Anionic Annulation of 3-Cyanophthalides with Allene Carboxylates: A

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Anionic annulation of 3-cyanophthalides with allene carboxylates: a carbon-conserved synthesis of naphtho[b]furanones Supriti Jana, and Dipakranjan Mal J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00272 • Publication Date (Web): 22 Mar 2018 Downloaded from http://pubs.acs.org on March 22, 2018

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The Journal of Organic Chemistry

Anionic annulation of 3-cyanophthalides with allene carboxylates: a carbon-conserved synthesis of naphtho[b]furanones Supriti Jana and Dipakranjan Mal* Department of Chemistry, Indian Institute of Technology Kharagpur, 721302, India

ABSTRACT The reaction of 3-cyanophthalides with allene carboxylates in the presence of tBuOLi results in a tandem annulation furnishing naphtho[b]furanones in good yields with no loss of carbon. The carbon economy is explained by a tandem process in which initially expelled cyanide induces the second annulation.

INTRODUCTION In a recent report, we reported the anionic annulation of unactivated phthalides 1 with allene carboxylates 2 providing 9-hydroxynaphthofuranones 3 in good yields. This tandem reaction was interpreted in terms of formal [4+2] annulation to form intermediates A, followed by transposition of the incipient hydroxy group (Scheme 1, equation 1).1 A short synthesis of justicidin B was achieved by application of the annulation. In a more recent report,2 Ham et al. demonstrated the synthetic utility of 4,9-dihydroxynaphthofuranones 5 (Scheme 1, equation 2), which differ from the naphthofuranones 3 in an additional hydroxy group. In order to access the former by

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extension of our annulation chemistry of allene carboxylates 2, we envisaged their reaction with activated phthalides 4 in the place of 1. The probable intermediate B could undergo Michael addition with water followed by lactonization to give dihydroxynaphthofuranones 5 (Scheme 1). But, the hypothesis proved to be wrong. The attempted annulation reactions of 2 with phthalides 4 in the presence of tBuOLi afforded naphtho[b]furanones (cf. 7) in good yields in single operations (Scheme 2). On the contrary, the reaction of 4-methoxy and 6-methoxy substituted cyanophthalides provided desired naphtho[c]furanones (cf. 5). Scheme 1. Synthetic background and working hypothesis

RESULTS AND DISCUSSION We initiated this annulation study with racemic allene-1-carboxylates 2.1 Accordingly, 3cyanophthalide (6)3a was reacted with allene carboxylate 2b in the presence of LDA in THF at -78 oC, as previously applied to unactivated phthalides 1. Routine work-up of the reaction


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mixture followed by chromatographic purification afforded two solid products. The preliminary examination of the 1H NMR spectra of the purified products revealed no correspondence to the desired product (cf. 5). The more polar product displayed a downfield –CH group at δ 5.3 ppm and an exchangeable hydrogen in the spectrum leading to the proposal of structure 7 for the major product. IR band of this product at 1803 cm-1, supported the presence of a 5-membered lactone ring of benzofuranones4. Finally, the structure 7 was confirmed by a single crystal X-ray data analysis (vide SI for details, Figure S1, Table S1) and its HRMS data. The minor and less polar product corresponded to the structure 8. It was fully characterized by NMR and HRMS data. We optimized the reaction with bases like LiHMDS, NaH and tBuOLi. From the results (Scheme 2), it is apparent that entry 3 is the best set of conditions for the annulation. Scheme 2. Annulation of cyanophthalide 6 with allene carboxylate 2b and optimization of reaction condition

The one-pot formation of the naphtho[b]furanone 7 can be explained by the mechanism shown in Scheme 3. The annulation cascade is initiated by tBuOLi promoted generation of 3lithiophthalide 6a, which undergoes cycloaddition with 2b to give tricyclic intermediate 9,



collapsing to tetralone 10. As cyanide group is a good leaving group, it is expelled from the intermediate 10 to give quinone methide 11, and then the expelled cyanide ion adds to the double bond of the intermediate 11, forming the naphthoquinone dianion 12. Under acidic work-up conditions, the dioxide and the cyanide groups in 12 are protonated to form 13. Intramolecular imidation to 14, followed by hydrolysis during acidic work-up conditions gives naphthofuranone 7. Alternatively, the addition of the cyanide group might take place in the acidic conditions. Scheme 3. Probable mechanism for the formation of naphtho[b]furanone 7

For the formation of quinol 8, addition of H2O to the double bond of 11 forming naphthoquinol 15, followed by aerial oxidation of naphthoquinol 15 to naphthoquinone 16 is proposed (Scheme 4). Under acidic work-up conditions, 1,2-hydride shift of intermediate 17a causes 17b. Aromatization of the intermediate 17b produces compound 8.


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Scheme 4. Probable mechanism for the formation of quinol 8

Intrigued by this unprecedented tandem annulation, we decided to test the generality of the reaction. Furthermore, benzofuranones are frequently found as core structural motifs in many natural products and drug scaffolds, including hopeahainol, abesinol E, ferrubietolide etc.5 Strikingly, the related naphthofuranone6 moieties are very rare in natural products. To generalize the reaction (Scheme 2), 3-cyanophthalide (6) was submitted to the reaction with 4-methoxyphenyl substituted allenoate 2c under the influence of

t

BuOLi.

Naphthofuranone 7a was obtained as the sole product in 87% yield (Table 1, entry 1). When the reaction was carried out with 5-bromocyanophthalide 183b with allene carboxylates 2b, compounds 7b and compound 8a were obtained in 63% and 19% yields respectively (Table 1, entry 2). Likewise, naphthofuranone 7c was obtained in 62% yield when the annulation of 5,7-dimethoxycyanophthalide 193c with allene carboxylate 2b (Table 1, entry 3) was conducted. When 5-methylcyanophthalide 203b was subjected to react with allene carboxylates 2b, naphtho[b]furanone 7d and 1,4-dihydroxynaphthol 8b were obtained in 56% and 25% yields respectively (Table 1, entry 4). Very interestingly, when benzo fused cyanophthalide 21 was reacted with the allene carboxylate 2b, we obtained two products, i.e.,



anthrafuranones 7e and 1,4-dihydroxy anthraquinone 8c in 59% and 27% yields respectively according to our expectation (Table 1, entry 5). Table 1. Substrate scope of the annulationa leading naphtho[b]furanones


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a: All reactions are carried out in the presence of tBuOLi (3 equiv.), THF, -78 °C to room temperature, 6–7 h, quenched with 3 M HCl.

