Synthesis of Spiro- and Fused Heterocycles via (4+4) Annulation of

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Synthesis of Spiro- and Fused Heterocycles via (4+4) Annulation of Sulfonylphthalide with o-Hydroxystyrenyl Derivatives Alati Suresh, Thekke Veettil Baiju, Tarun Kumar, and Irishi N. N. Namboothiri J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03039 • Publication Date (Web): 18 Feb 2019 Downloaded from http://pubs.acs.org on February 18, 2019

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The Journal of Organic Chemistry

Synthesis of Spiro- and Fused Heterocycles via (4+4) Annulation of Sulfonylphthalide with o-Hydroxystyrenyl Derivatives Alati Suresh, Thekke V. Baiju, Tarun Kumar and Irishi N. N. Namboothiri* Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, 400 076, India

ABSTRACT An expedient one-pot protocol for the synthesis of functionalized benzofuran containing fused and spiro-heterocycles has been accomplished by the modified Hauser–Kraus (HK) annulation

of

sulfonylphthalide

with

o-hydroxychalcones

and

o-

hydroxynitrostyrylisoxazoles. The multi-cascade process involves Michael addition, Dieckmann cyclization, and a series of cyclizations, eliminations and rearrangements to deliver the fused and spiro-heterocyclic products. An unusual transformation of fused indenofuran to naphthoquinone, the classical HK adduct, unraveled a novel pathway for the synthesis unsymmetrical naphthoquinones.

INTRODUCTION Diversity oriented strategy for the construction of complex molecules through cascade reactions reserved a distinct space in the arena of synthetic organic chemistry. 1 In particular, synthesis of complex fused and spiro-polycyclic frameworks in a step-economic fashion

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attracted the synthetic community owing to the broad applications of such compounds in the field of pharmaceuticals and agrochemicals.2 Distinct functional group distribution and structural diversity make them potential candidates for various biological applications.3 Benzofuran, a well-known structural motif known for divergent medicinal properties,4 and its synthetic variants in the fused and spiro-form also received considerable interest due to their synthetic as well as biological applications.5 Specifically, the benzofurans fused with indanone skeleton

exhibit

antiviral

properties6

and the molecules that contain

spiro(benzofuran-isobenzofuran) scaffold is present in influenza virus type B inhibitors7 and fluorescent probes.8 Moreover, the spiro(benzofuran-isobenzofuran) skeleton is typically synthesized from indanone fused benzofuran through rearrangement reaction.8 In recent years, the annulation strategy has been well established as a prominent synthetic approach for the preparation of pharmaceutically relevant polycyclic skeletons.9 The Hauser– Kraus (H-K) annulation,10,11 a classic route for the synthesis of polycyclic naphthoquinones from stabilized phthalide anions and various Michael acceptors constitutes a robust method for the construction of multi-heterocycles including bioactive molecules and natural products (Scheme 1a).12-14 Fundamentally, the reaction utilizes the 1,4-dipolar reactivity of phthalide when it reacts with Michael acceptors and involves a Michael addition-Dieckmann cyclization-elimination sequence which leads to overall (4+2) annulation products.12 Recently, we disclosed an unusual reactivity of Hauser donor such as 3-sulfonylphthalide with o-hydroxynitrostyrene as Michael acceptor and established a (4+4) annulation strategy towards the synthesis of complex fused as well as spiro heterocycles (Scheme 1b).15 Later, we also demonstrated an efficient H-K annulation of nitroalkene derived Rauhut-Currier adducts with sulfonylphthalide to provide functionalized naphthoquinones which in turn were transformed into functionalized phenanthrenes and azaphenanthrenes on reaction with


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various amine sources.16 Very recently, our group and Kesavan group independently explored the H-K annulation of sulfonylphthalide and 3-olefinic oxindoles for the synthesis of biologically relevant spiro-dihydronaphthoquinoneoxindoles.17 Our on-going interest towards the synthesis of complex polycyclic compounds by utilizing the 1,4-dipolar reactivity of sulfonylphthalide together with the interesting reactivity profile displayed by the Michael acceptors possessing an additional nucleophilic site, for instance, a hydroxyl group,15 encouraged us to evaluate the reactivity of other substrates such as o-hydroxychalcones and o-hydroxynitrostyrylisoxazoles as Michael acceptors (Scheme 1c). Thus, this manuscript is a full version of our communication on the unusual (4+4) annulation of sulfonylphthalides with o-hydroxynitrostyrenes.15 Besides the wide scope of the annulation partners, new insights into the mechanism of the multi-cascade process which is triggered by the unusual (4+4) annulation leading to fused and spiro-benzofurans are detailed here. An unusual transformation of the fused products to naphthoquinones, the classical H-K adducts, not involving the standard (4+2) annulation pathway for the synthesis of naphthoquinones, is also part of our report.

Scheme 1. Hauser-Kraus Annulation and Its Modifications 3 ACS Paragon Plus Environment


RESULTS AND DISCUSSION In order to probe the reactivity of sulfonylphthalide 1 in (4+4) annulation with various substrates, we initiated our investigation by choosing phenyl-3-sulfonylphthalide 1 and ohydroxychalcone 2a as model substrates and conducted the reaction in the presence of 1.0 equiv of Cs2CO3 in THF at room temperature (Table 1). Similar to the reactivity observed in the case of o-hydroxynitrostyrene,15 the reaction afforded benzoindenofuran 3a (60%) and spiro-lactone 4a (21%) after 24 h (entry 1). The expected, competitive HK-annulated naphthoquinone was not formed in this case. Unfortunately, the benzoindenofuran 3a, which is a hemiacetal, could not be isolated in pure form due to its poor stability. Similar results were obtained when K2CO3 was employed, although a slight decrease in the yield (58%) of 3a was observed (entry 2). Few organic bases such as Et3N and DBU were also screened, but were not effective for this transformation (entries 3 and 4). Based on the above results, Cs2CO3 was found to be the best base for this transformation. Then, due to the poor stability of 3a, efforts were directed to tune the reaction for obtaining spiro-benzofuran 4a as the major product by altering the base loading. When Cs2CO3 loading was reduced to 0.5 equiv, the yield of 4a decreased to 17% with concomitant increase in the yield of 3a to 65% (entry 5). Further reduction in the quantity of Cs2CO3 to 0.2 equiv led to low yields of both compounds 3a and 4a (entry 6). However, we were pleased to find improvement in the yield of 4a upon increasing the amount of Cs2CO3 to 2 equiv (entry 7). Further increase in the quantity of base (3 equiv) accelerated the reaction rate, but did not alter the yield of 4a (entry 8). Subsequently, the effect of temperature was tested by keeping the quantity of Cs2CO3 as 2 equiv (entries 9-10). Interestingly, the spiro-lactone 4a was formed almost exclusively in improved yield (60%) when the reaction was performed at 50 °C for 12 h (entry 9). The yield of 4a further improved to 67% upon refluxing the reaction mixture for 8 h (entry 10). These reaction conditions were considered as optimal for further investigations.


