtained by subject the crude residue to silica gel chromatography. Cyclopropanation A To a solution of 1,3-diketone (1 eq) in DMSO was added K2CO3 (3 eq) and trans-1,4dibromo-2-butene (1.1 eq) with stirring for 24 hours. After this time the reaction was diluted with water and extracted with ethyl acetate (x3). The combined organic extracts were washed with water (x3) and brine (x1), dried over Na2SO4 and reduced in vacuo to provide the desired cyclopropane. The residue was of sufficient purity to be used in the next step, but an analytically pure sample could be obtained by subject the crude residue to silica gel chromatography.


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Cyclopropanation B To a solution of 1,3-diketone (1 eq) in 1:1 DCM/H2O was added K2CO3 (3 eq) and the desired bromosulfonium bromide (2 eq) with stirring for 24 hours. After this time the reaction was extracted with DCM (x2). The combined organic extracts were washed with water (x1) and brine (x1), dried over Na2SO4 and reduced in vacuo to provide the desired cyclopropane. The residue was of sufficient purity to be used in the next step, but an analytically pure sample could be obtained by subject the crude residue to silica gel chromatography. Chromone To a solution of cyclopropane (1 eq) in degassed MeOH was added Pd(PPh3)4 (0.05 eq) with stirring for 5 minutes followed by the addition of K2CO3 (2 eq) with stirring for a further 45 minutes. The reaction was quenched water and extracted with EtOAc (x 2). The combined organic extracts were washed with water (x 1) and brine (x1), dried and reduced in vacuo. The crude residue was purified by flash chromatography (typically 1:4-1:1 EtOAc/40-60 Pet. Ether). 1-hydroxy-1-[2-(2-propen-1-yloxy)phenylbut-3-one [28b] Following the 1,3-diketone general procedure, to a suspension of 26b (3.05 g, 17.3 mmol) and NaH (60% in mineral oil, 499 mg, 20.8 mmol) in anhydrous THF (40 mL) was added EtOAc (3.40 mL, 34.7 mmol). The crude residue was purified by flash chromatograpy (1:9 EtOAc/40-60 Pet. Ether) to afford the title compound (2.98 g, 79%) as a yellow solid as an inseparable 4:1 mixture of enol:keto isomers. Enol: 1H NMR (500 MHz, CDCl3), δ (ppm): 7.88 (dd, 1H, J = 7.8, 1.8 Hz,), 7.41 (m, 1H), 7.04 (m, 1H, enol and keto), 6.95 (m, 1H, enol and keto), 6.50 (s, 1H), 6.07 (m, 1H, enol and keto), 5.47 (dq, 1H, J = 17.1, 1.5 Hz), 5.33 (dq, 1H, J = 10.6, 1.5 Hz), 4.64 (dt, J = 5.0, 1.5 Hz, 4H), 2.17 (s, 3H).



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13

C NMR (126 MHz, CDCl3), δ (ppm): δ 197.0, 183.9, 137.1, 135.4, 135.3, 132.9, 127.2,

123.6, 120.4, 115.6, 104.7, 72.0, 28.8. Keto: 1H NMR (500 MHz, CDCl3), δ (ppm): 7.83 (dd, J = 7.8, 1.8 Hz, 1H), 7.47 (m, 1H), 7.04 (m, 1H, enol and keto), 6.95 (m, 1H, enol and keto), 6.07 (m, 1H, enol and keto), 5.47 (dq, 1H, J = 17.1, 1.5 Hz), 5.33 (dq, 1H, J = 10.6, 2.8 Hz), 4.64 (dt, 2H, J = 5.2, 1.6 Hz), 4.10 (s, 2H), 2.24 (s, 3H). 13

C NMR (100 MHz, CDCl3), δ (ppm): 205.5, 197.8, 160.6, 137.1, 135.3, 134.9, 129.8,

127.2, 123.7, 121.7, 115.4, 61.6, 33.2. FTIR (ATR / cm-1): 2925, 1736, 1237, 1076, 754. HRMS-ESI calculated for C13H14O3Na+ [M+Na]+: 241.0835; found: 241.0836. MP:

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