In conjugation with the study of activated naphthalide, i.e., 21, we cursorily looked into the reactivity of unactivated naphthalide. i.e., 23. The attempted annulations between 23 and allene carboxylates 2a and 2b turned out to be unsuccessful. Scheme 5. Synthesis of cyanonaphthofuranone 21

Naphthalide 23 was prepared by LDA mediated annulation of phthalide 22 with allene carboxylate 2a, followed by the O-methylation reaction by the treatment of K2CO3 and MeI in overall 70% yield (Scheme 5). For a large-scale synthesis of the phthalide 23, Yu lactone annulation7 was applied to 1-methoxy-2-naphthoic acid (25), which was synthesized in 92% yield from commercially available 1-hydroxy-2-naphthoic acid (24) by the treatment with



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dimethyl sulfate and K2CO3 in acetone under reflux followed by the ester hydrolysis with LiOH in THF/H2O mixture. Treatment of 1-methoxy-2-naphthoic acid (25) with 10 mol% Pd(OAc)2 and KHCO3 in dibromomethane at 140 oC for 36 h furnished naphthofuranone 23 in 84% yield. Compound 23 was then treated8 with N,N-diethylamine and anhydrous AlCl3 in DCM as solvent to give amide derivative 26 in 94% yield. Compound 26 was oxidized9 by PCC in DCM, to provide aldehyde 27 in 89% yield. Finally, the aldehyde 27 was reacted8 with TMSCN and catalytic amount of KCN and 18-crown-6 in DCM as solvent, followed by evaporation of DCM and stirring the resultant reaction mixture in AcOH for 15 h to furnish cyanophthalide 21 in 89% yield. The tandem annulation described in the foregoing section is found to be very sensitive to substituents of phthalide components (Scheme 6). Cyanophthalides like 4-methoxy and 6methoxy

substituted

cyanophthalides

provided

desired

naphtho[c]furanones

29.

Naphthofuranone 29a was obtained in 82% yield, when the annulation of 4methoxycyanophthalide 28a3b with allene carboxylate 2b (Table 2, entry 1) was conducted. Scheme 6. General scheme for the annulation towards 29


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The annulation of 6,7- dimethoxy cyanophthalide 28b3b with the allene carboxylates 2b under the same set of reaction conditions (Table 2, entry 2), furnished 1,4-dihydroxynaphthalide Table 2. Scope of the annulation leading to 29a



a: All reactions are carried out in the presence of tBuOLi (3 equiv.), THF, -78 °C to room temperature, 6 –7 h, quenched with 3 M HCl.

29b in 65% yield, contrary to the synthesis of naphtho[b]furanones. Similarly, naphthofuranone 29c was obtained in 79% yield, when the annulation of 4,7dimethoxycyanophthalide 28c3d with allene carboxylate 2b (Table 2, entry 3) was conducted. When allene acceptor 2c was used in the place of 2b, the reaction provided 1,4-dihydroxy naphtho[2,3-c]furan-1(3H)-one 29d in 78% yield (Table 2, entry 4). No naphtho[b]furanones were formed in the above annulations. Next, we explored sulfonyl phthalide 28d as the donor. Unlike cyanophthalide analogue 6, it delivered naphthofuranone 29e in 89% yield (Table 2, entry 5). No product with incorporation of the sulfonyl group was obtained. This can be explained by the poorer nucleophilicity of the expelled arylsulfinate ion. We also performed the annulation reaction between 3-phenylsulfenylphthalide and ethyl 4-phenyl-2,3butadienoate (2b) with the optimized reaction conditions. But, we did not get the Michael addition product of SPh. This donor is not at all suitable for this type of annulation. We got only less than 15% of the H2O addition product i.e., naphtho[c]furanone 29e and selfdecomposition of the donor occurred. The formation of naphtho[c]furanone 29e may be explained by preferential addition of H2O under acidic work-up conditions, when PhSH is less nucleophilic than H2O. To trap the Michael type acceptor intermediate, we performed the reaction between the cyanophthalide 20 and ethyl 4-phenyl-2,3-butadienoate (2b) with the optimized reaction conditions followed by the addition of nBuNH2 as a nucleophile. Here, the additional amine did not affect the product formation and also the yield of the products, both the products 7d and 8b were obtained in 50% and 19% yields respectively. Under acidic conditions, amines remain protected, and no addition takes place.


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It is apparent that the formation of naphtho[b]furanones (Table 1) and naphtho[c]furanones (Table 2) is dependent on the effect of the substituents of the cyanophthalides. When the electron donating methoxy group is at 4 or 6 positions of cyanophthalides as in 28a-c, the resonance effect exerted by the methoxy groups reduces the electron density of the carbonyl group of the quinone methide unit (cf. 30 and 31) (Scheme 7). Consequently, the possibility Scheme 7. Explanations of naphtho[c]furanones formation for 4-methoxy and 6methoxy substituted cyanophthalides

of the conjugate addition of the cyanide ion is reduced, and the formation of naphtho[b]furanones is precluded. In these cases, during acidic work-up, H2O added to the double bond of the quinone methide unit (i.e., 30 and 31) forming the naphtho[c]furanones 29a-d (Scheme 7). When the electron donating methoxy group is not at 4 or 6 positions of



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cyanophthalides as in 19, 20 and in 21, the expelled cyanide can add to the quinone methide unites (cf. 32, 33 and 34) and naphtho[b]furanones were obtained. In order to divert above reactions to the formation of naphtho[b]furanones, we considered effecting cyanide addition from an additive in the reaction. Accordingly, we treated cyanophthalide 28b with allene carboxylate 2b followed by the treatment with a combination3b of PIDA-TMSCN-BF3·Et2O and tetrabutylammonium cyanide separately. But the reactions afforded naphtho[c]furanone 29b. There was no indication of any other product formation in TLC experiment. In another experiment, we considered ZnCl2 as an additive9, anticipating it would coordinate with nuclear methoxy group, thus making the intermediates (cf. 11) more electrophilic in nature, so that addition of cyanide is possible. However, the experiment conducted with 6,7-dimethoxy cyanophthalide 28b, showed no departure from the previous result. In this case also only naphtho[c]furanone 29b was obtained in 60% yield. This is due to that the intrinsic reactivity of the quinone methide 31 is not good enough so that external cyanide can attack, rather during acidic work-up condition H2O added to 31 and naphtho[c]furanones

were

obtained.