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Table 1. Optimization of Reaction Conditionsa

Base (equiv)

1

Cs2CO3 (1.0)

24

3a 60

4a 21

2

K2CO3 (1.0)

24

58

21

72

c

...

...

DBU (1.0)

72

c

...

...

Cs2CO3 (0.5)

30

65

17

Cs2CO3 (0.2)

72

11

Trace

Cs2CO3 (2.0)

24

42

35

Cs2CO3 (3.0)

6

31

36

Cs2CO3 (2.0)

12

Trace

60

Cs2CO3 (2.0)

8

Trace

67

3

TEA (1.0)

4 5 6

d

7 8 9

e

10 a

Yield (%)b

entry

f

time (h)

Reaction scale: o-hydroxychalcone 2a (0.2 mmol), sulfonylphthalide 1 (0.2 mmol) and THF (3 mL). bYield

after silica gel column chromatography. cNo reaction. dIncomplete reaction. eReaction performed at 50 oC. f

Under reflux.

With the optimized reaction conditions in hand, we assessed the scope of o-hydroxychalcones 2 for the preparation of various functionalized spiro-lactones 4 (Table 2). oHydroxychalcones 2 bearing various substituents of diverse electronic properties on both aryl rings (A and B) at different positions were treated with sulfonylphthalide 1 to afford the corresponding spiro-lactones 4a-g in good yields. Chalcone 2b, containing weakly electron withdrawing group such as chloro at para-position of B-aryl ring, provided the product 4b in yield (67%) identical to that of the product 4a obtained from parent unsubstituted chalcone 2a. In the case of meta-bromo substituted (B-ring) chalcone 2c, the product 4c was formed in much higher yield (71%). To evaluate the compatibility of substituents on the A-ring of ohydroxychalcone 2, an experiment was conducted by treating chalcone 2d, bearing a chlorosubstituent at para-position with respect to the hydroxyl group, with sulfonylphthalide 1. The 5 ACS Paragon Plus Environment


desired spiro-lactone 4d was formed in good yield (70%). Further, the reactivity of ohydroxychalcone 2e bearing an electron donating methyl group on A-ring was tested and it proved to be compatible for the preparation of the corresponding spiro-lactone 4e (73% yield). Subsequently, the substituent effect on both aryl rings of o-hydroxychalcones 2 was tested by employing those having electron withdrawing groups on both rings (2f and 2g). In these cases, the products 4f and 4g were isolated in 67% and 61% yields, respectively. Chalcone 2h bearing a strongly electron donating group (OMe) on B-ring also tolerated the reaction conditions and afforded the corresponding spiro-heterocycle 4h in 59% yield. The practical utility of the developed method was further demonstrated by a large scale preparation of 4a and the reaction successfully delivered the product 4a in 63% yield after 8 h (Table 2).


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Table 2. Scope of o-Hydroxychalcones for the Synthesis of Spiro-lactonesa,b

a

Reaction scale: Sulfonylphthalide 1 (0.2 mmol), o-hydroxychalcone 2 (0.2 mmol), Cs2CO3 (0.4

mmol) and THF (3 mL); bYield after silica gel column chromatography; cLarge scale reaction: Sulfonylphthalide 1 (2.0 mmol), o-hydroxychalcone 2 (2.0 mmol), Cs2CO3 (4.0 mmol) and THF (10 mL).

We further desired to expand the scope of our methodology by replacing o-hydroxychalcones 2 with other promising substrates having significant biological properties. Search for another potent reaction partner for the cascade reaction with sulfonylphthalide 1 ended up with nitroisoxazole tethered o-hydroxystyrenes 5 (Table 3). Isoxazoles belong to a unique class of heterocycles that are widely distributed in natural products, pharmaceuticals and agrochemicals18 and are well-known precursors of bioactive molecular skeletons such as 7 ACS Paragon Plus Environment


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coumaric acids.19 Additionally, the nitro group on isoxazole moiety induces electrophilicity at the

benzylic

olefinic

carbon

which

will

enhance

the

reactivity

of

o-

hydroxynitrostyrylisoxazoles 5 and also acts as an amenable functional group for further transformation. A model reaction was then conducted between isoxazole 5a and phthalide 1 in the presence of Cs2CO3 (1 equiv) in THF at room temperature. The anticipated products, fused benzoindenofuran 6a and spiro-lactone 7a having the isoxazole motif, were formed in 61% and 26% yields respectively after 24 h (Table 3, entry 1). Unlike in the previous case where the fused product 3a could not be isolated in pure form, both fused product 6a and spiro-product 7a were very stable and characterized by spectral analysis followed by unambiguous confirmation by single crystal X-ray analysis (see below). Optimization studies were then conducted for establishing the best conditions to obtain either of the products as the major one (Table 3). To this end, various organic and inorganic bases were screened. The mild inorganic base, K2CO3, was found to be equally effective as compared to Cs2CO3, in providing 6a though a slight decline in the yield of 7a was observed (entries 1-2). As observed in the case of o-hydroxychalcone 2, none of the organic bases were suitable for this transformation (entries 3-5). Subsequently, we attempted to change the quantity of base by choosing Cs2CO3 as optimal. Gratifyingly, the indanone fused furan 6a was formed as the sole product in 80% yield when the amount of Cs2CO3 was reduced to 0.5 equiv (entry 6). Only a trace amount of spiro-lactone 7a was formed in this reaction. Further reduction of base quantity (0.2 equiv) led to incomplete reaction (entry 7). Other solvents such as DCM, toluene and MeCN were then screened by keeping the base loading as 0.5 equiv (entries 8-10). However, there was no appreciable improvement in the yield of 6a. Therefore, the reaction conditions shown in entry 6 were found suitable for the synthesis of indenofuran 6a.


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Table 3. Optimization of Reaction Conditionsa

entry base (equiv)

time

yield (%)b

(h)

6a

7a

1

Cs2CO3 (1.0)

THF

24

61

26

2

K2CO3 (1.0)

THF

30

61

21

3

TEA (1.0)

THF

48c

...

...

4

DBU (1.0)

THF

30c

...

...

5

DABCO (1.0)

THF

78c

...

...

6

Cs2CO3 (0.5)

THF

30

80

Trace

7

Cs2CO3 (0.2)

THF

72

... d

...d

8

Cs2CO3 (0.5)

DCM

48

68

Trace

9

Cs2CO3 (0.5)

Toluene

48

56

Trace

10

Cs2CO3 (0.5)

MeCN

24

72

Trace

11

Cs2CO3 (2.0)

THF

18

38

42

12

Cs2CO3 (3.0)

THF

10

Trace

47

13e

Cs2CO3 (2.0)

THF

11

Trace

48

f

Cs2CO3 (2.0)

THF

6

...

60

14 a

solvent

Reaction scale: o-hydroxynitrostyrylisoxazole 5a (0.2 mmol), sulfonylphthalide 1 (0.2 mmol),

solvent (3 mL). bYield after silica gel column chromatography. cNo reaction. dIncomplete reaction. e

Reaction performed at 50 oC. fUnder reflux.

A series of experiments were then performed to establish the appropriate conditions for the exclusive synthesis of spiro-lactone 7a (Table 3, entries 11-14). Having established that Cs2CO3 was the best base to promote this cascade reaction, the base loading was increased as in the case of o-hydroxychalcone 2 to synthesize the corresponding spiro-lactone 7a. As expected, upon increasing the amount of base (2 equiv), the yield of 7a improved to 42% at 9 ACS Paragon Plus Environment


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the expense of indenofuran 6a which was also isolated in 38% yield (entry 11). Further increase in the quantity of base (3 equiv) had no appreciable beneficial effect, although a slight improvement in the yield of 7a and near disappearance of 6a were observed (entry 12). By keeping the stoichiometry of base as 2 equiv, the effect of temperature was investigated. When the reaction was performed at 50 °C, it afforded almost exclusively 7a in 48% yield along with a trace amount of 6a (entry 13). Substantial improvement in the yield (60%) and rate acceleration was observed when the reaction was refluxed in THF (entry 14). These conditions

were

found

optimal

for

synthesizing

spiro-lactones

7

from

o-

hydroxynitrostyrylisoxazole 5. Having established the best reaction conditions for the synthesis of both fused and spirobenzofurans 6a and 7a respectively, we proceeded to investigate the scope and generality of the reaction to prepare the individual products by treating various aryl substituted ohydroxynitrostyrylisoxazoles 5 with sulfonylphthalide 1. At first, the generality of benzoindenofuran 6 was investigated under the established reaction conditions, and the results are summarized in Table 4. Thus besides benzoindenofuran 6a, which was formed in 80% yield from isoxazole 5a and phthalide 1, other selected isolxazoles 5b-d were also subjected to the desired transformation. For instance, isoxazoles 5b and 5c, bearing weak electron withdrawing groups such as bromo- and chloro at the para-position, respectively, with respect to the hydroxyl group, furnished the corresponding fused products 6b (92%) and 6c (85%) in excellent yields. Unfortunately, 2-hydroxynaphthyl derived isoxazole 5d did not deliver the desired benzofuran 6d upon reaction with phthalide 1 which is probably due to the steric hindrance exerted by the bulky naphthyl group.


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Table 4. Scope of o-Hydroxynitrostyrylisoxazoles for the Synthesis of Fused Benzofuransa,b

a

Reaction scale: o-hydroxynitrostyrylisoxazole 5 (0.2 mmol), sulfonylphthalide 1 (0.2 mmol), Cs2CO3

(0.1 mmol) and THF (3 mL). bYield after silica gel column chromatography. c No reaction.

Subsequently, the scope of isoxazoles 5 towards the synthesis of spiro-lactones 7 was explored (Table 5). Thus, isoxazole 5a, having no substituent on aryl ring, and those bearing electron donating substituents at para- and ortho-positions of the aryl group with respect to hydroxyl group 5e and 5f provided the products 7a, 7e and 7f in good (60-65%) yields. Spirolactones 7b and 7c were formed in better yields (73% each) when isoxazoles 5b and 5c, bearing weakly electron withdrawing substituents such as bromine and chlorine on the aryl ring, were employed as substrates. 2-Hydroxynaphthyl derived isoxazole 5d, as observed in the previous case, is not a compatible substrate for this transformation, presumably for steric reasons.20



Table 5. Scope of o-Hydroxynitrostyrylisoxazoles for the Synthesis of Spiro-lactonesa,b

a

Reaction scale: o-hydroxynitrostyrylisoxazole 5 (0.2 mmol), sulfonylphthalide 1 (0.2 mmol), Cs2CO3

(0.4 mmol) and THF (3 mL). bYields after silica gel column chromatography. c No reaction.

The structures of both benzoindenofurans 6 and spiro-lactones 7 obtained from isoxazoles 5 were confirmed by evaluating their spectral data and further unambiguously established by single crystal X-ray analysis of representative compounds 6b (CCDC 1877343) and 7b (CCDC 1877793, See Supporting Information, Tables S1 and S2). Based on the above results and our own previous report,15 a plausible mechanism is proposed for the formation of indanone fused benzofuran 3 or 6 (Scheme 2). The initial event involves Cs2CO3-mediated deprotonation of 1 to generate a stabilized anion I which adds to hydroxylstyrenyl substrate 2 or 5 in a Michael fashion resulting the intermediate II. The intramolecular (4+4)-cyclization of phenoxide anion in II with the lactone moiety (trans-lactonization or Dieckmann cyclization) gives an oxa-bridged heterocyclic intermediate III which further rearranges to form an eight-membered ketolactone IV by the elimination of sulfonyl group. Further, base 12 ACS Paragon Plus Environment

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initiated intramolecular trans-annular cyclization of IV delivers the tetra-cyclic indanone fused benzofuran 3 or 6.

Scheme 2. Proposed Mechanism for the Formation of Fused Benzofurans The experimental results discussed above confirmed that increased amount of Cs2CO3 at a higher temperature would exclusively deliver spiro-lactone 4 or 7. This suggested that the spiro-lactone formation takes place via benzoindenofuran 3 or 6 as intermediate under our experimental conditions. To verify the mechanism of formation of spiro-lactones 4 or 7, a control experiment was conducted by refluxing a representative benzoindenofuran 6a in the presence of 2.5 equiv of Cs2CO3 in THF (Scheme 3). As expected, the reaction afforded spiro-lactone 7a in 58% yield after 10 h which unambiguously established that the spirolactones 4 and 7 were formed from the corresponding fused compounds 3 and 6 respectively.



Scheme 3. Conversion of fused benzoindenofuran to spiro-lactone On the basis of the aforementioned results, a possible mechanism for the formation of spirolactones 4 and 7 from fused benzofurans 3 and 6 respectively is proposed in Scheme 4. The base mediated deprotonation of hydroxyl group present in 3 or 6 triggers the ring opening and generates an eight-membered enolized lactone intermediate V which is the enolate of IV (Scheme 2). Intermediate V then undergoes intramolecular cyclization (trans-lactonization) to give intermediate VI. The 5-exo-trig cyclization of VI provides spiro-lactones 4 or 7.

Scheme 4. Proposed Mechanism for the Formation of Spiro-lactones Since benzoindenofurans 3, derived from o-hydroxychalcones 2, were not amenable for purification and complete characterization, it was planned to prepare their stable derivatives. With this objective, O-tosylation of crude benzoindenofuran 3h by TsCl was performed under standard conditions, that is, in the presence of Et3N and catalytic amount of DMAP in 14 ACS Paragon Plus Environment

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DCM at room temperature (Table 6). Unexpectedly, the reaction afforded naphthoquinone derivative 8a, the normal (4+2) HK-annulated product anticipated from sulfonylphthalide 1 and o-hydroxychalcone 2h, but in the protected form, in 71% yield. Later, substituted naphthoquinones 8b-c were synthesized in good yields (61-69%) from the corresponding benzoindenofurans 3c and 3i, derived from o-hydroxychalcones 2c and 2i. The same strategy worked well for the conversion of nitroisoxazole containing benzoindenofuran 6b to naphthoquinone derivative 8d. The structure of naphthoquinones 8a-d was confirmed by detailed spectroscopic analysis and further unambiguously established by single crystal X-ray analysis of a representative compound 8a (CCDC 1877288, See Supporting Information, Table S3).