The

driving

force

for

the

formation

of

naphtho[c]furanones might be the lactonization of intermediate hydroxy acid. To increase the yield of the major product i.e., naphtho[b]furanone 7, we used tetrabutylammonium cyanide as an additional cyanide source. But this was of no avail. CONCLUSION In conclusion, we have identified two trails in the reactions between 3-cyanophthalides and allene carboxylates. One leads to the formation of naphtho[b]furanones and the other to naphtho[c]furanones. This divergence of the tandem annulations is due to the in-situ Michael addition of CN–, which is released in the first annulation. The cyanide addition is seemingly controlled by the reactivity of the quinone methide intermediate formed after the first


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annulation. The results would serve as a starting point for further investigations for the development of naphtho[b]furanones which are scarcely studied. The easy accessibility of the starting materials and the mild reaction conditions combined with the importance of naphthofuranones, make this new annulation a useful advancement. EXPERIMENTAL SECTION General Experimental Methods. Melting points were determined in open end capillary tubes and are uncorrected. Solvents were dried and distilled following the standard procedures. TLC was carried out on precoated plates (silica gel 60, GF254), and the spots were visualized with UV and fluorescent lights. Column chromatography was performed on silica gel (60–120 or 230–400 mesh). 1H and

13

C NMR spectra for all the compounds were

recorded at 400/500/600 and 100/125/150 MHz. IR spectra were recorded on an FT-IR instrument using a KBr pellet. Mass analyser type was “TOF MS ESI” in every case. The phrase “usual workup” or “worked up in usual manner” refers to washing of the organic phase with water (2 x 1/3 the volume of the organic phase) and brine (1 x 1/4 the volume of the organic phase), drying (anhydrous Na2SO4), filtration, and concentration under reduced pressure. Method A: General Annulation Procedure with LDA. In a flame-dried flask, LDA (3.2 mmol) was prepared by adding nBuLi (3.2 mmol, 1.6 M in hexanes) in a solution of diisopropylamine (3.2 mmol) in THF (10 mL) at -78 oC under nitrogen atmosphere. After 30 min at -78 oC, an appropriate phthalide (1 mmol) in THF (5 mL) was added drop wise over 15 min. The reaction mixture was stirred at -78 oC for 30 min, and then a solution of the appropriate Michael acceptor (1.2 mmol) in THF (5 mL) was added drop wise over 15 min at -78 oC. The reaction mixture was further stirred for 1 h at the same temperature and allowed to warm under ambient conditions to room temperature over 5–6 h. The solution was then



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quenched with 3 M HCl (15 mL). The resulting mixture was concentrated under reduced pressure and the residue extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine, dried (Na2SO4), and concentrated to obtain the crude product, which was purified by column chromatography on silica gel using ethyl acetate and hexanes (5% – 20% ethyl acetate in hexanes). Method B: General Annulation Procedure with LiHMDS and tBuOLi. To a stirred solution of LiHMDS/ tBuOLi (9.84 mmol) in THF (40 mL) at -78 oC (ethyl acetate/liquid nitrogen bath) under an inert atmosphere was added a solution of a phthalide (3.28 mmol) in THF (10 mL). The resulting yellowish solution was stirred at -78 oC for 30 min, after which a solution of a Michael acceptor (1.0-1.5 equiv. unless otherwise stated) in THF (10 mL) was added to it. The cooling bath was removed after about 1 h at -78 oC and the reaction mixture was brought to room temperature over a period of 1 h and further stirred for 6–8 h. The reaction was then quenched with 3 M HCl (15 mL) and the resulting solution was concentrated. The residue was diluted with ethyl acetate (50 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 25 mL). The combined extracts were washed with H2O (15 mL), brine (15 mL), dried (anhydrous. Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography using ethyl acetate and hexanes on silica gel (5%–25% ethyl acetate in hexanes) or by recrystallization to obtain a pure product. Ethyl

5-hydroxy-2-oxo-3-phenyl-2,3-dihydronaphtho[1,2-b]furan-4-carboxylate

(7).

According to the general procedure for annulation, the condensation of cyanophthalide 6 (189 mg, 1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 2b (225.8 mg, 1.2 mmol) in the presence of

t

BuOLi

(256

mg,

3.2

mmol)

produced

ethyl

5-hydroxy-2-oxo-3-phenyl-2,3-

dihydronaphtho[1,2-b]furan-4-carboxylate (7) (purified by flash column chromatography (hexanes/EtOAc 20:1)) as white solid (219 mg, 63%), mp 163–165 oC. The structure of


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compound 7 was confirmed by the single crystal data analysis (vide SI for details). νmax (KBr, cm-1): 2983, 2931, 1803, 1659, 1598, 1453, 1397, 1378, 1335, 1240, 1132, 1020, 777, 713; 1

H NMR (600 MHz, CDCl3): δ 12.20 (s, 1H), 8.51 (dt, J = 8.4, 0.9 Hz, 1H), 8.03 (dt, J = 8.2,

0.9 Hz, 1H), 7.77 (m, 1H), 7.66 (m, 1H), 7.39 – 7.20 (m, 3H), 7.18 – 7.02 (m, 2H), 5.24 (s, 1H), 4.13 – 4.07 (m, 2H), 0.91 (t, J = 7.1 Hz, 3H);