Table 6. Transformation of Fused Benzoindenofurans to Naphthoquinonesa,b

a

Reaction conditions: 3 or 6 (0.2 mmol), tosyl chloride (0.24 mmol), triethylamine (0.4 mmol) and

catalytic amount of DMAP in DCM (3 mL). bYield after silica gel column chromatography.

The proposed mechanism for the formation of naphthoquinones 8 from benzoindenofurans 3 or 6 is illustrated in Scheme 5. The initial step involves Et3N mediated deprotonation of 3 or 6 leading to ring opening of the tetra-cyclic core. The resulting phenoxide anion VII containing indanedione moiety gets tosylated to give disubstituted indanedione VIII. Further deprotonation and intramolecular cyclization results in the formation of strained


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cyclopropane containing intermediate X which undergoes ring expansion to IX followed by protonation and air oxidation to deliver naphthoquinones 8.

Scheme 5. Proposed Mechanism for the Formation of Naphthoquinones from Benzoindenofurans CONCLUSIONS In conclusion, we have demonstrated an unusual (4+4) annulation trajectory for HauserKraus annulation which led to the synthesis of functionalized fused and spiro-benzofurans from sulfonylphthalide and chalcone or nitrostyrylisoxazole bearing an additional nucleophilic moiety. This pathway is fundamentally different from the normal (4+2) reaction pathway which lead to naphthoquinone derivatives. The synthesis involves a cascade of cyclizations and rearrangements leading to both fused and spiro heterocycles as exclusive products which make our methodology very attractive. The control experiments carried out to elucidate the mechanism suggest that the spiro-lactones are formed from the corresponding fused compounds. A serendipitous transformation of fused benzoindenofurans to 17 ACS Paragon Plus Environment


naphthoquinones was observed under the standard conditions of tosylation to protect the hydroxyl group. This unravelled a novel pathway involving (4+4) annulation for the synthesis of naphthoquinones as opposed to classical (4+2) annulation. The studies towards the synthesis of complex multi-heterocycles by employing 3-sulfonylphthalide as Hauser-Kraus donor with various acceptors possessing different electrophilic and nucleophilic centers are currently underway in our laboratory. EXPERIMENTAL SECTION General information. The melting points recorded are uncorrected. NMR spectra (1H, 1H decoupled

13

C and 1H-1H COSY) were recorded with TMS as the internal standard. The

coupling constants (J values) are given in Hz. High resolution mass spectra were recorded under ESI Q-TOF conditions. X-ray data were collected on a diffractometer equipped with graphite monochromated Mo K radiation. The structure was solved by direct methods shelxs97 and refined by full-matrix least squares against F2 using shelxl97 software. Sulfonylphthalide 121 o-hydroxychalcone 2,22 o-hydroxynitrostyrylisoxazole 523 and ohydroxystyrylisoxazole without nitro group20 were prepared by literature methods. The identity and purity of substrates 1, 2 and 5 were in general confirmed by comparison of their physical and spectroscopic data with those reported in the literature. General procedure for the synthesis spiro-isobenzofuranones 4. To a stirred solution of sulfonylphthalide 1 (55 mg, 0.2 mmol, 1.0 equiv) in THF (3 mL), Cs2CO3 (65 mg, 0.4 mmol, 2.0 equiv) was added. After 5 min, chalcone 2 (0.2 mmol, 1.0 equiv) was added and the reaction mixture was refluxed until completion of the reaction (monitored by TLC). It was then cooled and concentrated in vacuo. The crude residue was purified by silica gel column chromatography by gradient elution with ethyl acetate/petroleum ether (5:95) to afford pure product 4.


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3-(2-Oxo-2-phenylethyl)-3H,3'H-spiro[benzofuran-2,1'-isobenzofuran]-3'-one

(4a).

White solid; Yield 67%, 48 mg; mp 214-215 oC; IR (Neat, cm-1) 2892 (w), 1777 (s), 1664 (m), 1460 (w), 1276 (m), 1226 (m), 913 (m), 753 (s); 1H NMR (400 MHz, CDCl3) δ 3.41, 3.61 (ABqd, J = 18.2, 6.6 Hz, 2H), 4.70 (t, J = 6.6 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.80 (t, J = 7.4 Hz, 1H), 7.86-7.94 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 38.1, 45.7, 110.4, 122.7, 123.0, 124.3, 125.6, 126.8, 128.1, 128.3, 128.9, 129.3, 131.4, 133.4, 135.2, 136.3, 146.7, 157.1, 167.6, 197.5; HRMS (ES+) calcd for C23H16O4Na (MNa+) 379.0941, found 379.0942. Typical experimental procedure for the large scale synthesis spiro-isobenzofuranone 4a. To a stirred solution of sulfonylphthalide 1 (548 mg, 2.0 mmol, 1.0 equiv) in THF (10 mL), Cs2CO3 (1.3 g, 4.0 mmol, 2.0 equiv) was added. After 5 min, chalcone 2a ( 448 mg, 2.0 mmol, 1.0 equiv) was added and the reaction mixture was refluxed for 8 h. It was then cooled and concentrated in vacuo. The crude residue was purified by silica gel column chromatography by gradient elution with ethyl acetate/petroleum ether (5:95) to afford pure product 4a (63%, 476 mg). 5-Chloro-3-(2-(4-chlorophenyl)-2-oxoethyl)-3H,3'H-spiro[benzofuran-2,1'isobenzofuran]-3'-one (4b). White solid; Yield 75%, 58 mg; mp 196-197 oC; IR (Neat, cm-1) 2919 (m), 2854 (w), 1784 (s), 1687 (m), 1590 (w), 1460 (m), 1343 (w), 1272 (m), 1226 (m), 1090 (m), 1026 (m), 927 (m), 755 (s); 1H NMR (400 MHz, CDCl3) δ 3.40, 3.56 (ABqd, J = 18.2, 6.7 Hz, 2H), 4.67 (t, J = 6.7 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.63-7.74 (m, 2H), 7.80 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 7.5 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 38.2, 45.7, 110.5, 114.6, 122.8, 123.0, 124.3, 125.7, 126.6, 128.0,