13

C NMR (150 MHz, CDCl3): δ 175.5,

170.0, 159.2, 142.9, 136.5, 130.6, 129.0, 127.9, 127.4, 127.1, 125.3, 124.7, 123.5, 121.2, 117.3, 102.2, 61.6, 52.8, 13.6; HRMS (ESI) calcd. for C21H17O5 [M+H]+ 349.1076, found 349.1083. Ethyl 3-benzoyl-1,4-dihydroxy-2-naphthoate (8). According to the general procedure for annulation, the condensation of cyanophthalide 6 (189 mg, 1 mmol) with ethyl 4-phenylbuta2,3-dienoate 2b (225.8 mg, 1.2 mmol) in the presence of tBuOLi (256 mg, 3.2 mmol) produced ethyl 3-benzoyl-1,4-dihydroxy-2-naphthoate (8) (purified by flash column chromatography (hexanes/EtOAc 20:1)) as yellow solid (84 mg, 25%), mp 186–188 oC. νmax (KBr, cm-1): 3120, 2922, 1725, 1662, 1412, 1234, 1102, 771; 1H NMR (600 MHz, CDCl3): δ 11.30 (s, 1H), 10.90 (s, 1H), 8.56 – 8.33 (m, 2H), 7.81 – 7.65 (m, 4H), 7.57 – 7.47 (m, 1H), 7.43 (td, J = 7.3, 1.2 Hz, 2H), 3.68 (brs, 2H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 197.7, 170.1, 153.4, 152.1, 140.3, 132.4, 129.9, 129.7, 128.6, 128.5, 128.3, 127.9, 124.3, 124.2, 110.5, 103.9, 61.6, 13.4; HRMS (ESI) calcd. for C18H11O4 [M+H-EtOH]+ 291.0657, found 291.0653. Ethyl

5-hydroxy-3-(4-methoxyphenyl)-2-oxo-2,3-dihydronaphtho[1,2-b]furan-4-

carboxylate (7a). According to the general procedure for annulation, the condensation of cyanophthalide 6 (189 mg, 1 mmol) with ethyl 4-(4-methoxyphenyl)buta-2,3-dienoate 2c (298.0 mg, 1.2 mmol) in the presence of tBuOLi (256 mg, 3.2 mmol) produced ethyl 5hydroxy-3-(4-methoxyphenyl)-2-oxo-2,3-dihydronaphtho[1,2-b]furan-4-carboxylate

(7a)

(purified by flash column chromatography (hexanes/EtOAc 18:1)) as yellow solid (329.2 mg,



87%), mp 165–167 oC. νmax (KBr, cm-1): 3430, 2983, 2836, 1797, 1654, 1600, 1511, 1450, 1397, 1378, 1339, 1251, 1133, 1073, 1021, 908, 907, 769; 1H NMR (400 MHz, CDCl3): δ 12.17 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.76 – 7.72 (m, 1H), 7.66 – 7.62 (m, 1H), 7.10 – 6.97 (m, 2H), 6.87 – 6.81 (m, 2H), 5.14 (s, 1H), 4.15 – 4.10 (m, 2H), 3.76 (s, 3H), 0.99 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 175.8, 170.0, 159.3, 159.142.8, 130.5, 128.5, 128.4, 127.0, 125.2, 124.7, 123.4, 121.2, 117.7, 114.4, 102.2, 61.7, 55.3, 52.0, 13.8; HRMS (ESI) calcd. for C22H19O6 [M+H]+ 379.1182, found 379.1186. Ethyl

8-bromo-5-hydroxy-2-oxo-3-phenyl-2,3-dihydronaphtho[1,2-b]furan-4-

carboxylate (7b). According to the general procedure for annulation, the condensation of 5bromo cyanophthalide 18 (238 mg, 1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 2b (225.8 mg, 1.2 mmol) in the presence of tBuOLi (256 mg, 3.2 mmol) produced ethyl 8-bromo-5hydroxy-2-oxo-3-phenyl-2,3-dihydronaphtho[1,2-b]furan-4-carboxylate (7b) (purified by flash column chromatography (hexanes/EtOAc 20:1)) as white solid (269.0 mg, 63%), mp 182–184 oC. νmax (KBr, cm-1): 2925, 2370, 1804, 1648, 1440, 1425, 1331, 770; 1H NMR (400 MHz, CDCl3): ) δ 12.19 (s, 1H), 8.33 (d, J = 8.9 Hz, 1H), 8.16 (d, J = 1.9 Hz, 1H), 7.71 (dd, J = 9.0, 1.9 Hz, 1H), 7.30 (d, J = 6.9 Hz, 3H), 7.11 (dd, J = 7.1, 2.0 Hz, 2H), 5.23 (s, 1H), 4.10 (qd, J = 7.1, 1.7 Hz, 2H), 0.91 (t, J = 7.2 Hz, 3H);

13

C NMR (100 MHz, CDCl3): δ 174.9,

169.7, 159.0, 141.8, 136.1, 130.6, 129.1, 128.0, 127.3, 126.5, 125.7, 124.2, 123.7, 123.7, 118.9, 102.7, 61.8, 52.8, 13.6; HRMS (ESI) calcd. for C21H16BrO5 [M+H]+ 427.0181, found 427.0185. Ethyl 3-benzoyl-6-bromo-1,4-dihydroxy-2-naphthoate (8a). According to the general procedure for annulation, the condensation of 5-bromo cyanophthalide 18 (238 mg, 1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 2b (225.8 mg, 1.2 mmol) in the presence of tBuOLi (256 mg, 3.2 mmol) produced ethyl 3-benzoyl-6-bromo-1,4-dihydroxy-2-naphthoate (8a) (purified by flash column chromatography (hexanes/EtOAc 20:1)) as yellow solid (79.0 mg,


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19%), mp 183–185 oC. νmax (KBr, cm-1): 2927, 1728, 1652, 1582, 1475, 1403, 1263, 1155, 1107, 1022, 774; 1H NMR (400 MHz, CDCl3): δ 12.52 (s, 1H), 8.33 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.84 (dd, J = 8.4, 2.1 Hz, 1H), 7.70 (s, 1H), 7.45 – 7.12 (m, 5H), 3.63 (q, J = 7.1 Hz, 2H), 0.65 (t, J = 7.1 Hz, 3H);

13

C NMR (100 MHz, CDCl3): δ 185.5, 170.4,

160.6, 140.5, 137.7, 136.7, 134.1, 131.4, 130.3, 127.4, 128.9, 128.7, 128.5, 126.9, 126.3, 101.0, 61.4, 13.1; HRMS (ESI) calcd. for C20H16BrO5 [M+H]+ 415.0181, found 415.0185. Ethyl

5-hydroxy-6,8-dimethoxy-2-oxo-3-phenyl-2,3-dihydronaphtho[1,2-b]furan-4-

carboxylate (7c). According to the general procedure for annulation, the condensation of cyanophthalide 19 (219 mg, 1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 2b (225.8 mg, 1.2 mmol) in the presence of tBuOLi (256 mg, 3.2 mmol) produced ethyl 5-hydroxy-6,8dimethoxy-2-oxo-3-phenyl-2,3-dihydronaphtho[1,2-b]furan-4-carboxylate (7c) (purified by flash column chromatography (hexanes/EtOAc 15:1)) as dark brown solid (253 mg, 62%), mp 177–179 oC. νmax (KBr, cm-1): 3425, 2913, 2851, 1799, 1725, 1652, 1584, 1443, 1284, 1036, 772; 1H NMR (400 MHz, CDCl3): δ 12.71 (s, 1H), 7.35 – 7.27 (m, 3H), 7.13 (dd, J = 7.6, 1.8 Hz, 2H), 6.90 (d, J = 2.3 Hz, 1H), 6.61 (d, J = 2.3 Hz, 1H), 5.24 (s, 1H), 4.11 – 3.99 (m, 5H), 3.95 (s, 3H), 0.89 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 175.5, 169.9, 162.1, 160.8, 160.7, 142.1, 136.2, 129.0, 127.9, 127.4, 127.1, 119.3, 111.8, 100.9, 100.0, 92.8, 61.3, 56.4, 55.8, 53.2, 13.6; HRMS (ESI) calcd. for C23H21O7 [M+H]+ 409.1287, found 409.1283. Ethyl

5-hydroxy-8-methyl-2-oxo-3-phenyl-2,3-dihydronaphtho[1,2-b]furan-4-

carboxylate (7d). According to the general procedure for annulation, the condensation of 5methylcyanophthalide 20 (173 mg, 1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 2b (225.8 mg, 1.2 mmol) in the presence of tBuOLi (256 mg, 3.2 mmol) produced ethyl 5-hydroxy-8methyl-2-oxo-3-phenyl-2,3-dihydronaphtho[1,2-b]furan-4-carboxylate (7d) (purified by flash column chromatography (hexanes/EtOAc 20:1)) as white solid (203 mg, 56%), mp 165–167



Page 18 of 26

o

C. νmax (KBr, cm-1): 2984, 2926, 1806, 1646, 1470, 1338, 1238, 1142, 1072, 944, 802, 712;

1

H NMR (400 MHz, CDCl3): δ 12.18 (s, 1H), 8.38 (d, J = 8.6 Hz, 1H), 7.80 (s, 1H), 7.48 (dd,

J = 8.5, 1.7 Hz, 1H), 7.30 – 7.26 (m, 3H), 7.14 – 7.11 (m, 2H), 5.22 (s, 1H), 4.09 (qd, J = 7.2, 2.9 Hz, 2H), 2.59 (s, 3H), 0.90 (t, J = 7.2 Hz, 3H);

13

C NMR (126 MHz, CDCl3) δ 175.7,

170.1, 159.4, 142.6, 141.5, 136.7, 129.3, 129.1, 127.9, 127.5, 124.7, 123.8, 123.5, 120.5, 117.5, 101.6, 61.6, 53.0, 22.2, 13.7; HRMS (ESI) calcd. for C22H19O5 [M+H]+ 363.1232, found 363.1246. Ethyl 3-benzoyl-1,4-dihydroxy-6-methyl-2-naphthoate (8b). According to the general procedure for annulation, the condensation of 5-methylcyanophthalide 20 (173 mg, 1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 2b (225.8 mg, 1.2 mmol) in the presence of tBuOLi (256 mg, 3.2 mmol) produced ethyl 3-benzoyl-1,4-dihydroxy-6-methyl-2-naphthoate (8b) (purified by flash column chromatography (hexanes/EtOAc 25:1)) as dark yellow solid (88.0 mg, 25%), mp 186–188 oC. νmax (KBr, cm-1): 2982, 1738, 1646, 1552, 1494, 1286, 1238, 1024, 772, 696; 1H NMR (400 MHz, CDCl3): δ 12.59 (s, 1H), 8.02 – 7.99 (m, 2H), 7.66 (s, 1H), 7.54 (dd, J = 8.0, 1.8 Hz, 1H), 7.43 – 7.32 (m, 4H), 7.31 – 7.26 (m, 1H), 3.63 (q, J = 7.2 Hz, 2H), 2.49 (s, 3H), 0.65 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz, CDCl3): δ 187.4, 170.7, 162.0, 142.3, 139.3, 138.2, 134.8, 132.9, 130.2, 129.5, 128.7, 128.6, 127.8, 125.4, 100.0, 61.3, 21.8, 13.3; HRMS (ESI) calcd. for C21H18O5Na [M+Na]+ 373.1052, found 373.1047. 4-Methoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-1-carbonitrile

(21).

To

a

stirred

solution of formyl benzamide 27 (0.15 g, 0.56 mmol, 1.0 equiv.) in CH2Cl2 (11 mL) at 0 °C was added KCN (7.28 mg, 0.112 mmol, 0.2 equiv.), 18-crown-6 (29.0 mg, 0.112 mmol, 0.2 equiv), followed by TMSCN (0.08 mL, 0.672 mmol, 1.2 equiv.). The resulting mixture was warmed to room temperature and stirred at the same temperature for 2.0 h. The solvent was removed under reduced pressure, and the residue was co-evaporated with toluene (2 × 2 mL) to remove all traces of TMSCN. The resulting brown oil was dissolved in AcOH (3 mL). The


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resulting mixture was stirred for 24 h at 30 °C. The solvent was removed under reduced pressure and the obtained residue was purified by flash column chromatography (silica gel, 20 to 30% EtOAc in hexanes). Pure cyano phthalide 21 was obtained as white solid (0.12 g, 89% yield), mp 167–169 °C. νmax (KBr, cm-1): 3435, 2942, 1767, 1642, 1584, 1338, 1291, 1272, 1084, 1030, 888, 763; 1H NMR (400 MHz, CDCl3): δ 8.47 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.83 – 7.71 (m, 2H), 7.66 (dd, J = 8.5, 6.7 Hz, 1H), 6.16 (s, 1H), 4.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.5, 159.1, 137.8, 136.0, 130.7, 128.6, 128.1, 127.7, 124.6, 116.2, 114.7, 107.3, 65.2, 64.2; HRMS (ESI) calcd. for C14H10NO3 [M+H]+ 240.0661, found 240.0659. Ethyl