129.2, 129.4, 129.7, 131.5, 134.6, 135.3, 140.4, 146.7, 157.1, 167.5, 196.3; HRMS (ES+) calcd for C23H15ClO4Na (MNa+) 413.0551, found 413.0549. 3-(2-(3-Bromophenyl)-2-oxoethyl)-3H,3'H-spiro[benzofuran-2,1'-isobenzofuran]-3'-one (4c). White solid; Yield 71%, 62 mg; mp 150-151 oC; IR (Neat, cm-1) 3051 (w), 2920 (w), 2848 (w), 1777 (s), 1683 (m), 1265 (s), 905 (m), 745 (vs), 703 (m); 1H NMR (400 MHz, CDCl3) δ 3.42, 3.57 (ABqd, J = 18.3, 6.8 Hz, 2H), 4.67 (t, J = 6.8 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.65-7.74 (m, 3H), 7.80 (t, J = 7.8 Hz, 2H), 7.90 (d, J = 7.8 Hz, 1H), 8.00 (t, J = 1.8 Hz, 1H);

13

C{1H} NMR (125 MHz, CDCl3) δ 38.3, 45.6, 110.5, 114.6, 122.8, 123.0,

123.3, 124.2, 125.7, 126.6, 126.9, 127.8, 129.4, 130.5, 131.3 131.4, 135.3, 136.6, 137.9, 146.7, 157.0, 167.5, 196.2; HRMS (ES+) calcd for C23H15BrO4Na (MNa+) 457.0046, found 457.0049. 5-Chloro-3-(2-oxo-2-phenylethyl)-3H,3'H-spiro[benzofuran-2,1'-isobenzofuran]-3'-one (4d). White solid; Yield 70%, 55 mg; mp 200-201 oC; IR (Neat, cm-1) 2910 (vw), 1779 (vs), 1682 (m), 1468 (m), 1261 (m), 1229 (m), 1081 (m), 911 (s); 1H NMR (400 MHz, CDCl3) δ 3.39, 3.58 (ABqd, J = 18.3, 6.7 Hz, 2H), 4.68 (t, J = 6.7 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 7.18 (s, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.90 (d, J = 7.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 37.9, 45.6, 111.4, 115.1, 123.0, 124.8, 125.7, 126.7, 127.7, 128.3, 128.9, 129.2, 130.1, 131.6, 134.0, 135.4, 136.0, 146.1, 155.7, 167.3, 197.1; HRMS (ES+) calcd for C23H15ClO4Na (MNa+) 413.0551, found 413.0547. 5-methyl-3-(2-oxo-2-phenylethyl)-3H,3'H-spiro[benzofuran-2,1'-isobenzofuran]-3'-one (4e). White solid; Yield 73%, 54 mg; mp 121-122 oC; IR (Neat, cm-1) 3061 (w), 2920 (w), 1780 (vs), 1686 (m), 1488 (m), 1275 (w), 1231 (w), 1092 (w), 914 (m); 1H NMR (500 MHz, 20 ACS Paragon Plus Environment

Page 20 of 35

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CDCl3) δ 2.32 (s, 3H), 3.37, 3.41 (ABqd, J = 18.3, 6.6 Hz, 2H), 4.66 (t, J = 6.6 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 7.00 (s, 1H), 7.06 (d, J = 7.9 Hz, 1H), 7.44 (t, J = 8.6 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.78 (d, J = 7.4 Hz, 1H), 7.89 (t, J = 8.6 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 21.1, 38.1, 45.7, 110.0, 115.0, 123.0, 124.8, 125.6, 126.8, 128.1, 128.3, 128.9, 129.7, 131.4, 132.3, 133.8, 135.2, 136.3, 146.7, 155.1, 167.6, 197.6; HRMS (ES+) calcd for C24H18O4Na (MNa+) 393.1097, found 393.1096. 5-Bromo-3-(2-(4-bromophenyl)-2-oxoethyl)-3H,3'H-spiro[benzofuran-2,1'isobenzofuran]-3'-one (4f). White solid; Yield 67%, 68 mg; mp 221-222 oC; IR (Neat, cm-1) 3058 (m), 2913 (m), 1711 (vs), 1694 (vs), 1585 (s), 1477 (m), 1462 (m), 1290 (m), 1245 (s), 999 (m), 935 (m), 751 (s); 1H NMR (500 MHz, CDCl3) δ 3.39, 3.52 (ABqd, J = 18.3, 6.6 Hz, 2H), 4.66 (t, J = 6.6 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 7.30 (t, J = 1.5 Hz, 1H), 7.39 (dd, J = 8.5, 1.5 Hz, 1H), 7.59 (d, J = 8.6 Hz, 2H), 7.66 – 7.70 (m, 2H), 7.76 (d, J = 8.6 Hz, 2H), 7.81 (t, J = 7.5 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 38.0, 45.5, 112.1, 114.8, 123.0, 125.8, 126.6, 127.5, 129.3, 129.8, 130.4, 131.7 (×2), 132.3, 134.7, 135.4 (×2), 146.2, 156.2, 167.3, 196.1; HRMS (ES+) calcd for C23H14Br2O4Na (MNa+) 534.9151, found 534.9148. 5-Bromo-3-(2-(4-fluorophenyl)-2-oxoethyl)-3H,3'H-spiro[benzofuran-2,1'-isobenzofuran]-3'-one (4g). White solid; Yield 61%, 55 mg; mp 148-149 oC; IR (Neat, cm-1) 2921 (vw), 1780 (vs), 1685 (vs), 1651 (s), 1596 (vs), 1478 (w), 1461 (w), 1276 (m), 1231 (s), 912 (s), 755 (s); 1H NMR (500 MHz, CDCl3) δ 3.39, 3.53 (ABqd, J = 18.3, 6.6 Hz, 2H), 4.66 (t, J = 6.6 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 7.14 (t, J = 8.6 Hz, 2H), 7.30 (t, J = 1.5 Hz, 1H), 7.39 (dd, J = 8.5, 1.5 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.93 (dd, J = 8.6, 5.3 Hz, 2H); 13C{1H} NMR (125 MHz,



Page 22 of 35

CDCl3) δ 38.0, 45.5, 112.0, 114.8, 114.9, 116.1 (d, J = 22.5 Hz), 123.0, 125.8, 126.6, 127.5, 130.5, 131.1 (d, J = 10.0 Hz), 131.7, 132.3, 132.5 (d, J = 3.8 Hz), 135.4, 146.2, 156.2, 166.3 (d, J = 255.0 Hz), 167.3, 195.5; HRMS (ES+) calcd for C23H14BrFO4Na (MNa+) 474.9952, found 474.9959. 5-Bromo-3-(2-(4-methoxyphenyl)-2-oxoethyl)-3H,3'H-spiro[benzofuran-2,1'-isobenzofuran]-3'-one (4h). White solid; Yield 59%, 55 mg; mp 156-157 oC; IR (Neat, cm-1) 2919 (m), 1777 (vs), 1682 (s), 1651 (m), 1607 (m), 1466 (m), 909 (s); 1H NMR (500 MHz, CDCl3) δ 3.33, 3.51 (ABqd, J = 18.1, 6.3 Hz, 2H), 3.86 (s, 3H), 4.78 (t, J = 6.3 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 7.0 Hz, 2H), 7.31 (t, J = 1.6 Hz, 1H), 7.37 (dd, J = 8.5, 1.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 7.0 Hz, 2H), 7.89 (d, J = 7.6 Hz, 1H);

13

C{1H} NMR (100 MHz, CDCl3) δ 37.4, 45.6, 55.7, 111.9,

114.1, 114.8, 115.1, 123.0, 125.7, 126.7, 127.6, 129.2, 130.7, 130.8, 131.6, 132.1, 135.3, 146.1, 156.2, 164.2, 167.4, 195.4; HRMS (ES+) calcd for C24H17BrO5K (MK+) 502.9891, found 502.9891. General procedure for the synthesis of indenofurans 6.