5-hydroxy-6-methoxy-2-oxo-3-phenyl-2,3-dihydroanthra[1,2-b]furan-4-

carboxylate (7e). According to the general procedure for annulation, the condensation of cyanophthalide 21 (239 mg, 1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 2b (225.8 mg, 1.2 mmol) in the presence of tBuOLi (256 mg, 3.2 mmol) produced ethyl 5-hydroxy-6-methoxy2-oxo-3-phenyl-2,3-dihydroanthra[1,2-b]furan-4-carboxylate (7e) (purified by flash column chromatography (hexanes/EtOAc 25:1)) as light brown solid (252 mg, 59%), mp 179–181 oC. νmax (KBr, cm-1): 3429, 2924, 1802, 1729, 1599, 1461, 1377, 1245, 1218, 1064, 1031, 774; 1H NMR (400 MHz, CDCl3): δ 13.30 (s, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.35 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.63 (dddd, J = 15.0, 8.2, 6.8, 1.6 Hz, 2H), 7.31 (td, J = 7.0, 6.6, 3.5 Hz, 3H), 7.21 – 7.13 (m, 2H), 5.29 (s, 1H), 4.19 (s, 3H), 4.11 (m, 2H), 0.93 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 175.6, 170.5, 162.1, 157.4, 142.9, 136.4, 135.2, 129.0, 128.5, 128.3, 127.9, 127.4, 126.6, 123.7, 122.4, 116.5, 116.1, 115.0, 101.8, 100.1, 64.3, 61.6, 53.3, 13.6; HRMS (ESI) calcd. for C26H21O6 [M+H]+ 429.1338, found 429.1345. Ethyl 3-benzoyl-1,4-dihydroxy-9-methoxyanthracene-2-carboxylate (8c). According to the general procedure for annulation, the condensation of cyanophthalide 21 (239 mg, 1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 2b (225.8 mg, 1.2 mmol) in the presence of



t

BuOLi (256 mg, 3.2 mmol) produced ethyl 3-benzoyl-1,4-dihydroxy-9-methoxyanthracene-

2-carboxylate (8c) (purified by flash column chromatography (hexanes/EtOAc 25:1)) as dark yellow solid (112 mg, 27%), mp 177–179 oC. νmax (KBr, cm-1): 3420, 2928, 1738, 1653, 1403, 1265, 1216, 1102, 1022, 771; 1H NMR (400 MHz, CDCl3): δ 13.37 (s, 1H), 8.56 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.09 – 8.00 (m, 1H), 7.74 – 7.63 (m, 2H), 7.57 (s, 1H), 7.45 (d, J = 7.5 Hz, 2H), 7.37 (dd, J = 8.4, 6.7 Hz, 2H), 7.33 – 7.25 (m, 1H), 4.19 (s, 3H), 3.71 (q, J = 7.2 Hz, 2H), 0.68 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 187.4, 171.1, 163.3, 157.2, 137.8, 136.4, 134.9, 131.8, 130.2, 129.9, 129.3, 129.2, 129.0, 129.0, 128.5, 128.4, 125.4, 123.9, 118.5, 99.7, 64.0, 61.3, 13.2; HRMS (ESI) calcd. for C25H21O6 [M+H]+ 417.1338, found 417.1349. 9-Methoxynaphtho[2,3-c]furan-1(3H)-one (23)10. A 60 mL reaction tube equipped with a magnetic stir bar was charged with Pd(OAc)2 (100 mg, 0.445 mmol, 10 mol%) followed by KHCO3 (1.10 gm, 11.14 mmol), 1-methoxy-2-naphthoic acid (25) (0.9 g, 4.45 mmol), and dibromomethane (18.0 mL). The reaction tube was sealed with a Teflon tube and the reaction mixture was stirred at 140 oC for 36 h, after which it was filtered through a small pad of Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (20% ethyl acetate in hexanes) to give 9-methoxynaphtho[2,3c]furan-1(3H)-one (23) as a white solid (0.80 g, 84%). νmax (KBr, cm-1): 3473, 2946, 2853, 1749, 1636, 1462, 1329, 1290, 1208, 1087, 958, 763, ; 1H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.65 (ddd, J = 8.3, 6.7, 1.3 Hz, 1H), 7.56 (ddd, J = 8.2, 6.7, 1.2 Hz, 1H), 7.52 (s, 1H), 5.40 (s, 2H), 4.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.8, 157.9, 141.3, 137.8, 129.5, 127.8, 127.7, 126.3, 124.3, 114.9, 110.7, 69.0, 63.9. We note that our NMR and IR data do not coincide with the values11 given by Kraus et al. The 1H NMR data perfectly matched with the values10 given by Rickborn et al. but the IR data do not match. HRMS (ESI) calcd. for C13H11O3 [M+H]+ 215.0708, found 215.0699.


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N,N-Diethyl-3-(hydroxymethyl)-1-methoxy-2-naphthamide (26). To a stirred suspension of aluminum trichloride (0.346 g, 2.6 mmol, 2.6 equiv.) in dichloromethane (10 mL) at 0 °C was added diethylamine (0.53 mL, 5.0 mmol, 5.0 equiv.). The resulting mixture was warmed to room temperature and stirred at the same temperature for 30 min. A solution of phthalide 23 (0.214 g, 1.0 mmol, 1.0 equiv) in dichloromethane (5 mL) was added to the preformed mixture at 0 °C. After 45 min, the reaction was quenched by adding ice water (15 mL). The mixture was stirred for 30 min from 0 °C to room temperature, and filtered through Celite. The filtrate was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated. The obtained residue was purified by flash column chromatography (silica gel, 50% EtOAc in hexanes). Pure hydroxy benzamide 26 (2.70 g, 94%) as a colorless oil. νmax (KBr, cm-1): 3386, 2976, 2936, 1759, 1608, 1459, 1368, 1290, 1220, 1129, 1086, 1029, 772; 1H NMR (400 MHz, CDCl3): δ 8.17 – 7.94 (m, 1H), 7.92 – 7.77 (m, 1H), 7.67 (s, 1H), 7.52 (hept, J = 5.1 Hz, 2H), 4.71 (d, J = 12.7 Hz, 1H), 4.55 (d, J = 12.7 Hz, 1H), 4.13 (brs, 1H), 3.97 (s, 3H), 3.80 (dt, J = 14.2, 7.1 Hz, 1H), 3.51 (dq, J = 14.0, 7.1 Hz, 1H), 3.27 (dt, J = 14.4, 7.2 Hz, 1H), 3.16 (dt, J = 14.5, 7.2 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.7, 151.9, 136.4, 134.8, 128.2, 127.2, 127.0, 126.5, 125.6, 124.1, 122.3, 63.9, 62.9, 43.4, 39.4, 13.9, 12.7; HRMS (ESI) calcd. for C17H20NO2 [M+H-H2O]+ 270.1494, found 270.1486. N,N-Diethyl-3-formyl-1-methoxy-2-naphthamide (27). To a stirred solution of hydroxy benzamide 26 (0.176 g, 0.613 mmol, 1.0 equiv.) in CH2Cl2 (10 mL) was added PCC (0.40 g, 1.84 mmol, 3.0 equiv.) and 3Å molecular sieves (0.3 g) at room temperature. The suspension was stirred for overnight at room temperature, then filtered through a short pad of silica gel, rinsed with CH2Cl2 and concentrated. The residue was purified by flash column chromatography (silica gel, 40% EtOAc in hexanes). Formyl benzamide 27 (0.155 mg, 88.7% yield) as colorless oil. νmax (KBr, cm-1): 3446, 2933, 1697, 1629, 1457, 1363, 1273,