To a stirred solution of

sulfonylphthalide 1 (55 mg, 0.2 mmol, 1.0 equiv) in THF (3 mL), Cs2CO3 (16.3 mg, 0.1 mmol, 0.5 equiv) was added. After 5 min, isoxazole 5 (0.2 mmol, 1.0 equiv) was added and the reaction mixture was stirred at room temperature until completion of the reaction (monitored by TLC). It was then concentrated in vacuo and the crude residue was purified by silica gel column chromatography by gradient elution with ethyl acetate/petroleum ether (10:90) to afford pure product 6. 4b-Hydroxy-9b-((3-methyl-4-nitroisoxazol-5-yl)methyl)-4bH-benzo[d]indeno[1,2b]furan-10(9bH)-one (6a). White solid; Yield 80%, 60 mg; mp 161-162 oC; IR (Neat, cm-1) 3441 (br, vs), 2984 (w), 1723 (vs), 1603 (vs), 1519 (vs), 1493 (s), 1287 (s), 1146 (m), 1091 22 ACS Paragon Plus Environment

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(s), 937 (m), 770 (s), 736 (vs); 1H NMR (400 MHz, CDCl3)  2.45 (s, 3H), 3.84 (d, J = 16.7 Hz, 1H), 4.28 (br s, 1H), 4.40 (d, J = 16.7 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.93 (t, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)  11.7, 29.0, 63.0, 110.7, 112.6, 122.5, 124.3, 124.4, 124.5, 124.8, 131.0, 131.5, 134.9, 136.8, 137.1, 149.7, 155.7, 155.8, 171.2, 198.4; HRMS (ES+) calcd for C20H14N2O6Na (MNa+) 401.0744, found 401.0749. 8-Bromo-4b-hydroxy-9b-((3-methyl-4-nitroisoxazol-5-yl)methyl)-4bHbenzo[d]indeno[1,2-b]furan-10(9bH)-one (6b). White solid; Yield 92%, 84 mg; mp 162163 oC; IR (Neat, cm-1) 3404 (vs, br), 2993 (w), 1721 (m), 1603 (s), 1518 (m), 1469 (m), 1265 (w), 1150 (s), 1014 (m), 738 (s); 1H NMR (500 MHz, CDCl3) δ 2.47 (s, 3H), 3.86 (d, J = 17.1 Hz, 1H), 4.22 (br s, 1H), 4.32 (d, J = 17.1 Hz, 1H), 6.66 (d, J = 8.5 Hz, 1H), 7.30 (dd, J = 8.5, 2.2 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.61 (t, J = 7.3 Hz, 1H), 7.83 (t, J = 7.3 Hz, 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 11.7, 29.1, 62.8, 112.4, 113.2, 114.5, 124.2, 124.6, 127.0, 127.5, 131.0, 131.8, 134.0, 134.8, 137.1, 149.5, 155.0, 155.8, 170.8, 197.7; HRMS (ES+) calcd for C20H13BrN2O6Na (MNa+) 478.9849, found 478.9844; Selected X-ray data (CCDC 1877343): C20H13BrN2O6, M=457.24, orthorhombic, space group P212121, a= 8.1343(4) Å, b= 11.9258(6) Å, c= 18.2918(10) Å, α = 90°, β = 90°, γ = 90°, V=1774.46(17) Å3,Dx = 1.7114 g/cm3, Z= 4, F(000)= 919.4, λ =0.71073 Å, μ = 2.360 m-1, total/unique= 9696/3079 [Rint = 0.0399, Rsigma = 0.0627], T=293(2) K, θ range= θmax = 49.98°, θmin = 4.08, Final R indexes [I>=2σ (I)]: R1 = 0.0315, wR2 = 0.0689, R(all data): R1 = 0.0360, wR2 = 0.0710. 8-Chloro-4b-hydroxy-9b-((3-methyl-4-nitroisoxazol-5-yl)methyl)-4bHbenzo[d]indeno[1,2-b]furan-10(9bH)-one (6c). White solid; Yield 85%, 70 mg; mp 180-



Page 24 of 35

181 oC; IR (Neat, cm-1) 3433 (br, vs), 2982 (vw), 1723 (m), 1603 (s), 1521 (m), 1492 (w), 1378 (w), 1363 (w), 1287 (m), 1149 (w), 1092 (m), 734 (m); 1H NMR (400 MHz, CDCl3) δ 2.50 (s, 3H), 3.85 (d, J = 17.0 Hz, 1H), 4.31 (d, J = 17.0 Hz, 1H), 4.48 (br s, 1H), 6.69 (d, J = 8.7 Hz, 1H), 7.15 (dd, J = 8.7, 2.4 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H);

13

C{1H} NMR

(125 MHz, CDCl3) δ 11.7, 29.1, 62.8, 111.8, 113.1, 124.2, 124.5, 124.6, 126.4, 127.4, 131.0, 131.7, 134.7, 137.0, 137.4, 149.5, 154.4, 155.8, 170.8, 197.9; HRMS (ES+) calcd for C20H13ClN2O6Na (MNa+) 435.0354, found 435.0357. General procedure for the synthesis spiro-isobenzofuranones 7. To a stirred solution of sulfonylphthalide 1 (55 mg, 0.2 mmol, 1.0 equiv) in THF (3 mL), Cs2CO3 (65 mg, 0.4 mmol, 2.0 equiv) was added. After 5 min, isoxazole 5 (0.2 mmol, 1.0 equiv) was added and the reaction mixture was refluxed until completion of the reaction (monitored by TLC). It was then cooled and concentrated in vacuo. The crude residue was purified by silica gel column chromatography by gradient elution with ethyl acetate/petroleum ether (5:95) to afford pure product 7. 3-((3-Methyl-4-nitroisoxazol-5-yl)methyl)-3H,3'H-spiro[benzofuran-2,1'isobenzofuran]-3'-one (7a). White solid; Yield 60%, 55 mg; mp 167-168 oC; IR (Neat, cm-1) 3055 (w), 1787 (vs), 1604 (s), 1519 (s), 1378 (m), 1273 (m), 1221 (m), 914 (s), 755 (s), 740 (s); 1H NMR (400 MHz, CDCl3)  2.39 (s, 3H), 3.62, 3.81 (ABqd, J = 15.5, 7.5 Hz, 2H), 4.55 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)  11.5, 26.3, 47.2, 110.9, 113.7, 122.7, 123.1, 123.6, 125.8, 126.3, 126.9, 129.9, 130.4 131.7, 135.2, 145.1,