1088, 772; 1H NMR (400 MHz, CDCl3): δ 10.09 (s, 1H), 8.22 (s, 1H), 8.17 (dd, J = 8.5, 1.1 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.71 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.63 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 4.03 (s, 3H), 3.77–3.62 (m, 2H), 3.18–3.10 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 190.6, 166.6, 152.8, 133.6, 131.4, 130.9, 130.4, 130.0, 129.6, 127.9, 125.6, 122.8, 63.3, 43.2, 39.2, 13.7, 12.6; HRMS (ESI) calcd. for C17H20NO3 [M+H]+ 286.1443, found 286.1439. 4,9-Dihydroxy-5-methoxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (29a). According to the general procedure for annulation, the condensation of 4-dimethoxy cyanophthalide 28a (95 mg, 0.5 mmol) with ethyl 4-phenylbuta-2,3-dienoate 2b (113 mg, 0.6 mmol) in the presence of

t

BuOLi (128 mg, 1.6 mmol) produced 4,9-dihydroxy-5-methoxy-3-

phenylnaphtho[2,3-c]furan-1(3H)-one (29a) (purified by flash column chromatography (hexanes/EtOAc 20:1)) as pink solid (132 mg, 82%), mp 182–184 oC. νmax (KBr, cm-1): 3445, 3372, 2938, 1738, 1657, 1611, 1458, 1417, 1391, 1290, 1214, 1104, 1053, 968, 780, 578; 1H NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 9.09 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.48 (t, J = 8.1 Hz, 1H), 7.38–7.36 (m, 3H), 7.32–7.30 (m, 2H), 7.15 (d, J = 7.7 Hz, 1H), 6.60 (s, 1H), 3.96 (s, 3H);

13

C NMR (100 MHz, DMSO-d6): δ 169.0, 156.2, 145.2, 140.5, 137.1, 128.8,

128.5, 128.2, 127.7, 126.2, 123.9, 118.8, 116.5, 108.0, 107.0, 80.5, 56.2; HRMS (ESI) calcd. for C19H15O5 [M+H]+ 323.0919, found 323.0904. 4,9-Dihydroxy-7,8-dimethoxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (29b). According to the general procedure for annulation, the condensation of 6,7-dimethoxy cyanophthalide 28bb (219 mg, 1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 2b (225.8 mg, 1.2 mmol) in the presence of tBuOLi (256 mg, 3.2 mmol) produced 4,9-dihydroxy-7,8-dimethoxy-3phenylnaphtho[2,3-c]furan-1(3H)-one (29b) (purified by flash column chromatography (hexanes/EtOAc 20:1)) as yellow solid (229 mg, 65%), mp 181–183 oC. νmax (KBr, cm-1): 3341, 3259, 2942, 1730, 1655, 1617, 1399, 1378, 1279, 1221, 1065, 984, 916; 1H NMR (400


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MHz, DMSO-d6): δ 10.18 (s, 1H), 9.33 (s, 1H), 7.94 (d, J = 9.3 Hz, 1H), 7.63 (d, J = 9.3 Hz, 1H), 7.51 – 7.28 (m, 3H), 7.33 – 7.21 (m, 2H), 6.59 (s, 1H), 4.03 (s, 3H), 3.97 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 168.2, 148.9, 148.1, 144.9, 138.9, 137.8, 129.2, 129.0, 128.1, 127.0, 124.2, 119.7, 119.5, 118.1, 106.2, 80.0, 62.5, 57.3; HRMS (ESI) calcd. for C20H17O6 [M+H]+ 353.1025, found 353.1031. 4,9-Dihydroxy-5,8-dimethoxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (29c). According to the general procedure for annulation, the condensation of 4,7-dimethoxy cyano phthalide 28c (219 mg, 1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 2b (225.8 mg, 1.2 mmol) in the presence of tBuOLi (256 mg, 3.2 mmol) produced 4,9-dihydroxy-5,8-dimethoxy-3phenylnaphtho[2,3-c]furan-1(3H)-one (29c) (purified by flash column chromatography (hexanes/EtOAc 15:1)) as red solid (278 mg, 79%), mp 179–181 oC. νmax (KBr, cm-1): 3458, 3318, 1749, 1612, 1438, 1385, 1374, 1154, 1040, 1024, 735, 624; 1H NMR (400 MHz, CDCl3): δ 10.20 (s, 1H), 9.17 (s, 1H), 7.35 (m, 5H), 6.78 (d, J = 8.6 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 6.42 (s, 1H), 4.05 (s, 3H), 3.94 (s, 3H);