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155.8, 157.1, 166.7, 171.6; HRMS (ES+) calcd for C20H14N2O6Na (MNa+) 401.0744, found 401.0746. 5-Bromo-3-((3-methyl-4-nitroisoxazol-5-yl)methyl)-3H,3'H-spiro[benzofuran-2,1'isobenzofuran]-3'-one (7b). White solid; Yield 73%, 66 mg; mp 198-199 oC; IR (Neat, cm-1) 2961 (m), 2922 (m), 2851 (w), 1787 (s), 1604 (s), 1517 (m), 1467 (m), 1373 (w), 1261 (vs), 1088 (vs), 1022 (vs), 913 (s), 798 (vs); 1H NMR (500 MHz, CDCl3) δ 2.39 (s, 3H), 3.63, 3.77 (ABqd, J = 15.6, 7.4 Hz, 2H), 4.55 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 7.34 (s, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H);

13

C{1H} NMR (125 MHz, CDCl3) δ 11.5, 26.1, 47.0, 112.5,

113.9, 115.2, 122.7, 125.9, 126.8, 126.9, 128.8, 130.4, 131.9, 132.9, 135.3, 144.6, 155.8, 156.2, 166.4, 171.0; HRMS (ES+) calcd for C20H13BrN2O6Na (MNa+) 478.9849, found 478.9845; Selected X-ray data (CCDC 1877793): C20H13BrN2O6, M=457.23, triclinic, space group P-1, a= 6.90037(13) Å, b= 7.83220(17) Å, c= 16.9797(4) Å, α = 82.7874(18)°, β = 85.8772(17)°, γ = 79.2104(17)°, V=893.21(3) Å3,Dx = 1.700 g/cm3, Z= 2, F(000)= 460.0, λ =0.71073 Å, μ = 2.345 mm-1, total/unique= 15857/3148 [Rint = 0.0451, Rsigma = 0.0288], T=293(2) K, θ range= θmax = 49.994°, θmin = 4.842, Final R indexes [I>=2σ (I)]: R1 = 0.0290, wR2 = 0.0708, R(all data): R1 = 0.0325, wR2 = 0.0733. 5-Chloro-3-((3-methyl-4-nitroisoxazol-5-yl)methyl)-3H,3'H-spiro[benzofuran-2,1'isobenzofuran]-3'-one (7c). White solid; Yield 73%, 60 mg; mp 175-176 oC; IR (Neat, cm-1) 2920 (vw), 1789 (vs), 1605 (s), 1519 (s), 1468 (s), 1418 (m), 1379 (m), 1364 (m), 1271 (m), 1087 (m), 1025 (m), 940 (m), 912 (s), 765 (m); 1H NMR (500 MHz, CDCl3) δ 2.39 (s, 3H), 3.63, 3.77 (ABqd, J = 15.6, 7.5 Hz, 2H), 4.54 (t, J = 7.5 1H), 6.91 (d, J = 8.5 Hz, 1H), 7.18 (t, J = 1.5 Hz, 1H), 7.29 (dd, J = 8.5, 1.5 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3)



δ 11.5, 26.1. 47.1, 111.9, 114.0, 122.7, 124.0, 125.9, 126.8, 128.1, 128.3, 129.9, 131.9, 135.3 (×2), 144.6, 155.7, 155.9, 166.4, 171.0; HRMS (ES+) calcd for C20H13ClN2O6Na (MNa+) 435.0354, found 435.0357. 5-Methyl-3-((3-methyl-4-nitroisoxazol-5-yl)methyl)-3H,3'H-spiro[benzofuran-2,1'isobenzofuran]-3'-one (7e). White solid; Yield 63%, 49 mg; mp 174-175 oC; IR (Neat, cm-1) 2920 (m), 1787 (vs), 1603 (m), 1518 (w), 1361 (w), 1269 (m), 1240 (m), 1210 (m), 1150 (w), 1029 (w), 942 (m), 911 (s); 1H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 2.39 (s, 3H), 3.62, 3.79 (ABqd, J = 15.6, 7.4 Hz, 2H), 4.52 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 7.00 (s, 1H), 7.11 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.74 (t, J = 7.4 Hz, 1H), 7.86 (d, J = 7.4 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 11.5, 21.2, 26.4, 47.3, 110.4, 113.9, 122.7, 124.1, 125.8, 126.3, 126.9, 130.3, 130.4, 131.6, 132.7, 135.1, 145.2, 155.1, 155.8, 166.8, 171.6; HRMS (ES+) calcd for C21H16N2O6Na (MNa+) 415.0901, found 415.0897. 7-Ethoxy-3-((3-methyl-4-nitroisoxazol-5-yl)methyl)-3H,3'H-spiro[benzofuran-2,1'isobenzofuran]-3'-one (7f). White solid; Yield 65%, 55 mg; mp 171-172 oC; IR (Neat, cm-1) 2913 (w), 1786 (s), 1638 (vs), 1603 (vs), 1514 (m), 1373 (w), 1267 (m), 1084 (m), 908 (m), 765 (s), 740 (s); 1H NMR (500 MHz, CDCl3) δ 1.41 (t, J = 7.0 Hz, 3H), 2.39 (s, 3H), 3.61, 3.80 (ABqd, J = 15.6, 7.6 Hz, 2H), 4.14 (q, J = 7.0 Hz, 2H), 4.57 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 7.60-7.65 (m, 2H), 7.72 (t, J = 7.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H);

13

C{1H} NMR (125 MHz, CDCl3) δ 11.5, 14.9,

26.3, 47.5, 64.9, 113.9, 114.5, 115.3, 123.0, 123.8, 125.7, 127.1, 127.6, 130.4, 131.7, 135.1, 144.2, 144.9, 145.6, 155.8, 166.8, 171.6; HRMS (ES+) calcd for C22H18N2O7Na (MNa+) 445.1006, found 445.1009.


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General procedure for the synthesis of quinones 8. To a solution of indenofuranone 3 or 6 (0.2 mmol) in DCM (3 mL) were added tosyl chloride (45.6 mg, 0.24 mmol, 1.2 equiv) and Et3N (55.7 µL, 40.5 mg, 0.4 mmol, 2 equiv) and catalytic amount of DMAP (3 mg, 0.1 equiv). The reaction mixture was stirred at room temperature. After completion of the reaction (monitored by TLC), the resulting mixture was diluted with water (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The pure product 8 was isolated as a yellow solid. 2-(3-(4-Bromobenzoyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)phenyl 4-methylbenzenesulfonate (8a). Yellow solid; Yield 71%, 88 mg; mp 160-161 oC; IR (Neat, cm-1) 2921 (m), 2849 (w), 1708 (s), 1670 (vs), 1655 (vs), 1598 (s), 1586 (s), 1374 (m), 1277 (m), 1171 (m), 1089 (m), 1070 (m), 883 (m), 842 (m), 771 (m), 741 (m), 723 (m); 1H NMR (500 MHz, CDCl3) δ 2.34 (s, 3H), 7.00 (d, J = 8.2 Hz, 1H), 7.13 (d, J = 8.2 Hz, 2H), 7.19-7.21 (m, 2H), 7.27-7.30 (m, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.82-7.86 (m, 2H), 8.09-8.13 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 21.9, 122.4, 125.2, 126.6, 126.7, 127.2, 128.4, 129.8, 130.0, 131.0, 131.3, 131.5, 131.6, 132.0, 132.1, 132.2, 132.8, 134.4, 134.7, 143.0, 145.0, 145.7, 147.0, 182.6, 183.6, 191.4; HRMS (ES+) calcd for C30H19BrO6SNa (MNa+) 608.9978, found 608.9974. Selected X-ray data (CCDC 1877288): C30H19BrO6S, M=587.42, Triclinic, space group P -1, a= 7.8843(4) Å, b= 10.4889(5) Å, c= 16.2110(9) Å, α = 80.468(4)°, β = 87.624(4)°, γ = 73.089(5)°, V=1264.91(12) Å3,Dx = 1.542 Mg/m3, Z= 2, F(000)= 596, λ =0.71073 Å, μ = 1.753 cm-1, total/unique= 12223/4448 [R(int) = 0.0427], T=293(2) K, θ range= θmax = 25.00°, θmin = 2.06, final R indices [I>2sigma(I)]: R1 = 0.0397, wR2 = 0.0978, R(all data): R1 = 0.0482, wR2 = 0.1036.



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2-(3-(3-Bromobenzoyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)phenyl 4-methylbenzenesulfonate (8b). Yellow solid; Yield 61%, 71 mg; mp 161-162 oC; IR (Neat, cm-1) 2960 (m), 2924 (s), 2852 (m), 1712 (s), 1668 (vs), 1657 (vs), 1263 (vs), 1090 (vs), 1029 (vs), 804 (m), 742 (m); 1H NMR (400 MHz, CDCl3) δ 2.32 (s, 3H), 7.03 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 8.1 Hz, 2H), 7.18 (t, J = 8.3 Hz, 1H), 7.21 (t, J = 8.2 Hz, 1H), 7.27-7.31 (m, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.66 (dt, J = 7.8, 1.8 Hz, 1H), 7.74 (dt, J = 7.8, 1.8 Hz, 1H), 7.81-7.87 (m, 2H), 7.94 (t, J = 1.8 Hz, 1 H), 8.09-8.14 (m, 2H);

13

C{1H} NMR (125 MHz, CDCl3) δ 21.8, 122.5,

123.1, 125.0, 126.6, 126.7, 127.2, 128.5, 128.6, 130.0, 130.4, 131.3, 131.5, 131.6, 131.9, 132.0, 132.9, 134.5, 134.7, 137.1, 137.4, 143.0, 144.7, 145.6, 147.1, 182.6, 183.5, 191.0; HRMS (ES+) calcd for C30H20BrO6S (MH+) 587.0158, found 587.0153. 2-(3-(2,4-Dichlorobenzoyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)phenyl

4-methyl-

benzenesulfonate (8c). Yellow solid; Yield 69%, 80 mg; mp 167-168 oC; IR (Neat, cm-1) 3069 (w), 2925 (s), 2854 (m), 1712 (vs), 1673 (s), 1582 (s), 1464 (m), 1376 (vs), 1276 (s), 1195 (m), 1172 (m), 1089 (m), 884 (m), 848 (m), 761 (s), 737 (vs); 1H NMR (400 MHz, CDCl3) δ 2.25 (s, 3H), 7.04 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 1.7 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.11 (t, J = 8.5 Hz, 1H), 7.18 (t, J = 8.5 Hz, 1H), 7.29 (ABqd, J = 7.0, 1.7 Hz, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.81- 7.85 (m, 2H), 8.05-8.08 (m, 1H), 8.118.14 (m, 1H);

13

C{1H} NMR (100 MHz, CDCl3) δ 21.8, 122.7, 125.0, 126.5, 126.7, 127.1,

127.7, 128.5, 129.9, 130.7, 131.0, 131.2, 131.6, 131.9, 132.7, 133.0, 133.9, 134.1, 134.5, 134.5, 139.6, 141.0, 144.7, 145.5, 147.2, 182.7, 182.9, 189.4; HRMS (ES+) calcd for C30H19Cl2O6S (MH+) 577.0274, found 577.0271. 4-Bromo-2-(3-(3-methyl-4-nitroisoxazol-5-yl)-1,4-dioxo-1,4-dihydronaphthalen-2yl)phenyl 4-methylbenzenesulfonate (8d). Yellow solid; Yield 62%, 66 mg; mp 174-175 o

C; IR (Neat, cm-1) 2931 (vw), 1672 (s), 1593 (w), 1521 (w), 1373 (m), 1170 (s), 913 (m),


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734 (vs); 1H NMR (400 MHz, CDCl3) δ 2.23 (s, 3H), 2.60 (s, 3H), 6.94 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.53 (dd, J = 8.8, 2.4 Hz, 1H), 7.84-7.92 (m, 2H), 8.00-8.04 (m, 1H), 8.17- 8.20 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 11.5, 21.9, 120.3, 125.5, 126.4, 127.3, 127.4, 128.8, 130.1, 131.5, 131.6, 131.8, 134.2, 134.6, 134.7, 134.8, 134.9, 144.1, 145.3, 145.8, 155.7, 163.0, 179.5, 180.7, 185.8; HRMS (ES+) calcd for C27H17BrN2O8SNa (MNa+) 630.9781, found 630.9791. ASSOCIATED CONTENT Supporting Information Available. Copies of NMR spectra for all the new compounds and CIF for compounds 6b, 7b and 8a. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Phone: +22-2576-7196. Fax: +22-2576-7152, 2572-3480 (I.N.N.N.). ORCID Irishi N. N. Namboothiri: 0000-0002-8945-3932 Notes The authors declare no competing financial interest. ACKNOWLEDGEMENTS INNN thanks SERB, DST India for financial assistance. AS thanks IIT Bombay for a Senior Research Fellowship, TVB thanks IIT Bombay for an Institute Postdoctoral Fellowship and TK thanks CSIR India for a Senior Research Fellowship. REFERENCES



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und o-Heteroarylvinylphenolen. Synthesis 1979, 1979, 712-714. See also: (b) Franke, A.; Frickel,

F.

F.;

Gries,

J.;

Lenke,

D.;

Schlecker,

R.;

Thieme,

P.

D.

2-

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Synthesis of Spiro- and Fused Heterocycles via (4+4) Annulation of

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