13

C NMR (100 MHz, CDCl3): δ 168.8,

152.8, 151.1, 148.1, 140.7, 136.6, 128.9, 128.5, 128.4, 127.6, 120.4, 117.3, 108.0, 106.8, 104.7, 80.7, 56.9, 56.5; HRMS (ESI) calcd. for C20H17O6 [M+H]+ 353.1025, found 353.1035. 4,9-Dihydroxy-5,8-dimethoxy-3-(4-methoxyphenyl)naphtho[2,3-c]furan-1(3H)-one (29d). According to the general procedure for annulation, the condensation of 4,7-dimethoxy cyanophthalide 28c (219 mg, 1 mmol) with ethyl 4-(4-methoxyphenyl)buta-2,3-dienoate 2c (298.0 mg, 1.2 mmol) in the presence of tBuOLi (256 mg, 3.2 mmol) dihydroxy-5,8-dimethoxy-3-(4-methoxyphenyl)naphtho[2,3-c]furan-1(3H)-one

produced 4,9(29d)

(purified by flash column chromatography (hexanes/EtOAc 10:1)) as yellow solid (298 mg, 78%), mp 186–188 oC. νmax (KBr, cm-1): 3398, 2934, 1747, 1634, 1430, 1223, 1134, 1033, 914, 834, 774, 726; 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.24 (s, 1H), 7.20 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H),



6.48 (s, 1H), 4.03 (s, 3H), 3.92 (s, 3H), 3.74 (s, 3H);

13

C NMR (100 MHz, DMSO-d6): δ

167.9, 160.0, 152.4, 150.8, 147.8, 140.2, 129.5, 127.6, 120.3, 117.0, 114.4, 108.4, 107.7, 106.1, 79.8, 57.3, 57.0, 55.6; HRMS (ESI) calcd. for C21H19O7 [M+H]+ 383.1131, found 383. 1125. 4,9-Dihydroxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (29e). According to the general procedure for annulation, the condensation of sulfones phthalide 28d (288 mg, 1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 2b (225.8 mg, 1.2 mmol) in the presence of tBuOLi (256 mg, 3.2 mmol) produced 4,9-dihydroxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (29e) (purified by flash column chromatography (hexanes/EtOAc 15:1)) as white solid (260 mg, 89%), mp 181–183 oC. νmax (KBr, cm-1): 3468, 3247, 1707, 1392, 1330, 1226, 1145, 1082, 964, 855, 765, 708; 1H NMR (600 MHz, DMSO-d6): δ 10.17 (s, 1H), 9.35 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.69–7.67 (m, 1H), 7.62 – 7.56 (m, 1H), 7.37 (d, J = 6.8 Hz, 3H), 7.31 (dd, J = 7.5, 2.1 Hz, 2H), 6.68 (s, 1H); 13C NMR (150 MHz, DMSO-d6): δ 169.8, 147.5, 139.5, 137.7, 130,9, 129.3, 129.0, 128.8, 128.2, 126.7, 126.3, 125.2, 124.1, 122.7, 106.0, 80.8; HRMS (ESI) calcd. for C18H13O4 [M+H]+ 293.0814, found 293.0807. ASSOCIATED CONTENT Supporting Information NMR spectra and crystal data. “This material is available free of charge via the Internet at http://pubs.acs.org.” AUTHOR INFORMATION Corresponding Author * Email ID: [email protected] ACKNOWLEDGMENT


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We gratefully acknowledge the Council of Science & Industrial Research, New Delhi, India, for financial support. Supriti Jana is thankful to IIT KHARAGPUR for her research fellowship and contingency grant. We are also thankful to the DST-FIST for financial support for establishing an NMR facility. REFERENCES 1. Mal, D.; Jana, S. J. Org. Chem. 2016, 81, 11857. 2. Kim, T.; Jeong, K-H.; Kang, K-S.; Nakata, M.; Ham, J. Eur. J. Org. Chem. 2017, 1704. 3. (a) Morrow, G. W.; Swenton, J. S. J. Org. Chem. 1987, 52, 713. (b) Ghosh, B.; Chakraborty, S.; Mal, D. ChemistrySelect 2016, 1, 3097. (c) Brimble, M. A.; Houghton, S. I.; Woodgate, P. D. Tetrahedron 2007, 63, 880. (d) Freskos, J. N.; Morrow, G. W.; Swenton, J. S. J. Org. Chem. 1985, 50, 805. (e) Murty, K. V. S. N.; Pal, R.; Dutta, K.; Mal, D. Synth. Commun. 1990, 20, 1705. 4. Graf, K.; Ruhl, C. L.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem. Int. Ed. 2013, 52, 12727. 5. Li, Y.; Li, X.; Cheng, J-P. Adv. Synth. Catal. 2014, 356, 1172. 6. (a) Kalinin, A. V.; Miah, M. A. J.; Chattopadhyay, S.; Tsukazaki, M.; Wicki, M.; Nguen, T.; Coelho, A. L.; Kerr, M.; Snieckus, V. Synlett 1997, 7, 839. (b) Qi, X.; Li, H-P.; Wu, A-F. Chem. Asian J. 2016, 11, 2453. (c) Rajabi, M.; Khalilzadeh, M. A.; Tavakolinia, F.; Signorelli, P.; Ghidoni, R.; Santaniello, E. DNA and Cell Biology 2012, 31, 783. (d) Wang, M.; Zhang, X.; Ling, Z.; Zhang, Z.; Zhang, W. Chem. Commun. 2017, 53, 1381. (e) Li, G.; Sun, W.; Li, J.; Jia, F.; Hong, L.; Wang, R. Chem. Commun. 2015, 51, 11280. 7. Zhang,Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew.Chem. Int. Ed. 2009, 48, 6097.



8. Nicolaou, K. C.; Wang, Y.; Lu, M.; Mandal, D.; Pattanayak, M. R.; Yu, R.; Shah, A. A.; Chen, J. S.; Zhang, H.; Crawford, J. J.; Pasunoori, L.; Poudel, Y. B.; Chowdari, N. S.; Pan, C.; Nazeer, A.; Gangwar, S.;Vite, G.; Pitsinos, E. N. J. Am. Chem. Soc. 2016, 138, 8235. 9. Crawley, M. L.; Hein, K. J.; Markgarf, J, H. J. Chem. Res. (S) 2003, 470. 10. Makhlouf, M. A.; Rickborn, B. J. Org. Chem. 1981, 46, 4810. 11. Kraus, G. A.; Pezzanite, J. O.; Sugimoto, H. Tetrahedron Lett. 1979, 10, 853.


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Anionic Annulation of 3-Cyanophthalides with Allene Carboxylates: A

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